IL4I1 inhibitors and methods of use

Abstract

Compounds of Formula I or pharmaceutically acceptable salts thereof are described herein. Compounds of Formula I act as IL4I1 inhibitors and can be used to prevent, treat, or act as therapeutic agents for IL4I1-related diseases. #imgabs0#

Description

Field of the Invention

[0001] The present invention relates to IL4I1 inhibitors. Specifically, the IL4I1 inhibitors described herein can be used to prevent, treat, or serve as therapeutic agents for IL4I1-related diseases. Background of the Invention

[0003] IL4I1 is a glycosylated protein belonging to the L-amino acid oxidase (LAAO) family of flavin adenine dinucleotide (FAD)-binding enzymes. IL4I1 is secreted by certain cells and oxidatively deaminates phenylalanine to phenylpyruvate, releasing H2O2 and NH3.

[0004] The highest production of IL4I1 is found in cells of bone marrow origin (monocytes / macrophages and dendritic cells) of the human immune system, especially after stimulation with inflammatory and T helper type 1 (Th1) stimuli. Thus, IL4I1 is strongly produced by dendritic cell and macrophage populations from chronic Th1 granulomas of sarcoidosis and tuberculosis, but not Th2 granulomas (schistosomiasis). In addition, tumor-infiltrating macrophages from tumors of various histological types strongly produce IL4I1. Molinier-Frenkel V., Prévost-Blondel A. and Castellano F., The IL4I1 Enzyme: A NewPlayer in the Immunosuppressive Tumor Microenvironment, Cells, 2019, 8, 757-765.

[0005] The presence of IL4I1-producing cells in the tumor cell microenvironment inhibits antitumor immune responses as follows: by directly limiting the proliferation and function of cytotoxic T cells and Th1 cells, or indirectly by promoting the accumulation of Treg cells. Analysis of human tumor and normal tissue biopsies has identified increased expression of IL4I1 mRNA and protein in tumor-infiltrating myeloid cells. The Cancer Genome Atlas (TCGA) indicates that among solid tumors, endometrial cancer contains the highest level of IL4I1 mRNA expression, followed by severe ovarian cancer and triple-negative breast cancer. Phenylpyruvate, the phenylalanine oxidation product of IL411, is elevated in endometrial and ovarian tumor samples compared to matched adjacent tissues from the same patient. In addition, the accumulation of detectable phenylpyruvate in tumor samples depends on the presence of IL4I1 itself.

[0006] There are currently no available specific inhibitors for IL411. Some molecules have been shown to inhibit the relevant LAAO found in snake venom, but they are generally non-selective and have little activity. Therefore, specific inhibitors of IL4I1 are needed. More specifically, compounds that specifically inhibit IL411 and can be used to treat indications in which IL4I1 expression and / or activity are highest (including endometrial cancer, ovarian cancer, and triple-negative breast cancer) are needed.

[0007] Brief description of the invention

[0008] Described herein are compounds of Formula I and pharmaceutically acceptable salts thereof:

[0009]

[0010] Among them, X, Y, Z, A, L, R 1 , R 2 and R 3 Described below.

[0011] The compounds described herein are IL4I1 inhibitors, which can be used to prevent, treat or ameliorate IL4I1-related diseases.

[0012] Also described herein are methods of preventing, treating, or ameliorating symptoms of cancer comprising administering to a patient in need thereof a compound described herein or a pharmaceutically acceptable salt thereof.

[0013] Also described herein are uses of the compounds described herein, or pharmaceutically acceptable salts thereof, for preventing, treating, or ameliorating the condition of cancer in a patient in need thereof.

[0014] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0015] Also described herein are pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable carrier.

[0016] Also described herein are methods of preventing, treating, or ameliorating symptoms of cancer comprising administering to a patient in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

[0017] Also described herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent for preventing, treating, or ameliorating the condition of cancer in a patient in need thereof.

[0018] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, another therapeutic agent, and a pharmaceutically acceptable carrier.

[0019] Also described herein are pharmaceutical compositions comprising a compound described herein, another therapeutic agent, and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION

[0021] Described herein are compounds of Formula I or pharmaceutically acceptable salts thereof:

[0022]

[0023] in:

[0024] X is CH or S, wherein when X is S, Z is CH;

[0025] Y is CH or a bond;

[0026] Z is CH or S, wherein when Z is S, X is CH;

[0027] A is aryl, C3-C 10 Cycloalkyl, heteroaryl or heterocycloalkyl;

[0028] L is a linear or branched (C1-C5) alkylene group, wherein one or more -CH2- groups in L are optionally and independently replaced by a moiety selected from O and NH;

[0029] R 1 Each occurrence of is halogen, C1-C6 alkyl or heterocycloalkyl;

[0030] R 2 Each occurrence of is independently selected from -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkyl NR 4 COC1-C6 alkyl, -C1-C6 alkylCONR 4 C1-C6 alkyl, halogen, alkoxy, -C1-C6 alkylheterocycloalkyl, -C1-C6 alkylCONR 4 Aryl, C1-C6 alkyl, -C1-C6 alkylCO heterocycloalkyl, -C1-C6 alkylCONR 4 Heteroaryl, -C1-C6 alkyl NR 4 SO2C1-C6 alkyl, -C1-C6 alkyl NR 4 SO2C3-C6 cycloalkyl, C3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, -CONR 4 Haloalkyl, -CO heterocycloalkyl, CN, -CONR 4 C1-C6 alkyl, -CONR 4 C3-C6 cycloalkyl, heteroaryl, aryl, halogenated alkoxy, -C1-C6 alkyl, C3-C10 Cycloalkyl, oxo, -C1-C6 alkylheteroaryl, -NR 4 COC1-C6 alkyl, wherein the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, -C1-C6 alkyl CONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 Cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, haloC1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl;

[0031] R 3 is hydrogen, C1-C6 alkyl or halogenated C1-C6 alkyl;

[0032] R 4 is C1-C6 alkyl or hydrogen;

[0033] m is 0, 1 or 2; and

[0034] n is 0, 1, 2 or 3.

[0035] With respect to the compounds described herein, X is CH or S. In certain embodiments, X is CH. In other embodiments, X is S. In certain embodiments, wherein when X is S, Z is CH.

[0036] With respect to the compounds described herein, Y is CH or a bond. In certain embodiments, Y is CH. In other embodiments, Y is a bond.

[0037] With respect to the compounds described herein, Z is CH or S. In certain embodiments, Z is CH. In other embodiments, Z is S. In certain embodiments, wherein when Z is S, X is CH.

[0038] With respect to the compounds described herein, A is aryl, C3-C 10 In some embodiments, A is aryl. In some embodiments, A is monocyclic aryl. In other embodiments, A is bicyclic aryl. In other embodiments, A is polycyclic aryl. Suitable aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, A is aryl, wherein the aryl group is phenyl.

[0039] In other embodiments, A is C3-C10 In certain embodiments, A is a monocyclic cycloalkyl. In other embodiments, A is a bicyclic cycloalkyl. In other embodiments, A is a polycyclic cycloalkyl. Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl. In certain embodiments, A is C3-C 10 Cycloalkyl, wherein the C3-C 10 Cycloalkyl is:

[0040]

[0041] In certain embodiments, A is a heteroaryl. In certain embodiments, A is a nitrogen-containing heteroaryl. In certain embodiments, A is a monocyclic heteroaryl. In other embodiments, A is a bicyclic heteroaryl. In other embodiments, A is a polycyclic heteroaryl. Suitable heteroaryl groups include, but are not limited to, pyridyl, oxazolyl, imidazolyl, triazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, and isoquinolyl. In certain embodiments, A is a heteroaryl, wherein the heteroaryl is:

[0042]

[0043] In certain embodiments, A is heterocycloalkyl. In certain embodiments, A is monocyclic heterocycloalkyl. In other embodiments, A is polycyclic heterocycloalkyl. In still other embodiments, A is bicyclic heterocycloalkyl. In certain embodiments, A is nitrogen-containing heterocycloalkyl. In other embodiments, A is oxygen-containing heterocycloalkyl. In other embodiments, A is sulfur-containing heterocycloalkyl.

[0044] Suitable heterocycloalkyl groups include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridinyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolyl, benzoxazepinene, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, indolinyl, tetrahydropyran, and partially unsaturated non-aromatic monocyclic rings such as 2- or 4-pyridone or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through nitrogen. In certain embodiments, A is a heterocycloalkyl group, wherein the heterocycloalkyl group is:

[0045]

[0046] With respect to the compounds described herein, L is a linear or branched (C1-C5) alkylene group, wherein one or more -CH2- groups in L are optionally and independently replaced by a moiety selected from O and NH. In certain embodiments, L is a linear (C1-C5) alkylene group, wherein one or more -CH2- groups in L are optionally and independently replaced by a moiety selected from O and NH. In certain embodiments, L is a branched (C1-C5) alkylene group, wherein one or more -CH2- groups in L are optionally and independently replaced by a moiety selected from O and NH. In certain embodiments, L is a (C1-C5) alkylene group, wherein one or more -CH2- groups in L are independently replaced by a moiety selected from O and NH. In certain embodiments, L is a (C1-C5) alkylene group, wherein one or more -CH2- groups in L are independently replaced by an O moiety. In certain embodiments, L is a linear (C1-C5) alkylene group, wherein one or more -CH2- groups in L are independently replaced by an NH moiety. In certain embodiments, L is a linear or branched (C1-C5) alkylene group.

[0047] In certain embodiments, L is -CH2-, -CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2O-, or -CHCH3-.

[0048] In certain embodiments, L is

[0049]

[0050] In other embodiments, L is

[0051] In certain embodiments, L is

[0052] With respect to the compounds described herein, R 1 Each occurrence of is halogen, C1-C6 alkyl or heterocycloalkyl. 1 is a halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine or iodine groups. In certain embodiments, R 1 In certain embodiments, R 1 is chlorine. In other embodiments, R 1 It's fluorine.

[0053] In certain embodiments, R 1is C1-C6 alkyl. Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 1 is methyl or ethyl. In certain embodiments, R 1 In certain embodiments, R 1 It is ethyl.

[0054] In certain embodiments, R 1 In certain embodiments, R 1 is a monocyclic heterocycloalkyl. In other embodiments, R 1 In yet other embodiments, R 1 In certain embodiments, R 1 is a nitrogen-containing heterocycloalkyl. In other embodiments, R 1 In other embodiments, R 1 It is a sulfur-containing heterocycloalkyl group.

[0055] Suitable heterocycloalkyl groups include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridinyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolyl, benzoxazepinene, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, indolinyl, tetrahydropyran, and partially unsaturated non-aromatic monocyclic rings such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through nitrogen. In certain embodiments, R 1 It is pyrrolidino.

[0056] With respect to the compounds described herein, m is 0, 1 or 2. In certain embodiments, m is 0, meaning that the compounds of Formula I, Ia, Ib and Ic are not bound by R 1 In certain embodiments, m is 1, meaning that the compounds of Formula I, Ia, Ib and Ic are substituted with one R 1In certain embodiments, m is 2, meaning that the compounds of Formula I, Ia, Ib and Ic are substituted by two R 1 Substituent substitution.

[0057] In certain embodiments of the compounds described herein, m is 1 or 2 and R 1 is fluoro, chloro, pyrrolidinyl, methyl or ethyl. In certain embodiments of the compounds described herein, m is 1 and R 1 is fluoro, chloro, pyrrolidinyl, methyl or ethyl. In certain embodiments of the compounds described herein, m is 2 and R 1 is fluoro, chloro, pyrrolidinyl, methyl or ethyl. In certain embodiments of the compounds described herein, m is 1 and R 1 is fluorine. In certain embodiments of the compounds described herein, m is 1 and R 1 In certain embodiments of the compounds described herein, m is 1 and R 1 is pyrrolidinyl. In certain embodiments of the compounds described herein, m is 1 and R 1 is methyl. In certain embodiments of the compounds described herein, m is 1 and R 1 It is ethyl.

[0058] With respect to the compounds described herein, R 2 Each occurrence of is independently selected from -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkyl NR 4 COC1-C6 alkyl, -C1-C6 alkylCONR 4 C1-C6 alkyl, halogen, alkoxy, -C1-C6 alkylheterocycloalkyl, -C1-C6 alkylCONR 4 Aryl, C1-C6 alkyl, -C1-C6 alkylCO heterocycloalkyl, -C1-C6 alkylCONR 4 Heteroaryl, -C1-C6 alkyl NR 4 SO2C1-C6 alkyl, -C1-C6 alkyl NR 4 SO2C3-C6 cycloalkyl, C3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, -CONR 4 Haloalkyl, -CO heterocycloalkyl, CN, -CONR 4 C1-C6 alkyl, -CONR 4 C3-C6 cycloalkyl, heteroaryl, aryl, halogenated alkoxy, -C1-C6 alkyl, C3-C 10 Cycloalkyl, oxo, -C1-C6 alkylheteroaryl, -NR 4COC1-C6 alkyl, wherein the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, -C1-C6 alkyl CONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 Cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, haloC1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl.

[0059] In certain embodiments, R 2 Each occurrence of is independently selected from -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkyl NR 4 COC1-C6 alkyl, -C1-C6 alkylCONR 4 C1-C6 alkyl, halogen, alkoxy, -C1-C6 alkylheterocycloalkyl, -C1-C6 alkylCONR 4 Aryl, C1-C6 alkyl, -C1-C6 alkylCO heterocycloalkyl, -C1-C6 alkylCONR 4 Heteroaryl, -C1-C6 alkyl NR 4 SO2C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, -CONR 4 Haloalkyl, -CO heterocycloalkyl, CN, -CONR 4 C1-C6 alkyl, -CONR 4 C3-C6 cycloalkyl, heteroaryl, aryl, halogenated alkoxy, -C1-C6 alkyl, C3-C 10 Cycloalkyl, oxo, -C1-C6 alkylheteroaryl, -NR 4 COC1-C6 alkyl, wherein the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, -C1-C6 alkyl CONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10Cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, haloC1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl.

[0060] In certain embodiments, R 2 Independently selected from -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl. In certain embodiments, R 2 In certain embodiments, R 2 yes

[0061] In certain embodiments, R 2 Independently selected from -C1-C6 alkyl NR 4 COC1-C6 alkyl. In certain embodiments, R 2 is -C1-C6 alkylNHCOC1-C6 alkyl. In certain embodiments, R 2 yes

[0062] In certain embodiments, R 2 Independently selected from -C1-C6 alkyl CONR 4 C1-C6 alkyl. In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 yes

[0063] In certain embodiments, R 2 are independently selected from halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine or iodine groups. In certain embodiments, R 2 In certain embodiments, R 2 is chlorine. In other embodiments, R 2 In certain embodiments, R 2 It's iodine.

[0064] In certain embodiments, R 2 Independently selected from alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R2 is methoxy.

[0065] In certain embodiments, R 2 In certain embodiments, R 2 R2 is independently selected from -C1-C6 alkylheterocycloalkyl, which is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl. In certain embodiments, R2 is

[0066]

[0067] In certain embodiments, R 2 In certain embodiments, R 2 R is independently selected from -C1-C6 alkylheterocycloalkyl, which is unsubstituted or substituted by 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl. In certain embodiments, R 2 yes

[0068]

[0069] In certain embodiments, R 2 Independently selected from -C1-C6 alkyl CONR 4 In certain embodiments, R 2 In certain embodiments, R 2 yes

[0070] In certain embodiments, R 2 R is independently selected from C1-C6 alkyl. Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 2 is methyl, isobutyl or ethyl. In certain embodiments, R2 In certain embodiments, R 2 In certain embodiments, R 2 It is isobutyl.

[0071] In certain embodiments, R 2 In certain embodiments, R 2 yes

[0072] In certain embodiments, R 2 Independently selected from -C1-C6 alkyl CONR 4 In certain embodiments, R 2 yes

[0073] In certain embodiments, R 2 Independently selected from -C1-C6 alkyl NR 4 SO2C1-C6 alkyl. In certain embodiments, R 2 In certain embodiments, R 2 yes

[0074] In certain embodiments, R 2 Independently selected from -C1-C6 alkyl NR 4 SO2C3-C6 cycloalkyl. In certain embodiments, R 2 In certain embodiments, R 2 yes

[0075] In certain embodiments, R 2 In certain embodiments, R 2 is a monocyclic cycloalkyl group. In other embodiments, R 2 is a bicyclic cycloalkyl group. In other embodiments, R 2 is a polycyclic cycloalkyl. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl. In certain embodiments, R 2 It is C3-C 10 Cycloalkyl, wherein the C3-C 10 Cycloalkyl is

[0076] In certain embodiments, R 2Independently selected from -C1-C6 alkyl CONR 4 C3-C6 cycloalkyl. In certain embodiments, R 2 In certain embodiments, R 2 yes

[0077] In certain embodiments, R 2 In certain embodiments, R 2 R is independently selected from heterocycloalkyl, which is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkyl OH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkyl CN, -COC1-C6 alkyl and C3-C6 cycloalkyl. In certain embodiments, R 2 is a monocyclic heterocycloalkyl. In other embodiments, R 2 is a polycyclic heterocycloalkyl. In other embodiments, R 2 is a polycyclic heterocycloalkyl group which is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkyl OH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkyl CN, -COC1-C6 alkyl and C3-C6 cycloalkyl. In yet other embodiments, R 2 In yet other embodiments, R 2 is a bicyclic heterocycloalkyl group which is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkyl OH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkyl CN, -COC1-C6 alkyl and C3-C6 cycloalkyl. In certain embodiments, R 2 is a nitrogen-containing heterocycloalkyl. 2 is a nitrogen-containing heterocycloalkyl group which is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkyl OH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkyl CN, -COC1-C6 alkyl and C3-C6 cycloalkyl. In other embodiments, R 2 In other embodiments, R 2is an oxygen-containing heterocycloalkyl group which is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl. In other embodiments, R 2 is a sulfur-containing heterocycloalkyl. In other embodiments, R 2 is a sulfur-containing heterocycloalkyl group which is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl.

[0078] Suitable heterocycloalkyl groups include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridinyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolyl, benzoxazepinene, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, indolinyl, tetrahydropyran, and partially unsaturated non-aromatic monocyclic rings such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through nitrogen. In certain embodiments, R 2 is a heterocycloalkyl group, wherein the heterocycloalkyl group is: In certain embodiments, R 2 is a heterocycloalkyl group, wherein the heterocycloalkyl group is:

[0079] In certain embodiments, R 2 R is independently selected from halo C1-C6 alkyl. Suitable examples of halo alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. 2 In certain embodiments, R 2 In certain embodiments, R 2 are difluoromethyl and trifluoromethyl.

[0080] In certain embodiments, R 2 Independently selected from -CONR 4 In certain embodiments, R 2 In certain embodiments, R 2 yes

[0081] In certain embodiments, R 2 In certain embodiments, R 2 yes

[0082] In certain embodiments, R 2 Independently selected from CN.

[0083] In certain embodiments, R 2 Independently selected from oxo.

[0084] In certain embodiments, R 2 Independently selected from -CONR 4 C1-C6 alkyl. In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 yes

[0085] In certain embodiments, R 2 Independently selected from -NR 4 COC1-C6 alkyl. In certain embodiments, R 2 Independently selected from -NHCOC l -C6 alkyl. In certain embodiments, R 2 is independently selected from -N(C1-C6 alkyl)CO(C1-C6 alkyl). In certain embodiments, R 2 yes

[0086]

[0087] In certain embodiments, R 2 Independently selected from -CONR 4 C3-C6 cycloalkyl. In certain embodiments, R 2 Independently selected from -CONHC3-C6cycloalkyl.

[0088] In certain embodiments, R 2 In certain embodiments, R 2 yes

[0089] In certain embodiments, R 2 In certain embodiments, R 2 yes

[0090] In certain embodiments, R 2 In certain embodiments, R 2 yes

[0091] In certain embodiments, R 2 is independently selected from haloalkoxy. Suitable haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and monofluoromethoxy. In certain embodiments, R 2 It is trifluoromethoxy.

[0092] In certain embodiments, R 2 Independently selected from -C1-C6 alkyl C3-C 10 In certain embodiments, R 2 yes

[0093] In certain embodiments, R 2 It has not been replaced.

[0094] In other embodiments, when R 2 Yes -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 When the -C1-C6 alkyl group is cycloalkyl, 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 The cycloalkyl group is substituted with 1 to 3 substituents selected from alkoxy, CN, -C1-C6 alkyl OH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkyl CN, -COC1-C6 alkyl. In certain embodiments, the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10The cycloalkyl is substituted with a substituent selected from alkoxy, CN, -C1-C6 alkyl OH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkyl CN, -COC1-C6 alkyl. In other embodiments, the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 The cycloalkyl is substituted with 2 substituents selected from alkoxy, CN, -C1-C6 alkyl OH, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, oxo, OH, CN, -C1-C6 alkyl CN, COC1-C6 alkyl. In other embodiments, the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 The cycloalkyl is substituted by 3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, haloC1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl.

[0095] In certain embodiments, R 2 is chlorine, fluorine, methoxy, isopropoxy, methyl, difluoromethyl, trifluoromethoxy, isobutyl,

[0096]

[0097]

[0098] In certain embodiments, n is 1, 2 or 3 and R 2 is chlorine, fluorine, methoxy, methyl, difluoromethyl, trifluoromethoxy, isobutyl,

[0099]

[0100]

[0101] With respect to the compounds described herein, n is 0, 1, 2, or 3. In certain embodiments, n is 0, meaning that A is not replaced by R 2 In certain embodiments, n is 1, meaning that A is replaced by one R 2In certain embodiments, n is 2, which means that A is replaced by two R 2 In certain embodiments, n is 3, meaning that A is replaced by three R 2 Substituent substitution.

[0102] In certain embodiments, R2 is

[0103]

[0104]

[0105] In certain embodiments, when R 2 Yes -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 When the -C1-C6 alkyl group is cycloalkyl, 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 The cycloalkyl group is substituted by 1 to 3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl.

[0106] In certain embodiments, when R 2 Yes -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, -C1-C6 alkyl CONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 When it is cycloalkyl, it is unsubstituted or substituted by 1-3 substituents selected from alkoxy, CN, C1-C6 alkylOH, halogen, C1-C6 alkyl, haloC1-C6 alkyl, oxo, OH, CN, C1-C6 alkylCN, COC1-C6 alkyl and C3-C6 cycloalkyl.

[0107] In certain embodiments, R 2 is chlorine, fluorine, iodine, methoxy, isopropoxy, methyl, difluoromethyl, trifluoromethoxy, isobutyl,

[0108]

[0109]

[0110] With respect to the compounds described herein, R 3 Each occurrence of is hydrogen, C1-C6 alkyl or halo C1-C6 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C1-C6 alkyl. Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 3 It's methyl.

[0111] In certain embodiments, R 3 is a halogenated C1-C6 alkyl group. Suitable examples of halogenated alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. 3 It is difluoromethyl.

[0112] In certain embodiments, R 3 is hydrogen, methyl or difluoromethyl.

[0113] With respect to the compounds described herein, R 4 is C1-C6 alkyl or hydrogen. 4 is hydrogen. In certain embodiments, R 4 is C1-C6 alkyl. Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl. In certain embodiments, R 4 It's methyl.

[0114] Also described herein are compounds having Formula Ia or pharmaceutically acceptable salts thereof.

[0115]

[0116] Where A is aryl, C3-C 10 Cycloalkyl, heteroaryl or heterocycloalkyl;

[0117] L is a linear or branched (C1-C5) alkylene group, wherein one or more -CH2- groups in L are optionally and independently replaced by a moiety selected from O and NH;

[0118] R 1 Each occurrence of is independently selected from halogen, C1-C6 alkyl or heterocycloalkyl;

[0119] R 2 Each occurrence of is independently selected from -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkyl NR 4 COC1-C6 alkyl, -C1-C6 alkylCONR 4 C1-C6 alkyl, halogen, alkoxy, -C1-C6 alkylheterocycloalkyl, -C1-C6 alkylCONR 4 Aryl, C1-C6 alkyl, -C1-C6 alkylCO heterocycloalkyl, -C1-C6 alkylCONR 4 Heteroaryl, -C1-C6 alkyl NR 4 SO2C1-C6 alkyl, -C1-C6 alkyl NR 4 SO2C3-C6 cycloalkyl, C3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, -CONR 4 Haloalkyl, -CO heterocycloalkyl, CN, -CONR 4 C1-C6 alkyl, -CONR 4 C3-C6 cycloalkyl, heteroaryl, aryl, halogenated alkoxy, -C1-C6 alkyl, C3-C 10 Cycloalkyl, oxo, -C1-C6 alkylheteroaryl, -NR 4 COC1-C6 alkyl, wherein the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, -C1-C6 alkyl CONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10Cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, haloC1-C6 alkyl, oxo, OH, CN, C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl;

[0120] R 3 is C1-C6 alkyl or halogenated C1-C6 alkyl;

[0121] R 4 is C1-C6 alkyl or hydrogen;

[0122] m is 0, 1 or 2; and

[0123] n is 0, 1, 2 or 3.

[0124] Also described herein are compounds having Formula Ib or pharmaceutically acceptable salts thereof.

[0125]

[0126] Where A is aryl, C3-C 10 Cycloalkyl, heteroaryl or heterocycloalkyl;

[0127] L is a linear or branched (C1-C5) alkylene group, wherein one or more -CH2- groups in L are optionally and independently replaced by a moiety selected from O and NH;

[0128] R 1 Each occurrence of is independently selected from halogen, C1-C6 alkyl or heterocycloalkyl;

[0129] R 2 Each occurrence of is independently selected from -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkyl NR 4 COC1-C6 alkyl, -C1-C6 alkylCONR 4 C1-C6 alkyl, halogen, alkoxy, -C1-C6 alkylheterocycloalkyl, -C1-C6 alkylCONR 4 Aryl, C1-C6 alkyl, -C1-C6 alkylCO heterocycloalkyl, -C1-C6 alkylCONR 4 Heteroaryl, -C1-C6 alkyl NR 4 SO2C1-C6 alkyl, -C1-C6 alkyl NR 4 SO2C3-C6 cycloalkyl, C3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, -CONR 4Haloalkyl, -CO heterocycloalkyl, CN, -CONR 4 C1-C6 alkyl, -CONR 4 C3-C6 cycloalkyl, heteroaryl, aryl, halogenated alkoxy, -C1-C6 alkyl, C3-C 10 Cycloalkyl, oxo, -C1-C6 alkylheteroaryl, -NR 4 COC1-C6 alkyl, wherein the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, -C1-C6 alkyl CONR 4 Aryl, -C1-C6 alkyl heterocycloalkyl, -C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 Cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, haloC1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, COC1-C6 alkyl and C3-C6 cycloalkyl;

[0130] R 3 is C1-C6 alkyl or halogenated C1-C6 alkyl;

[0131] R 4 is C1-C6 alkyl or hydrogen;

[0132] m is 0, 1 or 2; and

[0133] n is 0, 1, 2 or 3.

[0134] Also described herein are compounds having Formula Ic or pharmaceutically acceptable salts thereof.

[0135]

[0136] Where A is aryl, C3-C 10 Cycloalkyl, heteroaryl or heterocycloalkyl;

[0137] L is a linear or branched (C1-C5) alkylene group, wherein one or more -CH2- groups in L are optionally and independently replaced by a moiety selected from O and NH;

[0138] R 1 Each occurrence of is independently selected from halogen, C1-C6 alkyl or heterocycloalkyl;

[0139] R 2 Each occurrence of is independently selected from -C1-C6 alkyl NR 4COC3-C6 cycloalkyl, -C1-C6 alkyl NR 4 COC1-C6 alkyl, -C1-C6 alkylCONR 4 C1-C6 alkyl, halogen, alkoxy, -C1-C6 alkylheterocycloalkyl, -C1-C6 alkylCONR 4 Aryl, C1-C6 alkyl, -C1-C6 alkylCO heterocycloalkyl, -C1-C6 alkylCONR 4 Heteroaryl, -C1-C6 alkyl NR 4 SO2C1-C6 alkyl, -C1-C6 alkyl NR 4 SO2C3-C6 cycloalkyl, C3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, heterocycloalkyl, halogenated C1-C6 alkyl, -CONR 4 Haloalkyl, -CO heterocycloalkyl, CN, -CONR 4 C1-C6 alkyl, -CONR 4 C3-C6 cycloalkyl, heteroaryl, aryl, halogenated alkoxy, -C1-C6 alkyl, C3-C 10 Cycloalkyl, oxo, -C1-C6 alkylheteroaryl, -NR 4 COC1-C6 alkyl, wherein the -C1-C6 alkyl NR 4 COC3-C6 cycloalkyl, -C1-C6 alkylCONR 4 C3-C6 cycloalkyl, -C1-C6 alkyl CONR 4 Aryl, C1-C6 alkyl heterocycloalkyl, C1-C6 alkyl CO heterocycloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, -C1-C6 alkyl C3-C 10 Cycloalkyl is unsubstituted or substituted with 1-3 substituents selected from alkoxy, CN, -C1-C6 alkylOH, halogen, C1-C6 alkyl, haloC1-C6 alkyl, oxo, OH, CN, -C1-C6 alkylCN, -COC1-C6 alkyl and C3-C6 cycloalkyl;

[0140] R 3 is C1-C6 alkyl or halogenated C1-C6 alkyl;

[0141] R 4 is C1-C6 alkyl or hydrogen;

[0142] m is 0, 1 or 2; and

[0143] n is 0, 1, 2 or 3.

[0144] Also described herein are compounds having the following structures:

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157] or a pharmaceutically acceptable salt thereof.

[0158] definition

[0159] The term "alkylene" or "alkylenyl" by itself or as part of another substituent refers to a divalent straight or branched chain hydrocarbon radical having the stated number of carbon atoms. For example, -(C1-C5)alkylene would include, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, or -CH2CH2CH2CH2CH2-.

[0160] The term "halogen" includes fluoro, chloro, bromo or iodo groups.

[0161] The term "C1-C6 alkyl" includes a straight chain alkyl group having a carbon number of 1 to 6 and a branched chain alkyl group having a carbon number of 3 to 6. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-1-methylpropyl and the like.

[0162] The term "C3-C6 cycloalkyl" includes bridged, saturated or unsaturated cycloalkyl groups having 3 to 6 carbons. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0163] The term "C3-C 10 "Cycloalkyl" includes bridged, saturated or unsaturated cycloalkyl groups having 3-10 carbons. "Cycloalkyl" also includes non-aromatic rings as well as monocyclic non-aromatic rings fused to saturated cycloalkyl groups and aromatic rings fused to saturated cycloalkyl groups. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, etc. Examples described by structure include:

[0164] The term "heteroaryl" refers to an aromatic heterocycloalkyl group containing at least one ring heteroatom selected from O, S and N. Examples of heteroaryl groups include pyridyl, oxazolyl, imidazolyl, triazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl and the like.

[0165] The term "heterocycloalkyl" refers to a monocyclic or bicyclic or bridged partially unsaturated or saturated ring containing at least one heteroatom selected from N, S and O, each of which has 3 to 10 atoms, wherein the point of attachment may be carbon or nitrogen. Examples include tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridinyl, benzoxazinyl, benzoxazolinyl, 2-H-phthalazinyl, isoindolyl, benzoxazepine, 5,6-dihydroimidazo[2,1-b]thiazolyl, tetrahydroquinolinyl, morpholinyl, tetrahydroisoquinolinyl, indolinyl and tetrahydropyranyl. The term also includes partially unsaturated non-aromatic monocyclic rings such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through nitrogen. The term also includes bridged rings such as 5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl and 3-azabicyclo[3.2.2]nonyl and azabicyclo[2.2.1]heptanyl. Examples described by structure include:

[0166]

[0167] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid (including an inorganic or organic base and an inorganic or organic acid). The salt of the basic compound included in the term "pharmaceutically acceptable salt" refers to a non-toxic salt of the compound of the present invention, which is usually prepared by reacting the free base with a suitable organic acid or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, p-hydroxyacetamidophenylarsonic acid salt, hexylresorcinol salt, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide The invention also includes the following pharmaceutically acceptable salts: iodine, isothiosulfate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthenate, nitrate, N-methyl reduced glucosamine ammonium salt, oleate, oxalate, pamoate (pamoate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, 8-chlorotheophylline salt, toluenesulfonate, triethyl iodide and valerate. In addition, in the case of the compound of the present invention carrying an acidic part, its suitable pharmaceutically acceptable salt includes, but is not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc salts, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidinyl, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl reduced glucosamine, morpholine, piperazine, piperidinyl, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0168] The term "patient" refers to a mammalian patient who is or is about to receive medical treatment, including a human, canine, feline, bovine or porcine patient, preferably a human patient.

[0169] The compounds of the present invention may contain one or more asymmetric centers and may therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is intended to include all such isomeric forms of these compounds.

[0170] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0171] Some of the compounds described herein contain substituted cycloalkanes having cis- and trans-isomers, and unless specified otherwise, are intended to include both cis- and trans-geometric isomers.

[0172] As known in the art, by appropriately modifying the methods disclosed herein, the independent synthesis of these diastereomers or their chromatographic separation can be achieved. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, and if necessary, the crystalline product or crystalline intermediate is derivatized with a reagent containing an asymmetric center of known absolute configuration. If necessary, the racemic mixture of the compound can be separated to separate the single enantiomer. The separation can be implemented by methods well known in the art, such as coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the single diastereomer by standard methods (such as fractional crystallization or chromatography). The coupling reaction is often to form a salt using an enantiomerically pure acid or base. The diastereomeric derivatives can then be converted into pure enantiomers by the cleavage of the added chiral residue. The racemic mixture of the compound can also be directly separated by chromatography using a chiral stationary phase, and the method is well known in the art.

[0173] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0174] It should be understood that the invention is intended to include pharmaceutically acceptable salts of the compounds described herein, as well as non-pharmaceutically acceptable salts when they are used as precursors to free compounds or their pharmaceutically acceptable salts or in other synthetic procedures.

[0175] Solvates and in particular hydrates of the compounds of the formulae described herein are also included in the present invention.

[0176] Some compounds described herein may exist as tautomers, which have different hydrogen attachment points and are accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The compounds of the present invention include individual tautomers and mixtures thereof.

[0177] In the compounds described herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number that predominantly occurs in nature. The present invention is intended to include all suitable isotopic variations of the compounds having the formulae described herein. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H). Protium is the predominant isotope of hydrogen found in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing half-life in vivo or reducing dosage requirements, or can provide compounds that can be used as standards for characterization of biological samples. Isotopically enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by methods similar to those described in the schemes and examples herein, using appropriate isotopically enriched reagents or intermediates.

[0178] It should be noted that chemically unstable compounds are excluded from the embodiments encompassed herein.

[0179] Treatment

[0180] The present invention also includes methods for preventing, treating or ameliorating IL4I1-related diseases. The compounds described herein can effectively prevent, treat or ameliorate various IL4I1-related diseases, such as cancer. Methods for treating cancers in patients showing cells expressing IL4I1 are described herein. Methods for preventing cancers in patients showing cells expressing IL4I1 are described herein. Methods for ameliorating cancers in patients showing cells expressing IL4I1 are described herein.

[0181] In one embodiment described herein, the cancer to be treated is selected from cancers showing cells expressing IL4I1 and lymphomas showing cells expressing IL411. In certain embodiments, the cancer to be treated is a solid tumor. In certain embodiments, the cancer to be treated is generally selected from carcinoma, sarcoma, mesothelioma, blastoma and germ cell tumor. In another specific embodiment, the cancer to be treated is generally selected from mesothelioma, non-small cell lung cancer, colon cancer, breast cancer, thyroid cancer, testicular germ cell tumor and ovarian cancer showing cells expressing IL4I1.

[0182] In another specific embodiment, the cancer to be treated is selected from lymphomas displaying cells expressing IL411, typically selected from B-cell lymphomas displaying cells expressing IL411.

[0183] In certain embodiments, the cancer to be treated is selected from PMBL (primary mediastinal large B-cell lymphoma), classical Hodgkin's lymphoma (cHL), NLPHL (nodular lymphocyte-predominant Hodgkin's lymphoma), non-mediastinal diffuse large B-cell lymphoma (DLBCL), and SLL / CLL (small, lymphocytic lymphoma / chronic lymphocytic leukemia) that display cells expressing IL411. In another specific embodiment, the cancer to be treated is selected from lymphomas that display cells expressing IL411.

[0184] In one embodiment described herein, the cancer to be prevented is selected from cancers showing cells expressing IL4I1 and lymphomas showing cells expressing IL4I1. In certain embodiments, the cancer to be prevented is a solid tumor. In certain embodiments, the cancer to be prevented is generally selected from carcinoma, sarcoma, mesothelioma, blastoma and germ cell tumor. In another specific embodiment, the cancer to be prevented is generally selected from mesothelioma, non-small cell lung cancer, colon cancer, breast cancer, thyroid cancer, testicular germ cell tumor and ovarian cancer showing cells expressing IL4I1.

[0185] In another specific embodiment, the cancer to be prevented is selected from lymphomas displaying cells expressing IL4I1, typically selected from B-cell lymphomas displaying cells expressing IL4I1.

[0186] In certain embodiments, the cancer to be prevented is selected from PMBL (primary mediastinal large B cell lymphoma), classical Hodgkin's lymphoma (cHL), NLPHL (Hodgkin's lymphoma with nodular lymphocyte dominance), non-mediastinal diffuse large B cell lymphoma (DLBCL) and SLL / CLL (small lymphocytic lymphoma / chronic lymphocytic leukemia) showing cells expressing IL4I1. In another specific embodiment, the cancer to be treated is selected from lymphomas showing cells expressing IL4I1.

[0187] In one embodiment described herein, the cancer to be improved is selected from cancers showing cells expressing IL4I1 and lymphomas showing cells expressing IL4I1. In certain embodiments, the cancer to be improved is a solid tumor. In certain embodiments, the cancer to be improved is generally selected from carcinoma, sarcoma, mesothelioma, blastoma and germ cell tumor. In another specific embodiment, the cancer to be improved is generally selected from mesothelioma, non-small cell lung cancer, colon cancer, breast cancer, thyroid cancer, testicular germ cell tumor and ovarian cancer showing cells expressing IL411.

[0188] In another specific embodiment, the cancer to be improved is selected from lymphomas displaying cells expressing IL411, typically selected from B-cell lymphomas displaying cells expressing IL411.

[0189] In certain embodiments, the cancer to be improved is selected from PMBL (primary mediastinal large B cell lymphoma), classical Hodgkin's lymphoma (cHL), NLPHL (Hodgkin's lymphoma with nodular lymphocyte advantage), non-mediastinal diffuse large B cell lymphoma (DLBCL) and SLL / CLL (small lymphocytic lymphoma / chronic lymphocytic leukemia) showing cells expressing IL4I1. In another specific embodiment, the cancer to be improved is selected from lymphomas showing cells expressing IL4I1.

[0190] Pharmaceutical composition

[0191] The compounds described herein can be administered orally or parenterally. When formulated into dosage forms suitable for administration, the compounds described herein can be used as pharmaceutical compositions for preventing, treating or ameliorating the above-mentioned diseases.

[0192] In the clinical application of the compounds described herein, the compounds are usually formulated into various products together with pharmaceutically acceptable additives according to the dosage form, which can then be applied. "Pharmaceutically acceptable" means that additives, carriers, diluents or excipients must be compatible with the other ingredients of the preparation and harmless to the recipient. Therefore, various additives commonly used in the field of pharmaceutical products can be used. Its specific examples include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminum metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid esters, polysorbate, sucrose fatty acid esters, polyoxyethylene, hardened castor oil, polyvinyl pyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, etc.

[0193] The products to be formed with those additives include, for example, solid products such as tablets, capsules, granules, powders and suppositories; and liquid products such as syrups, elixirs and injections. These can be formulated according to conventional methods known in the field of pharmaceutical products. Liquid products can also be in a form that can be dissolved or suspended in water or any other suitable medium during their use.

[0194] Particularly for injections, the preparation can be dissolved or suspended in physiological saline or glucose solution, if necessary, and a buffer or preservative can be optionally added thereto.

[0195] The pharmaceutical composition may contain the compound of the present invention in an amount of 1 to 99.9% by weight, preferably 1-60% by weight of the composition. The composition may further contain any other therapeutically effective compound.

[0196] In the case where the compound of the present invention is used to prevent or treat the above-mentioned diseases, dosage and administration frequency can vary according to the patient's gender, age, body weight and disease condition and the type and scope of the expected therapeutic effect. Generally speaking, when administered orally, the dosage can be 0.001 to 50 mg / kg body weight / day, and it can be administered once or several times. In a particular embodiment, the dosage is about 0.01 to about 25 mg / kg / day, in a specific embodiment, about 0.05 to about 10 mg / kg / day, or about 0.001 to about 50 mg / kg / day. For oral administration, the composition is preferably provided in the form of a tablet or capsule containing 0.01 mg to 1,000 mg. In specific embodiments, the dosage is 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 750, 850, or 1,000 mg of a compound described herein. The dosage regimen may be adjusted to provide the optimal therapeutic response.

[0197] Combination therapy

[0198] The compounds of the present invention may also be used in combination with other therapeutic agents in methods of preventing or treating the aforementioned diseases, disorders and conditions.

[0199] The compounds of the present invention can be used in combination with one or more other drugs to treat, prevent, inhibit or improve the diseases or conditions for which the compounds described herein or other drugs may be useful, wherein the combination of the drugs together is safer or more effective than any single drug. Therefore, such other drugs can be administered simultaneously or sequentially with the compounds described herein or their pharmaceutically acceptable salts in the amounts commonly used. When the compounds described herein are used simultaneously with one or more other drugs, the pharmaceutical composition may contain such other drugs and the compounds described herein or their pharmaceutically acceptable salts in a unit dosage form in a specific embodiment. However, the combination therapy may also include therapies in which the compounds described herein or their pharmaceutically acceptable salts and one or more other drugs are administered according to different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients may be used at lower doses than when each is used alone. Therefore, the pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compounds described herein or their pharmaceutically acceptable salts.

[0200] Examples of other active ingredients that can be co-administered with a compound of any formula described herein, or a pharmaceutically acceptable salt thereof, and administered separately or in the same pharmaceutical composition include, but are not limited to, pain relief agents, anti-angiogenic agents, anti-tumor agents, anti-diabetic agents, anti-infective agents, or gastrointestinal agents, or combinations thereof.

[0201] Suitable compounds that can be used in combination with the compounds according to the present invention include, but are not limited to, sildenafil, vardenafil, tadalafil and alprostadil, epoprostenol, iloprost, bosentan, amlodipine, diltiazem, nifedipine, ambrisentan and warfarin, fluticasone, budesonide, mometasone, flunisolide, beclomethasone, montelukast, zafirlukast, zileuton, salmeterol, formoterol, theophylline, salbutamol, levalbuterol, pirbuterol, ipratropium, prednisone, methylprednisolone, omalizumab, corticosteroids and cromolyn, atorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, rosuvastatin, gemfibrozil, fenofibrate, niacin, clopidogrel and pharmaceutically acceptable salts thereof.

[0202] In addition, the compounds of any formula disclosed herein can be used in combination with one or more other active agents, including, but not limited to, other anticancer agents for preventing, treating, controlling, improving specific diseases or conditions (e.g., cell proliferation disorders) or reducing their risk. In one embodiment, the compounds disclosed herein are combined with one or more other anticancer agents for preventing, treating, controlling, improving specific diseases or conditions for which the compounds disclosed herein are useful or reducing their risk. Such other active agents can be administered simultaneously or sequentially with the compounds of the present invention by the routes and amounts commonly used for them.

[0203] In one embodiment, the additional active agent is selected from vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothened inhibitors, alkylating agents, antitumor antibiotics, antimetabolites, retinoids, immunomodulators, including but not limited to anticancer vaccines, CTLA-4, LAG-3 and PD-1 antagonists.

[0204] PD-1 is believed to play an important role in immune regulation and maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T-cells, B-cells, and NKT-cells, and is upregulated by T-cell and B-cell receptor signaling on lymphocytes, monocytes, and myeloid cells (Sharpe et al., Nature Immunology (2007); 8: 239-245).

[0205] Two known ligands of PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers originating from various tissues. In large sample collections of, for example, ovarian, renal, colorectal, pancreatic, and liver cancers, as well as in melanoma, PD-L1 expression has been shown to be associated with poor prognosis and reduced overall survival, regardless of subsequent treatment (Dong et al., Nat Med. 8(8):793-800 (2002); Yang et al., Invest Ophthamol Vis Sci. 49:2518-2525 (2008); Ghebeh et al., Neoplasia 8:190-198 (2006); Hamanishi et al., Proc. Natl. Acad. Sci. USA 104:3360-3365 (2007); Thompson et al., Cancer 5:206-211 (2006); Nomi et al., Clin. Cancer Research 13:2151-2157 (2007); Ohigashi et al., Clin. Cancer Research 11:2947-2953; Inman et al., Cancer 109:1499-1505 (2007); Shimauchi et al., Int. J. Cancer 121:2585-2590 (2007); Gao et al., Clin. Cancer Research 15:971-979 (2009); Nakanishi J., Cancer Immunol Immunother. 56:1173-1182 (2007); and Hino et al., Cancer 00:1-9 (2010)).

[0206] Similarly, PD-1 expression on tumor-infiltrating lymphocytes was found to mark dysfunctional T cells in breast cancer and melanoma (Ghebeh et al., BMC Cancer. 2008 8: 5714-15 (2008); and Ahmadzadeh et al., Blood 114: 1537-1544 (2009)) and correlated with poor prognosis in renal cancer (Thompson et al., Clinical Cancer Research 15: 1757-1761 (2007)). Thus, it has been proposed that tumor cells expressing PD-L1 interact with PD-1-expressing T cells to attenuate T-cell activation and evade immune surveillance, thereby promoting an impaired immune response against the tumor.

[0207] Immune checkpoint therapy targeting the PD-1 axis has led to breakthrough improvements in clinical responses in a variety of human cancers (Brahmer et al., N Engl J Med 2012, 366:2455-65; Garon et al., N Engl J Med 2015, 372:2018-28; Hamid et al., N Engl J Med 2013, 369:134-44; Robert et al., Lancet 2014, 384:1109-17; Robert et al., N Engl J Med 2015, 372:2521-32; Robert et al., N Engl J Med 2015, 372:320-30; Topalian et al., N Engl J Med 2012, 366:2443-54; Topalian et al., J Clin Oncol 2014, 32:1020-30; and Wolchok et al., N Engl J Med 2013, 369: 122-33).

[0208] "PD-1 antagonist" refers to any compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T-cells, B-cells or NKT cells) and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed by immune cells. Alternative names or synonyms for PD-1 and its ligands include: for PD-1, PDCD1, PD1, CD279 and SLEB2; for PD-L1, PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H; and for PD-L2, PDCD1L2, PDL2, B7-DC, Btdc and CD273. In any of the methods of treatment, medicaments and uses of the present invention for treating human individuals, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of human PD-L1 and PD-L2 to human PD-1. The amino acid sequence of human PD-1 can be found in NCBI LocuS No.: NP 005009. The amino acid sequences of human PD-L1 and PD-L2 can be found in NCBI LocuS No.: NP_054862 and NP_079515, respectively.

[0209] PD-1 antagonists that can be used in any of the treatment methods, drugs, and uses of the present invention include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, and preferably specifically bind to human PD-1 or human PD-L1. The mAb can be a human antibody, a humanized antibody, or a chimeric antibody, and can include a human constant region. In certain embodiments, the human constant region is selected from IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In certain embodiments, the antigen-binding fragment is selected from Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments. Examples of PD-1 antagonists include, but are not limited to, pembrolizumab ( Merck and Co., Inc., Kenilworth, NJ, USA). "Pembrolizumab" (formerly known as MK-3475, SCH 900475, and pembrolizumab, sometimes referred to as "pembro") is a humanized IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013). Additional examples of PD-1 antagonists include nivolumab ( Bristol-Myers Squibb Company, Princeton, NJ, USA), atezolizumab (MPDL3280A; Genentech, San Francisco, CA, USA), durvalumab ( Astra Zeneca Pharmaceuticals, LP, Wilmington, Germany) and avelumab ( Merck KGaA, Darmstadt, Germany and Pfizer, Inc., New York, NY).

[0210] Examples of monoclonal antibodies (mAbs) that bind to human PD-1 and can be used in the methods of treatment, medicaments and uses of the present invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004 / 004771, WO2004 / 072286, WO2004 / 056875 and US2011 / 0271358.

[0211] Examples of mAbs that bind to human PD-L1 and can be used in the methods of treatment, medicaments and uses of the present invention are described in WO2013 / 019906, WO2010 / 077634A1 and US8383796. Specific anti-human PD-L1 mAbs that can be used as PD-1 antagonists in the methods of treatment, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C, and antibodies comprising the heavy and light chain variable regions of SEQ ID NO: 24 and SEQ ID NO: 21 of WO2013 / 019906, respectively.

[0212] Other PD-1 antagonists that can be used in any of the methods of treatment, drugs and uses of the present invention include immunoadhesins that specifically bind to PD-1 or PD-L1 and preferably specifically bind to human PD-1 or human PD-L1, for example, fusion proteins containing an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region of an immunoglobulin molecule (such as an Fc region). Examples of immunoadhesin molecules that specifically bind to PD-1 are described in WO2010 / 027827 and WO2011 / 066342. Specific fusion proteins that can be used as PD-1 antagonists in the methods of treatment, drugs and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1.

[0213] Thus, one embodiment provides a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In such an embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof and the PD-1 antagonist are administered concurrently or sequentially.

[0214] According to this embodiment, specific non-limiting examples of such cancers include melanoma (including unresectable or metastatic melanoma), head and neck cancer (including recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, hepatocellular carcinoma, clear cell renal carcinoma, colorectal cancer, breast cancer, squamous cell lung cancer, basal carcinoma, sarcoma, bladder cancer, endometrial cancer, pancreatic cancer, liver cancer, gastrointestinal cancer, multiple myeloma, renal cancer, mesothelioma, ovarian cancer, anal cancer, biliary tract cancer, esophageal cancer, and salivary gland cancer.

[0215] In one embodiment, a method for treating cancer is provided, comprising administering to a person in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist, wherein the cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), classical Hodgkin's lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, highly microsatellite instability (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0216] Pembrolizumab is approved by the U.S. FDA for the treatment of patients with unresectable or metastatic melanoma and for the treatment of certain patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, microsatellite instability-high (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma, as in KEYTRUDA TM The invention relates to a method of treating cancer, comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with pembrolizumab to a person in need thereof, wherein the cancer is selected from unresectable or metastatic melanoma, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), classical Hodgkin's lymphoma (cHL), urothelial carcinoma, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, high microsatellite instability (MSI-H) cancer, non-small cell lung cancer, and hepatocellular carcinoma.

[0217] In another embodiment, a method for treating cancer is provided, comprising administering to a person in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist, wherein the cancer is selected from melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), Hodgkin's lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, highly microsatellite instability cancer, gastric cancer, Merkel cell carcinoma, hepatocellular carcinoma, esophageal cancer, and cervical cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab. In other such embodiments, the agent is durvalumab or avelumab.

[0218] In another embodiment, a method of treating cancer is provided, comprising administering to a person in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist, wherein the cancer is selected from melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular carcinoma, lymphoma, kidney cancer, mesothelioma, ovarian cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, and salivary gland cancer. In one such embodiment, the agent is a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In another such embodiment, the agent is durvalumab. In another such embodiment, the agent is avelumab. In other such embodiments, the agent is durvalumab or avelumab.

[0219] In one embodiment, a method of treating unresectable or metastatic melanoma is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0220] In one embodiment, a method of treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is provided, comprising administering to a person in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0221] In one embodiment, a method of treating classical Hodgkin lymphoma (cHL) is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0222] In one embodiment, a method of treating urothelial carcinoma is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0223] In one embodiment, a method of treating gastric cancer is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0224] In one embodiment, a method of treating cervical cancer is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0225] In one embodiment, a method of treating primary mediastinal large B-cell lymphoma is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0226] In one embodiment, a method of treating microsatellite instability-high (MSI-H) cancer is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0227] In one embodiment, a method of treating non-small cell lung cancer is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0228] In one embodiment, a method of treating hepatocellular carcinoma is provided, comprising administering to a person in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with a PD-1 antagonist. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is atezolizumab. In other such embodiments, the agent is durvalumab or avelumab.

[0229] Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold by Genentech / Roche under the trade name AVASTIN), axitinib (N-methyl-2-[[3-[([E])-2-pyridin-2-ylvinyl]-1H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO01 / 002369), brivanib alanine ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1 H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide and described in PCT Publication No. WO 02 / 068470), pasireotide (also known as SO 230 and described in PCT Publication No. WO 02 / 010192), and sorafenib (sold under the trade name NEXAVAR).

[0230] Examples of topoisomerase II inhibitors include, but are not limited to, etoposide (also known as VP-16 and etoposide phosphate, sold under the trade names TOPOSAR, VEPESID, and ETOPOPHOS) and teniposide (also known as VM-26, sold under the trade name VUMON).

[0231] Examples of alkylating agents include, but are not limited to, 5-azacytidine (sold under the trade name VIDAZA), decitabine (sold under the trade name DECOGEN), temozolomide (sold under the trade names TEMODAR and TEMODAL by Schering-Plough / Merck), dactinomycin (also known as actinomycin-D and sold under the trade name COSMEGEN), melphalan (also known as L-PAM, L-sabolin and melphalan, sold under the trade name ALKERAN), hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trade name HEXALEN), carmustine (sold under the trade name BCNU), bendamustine (sold under the trade name TREANDA), busulfan (sold under the trade names BUSULFEX and MYLERAN), carboplatin (sold under the trade name PARAPLATIN), lomustine (also known as CCNU, sold under the trade name Ce eNU), cisplatin (also known as CDDP and sold under the trade names PLATINOL and PLATINOL-AQ), chlorambucil (sold under the trade name LEUKERAN), cyclophosphamide (sold under the trade names CYTOXAN and NEOSAR), dacarbazine (also known as DTIC, DIC and imidazolecarboxamide and sold under the trade name DTIC-DOME), hexamethylmelamine (also known as hexamethylmelamine (HMM) and sold under the trade name HEXALEN), ifosfamide (sold under the trade name IFEX), procarbazine (sold under the trade name MATULANE), mechlorethamine (also known as nitrogen mustard, mechlorethamine hydrochloride and mechlorethamine hydrochloride and sold under the trade name MUSTARGEN), streptozotocin (sold under the trade name ZANOSAR), thiotepa (also known as thiophosphoramide, TESPA and TSPA and sold under the trade name THIOPLEX).

[0232] Examples of antitumor antibiotics include, but are not limited to, doxorubicin (sold under the trade names doxorubicin and RUB EX), bleomycin (sold under the trade name LENOXANE), daunorubicin (also known as daunorubicin hydrochloride, daunomycin, and daunomycin hydrochloride, sold under the trade name CERUBIDINE), daunorubicin liposomal (daunorubicin liposomal citrate, sold under the trade name DAUNOXOME), mitoxantrone (also known as DHAD, sold under the trade name NOVANTRONE), epirubicin (sold under the trade name ELLENCE), idarubicin (sold under the trade names IDAMYCIN, IDAMYCIN PFS), and mitomycin C (sold under the trade name MUTAMYCIN).

[0233] Examples of antimetabolites include, but are not limited to, claribine (2-chlorodeoxyadenosine, sold under the trade name LEUSTATIN), 5-fluorouracil (sold under the trade name ADRUCIL), 6-thioguanine (sold under the trade name PURINETHOL), pemetrexed (sold under the trade name ALIMTA), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the trade name CYTOSAR-U), cytarabine liposome (also known as Ara-C liposome, sold under the trade name DEPOCYT), decitabine (sold under the trade name DACOGEN), hydroxyurea (sold under the trade names HYDREA, DROXIA, and MYLOCEL), fludarabine (sold under the trade name FLUDARA), floxuridine (sold under the trade name FUDR), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), sold under the trade name LEUSTATIN), methotrexate (also known as methotrexate, methotrexate sodium (MTX), sold under the trade names RHEUMATREX and TREXALL), and pentostatin (sold under the trade name NIPENT).

[0234] Examples of retinoids include, but are not limited to, alitretinoin (sold under the trade name PANRETIN), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the trade name VESANOID), isotretinoin (13-c / s-retinoic acid, sold under the trade names ACCUTANE, AMNESTEEM, CLARAVIS, CLARUS, DECUTAN, ISOTANE, IZOTECH, ORATANE, ISOTRET, and SOTRET), and bexarotene (sold under the trade name TARGRETIN).

[0235] In such a combination, the compound of the present invention and the other active agent may be administered separately or in combination. In addition, the administration of one component may be before, at the same time or after the administration of the other agent. Example

[0236] The meanings of abbreviations in the examples are shown below.

[0237] ACN=CH3CN=MeCN=acetonitrile

[0238] AcOH = acetic acid

[0239] APhos-Pd-G3 = Palladium G3-(4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine = [4-(di-tert-butylphosphino)-N,N-dimethylanilino-2-(2′-aminobiphenyl)]methanesulfonate palladium(II)

[0240] APhos-Pd-G4 = 4-di-tert-butylphosphinoyl-N,N-dimethylaniline; methanesulfonic acid; N-methyl-2-phenylaniline; palladium

[0241] Boc2O=di-tert-butyl dicarbonate

[0242] Boc-Ser(Bzl)-OH=N-(tert-butyloxycarbonyl)-O-benzyl-L-serine

[0243] CDI = 1,1′-carbonyldiimidazole

[0244] CELITE=Diatomaceous Earth

[0245] CF3CH2OH=2,2,2-trifluoroethanol

[0246] Conc.=concentrated

[0247] CO2 = Carbon dioxide

[0248] Cp*RuCl(PPh3)2=pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride

[0249] DCM = dichloromethane

[0250] DIEA=DIPEA=N,N-diisopropylethylamine=Hünig's base

[0251] DMA = dimethylacetamide

[0252] DMAP = 4-dimethylaminopyridine

[0253] DMF=N,N-dimethylformamide

[0254] DMSO = dimethyl sulfoxide

[0255] DPPE = 1,2-bis(diphenylphosphino)ethane

[0256] EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0257] EtOAc = Ethyl acetate

[0258] h = hours

[0259] H2=Hydrogen

[0260] H20=Water

[0261] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0262] HBr = Hydrogen bromide

[0263] HCl = Hydrochloric acid

[0264] HFBA = Heptafluorobutyric acid

[0265] HOBT = Hydroxybenzotriazole

[0266] K2CO3=Potassium carbonate

[0267] LCMS = Liquid Chromatography-Mass Spectrometry

[0268] LHMDS=LiHMDS=Lithium bis(trimethylsilyl)amide

[0269] LiAlH4 = Lithium Aluminum Hydride

[0270] LiF = Lithium Fluoride

[0271] LiOH = Lithium Hydroxide

[0272] min = minutes

[0273] MeOH = methanol

[0274] MgSO4 = Magnesium sulfate

[0275] NaBH4 = Sodium borohydride

[0276] NaCl = Sodium Chloride

[0277] NaHCO3 = Sodium bicarbonate

[0278] NaOH = Sodium Hydroxide

[0279] Na2SO4=Sodium sulfate

[0280] NaH = Sodium hydride

[0281] NH4Cl = Ammonium chloride

[0282] NH4OH = Ammonium hydroxide

[0283] Pd(OH)2 / C = Pearlman's catalyst = palladium hydroxide on carbon

[0284] Pd(dtbpf)Cl2=1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride

[0285] SFC = Supercritical Fluid Chromatography

[0286] sSPhos Pd G2 = chloro(sodium 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl-3′-sulfonate)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0287] TEA = triethylamine

[0288] TFA = trifluoroacetic acid

[0289] THF = Tetrahydrofuran

[0290] 1 standard atmosphere [atm] = 101325 Pascal [Pa] = 14.6959488 psi

[0291] The following shows the meaning of the abbreviations used in NMR spectroscopy:

[0292] s = singlet, d = doublet, dd = doublet of doublets, dt = doublet of triplets, ddd = doublet of doublets, Sept = septet, t = triplet, m = multiplet, br = broad, brs = broad singlet, q = quartet

[0293] J = coupling constant and Hz = Hertz.

[0294] The compounds of the invention may be prepared using the intermediates and methods outlined below. The various starting materials used are either commercially available or readily prepared by the following schemes.

[0295] Solution 1

[0296] Certain compounds of formula I were synthesized by converting alkyl borate ester 1 to 2 with the corresponding aryl bromide under palladium-catalyzed Suzuki conditions. Deprotection then completed the synthesis.

[0297]

[0298] Solution 2

[0299] Certain compounds of formula I were synthesized from diamino compounds 3 in the presence of CDI.

[0300]

[0301] Solution 3

[0302] Certain compounds of Formula I are synthesized by converting diamino compound 4 to 5 in the presence of CDI. 5 is then converted to 6 by deprotection. Coupling with the corresponding acid, anhydride, sulfonyl chloride or sulfonic anhydride completes the synthesis.

[0303]

[0304] Solution 4

[0305] Certain compounds of formula I are synthesized by converting the alkyl acid 7 to 8 with the corresponding aryl bromide under iridium and nickel catalyzed decarboxylative coupling conditions. Deprotection, if necessary, completes the synthesis.

[0306]

[0307] Solution 5

[0308] Certain compounds of formula I were synthesized by converting alkyl acid 9 to 10 with the corresponding aryl bromide under iridium and nickel catalyzed decarboxylative coupling conditions. Deprotection of 10 afforded compound 11. Coupling with the corresponding acid completed the synthesis.

[0309]

[0310] Solution 6

[0311] Certain compounds of formula I are synthesized from amine 12 in the presence of a base and an alkyl halide.

[0312]

[0313] Solution 7

[0314] Certain compounds of formula I are synthesized by converting amine 13 to 14 in the presence of a base and an alkyl halide. Deprotection completes the synthesis.

[0315]

[0316] Solution 8

[0317] Certain compounds of Formula I were synthesized from amine 15 by Mitsunobu reaction.

[0318]

[0319] Solution 9

[0320] Certain compounds of Formula I were synthesized by converting amine 16 to 17 via a Mitsunobu reaction. Deprotection completed the synthesis.

[0321]

[0322] Solution 10

[0323] Certain compounds of Formula I were synthesized from carbamate 18 using copper-catalyzed aryl amination followed by intramolecular cyclization.

[0324]

[0325] Solution 11

[0326] Certain compounds of Formula I were synthesized by converting carbamate 19 to 20 using a copper-catalyzed aryl amination reaction followed by intramolecular cyclization. Deprotection of 20 afforded 21. The synthesis was completed using amide coupling.

[0327]

[0328] Solution 12

[0329] Certain compounds of formula I were synthesized from aryl halides 22 and urea via palladium-catalyzed aryl amination.

[0330]

[0331] Solution 13

[0332] Certain compounds of formula I were synthesized by converting aryl azide 23 to 24 via a ruthenium catalyzed reaction. Deprotection completes the synthesis.

[0333]

[0334] Solution 14

[0335] Certain compounds of Formula I were synthesized by converting the boronate ester 25 to 26 via a palladium-catalyzed Suzuki reaction. 26 was converted to 27 via a palladium-catalyzed cyclopropanation reaction. Deprotection completed the synthesis.

[0336]

[0337] Solution 15

[0338] Certain compounds of Formula I were synthesized by converting the acid 28 to 29 in the presence of triphosgene. 29 was converted to 30 in the presence of sodium azide. Curtius rearrangement followed by intramolecular cyclization completed the synthesis.

[0339]

[0340] Scheme 16

[0341] Certain compounds of Formula I were synthesized by converting amine 31 to 32 via alkylation with a benzyl halide. 32 was converted to 33 via alkylation with an amine. Deprotection completed the synthesis.

[0342]

[0343] Solution 17

[0344] Certain compounds of Formula I were synthesized by converting amine 34 to 35 by alkylation with a di-iodoalkyl compound. 35 was converted to 36 by alkylation with triphenylphosphine. 36 was converted to 37 by Wittig reaction. 37 was converted to 38 by deprotection. The synthesis was completed by palladium catalyzed hydrogenation.

[0345]

[0346] Scheme 18

[0347] Certain compounds of Formula I were synthesized by converting amine 39 to 40 via alkylation with a benzyl halide. 40 was converted to 41 via nickel-catalyzed reductive coupling. Deprotection completed the synthesis.

[0348]

[0349] Intermediate 1:

[0350] 2-Oxo-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester

[0351]

[0352] tert-Butyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (194.0 g, 0.83 mol, 1 eq.), THF (3.8 L) and NaH (36.40 g, 0.91 mol, 1.10 eq.) were added to a round bottom flask. The reaction mixture was stirred at 0°C for 30 minutes. 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (228.6 g, 1.08 mol) was then added at 0°C and the reaction mixture was stirred overnight at 30°C. Water was added to quench the reaction and it was then extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and then slurried with MTBE to provide a solid. 1 HNMR (400MHz, CDCl3): δ7.80 (dd, J=7.8, 1.3Hz, 1H), 7.13 (dtd, J=24.0, 7.7, 1. 3Hz, 2H), 6.87 (dd, J=7.5, 1.4Hz, 1H), 3.43 (s, 2H), 1.63 (s, 9H), 1.27 (s, 12H).

[0353] Intermediate 2:

[0354] 2-(3-(tert-Butyloxycarbonyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid

[0355]

[0356] Step A: tert-Butyl 3-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0357]

[0358] 2-Oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (0.275 g, 1.174 mmol) and potassium carbonate (0.324 g, 2.348 mmol) were added to an 8 ml vial, followed by acetonitrile (2 ml) and then ethyl bromoacetate (0.261 ml, 2.348 mmol). The reaction mixture was then heated to 60 ° C for 3 hours. When the reaction was complete, the reaction mixture was evaporated under reduced pressure and then purified by silica gel column chromatography using hexane and ethyl acetate as eluents. LC / MS (m / z): 265 (M+H) + (observed as loss of tBu).

[0359] Step B: 2-(3-(tert-Butyloxycarbonyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid

[0360]

[0361] tert-Butyl 3-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (340 mg, 1.061 mmol) and lithium hydroxide (50.8 mg, 2.123 mmol) were added to a 20 ml vial. 1 ml of dioxane and water (1:1) were then added and the reaction mixture was stirred at room temperature for 1 hour. Water was added and the reaction mixture was extracted with ethyl acetate. The aqueous layer was then made acidic with 1 M HCl, extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to provide the desired product, which was used as is without further purification. LC / MS (m / z): 237 (M+H)+ (observed as loss of tBu).

[0362] Intermediate 3:

[0363] 1-(Difluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0364]

[0365] Step A: 2-Chloro-1-(difluoromethyl)-1H-benzo[d]imidazole

[0366]

[0367] 2-Chloro-1H-benzo[d]imidazole (0.63 g, 4.13 mmol) was dissolved in ACN (10 ml), and diethyl (bromodifluoromethyl)phosphonate (1.1 g, 4.12 mmol) and potassium fluoride (0.48 g, 8.26 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The solvent was then removed under reduced pressure, and the residue was dissolved in water (30 ml) and EtOAc (20 ml). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (20 ml x 2), and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate and petroleum ether as eluents. It was separated into solids. LCMS (ESI) m / z: 203 [M+H] + .

[0368] Step B: 1-(Difluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0369]

[0370] 2-Chloro-1-(difluoromethyl)-1H-benzo[d]imidazole (263 mg, 1.298 mmol) was dissolved in acetic acid (5 ml) and the mixture was stirred at 100° C. for 1 hour. After this time, the mixture was concentrated under reduced pressure to provide a crude solid, which was used directly in the next step without any further purification. LCMS (ESI) m / z: 185 [M+H] + .

[0371] Intermediate 4:

[0372] 3-((2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0373]

[0374] Step A: Methyl 3-((2-oxo-3-(prop-1-en-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0375]

[0376] Potassium carbonate (3173 mg, 22.96 mmol) and 1-(prop-1-ene-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2000 mg, 11.48 mmol) were added to a 250 mL round-bottom flask. Acetonitrile (25 ml) and methyl 3-(bromomethyl)benzoate (2630 mg, 11.48 mmol) were added portionwise over 5 minutes, and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then filtered through diatomaceous earth and evaporated in vacuo. LCMS (ESI) m / z: 323 [M+H] + .

[0377] Step B: Methyl 3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0378]

[0379] Methyl 3-((2-oxo-3-(prop-1-en-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (3700mg, 11.48mmol) was dissolved in methanol (25ml). Water (5ml) was added and the reaction mixture was placed in an ice bath. Then, hydrochloric acid (4M in dioxane, 8.61ml, 34.4mmol) was slowly added and the reaction mixture was stirred at room temperature for 1 hour. 6M HCl aqueous solution (1ml) was added and the reaction mixture was heated to 50°C for 2 hours. Then, the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography using hexane and ethyl acetate as eluents. LCMS(ESI)m / z:283[M+H] + .

[0380] Step C: 3-((2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0381]

[0382] Methyl 3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (1400 mg, 4.96 mmol) was added to a 20 ml vial and dissolved in THF:water (3:1) (10 ml). Lithium hydroxide (178 mg, 7.44 mmol) was added portionwise over 5 minutes and the mixture was stirred at room temperature for 2 hours. The resulting reaction was evaporated in vacuo. 10 ml of DCM was added followed by 5 ml of 0.5 M NaOH. The organic phase was removed and the aqueous layer was acidified with 6 M HCl until the pH was about 2-3. The solid formed was filtered, washed with DCM and used as is. LCMS (ESI) m / z: 269 [M+H]+ .

[0383] Intermediate 5:

[0384] 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid

[0385]

[0386] Step A: tert-Butyl 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetate

[0387]

[0388] Cuprous iodide (166 mg, 0.869 mmol), L-hydroxyproline (228 mg, 1.739 mmol), potassium phosphate (1845 mg, 8.69 mmol) and methyl (2-bromophenyl)carbamate (1000 mg, 4.35 mmol) were added to a vial under nitrogen. DMSO (11 ml) was added followed by tert-butyl 2-(3-(aminomethyl)phenyl)acetate (962 mg, 4.35 mmol). The reaction mixture was purged with nitrogen, sealed and heated to 130° C. After 18 hours, the reaction mixture was cooled to room temperature and filtered through celite, rinsing with ethyl acetate. The combined organic layers were concentrated under reduced pressure, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using hexane and ethyl acetate as eluents. LCMS (ESI) m / z: 361 [M+Na] + .

[0389] Step B: 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid

[0390]

[0391] Tert-butyl 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetate (451.4 mg, 1.334 mmol), TFA (2.00 mL) and dioxane (2.00 ml) were added to a vial. The vial was sealed, stirred and heated to 60° C. for 24 hours. DCM was added, the mixture was washed with brine, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. LCMS (ESI) m / z: 283 [M+H] + .

[0392] Intermediate 6:

[0393] 2-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid

[0394]

[0395] Step A: Ethyl 2-(4-(((2-nitrophenyl)amino)methyl)phenyl)acetate

[0396]

[0397] Ethyl 2-(4-(aminomethyl)phenyl)acetate, HCl was added to a 250 ml round bottom flask followed by DMF (15 mL) and the mixture was placed in a water bath. Potassium carbonate (4.04 g, 29.3 mmol) was added to the flask followed by dropwise addition of 1-fluoro-2-nitrobenzene (1.371 ml, 13 mmol). The reaction was filtered and evaporated in vacuo to provide a crude material which was used in the next step. LCMS (ESI) m / z: 315 [M+H] + .

[0398] Step B: Ethyl 2-(4-(((2-aminophenyl)amino)methyl)phenyl)acetate

[0399]

[0400] Zinc (4.67 g, 71.5 mmol) was added to a 500 ml round bottom flask followed by 75 ml of ethanol. The mixture was cooled to 0 °C and acetic acid (4.09 ml, 71.5 mmol) was added. After 5 minutes, ethyl 2-(4-(((2-nitrophenyl)amino)methyl)phenyl)acetate (4.09 g, 13 mmol) in 15 ml of ethanol was added and the reaction was stirred at room temperature under nitrogen. After 1 hour, additional zinc (500 mg) was added together with 1 ml of acetic acid. The reaction mixture was then heated to 35 °C for 5 hours, filtered through diatomaceous earth, and evaporated in vacuo. The product was dissolved in ethyl acetate and washed with sodium bicarbonate. The combined organic layers were then dried over magnesium sulfate, filtered, and evaporated in vacuo. The product was used as a crude product. LCMS (ESI) m / z: 285 [M+H] + .

[0401] Step C: Ethyl 2-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetate

[0402]

[0403] Ethyl 2-(4-(((2-aminophenyl)amino)methyl)phenyl)acetate (3.5 g, 12.31 mmol) was dissolved in 25 ml of DCM. CDI (1.996 g, 12.31 mmol) was added along with an additional 20 ml of DCM, a water bath was placed under the flask, and it was stirred at room temperature overnight. The reaction was then washed with 1 M HCl and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo to produce the desired crude material. The crude residue was purified by silica gel chromatography using hexane and ethyl acetate as eluents. LCMS (ESI) m / z: 311 [M+H] + .

[0404] Step D: 2-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid

[0405]

[0406] Ethyl 2-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetate (530 mg, 1.708 mmol), NaOH (1708 μl, 3.42 mmol) and dioxane (3.4 ml) were added to a vial. The vial was sealed and heated to 65°C overnight. After this time, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and acidified to pH 1 using 4M HCl / dioxane. The solvent was then removed in vacuo and the solid was further dried on a lyophilizer to provide the product. LCMS (ESI) m / z: 283 [M+H] + .

[0407] Embodiment 1:

[0408] Preparation of 1-(4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0409]

[0410] Step A: 1-(4-bromobenzyl)pyrrolidin-2-one

[0411]

[0412] Sodium hydride (2.376g, 59.4mmol) was added to a 500ml round-bottom flask with a stirring bar and purged with nitrogen. THF (80ml) was added, and the mixture was cooled to 0°C with an ice bath. The reaction mixture was stirred for 5 minutes. Pyrrolidine-2-one (4.10ml, 54mmol) was slowly added, and the reaction mixture was stirred for 30 minutes. A solution of 1-bromo-4-(bromomethyl)benzene (13.50g, 54.0mmol) in THF (40ml) was slowly added. The reaction mixture was slowly warmed to room temperature and then stirred for 3 days. The reaction mixture was slowly quenched with water while cooling the mixture by a water bath. The reaction mixture was added to a separatory funnel and extracted 3 times with ethyl acetate. The combined organic layer was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The crude material was purified by silica gel column chromatography with methanol / dichloromethane as eluent. LC / MS(m / z): 254(M+H)+.

[0413] Step B: tert-Butyl 2-oxo-3-(4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0414]

[0415] tert-Butyl 2-oxo-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (14.97 g, 40 mmol) (Intermediate 1), 1-(4-bromobenzyl)pyrrolidin-2-one (10.67 g, 42.0 mmol), cesium carbonate (39.1 g, 120 mmol), APhos Pd G3 (0.635 g, 1.000 mmol) and APhos Pd G4 (0.649 g, 1.000 mmol) were added to a 500 ml round bottom flask with a stirring bar. The flask was evacuated and backfilled with nitrogen twice. Dioxane (180 ml) and water (18 ml) were added. The reaction mixture was then sealed and heated to 75 °C for 15 hours. When completed, the reaction mixture was cooled to room temperature and diluted with water. The mixture was then extracted 3 times with ethyl acetate, and the organic layers were combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified on silica gel with methanol / dichloromethane as eluent. LC / MS (m / z): 444 (M+Na)+.

[0416] Step C: 1-(4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0417]

[0418] 2-Oxo-3-(4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (7.72 g, 18.32 mmol) was added to a 40 ml vial with a stirring bar. Formic acid (14.05 ml, 366 mmol) was then added to the vial. The reaction mixture was stirred at room temperature for 3 hours (alternatively, TFA can also be used for the deprotection) and diluted with water. The mixture was then extracted 3 times with dichloromethane, the organic layers were combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified on silica gel with methanol / dichloromethane as eluent. 1 H NMR (600MHz, DMSO-d6) δ10.94 (s, 1H), 7.28 (d, J = 8.1Hz, 2H), 7.16 (d, J = 8.1Hz, 2H), 7.05-6.91 (m , 4H), 4.97 (s, 2H), 4.31 (s, 2H), 3.18 (t, J=7.0Hz, 2H), 2.25 (t, J=8.1Hz, 2H), 1.93-1.85 (m, 2H). LC / MS(m / z): 322(M+H)+.

[0419] Embodiment 2:

[0420] Preparation of 1-(4-((2-oxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0421]

[0422] Step A: N-(4-bromobenzyl)prop-2-en-1-amine

[0423]

[0424] 3-Chloroprop-1-ene (0.823 g, 10.75 mmol) was added to a mixture of (4-bromophenyl)methylamine (2 g, 10.75 mmol) and Cs2CO3 (5.25 g, 16.12 mmol) in DMF (15 mL) at 20°C. The resulting mixture was stirred at 50°C for 12 hours. After 12 hours, the reaction mixture was dried over Na2SO4 and filtered. LC / MS (m / z): 228 (M+H)+.

[0425] Step B: N-allyl-N-(4-bromobenzyl)acrylamide

[0426]

[0427] A mixture of N-(4-bromobenzyl)prop-2-ene-1-amine (800 mg, 3.54 mmol), DIEA (1.236 mL, 7.08 mmol) and acryloyl chloride (0.288 mL, 3.54 mmol) in DMF (15 mL) was stirred at 20 ° C for 12 hours. After 12 hours, the reaction mixture was extracted with water (200 mL) and EtOAc (100 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 12g Purification on silica gel flash column, eluent 0-35% ethyl acetate / petroleum ether gradient, 40 mL / min) afforded N-allyl-N-(4-bromobenzyl)acrylamide. LC / MS (m / z): 280 (M+H)+.

[0428] Step C: 1-(4-bromobenzyl)-1,5-dihydro-2H-pyrrol-2-one

[0429]

[0430] A mixture of (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl)dichloro-(phenylmethylene)(tricyclohexylphosphine)ruthenium (0.909 g, 1.071 mmol) and N-allyl-N-(4-bromobenzyl)acrylamide (2 g, 7.14 mmol) in DCM (60 ml) was degassed and backfilled with N2 (3 times). The mixture was heated to 25°C for 16 hours. After 16 hours, the solvent was removed under reduced pressure and the residue was dissolved in water (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (10 mL*3), and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 12g Purification on silica gel flash column, [0-30]% ethyl acetate / petroleum ether gradient eluent, 35 mL / min) afforded 1-(4-bromobenzyl)-1,5-dihydro-2H-pyrrol-2-one. LC / MS (m / z): 254 (M+H)+.

[0431] Step D: 1-(4-((2-oxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0432]

[0433] A mixture of tert-butyl 2-oxo-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (742 mg, 1.983 mmol), K3PO4 (1052 mg, 4.96 mmol), 1-(4-bromobenzyl)-1,5-dihydro-2H-pyrrole-2-one (500 mg, 1.983 mmol) and Pd(dtbpf)Cl2 (129 mg, 0.198 mmol) in 1,4-dioxane (5 ml) and water (1 ml) was degassed and backfilled with N2 (3 times). The mixture was heated to 90°C for 12 hours. After 12 hours, the solvent was removed under reduced pressure and the residue was dissolved in water (10 mL) and EtOAc (10 mL). The organic layer is separated, and the water layer is extracted with EtOAc (10mL*3). The organic layer merged is washed with brine (10mL), through anhydrous Na2SO4 drying, filtered and concentrated under reduced pressure to provide a crude product. Residue is purified by normal phase chromatography. Use heptane (solvent A) and ethanol (solvent B) as mobile phase, run the gradient of 0% to 5% solvent B at 25mL / min for 9 minutes to provide 1-(4-((2-oxo-2,5-dihydro-1H-pyrroles-1-yl) methyl) benzyl)-1,3-dihydro-2H-benzo [d] imidazoles-2-one. 1 H NMR (400MHz, methanol-d4) δ = 7.31 (d, J = 8.1Hz, 2H), 7.27-7.19 (m, 3H), 7.09-6.95 (m, 4H), 6.15 (br d, J=5.9Hz, 1H), 5.07 (s, 2H), 4.61 (s, 2H), 3.98 (s, 2H). LC / MS(m / z): 320(M+H)+.

[0434] Embodiment 3:

[0435] Preparation of 1-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0436]

[0437] Step A: 2-(4-bromophenyl)acetylhydrazine

[0438]

[0439] Ethyl 2-(4-bromophenyl)acetate (15.25 g, 62.7 mmol) in ethanol (150 ml) was added to a round bottom flask under nitrogen. Hydrazine (35% in water) (11.25 ml, 125 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was then evaporated in vacuo and the precipitate was filtered off, washed with ether and dried. LC / MS (m / z): 229 (M+H)+.

[0440] Step B: 2-(4-bromobenzyl)-1,3,4-oxadiazole

[0441]

[0442] Ts-OH (0.673 g, 3.54 mmol) and 2-(4-bromophenyl)acetohydrazide (8.1 g, 35.4 mmol) were added to a 500 ml round bottom flask. Toluene (100 ml) and triethoxymethane (14.72 ml, 88 mmol) were added and the reaction mixture was heated to 100 ° C for 2 hours under nitrogen with a reflux condenser connected. The reaction mixture was then cooled to room temperature, evaporated in vacuo, dry loaded onto a cartridge equipped with silica gel, and purified by silica gel column chromatography using a gradient of hexane and ethyl acetate. LC / MS (m / z): 239 (M+H)+.

[0443] Utilizing the procedure outlined in Steps BC of Example 1, 2-(4-bromobenzyl)-1,3,4-oxadiazole was elaborated to the final product 1-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one in Steps C and D below.

[0444] Step C: tert-Butyl 3-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LC / MS (m / z): 429 (M+Na)+.

[0445] Step D: 1-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (600MHz, DMSO-d6) δ 10.94 (s, 1H), 9.10 (s, 1H), 7.31-7.22 (m, 4H), 7.03-6.90 (m, 4H), 4.97 (s, 2H), 4.25 (s, 2H). LC / MS(m / z): 306(M+H)+.

[0446] Embodiment 4:

[0447] Preparation of 1-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-chlorobenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0448]

[0449] Utilizing the procedures outlined in Example 3, Steps AD, ethyl 2-(4-bromo-2-chlorophenyl)acetate was elaborated to the final product, 1-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-chlorobenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one.

[0450] Step A: 2-(4-bromo-2-chlorophenyl)acetohydrazide. LC / MS (m / z): 265 (M+H)+.

[0451] Step B: 2-(4-bromo-2-chlorobenzyl)-1,3,4-oxadiazole. LC / MS (m / z): 275 (M+H)+.

[0452] Step C: tert-Butyl 3-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-chlorobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LC / MS (m / z): 341 (M+H)+ (observed as loss of Boc)

[0453] Step D: 1-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-chlorobenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (600MHz, DMSO-d6) δ10.98 (s, 1H), 9.11 (s, 1H), 7.46-7.40 (m, 2H), 7.27 (d, J =7.9Hz, 1H), 7.08 (d, J=7.8Hz, 1H), 7.03-6.92 (m, 3H), 5.01 (s, 2H), 4.36 (s, 2H). LC / MS(m / z): 341(M+H)+.

[0454] Embodiment 5:

[0455] Preparation of N-(3-methoxy-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0456]

[0457] Step A: N-(4-bromo-3-methoxybenzyl)acetamide

[0458]

[0459] 4-Bromo-3-methoxybenzonitrile (1 g, 4.72 mmol) and acetic anhydride (0.667 ml, 7.07 mmol) were added to a dry round-bottom flask and dissolved in THF (20 ml) under a nitrogen atmosphere. Raney nickel (0.554 g, 4.72 mmol) was then added to the flask. The mixture was degassed and backfilled with hydrogen (3 times). The resulting mixture was stirred at 25 ° C for 12 hours under hydrogen (pressure: 30 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluents. The substance was isolated as a solid. LCMS (ESI) m / z: 258 [M+H] + .

[0460] Using the procedure outlined in Example 1, Step BC, N-(4-bromo-3-methoxybenzyl)acetamide was elaborated to the final product, N-(3-methoxy-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide.

[0461] Step B: tert-Butyl 3-(4-(acetamidomethyl)-2-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LC / MS (m / z): 326 (M+H)+ (observed as loss of Boc).

[0462] Step C: N-(3-methoxy-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide. 1 H NMR (400MHz, MeOH-d4) δ7.10-7.05(m, 1H), 7.05-7.00(m, 1H), 7.00-6.90(m, 4 H), 6.78 (d, J=6.7Hz, 1H), 5.04 (s, 2H), 4.31 (s, 2H), 3.89 (s, 3H), 1.97 (s, 3H). LCMS (ESI) m / z: 326[M+H]+.

[0463] Embodiment 6:

[0464] Preparation of N-((5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)methanesulfonamide

[0465]

[0466] Step A: N-(Thien-2-ylmethyl)methanesulfonamide

[0467]

[0468] Thiophene-2-ylmethylamine (5.0g, 44.2mmol) is dissolved in DCM (50ml). At 0°C, pyridine (5.34ml, 66.3mmol) is added, followed by methanesulfonyl chloride (6.05g, 52.8mmol). After the mixture is stirred at room temperature for 15 hours, the reaction is quenched by adding 1M HCl solution (100ml). The reaction mixture is extracted with DCM (50ml x 2), washed with brine (30mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Residue is purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent. 1 H NMR (500MHz, CDCl3) δ7.29 (d, J=5.0Hz, 1H), 7.05 (d, J=2.9Hz, 1H), 6.99 (dd, J=3.6, 5.0Hz, 1H), 4.80 (br s, 1H), 4.53 (d, J=6.0Hz, 2H), 2.88 (s, 3H).

[0469] Step B: N-((5-bromothiophen-2-yl)methyl)methanesulfonamide

[0470]

[0471] N-(thiophene-2-ylmethyl) methanesulfonamide (1g, 5.23mmol) is dissolved in DCM (10ml).N-bromosuccinimide (1.02g, 5.73mmol) is added at room temperature, and the mixture is stirred for 1 hour.The reaction is saturated with Na2SO3 aqueous solution (20ml) is quenched.The mixture is extracted with DCM (50ml x 2), and the organic layer combined is washed with salt water (20mL), through anhydrous Na2SO4 drying, filtered and concentrated under reduced pressure.Residue is purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent. 1 H NMR (400MHz, CDCl3) δ6.93 (d, J=3.5Hz, 1H), 6.81 (d, J=3.9Hz, 1H), 4.83 (br s, 1H), 4.44 (d, J=5.5Hz, 2H), 2.91 (s, 3H).

[0472] Using the procedure outlined in Example 1, Step BC, N-((5-bromothiophen-2-yl)methyl)methanesulfonamide was elaborated to the final product, N-((5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)methanesulfonamide in the following Step CD.

[0473] Step C: tert-Butyl 3-((5-(methylsulfonamidomethyl)thiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LCMS (ESI) m / z: 338 [M+H] + (Observed as loss of Boc).

[0474] Step D: N-((5-((2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)methanesulfonamide. 1 H NMR (400MHz, MeOH-d4) δ7.15-7.09 (m, 1H), 7.08-7.02 (m, 3H), 7.00 (d, J=3.4Hz, 1H), 6.88 (d, J=3.4Hz, 1H), 5.21 (s, 2H), 4.34 (s, 2H), 2.77 (s, 3H). LCMS(ESI)m / z:338[M+H] + .

[0475] The examples in Table 1 were synthesized according to the procedure described in Example 1, Step BC, using appropriate aryl bromide starting materials.

[0476] Table 1

[0477]

[0478] Embodiment 11:

[0479] Preparation of N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0480]

[0481] Step A: N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0482]

[0483] N-(4-Bromobenzyl)acetamide (6.09 g, 26.7 mmol), cesium carbonate (26.1 g, 80 mmol), sSPhos PdG2 (2.198 g, 2.67 mmol) and tert-butyl 2-oxo-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (10 g, 26.7 mmol) (Intermediate 1) were added to a round bottom flask equipped with a stirring bar. The mixture was purged with nitrogen for 5 minutes. After 5 minutes, dioxane (81 ml) and water (8.10 ml) were added to the mixture. The reaction mixture was heated to 80° C. with stirring for 17 hours. After 17 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added and the reaction mixture was washed with water. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The material was dissolved in THF (40 mL) and HCl (4M in dioxane) (40 ml, 160 mmol) was added dropwise to the solution. The mixture was heated to 45 °C for 45 minutes. After 45 minutes, the material was filtered to provide the title compound. LC / MS (m / z): 296 (M+H)+.

[0484] Step B: N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0485]

[0486] N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide (17.7 g, 59.9 mmol) was added to a round bottom flask. Acetonitrile (144 ml) / water (55.4 ml) was added to the flask. A condenser was connected to the flask and the flask was heated to 80°C for 30 minutes. After 30 minutes, the temperature was raised to 95°C and stirring was continued. After 15 minutes, ACN (36 ml) and water (14 ml) were added and the temperature was raised to 105°C. After 1 hour, the mixture was slowly cooled to room temperature while stirring for 16 hours. After 16 hours, the mixture was filtered. The collected solids were rinsed with cold ACN (cooled to 0°C with an ice bath). The collected solids were dried on a freeze dryer for 16 hours to provide the title compound. LC / MS (m / z): 296 (M+H)+. 1H NMR (600MHz, DMSO-d6) δ10.94 (s, 1H), 8.28 (t, J=5.6Hz, 1H), 7.32-7.16 (m, 4H), 7.05-6.87 (m, 4H), 4.96 (s, 2H), 4.18 (d, J=5.9Hz, 2H), 1.83 (s, 3H).

[0487] Embodiment 12:

[0488] Preparation of N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)methanesulfonamide

[0489]

[0490] Step A: N-(4-bromobenzyl)methanesulfonamide

[0491]

[0492] (4-bromophenyl)methylamine (5g, 26.9mmol), TEA (9.36ml, 67.2mmol) and DCM (100ml) were added to a vial equipped with a stirring bar. Methanesulfonic anhydride (5.62g, 32.2mmol) was added portionwise at 20°C, and the mixture was stirred at 20°C for 2 hours. After 2 hours, water (100ml) was added, and the reaction mixture was washed with DCM (100ml x 3). The obtained organic phase was washed with brine (20mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent to provide the title compound. LCMS (ESI) m / z: 286 [M+Na] + .

[0493] Step B: tert-Butyl 3-(4-(methylsulfonamidomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0494]

[0495] Tert-butyl 2-oxo-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (3.18 g, 8.50 mmol), sSPhos Pd G2 (0.137 g, 0.167 mmol), cesium carbonate (5.43 g, 16.66 mmol)), dioxane (30 mL) and water (3 mL) were added to a flask equipped with a stirring bar at 20°C. The reaction mixture was bubbled with a stream of nitrogen for 2 minutes. After 2 minutes, the flask was sealed and heated to 80°C for 12 hours. After 12 hours, the reaction mixture was diluted with water (100 mL) and washed with ethyl acetate (100 mL*3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using ethyl acetate and petroleum ether as eluents to provide the title compound. LCMS (ESI) m / z: 376 [M+H] + . (Observed as loss of tBu).

[0496] Step C: N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)methanesulfonamide

[0497]

[0498] Tert-butyl 3-(4-(methylsulfonamidomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (3 g, 6.95 mmol), TFA (2.68 mL, 34.8 mmol) and DCM (15 mL) were added to a vial equipped with a stirring bar. The reaction mixture was stirred at 20 °C for 2 hours. After 2 hours, the reaction mixture was concentrated in vacuo. The resulting material was dissolved in water and CH3CN, and the material was dried on a freeze dryer to provide the title compound. LCMS (ESI) m / z: 332 [M+H] + . 1 H NMR (500MHz, MeOH-d4) δ7.44-7.27(m, 4H), 7.20-6.90(m, 4H), 5.10(s, 2H), 4.23(s, 2H), 2.83(s, 3H).

[0499] Embodiment 13:

[0500] Preparation of N-methyl-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophene-3-carboxamide:

[0501]

[0502] Step A: 5-Bromo-N-methylthiophene-3-carboxamide

[0503]

[0504] 5-Bromothiophene-3-carboxylic acid (100 mg, 0.483 mmol), 1-methyl-1H-imidazole (139 mg, 1.690 mmol), methylamine (0.966 mL, 1.932 mmol, 2M in THF), N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (163 mg, 0.580 mmol) and DCM (3 mL) were added to a vial equipped with a stirring bar. The reaction mixture was stirred at 20° C. for 2 hours. After 2 hours, the reaction mixture was filtered. The collected filtrate was concentrated under reduced pressure to provide a crude product. The material was purified by HPLC (water and ACN mobile phase, adjusted with TFA) to provide the title compound. MS (ESI) m / z: 222 [M+H] + .

[0505] Step B: tert-Butyl 3-((4-(methylcarbamoyl)thiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0506]

[0507] 5-Bromo-N-methylthiophene-3-carboxamide was elaborated to the title compound using the procedure in Example 12. LCMS (ESI) m / z: 288 [M+H] + . (Observed as loss of tBu).

[0508] Step C: N-methyl-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophene-3-carboxamide

[0509]

[0510] Tert-butyl 3-((4-(methylcarbamoyl)thiophen-2-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (20 mg, 0.052 mmol), TFA (1 mL, 12.98 mmol) and DCM (4 mL) were added to a vial equipped with a stirring bar. The resulting mixture was stirred at 20 °C for 2.2 hours. After 2.2 hours, the reaction mixture was concentrated under reduced pressure to provide the crude product. The material was purified by HPLC (eluting with an acetonitrile / water gradient with a TFA modifier) ​​to provide the title compound. LCMS (ESI) m / z: 288 [M+H] +.

[0511] 1 H NMR (500MHz, MeOH-d4) δ7.89 (d, J = 1.2Hz, 1H), 7.46 (s, 1H), 7.17-7.12 (m, 1H), 7.10-7.02 (m, 3H), 5.24 (s, 2H), 2.85 (s, 3H).

[0512] The examples in Table 2 were synthesized according to the procedure described in Example 13, Step B, using appropriate Br starting materials.

[0513] Table 2

[0514]

[0515] Embodiment 15:

[0516] Preparation of (R)-N-(1-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)ethyl)acetamide

[0517]

[0518] Step A: (R)-N-(1-(4-bromophenyl)ethyl)acetamide

[0519]

[0520] (R)-1-(4-bromophenyl)ethyl-1-amine (250 mg, 1.250 mmol), acetyl chloride (89 μl, 1.250 mmol) and DMA (1000 μl) were added to a vial equipped with a stirring bar. The reaction mixture was stirred for 18 hours. After 18 hours, the material was dry loaded onto silica gel. The material was loaded onto a 25 g column and the column was run from 100% hexane to 100% ethyl acetate / ethanol. The desired product was eluted and fractions were collected and concentrated under reduced pressure to provide the title compound. LC / MS (m / z): 242 (M+H)+.

[0521] Step B: (R)-N-(1-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)ethyl)acetamide

[0522]

[0523] Using the procedure of Example 12, (R)-N-(1-(4-bromophenyl)ethyl)acetamide was elaborated to the title compound using the corresponding bromide in step A. LC / MS (m / z): 310 (M+H) +. 1H NMR (600MHz, DMSO-d6) δ10.93 (s, 1H), 8.21 (d, J=8.0Hz, 1H), 7.31-7.18 (m, 4H), 7.04-7.00 (m, 1H), 7.00-6.91 (m, 3H), 4.95 (s, 2H), 4.83 (p, J=7.1Hz, 1H), 1.79 (s, 3H), 1.27 (d, J=7.0Hz, 3H).

[0524] The examples in Table 3 were synthesized according to the procedure described in Example 15 employing the appropriately substituted (4-bromophenyl)methanamine starting material in Step A using the conditions described above therein, or standard amide coupling conditions (eg, HATU / DIEA).

[0525] Table 3

[0526]

[0527] Embodiment 18:

[0528] Preparation of 1-(3-chloro-4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0529]

[0530] Sodium hydride (7.60 mg, 0.19 mmol) and 4-bromo-1-(bromomethyl)-2-chlorobenzene (48.3 mg, 0.17 mmol) and pyrrolidin-2-one (15.19 mg, 0.179 mmol) were added to an 8 mL vial, followed by DMA (0.75 ml). The resulting reaction mixture was stirred at room temperature for 60 minutes. The solution was retained for the next step. 4,4'-di-tert-butyl-2,2'-bipyridine (4.56 mg, 0.017 mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (3.74 mg, 0.017 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.717 mg, 1.700 μmol), 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (44.1 mg, 0.230 mmol) and cesium carbonate (74.8 mg, 0.230 mmol) were added to a separate 8 mL vial. 1 mL of DMA was then added, and the mixture was added to the alkylated pyrrolidone from above, the mixture was sealed and purged with argon for 2 minutes, and then stirred under LED blue light for 18 hours. After this time, the crude material was filtered and purified by HPLC (eluted with acetonitrile / water gradient containing NH4OH regulator). 1H NMR (600 MHz, DMSO-d 6 )δ10.98 (s, 1H), 7.42 (s, 1H), 7.26 (d, J = 7.9Hz, 1H), 7.21 (d, J = 7.9Hz, 1H), 7.08 (d, J = 6.9Hz, 1H), 7.03- 6.92 (m, 3H), 5.00 (s, 2H), 4.40 (s, 2H), 3.23 (t, J=6.9Hz, 2H), 2.28 (t, J=8.0Hz, 2H), 1.97-1.89 (m, 2H). LCMS(ESI). m / z: 356[M+H]+.

[0531] Embodiment 19:

[0532] Preparation of 1-(3-iodo-4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0533]

[0534] Step A: 1,4-bis(bromomethyl)-2-iodobenzene

[0535]

[0536] Triphenylphosphine (2295mg, 8.75mmol) was added to a mixture of (2-iodo-1,4-phenylene) dimethanol (770mg, 2.92mmol) and carbon tetrabromide (2901mg, 8.75mmol) in DCM (25mL) at 25°C. The resulting mixture was stirred at 25°C for 16 hours under N2. After 16 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure to provide a crude product. The residue was purified by flash silica gel chromatography ( 4g Purification by silica gel flash column, eluent 0-20% ethyl acetate / petroleum ether gradient, 40 mL / min) provided 1,4-bis(bromomethyl)-2-iodobenzene.

[0537] Step B: 1-(4-(Bromomethyl)-2-iodobenzyl)pyrrolidin-2-one

[0538]

[0539] NaH (111 mg, 2.77 mmol) was added to a stirred solution of pyrrolidine-2-one (0.264 mL, 3.46 mmol) in DMF (25 mL) at 0 ° C. After the addition was complete, the reaction was stirred at 0 ° C for 0.5 hours. After 0.5 hours, 1,4-bis (bromomethyl) -2-iodobenzene (900 mg, 2.309 mmol) was added. The reaction was stirred at 25 ° C for 4 hours. After 4 hours, saturated NH4C1 (200 mL) was added and the material was washed with EtOAc (200 mL). The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 40g Silica gel flash column, eluent 45% ethyl acetate / petroleum ether gradient, 35 mL / min) to provide 1-(4-(bromomethyl)-3-iodobenzyl)pyrrolidin-2-one and 1-(4-(bromomethyl)-2-iodobenzyl)pyrrolidin-2-one and 1-(4-(bromomethyl)-2-iodobenzyl)pyrrolidin-2-one-1-(4-(bromomethyl)-3-iodobenzyl)pyrrolidin-2-one. LCMS (ESI) m / z: 394 [M+H]+.

[0540] Step C: 1-(4-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-iodobenzyl)pyrrolidin-2-one

[0541]

[0542] NaH (18.27 mg, 0.457 mmol) was added to a stirred solution of 2-chloro-1H-benzo[d]imidazole (55.8 mg, 0.365 mmol) in DMF (5 mL) at 0°C. After the addition was complete, the reaction was stirred at 0°C for 0.5 hours. After 0.5 hours, 1-(4-(bromomethyl)-2-iodobenzyl)pyrrolidin-2-one (120 mg, 0.305 mmol) was added. The reaction was stirred at 25°C for 3.5 hours. After 3.5 hours, water (20 mL) was added. The material was washed with DCM (20 mL). The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC (eluting with acetonitrile / water gradient with NH4HCO3 modifier) ​​to afford 1-(4-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-iodobenzyl)pyrrolidin-2-one. LCMS (ESI) m / z: 466 [M+H]+.

[0543] Step D: 1-(3-iodo-4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0544]

[0545] A mixture of 1-(4-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-iodobenzyl)pyrrolidin-2-one (105 mg, 0.225 mmol)) in AcOH (3 mL) was stirred at 80 °C for 6 hours. After 6 hours, the solvent was filtered and concentrated under reduced pressure. The residue was diluted with toluene (10 mL) and concentrated under reduced pressure (2 times) to provide 1-(3-iodo-4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (500MHz, DMSO-d6) δ = 10.98 (s, 1H), 7.84 (s, 1H), 7.29 (d, J = 7.9Hz, 1H), 7.11-7.03 (m, 2H), 7.01-6.93 (m, 3H ), 4.96 (s, 2H), 4.28 (s, 2H), 3.22 (t, J=7.0Hz, 2H), 2.28 (t, J=8.0Hz, 2H), 1.99-1.98 (m, 1H), 1.99-1.89 (m, 1H). LCMS (ESI) m / z: 448[M+H]+.

[0546] Embodiment 20:

[0547] Preparation of 1-(4-((3,3-dioxido-1,3,4-oxathiazin-4-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0548]

[0549] Utilizing the procedure outlined in Example 18, 1-bromo-4-(bromomethyl)benzene and 1,3,4-oxathiazinane 3,3-dioxide were elaborated to the final product 1-(4-((3,3-dioxido-1,3,4-oxathiazinane-4-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (600MHz, DMSO-d6) δ10.94 (s, 1H), 7.34-7.28 (m, 4H), 7.04-6.91 (m, 4H), 4.99 (s, 2H), 4.83 (s, 2H), 4.26 (s, 2H), 3.81-3.76 (m, 2H), 3.31-3.28 (m, 2H). LCMS (ESI) m / z: 374[M+H]+.

[0550] The examples in Table 4 were synthesized according to the procedure described in Example 18 using the appropriate aryl bromide starting materials; alternatively, column chromatography may be used to work up after formation of the desired aryl bromide.

[0551] Table 4

[0552]

[0553]

[0554] Embodiment 26:

[0555] Preparation of 1-(4-((1,1-dioxidoisothiazolidin-2-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0556]

[0557] 4,4'-di-tert-butyl-2,2'-bipyridine (3.75 mg, 0.014 mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (3.07 mg, 0.014 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.940 mg, 0.930 μmol), 2-(3-(tert-butoxycarbonyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (0.037 g, 0.126 mmol) (Intermediate 2), 2-(4-bromobenzyl)isothiazolidine 1,1-dioxide (0.027 g, 0.093 mmol) and cesium carbonate (0.041 g, 0.13 mmol) were added to an 8 ml vial with a stirring bar. 1 mL of DMA was then added and the reaction mixture was purged with argon for 2 minutes and then sealed. The reaction mixture was then placed in a photoreactor and irradiated with LED blue light for 4 hours, filtered, evaporated under reduced pressure, then 2 mL of DCM:TFA (1:1) was added, and the reaction mixture was stirred for 3 hours. The reaction mixture was evaporated under reduced pressure and purified by HPLC (eluting with acetonitrile / water gradient containing TFA modifier). Isolate as a solid. 1 H NMR (600 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.32-7.26 (m, 4H), 7.05-6.90 (m, 4H), 4.98 (s, 2H), 4.03 (s, 2H), 3.24-3.19 (m, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.21-2.14 (m, 2H). LCMS (ESI) m / z: 358 [M+H]+. (Alternatively, 2-tert-butyl-1,1,3,3-tetramethylguanidine can be used as a base).

[0558] Embodiment 27:

[0559] Preparation of 1-(3-(1,3,4-oxadiazol-2-yl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0560]

[0561] 4,4'-di-tert-butyl-2,2'-bipyridine (7.16 mg, 0.027 mmol), nickel (II) chloride ethylene glycol dimethyl ether complex (5.86 mg, 0.027 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.795 mg, 1.777 μmol), 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (0.046 g, 0.240 mmol), 2-(3-bromophenyl)-1,3,4-oxadiazole (0.0400 g, 0.178 mmol) and cesium carbonate (0.078 g, 0.24 mmol) were added to an 8 ml vial with a stirring bar. 1.5 ml of DMA was then added, and the reaction vial was purged with argon for 2 minutes and then sealed. The reaction mixture was then irradiated with LED blue light for 18 hours. When completed, the reaction mixture was evaporated under reduced pressure and then purified by silica gel column chromatography using hexane and 3:1 blend of EtOAc:EtOH as eluent. 1 H NMR (600 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.32 (s, 1H), 7.98 (s, 1H), 7.95-7.90 (m, 1H), 7.60-7.56 (m, 2H), 7.09 (d, J = 7.1 Hz, 1H), 7.04-6.94 (m, 3H), 5.13 (s, 2H). LCMS (ESI) m / z: 293 [M+H]+. (Alternatively, 2-tert-butyl-1,1,3,3-tetramethylguanidine can also be used as a base in these procedures, and it can be purified by HPLC eluting with an acetonitrile / water gradient with a TFA modifier).

[0562] Embodiment 28:

[0563] Preparation of 1-((1,1-dioxido-2,3-dihydrobenzo[b]thien-6-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0564]

[0565] Utilizing the procedure outlined in Example 27, 6-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide was elaborated to 1-((1,1-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 HNMR (500MHz, DMSO-d6) δ11.01 (s, 1H), 7.65 (s, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.50 (d, J = 8.0Hz, 1H ), 7.15-7.07 (m, 1H), 7.04-6.91 (m, 3H), 5.11 (s, 2H), 3.58 (t, J=6.9Hz, 2H), 3.32-3.26 (m, 2H). LCMS (ESI) m / z: 315[M+H]+.

[0566] The examples in Table 5 were synthesized according to the procedure described in Example 27 using appropriate aryl bromide starting materials.

[0567] Table 5

[0568]

[0569]

[0570] Embodiment 36:

[0571] Preparation of 1-((4-chloro-5-((2-oxopyrrolidin-1-yl)methyl)thiophen-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0572]

[0573] Step A: (3-Chlorothiophen-2-yl)methanol

[0574]

[0575] Under nitrogen at 25 ℃ by LiAlH4(0.350g, 9.23mmol) add 3-chlorothiophene-2-carboxylic acid (1g, 6.15mmol) in the mixture of 20mL THF, and react and stir 2h at 25 ℃.Reactant mixture is quenched with 20mL saturated NH4Cl, and extracted with ethyl acetate (15mL x 3).By the organic phase merging salt water washing, use Na2SO4 drying, filter and concentrate under reduced pressure.Resistates is purified by silica gel chromatography with ethyl acetate and petroleum ether as eluent. 1HNMR (500MHz, CDCl3) δ7.25 (d, J=5.5Hz, 1H), 6.91 (d, J=5.3Hz, 1H), 4.81 (d, J=5.8Hz, 2H), 2.03 (t, J=6.2Hz, 1H).

[0576] Step B: 5-Bromo-2-(bromomethyl)-3-chlorothiophene

[0577]

[0578] Bromine (0.416mL, 8.07mmol) is added to the mixture of (3-chlorothiophene-2-yl) methanol (800mg, 5.38mmol) in AcOH (10mL), and the mixture is stirred at 25 ℃ for 12 hours.The reaction mixture is quenched with salt water (30mL), and extracted with ethyl acetate (15mL x 3).The organic phase merged is washed with salt water (15mL), through anhydrous Na2SO4 drying, filtered and concentrated under reduced pressure.Resistates is purified by silica gel chromatography with petroleum ether as eluent. 1 H NMR (400MHz, CDCl3) δ6.86 (s, 1H), 4.58 (s, 2H).

[0579] Step C: 1-((5-bromo-3-chlorothien-2-yl)methyl)pyrrolidin-2-one

[0580]

[0581] Under nitrogen at 0 ℃, NaH (188mg, 4.70mmol, 60% in oil) is added to the solution of pyrrolidine-2-one (200mg, 2.350mmol) in THF (10mL).After stirring 20min at 0 ℃, the solution of 5-bromo-2-(bromomethyl)-3-chlorothiophene (546mg, 1.880mmol) in THF (2mL) is added to the mixture. The mixture obtained is stirred for 2 hours at 20 ℃. The reaction mixture is quenched with saturated NH4Cl (20mL), and extracted with ethyl acetate (10mL x 3). The organic phase merged is washed with salt water (10mL), through anhydrous Na2SO4 drying, filtered and concentrated under reduced pressure. Residue is purified by silica gel chromatography with ethyl acetate and petroleum ether as eluent. 1 H NMR (500MHz, CDCl3) δ6.86 (s, 1H), 4.54 (s, 2H), 3.37 (t, J=7.1Hz, 2H), 2.39 (t, J=8.1Hz, 2H), 2.05-2.00 (m, 2H).

[0582] Utilizing the procedure outlined in Example 27, 1-((5-bromo-3-chlorothien-2-yl)methyl)pyrrolidin-2-one was elaborated to the final product 1-((4-chloro-5-((2-oxopyrrolidin-1-yl)methyl)thien-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one.

[0583] Step D: 1-((4-Chloro-5-((2-oxopyrrolidin-1-yl)methyl)thiophen-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (400MHz, MeOH-d4) δ7.15-7.10 (m, 1H), 7.08-7.06 (m, 3H), 6.99 (s, 1H), 5.16 ( s, 2H), 4.53 (s, 2H), 3.35 (t, J=7.0Hz, 2H), 2.38-2.30 (m, 2H), 2.04-1.92 (m, 2H). LCMS(ESI)m / z:362[M+H] + .

[0584] Embodiment 37:

[0585] Preparation of N,N-dimethyl-2-(6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-3-yl)acetamide

[0586]

[0587] Step A: 2-(6-bromopyridin-3-yl)-N,N-dimethylacetamide

[0588]

[0589] Dimethylamine hydrochloride (75 mg, 0.926 mmol), 2-(6-bromopyridin-3-yl)acetic acid (100 mg, 0.463 mmol), HATU (264 mg, 0.694 mmol) and TEA (0.18 mL, 1.291 mmol) were dissolved in DMF (2.5 mL) and stirred at room temperature for 3 hours. The reaction mixture was filtered and directly purified by HPLC (eluting with acetonitrile / water gradient containing TFA modifier).

[0590] LCMS (ESI) m / z: 245 [M+H] + .

[0591] Utilizing the procedure outlined in Example 27, 2-(6-bromopyridin-3-yl)-N,N-dimethylacetamide was elaborated to the final product N,N-dimethyl-2-(6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-3-yl)acetamide.

[0592] Step B: N,N-Dimethyl-2-(6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-3-yl)acetamide. 1 H NMR(500MHz, MeOH-d4)δ8.53(br s, 1H), 8.01-7.99 (m, 1H), 7.51 (d, J=8.0Hz, 1H), 7.14-7.07 (m, 2H), 7.05-7.00 (m, 2H), 5.32 (s, 2H), 3.91 (s, 2H), 3.14 (s, 3H), 2.95 (s, 3H). LCMS(ESI)m / z:311[M+H] + .

[0593] Embodiment 38:

[0594] Preparation of N-((3-chloro-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)acetamide

[0595]

[0596] Step A: 3-Chlorothiophene-2-carboxamide

[0597]

[0598] HOBT (1.9 g, 12.3 mmol) was added to a solution of 3-chlorothiophene-2-carboxylic acid (2 g, 12.3 mmol), TEA (5.1 mL, 36.9 mmol) and EDCI (2.8 g, 14.8 mmol) in DMF (50 mL) at room temperature, and the reaction mixture was stirred for 0.5 hours. Then, NH4Cl (2.0 g, 36.9 mmol) was added, and the reaction mixture was stirred for another 12 hours. The reaction mixture was quenched with H2O (150 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with petroleum ether and ethyl acetate as eluents. It was separated as a solid. LCMS (ESI) m / z 162 [M+H] + .

[0599] Step B: (3-Chlorothien-2-yl)methylamine

[0600]

[0601] LiAlH4 (188 mg, 4.95 mmol) was added to a mixture of 3-chlorothiophene-2-carboxamide (400 mg, 2.5 mmol) in THF (5 mL) at 0°C. The reaction was stirred at 0°C for 2 hours. 0.5 mL of water and 5 g of Na2SO4 were then added to quench the reaction. The mixture was filtered and the filtrate was concentrated under reduced pressure to the product without further purification. LCMS (ESI) m / z 148 [M+H] + .

[0602] Step C: N-((3-chlorothien-2-yl)methyl)acetamide

[0603]

[0604] Acetic anhydride (207 mg, 2.0 mmol) was added to a mixture of (3-chlorothiophen-2-yl)methylamine (150 mg, 1.0 mmol) and TEA (0.3 mL, 2.0 mmol) in DCM (3 mL) at 0 °C. The reaction was stirred at 0 °C for 1 hour. The reaction mixture was quenched with saturated NH4Cl (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether as eluent. LCMS (ESI) m / z 190 [M+H] + .

[0605] Step D: N-((5-bromo-3-chlorothien-2-yl)methyl)acetamide

[0606]

[0607] N-Bromosuccinimide (90 mg, 0.5 mmol) was added to a mixture of N-((3-chlorothiophen-2-yl)methyl)acetamide (80 mg, 0.4 mmol) in DCM (3 mL). The reaction was stirred at 20 °C for 1.5 hours. 4 mL of saturated NaHCO3 was added to quench the reaction. The reaction was extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether as eluent. LCMS (ESI) m / z 270 [M+H] + .

[0608] Step E: N-((3-chloro-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)acetamide

[0609]

[0610] Utilizing the procedure outlined in Example 27, N-((5-bromo-3-chlorothiophen-2-yl)methyl)acetamide was elaborated to the title compound. 1 H NMR (500MHz, MeOH-d4) δ7.17-7.13 (m, 1H), 7.11-7.07 (m, 3H), 6.99 (s, 1H), 5.18 (s, 2H), 4.43 (s, 2H), 1.93 (s, 3H). LCMS(ESI)m / z 336[M+H] + .

[0611] Embodiment 39:

[0612] N-((3-chloro-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)methanesulfonamide

[0613]

[0614] Step A: 5-Bromo-3-chlorothiophene-2-carboxamide

[0615]

[0616] HOBT (317 mg, 2.070 mmol) was added to a solution of 5-bromo-3-chlorothiophene-2-carboxylic acid (500 mg, 2.070 mmol), TEA (0.866 mL, 6.21 mmol) and EDC (476 mg, 2.485 mmol) in DMF (3 mL) at 20 °C. The reaction was stirred for 0.5 h. After 0.5 h, NH4Cl (554 mg, 10.35 mmol) was added, and the mixture was stirred for 12 h. After 12 h, water (30 mL) was added, and the mixture was washed with EtOAc (25 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to provide the title compound. LCMS (ESI) m / z 283 [M+H+CH3CN] + .

[0617] Step B: (5-bromo-3-chlorothiophen-2-yl)methanamine

[0618]

[0619] BH3·THF (5 mL, 5.00 mmol, 1 M in THF) was added to a stirred solution of 5-bromo-3-chlorothiophene-2-carboxamide (200 mg, 0.832 mmol) in THF (5 mL). The reaction was stirred at 75 °C for 16 hours. After 16 hours, MeOH (2 mL) was added to the mixture, and the reaction mixture was concentrated under reduced pressure to provide the title compound. LCMS (ESI) m / z: 211 [M+H-NH2] + .

[0620] Step D: N-((5-bromo-3-chlorothien-2-yl)methyl)methanesulfonamide

[0621]

[0622] (5-bromo-3-chlorothiophene-2-yl)methylamine (200mg, 0.883mmol), TEA (0.369mL, 2.65mmol) and DCM (3mL) were added to a vial equipped with a stirring bar. Methanesulfonyl chloride (0.138mL, 1.766mmol) was added and the reaction mixture was stirred at 20°C for 2 hours. After 2 hours, saturated NH4Cl (15mL) was added and the mixture was washed with EtOAc (15mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography with petroleum ether and ethyl acetate as eluent to provide the title compound. 1 H NMR (500MHz, CDCl3) δ6.89 (s, 1H), 5.06 (br s, 1H), 4.41 (s, 2H), 2.95 (s, 3H).

[0623] Step E: N-((3-chloro-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)methanesulfonamide

[0624]

[0625] Using the procedure in Example 27, N-((5-bromo-3-chlorothien-2-yl)methyl)methanesulfonamide was elaborated to the title compound. LCMS (ESI) m / z: 372 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 7.68 (t, J=6.3Hz, 1H), 7.22-7.17 (m, 1H), 7.10 (s, 1H), 7.03-6.95 (m, 3H), 5.11 (s, 2H), 4.19 (d, J=6.3Hz, 2H), 2.88 (s, 3H).

[0626] Embodiment 40:

[0627] N-((3-methyl-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)acetamide.

[0628]

[0629] Step A: (E)-5-Bromo-3-methylthiophene-2-carbaldehyde oxime

[0630]

[0631] 5-Bromo-3-methylthiophene-2-carboxaldehyde (100 mg, 0.488 mmol) and EtOH (5 mL) were added to a vial equipped with a stirring bar. Hydroxylamine hydrochloride (65 mg, 0.935 mmol) and sodium acetate (88 mg, 1.073 mmol) were added, and the reaction was stirred at 30 ° C for 16 hours. After 16 hours, the mixture was diluted with water (30 mL) and washed with ethyl acetate (20 mL×3). The combined organic layers were collected, washed with brine (10 mL), dried over Na2SO4, and filtered. The collected filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=2:1) ​​to provide the title compound. LCMS (ESI) m / z: 220 [M+H] + .

[0632] Step B: (5-bromo-3-methylthiophen-2-yl)methanamine

[0633]

[0634] (E)-5-bromo-3-methylthiophene-2-carbaldehyde oxime (90 mg, 0.409 mmol) and AcOH (1 mL) were added to a vial equipped with a stirring bar. Zinc (107 mg, 1.636 mmol) was added, the vial was sealed and heated to 70 ° C for 30 minutes. After 30 minutes, the reaction mixture was cooled to room temperature. HCl aqueous solution (5 mL, 2 M) was added, and the mixture was washed with ethyl acetate (5 mL×2). The combined aqueous phase was alkalized with NaOH aqueous solution (5 mL, 4 M) and washed with ethyl acetate (10 mL×3). The resulting organic layer was collected, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. LCMS (ESI) m / z206[M+H] + .

[0635] Step C: N-((5-bromo-3-methylthiophen-2-yl)methyl)acetamide

[0636]

[0637] (5-Bromo-3-methylthiophene-2-yl)methylamine (70 mg, 0.340 mmol) in DCM (1.5 mL) was added to a vial equipped with a stirring bar. TEA (0.104 mL, 0.747 mmol), DMAP (4 mg, 0.033 mmol) and acetic anhydride (42 mg, 0.411 mmol) were added and the reaction mixture was stirred at 15 ° C (room temperature) for 16 hours. After 16 hours, the mixture was diluted with water (5 mL), extracted with ethyl acetate (5 mL×3), the organic layer was collected, dried over Na2SO4, and filtered. The collected filtrate was concentrated in vacuo. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate=2:1) ​​to provide the title compound. LCMS (ESI) m / z 248 [M+H] + .

[0638] Step D: N-((3-methyl-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)thiophen-2-yl)methyl)acetamide

[0639]

[0640] Using the procedure of Example 27, N-((5-bromo-3-methylthiophen-2-yl)methyl)acetamide was elaborated to the title compound. LCMS (ESI) m / z: 316 [M+H] + . 1 H NMR (500MHz, MeOH-d4) δ7.18-7.11 (m, 1H), 7.09-7.05 (m, 3H), 6.86 (s, 1H), 5.15 (s, 2H), 4.37 (s, 2H), 2.16 (s, 3H), 1.94-1.86 (m, 3H).

[0641] Embodiment 41:

[0642] Preparation of 1-((6-((2-oxopyrrolidin-1-yl)methyl)pyridin-3-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0643]

[0644] Step A: 1-((5-bromopyridin-2-yl)methyl)pyrrolidin-2-one

[0645]

[0646] Pyrrolidin-2-one (68.1 μL, 0.89 mmol) was dissolved in 1.5 mL of THF at 0°C, and sodium hydride (40.6 mg, 1.016 mmol) was added thereto. The resulting solution was stirred at 0°C for 15 min, followed by the addition of a solution of 5-bromo-2-(bromomethyl)pyridine (150 mg, 0.59 mmol) in 1.5 mL of THF, and then stirred at room temperature for 2 hours. The reaction mixture was then quenched with saturated NH4Cl solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using hexane and 3EtOAc:1EtOH as eluents. LCMS (ESI) m / z 257 [M+H] + .

[0647] Step B: 1-((6-((2-oxopyrrolidin-1-yl)methyl)pyridin-3-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0648]

[0649] Utilizing the procedure outlined in Example 27, l-((5-bromopyridin-2-yl)methyl)pyrrolidin-2-one was elaborated to the title compound. 1 H NMR (500MHz, DMSO-d6) δ11.01 (s, 1H), 8.61 (d, J=1.8Hz, 1H), 7.82 (dd, J=8.1, 2.1Hz, 1H), 7.33 (d, J=8.1Hz, 1H), 7.14 (dt, J=6. 3, 3.4Hz, 1H), 7.02-6.90 (m, 4H), 5.07 (s, 2H), 4.48 (s, 2H), 3.32 (t, J=7.0Hz, 2H), 2.28 (t, J=8.1Hz, 2H), 1.95 (p, J=7.5Hz, 2H). LCMS(ESI)m / z 323[M+H] + .

[0650] Embodiment 42:

[0651] Preparation of 5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indazole-3-carbonitrile

[0652]

[0653] Step A: tert-Butyl 5-bromo-3-cyano-1H-indazole-1-carboxylate

[0654]

[0655] 5-Bromo-1H-indazole-3-carbonitrile (2 g, 9.01 mmol) and di-tert-butyl dicarbonate (3.14 mL, 13.51 mmol) were dissolved in acetonitrile (20 mL) and DMAP (0.055 g, 0.45 mmol) was added. The mixture was stirred for 2 hours. The solvent was evaporated. Hexane (30 mL) was added to the residue and stirred vigorously for 10 minutes. The solid was collected by filtration to provide the title compound. LCMS (ESI) m / z 344 [M+Na] + .

[0656] Step B: 5-((2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indazole-3-carbonitrile

[0657]

[0658] Utilizing the procedure outlined in Example 27, tert-butyl 5-bromo-3-cyano-1H-indazole-1-carboxylate was elaborated to the title compound. 1 H NMR (500MHz, DMSO-d6) δ10.99 (s, 1H), 7.91 (s, 1H), 7.74 (d, J=8.7Hz, 1H), 7. 51 (dd, J=8.8, 1.3Hz, 1H), 7.18-7.08 (m, 1H), 7.06-6.89 (m, 3H), 5.16 (s, 2H). LCMS(ESI)m / z 290[M+H] + .

[0659] Embodiment 43:

[0660] Preparation of 1-(4-((3,3-difluoro-2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0661]

[0662] Step A: 1-(4-bromobenzyl)-3,3-difluoropyrrolidin-2-one

[0663]

[0664] Sodium bis(trimethylsilyl)amide (200 μl, 0.20 mmol, 1 M in THF) was added to a solution of 3,3-difluoropyrrolidin-2-one (36 mg, 0.30 mmol) in THF (0.6 mL) at room temperature. The solution was stirred at room temperature for 15 minutes, after which a solution of 1-bromo-4-(bromomethyl)benzene (50 mg, 0.20 mmol) in THF (0.6 mL) was added. The resulting solution was stirred overnight. The reaction was quenched by dropwise addition of hydrochloric acid (200 μl, 0.20 mmol, 1 N solution). The reaction was then concentrated under reduced pressure, and the residue was dissolved in DMSO. The compound was purified by HPLC (eluted with acetonitrile / water gradient containing NH4OH regulator). LC / MS (m / z): 290 (M+H) + .

[0665] Step B: 1-(4-((3,3-difluoro-2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0666]

[0667] Utilizing the procedure outlined in Example 27, 1-(4-bromobenzyl)-3,3-difluoropyrrolidin-2-one was elaborated to the title compound. 1 H NMR (600MHz, DMSO-d6) δ10.95 (s, 1H), 7.32 (d, J=8.1Hz, 2H), 7.21 (d, J=8.1Hz, 2H), 7.04 (d, J= 7.3Hz, 1H), 7.02-6.92(m, 3H), 4.99(s, 2H), 4.45(s, 2H), 3.34-3.29(m, 2H), 2.59-2.49(m, 2H). LC / MS(m / z): 358(M+H) + .

[0668] Embodiment 44:

[0669] Preparation of N-(2-chloro-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0670]

[0671] Step A: tert-Butyl (2-chloro-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate

[0672]

[0673] 1-(4-bromobenzyl)-3,3-difluoropyrrolidin-2-one was elaborated to the title compound using the procedure outlined in Example 27. LC / MS (m / z): 332 (M+H)+ (loss of the tert-butyl group was observed).

[0674] Step B: 1-(4-(Aminomethyl)-3-chlorobenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0675]

[0676] Tert-butyl (2-chloro-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate (58 mg, 0.150 mmol), HCl (299 μl, 1.196 mmol) and THF (1000 μl) were added to a vial equipped with a stirring bar. The reaction mixture was stirred at room temperature for 20 minutes. After 20 minutes, the reaction mixture was heated to 40°C for 4 hours. After 4 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The material was used in the next step without further purification. LC / MS (m / z): 288 (M+H)+.

[0677] Step C: Preparation of N-(2-chloro-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0678]

[0679] Acetic acid (8.55 μl, 0.149 mmol), HATU (85 mg, 0.224 mmol) and DMF (1494 μl) were stirred at room temperature for 5 minutes. After 5 minutes, 1-(4-(aminomethyl)-3-chlorobenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (43 mg, 0.149 mmol) was added, followed by DIEA (78 μl, 0.448 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After 30 minutes, the reaction mixture was filtered and used directly for HPLC purification (purified by HPLC, eluting with acetonitrile / water gradient containing a basic modifier, linear gradient) to provide the title compound. LC / MS (m / z): 330 (M+H)+. 1H NMR (600MHz, DMSO-d6) δ10.97 (s, 1H), 8.29 (t, J=5.6Hz, 1H), 7.40-7.34 (m, 1H), 7.32-7.21 (m , 2H), 7.09-7.03 (m, 1H), 7.02-6.95 (m, 3H), 4.98 (s, 2H), 4.24 (d, J=5.7Hz, 2H), 1.86 (s, 3H).

[0680] Embodiment 45:

[0681] Preparation of N-(6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl)acetamide

[0682]

[0683] Step A: tert-Butyl (6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl)carbamate

[0684]

[0685] Tert-butyl (6-bromo-2,3-dihydro-1H-inden-1-yl)carbamate was elaborated to the title compound using the procedure outlined in Example 27. LC / MS (m / z): 324 (M+H)+ (loss of tert-butyl group observed).

[0686] Step B: 1-((3-amino-2,3-dihydro-1H-inden-5-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0687]

[0688] Tert-butyl (6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl)carbamate (427.8 mg, 1.127 mmol), HCl (4M in dioxane) (4.23 ml, 16.91 mmol) and dioxane (5 ml) were added to a vial equipped with a stirring bar. The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure to provide the title compound. LC / MS (m / z): 302 (M+H)+ (M+22 observed).

[0689] Step C: N-(6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl-acetamide

[0690]

[0691] Acetic acid (16.39 μl, 0.286 mmol), HATU (82 mg, 0.215 mmol) and DMF (1432 μl) were added to a vial equipped with a stirring bar. The reaction mixture was stirred at room temperature for 5 minutes. After 5 minutes, 1-((3-amino-2,3-dihydro-1H-inden-5-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazole-2-one (40 mg, 0.143 mmol) was added, followed by DIEA (75 μl, 0.430 mmol). The reaction mixture was stirred at room temperature for 18 hours. After 18 hours, the crude material was dissolved in 3 ml of DMSO, filtered, and used directly for HPLC purification (by HPLC purification, eluting with acetonitrile / water gradient containing TFA modifier, linear gradient) to provide the title compound. LC / MS (m / z): 322 (M+H)+.

[0692] Step D: N-(6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl)acetamide

[0693]

[0694] Preparative resolution of N-(6-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-inden-1-yl)acetamide was performed using supercritical fluid chromatography on a Sepiatec Prep 100. A Chiral Technologies IG column (5 μm, 21 mm X 250 mm, Chiral Tech., West Chester, PA) was used as a chiral stationary phase. The compound mixture was dissolved in a 1:1 mixture of methanol and acetonitrile. The following isocratic SFC conditions were used for injection and collection: 55% carbon dioxide and 45% methanol (containing 0.1% ammonium hydroxide) as mobile phases, 220 nm UV wavelength, 100 bar outlet pressure, 40°C column compartment temperature, 70 mL / min total flow rate. Retention times for peak collection were as follows: first eluting peak, 3.9 min; second eluting peak, 5.4 min.

[0695] LC / MS (m / z): 322 (M+H)+. 1H NMR (600MHz, DMSO-d6) δ10.92 (s, 1H), 8.14 (d, J=8.2Hz, 1H), 7.19-7.11 (m, 2H), 7.02-6.90 (m, 3H), 5.19 (q, J=7. 8Hz, 1H), 4.96 (s, 2H), 2.89-2.81 (m, 1H), 2.77-2.68 (m, 1H), 2.37-2.28 (m, 1H), 1.82 (s, 3H), 1.75-1.66 (m, 1H).

[0696] Embodiment 46:

[0697] N-methyl-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-indene-1-carboxamide

[0698]

[0699] Step A: 5-Bromo-N-methyl-2,3-dihydro-1H-indene-1-carboxamide

[0700]

[0701] 5-bromo-2,3-dihydro-1H-indene-1-carboxylic acid (200mg, 0.830mmol), HATU (473mg, 1.244mmol) and DMF (4148μl) were added to a vial equipped with a stirring bar. The mixture was stirred at room temperature for 5 minutes. After 5 minutes, methylamine (129μl, 1.659mmol) was added, followed by DIEA (435μl, 2.489mmol). The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the crude material was washed with ethyl acetate and water. The combined organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The material was dissolved in DCM and directly loaded onto a 40g column. The column was run from 100% hexane to 100% ethyl acetate. The desired product was eluted, fractions were collected, and concentrated under reduced pressure to provide the title compound. LC / MS (m / z): 254 (M+H)+.

[0702] Step B: N-methyl-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-indene-1-carboxamide

[0703]

[0704] 5-Bromo-N-methyl-2,3-dihydro-1H-indene-1-carboxamide was elaborated to the title compound using the procedure in Example 27. LC / MS (m / z): 322 (M+H)+.

[0705] Step C: N-methyl-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-indene-1-carboxamide

[0706]

[0707] Preparative separation of N-methyl-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-2,3-dihydro-1H-indene-1-carboxamide was performed using supercritical fluid chromatography on a Sepiatec Prep 100. A Chiral Technologies IG column (5 μm, 21 mm X 250 mm, Chiral Tech, West Chester, PA) was used as the chiral stationary phase. The compound mixture was dissolved in a 1:1 mixture of methanol and DMSO. The following isocratic SFC conditions were used for injection and collection: 60% carbon dioxide and 40% methanol (containing 0.1% ammonium hydroxide) as mobile phases, 220 nm UV wavelength, 100 bar outlet pressure, 40°C column compartment temperature, 70 mL / min total flow rate. The retention times for peak collection were as follows: first eluting peak, 3.9 min; second eluting peak, 5.9 min.

[0708] LC / MS (m / z): 322 (M+H)+. 1 H NMR (600MHz, DMSO-d6) δ10.97-10.86(m, 1H), 8.04-7.92(m, 1H), 7.21-7.05(m, 3H), 7.05-6.87(m, 4H), 4.94( s, 2H), 3.77 (t, J=7.5Hz, 1H), 2.98-2.87 (m, 1H), 2.81-2.72 (m, 1H), 2.60 (d, J=4.6Hz, 3H), 2.26-2.08 (m, 2H).

[0709] The Examples in Table 6 were synthesized according to the procedure described in Example 46 using appropriately substituted bromide and amine starting materials in Step A.

[0710] Table 6

[0711]

[0712] Embodiment 49:

[0713] Preparation of N-(2-methyl-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0714]

[0715] Step A: N-(2-methyl-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0716]

[0717] Acetyl chloride (35.7 μl, 0.500 mmol), (4-bromo-2-methylphenyl)methanamine (100 mg, 0.500 mmol), TEA (139 μl, 1.000 mmol) and DMA (1250 μl) were added to a vial equipped with a stirring bar. The mixture was stirred at room temperature for 96 hours. After 96 hours, acetyl chloride (53.3 μl, 0.750 mmol) was added and the reaction mixture was stirred for 72 hours. After 72 hours, 4,4'-di-tert-butyl-2,2'-bipyridine (20.12 mg, 0.075 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (16.47 mg, 0.075 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (5.61 mg, 5.00 μmol) and 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (130 mg, 0.675 mmol) were added to a second vial. The vial was purged with nitrogen for 5 minutes. After 5 minutes, DMA (1.0 ml) was added and the vial was purged with nitrogen for 10 minutes. After 10 minutes, the contents of vial 2 were added to the contents of vial 1. Finally, 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (118 μl, 1.000 mmol) was added to the combined reaction mixture. The mixture was sealed and placed in a Penn Optic photoreactor for 5 hours (fan speed 5200 rpm; stirring 700 rpm; LED 70%). After 5 hours, the crude reaction mixture was washed with ethyl acetate and water. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was directly used for HPLC purification (purified by HPLC, eluting with acetonitrile / water gradient containing a basic modifier, linear gradient) to provide the title compound. LC / MS (m / z): 310 (M+H)+. 1 H NMR (600MHz, DMSO-d6) δ10.91 (s, 1H), 8.11 (t, J=5.3Hz, 1H), 7.18-7.06 (m, 3H), 7.02-6.88 (m, 4H), 4.92 (s, 2H), 4.15 (d, J=5.6Hz, 2H), 2.20 (s, 3H), 1.82 (s, 3H).

[0718] The examples in Table 7 were synthesized according to the procedure described in Example 49 using the appropriately substituted (4-bromophenyl)methanamine starting material.

[0719] Table 7

[0720]

[0721] Embodiment 52:

[0722] Preparation of 1-(indolin-5-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0723]

[0724] Step A: tert-Butyl 5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)indoline-1-carboxylate

[0725]

[0726] tert-Butyl 5-bromoindoline-1-carboxylate was elaborated to the title compound using the procedure in Example 27. LC / MS (m / z): 310 (M+H)+ (loss of the tert-butyl group was observed).

[0727] Step B: 1-(Indolin-5-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0728]

[0729] Tert-butyl 5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)indoline-1-carboxylate (74.8 mg, 0.205 mmol), dioxane (3000 μl) and HCl (4.0 M in dioxane) (512 μl, 2.047 mmol) were added to a vial equipped with a stirring bar. The vial was sealed and stirred at room temperature for 22.5 hours. After 22.5 hours, the reaction mixture was heated to 50°C for 1.5 hours. After 1.5 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was dissolved in ACN / water, frozen and dried on a freeze dryer for 16 hours to provide the title compound. LC / MS (m / z): 266 (M+H)+. 1H NMR (600MHz, DMSO-d6) δ10.95 (s, 1H), 7.29 (s, 1H), 7.23 (d, J=7.6Hz, 1H), 7.20-7.07 (m, 1H), 7 .06-7.02 (m, 1H), 7.02-6.91 (m, 2H), 4.98 (s, 2H), 3.61 (t, J=7.9Hz, 2H), 3.08 (t, J=7.9Hz, 2H).

[0730] Embodiment 53:

[0731] Preparation of 1-(4-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0732]

[0733] Step A: 3-(4-bromobenzyl)-4-methyl-4H-1,2,4-triazole

[0734]

[0735] 2-(4-bromobenzyl)-1,3,4-oxadiazole (700mg, 2.93mmol) and dioxane (8mL) were added to a vial equipped with a stirring bar. Methylamine (4mL, 39.5mmol, 30% in EtOH) and AcOH (0.12mL, 2.096mmol) were added, the vial was sealed and heated to 130°C for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature. The reaction was concentrated under reduced pressure and purified by flash silica gel chromatography using methanol and DCM as eluents to provide the title compound. MS (ESI) m / z: 252 [M+H+].

[0736] Step B: 1-(4-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)benzyl)-1H-benzo[d]imidazol-2(3H)-one

[0737]

[0738] Using the procedure of Example 27, 3-(4-bromobenzyl)-4-methyl-4H-1,2,4-triazole was elaborated to the title compound. MS (ESI) m / z: 320 [M+H + ]. 1H NMR (500MHz, CD3OD) δ 8.85 (s, 1H), 7.37 (d, J=8.0Hz, 2H), 7.28 (d, J=8.0Hz, 2H), 7.14-6.97 (m, 4H), 5.10 (s, 2H), 4.34 (s, 2H), 3.70 (s, 3H).

[0739] Embodiment 54:

[0740] Preparation of 1-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one:

[0741]

[0742] Step A: (E)-5-Bromo-3-chlorothiophene-2-carbaldehyde oxime

[0743]

[0744] 2-(4-bromo-2-methylphenyl)acetic acid methyl ester (1.0 g, 4.11 mmol) and MeOH (10 mL) were added to a vial equipped with a stirring bar. Hydrazine (0.538 g, 16.45 mmol) (98%) was added at room temperature (26 ° C). After the addition was completed, the reaction was stirred at 65 ° C. The reaction was then heated to 75 ° C and stirred for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure to provide the title compound.

[0745] Step B: 2-(4-bromo-2-methylbenzyl)-1,3,4-oxadiazole

[0746]

[0747] 2-(4-bromo-2-methylphenyl)acetohydrazide (0.5 g, 2.057 mmol), xylene (12 mL) and AcOH (2 mL) were added to a vial equipped with a stirring bar. Triethoxymethane (1.219 g, 8.23 ​​mmol) was added at 26 ° C (room temperature), and the reaction was stirred at 150 ° C for 2 hours. After 2 hours, the reaction mixture was cooled to room temperature. Water (30 mL) was added to the mixture, and the mixture was washed with EtOAc (30 mL×2). The combined organic layers were collected, washed with brine (10 mL), dried over Na2SO4, and filtered. The collected filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography using petroleum ether and ethyl acetate as eluents to provide the title compound. LCMS (ESI) m / z: 255 [M+H] + .

[0748] Step C: 1-(4-((1,3,4-oxadiazol-2-yl)methyl)-3-methylbenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0749]

[0750] 2-(4-bromo-2-methylbenzyl)-1,3,4-oxadiazole was elaborated to the title compound using the procedure of Example 27. LC / MS (ESI) m / z: 321 [M+H] + . 1 H NMR (500MHz, MeOH-d4) δ 8.83 (s, 1H), 7.23-7.00 (m, 7H), 5.05 (s, 2H), 4.28 (s, 2H), 2.32 (s, 3H).

[0751] Embodiment 55:

[0752] Preparation of 1-((2,3-dihydro-1H-inden-5-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0753]

[0754] Cuprous iodide (15.24 mg, 0.080 mmol), L-hydroxyproline (20.98 mg, 0.160 mmol), potassium phosphate (0.066 ml, 0.8 mmol) and methyl (2-bromophenyl)carbamate (92 mg, 0.4 mmol) were added to a vial and placed under nitrogen. DMSO (1 ml) and (2,3-dihydro-1H-inden-5-yl)methanamine (0.050 ml, 0.400 mmol) were added to the vial and the vial was heated to 70° C. for 2 hours. The temperature was then raised to 130° C. for 12 hours. After this time, the reaction mixture was cooled to room temperature and then filtered through a syringe filter and purified by HPLC (gradient elution with acetonitrile / water with TFA modifier). 1 H NMR (500MHz, DMSO-d6) δ10.95 (s, 1H), 7.17-7.10 (m, 2H), 7.06 (d, J=8.6Hz, 1 H), 7.01-6.91 (m, 4H), 4.92 (s, 2H), 2.77 (t, J=7.4Hz, 4H), 1.98-1.90 (m, 2H). LCMS(ESI)m / z:265[M+H] + .

[0755] Embodiment 56:

[0756] Preparation of 1-(pyridin-3-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0757]

[0758] Using the procedure of Example 55, pyridin-3-ylmethanamine was elaborated to the final product 1-(pyridin-3-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (500MHz, DMSO-d6) δ11.04 (s, 1H), 8.84 (br s, 1H), 7.87 (d, J=6.9Hz, 1H), 7.65-7.54 (m, 1H), 7.10 (d, J=7.1Hz, 1H), 7.03-6.93 (m, 4H), 5.10 (s, 2H). LCMS(ESI)m / z:226[M+H] + .

[0759] The examples in Table 8 were synthesized according to the procedure described in Example 55 using the appropriate amine starting materials.

[0760] Table 8

[0761]

[0762]

[0763] Embodiment 64:

[0764] Preparation of N-(4-((6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0765]

[0766] Step A: tert-Butyl (4-((6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate

[0767]

[0768] Using the procedure of Example 55, tert-butyl (4-(aminomethyl)benzyl)carbamate and methyl (2-bromo-4-chlorophenyl)carbamate were elaborated to give the title compound. 1H NMR (500MHz, DMSO-d6) δ11.12 (br s, 1H), 7.25 (brd, J=8.2Hz, 2H), 7.18 (br d, J=8.2Hz, 3H), 7.02-6.96 (m, 2H), 4.96-4.70 (m, 2H), 4.07 (brd, J=5.8Hz, 2H), 1.37 (s, 9H).

[0769] Step B: 1-(4-(Aminomethyl)benzyl)-6-chloro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0770]

[0771] A mixture of tert-butyl 4-((6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzylcarbamate (90.0 mg, 0.232 mmol) and TFA (0.018 mL, 0.232 mmol) in DCM (5 mL) was stirred at 25 °C for 3 hours. The mixture was concentrated under reduced pressure. The compound was used as is in the next step. LCMS (ESI) m / z: 288 [M+H] + .

[0772] Step C: N-(4-((3-acetyl-6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0773]

[0774] 1-(4-(Aminomethyl)benzyl)-6-chloro-1,3-dihydro-2H-benzo[d]imidazol-2-one (50.0 mg, 0.174 mmol), Ac2O (0.016 mL, 0.174 mmol) and triethylamine (0.097 mL, 0.695 mmol) in DCM (2 mL) were stirred at 25°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide the crude product, which was used directly in the next step. LCMS (ESI) m / z: 394 [M+Na] + .

[0775] Step D: N-(4-((6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0776]

[0777] N-(4-((3-acetyl-6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide (50.0mg, 0.134mmol) and 2M HCl (0.067mL, 0.134mmol) were stirred at 25°C in 1,4-dioxane (4mL) for 2 hours. Thereafter, the mixture was poured into saturated NaHCO3 solution (5mL). The reaction mixture was diluted with water (10mL) and extracted with EtOAc (10mL x 3). The combined organic phases were washed with brine (10mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a crude product. It was purified by HPLC (eluted with acetonitrile / water gradient containing TFA regulator). It was isolated as a solid. 1 H NMR (500MHz, MeOH-d4) δ7.30-7.25 (m, 4H), 7.04-7.01 (m, 2H), 6.97 (s, 1H), 5.04 (s, 2H), 4.38 (s, 2H), 1.96 (s, 3H). LCMS(ESI)m / z:330[M+H] + .

[0778] Embodiment 65:

[0779] Preparation of N-(4-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0780]

[0781] Step A: tert-Butyl (4-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate

[0782]

[0783] Using the procedure of Example 55, tert-butyl (4-(aminomethyl)benzyl)carbamate and methyl (2-bromo-4-methylphenyl)carbamate were elaborated to the title compound. LCMS (ESI) m / z: 368 [M+H] + .

[0784] Step B: 1-(4-(Aminomethyl)benzyl)-6-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0785]

[0786] A mixture of tert-butyl 4-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzylcarbamate (50 mg, 0.136 mmol) and TFA (1 mL, 12.98 mmol) in DCM (5 mL) was stirred at room temperature for 4 hours. It was then concentrated under reduced pressure to give a solid which was used directly in the next step. 1 H NMR (400MHz, MeOH-d4) δ7.44-7.37 (m, 4H), 6.98-6.94 (m, 1H), 6.90-6.85 (m, 1H), 6.78 (s, 1H), 5.09 (s, 2H), 4.08 (s, 2H), 2.29 (s, 3H).

[0787] Step C: N-(4-((6-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0788]

[0789] A mixture of 1-(4-(aminomethyl)benzyl)-6-methyl-1H-benzo[d]imidazole-2(3H)-one (30mg, 0.112mmol), TEA (0.063mL, 0.449mmol) and N-acetoxysuccinimide (17.63mg, 0.112mmol) in DCM (3mL) was stirred at room temperature for 16h. The reaction mixture was dissolved with water (10mL) and extracted with DCM (10mL x 3). The combined organic phases were washed with saline (10mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a crude product, which was purified by HPLC (eluted with acetonitrile / water gradient containing TFA regulator). It was separated as a solid. 1 H NMR (500MHz, DMSO-d6) δ10.80 (s, 1H), 8.32-8.23 (m, 1H), 7.26-7.23 (m, 2H), 7.21-7.17 (m, 2H), 6.86 (d, J=8 .0Hz, 1H), 6.83 (s, 1H), 6.77 (d, J=7.8Hz, 1H), 4.93 (s, 2H), 4.18 (d, J=6.0Hz, 2H), 2.25 (s, 3H), 1.83 (s, 3H). LCMS(ESI)m / z:310[M+H] + .

[0790] Embodiment 66:

[0791] Preparation of 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-N,N-dimethylacetamide

[0792]

[0793] Step A: Methyl (2-bromo-4-fluorophenyl)carbamate

[0794]

[0795] 2-Bromo-4-fluoroaniline (5.0g, 26.3mmol) was dissolved in DCM (37.6ml). Pyridine (5.32ml, 65.8mmol) was added to the mixture. The mixture was cooled to 0°C in an ice bath, and methyl chloroformate (2.446ml, 31.6mmol) was added dropwise through an addition funnel. Once the addition was completed, the reaction mixture was stirred at 0°C for 75 minutes. After 75 minutes, the reaction mixture was washed with 100ml of 0.5M HCl. The water layer was extracted with DCM (100ml) for another 2 times. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Ether was added and the mixture was stirred. The resulting material was filtered and provided as a solid title compound. The remaining filtrate was purified by silica gel column chromatography with hexane and ethyl acetate as eluents to provide the title compound. LC / MS(m / z): 248(M+H)+.

[0796] Step B: tert-Butyl 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetate

[0797]

[0798] In a glove box, di[(tetrabutylammonium iodide)copper(I) iodide] (0.448 g, 0.400 mmol) and 1,10-phenanthroline (0.144 g, 0.800 mmol) were added to a 40 mL vial equipped with a stirring bar. DMSO (5 mL) was added and the mixture was stirred for 10 minutes. Methyl (2-bromo-4-fluorophenyl)carbamate (0.992 g, 4 mmol), tert-butyl 2-(4-(aminomethyl)phenyl)acetate, oxalic acid (1.308 g, 4.20 mmol) and potassium phosphate (2.55 g, 12.00 mmol) were added to a second vial. The Cu / ligand solution was added to the reagent solution and rinsed with DMSO (15 mL). The vial was sealed, taken out of the glove box, and heated to 100° C. for 22 hours. After 22 hours, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and rinsed with EtOAc. The mixture was washed with water and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography eluting with 30-60% EtOAc / hexanes to provide the title compound. LC / MS (m / z): 379 (M+Na)+.

[0799] Step C: 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid

[0800]

[0801] Tert-butyl 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetate (828.8 mg, 2.325 mmol) was added to a 40 mL vial equipped with a stirring bar. Dioxane (5814 μl) was added followed by trifluoroacetic acid (3583 μl, 46.5 mmol). The vial was sealed and heated to 60°C for 24 hours. After 24 hours, the reaction mixture was cooled to room temperature. Trifluoroacetic acid (500 μl, 6.49 mmol) was added and stirring was continued at 60°C for 68 hours. After 68 hours, the material was filtered and rinsed with ethyl acetate and water. The collected solid provided the title compound. The collected filtrate was washed with ethyl acetate, dried over MgSO4, filtered, and concentrated under reduced pressure to provide the title compound. LC / MS (m / z): 301 (M+H)+.

[0802] Step D: 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-N,N-dimethylacetamide

[0803]

[0804] 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid (485.7 mg, 1.617 mmol), HATU (923 mg, 2.426 mmol) and DMF (8087 μl) were added to a vial equipped with a stirring bar. The reaction mixture was stirred at room temperature for 5 minutes. After 5 minutes, dimethylamine (2M in THF) (1617 μl, 3.23 mmol) and DIEA (847 μl, 4.85 mmol) were added. The reaction mixture was stirred at 45°C for 3 hours. After 3 hours, the crude material was washed with ethyl acetate and saturated NaHCO3. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and loaded directly onto an 80 g column. The column was run from 100% hexane to 100% ethyl acetate. The column was then flushed from 100% DCM to 30% methanol. The desired product was eluted, fractions were collected, and concentrated under reduced pressure. The material was then dissolved in ACN / water and heated to 80°C while stirring for 20 minutes. After 20 minutes, the mixture was cooled to room temperature while stirring for 48 hours. After 48 hours, the material was filtered and rinsed with acetonitrile. The collected solid provided the title compound. LC / MS (m / z): 328 (M+H)+. 1 H NMR (600MHz, DMSO-d6) δ10.98 (s, 1H), 7.21 (dd, J=54.7, 8.1Hz, 3H), 7.02 (dd, J=9.1, 2.4Hz, 1 H), 6.98-6.91(m, 1H), 6.84-6.71(m, 1H), 4.95(s, 2H), 3.63(s, 2H), 2.97(s, 3H), 2.79(s, 3H).

[0805] Embodiment 67:

[0806] Preparation of 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-N-methylacetamide

[0807]

[0808] Step A: 5-Fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0809]

[0810] Triethylamine (33.2mL, 238mmol) and 1,1′-carbonyldiimidazole (CDI) (19.28g, 119mmol) were added to a stirred solution of 4-fluorobenzene-1,2-diamine (5.0g, 39.6mmol) in THF (100mL) at 30°C. After the addition was complete, the reaction was stirred at 80°C for 15 hours. After 15 hours, the reaction was cooled to room temperature. Water (50mL) was added and the mixture was extracted with EtOAc (50mL*2). The organic layer was collected, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography ( Flash column silica gel-CS (12 g, 0-70% ethyl acetate / petroleum ether gradient eluent, 30 mL / min) purification afforded 5-fluoro-1H-benzo[d]imidazol-2(3H)-one. LC / MS (m / z): 153 (M+H)+.

[0811] Step B: tert-Butyl 5-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0812]

[0813] NaH (67 mg, 1.675 mmol) (60% in oil) was added dropwise to a stirred solution of 5-fluoro-1H-benzo [d] imidazole-2 (3H) -one (240 mg, 1.578 mmol) in DMF (5 mL) at 0 ° C. The reaction was stirred for 1 hour, after which BOC2O (0.366 mL, 1.578 mmol) in DMF (2 mL) was added dropwise. After the addition was complete, the reaction was stirred at 15 ° C for 2 hours. After 2 hours, the mixture was concentrated and extracted with EtOAc (300 mL * 3). The combined organic layers were collected, washed with brine (100 mL), and dried over Na2SO4. The mixture was filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography ( Flash column silica gel-CS (12 g, 0-30% ethyl acetate / petroleum ether gradient eluent, 90 mL / min) purification provided tert-butyl 5-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LC / MS (m / z): 197 (M+H)+.

[0814] Step C: tert-Butyl 5-fluoro-3-(4-(2-methoxy-2-oxoethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0815]

[0816] Methyl 2-(4-(hydroxymethyl)phenyl)acetate (89 mg, 0.492 mmol), di-tert-butyl (E)-diazene-1,2-dicarboxylate (170 mg, 0.737 mmol) and diphenyl(p-tolyl)phosphine (204 mg, 0.737 mmol) were added to a stirred solution of tert-butyl 5-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (124 mg, 0.492 mmol) in THF (3 mL) at 0°C. After the addition was complete, the reaction was stirred at 80°C for 15 hours. After 15 hours, the mixture was concentrated and purified by HPLC (eluting with an acetonitrile / water gradient with a TFA modifier) ​​to provide tert-butyl 5-fluoro-3-(4-(2-methoxy-2-oxoethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LC / MS (m / z): 437 (M+H)+.

[0817] Step D: 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid

[0818]

[0819] Lithium hydroxide (12 mg, 0.501 mmol) was added to a stirred solution of tert-butyl 5-fluoro-3-(4-(2-methoxy-2-oxoethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (42 mg, 0.101 mmol) in MeOH (5 mL), THF (5 mL) and water (2.5 mL) at 30°C. After the addition was complete, the reaction was stirred at 30°C for 2 hours. After 2 hours, the reaction was adjusted to pH ~5 with HCl (2N in water) and concentrated in vacuo. The residue was purified by HPLC (eluting with an acetonitrile / water gradient with a TFA modifier) ​​to provide 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid. LC / MS (m / z): 323 (M+H)+.

[0820] Step E: 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-N-methylacetamide

[0821]

[0822] Methylamine hydrochloride (17 mg, 0.252 mmol), triethylamine (0.07 mL, 0.502 mmol) and HATU (82 mg, 0.216 mmol) were added to a stirred solution of 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid (50 mg, 0.167 mmol) in DMF (2 mL) at 30°C. After the addition was complete, the reaction was stirred at 30°C for 5 hours. The reaction mixture was then filtered and purified by HPLC (eluting with an acetonitrile / water gradient with a TFA modifier) ​​to provide 2-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-N-methylacetamide. 1 H NMR (400 MHz, methanol-d4) δ = 7.22-7.32 (m, 4H) 6.97-7.05 (m, 1H) 6.73-6.83 (m, 2H) 5.03 (s, 2H) 3.46 (s, 2H) 2.66-2.71 (m, 2H) 2.66-2.71 (m, 1H). LC / MS (m / z): 314 (M+H)+.

[0823] Embodiment 68:

[0824] Preparation of 1-benzyl-4-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0825]

[0826] Step A: 1-Benzyl-4-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0827]

[0828] Potassium phosphate (339 mg, 1.595 mmol), phenylmethylamine (87 μl, 0.797 mmol), methyl (2-bromo-6-fluorophenyl)carbamate (197.8 mg, 0.797 mmol), cuprous iodide (30.4 mg, 0.159 mmol) and L-hydroxyproline (41.8 mg, 0.319 mmol) were added to a vial equipped with a stirring bar. The vial was purged with nitrogen for 5 minutes. After 5 minutes, DMSO (2658 μl) was added. The vial was sealed and heated to 40°C for 3 hours. After 3 hours, the reaction mixture was heated to 130°C for 16 hours. After 16 hours, the crude reaction mixture was filtered on diatomaceous earth and rinsed with ethyl acetate. The material was concentrated under reduced pressure, and the resulting residue was washed with ethyl acetate and brine. The resulting material was concentrated under reduced pressure. The resulting material was dissolved in DCM and loaded onto a 25 g silica gel column. The column was run from 100% hexanes to 100% ethyl acetate. The desired product was eluted and the fractions were collected and concentrated under reduced pressure. The material was dissolved in ACN / water; frozen and dried on a freeze dryer for 48 hours to provide the title compound. LC / MS (m / z): 243 (M+H)+. 1 H NMR (600MHz, DMSO-d6) δ 11.52 (s, 1H), 7.36-7.28 (m, 4H), 7.28-7.21 (m, 1H), 6.99-6.91 (m, 1H), 6.91-6.84 (m, 2H), 5.01 (s, 2H).

[0829] The examples in Table 9 were synthesized according to the procedure described in Example 68 using the appropriate substituted methyl (2-bromophenyl)carbamate starting material (in Step A) and the appropriate substituted methylamine.

[0830] Table 9

[0831]

[0832] Embodiment 71:

[0833] Preparation of 1-(3-isopropoxybenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0834]

[0835] Sodium hydride (10mg, 0.25mmol) is added in the 8mL vial and is placed under nitrogen.Add 0.50mL of DMF, then add 1,3-dihydro-2H-benzo [d] imidazoles-2-one (33mg, 0.25mmol) solution in 0.50mL of DMF, and reaction mixture was stirred for 1 hour.Then, add 1-(bromomethyl)-3-isopropoxybenzene (57mg, 0.25mmol), and it was stirred at room temperature 15 hours.After this time, reaction mixture is filtered and purified by HPLC (with acetonitrile / water gradient elution containing TFA regulator). 1 H NMR (500MHz, DMSO-d6) δ10.97 (s, 1H), 7.20 (t, J=7.7Hz, 1H), 7.07-6.90 (m, 4 H), 6.85-6.76 (m, 3H), 4.93 (s, 2H), 4.56-4.48 (m, 1H), 1.20 (d, J=6.0Hz, 6H). LCMS(ESI)m / z:283[M+H] + .

[0836] The examples in Table 10 were synthesized according to the procedure described in Example 71 using the appropriate benzyl bromide starting material.

[0837] Table 10

[0838]

[0839] Embodiment 73:

[0840] N-Methyl-N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0841]

[0842] Step A: N-(4-(Bromomethyl)benzyl)-N-methylacetamide

[0843]

[0844] N-methylacetamide (200mg, 2.74mmol) and DMF (5mL) were added to a vial equipped with a stirring bar. The mixture was cooled to 0°C and NaH (120mg, 3.01mmol) (60% in oil) was added. The mixture was stirred at 0°C for 30 minutes. After 30 minutes, the mixture was added to a solution of 1,4-bis(bromomethyl)benzene (1083mg, 4.10mmol) in DMF (5mL). After addition, the reaction was stirred at 30°C for 16 hours. After 16 hours, the reaction mixture was diluted with water (50mL) and extracted with ethyl acetate (30mL×3). The organic layer was collected, washed with brine, and dried over Na2SO4. The obtained material was filtered and concentrated in vacuo. The obtained residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent to provide the title compound. MS (ESI) m / z: 256 [M+H + ].

[0845] Step B: tert-Butyl 3-(4-((N-methylacetamido)methyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0846]

[0847] 2-Oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (0.1 g, 0.427 mmol) and DMF (3 mL) were added to a vial equipped with a stirring bar. K2CO3 (0.118 g, 0.854 mmol) and N-(4-(bromomethyl)benzyl)-N-methylacetamide (0.120 g, 0.470 mmol) were added, and the reaction mixture was stirred at 30°C for 16 hours. After 16 hours, the reaction mixture was washed with water (30 mL) and ethyl acetate (30 mL×2). The resulting organic layer was collected, washed with brine (10 mL), dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo to provide the title compound. MS (ESI) m / z: 432 [M+22 observed + ].

[0848] Step C: N-methyl-N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0849]

[0850] Tert-butyl 3-(4-((N-methylacetamido)methyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (175 mg, 0.427 mmol) and DCM (2 mL) were added to a vial equipped with a stirring bar. TFA (2 mL, 26.0 mmol) was added and the reaction mixture was stirred at 30° C. for 16 hours. After 16 hours, the reaction mixture was concentrated in vacuo. The resulting residue was purified by preparative HPLC (method: column Phenomenex Synergi C18 150*30mm*4um, condition: water (0.1% TFA)-ACN, start B 26, end B 46, gradient time (min) 10, 100% B hold time (min) 2, flow rate (mL / min) 25, injection 3 times) to provide the title compound. MS (ESI) m / z: 310 [M+H + ]. 1 HNMR (500MHz, CD3OD) δ7.39-7.28(m, 2H), 7.26-7.17(m, 2H), 7.13-6.95(m, 4H ), 5.14-5.05(m, 2H), 4.62-4.51(m, 2H), 2.99-2.86(m, 3H), 2.17-2.12(m, 3H).

[0851] The examples in Table 11 were synthesized according to the method described in Example 73 using appropriate amide (or lactam) starting materials.

[0852] Table 11

[0853]

[0854] Embodiment 75:

[0855] Preparation of N-methyl-N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)cyclopropanesulfonamide

[0856]

[0857] Step A: Methyl 4-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0858]

[0859] NaH (0.849 g, 21.23 mmol) in oil was added to a mixture of 2-chloro-1H-benzo[d]imidazole (3 g, 19.66 mmol) and DMF (40 mL) at 0 °C and stirred at 20 °C for 30 minutes. After 30 minutes, methyl 4-(bromomethyl)benzoate (4.95 g, 21.63 mmol) was added and the reaction was stirred at 20 °C for 12 h. After 12 hours, the reaction mixture was added to saturated aqueous ammonium chloride solution (200 mL) and extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 40g Silica gel flash column, [0-30]% ethyl acetate / petroleum ether gradient eluent, 40 mL / min) to provide methyl 4-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzoate. MS (ESI) m / z: 302 [M+H + ].

[0860] Step B: Methyl 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate

[0861]

[0862] A mixture of methyl 4-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (300 mg, 0.998 mmol) in acetic acid (3 ml) was degassed and backfilled with N2 (3 times). The mixture was stirred at 80°C for 16 hours. After 16 hours, the mixture was concentrated under reduced pressure to provide methyl 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate. MS (ESI) m / z: 283 [M+H + ].

[0863] Step C: 4-((2-Oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid

[0864]

[0865] A mixture of methyl 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoate (240 mg, 0.850 mmol) and lithium hydroxide (61.1 mg, 2.55 mmol) in water (1 ml) and THF (5) and MeOH (5 ml) was degassed and backfilled with N2 (3 times) and stirred at 60°C for 1 hour. After 1 hour, the mixture was concentrated under reduced pressure and adjusted to pH=3-6 with aqueous HCl (2M) and filtered. The filtrate was concentrated under reduced pressure to provide 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid. MS (ESI) m / z: 269 [M+H + ].

[0866] Step D: N-methyl-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzamide

[0867]

[0868] Triethylamine (9.43 mg, 0.093 mmol) and HATU (17.01 mg, 0.045 mmol) were added to a solution of 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid (10 mg, 0.037 mmol) in DMF (2 ml) at 25°C. The reaction mixture was stirred at 25°C for 30 min. After 30 minutes, methylamine (1.273 mg, 0.041 mmol) was added to the mixture. The mixture was stirred at 25°C for 2 hours. After 2 hours, the mixture was filtered and concentrated under reduced pressure to provide N-methyl-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzamide.

[0869] MS (ESI) m / z: 282 [M+H + ].

[0870] Step E: 1-(4-((methylamino)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0871]

[0872] A mixture of N-methyl-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzamide (130 mg, 0.462 mmol) and LiAlH4 (26.3 mg, 0.693 mmol) in THF (40 ml) was degassed and backfilled with N2 (3 times) and stirred at 70°C for 16 h. After 16 hours, Na2SQ4.H2O (130 mg) was added to the reaction and stirred at 25°C for 30 min. After 30 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure and purified by HPLC (with TFA modifier) ​​to provide 1-(4-((methylamino)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. MS (ESI) m / z: 268 [M+H + ].

[0873] Step F: N-methyl-N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)cyclopropanesulfonamide

[0874]

[0875] A mixture of 1-(4-((methylamino)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.112 mmol), TEA (0.031 ml, 0.224 mmol) and cyclopropanesulfonyl chloride (12.62 mg, 0.090 mmol) in DCM (10 ml) was degassed and backfilled with N2 (3 times). The mixture was stirred at 25 °C for 16 h. After 16 hours, the mixture was concentrated under reduced pressure and purified by HPLC (with TFA regulator) to provide N-methyl-N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)cyclopropanesulfonamide. 1 H NMR (400MHz, MeOD): δ7.97-7.88 (m, 4H), 7.71-7.53 (m, 4H), 5.67 (s, 2H), 4.91 (s, 2H), 3.31 (s, 3H), 3.13-3.03 (m, 1H), 1.73-1.53 ​​(m, 4H). MS(ESI)m / z:372[M+H + ].

[0876] Embodiment 76:

[0877] Preparation of N-(4-((3-(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0878]

[0879] Step A: tert-Butyl (4-((3-(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate

[0880]

[0881] 1-(Difluoromethyl)-1H-benzo[d]imidazole-2(3H)-one (47 mg, 0.255 mmol) and KCO (65 mg, 0.470 mmol) in DMF (3 mL) were added to a vial equipped with a stirring bar. 4-(bromomethyl)benzylcarbamic acid tert-butyl ester (70 mg, 0.233 mmol) was added at 20°C. The resulting mixture was stirred at 20°C for 15 hours. After 15 hours, the mixture was filtered and the filtrate was purified by HPLC (gradient elution with acetonitrile / water containing TFA modifier). The desired product was isolated as a solid. LCMS (ESI) m / z: 426 [M+Na] + .

[0882] Step B: (4-((3-(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)methylammonium chloride

[0883]

[0884] Tert-butyl 4-((3-(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzylcarbamate (53 mg, 0.131 mmol) was dissolved in hydrogen chloride (2 mL, 8.00 mmol) (4M in dioxane) and the mixture was stirred at 20°C for 2 hours. After 2 hours, the mixture was concentrated under reduced pressure to give a crude material, which was used directly in the next step without further purification. LCMS (ESI) m / z: 345 [M+MeCN] + .

[0885] Step C: N-(4-((3-(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[0886]

[0887] Triethylamine (0.06 mL, 0.430 mmol) and acetic anhydride (0.02 mL, 0.212 mmol) were added to a solution of (4-((3-(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)methylammonium chloride (44 mg, 0.130 mmol) in DCM (5 mL) at 20°C and the mixture was stirred at 20°C for 2 hours. After 2 hours, the mixture was concentrated in vacuo and purified by HPLC (eluting with an acetonitrile / water gradient with a TFA modifier). LCMS (ESI) m / z: 346 [M+H] + . 1 H NMR (500MHz, CD3OD) δ7.61-7.38 (t, J=58.5, 1H), 7.49 (s, 1H), 7.40-7.37 (m, 1H), 7.34-7.29 (m, 2H ), 7.29-7.24(m, 2H), 7.18-7.13(m, 2H), 7.11-7.05(m, 1H), 5.08(s, 2H), 4.32(s, 2H), 1.96(s, 3H).

[0888] Embodiment 77:

[0889] Preparation of N-(4-((3-(difluoromethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)methanesulfonamide

[0890]

[0891] Utilizing the procedure outlined in Example 76 using methanesulfonyl chloride in step C provided the title compound. 1 HNMR (400MHz, CDCl3) δ7.45-7.08(m, 1H), 7.36-7.32(m, 1H), 7.29(br s, 2H), 7.22-7.20 (m, 1H), 7.16 (s, 1H), 7.12-7.02 (m, 2H), 6.87-6.81 (m, 1H), 4.99 (s, 2H), 4.58 (br s, 1H), 4.24 (d, J=5.9Hz, 2H), 2.82 (s, 3H). LCMS(ESI)m / z:382[M+H] + .

[0892] Embodiment 78:

[0893] Preparation of 1-benzyl-3-(difluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0894]

[0895] 1-(Difluoromethyl)-1H-benzo[d]imidazole-2(3H)-one (90 mg, 0.489 mmol) and DMF (2 mL) were added to a vial equipped with a stirring bar. K2CO3 (101 mg, 0.733 mmol) and (bromomethyl)benzene (84 mg, 0.489 mmol) were added and the reaction mixture was stirred at 20°C (room temperature) under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours. After 2 hours, the reaction mixture was concentrated in vacuo. The resulting residue was purified by preparative HPLC (column Boston Green ODS 150*30mm*5um, condition: water (0.1% TFA)-MeCN, start B 59, end B 79, gradient time (min) 10, 100% B hold time (min) 2, flow rate (mL / min) 25) to provide the title compound. LCMS (ESI) m / z: 275 [M+H] + . 1 H NMR (500MHz, MeOH-d4) δ7.65-7.40(m, 1H), 7.39-7.37(m, 1H), 7.36-7.32(m , 4H), 7.32-7.26(m, 1H), 7.20-7.14(m, 2H), 7.12-7.10(m, 1H), 5.10(s, 2H).

[0896] Embodiment 79:

[0897] Preparation of 1-((3-chloro-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-2-yl)methyl)cyclobutane-1-carbonitrile

[0898]

[0899] Step A: tert-Butyl 3-((6-bromo-5-chloropyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0900]

[0901] Tert-butyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (164 mg, 0.70 mmol) and 2-bromo-5-(bromomethyl)-3-chloropyridine (210 mg, 0.74 mmol) were dissolved in DMF (3.8 mL) and potassium carbonate (203 mg, 1.47 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1.5 hours. After 1.5 hours, saturated NaHCO3 was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with water and brine, then dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography using hexane and ethyl acetate as eluents. LCMS (ESI) m / z: 338 [M+H] + (Observed as loss of Boc).

[0902] Step B: tert-Butyl 3-((5-chloro-6-((1-cyanocyclobutyl)methyl)pyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0903]

[0904] 1-(Bromomethyl)cyclobutane-1-carbonitrile (13.09 mg, 0.075 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (8.26 mg, 0.038 mmol), guanylpyridine hydrochloride (5.93 mg, 0.038 mmol), zinc (9.84 mg, 0.150 mmol), tetrabutylammonium iodide (41.7 mg, 0.113 mmol) and tert-butyl 3-((6-bromo-5-chloropyridin-3-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (33 mg, 0.075 mmol) were added to a 4 mL vial and DMA (0.75 mL) was added. The reaction vial was sealed, degassed and flushed with nitrogen for 1 minute, and the resulting reaction mixture was stirred for 4 hours. After 4 hours, the mixture was filtered through celite and purified by HPLC (eluting with an acetonitrile / water gradient with TFA as a modifier). LCMS (ESI) m / z: 475 [M+Na] + .

[0905] Step C: 1-((3-chloro-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-2-yl)methyl)cyclobutane-1-carbonitrile

[0906]

[0907] 1-((3-chloro-5-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-2-yl)methyl)cyclobutane-1-carbonitrile was dissolved in 1 mL of TFA:DCM (1:1) and stirred at room temperature for 30 minutes. The resulting mixture was concentrated and purified by HPLC (eluting with an acetonitrile / water gradient with TFA modifier). 1 H NMR (500MHz, DMSO-d6) δ10.90 (s, 1H), 8.32 (d, J = 1.6Hz, 1H), 7.93 (d, J = 1.6Hz, 1H), 7.06-6.84 (m, 4H), 5.21 (s, 2H), 3.08 (s, 2H), 2.34 (dt, J=11.5, 8.2Hz, 2H), 2.30-2.21 (m, 2H), 2.09-1.99 (m, 2H). LCMS(ESI)m / z:353[M+H] + .

[0908] Embodiment 80:

[0909] Preparation of 1-(3-(4-methylpiperazin-1-yl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0910]

[0911] Step A: tert-Butyl 3-(3-iodobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0912]

[0913] NaH (0.205 g, 5.12 mmol) (60% in oil) was added portionwise to a stirred solution of tert-butyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (1.0 g, 4.27 mmol) in DMF (10 mL) at 0°C. The reaction was stirred for 1 hour. After 1 hour, 1-(bromomethyl)-3-iodobenzene (1.394 g, 4.70 mmol) in DMF (10 mL) was added dropwise. After the addition was complete, the reaction was stirred at 25°C for 16 hours. After 16 hours, water (50 mL) was added and the mixture was extracted with EtOAc (30 mL*2). The organic layer was collected, washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to provide tert-butyl 3-(3-iodobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. 1H NMR (400 MHz, chloroform-d) δ 7.78-7.89 (m, 1H), 7.67 (s, 1H), 7.61 (d, J = 7.83 Hz, 1H), 7.28 (br d, J = 7.58 Hz, 1H), 6.99-7.15 (m, 3H), 6.78-6.87 (m, 1H), 4.97 (s, 2H), 1.69 (s, 9H). LCMS (ESI) m / z: 287.0 [M-56+H].

[0914] Step B: 1-(3-(4-methylpiperazin-1-yl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0915]

[0916] K3PO4 (283 mg, 1.333 mmol), copper (I) iodide (21.57 mg, 0.113 mmol), (2S, 4R)-4-hydroxypyrrolidine-2-carboxylic acid (29.7 mg, 0.227 mmol) and 1-methylpiperazine (66.7 mg, 0.666 mmol) were added to a stirred mixture of tert-butyl 3-(3-iodobenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (300 mg, 0.666 mmol) in DMSO (6 ml) at 20° C. After the addition was complete, the reaction was stirred at 80° C. for 2.5 hours. After 2.5 hours, the reaction was filtered and the residue was purified by HPLC (eluting with an acetonitrile / water gradient with NH4HCO3 modifier) ​​to provide 1-(3-(4-methylpiperazin-1-yl)benzyl)-1H-benzo[d]imidazol-2(3H)-one. 1H NMR (400 MHz, Methanol-d4) δ = 7.27-7.16 (m, 1H), 7.12-7.03 (m, 2H), 7.03-6.98 (m, 2H), 6.96 (s, 1H), 6.90 (br d, J = 8.3 Hz, 1H), 6.80 (br d, J = 7.5 Hz, 1H), 5.04 (s, 2H), 3.24-3.07 (m, 4H), 2.67-2.53 (m, 4H), 2.35 (s, 3H). LCMS (ESI) m / z: 323 [M+H] + .

[0917] Embodiment 81:

[0918] Preparation of 1-(4-((5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0919]

[0920] Step A: tert-Butyl 3-(4-(bromomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0921]

[0922] 2-Oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (3.0 g, 12.81 mmol) was slowly added to a mixture of 1,4-bis(bromomethyl)benzene (4.06 g, 15.37 mmol) and potassium carbonate (5.31 g, 38.4 mmol) in DMF (60 mL) at 20 ° C. The resulting mixture was stirred at 20 ° C for 15 h. After 15 hours, the solvent was removed under reduced pressure and the residue was dissolved in water (30 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography ( 40g Purification by silica gel flash column, eluent 0-30% ethyl acetate / petroleum ether gradient, 35 mL / min) provided tert-butyl 3-(4-(bromomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate.

[0923] 1H NMR (400 MHz, CHLOROFORM-d) δ=7.89-7.81 (m, 1H), 7.38-7.30 (m, 4H), 7.16-7.07 (m, 2H), 6.89-6.84 (m, 1H), 5.04 (s, 2H), 4.46 (s, 2H), 1.70 (s, 9H).

[0924] Step B: tert-Butyl 3-(4-(azidomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0925]

[0926] Sodium azide (0.27 g, 4.15 mmol) was added to a solution of tert-butyl 3-(4-(bromomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (1.6 g, 3.83 mmol) in DMF (10 mL) at 0°C, and the mixture was stirred at 25°C for 2 h. After 2 hours, the mixture was adjusted to pH ~ 10 with Na2CO3 solution and poured into water (50 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (20 mL*2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The aqueous layer was poured into a saturated sodium hypochlorite solution (20 mL) and stirred for 15 h. After 15 hours, the residue was purified by flash silica gel chromatography ( 12g Purification on silica gel flash column, 0-20% ethyl acetate / petroleum ether gradient eluent, 35 mL / min) afforded tert-butyl 3-(4-(azidomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LCMS (ESI) m / z: 324 [M+H-C4H8]+.

[0927] Step C: tert-Butyl 3-(4-((4 or 5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0928]

[0929] Prop-2-yn-1-ol (0.013 mL, 0.221 mmol) and Cp*RuCl(PPh3)2 (1.469 mg, 1.845 μmol) were added to a solution of tert-butyl 3-(4-(azidomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (70 mg, 0.184 mmol) in THF (10 mL) at 20°C. The reaction mixture was stirred at 80°C for 60 h. After 60 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure to provide crude tert-butyl 3-(4-((4 or 5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LCMS (ESI) m / z: 336.0 [M+H]+.

[0930] Step D: 1-(4-((4 or 5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0931]

[0932] TFA (0.068 mL, 0.886 mmol) was added to a solution of tert-butyl 3-(4-((4 or 5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (80 mg, 0.177 mmol) in DCM (2 mL). The reaction mixture was stirred at 20 °C for 1 h. After 1 hour, the solvent was removed under reduced pressure. The residue was purified by HPLC (eluting with acetonitrile / water gradient containing NH4HCO3 modifier) ​​to provide 1-(4-((5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1H-benzo[d]imidazole-2(3H)-one. LCMS (ESI) m / z: 336 [M+H] + .

[0933] Step E: 1-(4-((5-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0934]

[0935] Preparative separation of 1-(4-((4 or 5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1H-benzo[d]imidazol-2(3H)-one was performed using supercritical fluid chromatography on an MGII preparative SFC. A Chiral Technologies AD-H column (10 μm, 30 mm x 250 mm, Chiral Technologies, West Chester, PA) was used as a chiral stationary phase. The compound mixture was dissolved in EtOH. The following isocratic SFC conditions were used for injection and collection: 45% carbon dioxide and 55% ethanol (containing 0.1% ammonium hydroxide) as mobile phases, 220 nm UV wavelength, 100 bar outlet pressure, 38°C column compartment temperature, 70 mL / min total flow rate. Retention times for peak collection were as follows: expected first eluting peak, 1.040 min; second eluting peak, 2.588 min. 1H NMR (400 MHz, methanol-d4) δ 7.64 (s, 1H), 7.32-7.27 (m, 2H), 7.25-7.18 (m, 2H), 7.11-7.02 (m, 2H), 7.02-6.97 (m, 1H), 6.97-6.92 (m, 1H), 5.62 (s, 2H), 5.05 (s, 2H), 4.55 (s, 2H). LCMS (ESI) m / z: 336.2 [M+H]+.

[0936] Embodiment 82:

[0937] Preparation of 1-(4-((1H-1,2,3-triazol-1-yl)methyl)benzyl)-1H-benzo[d]imidazol-2(3H)-one

[0938]

[0939] Step A: tert-Butyl 3-(4-(bromomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0940]

[0941] 2-Oxo-2,3-dihydro-1H-benzo [d] imidazole-1-carboxylic acid tert-butyl ester (11.7g, 49.9mmol) and DMF (300mL) were added to a vial equipped with a stirring bar. 1,4-bis (bromomethyl) benzene (19.5g, 73.9mmol) and K2CO3 (10.35g, 74.9mmol) were added, and the vial was stirred at 30°C for 3 hours. After 3 hours, the reaction was concentrated under reduced pressure and diluted with water (300mL). The obtained material was washed with ethyl acetate (300mL×3). The combined organic layer was collected, dried over Na2SO4, and filtered. The combined filtrate was concentrated in vacuo. The obtained residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent to provide the title compound. 1 H NMR (500 MHz, CHLOROFORM-d) δ 7.80-7.73 (m, 1H), 7.28-7.25 (m, 2H), 7.25-7.22 (m, 2H), 7.07-7.00 (m, 2H), 6.81-6.75 (m, 1H), 4.99-4.92 (m, 2H), 4.40-4.34 (m, 2H), 1.61 (s, 9H).

[0942] Step B: tert-Butyl 3-(4-((1H-1,2,3-triazol-1-yl)methyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0943]

[0944] Tert-butyl 3-(4-(bromomethyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.120 mmol) and THF (5 mL) were added to a vial equipped with a stirring bar. 1,2,3-triazole (10 mg, 0.145 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL, 0.145 mmol) were added at 0°C with stirring. The reaction mixture was warmed to room temperature (28°C) and stirred at room temperature for 12 hours. After 12 hours, the solvent was concentrated in vacuo to provide the title compound. LCMS (ESI) m / z: 406 [M+H] + .

[0945] Step C: 1-(4-((1H-1,2,3-triazol-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0946]

[0947] tert-Butyl 3-(4-((1H-1,2,3-triazol-1-yl)methyl)benzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.247 mmol) and DCM (5 mL) were added to a vial equipped with a stirring bar. TFA (1 mL, 12.98 mmol) was added and the mixture was stirred at 28° C. for 12 hours. After 12 hours, the solvent was concentrated in vacuo. The resulting residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with a YMC-Actus Triart C18 150*30mm*5um using water (0.1% TFA)-MeCN and acetonitrile as eluents, followed by lyophilization to provide the title compound. LCMS (ESI) m / z: 306 [M+H] + . 1 H NMR (500MHz, CD3OD) δ7.94 (d, J=1.0Hz, 1H), 7.71 (d, J=1.0Hz, 1H), 7.35-7. 30 (m, 2H), 7.30-7.25 (m, 2H), 7.09-6.94 (m, 4H), 5.60 (s, 2H), 5.08 (s, 2H).

[0948] According to the method described in Example 82, the examples in Table 12 were synthesized in Step B using appropriately substituted starting materials under appropriate conditions (eg, K 2 CO 3 / MeCN / 70° C. / 16 hours).

[0949] Table 12

[0950]

[0951] Embodiment 84:

[0952] Preparation of 6-fluoro-1-(4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0953]

[0954] Step A: 1-(4-((2-chloro-6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)pyrrolidin-2-one

[0955]

[0956] 2-Chloro-5-fluorobenzimidazole (199 mg, 1.169 mmol) and 1-(4-(hydroxymethyl)benzyl)pyrrolidin-2-one (240 mg, 1.169 mmol) in DCM (2 mL) were added to triphenylphosphine (368 mg, 1.403 mmol) and diisopropyl azodicarboxylate (DIAD) (0.341 mL, 1.754 mmol) at 0 ° C. The resulting mixture was stirred at 20 ° C for 2 h. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether as eluents. The title compound was obtained as a mixture with its positional isomer 1-(4-((2-chloro-6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)pyrrolidin-2-one. LCMS(ESI)m / z:358[M+H] + .

[0957] Step B: 6-Fluoro-1-(4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0958]

[0959] A mixture of 1-(4-((2-chloro-5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)pyrrolidin-2-one and its positional isomer 1-(4-((2-chloro-6-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)pyrrolidin-2-one (200 mg (total of the mixture), 0.559 mmol) in AcOH (2 mL) was stirred at 80° C. for 12 hours. After 12 hours, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (eluting with acetonitrile / water gradient containing TFA modifier) ​​and the mixture of positional isomers was then separated by SFC (column DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 um), conditions: 0.1% NH3.H2O EtOH, start B 45%, end B 45%, gradient time (min) 100% B hold time (min), flow rate (mL / min) 50) to produce the title compound as the first eluting peak. 1 H NMR (500MHz, MeOH-d4) δ7.17 (d, J=7.9Hz, 2H), 7.06 (d, J=8.1Hz, 2H), 6.86 (dd, J=4.6, 8.4Hz, 1H), 6.67-6.59 (m, 1 H), 6.67-6.59 (m, 1H), 4.89 (s, 2H), 4.25 (s, 2H), 3.11 (t, J=7.1Hz, 2H), 2.26 (t, J=8.1Hz, 2H), 1.84-1.78 (m, 2H). LCMS(ESI)m / z:340[M+H] + .

[0960] Embodiment 85:

[0961] Preparation of 5-fluoro-1-(4-((2-oxopyrrolidin-1-yl)methyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0962]

[0963] Utilizing the same procedures outlined in Steps AB of Example 84, except collecting the 2nd eluting peak by SFC in Step B, provided the title compound. 1H NMR (500MHz, MeOH-d4) δ7.17 (d, J=7.9Hz, 2H), 7.08 (d, J=8.1Hz, 2H), 6.78 (dd, J=4.3, 8.6Hz, 1H), 6.73 (dd, J=2.4, 8.6 Hz, 1H), 6.64-6.57 (m, 1H), 4.91 (s, 2H), 4.27 (s, 2H), 3.15 (t, J=7.2Hz, 2H), 2.28 (t, J=8.1Hz, 2H), 1.87-1.81 (m, 2H). LCMS(ESI)m / z:340[M+H] + .

[0964] Embodiment 86:

[0965] Preparation of 1-(2-methoxybenzyl)-6-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0966]

[0967] Step A: Preparation of tert-butyl 3-(2-methoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[0968]

[0969] tert-Butyl 5-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (25 mg, 0.101 mmol), (2-methoxyphenyl)methanol (28 mg, 0.203 mmol) and polymer-bound triphenylphosphine (27 mg, 0.103 mmol) in THF (0.5 mL) were added to a vial equipped with a stirring bar. Di-tert-butyl azodicarboxylate (47 mg, 0.204 mmol) in THF (0.5 mL) was added at 0°C. The reaction mixture was heated to 80°C for 16 hours. After 16 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure and used in the next step without further purification. LCMS (ESI) m / z: 313 [M+H] + (Observed as loss of tBu).

[0970] Step B: 1-(2-methoxybenzyl)-6-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0971]

[0972] TFA (0.1 mL, 1.298 mmol) was added to a stirred solution of tert-butyl 3-(2-methoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (30 mg, 0.081 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred for 30 minutes. After 30 minutes, the solvent was removed under reduced pressure and the residue was purified by HPLC (eluting with acetonitrile / water gradient containing TFA as a modifier). 1 H NMR (500MHz, CDCl3) δ9.76 (br s, 1H), 7.20-7.26 (m, 1H), 7.06-7.10 (m, 1H), 6.94 (s, 1H), 6.90 (d, J=7.93Hz, 1H), 6.86 (t, J=7.48Hz, 1H), 6.81 (s, 2H), 5.11 (s, 2H), 3.85-3.94 (m, 3H), 2.35 (s, 3H). LCMS(ESI)m / z:269[M+H] + .

[0973] Embodiment 87:

[0974] Preparation of 1-(1-phenylethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0975]

[0976] Using the procedures of Example 86, Steps AB, tert-butyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate and 1-phenylethan-1-ol were elaborated to the final compounds.

[0977] Step A: tert-Butyl 2-oxo-3-(1-phenylethyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LCMS (ESI) m / z: 283 [M+H] + (Observed as loss of tBu).

[0978] Step B: 1-(1-Phenylethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (500MHz, MeOH-d4) δ7.42-7.34(m, 4H), 7.31-7.26(m, 1H), 7.11-7.07(m, 1H), 7.02(t, J=7.7H z, 1H), 6.90 (t, J=7.7Hz, 1H), 6.77 (d, J=7.9Hz, 1H), 5.81 (q, J=7.2Hz, 1H), 1.92 (d, J=7.2Hz, 3H). LCMS(ESI)m / z:239[M+H]+ .

[0979] Embodiment 88:

[0980] Preparation of 1-(1-cyclohexylethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0981]

[0982] Using the procedures of Example 86, Steps AB, tert-butyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate and 1-cyclohexylethan-1-ol were elaborated to the final compounds.

[0983] Step A: tert-butyl 3-(1-cyclohexylethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LCMS (ESI) m / z: 345 [M+H] + .

[0984] Step B: 1-(1-Cyclohexylethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (500MHz, MeOH-d4) δ7.25-7.23 (m, 1H), 7.09-7.06 (m, 3H), 4.19-4.13 (m, 1H), 2.08-2.05 (m, 2H), 1.86-1. 84 (m, 1H), 1.68-1.62 (m, 2H), 1.53 (d, J=7.0Hz, 3H), 1.35-1.32 (m, 2H), 1.13-1.08 (m, 3H), 0.93-0.92 (m, 1H). LCMS (ESI) m / z: 245[M+H+].

[0985] Embodiment 89:

[0986] Preparation of 1-methyl-3-(3-(trifluoromethoxy)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0987]

[0988] Using the procedure of Example 86, Step A, 1-methyl-1H-benzo[d]imidazol-2(3H)-one and (3-(trifluoromethoxy)phenyl)methanol were elaborated to the final compounds. 1H NMR (500MHz, MeOH-d4) δ7.47-7.42 (m, 1H), 7.32 (d, J=7.6Hz, 1H), 7.26 (s, 1H), 7. 23-7.19 (m, 2H), 7.18-7.15 (m, 1H), 7.12-7.05 (m, 2H), 5.18 (s, 2H), 3.50 (s, 3H). LCMS(ESI)m / z:323[M+H] + .

[0989] Embodiment 90:

[0990] Preparation of 5-chloro-1-(3-methoxybenzyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0991]

[0992] Utilizing the procedures of Example 86, Steps AB, tert-butyl 6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate and (3-methoxyphenyl)methanol were elaborated to give 5-chloro-1-(3-methoxybenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one.

[0993] Step A: tert-butyl 6-chloro-3-(3-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate. LCMS (ESI) m / z: 389 [M+H] + .

[0994] Step B: 5-chloro-1-(3-methoxybenzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. LCMS (ESI) m / z: 289 [M+H] + .

[0995] Step C: 5-Chloro-1-(3-methoxybenzyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0996]

[0997] 5-Chloro-1-(3-methoxybenzyl)-1H-benzo[d]imidazol-2(3H)-one (20 mg, 0.069 mmol) was dissolved in DMF (2 mL) and iodomethane (98 mg, 0.693 mmol) and cesium carbonate (68 mg, 0.209 mmol) were added at 0° C. After the addition was complete, the reaction was stirred at 50° C. for 15 hours. The mixture was filtered and purified by HPLC (eluting with an acetonitrile / water gradient containing a TFA modifier). 1H NMR (400MHz, CDCl3) δ7.24 (t, J=7.8Hz, 1H), 7.00-6.96 (m, 2H), 6.87 (d, J=7.8Hz, 1H ), 6.84-6.79 (m, 2H), 6.77 (d, J=9.0Hz, 1H), 5.03 (s, 2H), 3.77 (s, 3H), 3.45 (s, 3H). MS(ESI)m / z:303[M+H + ].

[0998] Embodiment 91:

[0999] Preparation of 1-(2-methoxybenzyl)-7-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1000]

[1001] Step A: N-(2-methoxybenzyl)-2-methyl-6-nitroaniline

[1002]

[1003] 2-Fluoro-1-methyl-3-nitrobenzene (200mg, 1.289mmol) in THF (5mL) was added to a vial equipped with a stirring bar. (2-methoxyphenyl)methylamine (177mg, 1.289mmol) and K2CO3 (356mg, 2.58mmol) were added at room temperature. After the addition was complete, the reaction was stirred at 80°C for 15 hours. After 15 hours, the reaction was cooled to room temperature and water (30mL) was added. The mixture was washed with ethyl acetate (30mL x 2). The organic layer was collected, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate and petroleum ether as eluent. LCMS (ESI) m / z: 273 [M+H] + .

[1004] Step B: N1-(2-methoxybenzyl)-6-methylbenzene-1,2-diamine

[1005]

[1006] N-(2-methoxybenzyl)-2-methyl-6-nitroaniline (100 mg, 0.367 mmol) was dissolved in MeOH (3 mL) under argon, and then 10% Pd-C (39.1 mg, 0.037 mmol) was added at room temperature. The resulting mixture was stirred at room temperature under a hydrogen (15 psi) atmosphere and stirred at room temperature for 15 minutes. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative TLC using ethyl acetate and petroleum ether as eluents. LCMS (ESI) m / z: 243 [M+H] + .

[1007] Step C: 1-(2-methoxybenzyl)-7-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1008]

[1009] CDI (40 mg, 0.247 mmol) was added to a mixture of N1-(2-methoxybenzyl)-6-methylbenzene-1,2-diamine (30 mg, 0.124 mmol) in THF (5 mL), followed by triethylamine (0.06 mL, 0.430 mmol). The reaction was stirred and heated at 80 ° C for 15 hours. After 15 hours, the reaction mixture was cooled to room temperature. Water (30 mL) was added and the mixture was washed with ethyl acetate (30 mL x 2). The organic layer was collected, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC (gradient elution with acetonitrile / water containing TFA regulator). 1 H NMR(500MHz, CDCl3)δ9.68(br s, 1H), 7.25-7.24 (m, 1H), 6.99-6.90 (m, 3H), 6.83-6.80 (m, 1H), 6.77-6.76 (m, 2H), 5.32 (s, 2H), 3.92 (s, 3H), 2.26 (s, 3H). LCMS(ESI)m / z:269[M+H] + .

[1010] Embodiment 92:

[1011] Preparation of 1-(2-methoxybenzyl)-4-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1012]

[1013] Utilizing the same procedures shown above in Steps AC of Example 91, except using 1-fluoro-3-methyl-2-nitrobenzene in Step A, the title compound was provided.

[1014] Step A: N-(2-methoxybenzyl)-2-methyl-6-nitroaniline. LCMS (ESI) m / z: 273 [M+H] + .

[1015] Step B: N 1 -(2-methoxybenzyl)-6-methylbenzene-1,2-diamine. LCMS (ESI) m / z: 243 [M+H] + .

[1016] Step C: 1-(2-Methoxybenzyl)-4-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one. 1 H NMR (400MHz, CDCl3) δ9.59 (br s, 1H), 7.25-7.23 (m, 1H), 7.14-7.12 (m, 1H), 6.93-6.79 (m, 5H), 5.12 (s, 2H), 3.91 (s, 3H), 2.40 (s, 3H). LCMS(ESI)m / z:269[M+H] + .

[1017] Embodiment 93:

[1018] Preparation of 1-benzyl-4-(pyrrolidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1019]

[1020] Step A: 1-(3-Fluoro-2-nitrophenyl)pyrrolidine

[1021]

[1022] 1,3-difluoro-2-nitrobenzene (500mg, 3.14mmol) was dissolved in DMSO (5mL). Pyrrolidine (224mg, 3.14mmol) and K2CO3 (956mg, 6.91mmol) were added and the reaction was stirred at room temperature for 1 hour. After 1 hour, the mixture was diluted with water (40mL) and extracted with EtOAc (30mL x 3). The resulting organic layer was collected, washed with brine (10mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents. LCMS (ESI) m / z: 211 [M+H + ].

[1023] Step B: N-Benzyl-2-nitro-3-(pyrrolidin-1-yl)aniline

[1024]

[1025] 1-(3-Fluoro-2-nitrophenyl)pyrrolidine (200 mg, 0.951 mmol) was dissolved in DMSO (5 mL). Benzylamine (112 mg, 1.047) and K2CO3 (263 mg, 1.903 mmol) were added, and the reaction was heated to 110 ° C for 16 hours. After 16 hours, the mixture was diluted with water (40 mL) and extracted with EtOAc (30 mL x 3). The resulting organic layer was collected, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents. LCMS (ESI) m / z: 298 [M+H + ].

[1026] Step C: N1-Benzyl-3-(pyrrolidin-1-yl)benzene-1,2-diamine

[1027]

[1028] N-Benzyl-2-nitro-3-(pyrrolidin-1-yl)aniline (75 mg, 0.252 mmol) was dissolved in MeOH (5 mL). Pd-C (3 mg, 0.028 mmol) was added to the reaction and the reaction was placed under a hydrogen atmosphere for 5 minutes. After 5 minutes, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to provide the title compound as an oil. MS (ESI) m / z: 268 [M+H + ].

[1029] Step D: 1-Benzyl-4-(pyrrolidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1030]

[1031] N1-benzyl-3-(pyrrolidin-1-yl)benzene-1,2-diamine (20mg, 0.075mmol) is dissolved in THF (5mL). CDI (36mg, 0.222mmol) and triethylamine (0.06mL, 0.430mmol) are added at 20°C. After the addition is completed, the reaction is stirred and heated at 80°C for 15 hours. After 15 hours, the reaction is cooled to room temperature. Water (30mL) is added, and the mixture is extracted with EtOAc (30mL x 2). The organic layer obtained is collected, washed with brine (20mL), dried over Na2SO4, and filtered. The filtrate obtained is concentrated in a vacuum, and the residue is purified by HPLC (eluted with acetonitrile / water gradient containing TFA regulator) to provide the title compound. 1HNMR (500MHz, MeOH-d4) δ7.36-7.31 (m, 4H), 7.28 (br d, J=6.3Hz, 1H), 6.91 (t, J=8.0Hz, 1H), 6.50 (br d, J=7.8Hz, 2H), 5.07 (s, 2H), 3.42-3.37 (m, 4H), 2.04 (td, J=3.3, 6.4Hz, 4H). LCMS(ESI)m / z:294[M+H + ].

[1032] Embodiment 94:

[1033] Preparation of N-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[1034]

[1035] Step A: tert-Butyl (4-(((5-fluoro-2-nitrophenyl)amino)methyl)benzyl)carbamate

[1036]

[1037] 2,4-difluoro-1-nitrobenzene (469 μl, 4.27 mmol), tert-butyl (4-(aminomethyl)benzyl)carbamate (1010 mg, 4.27 mmol), K2CO3 (886 mg, 6.41 mmol) and THF (1.07E+04 μl) were added to a vial equipped with a stirring bar. The vial was sealed and heated to 80°C for 18 hours. After 18 hours, the crude was washed with water and ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material was dissolved in DCM and loaded onto an 80 g silica gel column. The column was run from 100% hexane to 100% ethyl acetate. The desired material was eluted; the fractions were collected and concentrated under reduced pressure. LC / MS (m / z): 398 (M+H)+ (observed +22).

[1038] Step B: tert-Butyl (4-(((2-amino-5-fluorophenyl)amino)methyl)benzyl)carbamate

[1039]

[1040] Zinc (355 mg, 5.44 mmol) and ethanol (1853 μl) were added to a vial equipped with a stirring bar. The vial was cooled to 0°C and acetic acid (311 μl, 5.44 mmol) was added. The mixture was stirred for 5 minutes. After 5 minutes, tert-butyl (4-(((5-fluoro-2-nitrophenyl)amino)methyl)benzyl)carbamate (371 mg, 0.988 mmol) in ethanol (618 μl) was added. The mixture was heated to 35°C for 45 minutes. After 45 minutes, the mixture was filtered through diatomaceous earth and rinsed with ethyl acetate. The mixture was concentrated under reduced pressure. The resulting material was dissolved in DCM and loaded onto a 40 g silica gel column, eluted with 100% hexane to 100% ethyl acetate. The desired product was eluted; the fractions were collected and concentrated under reduced pressure to provide the desired intermediate. LC / MS (m / z): 346 (M+H)+.

[1041] Step C: tert-Butyl (4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate

[1042]

[1043] Tert-butyl (4-(((2-amino-5-fluorophenyl)amino)methyl)benzyl)carbamate (303 mg, 0.877 mmol), CDI (142 mg, 0.877 mmol), TEA (367 μl, 2.63 mmol) and DMF (2193 μl) were added to a vial equipped with a stirring bar. The vial was sealed and heated to 80°C for 4.5 hours. After 4.5 hours, the reaction mixture was cooled to room temperature. CDI (71.1 mg, 0.439 mmol) and TEA (122 μl, 0.877 mmol) were added to the reaction mixture, and heating was continued at 80°C for 1 hour. After 1 hour, the reaction mixture was cooled to room temperature. The reaction mixture was washed with ethyl acetate and water. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting material was used without purification. LC / MS (m / z): 316 (M+H)+ (loss of tert-butyl group was observed).

[1044] Step D: 1-(4-(Aminomethyl)benzyl)-6-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1045]

[1046] Tert-butyl (4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate (326 mg, 0.878 mmol), HCl (2194 μl, 8.78 mmol) and THF (2194 μl) were added to a vial equipped with a stirring bar. The reaction mixture was stirred at room temperature for 18 hours. After 18 hours, the reaction mixture was concentrated under reduced pressure. The resulting material was dissolved in ACN / water. The material was frozen and dried on a freeze dryer for 16 hours to provide the desired intermediate. LC / MS (m / z): 272 (M+H)+.

[1047] Step E: N-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)acetamide

[1048]

[1049] Acetic acid (21.10 μl, 0.369 mmol), HATU (210 mg, 0.553 mmol) and DMF (3686 μl) were added to a vial equipped with a stirring bar. The reaction mixture was stirred for 5 minutes. After 5 minutes, 1-(4-(aminomethyl)benzyl)-6-fluoro-1,3-dihydro-2H-benzo[d]imidazole-2-one (100 mg, 0.369 mmol) was added, followed by DIEA (193 μl, 1.106 mmol). The reaction mixture was stirred at room temperature for 24 hours. After 24 hours, the reaction mixture was filtered and used directly for HPLC purification (purified by HPLC, eluted with acetonitrile / water gradient containing alkaline modifier, linear gradient) to provide the title compound. LC / MS (m / z): 314 (M+H)+. 1 H NMR (600MHz, DMSO-d6) δ10.98 (s, 1H), 8.34-8.15 (m, 1H), 7.24 (dd, J=50.0, 8.0Hz, 4H), 6.99 (dd, J=9. 1, 2.4Hz, 1H), 6.97-6.90 (m, 1H), 6.83-6.73 (m, 1H), 4.95 (s, 2H), 4.18 (d, J=5.9Hz, 2H), 1.83 (s, 3H).

[1050] Embodiment 95:

[1051] Preparation of N-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)propane-1-sulfonamide

[1052]

[1053] Step A: N-(4-((6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)propane-1-sulfonamide

[1054]

[1055] 1-(4-(Aminomethyl)benzyl)-6-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.111 mmol), TEA (46.2 μl, 0.332 mmol) and DMF (1106 μl) were added to a vial equipped with a stirring bar. Finally, propane-1-sulfonyl chloride (17.35 mg, 0.122 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was filtered and used directly for HPLC purification (purified by HPLC, eluting with acetonitrile / water gradient containing a basic modifier, linear gradient) to provide the title compound. LC / MS (m / z): 378 (M+H)+. 1 H NMR (600MHz, DMSO-d6) δ10.99 (s, 1H), 7.55 (t, J=6.3Hz, 1H), 7.37-7.21 (m, 4H), 6.98 (dd, J=9.1, 2.4Hz, 1H), 6.96-6.93 (m , 1H), 6.80-6.75 (m, 1H), 4.97 (s, 2H), 4.09 (d, J=6.3Hz, 2H), 2.87-2.77 (m, 2H), 1.66-1.48 (m, 2H), 0.82 (t, J=7.4Hz, 3H).

[1056] Embodiment 96:

[1057] Preparation of 1-methoxy-N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)cyclopropane-1-carboxamide

[1058]

[1059] Step A: tert-Butyl (4-(((2-nitrophenyl)amino)methyl)benzyl)carbamate

[1060]

[1061] 1-Fluoro-2-nitrobenzene (2.242 ml, 21.26 mmol), tert-butyl (4-(aminomethyl)benzyl)carbamate (5024 mg, 21.26 mmol), K2CO3 (4408 mg, 31.9 mmol) and THF (100 ml) were added to a vial equipped with a stirring bar. The reaction mixture was sealed and heated to 80°C for 16 hours. After 16 hours, the crude material was washed with water and ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. LC / MS (m / z): 380 (M+H)+ (M+22 observed).

[1062] Step B: tert-Butyl (4-(((2-aminophenyl)amino)methyl)benzyl)carbamate

[1063]

[1064] Zinc (7645 mg, 117 mmol) and ethanol (3.99E+04 μl) were added to a vial equipped with a stirring bar. The vial was cooled to 0°C and acetic acid (6694 μl, 117 mmol) was added. The mixture was stirred for 5 minutes. After 5 minutes, tert-butyl (4-(((2-nitrophenyl)amino)methyl)benzyl)carbamate (7599 mg, 21.26 mmol) in ethanol (1.33E+04 μl) was added. The mixture was heated to 35°C for 10 minutes. After 10 minutes, the mixture was cooled to room temperature and filtered through diatomaceous earth, rinsed with ethyl acetate. The obtained material was concentrated under reduced pressure. The obtained residue was dissolved in DCM and loaded onto a 120 g silica gel column. The desired product was eluted; the fractions were collected and concentrated under reduced pressure to provide the title compound. LC / MS (m / z): 328 (M+H)+.

[1065] Step C: tert-Butyl (4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate

[1066]

[1067] tert-Butyl (4-(((2-aminophenyl)amino)methyl)benzyl)carbamate (3.57 g, 10.90 mmol), CDI (1.768 g, 10.90 mmol), TEA (4.56 ml, 32.7 mmol) and DMF (27.3 ml) were added to a round bottom flask equipped with a stirring bar. The reaction mixture was heated to 80°C for 16 hours. After 16 hours, the reaction mixture was washed with ethyl acetate and water. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. LC / MS (m / z): 298 (M+H)+ (loss of tert-butyl group was observed).

[1068] Step D: 1-(4-(Aminomethyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1069]

[1070] tert-Butyl (4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)carbamate (3.85 g, 10.89 mmol), HCl (16.34 ml, 65.4 mmol) and THF (27.2 ml) were added to a round bottom flask equipped with a stirring bar. The mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction mixture was heated to 40°C for 19 hours. After 19 hours, the reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. The material was triturated with ethyl acetate / hexanes / DCM. The material was filtered to give the title compound. LC / MS (m / z): 254 (M+H)+.

[1071] Step E: 1-methoxy-N-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzyl)cyclopropane-1-carboxamide

[1072]

[1073] 1-(4-(Aminomethyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.118 mmol), HATU (67.5 mg, 0.178 mmol) and DMF (1500 μl) were stirred at room temperature for 5 minutes. After 5 minutes, 1-(4-(aminomethyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (30 mg, 0.118 mmol) was added followed by DIEA (62.1 μl, 0.355 mmol). The reaction mixture was stirred at room temperature for 19 hours. After 19 hours, the reaction mixture was filtered and used directly for HPLC purification eluting with an acetonitrile / water gradient (linear gradient) containing a basic modifier to provide the title compound. LC / MS (m / z): 352 (M+H)+. 1 H NMR (600MHz, DMSO-d6) δ10.93 (s, 1H), 8.60 (t, J=6.2Hz, 1H), 7.31-7.17 (m, 4H), 7.0 2-6.90 (m, 4H), 4.96 (s, 2H), 4.28 (d, J=6.2Hz, 2H), 3.24 (s, 3H), 1.10-0.92 (m, 4H).

[1074] Embodiment 97:

[1075] Preparation of 1-(3-(quinolin-8-yloxy)propyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1076]

[1077] Step A: tert-Butyl (3-(quinolin-8-yloxy)propyl)carbamate

[1078]

[1079] Quinoline-8-alcohol (0.5g, 3.44mmol) and THF (10mL) are added to a vial equipped with a stirring rod. (3-hydroxypropyl) tert-butyl carbamate (0.604g, 3.44mmol), (E)-diazene-1,2-dicarboxylic acid di-tert-butyl ester (1.190g, 5.17mmol), diphenyl (p-tolyl) phosphine (1.428g, 5.17mmol) and (3-hydroxypropyl) tert-butyl carbamate (0.604g, 3.44mmol) are added to the reaction mixture and stirred at 0°C simultaneously. The reaction mixture is stirred at 80°C for 16 hours. After 16 hours, the reaction mixture is cooled to room temperature and concentrated under reduced pressure. Water (50mL) is added to residue and extracted with EtOAc (50mL*2). The combined organic layer is collected, washed with brine (30mL), dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo and purified by flash silica gel chromatography using ethyl acetate and petroleum ether as eluents to provide the title compound. MS (ESI) m / z: 303 [M+H + ].

[1080] Step B: 3-(Quinolin-8-yloxy)propan-1-amine

[1081]

[1082] Tert-butyl (3-(quinolin-8-yloxy)propyl)carbamate (830 mg, 2.74 mmol) and DCM (10 ml) were added to a vial equipped with a stirring bar. TFA (1.9 ml, 24.66 mmol) was added and the reaction mixture was stirred at 30° C. for 16 hours. After 16 hours, the reaction mixture was concentrated in vacuo to provide the title compound. MS (ESI) m / z: 203 [M+H + ].

[1083] Step C: 2-nitro-N-(3-(quinolin-8-yloxy)propyl)aniline

[1084]

[1085] 3-(Quinoline-8-yloxy)propan-1-amine (555mg, 2.74mmol) and THF (15mL) were added to a vial equipped with a stirring bar. 1-Fluoro-2-nitrobenzene (387mg, 2.74mmol) and K2CO3 (1138mg, 8.23mmol) were added, and the reaction mixture was heated to 80°C for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature. Water (80mL) was added, and the mixture was washed with EtOAc (30mL*3). The obtained organic layer was collected, washed with brine (20mL), dried over Na2SO4, and filtered. The obtained filtrate was concentrated in vacuo. The obtained residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent to provide the title compound. MS (ESI) m / z: 324 [M+H + ].

[1086] Step D: N 1 -(3-(Quinolin-8-yloxy)propyl)benzene-1,2-diamine

[1087]

[1088] 2-Nitro-N-(3-(quinolin-8-yloxy)propyl)aniline (150 mg, 0.464 mmol) and MeOH (5 mL) were added to a vial equipped with a stirring bar. NH4Cl (aqueous solution) (5 mL) and zinc (607 mg, 9.28 mmol) were added, and the reaction was stirred at 30 ° C for 16 hours. After 16 hours, water (50 mL) was added, and the resulting material was washed with EtOAc (30 mL * 2). The combined organic layers were collected, washed with brine (20 mL), dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography using ethyl acetate and petroleum ether as eluents to provide the title compound. MS (ESI) m / z: 294 [M+H + ].

[1089] Step E: 1-(3-(Quinolin-8-yloxy)propyl)-1H-benzo[d]imidazol-2(3H)-one

[1090]

[1091] N 1-(3-(Quinolin-8-yloxy)propyl)benzene-1,2-diamine (60 mg, 0.205 mmol) and THF (2.5 mL) were added to a vial equipped with a stirring bar. Triethylamine (0.34 mL, 2.439 mmol) and CDI (199 mg, 1.227 mmol) were added, and the reaction mixture was stirred at 80° C. for 15 hours. After 15 hours, the resulting residue was purified by HPLC (using water (0.1% TFA)-MeCN, mobile phase B acetonitrile, detection wavelength: 220 nm) on a GILSON 281 instrument equipped with Waters BostonGreen ODS 150*305u to provide the title compound. MS (ESI) m / z: 320 [M+H + ]. 1 H NMR (500MHz, CD3OD) δ9.15-9.08 (m, 2H) 8.07 (dd, J=8.4, 5.2Hz, 1H) 7.84-7.82 (m, 2H) 7.58-7.54 (m, 1H )7.19-7.16 (m, 1H) 6.04-7.98 (m, 3H) 4.41 (t, J = 5.7Hz, 2H) 4.26 (t, J = 6.7Hz, 2H) 2.45 (q, J = 6.3Hz, 2H).

[1092] Embodiment 98:

[1093] Preparation of N-(((1r,4r)-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)methyl)methanesulfonamide

[1094]

[1095] Step A: tert-Butyl (((1r,4r)-4-(aminomethyl)cyclohexyl)methyl)carbamate

[1096]

[1097] Tert-butyl (((1r, 4r)-4-(aminomethyl)cyclohexyl)methyl)carbamate (500mg, 2.063mmol) and DMF (10mL) were added to a vial equipped with a stirring bar. 1-Fluoro-2-nitrobenzene (349mg, 2.476mmol) and K2CO3 (570mg, 4.13mmol) were added, and the reaction mixture was stirred at 26°C for 16 hours. After 16 hours, water (80mL) was added and the mixture was washed with ethyl acetate (50mL*3). The combined organic layers were collected, dried over Na25O4, and filtered. The combined filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography using ethyl acetate and petroleum ether as eluents to provide the title compound. LCMS (ESI) m / z: 386 [M+Na] + .

[1098] Step B: tert-Butyl (((1r,4r)-4-(((2-aminophenyl)amino)methyl)cyclohexyl)methyl)carbamate

[1099]

[1100] Tert-butyl (((1r,4r)-4-(((2-nitrophenyl)amino)methyl)cyclohexyl)methyl)carbamate (700 mg, 1.926 mmol) and MeOH (20 mL) were added to a vial equipped with a stir bar. 10% Pd-C (70 mg) was added at 26°C and the reaction was stirred under hydrogen (15 psi) at 26°C for 2 hours. After 2 hours, the reaction was filtered and concentrated in vacuo to provide the title compound. LCMS (ESI) m / z: 278 [M+H-56] + .

[1101] Step C: tert-Butyl (((1r,4r)-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)methyl)carbamate

[1102]

[1103] Tert-butyl (((1r, 4r)-4-(((2-aminophenyl)amino)methyl)cyclohexyl)methyl)carbamate (600mg, 1.799mmol) and THF (10mL) were added to a vial equipped with a stirring bar. CDI (875mg, 5.40mmol) and TEA (1.52mL, 10.91mmol) were added, and the reaction mixture was heated to 80°C for 16 hours. After 16 hours, the reaction was cooled to room temperature. Water (40mL) was added, and the mixture was washed with ethyl acetate (30mL*3). The obtained organic layer was collected, dried over Na2SO4, and filtered. The obtained filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluents to provide the title compound. LCMS (ESI) m / z: 304 [M+H-56] + .

[1104] Step D: 1-(((1r,4r)-4-(aminomethyl)cyclohexyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

[1105]

[1106] Tert-butyl (((1r,4r)-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)methyl)carbamate (240 mg, 0.668 mmol) and DCM (4 mL) were added to a vial equipped with a stir bar. TFA (2 mL, 26.0 mmol) was added and the reaction mixture was stirred at 26 °C for 2 hours. After 2 hours, the solvent was concentrated in vacuo to provide the title compound. LCMS (ESI) m / z: 260 [M+H] + .

[1107] Step E: N-(((1r,4r)-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)methyl)methanesulfonamide

[1108]

[1109] 1-(((1r,4r)-4-(aminomethyl)cyclohexyl)methyl)-1H-benzo[d]imidazole-2(3H)-one (50 mg, 0.193 mmol) and DMF (2 mL) were added to a vial equipped with a stirring bar. TEA (0.08 mL, 0.574 mmol) and methanesulfonic anhydride (33 mg, 0.189 mmol) were added and the reaction was stirred at 26 °C for 16 hours. After 16 hours, the solvent was concentrated in vacuo. The resulting residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with Boston Green ODS 150×305u using water (0.1% TFA)-MeCN and acetonitrile as eluents and then lyophilized to provide the title compound. MS (ESI) m / z: 338 [M+H + ].

[1110] 1 H NMR (400MHz, CD3OD) δ7.15-7.00 (m, 4H), 3.73 (d, J=7.4Hz, 2H), 2.92-2.84 (m, 5H), 1.87-1.84 (m, 3H), 1.75-1.73 (m, 2H), 1.46 (br s, 1H), 1.19-1.05 (m, 2H), 1.01-0.89 (m, 2H).

[1111] Embodiment 99:

[1112] Preparation of N-((1r,4r)-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)acetamide

[1113]

[1114] Step A: tert-Butyl ((1s,4s)-4-(((2-nitrophenyl)amino)methyl)cyclohexyl)carbamate

[1115]

[1116] Tert-butyl ((1r, 4r)-4-(aminomethyl) cyclohexyl) carbamate (1 g, 4.38 mmol) and DMF (15 mL) were added to a vial equipped with a stirring bar. 1-Fluoro-2-nitrobenzene (0.742 g, 5.26 mmol) and K2CO3 (1.211 g, 8.76 mmol) were added, and the reaction was heated to 80 ° C for 16 hours. After 16 hours, water (100 mL) was added, and the mixture was washed with ethyl acetate (100 mL). The resulting organic layer was collected, dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluents to provide the title compound. MS (ESI) m / z: 294 [M+H + ](loss of tert-butyl group was observed).

[1117] Step B: tert-Butyl ((1s,4s)-4-(((2-aminophenyl)amino)methyl)cyclohexyl)carbamate

[1118]

[1119] Tert-butyl ((ls,4s)-4-(((2-nitrophenyl)amino)methyl)cyclohexyl)carbamate (500 mg, 1.431 mmol) and MeOH (10 mL) were added to a vial equipped with a stir bar. Pd-C (50 mg, 0.047 mmol) was added and the reaction was stirred under hydrogen (15 psi) at 26 °C for 4 hours. After 4 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to provide the title compound. MS (ESI) m / z: 320 [M+H+].

[1120] Step C: tert-Butyl ((1s,4s)-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)carbamate

[1121]

[1122] Tert-butyl ((1s, 4s)-4-(((2-aminophenyl)amino)methyl)cyclohexyl)carbamate (450 mg, 1.409 mmol) and THF (10 mL) were added to a vial equipped with a stirring bar. CDI (685 mg, 4.23 mmol) and TEA (1.2 mL, 8.61 mmol) were added, and the reaction was stirred at 80 ° C for 16 hours under nitrogen. After 16 hours, water (30 mL) was added, and the material was washed with ethyl acetate (30 mL*3). The obtained organic layer was collected, dried over Na2SO4, and filtered. The obtained filtrate was concentrated in vacuo. The obtained residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluents to provide the title compound. MS (ESI) m / z: 290 [M+H + ](loss of tert-butyl group was observed).

[1123] Step D: 1-(((1s,4s)-4-aminocyclohexyl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1124]

[1125] Tert-butyl ((1s,4s)-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)carbamate (200 mg, 0.579 mmol) and DCM (15 mL) were added to a vial equipped with a stir bar. TFA (8 mL, 104 mmol) was added and the reaction was stirred at 26 °C for 16 hours. After 16 hours, the solvent was concentrated in vacuo to provide the title compound. MS (ESI) m / z: 246 [M+H+].

[1126] Step E: N-((1s,4s)-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclohexyl)acetamide

[1127]

[1128] 1-(((1s,4s)-4-aminocyclohexyl)methyl)-1H-benzo[d]imidazole-2(3H)-one (70 mg, 0.285 mmol) in DMF (2 mL) was added to a vial equipped with a stirring bar. TEA (0.14 mL, 1.004 mmol) and acetic anhydride (30 mg, 0.294 mmol) were added and the reaction was stirred at 26°C for 16 hours. After 16 hours, the solvent was concentrated in vacuo. The resulting residue was purified by reverse phase HPLC on a GILSON 281 instrument equipped with Waters XSELECT C18 150*30mm*5um using water (0.1% TFA)-MeCN and acetonitrile as eluents, followed by lyophilization to provide the title compound. MS (ESI) m / z: 288 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.59 (br s, 1H), 7.14-7.07 (m, 3H), 6.98 (d, J=7.0Hz, 1H), 5.25 (br d, J=8.0Hz, 1H), 3.72 (d, J=7.0Hz, 2H), 3.80-3.66 (m, 1H), 2.06-1.98 (m, 2 H), 1.95 (s, 3H), 1.82-1.78 (m, 3H), 1.27-1.21 (m, 2H), 1.09-1.06 (m, 2H).

[1129] Embodiment 100:

[1130]

[1131] Step A: 2-(4-bromobenzyl)-1,3,4-oxadiazole

[1132]

[1133] 2-(4-bromophenyl)acetohydrazide (2.7g, 11.79mmol) and xylene (10mL) were added to a tubular bottle equipped with a stirring rod. AcOH (2mL) and triethoxymethane (3.49g, 23.57mmol) were added at 26°C (room temperature). The reaction was sealed and heated to 150°C for 5 hours. After 5 hours, the reaction was cooled to room temperature. Water (30mL) was added to the reaction mixture, and the material was washed with EtOAc (30mL x 2). The obtained organic layer was collected, washed with brine, dried over Na2SO4, and filtered. The obtained filtrate was concentrated in vacuo. The obtained residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent to provide the title compound. LCMS (ESI) m / z: 239 [M+H] + .

[1134] Step B: tert-Butyl (4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)carbamate

[1135]

[1136] Potassium (((tert-butoxycarbonyl)amino)methyl)trifluoroborate (927 mg, 3.91 mmol), 2-(4-bromobenzyl)-1,3,4-oxadiazole (850 mg, 3.56 mmol), dioxane (20 mL) and water (2 mL) were added to a vial equipped with a stirring bar. K2CO3 (1474 mg, 10.67 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (339 mg, 0.711 mmol) and palladium (II) acetate (80 mg, 0.356 mmol) were added and the vial was sealed and heated to 110°C under nitrogen. The reaction was stirred for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature and water (20 mL) was added. The material was washed with EtOAc (20 mL×3), the organic layer was collected, washed with brine (10 mL), dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography using ethyl acetate and petroleum ether as eluents to provide the title compound. MS (ESI) m / z: 290 [M+H] + .

[1137] Step C: (4-((1,3,4-oxadiazol-2-yl)methyl)phenyl)methanamine

[1138]

[1139] Tert-butyl 4-((1,3,4-oxadiazol-2-yl)methyl)benzylcarbamate (250 mg, 0.864 mmol) in DCM (10 mL) was added to a vial equipped with a stirring bar. TFA (1 mL, 12.98 mmol) was added at 0°C, and the reaction was stirred at 0°C for 2 hours. After 2 hours, NaHCO3 aqueous solution (~5 mL) was added to adjust the pH to ~9. The mixture was then diluted with water (~10 mL) and extracted with DCM (25 mL×6). The resulting organic layer was collected, dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo to provide the title compound. LCMS (ESI) m / z: 190 [M+H] + .

[1140] Step D: N-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-4-chloro-2-nitroaniline

[1141]

[1142] (4-((1,3,4-oxadiazole-2-yl)methyl)phenyl)methylamine (150mg, 0.80mmol) and DMF (5mL) were added to a vial equipped with a stirring bar. K2CO3 (220mg, 1.6mmol) and 4-chloro-1-fluoro-2-nitrobenzene (153mg, 0.87mmol) were added to the reaction mixture, and the reaction mixture was heated to 50°C for 6 hours. After 6 hours, water (30mL) was added, and the reaction mixture was extracted with ethyl acetate (10mL×3). The obtained organic layer was collected, dried over Na2SO4, and filtered. The obtained filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluents. LCMS (ESI) m / z: 367 [M+Na] + .

[1143] Step E: N1-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-4-chlorobenzene-1,2-diamine

[1144]

[1145] N-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-4-chloro-2-nitroaniline (113 mg, 0.33 mmol) and MeOH (5 mL) were added to a vial equipped with a stirring bar. Saturated NH4Cl aqueous solution (5 mL) and zinc (430 mg, 6.6 mmol) were added at room temperature, and the reaction was stirred for 5 hours. After 5 hours, water (10 mL) was added. The resulting mixture was extracted with ethyl acetate (10 mL×3). The resulting organic layer was collected, dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo to provide the title compound. LCMS (ESI) m / z: 315 [M+H] + .

[1146] Step F:

[1147]

[1148] N1-(4-((1,3,4-oxadiazol-2-yl)methyl)benzyl)-4-chlorobenzene-1,2-diamine (82 mg, 0.26 mmol) in THF (5 mL) was added to a vial equipped with a stirring bar. TEA (160 mg, 1.6 mmol) and CDI (127 mg, 0.78 mmol) were added and the reaction was heated to 80°C and stirred for 16 hours. After 16 hours, the solvent was concentrated in vacuo. The resulting residue was purified by reverse phase HPLC with water and acetonitrile as eluents and ammonium hydroxide as alkaline modifier. Lyophilization provided the title compound. LCMS (ESI) m / z: 341 [M+H] + . 1 H NMR (500 MHz, methanol-d4) δ 8.82 (s, 1H); 7.30 (s, 4H); 7.08 (d, J=1.98 Hz, 1H); 6.97-7.01 (m, 1H); 6.91-6.94 (m, 1H); 5.05 (s, 2H); 4.26 (s, 2H).

[1149] Embodiment 101:

[1150] Preparation of 3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-N-(2,2,2-trifluoroethyl)benzamide

[1151]

[1152] 3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)benzoic acid (9.3 mg, 0.037 mmol) (Intermediate 4) was added to a vial containing 2,2,2-trifluoroethane-1-amine hydrochloride (11.1 mg, 0.082 mmol). DMA (0.40 mL) was added followed by propylphosphonic anhydride, cyclic trimer (23.5 mg, 0.074 mmol) and DIPEA (0.032 mL, 0.185 mmol). The mixture was then stirred at room temperature for 18 hours. After 18 hours, the reaction mixture was filtered and the residue was purified by HPLC (gradient elution with acetonitrile / water with TFA modifier). 1 H NMR (500MHz, DMSO-d6) δ11.00 (s, 1H), 9.11 (t, J=6.2Hz, 1H), 7.82 (s, 1H), 7.76 (d, J =7.1Hz, 1H), 7.49-7.42(m, 2H), 7.03-6.91(m, 4H), 5.05(s, 2H), 4.10-4.00(m, 2H). LCMS(ESI)m / z:350[M+H + ].

[1153] Embodiment 102:

[1154] Preparation of 1-(3-(azetidine-1-carbonyl)benzyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1155]

[1156] Utilizing the same procedure shown in Example 101 with the corresponding amine (azetidine) provided the title compound. 1 H NMR (500MHz, DMSO-d6) δ11.00 (s, 1H), 7.54-7.35 (m, 4H), 7.08-6.91 (m, 4H), 5. 04 (s, 2H), 4.18 (t, J=7.6Hz, 2H), 4.00 (t, J=7.7Hz, 2H), 2.21 (p, J=7.7Hz, 2H). LCMS(ESI)m / z:308[M+H + ].

[1157] Embodiment 103:

[1158] Preparation of 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-N-(pyridin-3-yl)acetamide

[1159]

[1160] Utilizing the same procedure shown in Example 101, 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid (Intermediate 5) and 3-aminopyridine were elaborated to the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.41 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.25 (dd, J = 4.7, 1.3 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.36-7.27 (m, 3H), 7.25-7.17 (m, 2H), 7.03-6.86 (m, 4H), 4.99 (s, 2H), 3.63 (s, 1H) (1H is missing due to overlap with water peak). LCMS (ESI) m / z: 359 [M+H + ].

[1161] Embodiment 104:

[1162] Preparation of N-(3-cyanophenyl)-2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetamide

[1163]

[1164] Utilizing the same procedure shown in Example 101, 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid (Intermediate 5) and 3-aminobenzonitrile were elaborated to the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.52 (s, 1H), 8.03 (s, 1H), 7.76 (dt, J = 7.1, 2.3 Hz, 1H), 7.54-7.49 (m, 2H), 7.31-7.27 (m, 2H), 7.25-7.17 (m, 2H), 7.01-6.94 (m, 3H), 6.92-6.88 (m, 1H), 4.98 (s, 2H), 3.63 (s, 1H) (1H is missing due to overlap with water peak). LCMS (ESI) m / z: 383 [M+H + ].

[1165] Embodiment 105:

[1166] Preparation of N,N-dimethyl-2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetamide

[1167]

[1168] Utilizing the same procedure shown in Example 101, 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid (Intermediate 5) and 3-aminobenzonitrile were elaborated to the title compound. 1 H NMR (500MHz, CDCl3) δ 8.71 (s, 1H), 7.24-7.15 (m, 3H), 7.09-6.99 (m, 3H), 6.88 (d, J = 7.5Hz, 1H), 5.06 (s, 2H), 3.69 (s, 2H), 2.95 (s, 6H). LCMS (ESI) m / z: 310[M+H]+.

[1169] Embodiment 106:

[1170] Preparation of N-(3-fluorocyclopentyl)-2-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetamide

[1171]

[1172] Using the same procedure shown in Example 101, 2-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid (Intermediate 6) and (3-fluorocyclopentyl)-λ 2 The -azane was elaborated to the title compound. 1 H NMR (500MHz, DMSO-d6) δ10.97 (s, 1H), 8.18 (d, J=7.0Hz, 1H), 7.23-7.16 (m, 4H), 7.03-6.91 (m, 4H), 5.23-5.08 (m, 1H), 4.95 (s, 2H), 4.16-4.08 (m, 1H), 3.31 (s, 2H), 2.14-1.91 (m, 3H), 1.80-1.55 (m, 2H), 1.43-1.36 (m, 1H). LCMS(ESI)m / z:368[M+H + ].

[1173] Embodiment 107:

[1174] Preparation of N-methyl-2-(4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetamide

[1175]

[1176] Using the same procedure as shown in Example 101, 2-(3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)acetic acid (Intermediate 5) and methylamine hydrochloride were elaborated to the title compound. MS (ESI) m / z: 296 [M+H + ]. 1 H NMR (500MHz, CD3OD) δ7.33-7.20 (m, 4H), 7.12-6.93 (m, 4H), 5.06 (s, 2H), 3.47 (s, 2H), 2.72-2.65 (m, 3H).

[1177] The examples in Table 13 were synthesized according to the method described in Example 107 using the corresponding amine starting materials.

[1178] Table 13

[1179]

[1180] Embodiment 109:

[1181] Preparation of 1-benzyl-5-ethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1182]

[1183] Step A: 1-Benzyl-5-ethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1184]

[1185] Brettphos Pd G3 (30.2 mg, 0.033 mmol), potassium phosphate (339 mg, 1.598 mmol), 2-bromo-1-chloro-4-ethylbenzene (219 mg, 0.999 mmol) and 1-benzylurea (100 mg, 0.666 mmol) were added to a vial equipped with a stirring bar. The vial was purged with nitrogen and t-BuOH (6659 μl) was added to the reaction flask. The vial was sealed and heated to 110° C. for 19 hours. After 19 hours, the crude was washed with ethyl acetate and saturated NaHCO3. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and loaded onto a 40 g column. The column was run from 100% hexane to 100% ethyl acetate. The desired product was eluted; the fractions were collected and concentrated under reduced pressure. The resulting material was dissolved in ACN / water; frozen and dried on a freeze dryer for 16 hours to provide the title compound. LC / MS (m / z): 253 (M+H)+. 1 H NMR (600MHz, DMSO-d6) δ10.87 (s, 1H), 7.39-7.27 (m, 4H), 7.27-7.20 (m, 1H), 6.89 (d, J=7.9Hz, 1H ), 6.82 (s, 1H), 6.77 (d, J=7.8Hz, 1H), 4.96 (s, 2H), 2.56 (q, J=7.4Hz, 2H), 1.13 (t, J=7.5Hz, 3H).

[1186] The examples in Table 14 were synthesized according to the procedure described in Example 109 using the appropriate Br / Cl benzene starting materials.

[1187] Table 14:

[1188]

[1189] Embodiment 111:

[1190] Preparation of 1-((2-(5-methylpyridin-2-yl)cyclopropyl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1191]

[1192] Step A: (E)-tert-butyl 3-(3-(5-methylpyridin-2-yl)allyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[1193]

[1194] (E)-2-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (755mg, 1.886mmol), CH3CN (2mL) and water (0.2mL) were added to a vial equipped with a stirring bar. K3PO4 (801mg, 3.77mmol), 2-bromo-5-methylpyridine (397mg, 2.263mmol) and Pd(dtbpf)Cl2 (49mg, 0.075mmol) were added to the vial. The vial was sealed and heated to 105°C for 15 hours. After 15 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent to provide the title compound. LC / MS (ESI) m / z: 366 [M+H] + .

[1195] Step B: tert-Butyl 3-((2-(5-methylpyridin-2-yl)cyclopropyl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[1196]

[1197] 1-Methyl-1-nitrosourea (815 mg, 7.91 mmol) was added to a conical flask containing a cooled (cooled to 0°C in an ice bath) mixture of Et2O (20 mL) and 40% aqueous KOH (4.2 mL). The resulting mixture was allowed to stand for 30 min and was carefully shaken several times. The resulting organic phase was decanted and dried (with KOH pellets) at 0°C for 1 hour. After 1 hour, tert-butyl (E)-3-(3-(5-methylpyridin-2-yl)allyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (289 mg, 0.791 mmol) and diacetoxypalladium (17.76 mg, 0.079 mmol) were dissolved in Et2O (10 mL) and cooled to 0°C. A solution of diazomethane in Et2O was added dropwise. The reaction was stirred at 20°C (room temperature) for 15 hours. After 15 hours, CH3COOH (5 mL) was added. The resulting crude material provided the title compound. LC / MS (ESI) m / z: 380 [M+H] + .

[1198] Step C: 1-((2-(5-methylpyridin-2-yl)cyclopropyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

[1199]

[1200] Tert-butyl 3-((2-(5-methylpyridin-2-yl)cyclopropyl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate (150 mg, 0.395 mmol) and CH2Cl2 (10 mL) were added to a vial equipped with a stirring bar. 2,2,2-Trifluoroacetic acid (135 mg, 1.186 mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. After 15 hours, the reaction mixture was concentrated in vacuo. The resulting residue was filtered and purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex Synergi C18 (250*21.2 mm*4 μm) using water (0.1% TFA) and acetonitrile as eluents (mobile phase A water (0.1% TFA), mobile phase B acetonitrile, detection wavelength: 220 nm), followed by lyophilization to provide the title compound. LC / MS (ESI) m / z: 280 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.27 (br s, 1H), 8.61 (s, 1H), 7.88 (br d, J=7.9Hz, 1H), 7.20 (d, J=8.2Hz, 1H), 7.14-7.09 (m, 3H), 4.04-4.02 (m, 2H), 2.71- 2.63 (m, 1H), 2.43 (s, 3H), 2.05-1.95 (m, 1H), 1.56-1.49 (m, 1H), 1.46-1.40 (m, 1H).

[1201] Step D: 1-((2-(5-methylpyridin-2-yl)cyclopropyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

[1202]

[1203] Preparative separation of 1-((2-(5-methylpyridin-2-yl)cyclopropyl)methyl)-1H-benzo[d]imidazol-2(3H)-one was performed using supercritical fluid chromatography. A Chiralpak AS-H column (10 μm, 30 mm × 250 mm, Chiral Technologies, West Chester, PA) was used as the chiral stationary phase. The following gradient SFC conditions were used for injection and collection: A: CO2, B: 0.1% NH3·H2OMeOH, gradient: 5% to 40% B, 220 nm UV wavelength, 100 bar outlet pressure, 38°C column compartment temperature, 80 mL / min total flow rate. The retention times for peak collection were as follows: first eluting peak, 3.6 min; second eluting peak, 4.0 min. The title compound was provided as Peak 2. LC / MS (ESI) m / z: 280 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.43 (br s, 1H), 8.22 (s, 1H), 7.30 (br d, J=7.8Hz, 1H), 7.11-7.08 (m, 3H), 7.08-7.04 (m, 1H), 7.02 (d, J=7.9Hz, 1H), 4.03-3.92 (m, 2 H), 2.24 (s, 3H), 2.19-2.15 (m, 1H), 1.92-1.81 (m, 1H), 1.30-1.25 (m, 1H), 1.16-1.11 (m, 1H).

[1204] Embodiment 112:

[1205] Preparation of 1-benzyl-1,3-dihydro-2H-thieno[2,3-d]imidazol-2-one

[1206]

[1207] Step A: 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione

[1208]

[1209] 3-aminothiophene-2-carboxylic acid (736mg, 2.57mmol) and dioxane (15ml) are added in a vial equipped with a stirring rod and heated to 70°C under argon. Triphosgene (305mg, 1.03mmol) is added in small portions over 20 minutes. The resulting solution is stirred at 70°C for 1 hour. After 1 hour, the reaction mixture is concentrated in a vacuum. Residue is purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluent to provide the title compound. 1H NMR (400MHz, DMSO-d6) δ12.24 (br s, 1H), 8.24 (d, J=5.5Hz, 1H), 6.94 (d, J=5. 1 Hz, 1H).

[1210] Step B: 1-Benzyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione

[1211]

[1212] 1H-thieno[3,2-d][1,3]oxazine-2,4-dione (230 mg, 1.360 mmol) and DMF (4 mL) were added to a vial equipped with a stirring bar. K2CO3 (225 mg, 1.632 mmol) and (bromomethyl)benzene (233 mg, 1.360 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL×2). The resulting organic layer was collected, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to provide the title compound. 1 H NMR (400MHz, DMSO-d6) δ 8.28 (d, J=5.5Hz, 1H), 7.42-7.34 (m, 5H), 7.25 (d, J=5.1Hz, 1H), 5.21 (s, 2H).

[1213] Step C: 3-(Benzylamino)thiophene-2-carbonyl azide

[1214]

[1215] 1-Benzyl-1H-thieno[3,2-d][1,3]oxazine-2,4-dione (50 mg, 0.193 mmol) in acetone (5 mL) was added to a vial equipped with a stirring bar. Sodium azide (63 mg, 0.969 mmol) in water (0.5 mL) was added, and the reaction mixture was stirred at 20 ° C (room temperature) for 15 hours. After 15 hours, the reaction mixture was concentrated in vacuo. The obtained residue was treated with water (50 mL). The obtained material was filtered, washed with ether (30 mL), dried, and concentrated in vacuo. The obtained residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluents to provide the title compound. LCMS (ESI) m / z: 259 [M+H] + .

[1216] Step D: 1-Benzyl-1H-thieno[2,3-d]imidazol-2(3H)-one

[1217]

[1218] 3-(Benzylamino)thiophene-2-carbonyl azide (72 mg, 0.279 mmol) in toluene (5 mL) was added to a vial equipped with a stirring bar. The reaction mixture was heated to 110° C. for 15 hours. After 15 hours, the mixture was concentrated in vacuo. The resulting residue was filtered and purified by reverse phase HPLC on a GILSON 281 instrument equipped with a Phenomenex Synergi C18 (250*21.2 mm*4 μm) using water (0.1% TFA) and acetonitrile as eluents (mobile phase A water (0.1% TFA), mobile phase B acetonitrile, detection wavelength: 220 nm), followed by freeze drying to provide the title compound. LCMS (ESI) m / z: 231 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 7.38-7.24 (m, 5H), 6.92 (d, J=5.4Hz, 1H), 6.80 (d, J=5.1Hz, 1H), 4.92 (s, 2H).

[1219] The examples in Table 15 were synthesized according to the method described in Example 112 using the corresponding commercially available starting materials in Step B.

[1220] Table 15

[1221]

[1222] Embodiment 114:

[1223] Preparation of 1-(4-(quinolin-8-yl)butyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1224]

[1225] Step A: tert-Butyl 3-(3-iodopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[1226]

[1227] 1,3-Diiodopropane (3.79 g, 12.81 mmol) and DMF (20 mL) were added to a vial equipped with a stirring bar. 2-Oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (1.0 g, 4.27 mmol) and K2CO3 (0.885 g, 6.40 mmol) were added, and the reaction was stirred at 30 ° C for 16 hours. After 16 hours, the mixture was concentrated and diluted with water (150 mL). The material was washed with ethyl acetate (80 mL×3), and the combined organic layer was washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo, and the residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluents to provide the title compound. MS (ESI) m / z: 347 [M+H+] (loss of tert-butyl was observed).

[1228] Step B: (3-(3-(tert-Butoxycarbonyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)triphenylphosphonium iodide

[1229]

[1230] 3-(3-iodopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (200mg, 0.497mmol) and toluene (5mL) are added to a vial equipped with a stirring rod. Triphenylphosphine (143mg, 0.547mmol) is added, and the reaction is heated to 110°C under nitrogen for 16 hours. After 16 hours, the mixture is filtered and washed with toluene (3mL×3). The resulting material is concentrated in a vacuum to provide the title compound. 1 H NMR (500MHz, CDCl3) δ7.83-7.60 (m, 15H), 7.55 (d, J=8.0Hz, 1H), 7.17-7.15 (m, 1H), 7.12-7.09 (m, 1H), 7.04-6.99 (m, 1H), 4.34 (br t, J=7.0Hz, 2H), 3.98-3.89(m, 2H), 2.22-2.15(m, 2H), 1.64(s, 9H)

[1231] Step C: tert-Butyl 2-oxo-3-(4-(quinolin-8-yl)but-3-en-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylate

[1232]

[1233] (3-(3-(tert-butoxycarbonyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)triphenylphosphonium iodide (660 mg, 0.993 mmol) and DMSO (8 mL) were added to a vial equipped with a stirring bar. Potassium tert-butoxide (121 mg, 1.075 mmol) and quinoline-8-carboxaldehyde (130 mg, 0.827 mmol) were added, and the reaction was stirred at 30 ° C for 16 hours. After 16 hours, the mixture was concentrated and diluted with water (150 mL). The resulting material was extracted with ethyl acetate (80 mL×3), and the combined organic layers were collected, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo to provide the title compound. MS (ESI) m / z: 416 [M+H + ].

[1234] Step D: (E)-1-(4-(Quinolin-8-yl)but-3-en-1-yl)-1H-benzo[d]imidazol-2(3H)-one

[1235]

[1236] 2-Oxo-3-(4-(quinolin-8-yl)but-3-ene-1-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-carboxylic acid tert-butyl ester (350 mg, 0.842 mmol) and DCM (5 mL) were added to a vial equipped with a stirring bar. TFA (5 mL, 64.9 mmol) was added, and the reaction was stirred at 30 ° C for 16 hours. After 16 hours, the mixture was concentrated under reduced pressure. Water (150 mL) was added, and the material was washed with ethyl acetate (80 mL×3). The obtained organic layer was collected, washed with brine, dried over Na2SO4, and filtered. The obtained filtrate was concentrated in vacuo. The obtained residue was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluents to provide the title compound. MS (ESI) m / z: 316 [M+H + ]. 1 H NMR (500MHz, CDCl3) δ9.18 (br d, J=4.5Hz, 1H), 8.75 (br s, 1H), 8.38 (d, J=8.0Hz, 1H), 7.86 (d, J=6.5Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.63-7.54 (m, 3H), 7.16-7.01 (m, 4H), 6.40 (dd, J=7.0, 15.5Hz, 1H), 4.15 (t, J=7.0Hz, 2H), 2.84 (q, J=7.0Hz, 2H).

[1237] Step E: 1-(4-(Quinolin-8-yl)butyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1238]

[1239] (E)-1-(4-(Quinolin-8-yl)but-3-en-1-yl)-1H-benzo[d]imidazol-2(3H)-one (35 mg, 0.111 mmol) and MeOH (2 mL) were added to a vial equipped with a stir bar. Pd / C (5 mg, 0.047 mmol) was added at 25°C and the reaction was stirred at 25°C under H2 (15 psi) for 1 hour. After 1 hour, the reaction mixture was filtered and washed with MeOH. The resulting filtrate was purified by preparative HPLC (method, column: Boston Green ODS 150×305u, conditions: water (0.1% TFA)-ACN, start B 22, end B 52, gradient time (min) 10, 100% B hold time (min) 2, flow rate (mL / min) 25, injection 2) to provide the title compound. MS (ESI) m / z: 318 [M+H + ].

[1240] 1 HNMR (500MHz, CDCl3) δ10.59 (br s, 1H), 9.62 (br d, J=4.5Hz, 1H), 8.68 (d, J=7.5Hz, 1H), 7.95-7.87 (m, 2H), 7.80 (d, J=6.5 Hz, 1H), 7.72-7.66 (m, 1H), 7.20-7.14 (m, 1H), 7.12-6.98 (m, 3H), 4.08 (br t, J=6.5Hz, 2H), 3.50-3.37(m, 2H), 2.02-1.91(m, 2H), 1.76-1.62(m, 2H).

[1241] Embodiment 115:

[1242] Preparation of 1-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1243]

[1244] Step A: tert-Butyl 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidine-1-carboxylate

[1245]

[1246] 1H-benzo[d]imidazole-2(3H)-one (500mg, 3.73mmol) and DMF (15ml) were added to a vial equipped with a stirring bar. NaH (142mg, 3.54mmol) was added, and the mixture was stirred for 30 minutes. After 30 minutes, tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (1037mg, 3.73mmol) was added dropwise while stirring at 0°C. After the addition was completed, the reaction was stirred at 25°C for 16 hours. After 16 hours, water (40mL) was added, and the mixture was washed with EtOAC (50mL*3). The combined organic layers were collected, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated in vacuo. The resulting material was purified by flash silica gel chromatography with ethyl acetate and petroleum ether as eluents, and concentrated under reduced pressure to provide the title compound. LCMS(ESI)m / z:276[M+H] + (Loss of the tert-butyl group was observed).

[1247] Step B: 1-(Piperidin-4-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1248]

[1249] 4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (230mg, 0.694mmol) and DCM (20ml) were added to a vial equipped with a stirring bar. TFA (2ml, 26.0mmol) was added and the mixture was stirred at 25°C for 16 hours. After 16 hours, water (100mL) was added and the material was washed with ethyl acetate (50mL x 3). The obtained organic layer was collected, washed with brine, dried over Na2SO4, and filtered. The obtained filtrate was concentrated in vacuo. The obtained residue was used in the next step without further purification. LCMS (ESI) m / z: 232[M+H] + .

[1250] Step C: 1-((1-(pyridin-2-yl)piperidin-4-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1251]

[1252] 2-Fluoropyridine (12.59 mg, 0.130 mmol) and DMF (2 mL) were added to a vial equipped with a stirring bar. 1-(piperidin-4-ylmethyl)-1H-benzo [d] imidazole-2 (3H)-one (30 mg, 0.130 mmol) and K2CO3 (17.93 mg, 0.130 mmol) were added at 20 ° C under nitrogen. The reaction was stirred at 120 ° C for 16 hours. After 16 hours, the reaction was cooled to room temperature. The mixture was filtered and concentrated in a vacuum. The obtained residue was purified by preparative HPLC (column Boston Green ODS 150*30mm*5um, condition: water (0.1% TFA)-MeCN, start B 47, end B67, gradient time (min) 10, 100% B holding time (min) 2, flow rate (mL / min) 25) to provide the title compound. LCMS (ESI) m / z: 309 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.00-7.90 (m, 1H), 7.89-7.87 (m, 1H), 7.39 (d, J = 9.4 Hz, 1H), 7.22-7.15 (m, 1H), 7.14-7.06 (m, 3H), 6.95 (t, J = 6.7 Hz, 1H), 4.18 (br d, J = 13.7 Hz, 2H), 3.86-3.84 (m, 2H), 3.29-3.21 (m, 2H), 2.36-2.32 (m, 1H), 1.91-1.87 (m, 2H), 1.56-1.45 (m, 2H).

[1253] Determination

[1254] IL4I1 enzymatic assay

[1255] Interleukin 4-induced protein 1 (IL411) is an L-amino oxidase that catalyzes the oxidation of aromatic residues (Phe, Trp, and Tyr): L-amino acid + H2O + O2 → 2-oxo acid + NH3 + H2O2. When IL4I1 and substrate are added, equimolar amounts of H2O2 and the corresponding α-keto acid are produced. In this assay, the hydrogen peroxide produced by IL4I1 is subsequently detected by a coupled reaction with Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine) and horseradish peroxidase (HRP) to produce a resorufin product that can be detected as a fluorescent signal. The inhibitory effect of small molecules on IL4I1 is measured by the effectiveness of the compound in inhibiting the production of H2O2 (EC 50 ) assessment.

[1256] Using this assay, the potency (EC) of each compound was determined from a 10-point (1:3 serial dilution) titration curve using the procedure outlined below. 50 ). 25 nL of compound (0.1% DMSO, final assay volume of 25 μL) was dispensed into each well of a black flat-bottom Greiner (Cat. No. 781076) 384-well plate, followed by the addition of 12.5 μL of 1x assay buffer (50 mM Hepes 7.0 and 0.005% Tween 20 (Sigma, Cat. No. P8341; low peroxide grade)) containing 2 nM of recombinant IL4I1 (R&D Systems, Cat. No. 5684-AO-020). The plate was pre-incubated with the compound in an ambient temperature controlled humidity chamber for 4 hours. Subsequently, each reaction was started by adding 12.5 μL of 1x assay buffer containing 2 mM of each aromatic amino acid (Phe / Tyr / Trp), 0.1 mM Amplex Red, and 2 U / mL of HRP. The final reaction of 25 μL in each well consisted of 1 nM IL4I1, 1 mM of each residue (Phe, Tyr and Trp), 0.05 mM Amplex Red and 1 U / mL HRP. It should be noted that the concentrations of Amplex Red and HRP used here were in excess so that the conversion of H2O2 to the resorufin product occurred instantaneously and was not rate limited. The reaction was allowed to proceed for 120 minutes and then the fluorescence was read on a Spectramax using the following settings: 544 nm excitation / 590 nm emission, 570 nm cutoff (EnVision is an alternative reader). The fluorescence was measured relative to the Log 10 Dose-response curves were generated by plotting the percent effect (% product conversion; Y-axis) against compound concentration (X-axis). EC was calculated using a nonlinear regression, four-parameter sigmoidal dose-response model. 50 The values ​​are shown in Table 16.

[1257] Table 16:

[1258]

[1259]

[1260]

[1261]

[1262]

Claims

1. A compound having formula Ia or a pharmaceutically acceptable salt thereof in, A is phenyl; L is a linear or branched (C1-C5) alkylene group; R 1 Each occurrence of is independently halogen, C1-C6 alkyl or pyrrolidinyl; R 2 Each occurrence of is independently R 3 is hydrogen, C1-C6 alkyl or halogenated C1-C6 alkyl; m is 0 or 1; and n is 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -CH2CH2-, -CH2CH2CH2CH2- or -CHCH3-.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 1 is fluoro, chloro, pyrrolidinyl, methyl or ethyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, methyl or difluoromethyl.

6. A compound selected from: or a pharmaceutically acceptable salt thereof.

7. Use of the compound according to claim 1 or claim 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer by inhibiting IL4I1.

8. A pharmaceutical composition comprising the compound according to claim 1 or claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising the compound according to claim 1 or claim 6 and a pharmaceutically acceptable carrier.

10. Compounds having the following structure 11. Compounds having the following structure or a pharmaceutically acceptable salt thereof.

12. Use of the compound according to claim 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer by inhibiting IL4I1.

13. A pharmaceutical composition comprising the compound according to claim 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising the compound according to claim 10 and a pharmaceutically acceptable carrier.

15. Compounds with the following structure 16. Compounds having the following structure or a pharmaceutically acceptable salt thereof.

17. Use of the compound according to claim 16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer by inhibiting IL4I1.

18. A pharmaceutical composition comprising the compound according to claim 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising the compound according to claim 15 and a pharmaceutically acceptable carrier.

20. Compounds with the following structure 21. Compounds with the following structure or a pharmaceutically acceptable salt thereof.

22. Use of the compound according to claim 21 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer by inhibiting IL4I1.

23. A pharmaceutical composition comprising the compound according to claim 21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising the compound according to claim 20 and a pharmaceutically acceptable carrier.

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