ATM kinase inhibitors

Abstract

The present invention relates to general formula (Ia) or general formula (Ib): The compound JPEG2026511081000404.jpg33134, pharmaceutical compositions containing the compound, and their use in the treatment of diseases (particularly cancer) are disclosed. Furthermore, methods for treating diseases in humans or warm-blooded animals or mammals that require intervention on ATM kinase, e.g., inhibition, control, and / or modulation of ATM kinase, are disclosed.

Description

[Technical Field]

[0001] This invention relates to the treatment of disorders, particularly cancer. Specifically, this application relates to an inhibitor of ataxia telangiectasia mutation (ATM) protein kinase. [Background technology]

[0002] ATM is a promising target for cancer therapy because it is an important regulator of the cellular response to DNA double-strand breaks. It may be possible to confer sensitivity to DNA damage therapy to cancer cells or enhance the effects of drug-targeted proteins in the DNA damage response (DDR) (Zimmermann, A. et al., A New Class of Selective ATM Inhibitors as Combination Partners of DNA Double-Strand Break Inducing Cancer Therapies. Molecular cancer therapeutics 2022, 21 (6), 859-870. DOI: 10.1158 / 1535-7163.mct-21-0934 PubMed; Sarkaria, JN; Eshleman, JS ATM as a target for novel radiosensitizers. Semin Ra-diat Oncol 2001, 11 (4), 316-327. DOI: 10.1053 / srao.2001.26030 (obtained from the U.S. National Library of Medicine (NLM)). ATM is itself part of DDR and a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, but it has a relatively large size of 370 kDa, and the kinase domain constitutes a very small portion of this protein (Canman, CE et al., Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53. Science 1998, 281 (5383), 1677-1679. DOI: 10.1126 / science.281.5383.1677; Chen, G.; Lee, E. The product of the ATM gene is a 370-kDa nuclear phosphoprotein. J Biol Chem 1996, 271 (52), 33693-33697. DOI: 10.1074 / jbc.271.52).(33693; obtained from NLM). Inactive homodimers of ATM are mainly found in the cell nucleus (Chen, G.; Lee, E. The product of the ATM gene is a 370-kDa nuclear phosphoprotein. J Biol Chem 1996, 271 (52), 33693-33697. DOI: 10.1074 / jbc.271.52.33693; obtained from NLM; Bakkenist, CJ; Kastan, MB DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003, 421 (6922), 499-506. DOI: 10.1038 / nature01368). When DNA undergoes a double-strand break (DBS), the MRE11-RAD-50-NBS1 (MRN) complex is formed. This complex activates ATM (autophosphorylation of S1981), activating a downstream signaling cascade with numerous targets, thereby regulating DNA repair, cell cycle arrest, or inducing autophagy (Bakkenist, CJ; Kastan, MB; *DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003, 421 (6922), 499-506. DOI: 10.1038 / nature01368; *Uziel, et al., *Requirement of the MRN complex for ATM activation by DNA damage. The EMBO Journal 2003, 22 (20), 5612-5621. DOI: https: / / doi.org / 10.1093 / emboj / cdg541; Pusapati, RV et al. ATM promotes apoptosis and suppresses tumorigenesis in response to Myc.Proceedings of the National Academy of Sciences 2006, 103 (5), 1446-1451. DOI: doi:10.1073 / pnas.0507367103). Based on the fact that cells with ATM loss of function in patients with Louis-Bar syndrome (also known as ataxia telangiectasia (AT)) cannot stop DNA replication when exposed to ionizing radiation, the idea arose to induce apoptosis in cancer cells by accumulating genotoxic stress through the combined use of ATM kinase and double-strand break inducers in targeted therapy (Sarkaria, JN; Eshleman, JS ATM as a target for novel radiosensitizers. Semin Radiat Oncol 2001, 11 (4), 316-327. DOI: 10.1053 / srao.2001.26030; obtained from NLM; Houldsworth, J.; Lavin, MF Effect of ionizing radiation on DNA synthesis in ataxia telangiectasia cells. Nucleic Acids Res 1980, 8 (16), 3709-3720. DOI: (10.1093 / nar / 8.16.3709; obtained from NLM). Early proof-of-concept studies have shown that combining ATM inhibition with ionizing radiation (IR) and PARP or topoisomerase I / II inhibitors yields synergistic effects both in vitro and in vivo (Zimmermann, A. et al., A New Class of Selective ATM Inhibitors as Combination Partners of DNA Double-Strand Break Inducing Cancer Therapies. Molecular cancer therapeutics 2022, 21 (6), 859-870. DOI: 10.1158 / 1535-7163.mct-21-0934 PubMed; Durant, ST et al.).The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Science advances 2018, 4 (6), eaat1719-eaat1719. DOI: 10.1126 / sciadv.aat1719 PubMed; Pike, K. G. et al. The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one). Journal of Medicinal Chemistry 2018, 61 (9), 3823-3841. DOI: 10.1021 / acs.jmedchem.7b01896; Golding, S. E. et al. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Molecular Cancer Therapeutics 2009, 8 (10), 2894-2902. DOI: 10.1158 / 1535-7163.Mct-09-0519; Batey, M. A. et al.Preclinical Evaluation of a Novel ATM Inhibitor, KU59403, In Vitro and In Vivo in p53 Functional and Dysfunctional Models of Human Cancer. Molecular Cancer Therapeutics 2013, 12 (6), 959-967. DOI: 10.1158 / 1535-7163.Mct-12-0707)。.

[0003] Caffeine (low affinity and non-selective) (Blasina, A.; et al., Caffeine inhibits the checkpoint kinase ATM. Current Biology 1999, 9 (19), 1135-1138. DOI: https: / / doi.org / 10.1016 / S0960-9822(99)80486-2; Sarkaria, JN et al.; Inhibition of ATM and ATR Kinase Activities by the Radiosensitizing Agent, Caffeine1. Cancer Research 1999, 59 (17), 4375-4382. (Accessed April 9, 2022)) and wortmannin (toxic, non-selective and irreversible; see Figure 2) (Sarkaria, JN et al., Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res 1998, In addition to natural ATM inhibitors such as PX-866 (58 (19), 4375-4382; obtained from NLM; Ihle, NT et al., Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 2004, 3 (7), 763-772; obtained from NLM), a great many types of synthetic compounds have been described in the academic literature.Several morpholine-based ATM kinase inhibitors related to LY294002, a nonspecific PI3K / PIKK inhibitor, have also been reported (Vlahos, CJ et al., A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994, 269 (7), 5241-5248.; obtained from NLM). Among this group of inhibitors, the most significant representative compound is KU-60019 (see Figure 2), which exhibits improved solubility, potency, and selectivity compared to its precursor, KU-55933 (Golding, SE et al., Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Molecular Cancer Therapeutics 2009, 8 (10), 2894-2902. DOI: 10.1158 / 1535-7163.Mct-09-0519; Hickson, I. et al., Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM. Cancer Research 2004, 64 (24), 9152-9159. DOI: 10.1158 / 0008-5472.Can-04-2727). Currently, the most important group of ATM kinase inhibitors are compounds based on the imidazo[4,5-c]quinoline-2-one scaffold.The inhibitor M3541 and its atrop isomer M4076 have sub-nanomolecular activity and exhibit potent synergistic effects in cooperation with PARP, topoisomerase I inhibitors, and topoisomerase II inhibitors (Zimmermann, A. et al., A New Class of Selective ATM Inhibitors as Combination Partners of DNA Double-Strand Break Inducing Cancer Therapies. Molecular cancer therapeutics 2022, 21 (6), 859-870. DOI: 10.1158 / 1535-7163.mct-21-0934 PubMed). Other ATM kinase inhibitors in the imidazo[4,5-c]quinoline-2-one group include AZD1390 and AZD0156 (see Figure 2). AZD0156 exhibits sub-nanomolelic potency in biochemical assays, possesses favorable pharmacokinetic properties, and shows a good selectivity profile against 397 kinases, demonstrating inhibition rates of over 87% against mTOR and LRRK2 at a concentration of 1 μM (Pike, KG et al., The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one). Journal of Medicinal Chemistry 2018, 61 (9), 3823-3841. DOI: 10.1021 / acs.jmedchem.7b01896).Several related urea-based inhibitors belonging to the same structural class as the ATM kinase inhibitors mentioned above have also been proposed. Among them, compound 34 (see Figure 2) exhibits higher metabolic stability than AZD0156 and higher selectivity for LRRK2 (showing an 8% inhibition rate at a concentration of 1 μM). However, the affinity of compound 34 for mTOR could not be optimized and is similar to that of AZD0156 (Dimitrov, T. et al., Development of novel urea-based ATM kinase inhibitors with sub-nanomolar cellular potency and high kinome selectivity. European Journal of Medicinal Chemistry 2022, 235, 114234. DOI: https: / / doi.org / 10.1016 / j.ejmech.2022.114234). In a study by Guo et al., a cell-based HTS assay for ATM inhibitors has been developed, and a library of over 7000 compounds has been screened. SJ000573017, a PLK1 inhibitor, has a moderate IC of 0.48 μM. 50It has been identified as a moderate ATM inhibitor with a certain value (Emmitte, KA et al., Design of potent thiophene inhibitors of polo-like kinase 1 with improved solubility and reduced protein binding. Bioorganic & Medicinal Chemistry Letters 2009, 19 (6), 1694-1697. DOI: https: / / doi.org / 10.1016 / j.bmcl.2009.01.094; Guo, K. et al., Development of a cell-based, high-throughput screening assay for ATM kinase inhibitors. J Biomol Screen 2014, 19 (4), 538-546. DOI: 10.1177 / 1087057113520325).

[0004] ATM kinase has been known for over 20 years, but there are still no approved ATM inhibitors. [Overview of the project] [Problems that the invention aims to solve]

[0005] The present invention aims to provide compounds effective in inhibiting, controlling, and / or regulating ATM kinase. Furthermore, the present invention aims to provide such compounds having high potency and / or high selectivity. Moreover, the present invention aims to provide such compounds having low toxicity to humans and / or warm-blooded animals or mammals. Furthermore, the present invention aims to provide ATM kinase inhibitors, ATM kinase regulators, and / or ATM kinase modifiers as pharmaceuticals. Furthermore, the present invention aims to provide ATM kinase inhibitors, ATM kinase regulators, and / or ATM kinase modifiers efficient for use in the treatment of cancer. [Means for solving the problem]

[0006] Surprisingly, the above object is represented by the general formula (Ia) or the general formula (Ib):

Chemical formula

Chemical formula

[0007] In this specification, the term "alkyl" includes, for example, linear or branched carbon chains having 1 to 20 carbon atoms, such as 2 to 12, 3 to 10, 4 to 8, or 5 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, and n-hexyl. The definition of alkyl can also be applied to any group containing alkyl groups, such as alkoxys and thioalkoxys.

[0008] In this specification, the term “ring” includes, for example, cyclic compounds having 3 to 8 carbon atoms, such as 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms, which are saturated or at least partially unsaturated. Ring residues also include aryl residues such as phenyl. The definition of a ring can also be applied to any group that contains a ring group, such as phenoxy. The ring group may be bonded to an adjacent group, such as another ring residue, via carbon atoms (C bonds). Furthermore, ring residues may exist as fused ring residues in which two or more carbon atoms (e.g., two carbon atoms) of the first ring residue can form part of the second ring residue.

[0009] In this specification, the term “heterocyclic” refers to a ring residue containing 1 to 3 heteroatoms, which may be independently selected from S, O, and N. The heterocyclic group may be bonded to an adjacent group, such as another ring residue, via, for example, a carbon atom (C bond) or a nitrogen heteroatom (N bond). The definition of heterocyclic can be similarly applied to any group containing a heterocyclic group. A heterocyclic residue may exist as a fused heterocyclic residue in which two or more atoms of the first heterocyclic residue can form part of a second heterocyclic residue or a ring residue. Examples of heterocyclic groups include pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydroquinoline, and indoline.

[0010] In this specification, the terms “substituted” or “substituted” may refer to residues including alkyl, heteroalkyl, ring, heterocycle, fused ring, fused heterocycle, and combinations thereof. In addition, or in another embodiment, the term “substituted” may refer to residues containing F, Cl, Br, or I; carbon modification by the introduction of one or more heteroatoms such as N, S, or O; carboxylic acid function, primary amine, secondary amine, or tertiary amine function (these may be further substituted); substituted O atom; or carboxylic acid group (which may be further substituted). The total molecular weight of the substituents is preferably 1000 g / mol or less, more preferably 750 g / mol or less, or 500 g / mol or less.

[0011] The molecular size of the residues in the present invention is selected so that the compounds of the present invention do not exhibit steric hindrance that adversely affects or interferes with biological activity.

[0012] The terms “compounds of the present invention” or “compounds of formula (I)” or compounds of other formulas and / or other structures include their pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates and stereoisomers.

[0013] A pharmaceutically acceptable salt may be an acid addition salt with a pharmaceutically acceptable acid. Suitable examples of pharmaceutically acceptable organic and inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfamic acid; C1-C4 alkyl sulfonic acids, e.g., methanesulfonic acid; alicyclic sulfonic acids, e.g., S-(+)-10-camphorsulfonic acid; aromatic sulfonic acids, e.g., benzenesulfonic acid and toluenesulfonic acid; and C2-C10 dicarboxylic and tricarboxylic acids and hydroxycarboxylic acids, e.g., oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, glycolic acid, adipic acid, and benzoic acid. Further preferred pharmaceutically acceptable acids are, for example, Remington: The Science and Practice of Pharmacy, 23. rd You may also refer to edition, October 30, 2020, Adeboye Adejare.

[0014] Furthermore, the present invention includes tautomers, crystalline forms and polymorphs of the compound and its salts, as well as mixtures thereof.

[0015] Furthermore, the present invention includes solvates such as hydrates.

[0016] The compounds of the present invention may contain one or more chiral centers and may exist in various optically active forms such as enantiomers and diastereomers.

[0017] In this specification, the term "prodrug" means a compound that is converted to a parent drug by a physiological chemical process in vivo. An example of a prodrug may be, but is not limited to, the compound of the present invention in the form of an ester.

[0018] Prodrugs possess many useful properties. For example, prodrugs may have higher solubility in water than the final drug, which can facilitate intravenous administration. Prodrugs may also have higher oral bioavailability than the final drug. After administration, prodrugs are enzymatically or chemically cleaved to deliver the final drug into the blood or tissues. Suitable prodrugs are known to those skilled in the art.

[0019] The compounds of the present invention are useful in therapy because they can mediate ATM kinase (i.e., inhibit, control, and / or modulate ATM kinase), and are particularly useful in the treatment of diseases or conditions in which ATM kinase is at least partially mediated. The compounds of the present invention may be particularly useful in the treatment of cancer, including non-metastatic and metastatic cancers, and this treatment includes the treatment of primary and metastatic tumors.

[0020] Examples of cancers include colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, squamous cell carcinoma of the head and neck, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer in humans, warm-blooded animals, or mammals.

[0021] A is [ka] (In the formula, Z 3 Z is selected from substituted alkyl groups and may be a substituted ring or a substituted fused heterocycle. 4 (is H) It is preferable that this be the case.

[0022] A is [ka] (In the formula, X 4 is N or CH, V 1 is O or NH, preferably O. V 2 It is CH2, NH or 3-(1-methylpyrrolidine), V 3 It is CH2 or CO, V 4 is hydroxyl or -N(R 7 )(R 8 ) and R 7 and R 8 Each is independently selected from H, an unsubstituted C1-C5 alkyl, and an unsubstituted C1-C5 cycloalkyl, preferably R 7 and R 8 Each is independently selected from H, methyl, ethyl, and cyclopropyl, and R 7 and R 8 These may combine to form a ring, forming a substituted pyrrolidine or substituted piperidine. n is 0, 1, or 2. It is preferable that it be so.

[0023] A is [ka] (In the formula, X 4 and X 5 Each is independently selected from CH, CF, and N, preferably X 4 and X 5 However, each is CH, V 1 and V 2 Each is independently selected from NH, S, and O. V 3 It is CH2 or CO, V 4 is -N(R 7 )(R 8 ), substituted 1-azetidine, substituted 2-pyrrolidine, substituted 3-pyrrolidine, or unsubstituted 1-piperidine, R 7 and R 8 These are independently selected from H and methyl, V5 (CH2) n or (CHCH3) n (where n is 0, 1, or 2) It is even more preferable that this be the case.

[0024] According to one preferred embodiment, R 1 and R 2 All of these are H, R 3 is H or methyl and / or A is the following a)~e): a) 4-anilinyl, 2-(4-(7-methyl-3-oxohexahydroimidazo[1,5-a]pyrazine-2(3H)-yl)phenyl), 4-(hydroxymethyl)phenyl, 2-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazole-5-yl, 6-(3-hydroxypropoxy)pyridine-3-yl, or 1-(3-(dimethylamino)propyl)-1H-pyrazole-4-yl; b) B, a residue of general formula (II) [ka] (In the formula, X is CR a Or it is N, R a is either H, or a substituted or unsubstituted alkyl group, or is absent. R c is H, methyl or methylene, R b and R d It is either H or F, V 1 These are NH, N-CH3, or CH2. V 2 It is NH, N-CH3, or O. R a If not, then B is X=C and V 1 It forms a fused ring with =N, creating a substituted indoline. R cIf C is a methylene group, then C is a ring that forms a substituted pyrrolidine ring or a substituted piperidine ring, or D is a ring that forms a substituted difluoroazetidine or a substituted monofluoroazetidine. n is 0, 1, or 2; c) Residues of general formula (III) [ka] (In the formula, X is either N or CH. R is a substituted or unsubstituted alkyl, a substituted or unsubstituted benzyl, or N(R) 1 )(R 2 ) d) Residues of general formula (IV) [ka] (In the formula, X is CH, CR a Or it is N, R a H is either a substituted or unsubstituted alkyl group, or it is absent. Q is O, S, or N. F may be a condensed ring that forms a substituted benzimidazole. R 5 and R 6 These are independently selected from H and methyl, R 5 and R 6 These may together form unsubstituted or substituted pyrrolidines, or unsubstituted or substituted piperidines. n is 0, 1, or 2; e) Residues of general formula (V) [ka] (In the formula, R is either methyl or methylene. If R is a methylene group, then I is a ring that forms a substituted azetidine, or J is a ring that forms a substituted piperazine; and f) Residues of the following formula

Chemical formula

[0025] According to another preferred embodiment X 1 is N, X 2 is C, X 3 is CH or N, R 1 R 2 and R 3 are each H, R 4 is

Chemical formula

Chemical formula

[0026] According to yet another preferred embodiment, X 1 is N, X 2 is C, X 3 is CH or N, R 1 and R 2 are each H, R 3 is H or unsubstituted C1-C5 alkyl, preferably H or methyl, R 4 is a substituted ring, 2-R-phenyl, 3-R-phenyl, 4-R-phenyl, or

Chemical formula

Chemical formula

[0027] According to another preferred embodiment, in the compound of formula (Ia), X 1 is N, and X 2 C is X 3 Is it CH or X? 1 and X 3 is N, and X 2 is C, or the compound of formula (Ia) is the compound of formula (IIb).

[0028] According to yet another preferred embodiment, R 4 teeth, [ka] Selected from (In the formula, R is an unsubstituted alkyl or unsubstituted cycloalkyl, preferably methyl, ethyl, or cyclopropyl, or 3-R9 - or 4-R 9 -phenyl, R 9 teeth, [ka] (That is.)

[0029] According to one preferred embodiment, A is [ka] That is the case.

[0030] In another preferred embodiment, (a) The compound is of general formula (VIa): [ka] (In the formula, R is, [ka] (is) Do you have it? (b) The compound is of general formula (VIb): [ka] (In the formula, R is, [ka] (is) Do you have it? (c) The compound has the general formula (VIc): [ka] (In the formula, R is, [ka] (is) Do you have it? (d) The compound has the general formula (VId): [ka] (In the formula, R 1 teeth, [ka] And, X is CH, R 2 teeth, [ka] is; or R 1 teeth, [ka] And, X is N, R 2 teeth, [ka] (is) Do you have it? (e) The compound is of general formula (VIe): [ka] (In the formula, R is, [ka] (is) Do you have it? (f) The compound has the general formula (VIf): [ka] (In the formula, R 1 is Me, Et or cPr, X is CH, R 2 is Me, and R 3 teeth, [ka] Is it; R 1is Me, X is N, and R 2 H is R 3 teeth, [ka] is; or R 1 is Me, X is N, and R 2 H is R 3 teeth, [ka] (is) Do you have it? (g) The compound is of general formula (VIg): [ka] (In the formula, R 1 teeth, [ka] And, X is CH, R 2 teeth, [ka] Is it; R 1 teeth, [ka] And, X is CH, R 2 teeth, [ka] Is it; R 1 teeth, [ka] And, X is N, R 2 teeth, [ka] is; or R 1 teeth, [ka] And, X is N, R 2 teeth, [ka] (is) Having; or (h) The compound is of the general formula (VIh): [ka] (In the formula, R 1 teeth, [ka] And, R 2 teeth, [ka] is; or R 1 teeth, [ka] And, R 2 teeth, [ka] (is) It holds.

[0031] According to one preferred embodiment, the compound is [ka] The filename is JPEG2026511081000052.jpg96153.

[0032] According to one preferred embodiment, the compound is [ka] The files are JPEG2026511081000054.jpg219153 and JPEG2026511081000055.jpg78153.

[0033] In another preferred embodiment, a pharmaceutical composition is provided comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, a prodrug, a biologically active metabolite, a solvate or stereoisomer, and which may comprise an inert carrier and / or one or more other therapeutic agents.

[0034] In yet another preferred embodiment, the compounds of the present invention, or pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates or stereoisomers thereof, or compositions of the present invention are intended for use in the treatment of a disease, which is preferably an ATM kinase-mediated disease.

[0035] According to one preferred embodiment, the disease is cancer, and is preferably selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer.

[0036] According to another preferred embodiment, a method for treating a disease in which disease intervention to ATM kinase, preferably inhibition, control, and modulation of ATM kinase, is beneficial in a human or warm-blooded animal or mammal requiring treatment of such a disease, A method is provided comprising the step of administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, prodrug, biologically active metabolite, solvate or stereoisomer thereof, or composition of the present invention to a human or warm-blooded or mammalian animal in need of the aforementioned treatment.

[0037] In yet another preferred embodiment, the disease is cancer, preferably selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer.

[0038] Preferred compounds of the present invention include those described in Tables 1 to 13, Schemes 1 to 15, and Examples below.

[0039] Particularly preferred compounds of the present invention include FM-992, TD-454, FM-994, TD-430, TD-581, TD-582, TD-583, TD-608, TD-609, TD-665, TD-561, TD-595, TD-600, TD-601, TD-420, TD-416, TD-429, TD-439, TD-440, TD-441, TD-444, TD-442, TD-504, TD-546, TD Examples include 417, TD-533, TD-560, FM-987, TD-344, TD-339, TD-607, TD-339, LS-48, FM-993, TD-516, TD-337, TD-347, TD-398, TD-386, TD-541, TD-532, TD-512, TD-534, TD-527, TD-559, TD-679, TD-641, TD-640, TD-678, TD-674, TD-683, TD-685, TD-676, TD-684, and TD-686.

[0040] The most preferred compounds of the present invention include FM-987, LS-48, FM-993, TD-516, TD-337, TD-347, TD-398, TD-386, TD-541, TD-532, TD-512, TD-534, TD-527, TD-559, TD-679, TD-641, TD-640, TD-678, TD-674, TD-683, TD-685, TD-676, TD-684, and TD-686.

[0041] According to one embodiment, a pharmaceutical composition is provided. The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof, a prodrug, a biologically active metabolite, a solvate or stereoisomer, and may also comprise an inert carrier and / or one or more other therapeutic agents.

[0042] According to one embodiment, the compounds of the present invention, or pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates or stereoisomers thereof, or compositions of the present invention are for use in the treatment of a disease, which is preferably an ATM kinase-mediated disease.

[0043] In yet another embodiment, the compounds of the present invention, or their pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates or stereoisomers, or compositions of the present invention are intended for use in the treatment of cancer.

[0044] According to one embodiment, the compounds of the present invention, or pharmaceutically acceptable salts, prodrugs, biologically active metabolites, solvates or stereoisomers thereof, or compositions of the present invention are intended for use in the treatment of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, or non-small cell lung cancer.

[0045] According to another embodiment, a method for treating a disease in which intervention of ATM kinase is beneficial in a human, warm-blooded animal, or mammal requiring treatment of such a disease, A method is provided comprising the step of administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, prodrug, biologically active metabolite, solvate or stereoisomer thereof, or composition of the present invention to a human or warm-blooded or mammalian animal in need of the aforementioned treatment.

[0046] In yet another embodiment, a method for treating a disease in which inhibition, control, and modulation of ATM kinase is beneficial in a human or warm-blooded animal or mammal requiring treatment of the disease, A method is provided comprising the step of administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, prodrug, biologically active metabolite, solvate or stereoisomer thereof, or composition of the present invention to a human or warm-blooded or mammalian animal in need of the aforementioned treatment.

[0047] According to one embodiment, a method for treating a disease in which intervention of ATM kinase is beneficial in a human, warm-blooded animal, or mammal requiring treatment of such a disease, A method is provided comprising the step of administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, prodrug, biologically active metabolite, solvate or stereoisomer thereof, or composition of the present invention to a human or warm-blooded or mammalian animal in need of the aforementioned treatment.

[0048] According to one embodiment, a method for treating cancer, specifically colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer, in a human or warm-blooded animal or mammal requiring cancer treatment, A method is provided comprising the step of administering a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, prodrug, biologically active metabolite, solvate or stereoisomer thereof, or composition of the present invention to a human or warm-blooded or mammalian animal in need of the aforementioned treatment.

[0049] The compounds of the present invention may be administered in the form of a pharmaceutical composition, which may contain at least one compound of the present invention and further contain a carrier such as a pharmaceutically acceptable excipient, and may further contain one or more other drugs such as an anticancer drug or a combination of different types of anticancer drugs.

[0050] The compositions of the present invention can be administered, for example, by oral, rectal, transdermal, subcutaneous, intraperitoneal, intravenous, intramuscular, or intranasal administration. Examples of suitable pharmaceutical compositions include solid pharmaceutical forms such as powders, granules, tablets (more specifically, film tablets), lozenges, sachets, cachets, sugar-coated tablets, capsules (e.g., hard gelatin capsules and soft gelatin capsules), and suppositories; semi-solid pharmaceutical forms such as ointments, creams, hydrogels, pastes, and hard ointments; and liquid pharmaceutical forms such as solutions, emulsions (more specifically, oil-in-water emulsions), suspensions (e.g., lotions), injectable formulations, and infusion formulations. Furthermore, liposomes and / or microspheres may also be used.

[0051] When preparing the composition of the present invention, the compound of the present invention may be mixed with one or more carriers, such as pharmaceutically acceptable excipients, or diluted with such one or more carriers. The carrier, such as a pharmaceutically acceptable excipient, may be a solid, semi-solid, or liquid material that functions as a solvent, carrier, or medium for the compound of the present invention.

[0052] Suitable carriers, such as pharmaceutically acceptable excipients, are known to those skilled in the art and can be readily referred to in textbooks. Formulations of suitable carriers, such as pharmaceutically acceptable excipients, may also contain pharmaceutically acceptable adjuvants, such as humectants; emulsifiers and suspending agents; preservatives; antioxidants; anti-irritants; chelating agents; coating aids; emulsifying stabilizers; film-forming agents; gel-forming agents; odor-masking agents; flavoring agents; resins; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; fatliquoring and superfatting agents; raw materials for ointments, creams or oils; silicone derivatives; spreadable agents; stabilizers; sterilizing agents; suppository bases; tablet adjuvants such as binders, fillers, lubricants, disintegrants, and coating agents; propellants; drying agents; emulsifiers; thickeners; waxes; plasticizers; and white mineral oils. Suitable carrier formulations may be prepared, for example, according to Fiedler, HP, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.

[0053] The compounds of the present invention are administered in a concentration of 2.5 to 5000 mg / m² per body surface area of ​​humans or animals, particularly warm-blooded animals or mammals. 2 It can be administered in a unit dose within the range of 0.05 to 100 mg / kg of body weight. The unit dose form may contain 0.1 to 250 mg of the compound of the present invention. The daily dose will inevitably vary depending on the patient being treated, the route of administration, whether or not concomitant therapy is used, and the severity of the disorder.

[0054] The compounds of the present invention may also be suitable for use in combination with other therapeutic agents or other therapeutic agents. Therefore, the present invention further relates to combinations of the compounds of the present invention with one or more further therapeutic agents, particularly combinations of the compounds of the present invention with one or more further therapeutic agents for use in the treatment of cancer or related diseases. The combination therapy of the present invention may be administered adjunctly. Adjunct administration means administering each component in the form of a separate pharmaceutical composition or device, at overlapping or partially overlapping times. Such a therapeutic administration plan of two or more therapeutic agents is generally referred to as “adjunct therapeutic administration” and is also known as add-on therapeutic administration by those skilled in the art and herein. Any therapeutic plan in which the compounds of the present invention and at least one further therapeutic agent are administered to a patient in separate forms, at overlapping or partially overlapping times, is also within the scope of the present invention. In one embodiment of the adjunct therapeutic administration described herein, the patient typically receives administration of another component after being stabilized for a period of time by therapeutic administration of one or more components.

[0055] The combination therapy of the present invention may be administered simultaneously or sequentially. Simultaneous administration means a treatment plan in which each component is administered together, which may be in the form of a single pharmaceutical composition or device containing both components, or it may be administered simultaneously as separate compositions or devices each containing only one of several components. Such combinations of separate components for simultaneous administration may be provided in the form of a kit.

[0056] Suitable agents to be used in combination with the compounds of the present invention include, for example, a) Antineoplastic agents and combinations thereof, e.g., DNA alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustards (e.g., ifosfamide, bendamustine, melphalan, chlorambucil, busulfan), temozolomide, and nitrosoureas (e.g., carmustine)); antimetabolites (e.g., gemcitabine and folate antagonists (e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, larcitrexed, methotrexate, cytosine arabinoside, and hydroxyureas); antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, barurubicin, epirubicin, idarubicin, mitomycin C, Anthracyclines such as dactinomycin, amrubicin, and mitramycin; antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine; taxoids such as taxol and taxotere; and polokinase inhibitors); topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide; amsacrin, irinotecan, topotecan, and camptothecin); DNA repair mechanism inhibitors such as CHK kinase; DNA-dependent protein kinase inhibitors; poly(ADP-ribose) polymerase inhibitors (e.g., PARP inhibitors such as olaparib); Hsp90 inhibitors (e.g., tanespimycin and letaspimycin); ATR kinase inhibitors (e.g., AZD6738); and WEEI kinase inhibitors); b) Angiogenesis inhibitors, for example, angiogenesis inhibitors that inhibit the action of vascular endothelial growth factor (VEGF) (e.g., bevacizumab, an anti-vascular endothelial growth factor antibody, and VEGF receptor tyrosine kinase inhibitors such as bandatanib (ZD6474), sorafenib, batalanib (PTK787), sunitinib (SUI 1248), axitinib (AG-013736), and pazopanib (GW Compounds such as those disclosed in WO97 / 22596, WO97 / 30035, WO97 / 32856 and WO98 / 13354 (786034) and cediranib (AZD2171); and compounds acting by other mechanisms (e.g., linamide, integrin αvβ3 function inhibitors, angiostatins), inhibitors of angiopoietin and its receptors (Tie-1 and Tie-2), PLGF inhibitors, or delta-like ligand (DLL-4) inhibitors); c) Other small molecule drugs, e.g., protein phosphorylation inhibitors (e.g., abemaciclib, acalabrutinib, afatinib, alectinib, avapritinib, axitinib, binimetinib, bosutinib, brigutinib, cabozantinib, capmatinib, ceritinib, cobimetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, entrectinib, erdafitinib, erlotinib, everolimus, fedratinib, hostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, lapatinib, lalotrectinib, lenvatinib, lorlatinib, midostaurin, neratinib, niro Protein-protein interaction inhibitors (e.g., vencrexta and navitocrax), or proteasome inhibitors (e.g., bortezomib, nintedanib, osimertinib, palbociclib, pazopanib, pemigatinib, pexidartinib, ponatinib, pralcetinib, regorafenib, ribociclib, lipretinib, ruxolitinib, serpercatinib, selumetinib, sirolimus, sorafenib, sunitinib, temsirolimus, trametinib, tucatinib, upadacitinib, vandetanib, vemurafenib, and zanubrutinib); protein-protein interaction inhibitors (e.g., vencrexta and navitocrax); d) Immunotherapy approaches, such as ex vivo or in vivo approaches that increase the immunogenicity of the patient's tumor cells, including transfection with cytokines such as interleukin-2, interleukin-4, and granulocyte-macrophage colony-stimulating factor; approaches that impair T cell unresponsiveness or regulatory T cell function; approaches that enhance the T cell response to the tumor, such as blocking antibodies against CTLA4 (e.g., ipilimumab and tremelimumab), blocking antibodies against B7HI, blocking antibodies against PD-1 (e.g., BMS-936558 and AMP-514), blocking antibodies against PD-L1 (e.g., MED14736), agonist antibodies against CD137, and the Other immune checkpoint inhibitors; approaches using transfected immune cells such as dendritic cells transfected with cytokines; approaches using tumor cell lines transfected with cytokines; approaches using antibodies against tumor-associated antigens; approaches using antibodies that eliminate target cell types (e.g., unlabeled anti-CD20 antibodies such as rituximab, radiolabeled anti-CD20 antibodies such as Vexar and Zevalin, and anti-CD54 antibodies such as Campus); approaches using anti-idiotype antibodies; approaches that enhance the function of natural killer cells; approaches using antibody-toxin complexes (e.g., Mylotarg, an anti-CD33 antibody); immunotoxins such as moxetumomab Pasdotox; Toll-like receptor 7 agonists or Toll-like receptor 9 agonists; cell immunotherapy such as CAR-T cell therapy, NK cell therapy, CAR-NK cell therapy, tumor-infiltrating lymphocytes, recombinant T cells; vaccinations, such as anti-tumor peptide vaccines, mRNA vaccines and dendritic cell vaccines; and e) Efficacy enhancers such as leucovorin These are some examples.

[0057] This invention is based on the discovery of a new class of specific benzimidazole ATM kinase inhibitors that exhibit high efficacy and favorable selectivity in related kinases of the PIKK and PI3K families. Surprisingly, during the research leading to this invention, two subgroups of promising inhibitors with significantly different physicochemical properties were assigned (see Figures 3 and 4). As a result of this research, many highly active inhibitors with picomolar activity against the isolated enzymes were found. Furthermore, although cellular activity was low in the initial stages, it could be significantly increased in many cases, resulting in intracellular IC50 in the subnanomolar range. 50 I was able to obtain the value. [Modes for carrying out the invention]

[0058] Based on the above findings, we initiated a development program for ATM inhibitors with a benzimidazole scaffold. The initial rationale for the present invention is that the benzimidazole scaffold can address the ATP binding pocket in a manner similar to that of previously reported quinoline compounds (Pike, KG et al., The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one). Journal of Medicinal Chemistry 2018, 61 (9), 3823-3841. DOI: 10.1021 / acs.jmedchem.7b01896; Dimitrov, T. et al.; Barlaam, B. et al., Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors. ACS Medicinal Chemistry Letters 2018, 9 (8), 809-814. DOI: 10.1021 / acsmedchemlett.8b00200; Stakyte, K. et al., Molecular basis of human ATM kinase inhibition. Nature Structural & Molecular Biology 2021, 28 (10), 789-798. DOI: 10.1038 / s41594-021-00654-x). As a starting point, two side chains were introduced into the core portion consisting of benzimidazole.As the first side chain, a nonspecific six-membered hydrophobic ring is used to address hydrophobic region II (HRII) (see the northern side chain in Figure 3), thereby increasing the possibility of derivatization in various directions. As the second side chain, a highly specific eastern side chain is introduced to address hydrophobic region I (HRI; back pocket) and the distal part of the ATM kinase.

[0059] Therefore, we employ two motifs that efficiently bind to the back pocket of ATM kinase containing various aspartic acid residues (D2720, D2721, D2725, and D2889; see Figure 1C). The human ATM sequence and each domain are shown in Figure 1A, and the dimer structure of ATM is shown in Figure 1B.

[0060] The initial eastern side chain motif is N,N-dimethyl-3-(pyridine-2-yloxy)propan-1-amine, whose pyridine-2-yloxy portion can act as a hydrogen bond acceptor for L2717, and whose terminal dimethylamine group can form an ionic bond with the aspartic acid residue (Dimitrov, T et al.). Another eastern side chain used is 1-(2-(dimethylamino)ethyl)-3-phenylurea (Dimitrov, T et al.). In this case, this urea can act as a hydrogen bond acceptor for L2717 and at the same time as a hydrogen bond donor for D2725, and the terminal dimethylamine can interact with the aspartic acid residue in a similar manner to the above.

[0061] [Table 1]

[0062] For proof-of-concept purposes, phenyl or cyclohexyl residues were used as the northern side chains of the first inhibitors (TD-228 to LS-13 in Table 1). Comparing TD-228 and TD-225, the more rigid 1-phenylbenzimidazole was found to be superior to the corresponding 1-cyclohexylbenzimidazole (IC1). 50Compared to 283nM (Table 1), the activity (IC) is significantly higher. 50 It showed (=66nM). On the other hand, the inhibitor LS-13, which contains the eastern side chain of the urea system, compared to TD-228, showed IC25 to ATM. 50 It exhibits similar inhibitory activity with a value of 60 nM. The urea-based side chain is more readily derivatizable and has therefore been selected as a preferred residue for the creation of further inhibitors. The docking model of this inhibitor is shown in Figure 5. The core portion consisting of benzimidazole is bound to C2770 in the hinge region, the eastern side chain forms hydrogen bonds with K2717 and D2725 via the urea moiety, and the protonated terminal amine forms an ionic bond with D2889.

[0063] To investigate the importance of hydrogen bond donors in urea, methylation was performed. Monomethylation and dimethylation of TD-336 and TD-348 were not tolerated by ATM kinase, which is thought to be due to the unfavorable cis-trans conformation of methylated urea (Matsumura, M. et al., Unusual conformational preference of an aromatic secondary urea: solvent-dependent open-closed conformational switching of N,N'-bis(porphyrinyl)urea). This is probably due to simple steric hindrance, for which there are several other derivatives with substituents on the nitrogen atom of urea that do not cause such a significant decrease in potency (see Table 8).

[0064] Further development was carried out from the first compound in Table 1, and a broad SAR search was initiated from the northern side chain. SAR search of the northern side chain: Various substitution patterns with halogens, aminos, and methoxys were introduced to the northern phenyl ring, and their effects on inhibitory activity were evaluated (Table 2). Regarding ortho substitution of LS-24 and TD-360, 2-fluorophenyl, which has low stereorequirements, showed inhibitory activity similar to that of the parent compound LS-13 (IC2). 50While it shows an activity of 78 nM (IC), the 2-methoxyphenyl analog TD-360 shows significantly lower activity (IC). 50 =197nM, Table 2). Also, even if an amino group is introduced at the meta position (TD-310, IC 50 =71nM), unsubstituted inhibitor LS-13 (IC) 50 There is no advantage in terms of activity compared to (60 nM). On the other hand, when a methoxy substitution is introduced at the meta position, the IC50 is 31 nM. 50 Activity increases slightly up to the specified value (LS-14, Table 2). Furthermore, when amino, methoxy, or fluorine substitutions are introduced at the para position, amino (TD-316) and methoxy (LS-07) are shown to be slightly preferable to fluoro in LS-10 (each IC2). 50 = 42nM, IC 50 =34nM and IC 50 (=75nM).

[0065] [Table 2] JPEG2026511081000058.jpg60153

[0066] By substituting the fluoro substituent with a larger halogen, the efficacy of the bromine compound FM-992 was improved to a single-digit nanomolar value, and in the case of FM-987 (which has a chloro substituent), the efficacy was improved to a value of less than nanomolar, below the detection limit of the assay (Table 2).

[0067] Inspired by the results shown in Table 2, further modifications were made to the para and meta positions of the phenyl ring. Regarding the para position modification, the inhibitors can be formally classified into derivatives of TD-316 (aniline) (Table 3a) and other derivatives (non-TD-316) (Table 3b).

[0068] [Table 3] JPEG2026511081000060.jpg145153

[0069] As shown by the anilide series TD-313 to TD-397 (Table 3a), IC 50 The values ​​range from 67 nM for TD-397 to 18 nM for acetanilide TD-313, suggesting that small aliphatic side chains are generally preferred. The introduction of sulfonamide groups into TD-351 and TD-355 resulted in a moderate increase in activity compared to the parent compound TD-316 (each with respect to IC50). 50 =22nM and IC 50 =12nM; Table 3a). For inhibitors TD-510 and TD-505, it has been clearly shown that piperidine residues are preferable to morpholine (Table 3a). When converted to the more rigid inhibitor FM-1000, which has cross-linked morpholine ((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane), it showed activity intermediate between TD-505 and TD-510, and was comparable to the activity of TD-316.

[0070] In addition to the regular TD-316 derivatives shown in Table 3a, a series of non-TD-316 derivatives were synthesized, and the inhibitory profiles of this series of compounds are shown in Table 3b. Referring to inhibitors TD-459 to LS-48, an increase in activity from 89 nM to less than nanomolar potency can be observed, in order of decreasing flexibility: cyclohexyl < cyclohexa-1-enyl ≤ phenyl (Table 3b). When various heterocyclic aromatics other than the biphenyl motif of LS-48 were tested (FM-994 to TD-516; Table 3b), the inhibitory power in this series was similar. Using a similar method, various substituted motifs with different meta positions derived from TD-310 were screened (Table 4).

[0071] [Table 4]

[0072] Acetanilide in TD-337 results in an order of magnitude higher IC50% compared to its parent compound, TD-310.50 Activity is enhanced up to the value (1 nM vs. 71 nM; Tables 4 and 2). In LS-35, where the NH group of TD-337 was removed and converted to the corresponding 3-acetylphenyl residue, a decrease in inhibition was shown (IC 50 = 14 nM). On the other hand, in TD-347, where a large methylsulfonamide group was introduced (Table 4), inhibition of ATM kinase was enhanced to sub-nanomolar levels (in contrast to TD-351, the p-sulfonamide in Table 3a). Therefore, the increase in activity can be induced in the order of m-Ac < m-NHAc ≦ m-NHM. For the long cyclic aliphatic chains of TD-398 and TD-386, no detectable difference in inhibition was observed compared to TD-347, and only a slight decrease in activity was seen in TD-430 (Table 4). From the precursor TD-307 protected with Boc, the last inhibitor in this series, it was demonstrated that even more sterically demanding residues are tolerated by the HRII pocket and exhibit activity similar to the parent inhibitor TD-310.

[0073] Regarding the first structure-activity correlation outlined in Figure 6, the biphenyl-based compounds (related to LS-48) and the group of sulfonamide inhibitors (related to TD-347) were further optimized simultaneously. To perform this optimization, specific properties of both compounds were evaluated, including initial drug metabolism and pharmacokinetics (Figures 8 and 9), as well as screening for selectivity within the PIKK family (Figure 9). Additionally, in the ATM kinase enzyme assay, a regulated concentration range was selected to obtain a higher resolution in the range from low nanomolar to sub-nanomolar (IC 50 II(As shown in the figure). In this modified assay, both inhibitor groups showed similar activity (Table 5). Furthermore, when the stability of LS-48 and TD-347 in mouse microsomes was evaluated, both compounds showed sufficient stability (Figure 8). LS-48 was more stable, with 63% of LS-48 still detectable after 120 minutes, compared to 43% of TD-347. The difference can be seen in the total polar surface area (tPSA) values ​​of these inhibitor groups (Table 5). Sulfonamide inhibitors showed tPSA values ​​exceeding 110, while LS-48 had a tPSA value of 67. Taking into account the potential risks associated with the high lipophilicity of LS-48, both inhibitor groups were developed simultaneously (Figure 6).

[0074] [Table 5]

[0075] Screening of the selectivity of both inhibitor groups within the PIKK family revealed that none of the tested compounds exhibited detectable affinity for ATR kinase at a concentration of 1 μM (Figure 9). For mTOR, the sulfonamides TD-347 and TD-386 showed stronger inhibition with values ​​of 32–47%. Interestingly, the biphenyl LS-48 exhibited residual kinase activity exceeding 90%, demonstrating a weaker inhibition favorable to mTOR. Furthermore, while all compounds showed reduced selectivity for DNA-PK compared to mTOR, LS-48 again showed significantly lower inhibition with 85% residual kinase activity. In addition to these two inhibitor groups, we synthesized TD-541, a hybrid molecule combining the biphenyl motif of LS-48 with the methylsulfonamide group of TD-347 (Figure 7).

[0076] This molecule showed favorably high activity in the picomolar range against ATM kinase (IC) 50 IIUnfortunately, with a concentration of 0.9 nM, it was not possible to maintain the high selectivity of the parent molecule LS-48 for mTOR and DNA-PK (Figure 9).

[0077] To further evaluate the efficacy of benzimidazole inhibitors in cells, we employed the in-cell Western assay using A549 cells as described by Guo et al. (Table 5, IC) 50 ICW (Guo, K. et al, Development of a cell-based, high-throughput screening assay for ATM kinase inhibitors. J Biomol Screen 2014, 19 (4), 538-546. DOI: 10.1177 / 1087057113520325). In the case of sulfonamide inhibitors, it was observed that inhibition at the cellular level increased with increasing aliphatic side chain length (Table 5), and TD-347, which has the shortest mesyl group, showed the lowest inhibition in the micromolar range. IC5 of TD-398 and TD-386 50 ICW The measured values ​​were 0.61 μM and 0.36 μM, respectively, and LS-48 produced a cellular IC of 0.63 μM. 50 ICW The values ​​show that the hybrid molecule TD-541 exhibits the highest potency at 0.26 μM.

[0078] Next, before investigating further structure-activity relationships, the pharmacokinetic properties of both inhibitor groups were evaluated. For this evaluation, TD-347 was predicted to have poor oral absorption (using QikProp (Schrodinger, L. Schrodinger Release 2022-3: QikProp, New York, NY, 2021)), so LS-48 and TD-541 were selected, excluding TD-347. When each inhibitor was orally administered to mice at a dose of 10 mg / kg, the inhibitor LS-48 showed C max The concentration was 72 ng / ml. 1 / 2It was shown that the time was 3.1 hours, and the hybrid inhibitor TD-541 showed a promising high C of 240 ng / ml. max And, a slightly lower t of 2.5 hours 1 / 2 This was shown (Figure 10).

[0079] Structure-activity relationship analysis of biphenyl-based inhibitors A broad structure-activity relationship search was initiated starting with LS-48. The search began with the terminal ring of the biphenyl residue because it offers advantageous synthetic access via Suzuki coupling in later steps from FM-987.

[0080] [Table 6] JPEG2026511081000064.jpg80153

[0081] Regarding the modifications to the northern terminal ring shown in Table 6, a clear pattern is observed in the structure-activity relationship. Comparing the ortho, meta, and para substitutions of fluorocarbons (TD-580 to TD-567), all of these inhibitors showed similar activity in the range of 14 to 17 nM, and no particular position was found to be preferable. Inhibitors with methoxy substitution at the northern terminal ring also showed IC50 activity in the range of 6.4 to 9.3 nM. 50 Values ​​were obtained (TD-581~TD-583), and ICs in the range of 21~25 nM were obtained even with substitution by difluoro motifs. 50 The same conclusion was reached from the values ​​obtained (TD-568~TD-586). In compound TD-609, which had a second methoxy group added, the activity was increased to 2.3 nM, while in the compound with only a nitro group (TD-608), the IC was 4.8 nM. 50 The values ​​were shown. Overall, regardless of the position of the individual substituents, a trend of increasing activity was observed in the order of -difluoro <-fluoro <-methoxy <-nitro <-dimethoxy, but the increase in activity was highly dependent on the type of substituent. In TD-665, which had a third methoxy group added, the potency could not be further enhanced compared to TD-609.

[0082] [Table 7] JPEG2026511081000066.jpg36153

[0083] In addition to the modifications shown in Table 6, various variations of the core portion consisting of the eastern side chain and benzimidazole to address HRI were screened (Table 7). In TD-561, introducing the N,N-dimethyl-3-(pyridine-2-yloxy)propan-1-amine side chain into the 1-(biphenyl-4-yl)-benzimidazole core (compared with Table 1) resulted in a very slight decrease in activity compared to LS-48 (IC). 50 II (LS-48) = 5.8nM for IC 50 II (TD-561) = 9.9 nM (Tables 7 and 3). Since TD-561 does not have hydrogen bond donors, C max Although it has increased 9 to 10 times (Figure 10), the cellular activity of this compound is about the same as that of the parent molecule LS-48 (IC 50 ICW (LS-48) = 626nM for IC 50 ICW (TD-561) = 609 nM). Based on TD-561, further modifications are made as follows. In TD-574, when the terminal aliphatic N,N-dimethylpropylamine was rigidified to pyrrolidine, the potency against isolated ATM kinase decreased (Table 7), and in the structural isomer TD-575, an even more abrupt decrease in potency was observed. In addition to the modification of the basic side chain on the east side, 3H-imidazo[4,5-b]pyridine is tested as another hinge bond motif. To carry out this test, three types of northern side chains (R 1 ; chlorophenyl and p-methoxyphenyl) and two basic side chains on the eastern side (R 2The following were introduced (TD-590~TD-601; Table 7). As a result, phenyl and p-methoxyphenyl were clearly preferred over chloro substituents, and the urea side chains introduced into compounds TD-588~TD-601 resulted in moderately high efficacy against the isolated enzyme in the case of (bi)phenylbenzimidazole. No advantage in terms of activity against the isolated enzyme was observed when comparing TD-561 and TD-594. Compared to the combination of benzimidazole core and urea side chain, 3H-imidazo[4,5-b]pyridine was observed to be slightly preferred (comparison of TD-600 and TD-601 with LS-48 and TD-583, Tables 5, 6, and 7). Although various highly active inhibitors were found among biphenyl-based inhibitors, unfortunately, no inhibitors increased the effect on A549 cells in the ICW assay. Therefore, in this ongoing optimization effort, we decided to focus on sulfonamide-based inhibitors.

[0084] Structure-activity relationship analysis of sulfonamide inhibitors The first sulfonamide inhibitors synthesized were shown to have insufficient activity at the cellular level (Table 5), so we tried a different approach to optimize this class of compounds. One of these alternative approaches involves modifying the urea side chain on the eastern side by reducing its hydrophilicity.

[0085] [Table 8] JPEG2026511081000068.jpg161153

[0086] One approach for optimization involves introducing a fluorosubstitution to the phenyl linker between the hinge binder and the urea residue. Two compounds were synthesized: one with a fluoro group at the ortho position (TD-416) and another with a fluoro group at the meta position (TD-420). This allowed for the development of the enzyme's IC50. 50 A slight improvement in the value is observed, down to the range of one order of magnitude nanomoles (Table 8; ICs less than 1 nM in Table 4). 50I (Comparison with the value (TD-347)).

[0087] Another strategy involves substituting the hydrogen bond donor group of urea. By removing the NH group between the phenyl and carbonyl groups, the amide TD-477 is obtained (Table 8), and compared to its parent molecule TD-347 (Table 4), it exhibits a different enzyme IC50 rate. 50 The value was a very high 280 nM. Furthermore, a similar low activity was observed due to the rigidification of urea in compound TD-411 (IC). 50 (=264nM). On the other hand, inhibitors TD-429 to TD-542 were obtained by substituting the terminal NH of urea, and various results were shown (Table 8). In the case of TD-429, which is a carbamate ester, the activity decreased to the range of one order of magnitude nanomoles, but this was still considered to be within an acceptable range (IC). 50 =3.9nM, Table 8). Furthermore, this inhibitor showed promising activity at the cellular level (IC). 50 ICW(=24nM). However, this compound showed low metabolic stability, with only 9% of the compound remaining after 120 minutes in a mouse microsome incubation assay. By rigidifying the urea group, TD-391 (methylpiperazine) or TD-392 (N,N-dimethylpiperidine-4-amine) were obtained, and the activity decreased sharply (Table 8). Similar structure-activity relationships have been shown for several recently reported quinoline ATM kinase inhibitors, but the relative decrease in activity is very large for benzimidazole inhibitors (Dimitrov, T. et al., Development of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity. European Journal of Medicinal Chemistry 2022, 235, 114234. DOI: https: / / doi.org / 10.1016 / j.ejmech.2022.114234). Surprisingly, the inhibitor TD-412, which has a very large 4-benzylpiperazine-1-carboxamide, somehow achieved a 343 nM IC compared to TD-391. 50 The activity was restored to the specified value (Table 8b). By removing the terminal NH of urea and converting it to a more flexible anilide, TD-506 to TD-542 were obtained, and it appeared that the tolerance of the kinase binding pocket increased compared to the aforementioned modification. In particular, in the primary assay, no difference in activity was observed between TD-532 and the parent inhibitor TD-347 (Table 4). When the basic side chain of TD-506 was extended, the activity decreased slightly (IC). 50 (IC₀ = 20 nM). In TD-542, in which the 2-(4-methylpiperazine-1-yl)-N-phenylacetamide side chain was rigidified, a decrease in activity was shown, although not as pronounced as in piperazine TD-391 (IC₀). 50 =166nM and IC 50 (=1576nM).

[0088] The final strategy in this group of side-chain modifications was modification of the terminal dimethylaminoethyl residue of the side chain of TD-347. TD-439 and TD-440, with the introduction of a terminal five-membered or terminal six-membered ring, yielded highly active inhibitors with activity in the single-digit nanomolar range. TD-441, which can be considered a ring-opened derivative of TD-439, showed activity similar to the parent compound in primary biochemical assays. To observe the pKa dependence of the terminal basic amine, the terminal dimethylamine was substituted with monofluoroazetidine or difluoroazetidine (TD-444 or TD-442). Weak basic amines reduced the potency of the inhibitor (Table 8).

[0089] Regarding the inhibitors listed in Table 8, modifications that increased intracellular efficacy in the desired manner have not yet been identified, with the exception of TD-429, which demonstrated metabolic stability.

[0090] [Table 9]

[0091] In parallel with the modifications described in Table 8, two variations of the benzimidazole core with hinges were tested (Table 9). The first modification of the benzimidazole core was the addition of a methyl substituent to the imidazole ring (TD-504 to TD-546), resulting in decreased activity in all of these inhibitors compared to their corresponding parent compounds (TD-347 to TD-386, Table 4). On the other hand, TD-512 and TD-534, in which the hinge-binding motif consisting of 3H-imidazo[4,5-b]pyridine (compared to Table 7) was moved to sulfonamide inhibitors, showed promising results with sub-nanomolecular activity. Based on this, this hinge-binding motif was further investigated in an additional set of inhibitors.

[0092] [Table 10] JPEG2026511081000071.jpg85153

[0093] Because of concerns that the polarity of the sulfonamide group is detrimental to the cellular activity and pharmacokinetic properties of inhibitors, several strategies are employed to mask the NH group of the sulfonamide and increase its overall lipophilicity (Table 10). The simplest representative inhibitor is the N-methylated compound TD-417. In a secondary enzyme ATM assay, this compound is found to be superior to the parent compound TD-347 (IC1). 50 II (IC) Similar affinity (IC) = 3.7nM 50 II It showed an IC50 of 5.5 nM. Furthermore, this inhibitor showed an IC50 of 110 nM. 50 ICW The enzyme exhibited favorable activity at the cellular level, as shown in Table 11, a result that contrasted sharply with the micromolar activity of the inhibitor TD-347 (Table 5). Furthermore, a rigid form of TD-417 was synthesized to obtain the indoline derivative TD-527 (Table 10). This compound yielded a 0.68 nM IC50 relative to the isolated enzyme. 50 It shows an increased affinity within the picomolar range, and in the ICW assay, it showed a 207 nM higher IC50 compared to TD-417. 50 ICW It showed a slight decrease in activity (IC). To further optimize cellular activity, various eastern side chains with a reduced number of hydrogen bond donors were introduced. The first compound in this set was anilide TD-533, which unfortunately showed slightly reduced potency against the isolated enzyme (IC). 50 II (=6.5nM). However, this compound shows high responsiveness at the cellular level (IC). 50 ICW =1.2nM, Table 11). The second compound in this series is TD-560, which uses the ether side chain of TD-225 (Table 1). Furthermore, this inhibitor showed a slightly reduced potency in the enzyme assay, by an order of magnitude nanomolar range compared to TD-527 (IC). 50 II(10) = 2.5 nM, and the activity in cell assays dramatically increased to 9.4 nM (Table 11). Further attempts to rigidify the terminal amine failed, as shown for compound TD-577, a result consistent with the structure-activity relationship results for biphenyl shown in Table 7. Furthermore, when the 3H-imidazo[4,5-b]pyridine scaffold (see Table 9) was combined with the northern side chain of the indoline system, the resulting TD-559 showed a further increase in potency against the isolated ATM kinase to the picomolar level (Table 10). This high inhibitory activity was well translated into cell activity, with an IC50 of 1.4 nM. 50 ICW Values ​​were obtained (Table 11). Similar activity was observed with the ethyl derivative TD-679 and the inhibitor TD-641, which has a cyclopropyl ring on a sulfonamide, and even higher activity was shown at the cellular level (Tables 10 and 11). Furthermore, this compound showed higher cellular activity than the clinical candidate compound AZD0156.

[0094] The crucial final modification in this series was ring expansion from indoline to tetrahydroquinoline, which yielded the inhibitor TD-640. This compound also produced a 0.96 nM enzyme IC50. 50 The values ​​showed sub-nanomole affinity for ATM and sub-nanomole cellular activity (Table 11). By adding a urea side chain to TD-640, the inhibitor TD-678 was obtained, which exhibited a slightly lower IC50 compared to the isolated enzyme. 50 The value shown was a high intracellular IC of 59 nM. 50 The value was shown (likely due to high polarity). On the other hand, TD-672, a positional isomer of TD-640, has an IC of 249 nM. 50 The observed values ​​clearly indicated a significant decrease in enzyme activity, leading to the conclusion that sulfonamides are causing directional interactions within the ATM kinase binding pocket.

[0095] [Table 11]

[0096] Among sulfonamide inhibitors, TD-559, TD-641, and TD-640 were selected and further characterized. When the stability of these inhibitors in mouse microsomes was examined, TD-559 showed the highest stability with a 35% retention rate after 120 minutes, followed by TD-640 with a retention rate of 23%, and then TD-641 with a retention rate of 10%.

[0097] In addition to their stability within microsomes, the selectivity of these three inhibitors for PIKK family-related kinases and PI3K family-related lipid kinases was further evaluated (Figure 12). For these ATR kinases, all three inhibitors showed reduced selectivity compared to benzimidazole, which was tested in Figure 9. However, the residual activity of these ATR kinases still exceeded 80% in all cases, which is still considered advantageous.

[0098] Regarding the residual activity of mTOR and DNA-PK at a concentration of 1 μM, compound TD-559 showed lower selectivity than its parent inhibitor, TD-347. A similar pattern was observed in the comparison of TD-641 and TD-386 (Figures 9 and 12), with TD-386 showing overall lower selectivity compared to TD-559. Interestingly, TD-640 showed the highest selectivity not only for mTOR and DNA-PK but for all PI3K kinases tested. Furthermore, this compound showed higher selectivity compared to AZD0156 in the tested PIKK kinase and PI3K kinase, excluding ATR and PI3Kd (Pike, KG et al., The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one). Journal of Medicinal Chemistry 2018, 61 (9), 3823-3841. DOI: 10.1021 / acs.jmedchem.7b01896).

[0099] As shown in Figure 11, TD-641 exhibited the lowest stability in microsomes; therefore, derivatives of TD-559 and TD-640 were synthesized to adjust their lipophilicity and basicity (Table 12).

[0100] [Table 12]

[0101] The inhibitor TD-659 is a non-methylated version of TD-559. This compound has a 5 nM IC50 ratio. 50The value showed a decrease in activity, and at the cellular level, the activity decreased even more significantly (IC). 50 ICW (=77nM). When the amino group of this compound was substituted with an alcohol in TD-642 for bioequivalent replacement, the potency decreased even more rapidly, supporting the hypothesis that the basic residue is ionically interacting with the aspartic acid residue in the back pocket. Even in TD-674, a derivative with even higher lipophilicity (compared to TD-659), the IC50 was less than nanomolar. 50 The values ​​were shown. Due to the high lipophilicity of TD-683 and TD-685, a slight increase in activity was observed. Similar SARs can be seen in TD-676 to TD-686, which are analogs of TD-640. The selectivity of these pyrrolidine and piperidine inhibitors for the PIKK and PI3K families was found to be similar to that of the parent compounds TD-559 and TD-640.

[0102] To further evaluate the pharmacokinetics, inhibitors TD-559 and TD-640 were selected, as they showed a compromise between lipophilicity and overall ligand efficiency in terms of molecular weight (Figure 13). Compared to the previous compounds, C max Although low, the C of the TD-559 max It is 57nM, and the C of the TD-640 max Since it is 42nM, IC 50 ICW Values ​​40 to 70 times higher are shown (Figure 13).

[0103] Starting from the initial inhibitor design concept, we created over 30 inhibitor clusters, identifying biphenyl-based inhibitors and sulfonamide-based inhibitors. Since both groups demonstrated high enzymatic activity, we optimized both groups simultaneously.

[0104] Among the biphenyl-based inhibitors, the first inhibitor, LS-48, showed excellent selectivity for the PIKK family and good PK properties, but unfortunately, its cellular activity was limited to 0.6 μM IC5. 50 ICWOnly moderate activity was observed. Many derivatives of LS-48 showed enzyme IC50 activity below 10 nM. 50 Although values ​​were shown, none of the biphenyl-based inhibitors showed sufficient ATM inhibition at the cellular level (A549 cells). In mice, LS-48 showed a high C25 level of 9-10 times. max TD-561, which showed the following, is the most promising. C of this compound max Intracellular IC 50 It is about twice as much as (IC 50 ICW =0.61μM, C max (=1.54 μM), and given the large difference between enzyme activity and cellular activity, it was decided not to further evaluate this group of inhibitors.

[0105] Regarding sulfonamide inhibitors, the first representative one, TD-347, showed high activity against the isolated enzyme (IC). 50 II (IC = 3.7 nM), and due to its unfavorable high polarity and hydrogen bond donor group, its activity at the cellular level is low (IC 50 ICWAt >>1 μM, it exhibited only moderate to low selectivity for mTOR and DNA-PK. To improve cellular activity, we employed alternative methods. Removal of the hydrogen-donating group from the eastern side chain of the urea system did not enhance cellular activity in the desired manner, except for the carbamate ester TD-429. Unfortunately, TD-429 had the drawback of poor metabolic stability during incubation in mouse microsomes. On the other hand, modification of the sulfonamide group by N-methylation masking of NH in TD-417, or by introduction of an indoline ring in TD-527, was found to increase cellular activity. Simultaneously, these modifications in TD-527 resulted in sub-nanomolecal activity increases compared to the isolated enzyme. Furthermore, substitution of the benzimidazole-based hinge motif with a 3H-imidazo[4,5-b]pyridine scaffold and substitution of the eastern side chain of the urea system with N,N-dimethyl-3-(pyridine-2-yloxy)propan-1-amine enhanced the cellular activity of TD-559 to 1.4 nM, and further enhanced the cellular activity of TD-679 and TD-641 to sub-nanomole values. Moreover, TD-641 showed higher cellular activity than AZD0156. The key final modification was ring expansion to 1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline in TD-640, which significantly increased selectivity for closely related kinases within the PIKK family (ATR, mTOR, DNA-PK) as well as for all related kinases tested in the PI3K family (PI3Ka / b / d / g). Furthermore, TD-640 showed improved overall selectivity for all members of the PIKK and PI3K families tested, while maintaining sub-nanomolecular potency at the isolated enzyme and cellular levels. Many derivatives of TD-559 and TD-640 are synthesized with regulated lipophilicity. Moreover, most of these inhibitors showed favorable selectivity for the PIKK and PI3K families, exhibiting sub-nanomolecular enzyme and cellular activity. Pharmacokinetic profile analysis of compounds TD-559 and TD-640 in mice revealed that these inhibitors enhance their own intracellular IC50.50 C is 40 to 70 times the value. max It became clear that the value indicates oral bioavailability.

[0106] [Table 13] JPEG2026511081000075.jpg174153

[0107] In summary, this study has presented numerous novel ATM kinase inhibitors. Their enzymatic and cellular activity increased to picomolar levels. Furthermore, TD-559 and TD-640 inhibitors demonstrated significant selectivity for the PIKK and PI3K families, as well as favorable pharmacokinetic properties.

[0108] The synthesis of the compounds of the present invention will be described below using general terminology.

[0109] All benzimidazole inhibitors begin with 4-bromo-2-fluoro-1-nitrobenzene. This compound can be readily derivatized by introducing the desired northern side chain via a nucleophilic aromatic substitution reaction using the corresponding aniline (Scheme 1). Next, the nitro group is reduced with zinc and ammonium chloride (or EtOH solution of SnCl2·H2O), and the resulting phenylenediamine intermediate is cyclized by treatment with triethyl orthoformate (or triethyl orthoacetate in the case of TD-504, TD-545, and TD-546) and a catalytic amount of p-toluenesulfonic acid to obtain the corresponding benzimidazole. In many cases, chromatographic purification is not required for the production of 6-bromobenzimidazole derivatives.

[0110] [ka]

[0111] The modification of 6-bromobenzimidazole-1-ylaniline (BH or BM) to the corresponding anilide or sulfonanilide is summarized in Scheme 2 below.

[0112] [ka]

[0113] To obtain imidazo[4,5-b]pyridine, S n 2,6-dibromo-3-nitropyridine is used as the starting material for the Ar reaction (Scheme 3). Because this molecule is highly reactive, heating is not required in this reaction. Furthermore, in some cases (especially with para-substituted anilines), replacing the solvent DMF with MeOH or EtOH (Rueckle, T. et al., Preparation of pyridine methylene thioxothiazolidinones as phosphoinositide inhibitors. WO2006024666, 2006) induces precipitation of the product and avoids the formation of disubstituted byproducts. Changing the solvent doubles the yield in the case of TD-589. Usually, the product can be obtained without further chromatographic purification. The reduction of the nitro group and the subsequent ring-closing reaction to produce imidazo[4,5-b]pyridine (Scheme 3) are carried out in the same manner as with benzimidazole described above.

[0114] [ka]

[0115] The basic side chain on the east side can be synthesized from p-bromobenzoic acid by a Curtius rearrangement using DPPA, or directly from 4-bromophenyl isocyanate (Scheme 4) (Dimitrov, T.; Anli, C.; Moschopoulou, AA; Kronenberger, T.; Kudolo, M.; Geibel, C.; Schwalm, MP; Knapp, S.; Zender, L.; Forster, M.; et al. Development of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity. European Journal of Medicinal Chemistry 2022, 235, 114234. DOI: https: / / doi.org / 10.1016 / j.ejmech.2022.114234). Alternatively, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as a starting material, the corresponding pinacol boronic acid ester can be prepared, and then treated with phenyl chloroformate to obtain SSA, which is a carbamic acid ester (Scheme 4).This carbamic acid ester can be isolated or directly converted to a urea derivative by treatment with the corresponding amine under heating (Dimitrov, T.; Anli, C.; Moschopoulou, AA; Kronenberger, T.; Kudolo, M.; Geibel, C.; Schwalm, MP; Knapp, S.; Zender, L.; Forster, M.; et al. Development of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity. European Journal of Medicinal Chemistry 2022, 235, 114234. DOI: https: / / doi.org / 10.1016 / j.ejmech.2022.114234; Kitteringham, J.; Shipton, MR; Voyle, M. A Simple Method for the Synthesis of Unsymmetrical Ureas. Synthetic Communications 2000, 30 (11)). 1937-1943. DOI: 10.1080 / 00397910008087243). The side chains shown in Table 12 are S using the corresponding alcohol. n It is synthesized by an Ar reaction (Scheme 4, DCA~DCE).

[0116] [ka]

[0117] Generally, there are two routes for introducing the basic side chain from the east. The first route involves directly converting 6-bromobenzimidazole via the Suzuki coupling reaction when the basic side chain is obtained as pinacol boronic acid ester. If necessary, benzimidazole can be converted to pinacol boronic acid ester via the Miyaura borylation reaction, followed by modifications as needed (see QA-QF), and then the Suzuki coupling reaction as the final conversion (Scheme 5).

[0118] [ka]

[0119] For indoline and tetrahydroquinoline derivatives, two pathways are used. In the first pathway (A), indoline is protected with a Boc group, allowing for the introduction of various sulfonamide residues in later steps (Scheme 6). If only one sulfonamide residue is required, a shorter two-step synthetic pathway (B) can be taken by directly introducing this sulfonamide residue.

[0120] [ka]

[0121] The initial biphenyl inhibitor, LS-48, was synthesized according to Scheme 1 (starting from the highly carcinogenic 4-aminobiphenyl), but the synthesis was later optimized by performing Suzuki coupling at a later stage (Scheme 7). All compounds shown in Tables 6 and 7 were synthesized following this pathway.

[0122] [ka]

[0123] The starting material for the synthesis of the hybrid molecule TD-541 is 2-bromo-5-nitroaniline. In the following steps, direct mesylation of the starting material generated a large amount of by-reactants, so a Boc group was introduced at the start (Scheme 8). By Suzuki coupling and reduction of the nitro group, compound TD-502 was obtained, and this compound was S n It is converted to TD-523 by the Ar reaction. Therefore, this condition is the same as above S n This is a modified version of the Ar reaction, in which TD-502, an aniline, is deprotonated using NaH in THF. Furthermore, reflux conditions are required. The subsequent steps are the same as the reaction described in the scheme above (compare with Scheme 2 and Scheme 5).

[0124] [ka]

[0125] Some compounds have separate synthetic routes (though they are related), so for simplicity, only an overview is provided below. These include compounds TD-510, TD-505, FM-1000, TD-359, TD-454, TD-516, TD-574, TD-575, TD-577, TD-506, TD-532, TD-412, TD-411, TD-659, and TD-672 (see "Branched Synthetic Routes" in the supplementary materials).

[0126] Further synthesis routes for compounds of the present invention are shown with reference to schemes 9-15 below.

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] [ka] [Brief explanation of the drawing]

[0134] [Figure 1] A) Sequence and domains of the ATM dimer, B) Dimer structure of ATM (PDB: 6K9L), and C) ATP-binding pocket of the kinase domain (KD). Cyan: Hinge region. Green: G-rich loop. Orange: Gatekeeper (L2767). Purple: DLG motif (D2889 / L2890 / G2891). Blue: αC helix.

[0135] [Figure 2] This document lists known ATM kinase inhibitors selected from academic literature.

[0136] Figures 1 and 4 show rational designs for benzimidazole-based ATM kinase inhibitors.

[0137] [Figure 5]This shows a model of the binding modes of LS-13. Benzimidazole acts as a hinge binder, forming a single hydrogen bond to C2770. The urea side chain exhibits multiple interactions, forming hydrogen bonds to K2717 and D2725. The terminal amine shows an ionic bond to D2889. The northern phenyl side chain shows no specific interactions.

[0138] [Figure 6] The initial structure-activity relationship and lead structures derived from LS-13 are shown. LS-48, with p-biphenyl, and TD-347, with m-methylsulfonamide, exhibit significantly enhanced potency against the isolated ATM kinase. Both groups are further optimized simultaneously.

[0139] [Figure 7] This shows TD-541, a hybrid inhibitor possessing the biphenyl motif of LS-48 and the sulfonamide motif of TD-347.

[0140] [Figure 8] It exhibits stability within 120 minutes in mouse liver microsomes. 43% of TD-347 and 63% of LS-48 can be detected after 120 minutes.

[0141] [Figure 9] This demonstrates the selectivity of LS-48, TD-347, TD-386, and the hybrid molecule TD-541 within the PIKK family (n=2).

[0142] [Figure 10] The pharmacokinetics of LS-48, TD-541, and TD-561 in mice are shown. Each inhibitor was administered orally as a single dose of 10 mg / kg (n=3).

[0143] [Figure 11] This demonstrates the stability of TD-559, TD-641, and TD-640 in mouse microsomes.

[0144] [Figure 12] The selectivity of TD-559, TD-641, and TD-640 for various a) PIKK kinases and b) PI3K kinases is demonstrated (n=2).

[0145] [Figure 13] The pharmacokinetics of TD-559 and TD-640 in mice after oral administration at a dose of 10 mg / kg are shown. Cmax(TD-559) = 57 nM. Cmax(TD-640) = 42 nM. (n=3).

[0146] [Figure 14] This study demonstrates assay correlation between the Eurofins KinaseProfiler™ assay and the Reaction Biology assay. To determine the correlation, seven inhibitors (LS-48, TD-347, TD-386, TD-512, TD-527, TD-533, and TD-541) were measured under the same assay conditions (five dose levels, 4-fold serial dilutions starting from 0.1 μM).

[0147] [Figure 15] An example of the ICW assay is shown.

[0148] [Figure 16] The drug exhibits stability within 120 minutes in mouse liver microsomes. 43% of TD-347 and 63% of LS-48 can be detected after 120 minutes. TD-429, a carbamate salt, shows a residual amount of 9%. [Examples]

[0149] Molecular modeling was performed according to the method described at https: / / doi.org / 10.1016 / j.ejmech.2022.114234 (Zimmermann, A.; Zenke, FT; Chiu, L.-Y.; Dahmen, H.; Pehl, U.; Fuchss, T.; Grombacher, T.; Blume, B.; Vassilev, LT; Blaukat, A. A New Class of Selective ATM In-hibitors as Combination Partners of DNA Double-Strand Break Inducing Cancer Therapies. Molecular cancer therapeutics 2022, 21 (6), 859-870. DOI: 10.1158 / 1535-7163.mct-21-0934 PubMed).

[0150] Biological assays The biochemical efficacy of ATMs All compounds were prepared as stock solutions in 10 mM DMSO.

[0151] Reaction Biology The biochemical potency of isolated ATM kinases was measured by Reaction Biology (https: / / www.reactionbiology.com) using a FRET-based assay. Each compound was measured at five different doses using serial dilutions starting from a concentration of 10 μM. 50 The test was conducted in a specific mode. Compound 6 (AZD0156) as a control compound was used in 10 step dose ICs using 3-fold serial dilutions starting from a concentration of 100 nM. 50 The test was performed in a specific mode. The FRET assay consisted of two steps: 1. an enzymatic step in which substrate p53 is phosphorylated with ATP via ATM, and 2. a stop-detection step in which the reaction is stopped using a stop reagent and the detection reagent is bound to the p53 with the 15th serine phosphorylated. The resulting FRET signal is proportional to the phosphorylation level.

[0152] Eurofins KinaseProfiler TM Furthermore, the biochemical efficacy of isolated ATM kinases within a controlled concentration range was measured using Eurofins KinaseProfiler. TM The results were measured using (14-933KP10). The correlation between the two assays was calculated for seven different inhibitors (Figure 14). Summary of the procedure: "Incubate ATM(h) in assay buffer containing 30 nM GST-cMyc-p53 and Mg / ATP (at the required concentration). Initiate the reaction by adding the Mg / ATP mix. After incubation at room temperature for 30 minutes, stop the reaction by adding a stop solution containing EDTA. Finally, add a detection buffer containing d2-labeled anti-GST monoclonal antibody and europium-labeled anti-phosphorylated Ser15 antibody against phosphorylated p53. Next, read the plate in time-resolved fluorescence mode and determine the homogeneous time-resolved fluorescence (HTRF) signal using the following formula: HTRF = 10000 × (Em665 nm / Em620 nm)." (Source and details: https: / / www.eurofinsdiscoveryservices.com / , ITEM 14-933KP10). Correlations of an exemplary assay are shown in Figure 14.

[0153] ATM cell activity The in-cell Western blotting protocol for testing novel ATM inhibitors in A549 cells was based on the report by Guo et al. Briefly, the day before the experiment, 1.5 × 10⁶ 4A549 cells were seeded. Cells were treated with a combination of serially diluted novel ATM inhibitors and 25 μM etoposide. After 1 hour of treatment, cells were fixed and stained with 4% PFA according to the ICW protocol reported by Guo et al. Fluorescence images were obtained by scanning plates with an Odyssey classic automated infrared imaging system (LI-COR Biosciences) using a 700 nm detector (DRAQ5) or an 800 nm detector (pKap1). Signal intensity was then quantified using Image Studio software. Dose-response curves were analyzed using GraphPad Prism (version 9.1.2, San Diego, California, USA) (4-parameter nonlinear dose-response - variable slope) (Zimmermann et al.).

[0154] Screening for selectivity against related kinases and common off-targets Eurofins KinaseProfiler TM Selectivity data was obtained using the following biochemical assays. The assays were performed in double-chain configurations at a concentration of 1 μM (unless otherwise specified), using DMSO and 10 μM ATP as controls (=100% activity). Lower values ​​indicate a stronger hit. For all compounds, a stock solution in 10 mM DMSO was used.

[0155] [Table 14]

[0156] Table 143: Selectivity of TD-683, TD-685, TD-684, and TD-686 in the PIKK and PI3K families.

[0157] Drug metabolism and pharmacokinetic (DMPK) experiments Stability within microsomes Liver microsomes pooled from male mice were purchased from Xenotech. Incubation of each compound was performed using an NADPH regeneration system (5 mM glucose-6-phosphate, 5 U / mL glucose-6-phosphate dehydrogenase, and 1 mM NADP). + The reaction was carried out in the presence of ( ). Each compound (100 μM), NADPH regeneration system, and 4 mM MgCl2·6H2O were pre-incubated in 0.1 M Tris buffer (pH 7.4) on a shaker at 37°C and 750 rpm for 5 minutes. The incubated mixture was divided into 50 μL samples, and the reaction was initiated by adding mouse liver microsomes. The reaction was stopped at selected time points (0, 10, 20, 30, 60, and 120 minutes) by adding 100 μL of 50 μM internal standard MeCN solution. The samples were vortexed for 30 seconds and centrifuged (19,800 g, 4°C, 15 minutes). The supernatant was used directly for LC-MS analysis. All incubations were performed in triplicate, and the amount of added organic solvent was limited to 1%.

[0158] Sample separation was performed using an Alliance 2695 HPLC (Waters, Eschborn) equipped with a Phenomenex Synergi column (4 μm, polar C18, 100 Å, 75 × 4.60 mm) by a 15-minute gradient. Mobile phase A: H2O water / acetonitrile with 0.1% (v / v) formic acid = 90% / 10%; Mobile phase B: acetonitrile with 0.1% (v / v) formic acid. The gradient conditions were set to 5%B (0-2.5 min) → 5-25%B (2.5-10.0 min) → 25%B (10.0-12.0 min) → 25-5%B (12.0-12.01 min) at a flow rate of 1.4 mL / min. The sample was maintained at 10°C, the column temperature was set to 40°C, and the injection volume was 5 μL. Detection was performed using positive-mode electrospray ionization with a Micromass Quattro micro triple quadrupole mass spectrometer (Waters, Eschborn). The spray voltage was set to 4kV, the cone voltage to 30V, the extraction voltage to 5V, and the RF lens voltage to 1V. The desolvation temperature was set to 350°C, and the desolvation gas flow rate was 650 l / h. The data were analyzed using MassLynx 4.0. The stability of TD-347, LS-48, and TD-429 in microsomes is shown in Figure 16.

[0159] Pharmacokinetics (mouse) Pharmacokinetic studies were conducted at Pharmacelsus (GBA Holding GmbH Group). Each compound was administered at a dose of 10 mg / kg as an oral formulation containing 10% EtOH, 30% PEG400, and 60% Phosal 50PG (cassette dosing, n=3, sex: male, strain: C57BL6). Blood samples from each mouse were collected from the tail vein and placed in a lithium heparin tube. Blood concentrations were measured 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, or 24 hours after administration, or 0.5 hours, 1 hour, 2 hours, 4 hours, or 8 hours after administration.

[0160] Minikinase Panel To further evaluate the selectivity of the compounds of the present invention, a minikinase panel was designed. This minikinase panel contains a total of 33 kinases from various groups, covering most representative examples of human kinomes evaluated based on various kinase inhibitor analytical methods (see experimental procedure). Table 6 reports on these kinases and the assay results.

[0161] Representative kinases covering the human kinome were selected based on two independent studies and those available in the Eurofin KinaseProfiler assay. First, a network of inhibitor-based kinase relationships was constructed using a set of 36,626 multi-kinase inhibitors active against 420 human kinases to identify kinases that share at least 50 inhibitors with other kinases (Laufkotter, O.; Laufer, S.; Bajorath, J. Identifying representative kinases for inhibitor evaluation via systematic analysis of compound-based target relationships. European Journal of Medicinal Chemistry 2020, 204, 112641. DOI: https: / / doi.org / 10.1016 / j.ejmech.2020.112641). We selected the top 15 kinases that formed compound-based relationships with over 100 other kinases, and 14 of these were found to be usable in KinaseProfiler (Kinase group TK: FLT3, ABL1, KDR, LCK, FRK, and JAK3; CMGC: GSK3B, CLK4, CDK2, DYRK1A, HIPK2, and CDC2; Variant: P110a; Others: AURB). If activity is shown for any of these kinases, it indicates a high degree of ambiguity regarding specificity to the human kinome (Laufkotter et al.). These 14 kinases were named Subset 1.

[0162] Next, based on the kinase hit (selectivity) index obtained from a series of profile analyses of 3,000 inhibitors against 414 human kinases, another kinase that best reproduced the assay data was selected from the mini-panel (Bembenek, SD; Hirst, G.; Mirzadegan, T. Determination of a Focused Mini Kinase Panel for Early Identification of Selective Kinase Inhibitors. Journal of Chemical Information and Modeling 2018, 58 (7), 1434-1440. DOI: 10.1021 / acs.jcim.8b00222). The original mini-panel has been reported to contain 20 or 50 kinases, covering a broad range of kinomes. Of these, 14 kinases were available in KinaseProfiler, and these 14 kinases were named Subset 2 (TK: BRK, PDGFRB, PYK2, ALK, EGFR; CMGC: CDKL1; CAMK: CHEK2; Others: CAMKK2, IKKε, STK35, TLK1; AGC: GRK1, PRKCQ; STE: PAK1). Two other suitable and available kinases (HIPK3 and CDC2L5) were excluded from Subset 2 because corresponding isoforms (HIPK2 and CDC2, respectively) were present in Subset 1. Furthermore, ABL1 is common to both subsets and is already included in Subset 1. In addition, the wild type is already included for EGFR mutations.Therefore, subsets 1 and 2 contained a total of 28 kinases for the proposed mini-panel, prioritized by two characteristic analytical methods (Laufkotter et al.; Bembenek, SD; Hirst, G.; Mirzadegan, T. Determination of a Focused Mini Kinase Panel for Early Identification of Selective Kinase Inhibitors. Journal of Chemical Information and Modeling 2018, 58 (7), 1434-1440. DOI: 10.1021 / acs.jcim.8b00222).

[0163] Synthesis of the Compound of the Present Invention General Matters Unless otherwise specified, all starting materials and reagents are of commercial quality and are used as is without further purification. Thin-layer chromatography (TLC) is performed on Merck 60 F254 silica plates and Macherey-Nagel ALUGRAM® Xtra SIL G / UV254 silica plates, and visualization is performed using UV light (254 nm and 366 nm) or color development with appropriate staining reagents. Preparative column chromatography is performed using an Interchim PuriFlash 430 automated flash chromatography system or a PuriFlash XS420 automated flash chromatography system, and unless otherwise specified, normal-phase silica gel (Grace Davison Davisil® LC60A 20-45 μm or Merck Geduran® Si60 63-200 μm) or reverse-phase silica gel (Merck LiChroprep® RP-18 40-63 μm) is used. 1 H spectrum and 131C spectra were recorded using a Bruker Avance 200, Bruker Avance 400, or Bruker Avance III HD instrument. Each sample was dissolved in a deuterated solvent, and the chemical shift was reported relative to tetramethylsilane (TMS). Each spectrum was calibrated using the residual peak of the solvent used. Mass spectrometry was performed in cation and / or anion modes by electron spray ionization (ESI) using an Advion TLC-MS interface. The TLC-MS instrument settings were: ESI voltage: 3.50kV, capillary voltage: 187V, power supply voltage: 44V, capillary temperature: 250°C, desolvation gas temperature: 250°C, and gas flow rate: 5L / min (nitrogen). The purity of the final compound was measured by one of the following methods. Method A (used for all compounds unless otherwise specified) is performed using an Agilent 1100 series LC equipped with a Phenomenex Luna C8 column (150 × 4.6 mm, 5 μm) and detection is performed at wavelengths of 254 nm and 230 nm by UV DAD. The elution gradient is prepared using 0.01 M KH2PO4 (pH 2.30) (solvent A) and MeOH (solvent B), with 40%B to 85%B for 8 minutes, 85%B for 5 minutes, 85%B to 40%B for 1 minute, 40%B for 2 minutes, a stop time of 16 minutes, and a flow rate of 1.5 ml / min. In Method B, detection is performed using an Agilent 1100 series LC equipped with a Phenomenex Luna C8 column (150 × 4.6 mm, 5 μm) and detection is performed at wavelengths of 254 nm and 230 nm by UV DAD. The elution gradient is created using 0.01 M KH2PO4 (pH 2.30) (solvent A) and MeOH (solvent B), with 40%B to 90%B for 10 minutes, 90%B for 13 minutes, 90%B to 40%B for 1 minute, 40%B for 1 minute, a 24-minute stop, and a flow rate of 1.5 ml / min. Method C uses an Agilent 1260 HPLC system from Agilent Technologies (Waldbronn, Germany) equipped with a UV-DAD detector, degasser, autosampler, and quaternary pump. Column: YMC Triart C18, particle size: 1.9 μm, 100 mm × 2 mm (length × inner diameter).The mobile phases are A: water + 0.1% formic acid, and B: acetonitrile + 0.1% formic acid. The gradient is A: 90% at 0.00 min, A: 20% at 15.00 min, A: 20% at 20.00 min, and A: 90% at 20.01 min. The flow rate is 0.5 mL / min, the column temperature is 25°C, and the wavelengths are 230 nm and 254 nm.

[0164] Compounds of Scheme 1 5-Bromo-2-nitro-N-phenylaniline (TD-324, AA) [ka] To a solution of 1100 mg of 4-bromo-2-fluoro-1-nitrobenzene (5.00 mmol) in anhydrous DMF (7 ml), 605 mg of aniline (6.50 mmol) and 0.9 ml of Et3N (6.5 mmol) were added. The reaction mixture was heated overnight at 70°C until HPLC indicated that the starting materials were completely consumed. The reaction mixture was diluted with water, and the product was recovered by filtration. The resulting orange solid was dried in a convection oven at 70°C. Yield: 1347 mg, orange solid (92%). 1 H NMR (200 MHz, DMSO) δ 9.49 (s, 1H), 8.08 - 8.00 (m, 1H), 7.52 - 7.41 (m, 2H), 7.39 - 7.21 (m, 3H), 7.16 (d, J = 1.8 Hz, 1H), 7.05 - 6.96 (m, 1H). 13 C NMR (50 MHz, DMSO) δ 143.2, 138.5, 132.3, 130.0, 129.7, 128.2, 125.8, 124.7, 120.5, 118.3. HPLC t ret = 9.96 min.

[0165] 5-Bromo-N-(4-fluorophenyl)-2-nitroaniline (LS-05, AB) [ka] The procedure was the same as for TD-324 and AA, except that 209 mg of 4-bromo-2-fluoro-1-nitrobenzene (0.95 mmol), 0.26 ml of 4-fluoroaniline (2.67 mmol), and 0.2 ml of Et3N (1.4 mmol) were used in 2 ml of anhydrous DMF. Yield: 282 mg, orange-brown solid (95%). 1 H NMR (200 MHz, DMSO) δ 9.47 (s, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.45 - 7.23 (m, 4H), 7.07 - 6.95 (m, 2H). 13 C NMR (50 MHz, DMSO) δ 160.0 (d, J = 242.9 Hz), 143.7, 134.8 (d, J = 2.9 Hz), 132.1, 130.1, 128.2, 127.5 (d, J = 8.5 Hz), 120.3, 118.1, 116.5 (d, J = 22.6 Hz). HPLC t ret = 9.83 min.

[0166] 5-Bromo-N-(4-methoxyphenyl)-2-nitroaniline (LS-02, AE) [ka] The procedure was the same as for TD-324 and AA, except that 209 mg of 4-bromo-2-fluoro-1-nitrobenzene (0.95 mmol), 152 mg of 4-methoxyaniline (1.24 mmol), and 0.2 ml of Et3N (1.4 mmol) were used in 2 ml of anhydrous DMF. Yield: 273 mg, orange solid (89%). 1 H NMR (200 MHz, DMSO) δ 9.45 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.34 - 7.20 (m, 2H), 7.09 - 6.99 (m, 2H), 6.98 - 6.87 (m, 2H), 3.79 (s, 3H). 13C NMR (50 MHz, DMSO) δ 157.7, 144.6, 131.3, 130.7, 130.2, 128.2, 127.5, 119.6, 117.8, 115.0, 55.3. HPLC t ret = 10.10 min.

[0167] (4-((5-bromo-2-nitrophenyl)amino)phenyl)carbamate tert-butyl (TD-343, AF) [ka] The same procedure as for the preparation of TD-324, AA described above was followed, except that 5200 mg of 4-bromo-2-fluoro-1-nitrobenzene (23.67 mmol), 5415 mg of tert-butyl (4-aminophenyl)carbamate (26.00 mmol), and 3.28 ml of Et3N were used in 20 ml of anhydrous DMF and the reaction was carried out at 75°C. The reaction was stopped with 100 ml of water. The desired product was recovered by filtration, washed with water, and air-dried. The crude product was suspended in 250 ml of hot MeOH. The suspension was cooled to -10°C and the product was recovered by filtration. Yield: 8644 mg, orange solid (87%). 1 H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 9.45 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 1.7 Hz, 1H), 6.93 (dd, J = 9.1, 1.8 Hz, 1H), 1.48 (s, 9H). 13 HPLC t ret = 10.45 min.

[0168] N-(4-((5-bromo-2-nitrophenyl)amino)phenyl)acetamide (TD-290, AG) [ka] The same procedure as for the preparation of TD-324, AA described above was followed, except that 471 mg of 4-bromo-2-fluoro-1-nitrobenzene (2.14 mmol), 369 mg of N-(4-aminophenyl)acetamide (2.45 mmol), and 0.34 ml of Et3N were used in 6 ml of anhydrous DMF and the reaction was carried out at 60°C. Stirring was continued for 2 days until TLC indicated that the starting materials had been completely consumed. The reaction was stopped with water. The desired product was recovered by filtration, washed with water, and then air-dried. Yield: 665 mg, orange solid (89%). 1 H NMR (200 MHz, DMSO) δ 10.05 (s, 1H), 9.46 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.10 - 7.00 (m, 1H), 7.00 - 6.91 (m, 1H), 2.06 (s, 3H). 13 C NMR (50 MHz, DMSO) δ 168.3, 144.0, 137.5, 133.0, 131.7, 130.1, 128.2, 125.9, 120.0, 120.0, 118.0, 24.0. ret = 8.96 min. ESI-MS m / z: 358.1 [MH] - , 372.2 [M+Na] + .

[0169] 5-Bromo-N-(4-cyclohexylphenyl)-2-nitroaniline (TD-456, AAA) [ka] The same procedure as for the preparation of Example TD-324 was followed, except that 736 mg of 4-bromo-2-fluoro-1-nitrobenzene (4.2 mmol), 770 mg of 4-cyclohexylaniline* (3.5 mmol), and 0.6 ml of Et3N were used in 5 ml of anhydrous DMF, and the reaction was carried out overnight at 70°C until HPLC indicated that the starting materials were completely consumed. The reaction was stopped with saline. The product was extracted with ethyl acetate. The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (PE / EA = 0-1%). MeOH was overlaid on the product and allowed to solidify. The resulting suspension was heated under reflux and stored at -18°C. The mother liquor was removed by decantation, and the product was washed with a small amount of MeOH. Yield: 854 mg (71%). 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 9.1, 2.0 Hz, 1H), 2.59 - 2.52 (m, 1H), 1.88 - 1.76 (m, 4H), 1.75 - 1.68 (m, 1H), 1.48 - 1.31 (m, 4H), 1.30 - 1.20 (m, 1H). 13 HPLC t ret = 13.53min. ESI-MS m / z: 373.4 [MH] - .

[0170] *4-Cyclohexylaniline synthesis: To a solution of 1.5 mol of 1189 mg of 2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-amine (0.40 mmol) in EtOH, 2144 mg of NH4HCOO was added, followed by 60 mg of Pd / C. The reaction mixture was heated under reflux until HPLC indicated that the starting materials were completely consumed. The reaction mixture was cooled to room temperature and filtered through Celite. The crude product was purified by flash chromatography using petroleum ether and ethyl acetate (0-70%) to obtain the desired product as a red oily substance. This product solidified rapidly. Yield: 744 mg, solid (62%). 1 H NMR (400 MHz, DMSO) δ 6.84 (d, J = 8.3 Hz, 2H), 6.47 (d, J = 8.4 Hz, 2H), 4.84 (s, 2H), 2.35 - 2.22 (m, 1H), 1.81 - 1.62 (m, 5H), 1.38 - 1.11 (m, 5H). 13 C NMR (101 MHz, DMSO) δ 146.4, 135.0, 126.8, 113.9, 42.9, 34.4, 26.5, 25.7. HPLC t ret = 5.72min. ESI-MS m / z: 176.2 [M+H] + .

[0171] N-(5-bromo-2-nitrophenyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-amine (TD-449, AAB) [ka] The same procedure as for the preparation of Example TD-324 was followed, except that 1100 mg of 4-bromo-2-fluoro-1-nitrobenzene (5.0 mmol), 1040 mg of aniline (6.0 mmol), and 0.83 ml of Et3N were used in 5 ml of anhydrous DMF and the reaction was carried out at 70°C for 2 days. Stirring was continued until TLC indicated that the starting materials had been completely consumed. The reaction was stopped with water. The crude product was suspended in MeOH and heated under reflux. The resulting suspension was cooled in an ice bath, and the desired product was recovered by filtration. Yield: 1614 mg, red crystals / solid (86%). 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 9.0, 2.0 Hz, 1H), 6.25 - 6.17 (m, 1H), 2.42 - 2.33 (m, 2H), 2.24 - 2.14 (m, 2H), 1.77 - 1.68 (m, 2H), 1.65 - 1.56 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 143.1, 139.1, 136.9, 135.0, 132.2, 130.0, 128.2, 125.7, 124.4, 124.3, 120.4, 118.3, 26.5, 25.4, 22.5, 21.7. HPLC t ret = 13.19 min.

[0172] 5-Bromo-N-(3-methoxyphenyl)-2-nitroaniline (LS-03, AJ) [ka] The procedure was the same as for TD-324 and AA, except that 209 mg of 4-bromo-2-fluoro-1-nitrobenzene (0.95 mmol), 0.14 ml of 3-methoxyaniline (1.24 mmol), and 0.2 ml of Et3N (1.4 mmol) were used in 2 ml of anhydrous DMF. Yield: 256 mg, orange-brown solid (83%). 1 H NMR (200 MHz, DMSO) δ 9.43(s, 1H), 8.04 (d, J = 9.0Hz, 1H), 7.41 - 7.29 (m, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 9.0, 2.1 Hz, 1H), 6.96 - 6.88 (m, 2H), 6.87 - 6.78 (m, 1H), 3.76 (s, 3H). 13 HPLC t ret = 10.06 min.

[0173] 1-(3-((5-bromo-2-nitrophenyl)amino)phenyl)ethane-1-one (LS-29, AK) [ka] The procedure was the same as for TD-324 and AA, except that 209 mg of 4-bromo-2-fluoro-1-nitrobenzene (0.95 mmol), 167 mg of 1-(3-aminophenyl)ethane-1-one (1.24 mmol), and 0.2 ml of Et3N (1.4 mmol) were used in 2 ml of anhydrous DMF. Yield: 246 mg, yellow solid (77%). 1H NMR (200 MHz, DMSO) δ 9.54 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.85 - 7.74 (m, 1H), 7.67 - 7.54 (m, 2H), 7.28 - 7.17 (m, 1H), 7.13 - 7.00 (m, 1H), 2.59 (s, 3H). 13 HPLC t ret = 9.03 min.

[0174] 5-Bromo-N-(2-fluorophenyl)-2-nitroaniline (LS-12, AM) [ka] The procedure was the same as for TD-324 and AA, except that 209 mg of 4-bromo-2-fluoro-1-nitrobenzene (0.95 mmol), 0.13 ml of 2-fluoroaniline (1.24 mmol), 0.2 ml of Et3N (1.4 mmol), and 38 mg of NaH (0.95 mmol, 60 wt%) were used in 2 ml of anhydrous DMF. The resulting product was purified by flash chromatography (PE=100%). Yield: 130 mg, yellow solid (44%). 1 H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 8.07 (d, J = 9.1Hz, 1H), 7.55 - 7.23 (m, 4H), 7.10 - 6.99 (m, 1H), 6.86 (t, J = 1.9 Hz, 1H). HPLC tret = 9.70 min.

[0175] 5-Bromo-N-(2-methoxyphenyl)-2-nitroaniline (TD-353, AO) [ka] The same procedure as for the preparation of TD-324 and AA described above was followed, except that 660 mg of 4-bromo-2-fluoro-1-nitrobenzene (3.00 mmol), a total of 526 mg of 2-methoxyaniline (3.92 mmol), and 1.0 ml of Et3N were used in anhydrous DMF and the reaction was carried out at 70°C. Stirring was continued overnight. The reaction was stopped with water, the desired product was recovered by filtration, washed with water, and air-dried. The crude product was purified by stirring in hot methanol. After the suspension was cooled to room temperature, the product was recovered as a red solid (482 mg, 50%) by filtration. 1 H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.38 (dd, J = 7.8, 1.5 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.18 (dd, J = 8.3, 1.1 Hz, 1H), 7.05 (dd, J = 7.6, 1.2 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 9.0, 2.1 Hz, 1H), 3.81 (s, 3H). 13 HPLC t ret = 10.02 min.

[0176] 6-Bromo-1-phenyl-1H-benzo[d]imidazole (TD-326, BA) [ka] Step 1: An EtOH solution of 586 mg of TD-324 (2.0 mmol) and 1900 mg of SnCl2·2H2O (8.4 mmol) was heated to 70°C. After successful control of the reaction was confirmed by TLC, the reaction was stopped with saturated NaHCO3 and extracted three times with EA. The organic phase was dried with Na2SO4 and the solvent was removed under reduced pressure. The resulting crude diamine was used directly in Step 2.

[0177] Step 2: To a toluene (10 ml) solution of the above diamine, 0.99 ml of triethyl orthoformate (6.0 mmol) and 38 mg of p-TsOH·H2O (0.2 mmol) were added, and the reaction mixture was stirred overnight at 70°C. The crude product was purified by flash chromatography (DCM / MeOH = 0.5-5%) to obtain 403 mg of the desired product (74%). 1 H NMR (200 MHz, DMSO) δ 8.61 (s, 1H), 7.78 - 7.71 (m, 2H), 7.70 - 7.58 (m, 4H), 7.57 - 7.41 (m, 2H). 13 C NMR (50 MHz, DMSO) δ 144.4, 142.9, 135.4, 134.3, 130.2, 128.1, 125.5, 123.9, 121.7, 115.9, 113.4. HPLC t ret = 8.89 min.

[0178] 6-Bromo-1-(4-fluorophenyl)-1H-benzo[d]imidazole (LS-09, BB) [ka] The same procedure as for the preparation of TD-326 described above was followed, except that 200 mg of LS-05 (0.643 mmol) and 580 mg of SnCl2·2H2O (2.57 mmol) were used in 15 ml of EtOH. Step 2: A solution of 0.32 ml of triethyl orthoformate (1.9 mmol) and 12 mg of p-TsOH·H2O (0.064 mmol) in toluene (10 ml) was used. Flash chromatography gradient: PE / EA = 5-40%. Yield: 174 mg (93%).1 H NMR (200 MHz, DMSO) δ 8.57 (s, 1H), 7.81 - 7.68 (m, 4H), 7.53 - 7.41 (m, 3H). HPLC t ret = 8.81 min. ESI-MS m / z: 290.9 [M+H] + .

[0179] 6-Bromo-1-(4-methoxyphenyl)-1H-benzo[d]imidazole (LS-06, BE) [ka] The same procedure as for the preparation of TD-326 described above was followed, except that 201 mg of LS-02 (0.622 mmol) and 562 mg of SnCl2·2H2O (2.49 mmol) were used in 10 ml of EtOH. Step 2: A solution of 0.31 ml of triethyl orthoformate (1.9 mmol) and 12 mg of p-TsOH·H2O (0.064 mmol) in toluene (10 ml) was used. Flash chromatography gradient: PE / EA = 40-70%. Yield: 174 mg, solid (93%). 1 H NMR (200 MHz, DMSO) δ 8.51 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.65 - 7.55 (m, 3H), 7.43 (dd, J = 8.6, 1.8 Hz, 1H), 7.20 - 7.12 (m, 2H), 3.84 (s, 3H). 13 C NMR (50 MHz, DMSO) δ 158.9, 144.5, 142.6, 134.8, 128.2, 125.7, 125.3, 121.6, 115.7, 115.2, 113.2, 55.5. ret = 8.95 min. ESI-MS m / z: 303.0 [M+H] + .

[0180] (4-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)carbamate tert-butyl (TD-345, BF) [ka] Step 1: The same procedure as for the preparation of TD-280 was followed, except that 2858 mg of TD-343 (7.00 mmol), 3744 mg of NH4Cl (70.0 mmol), and 4577 mg of zinc powder (70.0 mmol) were used in 50 ml of MeOH. Step 2: 3.5 ml of triethyl orthoformate (21 mmol) and 133 mg of p-TsOH·H2O (0.7 mmol) were reacted overnight at 70°C until TLC indicated that the starting materials were completely consumed. Flash chromatography gradient: DCM / MeOH = 1-6%. Yield: 2668 mg, brown solid (98%). 1 H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 8.54 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.72 - 7.67 (m, 3H), 7.56 (d, J = 8.9 Hz, 2H), 7.44 (dd, J = 8.6, 1.8 Hz, 1H), 1.49 (s, 9H). 13 HPLC t ret = 9.84 min. ESI-MS m / z: 410.0 [M+Na] + , 444.1 [M+MeOH+Na] + .

[0181] N-(4-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)acetamide (TD-312, BG) [ka] Step 1: The same procedure as for the preparation of TD-326 was followed, except that 350 mg of TD-290 (1.0 mmol) and 1800 mg of SnCl2·2H2O (8.0 mmol) were used in 40 ml of EtOH. After successful control of the reaction was confirmed by TLC (after 4 hours), the reaction was stopped with saturated NaHCO3 and extracted three times with diethyl ether. Step 2: The same procedure as for the preparation of TD-280 was followed, except that 0.50 ml of triethyl orthoformate (3.0 mmol) and 19 mg of p-TsOH·H2O (0.1 mmol) were used in EtOH (reaction time: 2 hours). The crude product was purified by flash chromatography (DCM / MeOH = 1.5-5%) to obtain 215 mg of the desired product (65%). 1 H NMR (200 MHz, DMSO) δ 10.21 (s, 1H), 8.54 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.77 - 7.68 (m, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.43 (dd, J = 8.8, 1.6 Hz, 1H), 2.10 (s, 3H). 13 C NMR (DMSO) δ:168.6, 144.3, 142.7, 139.2, 134.5, 130.1, 125.4, 124.5, 121.6, 120.1, 115.8, 113.4, 24.0. HPLC t ret = 7.45 min. ESI-MS m / z: 329.9 [M+H] + .

[0182] 4-(6-bromo-1H-benzo[d]imidazole-1-yl)aniline (TD-314, TD-346, BH) [ka] In a microwave reaction vial, 500 mg of TD-312 (1.51 mmol) was suspended in 9 ml of KOH (1 M) methanol solution and an excess amount of water. The reaction mixture was stirred in a microwave oven at 140°C for 25 minutes. The reaction mixture was poured into saline solution, and the resulting product was extracted by DCM. The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH = 0.5-5%) to obtain 351 mg of the desired product as a solid (80%). 1 H NMR (200 MHz, DMSO) δ 8.39 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.39 (dd, J = 8.5, 1.9 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 5.48 (s, 2H). 13 C NMR (50 MHz, DMSO) δ 149.1, 144.6, 142.5, 135.2, 125.3, 124.9, 123.4, 121.5, 115.4, 114.3, 113.2. HPLC t ret = 6.31 min. ESI-MS m / z: 288.0 [M+H] + .

[0183] Alternative synthesis: Using a 2020 mg solution of TD-345 (5.18 mmol) in EtOH (150 ml) as a starting material, the same procedure as for the preparation of TD-319 can be followed. HCl (gas, excess) was added, and the reaction mixture was stirred under heating (50°C) until TLC indicated that the starting material had been completely consumed. The reaction mixture was diluted with approximately 150 ml of diethyl ether, and the product was recovered by filtration as hydrochloride. Yield: 1408 mg, pinkish-white solid (84%).

[0184] N-(4-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)isobutylamide (TD-402, BBM) [ka] The same procedure as for the preparation of TD-334 was followed, except that 144 mg of TD-314 (0.50 mmol), 153 mg of EDC·HCl (0.80 mmol), and 73 μl of thiazole-4-carboxylic acid (0.81 mmol) were used in 3 ml of anhydrous DCM. Flash chromatography gradient: DCM / MeOH = 0.5-5%. Yield: 145 mg, colorless solid (81%). 1 H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 8.53 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.76 - 7.68 (m, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.48 - 7.41 (m, 1H), 2.71 - 2.58 (m, 1H), 1.14 (d, J = 6.7 Hz, 6H). 13 HPLC t ret = 8.77 min. ESI-MS m / z: 356.3 [MH] - , 392.4 [M+Cl] - .

[0185] 6-Bromo-1-(4-cyclohexylphenyl)-1H-benzo[d]imidazole (TD-457, TD-458, BAA) [ka] Step 1: The same procedure as for the preparation of Example TD-280 was followed, except that 804 mg of TD-456 (2.14 mmol), 916 mg of NH4Cl (17.1 mmol), and 1.373 mg of zinc powder (25.7 mmol) were used in 50 ml of MeOH. Step 2: 1.1 ml of triethyl orthoformate (6.4 mmol) and 70 mg of p-TsOH·H2O (0.24 mmol) were used in 50 ml of toluene and reacted overnight at 70-75°C until TLC indicated that the starting materials were completely consumed. Flash chromatography gradient: DCM / MeOH (%). Yield: 516 mg (68%). 1 H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.49 - 7.43 (m, 3H), 2.66 - 2.57 (m, 1H), 1.88 - 1.78 (m, 4H), 1.76 - 1.68 (m, 1H), 1.51 - 1.33 (m, 4H), 1.31 - 1.20 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 147.7, 144.4, 142.6, 134.4, 133.1, 128.3, 125.5, 123.9, 121.6, 115.9, 113.4, 43.3, 33.8, 26.3, 25.5. HPLC t ret = 12.87 min. ESI-MS m / z: 355.4 [M+H] + .

[0186] 6-Bromo-1-(2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole (TD-451, TD-452, BAB) [ka] Step 1: The same procedure as for the preparation of Example TD-280 was followed, except that 1432 mg of TD-449 (3.83 mmol), 2048 mg of NH4Cl (38.3 mmol), and 2504 mg of zinc powder (38.3 mmol) were used in 50 ml of MeOH. Step 2: Using a toluene (50 ml) solution of 1.9 ml of triethyl orthoformate (11.5 mmol) and 73 mg of p-TsOH·H2O (0.38 mmol), the mixture was reacted overnight at 70°C until TLC indicated that the starting materials were completely consumed. Flash chromatography gradient: DCM / MeOH = 0-1.9%. Yield: 862 mg (64%). 1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 7.76 - 7.72 (m, 2H), 7.65 - 7.60 (m, 4H), 7.45 (dd, J = 8.6, 1.8 Hz, 1H), 6.30 - 6.25 (m, 1H), 2.45 - 2.39 (m, 2H), 2.25 - 2.18 (m, 2H), 1.79 - 1.72 (m, 2H), 1.67 - 1.59 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 144.3, 142.8, 141.5, 135.0, 134.3, 133.8, 126.2, 125.5, 125.5, 123.7, 121.7, 115.9, 113.4, 26.6, 25.4, 22.5, 21.6. HPLCt ret = 12.40 min. ESI-MS m / z: 355.3 [M+H] + .

[0187] 6-Bromo-1-(3-methoxyphenyl)-1H-benzo[d]imidazole (LS-11, BK) [ka] The same procedure as for the preparation of TD-326 described above was followed, except that 200 mg of LS-03 (0.62 mmol) and 559 mg of SnCl2·2H2O (2.48 mmol) were used in 15 ml of EtOH. Step 2: A solution of 0.31 ml of triethyl orthoformate (1.9 mmol) and 12 mg of p-TsOH·H2O (0.062 mmol) in toluene (ml) was used. Flash chromatography gradient: PE / EA = 10-50%. Yield: 189 mg (78%). 1 H NMR (200 MHz, DMSO) δ 8.61 (s, 1H), 7.79 - 7.70 (m, 2H), 7.59 - 7.48 (m, 1H), 7.44 (dd, J = 8.6, 1.9 Hz, 1H), 7.29 - 7.21 (m, 2H), 7.14 - 7.04 (m, 1H), 3.85 (s, 3H). 13 HPLC t ret = 9.24 min. ESI-MS m / z: 303.0 [M+H] + .

[0188] 1-(3-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)ethane-1-one (LS-33, BL) [ka] The same procedure as for the preparation of TD-326 described above was followed, except that 200 mg of LS-29 (0.60 mmol) and 539 mg of SnCl2·2H2O (2.39 mmol) were used in 15 ml of EtOH. Step 2: 294 μl of triethyl orthoformate (1.79 mmol) and 11 mg of p-TsOH·H2O (0.060 mmol) were used. The crude product was purified by flash chromatography (PE / EA = 20-70%) to obtain 67 mg (36%) of the desired product. 1H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.18 (t, J = 1.8 Hz, 1H), 8.10 - 8.06 (m, 1H), 8.00 - 7.96 (m, 1H), 7.82 - 7.78 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.6, 1.8 Hz, 1H), 2.68 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 197.4, 144.5, 142.9, 138.5, 135.8, 134.3, 130.6, 128.5, 127.5, 125.7, 123.7, 121.8, 116.1, 113.4, 27.0. HPLC t ret = 8.15 min. ESI-MS m / z: 315.1 [M+H] + .

[0189] N-(3-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)acetamide (TD-334, BY) [ka] To a solution of TD-319 (49 mg, 0.17 mmol) in anhydrous DCM (1.5 ml), EDC·HCl (39 mg, 0.204 mmol) and 12 μl of acetic acid (0.204 mmol) were added. The reaction mixture was stirred at ambient temperature until TLC (solvent for TLC: DCM / MeOH 5% + formic acid) indicated that the starting materials had been completely consumed. The DCM was removed under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH = 0-5%) to obtain a pinkish solid (45 mg, 80%). 1 H NMR (200 MHz, CDCl3) δ 8.05 (s, 1H), 7.88 - 7.76 (m, 1H), 7.71 - 7.52 (m, 3H), 7.50 - 7.35 (m, 2H), 7.19 - 7.08 (m, 1H), 2.16 (s, 3H). 13C NMR (50 MHz, CDCl3) δ 169.6, 142.8, 142.4, 140.3, 136.0, 134.6, 130.6, 126.5, 121.5, 119.4, 119.0, 117.4, 115.2, 113.9, 24.2. HPLC t ret = 7.78 min. ESI-MS m / z: 328.0 [M+H] + .

[0190] 3-(6-bromo-1H-benzo[d]imidazole-1-yl)-N-methylaniline (TD-404 / TD-407, BX) [ka] Step 1: 42 mg of NaH (60 wt%, mineral oil dispersion) was added to a solution of 272 mg of TD-280 (0.70 mmol) in anhydrous DMF (4 ml). After stirring at room temperature for 1 hour, 50 μl of MeI (0.84 mmol) was added. Stirring was continued for a further 1.5 hours until the starting material was completely consumed and HPLC indicated that the desired product had formed. The solvent was removed by distillation, and the desired product was purified by flash chromatography (DCM / MeOH = 0.5-2%). This product was used without further characterization (HPLC purity: >92%). HPLC t ret = 10.02 min.

[0191] Step 2: The same procedure as for the preparation of TD-319 described above was followed, except that 185 mg of the product obtained in Step 1 and 1 ml of HCl (EtOH solution, 2.5 M) were used in 2 ml of EtOH. The resulting salt was treated with saturated NaHCO3 solution (excess amount) and converted to free base by extraction (3 times) using DCM. The organic layer was dried over Na2SO4, and the solvent was removed by distillation to obtain the free base as a brownish solid (126 mg, 91%). 1H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 7.76 - 7.70 (m, 2H), 7.46 - 7.41 (m, 1H), 7.35 - 7.27 (m, 1H), 6.78 - 6.71 (m, 2H), 6.68 - 6.63 (m, 1H), 6.15 - 6.07 (m, 1H), 2.74 (d, J = 4.5 Hz, 3H). 13 HPLC t ret = 9.08 min. ESI-MS m / z: 302.4 [M+H] + , 300.3 [MH] - .

[0192] 5-Bromo-N-(2-fluorophenyl)-2-nitroaniline (LS-18, BN) [ka] The same procedure as for the preparation of TD-326 described above was followed, except that 116 mg of LS-12 (0.37 mmol) and 338 mg of SnCl2·2H2O (1.49 mmol) were used in 15 ml of EtOH. Step 2: A solution of 0.18 ml of triethyl orthoformate (1.1 mmol) and 7 mg of p-TsOH·H2O (0.037 mmol) in toluene (10 ml) was used. Flash chromatography gradient: PE / EA = 5-20%. Yield: 127 mg (67%). 1 H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 7.80 - 7.74 (m, 2H), 7.65 - 7.53 (m, 3H), 7.50 - 7.44 (m, 2H). HPLC t ret = 8.75 min. ESI-MS m / z: 290.9 [M+H] + .

[0193] 6-Bromo-1-(2-methoxyphenyl)-1H-benzo[d]imidazole (TD-354, BO) [ka] Step 1: The same procedure as for the preparation of TD-280 was followed, except that 418 mg of TD-353 (1.29 mmol), 692 mg of NH4Cl (12.9 mmol), and 846 mg of zinc powder (12.9 mmol) were used in 30 ml of MeOH. Step 2: 0.64 ml of triethyl orthoformate (3.88 mmol) and 25 mg of p-TsOH·H2O (0.13 mmol) were reacted overnight at 70°C until TLC indicated that the starting materials were completely consumed. Flash chromatography gradient: DCM / MeOH = 1-6%. Yield: 375 mg, brownish oily substance. Solidified over time (96%). 1 H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.44 (dd, J = 8.6, 1.9 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.34 (dd, J = 8.3, 1.0 Hz, 1H), 7.17 (td, J = 7.6, 1.2 Hz, 1H), 3.79 (s, 3H). 13 HPLC t ret = 8.73 min. ESI-MS m / z: 303.1 [M+H] + .

[0194] (3-(6-bromo-2-methyl-1H-benzo[d]imidazole-1-yl)phenyl)carbamate tert-butyl (TD-496, CA) [ka] The same procedure as for the preparation of TD-280 was followed, except that 826 mg of TD-276 (2.0 mmol) was used as the starting material. In step 2, triethyl orthoacetate (6.0 mmol, 1.1 ml) was used under the same conditions. Yield: 795 mg, solid (98%). 1 H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 7.65 - 7.60 (m, 2H), 7.60 - 7.56 (m, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.17 - 7.13 (m, 1H), 2.43 (s, 3H), 1.47 (s, 9H). 13 C NMR (101 MHz, DMSO) δ 152.7, 152.6, 141.2, 141.1, 136.9, 135.1, 130.4, 125.1, 120.3, 120.2, 118.4, 115.9, 114.7, 112.6, 79.6, 28.1, 14.1. HPLCt ret = 10.93 min. ESI-MS m / z: 424.2 [M+Na] + .

[0195] 3-(6-bromo-2-methyl-1H-benzo[d]imidazole-1-yl)aniline (TD-500, CB) [ka] The same procedure as for the preparation of TD-319 was followed, except that 756 mg of TD-496 was used in 15 ml of EtOH. When HCl-ethanol solution (1.25 M, 7.5 ml) was added to the resulting solution, the reaction mixture turned brownish. The solution was stirred at 50°C for 6 hours until the starting material was almost completely consumed (<3%) as indicated by HPLC. Yield: 1397 mg (74%). 1H NMR (400 MHz, DMSO) δ 7.56 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.5, 1.9 Hz, 1H), 7.27 - 7.22 (m, 2H), 6.73 (dd, J = 8.1, 1.3 Hz, 1H), 6.63 - 6.56 (m, 2H), 5.51 (s, 2H), 2.42 (s, 3H). 13 HPLC t ret = 6.25 min.

[0196] Scheme 2 N-(4-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-349, DA) [ka] To a solution of 114 mg of TD-346 (0.350 mmol, hydrochloride), 41 μl of MsCl (0.42 mmol) in anhydrous THF (4 ml) was added. Next, 121 μl of triethylamine (0.875 mmol) was added to the reaction mixture. The suspension was stirred at room temperature until HPLC indicated that the starting materials had been completely consumed. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography (DCM / MeOH = 1-6%) to obtain the desired product as a solid (86 mg, 67%). 1 H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 8.54 (s, 1H), 7.75 - 7.71 (m, 2H), 7.68 - 7.63 (m, 2H), 7.46 - 7.41 (m, 3H), 3.09 (s, 3H). 13C NMR (101 MHz, DMSO) δ 144.3, 142.7, 138.2, 134.5, 131.0, 125.4, 125.2, 121.6, 120.6, 115.9, 113.4, 39.5. ret = 7.16 min. ESI-MS m / z: 363.6 [MH] - , 366.1 [M+H] + .

[0197] N-(4-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)cyclopropanesulfonamide (TD-352, DC) [ka] In a microwave vial, 114 mg of TD-346 (hydrochloride, 0.350 mmol) was suspended in anhydrous pyridine (1 ml), and 86 μl of cyclopropanesulfonyl chloride was added. The sealed vial was stirred at 135°C for 1.5 hours until HPLC indicated that the starting material had been completely consumed. The pyridine was removed under reduced pressure, and the crude product was purified by flash chromatography using DCM / MeOH = 1-5.5% to obtain 95 mg of the desired product as a solid (69%). 1 H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.55 (s, 1H), 7.76 - 7.71 (m, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.49 - 7.43 (m, 3H), 2.78 - 2.69 (m, 1H), 1.03 - 0.97 (m, 4H). 13 HPLC t ret = 7.79 min. ESI-MS m / z: 389.6 [MH] - , 392.0 [M+H] + .

[0198] N-(3-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)ethanesulfonamide (TD-383, DE) [ka] To a solution of 100 mg of TD-319 (0.35 mmol) in anhydrous pyridine (1 ml), 37 μl of ethanesulfonyl chloride (0.39 mmol) was added and stirred overnight at ambient temperature. (The product remained in the aqueous phase and precipitated as gray needle-shaped crystals over time, so extraction should be avoided.) The crude products obtained from the organic phase and the aqueous phase were combined and purified by flash chromatography (DCM / MeOH = 1-8%) to obtain 71 mg of the desired product (54%). 1 H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 8.63 (s, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.43 - 7.38 (m, 1H), 7.33 (dd, J = 8.1, 1.5 Hz, 1H), 3.23 (q, J = 7.3 Hz, 2H), 1.24 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 144.0, 142.9, 140.0, 136.1, 134.0, 131.1, 125.6, 121.7, 118.4, 118.2, 115.9, 113.7, 113.4, 45.6, 8.0. HPLCt ret = 7.90 min. ESI-MS m / z: 378.2 [MH] - .

[0199] N-(3-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)cyclopropanesulfonamide (TD-382, DF) [ka] To a 1 ml solution of TD-319 in anhydrous DCM (104 mg / 0.361 mmol), 1 ml of pyridine and 50 μl of cyclopropanesulfonyl chloride (0.49 mmol) were added. The dark reaction mixture was stirred for 2 hours until HPLC indicated that the starting materials were completely consumed. The reaction mixture was diluted with 10% HCl and extracted with ethyl acetate. (The crude product from the organic phase could not be purified by flash chromatography and contained many impurities.) A large amount of product remained in the aqueous phase and precipitated as a brownish solid overnight, which was recovered by filtration. Yield: 78 mg, HCl salt (50%). 1 H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.32 (s, 1H), 8.30 (bs, 1H), 7.91 - 7.82 (m, 2H), 7.70 - 7.54 (m, 3H), 7.51 - 7.39 (m, 2H), 2.87 - 2.77 (m, 1H), 1.05 - 0.95 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 143.5, 140.1, 137.1, 135.0, 133.2, 131.1, 127.6, 120.1, 119.7, 119.4, 117.5, 115.2, 114.5, 29.8, 5.1. HPLC ret = 8.04 min. ESI-MS m / z: 390.1 [M+H] + .

[0200] N-(3-(6-bromo-2-methyl-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-501, DO) [ka] The same procedure as for the preparation of TD-342 described above was followed, except that a solution of 105 mg of TD-500 (0.347 mmol) in anhydrous pyridine (2 ml) and 0.03 ml of MsCl (0.42 mmol) were used. Flash chromatography: DCM / MeOH = 0-6%. Yield: 51 mg, solid (40%). 1H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 7.63 - 7.58 (m, 2H), 7.40 - 7.35 (m, 2H), 7.33 - 7.28 (m, 3H), 3.12 (s, 3H), 2.44 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 152.5, 141.5, 139.9, 136.9, 135.7, 131.0, 125.0, 121.7, 120.3, 119.6, 117.3, 114.7, 112.6, 39.8, 14.2. HPLCt ret = 7.16 min.

[0201] N-(3-(6-bromo-2-methyl-1H-benzo[d]imidazole-1-yl)phenyl)ethanesulfonamide (TD-538, DP) [ka] To a solution of TD-500 (100 mg, 0.330 mmol) in anhydrous pyridine (2 ml), 51 μl of ethanesulfonyl chloride (0.396 mmol) was added. The resulting orange-brown reaction mixture was stirred overnight at room temperature. The reaction was stopped with MeOH, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (DCM / MeOH = 1.5%). The product was dissolved in a small amount of DCM, precipitated with n-pentane, and the precipitate was collected by filtration. Yield: 90 mg, colorless solid (69%). 1 H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 7.62 - 7.56 (m, 2H), 7.40 - 7.36 (m, 2H), 7.33 - 7.27 (m, 3H), 3.22 (q, J = 7.3 Hz, 2H), 2.44 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H). HPLC t ret = 8.82 min. ESI-MS m / z: 392.0 [MH] - , 394.0 [M+H] + .

[0202] N-(3-(6-bromo-2-methyl-1H-benzo[d]imidazole-1-yl)phenyl)cyclopropanesulfonamide (TD-539, DQ) [ka] The same procedure as for the preparation of TD-538 was followed, except that 100 mg of TD-500 (0.330 mmol) and 46 μl of cyclopropanesulfonyl chloride (0.424 mmol) were used. Flash chromatography was performed using DCM / MeOH = 1.5-3.5%. Yield: 86 mg, colorless solid (64%). 1 H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 7.63 - 7.57 (m, 2H), 7.43 - 7.39 (m, 1H), 7.38 (dd, J = 8.5, 1.9 Hz, 1H), 7.33 - 7.28 (m, 3H), 2.82 - 2.74 (m, 1H), 2.44 (s, 3H), 1.00 - 0.95 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 152.5, 141.5, 139.9, 136.9, 135.6, 130.9, 125.0, 122.0, 120.4, 120.3, 117.9, 114.7, 112.5, 29.8, 14.2, 5.1. HPLC t ret = 7.04 min. ESI-MS m / z: 404.1 [MH] - .

[0203] Scheme 3 (3-((6-bromo-3-nitropyridine-2-yl)amino)phenyl)carbamate tert-butyl (TD-492, FA) [ka] To a solution of 988 mg of 2,6-dibromo-3-nitropyridine (3.51 mmol) in anhydrous DMF (12 ml), 695 mg of tert-butyl (3-aminophenyl)carbamate (3.34 mmol) was added in several portions. After 5 minutes, 0.6 ml of triethylamine (4.2 mmol) was added to the reaction mixture, causing the solution to immediately turn brown, and then dark reddish-orange. The reaction mixture was stirred at room temperature until TLC indicated that the starting materials had been completely consumed (approximately 6 hours). The reaction was stopped by adding water to the reaction mixture, causing the product to become semi-solid. Crystallization was initiated by adding a small amount of MeOH to a small amount of product and rubbing. The solid product was added to the reaction mixture from which the reaction had been stopped to initiate crystallization of the residual product. The product was recovered by filtration (air-dried on frit glass). Yield: 1158 mg, reddish-orange solid (85%). 1 H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 9.45 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.30 - 7.21 (m, 3H), 7.13 (d, J = 8.5 Hz, 1H), 1.48 (s, 9H). 13 HPLC t ret = 10.46 min. ESI-MS m / z: 407.3 [MH] - , 431.3 [M+Na] + .

[0204] (3-(5-bromo-3H-imidazo[4,5-b]pyridine-3-yl)phenyl)carbamate tert-butyl (TD-508, FC) [ka] The same procedure as for the preparation of TD-280 was followed, except that 418 mg of TD-492 was used. After 1.5 hours from the start of the reaction, TLC confirmed that the starting materials in step 1 had been completely consumed. In step 2, the reaction mixture was stirred at 60-70°C for 1.5 hours, and TLC confirmed that only the desired product was produced (identified by TLC-MS). Flash chromatography gradient: DCM / MeOH = 0-3%. Yield: 240 mg, solid (60%). 1 H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 8.81 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.38 - 7.34 (m, 1H), 1.49 (s, 9H). 13 C NMR (101 MHz, DMSO) δ 152.7, 146.1, 144.9, 140.7, 135.2, 134.7, 134.7, 130.9, 129.9, 122.6, 117.7, 117.6, 113.5, 79.5, 28.1. HPLC t ret = 10.35 min. ESI-MS m / z: 411.3 [M+H] + .

[0205] 3-(5-bromo-3H-imidazo[4,5-b]pyridine-3-yl)aniline (TD-509, FE) [ka] A solution containing 226 mg of TD-508 was dissolved in approximately 4 ml of EtOH. 4 ml of HCl-ethanol solution (1.25 M) was added, and the reaction mixture was heated overnight at 50°C. To control the reaction, TLC was performed, and only the desired product was observed. The grayish-white suspension was diluted with diethyl ether (approximately 8 ml), and the hydrochloride salt of the product was recovered by filtration. This product was stirred in saturated NaHCO3 solution, and the resulting free base was extracted by DCM (four times). After drying the organic phase, the solvent was removed by distillation to obtain the product as a solid. 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.94 (t, J = 2.1 Hz, 1H), 6.86 - 6.82 (m, 1H), 6.69 - 6.65 (m, 1H), 5.51 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 149.9, 146.1, 145.0, 135.1, 135.0, 134.8, 130.8, 130.0, 122.3, 113.5, 110.7, 108.7. HPLC tret = 8.24 min. ESI-MS m / z: 289.0 [M+H] + .

[0206] N-(3-(5-bromo-3H-imidazo[4,5-b]pyridine-3-yl)phenyl)methanesulfonamide (TD-511, FF) [ka] TD-509 was dissolved in anhydrous pyridine (approximately 3 ml), and MsCl (62 μl, 0.64 mmol) was added to the resulting brown solution. After stirring at room temperature for 12 hours, HPLC indicated that the starting material had been completely consumed. The reaction was stopped with an excess amount of MeOH, and after removing the solvent by distillation, the crude product was purified by flash chromatography (DCM / MeOH = 0-5%). The desired product was obtained as a white foam by drying under reduced pressure. Yield: 151 mg (2-step yield: 74%). 1 H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 8.90 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.55 - 7.51 (m, 1H), 7.32 - 7.27 (m, 1H), 3.16 (s, 3H). 13 HPLC t ret = 8.12 min.

[0207] Scheme 4: Synthesis of the eastern side chain 1-(4-bromophenyl)-3-(2-(dimethylamino)ethyl)urea (TD-396, SA) [ka] To a solution of 243 mg of 1-bromo-4-isocyanatobenzene (1.23 mmol) in anhydrous toluene, 147 μl of N,N-dimethylethylenediamine was added, and the reaction mixture was stirred at room temperature. After 15 minutes, the product precipitated, and the reaction mixture was heated to 50°C until TLC (DCM / MeOH + 10% 2N NH3) indicated that the starting materials had been completely consumed, thereby obtaining a stirable solution. The solvent was removed under reduced pressure to obtain the desired product as a white solid (100%). 1H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 7.40 - 7.33 (m, 4H), 6.10 (t, J = 5.2 Hz, 1H), 3.16 (app. dd, J = 11.6, 6.0 Hz, 1H), 2.31 (t, J = 6.2 Hz, 2H), 2.15 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 154.9, 140.0, 131.2, 119.3, 112.0, 58.4, 44.9, 36.9. HPLC t ret = 3.37 min.

[0208] 3-(4-bromophenyl)-1-(2-(dimethylamino)ethyl)-1-methylurea (TD-323, SB) [ka] 250 mg of 1-bromo-4-isocyanatobenzene (1.26 mmol) in a 5 ml solution of anhydrous toluene, with 196 μl of N2 added. 1 ,N 1 ,N 2 -Trimethylethane-1,2-diamine was added (slightly exothermic). The reaction mixture was stirred overnight until the starting materials were completely consumed and TLC indicated that the desired product had been formed. Toluene was removed under reduced pressure to obtain an oily substance, which was then cooled to crystallize and obtain a yellowish solid (377 mg, 100%). 1 H NMR (200 MHz, DMSO) δ 9.22 (s, 1H), 7.50 - 7.27 (m, 4H), 3.42 - 3.34 (m, 2H), 2.91 (s, 3H), 2.41 (t, J = 5.9 Hz, 2H), 2.21 (s, 6H). 13 C NMR (50 MHz, DMSO) δ 155.5, 140.4, 131.1, 121.0, 112.7, 57.8, 46.6, 45.3, 34.9. HPLC t ret = 2.77 min. ESI-MS m / z: 254.9 [M-NMe2] + .

[0209] 1-(4-bromophenyl)-3-(2-(dimethylamino)ethyl)-1,3-dimethylurea (TD-340, SC) [ka] In a reaction vial, 100 mg of TD-323 was dissolved in 2 ml of anhydrous DMF. Sodium hydride (16 mg, 0.40 mmol, 60% dispersion in mineral oil) was added to the reaction mixture in several batches, and the mixture was stirred for approximately 15 minutes until no more gas was produced. Methyl iodide (approximately 0.4 mmol) was added, and the reaction mixture was stirred overnight until TLC indicated that the starting materials were completely consumed and the desired product had been formed (confirmed by TLC-MS). The reaction was stopped with saturated NaHCO3 (6 ml). The resulting product was extracted by EA and purified by flash chromatography (DCM / MeOH + 2N NH3 = 1.5~8.5%). HPLC confirmed that the resulting product still contained iodine. Yield: 73 mg, oily substance. This oily substance solidified after long-term storage. HPLC t ret = 3.31 min. ESI-MS m / z: 269.1 [M-NMe2] + It was used without further characterization.

[0210] (4-bromophenyl)carbamate 2-(dimethylamino)ethyl (TD-428, SD) [ka] To a solution of 4-bromophenyl cyanate (99 mg, 0.50 mmol) in anhydrous toluene (3 ml), N,N-dimethylaminoethanol (48 mg, 0.54 mmol) was added, and the reaction mixture was heated briefly to 150°C until TLC indicated that the starting materials had been completely consumed. The reaction was stopped with MeOH, and the solvent was removed under reduced pressure to obtain the product as a colorless solid (139 mg, 97%). 1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 6.65 - 6.60 (m, 4H), 3.33 (t, J = 5.7 Hz, 2H), 1.70 - 1.65 (m, 2H), 1.36 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 153.4, 138.6, 131.5, 120.0, 113.8, 61.9, 57.6, 45.2. HPLC t ret = 3.94 min. ESI-MS m / z: 287.3 [M+H] + , 242.2 [M-NMe] + .

[0211] 1-(4-bromophenyl)-3-(1-methylpiperidine-4-yl)urea (TD-325, SE) [ka] The same procedure as for the preparation of TD-323 described above was followed, except that 198 mg of 1-bromo-4-isocyanatobenzene (1.0 mmol) and 145 μl of 1-methylpiperidine-4-amine (1.15 mmol) were used in 10 ml of toluene. The product precipitated as a white solid. The reaction mixture was stirred at ambient temperature until TLC indicated that the starting materials were completely consumed and the desired product had been formed. The solvent was removed under reduced pressure, and the product was obtained as a white solid (quantitative conversion). 1 H NMR (200 MHz, DMSO) δ 8.45 (s, 1H), 7.44 - 7.28 (m, 4H), 6.14 (d, J = 7.6 Hz, 1H), 3.54 - 3.37 (m, 1H), 2.72 - 2.54 (m, 2H), 2.14 (s, 3H), 2.07 - 1.89 (m, 2H), 1.85 - 1.68 (m, 2H), 1.50 - 1.25 (m, 2H). 13 C NMR (50 MHz, DMSO) δ 154.6, 140.2, 131.7, 119.8, 112.5, 54.2, 46.3, 46.0, 32.4. HPLC tret = 3.80 min. ESI-MS m / z: 312.1 [M+H] + .

[0212] (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate phenyl (TD-366, SSA) [ka] To a 5.00 mmol solution of phenyl chloroformate in 20 ml of anhydrous THF, 1096 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in a 10 ml solution of anhydrous THF was added dropwise over 10 minutes. Triethylamine (5.0 mmol) was added to the reaction mixture over 1 minute. The reaction mixture was stirred at ambient temperature for 15 minutes, and the resulting suspension was filtered through Celite. Half of the solvent was removed by distillation, and 150 ml of n-pentane was added to the reaction mixture. The product was precipitated by sonication and recovered by filtration to obtain a grayish-white solid (1356 mg, 80%). 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.46 - 7.40 (m, 2H), 7.30 - 7.21 (m, 3H), 1.28 (s, 12H). HPLC t ret = 9.13 min.

[0213] 4-Methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxamide (TD-389, DBaa) [ka] To a solution of TD-366 (254 mg, 0.750 mmol) in anhydrous THF (2 ml), 1-methylpiperazine (75 mg, 0.75 mmol) was added, and the reaction mixture was stirred overnight at 70°C. The reaction mixture was diluted with ACN / n-pentane (approximately 2 ml, 1+1, two-phase system), and the solvent was removed by distillation to obtain the crude product as a solid. This solid was suspended in diethyl ether, and the product was recovered by filtration. Yield: 110 mg (42%). 1 H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.59 - 7.45 (m, 4H), 3.49 - 3.41 (m, 4H), 2.42 - 2.30 (m, 4H), 2.23 (s, 3H), 1.27 (s, 12H). HPLC t ret = 4.283 min. ESI-MS m / z: 346.3 [M+H] + .

[0214] 4-(dimethylamino)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxamide (TD-373, DBa) [ka] To a 150 mg (0.442 mmol) solution of TD-366 in anhydrous dioxane (3 ml), 57 mg of N,N-dimethylpiperidine-4-amine was added, and the reaction mixture was heated to 80°C. After 3 hours, the reaction mixture was diluted with 3 ml of NaOH solution (2N) and extracted with DCM. The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the product as a crude oil. This product was used without further characterization.

[0215] 1-(2-(dimethylamino)ethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (TD-306, DBb) [ka] Alternative route: To a 5.00 mmol solution of phenyl chloroformate in 20 ml of anhydrous THF, 1096 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in a 10 ml solution of anhydrous THF was added dropwise over 10 minutes. Triethylamine (10.0 mmol) was added to the reaction mixture over 1 minute. After stirring the reaction mixture at ambient temperature for 15 minutes, 0.55 ml of N,N-dimethylethylenediamine was added, and the reaction mixture was refluxed for 3-4 hours. The reaction mixture was diluted with DCM and washed with 2N NaOH. The organic phase was dried, and the solvent was removed under reduced pressure to obtain the crude product as a brown oil. The oil was heated in a small amount of ethyl acetate (10-15 ml), and the mixture was stored overnight at room temperature to obtain the product as colorless crystals.

[0216] 2-Chloro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (TD-535, SSB) [ka] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (657 mg, 3.00 mmol) was dissolved in 12 ml of anhydrous dioxane, and chloroacetyl chloride (0.24 ml, 3.0 mmol) was added dropwise. After stirring at room temperature for 5-10 minutes, 0.46 ml of Et3N (3.3 mmol) was added to the reaction mixture (resulting in vigorous fume). After 30 minutes, the reaction mixture was filtered through Celite, and the brown filtrate was concentrated until its volume was reduced by approximately half. The residue was triturated with n-pentane, and the desired product was isolated as a colorless product by filtration (740 mg, 84%). 1 H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 7.67 - 7.58 (m, 4H), 4.26 (s, 2H), 1.28 (s, 12H). 13 C NMR (101 MHz, DMSO) δ 164.9, 141.3, 135.4, 118.4, 83.5, 43.6, 24.7. HPLC t ret = 9.50 min.

[0217] 2-(3-(dimethylamino)azetidine-1-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (TD-515, DBc) [ka] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (328 mg, 1.5 mmol) was dissolved in 10 ml of anhydrous dioxane. Chloroacetyl chloride (0.12 mol, 1.5 mmol) was added dropwise to this solution. Triethylamine (0.25 ml, 1.8 mmol) was added to the reaction mixture. The reaction mixture was stirred for 15 minutes until TLC indicated that the starting materials had been completely consumed. N,N-dimethylazetidine-3-amine (260 mg, 1.5 mmol, dihydrochloride salt) was added to the reaction mixture, followed by the addition of 0.25 ml of trimethylamine (1.8 mmol). The reaction mixture was stirred at 50°C for 2.5 hours. The reaction mixture was diluted with 2N NaOH aqueous solution, and the product was extracted by DCM. After drying the organic phase and removing the solvent by distillation, the crude product was obtained as a brown semi-solid (411 mg, 76%). 1 H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 3.51 (dd, J = 7.2, 6.3 Hz, 2H), 3.22 (s, 2H), 2.93 (t, J = 7.0 Hz, 2H), 2.86 - 2.80 (m, 1H), 2.00 (s, 6H), 1.28 (s, 12H). HPLC t ret = 6.32 min. ESI-MS m / z: 360.1 [M+H] + .

[0218] 2-(4-methylpiperazine-1-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (TD-536, DBd) [ka] To a solution of 295 mg of TD-535 (1.00 mmol) in anhydrous THF (5 ml), 100 mg of 1-methylpiperazine (1.00 mmol) was added, and the reaction mixture was stirred overnight at 50°C. HPLC analysis was performed to control the reaction, indicating complete consumption of the starting materials. Triethylamine (3 mmol) was added to the reaction mixture at room temperature, and the mixture was filtered through Celite. The filtrate was removed by distillation to obtain the crude product as a brown oily substance. This crude product was purified by flash chromatography (DCM / MeOH + 2N NH3 = 5-10%). Yield: 113 mg, white solid (32%). ESI-MS m / z: 360.3 [M+H] + It was used without further characterization.

[0219] 3-((5-bromopyridine-2-yl)oxy)propan-1-ol (TD-637, DCA) [ka] 5-bromo-2-fluoropyridine (1251 mg, 7.108 mmol) and propane-1,3-diol (2306 mg, 30.30 mmol) were dissolved in 15 ml of anhydrous THF. 296 mg of NaH (60 wt%, 7.40 mmol) was added in several portions. After no gas was observed, the reaction mixture was heated to 50°C. After approximately 5 hours, HPLC was performed to control the reaction, indicating that the starting materials had been completely consumed. The reaction was stopped by adding saline solution. The product was extracted with EA, and the organic phase was dried over Na2SO4. The solvent was removed, and the product was purified by flash chromatography (DCM / MeOH = 0-1%). Yield: 1596 mg, yellowish solid (97%). 1H NMR (400 MHz, DMSO) δ 8.26 (dd, J = 2.6, 0.6 Hz, 1H), 7.87 (dd, J = 8.8, 2.6 Hz, 1H), 6.81 (dd, J = 8.8, 0.6 Hz, 1H), 4.53 (t, J = 5.2 Hz, 1H), 4.28 (t, J = 6.6 Hz, 2H), 3.56 - 3.50 (m, J = 11.5, 6.2 Hz, 2H), 1.84 (p, J = 6.4 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 162.4, 147.2, 141.5, 112.9, 111.2, 63.3, 57.3, 31.8. HPLC t ret = 6.23 min. ESI-MS m / z: 253.8 [M+Na] + .

[0220] 3-((5-bromopyridine-2-yl)oxy)-N-methylpropan-1-amine (TD-673, DCB) [ka] The procedure was the same as for TD-637, except that 996 mg of 5-bromo-2-fluoropyridine (5.66 mmol), 604 mg of 3-(methylamino)propan-1-ol (6.78 mmol), and 793 mg of KOtBu (7.07 mmol) were used in 14 ml of anhydrous THF. After 1 hour, the reaction mixture was diluted with NaOH (2N) and extracted by DCM. Yield: 1293 mg (93%). 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 2.5 Hz, 1H), 7.62 (dd, J = 8.8, 2.6 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 4.33 (t, J = 6.4 Hz, 2H), 2.73 (t, HPLC t ret= 2.58 min. ESI-MS m / z: 245.0 [M+H].

[0221] 5-Bromo-2-(3-(pyrrolidine-1-yl)propoxy)pyridine (TD-681, DCC) [ka] The procedure was the same as for TD-673, except that 982 mg of 5-bromo-2-fluoropyridine (5.58 mmol), 666 mg of 3-(pyrrolidine-1-yl)propan-1-ol (5.15 mmol), and 636 mg of KOtBu (5.67 mmol) were used in 15 ml of anhydrous THF. (Since this reaction is exothermic, cooling may be advantageous.) Yield: 1539 mg, yellow solid (crude product). 1 H NMR (400 MHz, DMSO) δ 8.25 (dd, J = 2.6, 0.5 Hz, 1H), 7.87 (dd, J = 8.8, 2.6 Hz, 1H), 6.80 (dd, J = 8.8, 0.6 Hz, 1H), 4.25 (t, J = 6.6 Hz, 2H), 2.50 - 2.46 (m, 2H), 2.44 - 2.37 (m, 4H), 1.86 (p, J = 6.8 Hz, 2H), 1.69 - 1.63 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 162.3, 147.1, 141.5, 112.8, 111.2, 64.5, 53.5, 52.2, 27.8, 23.1. ESI-MS m / z: 285.0 [M+H].

[0222] 5-Bromo-2-(3-(piperidine-1-yl)propoxy)pyridine (TD-682, DCD) [ka] The procedure was the same as for TD-673, except that 981 mg of 5-bromo-2-fluoropyridine (5.58 mmol), 742 mg of 3-(piperidine-1-yl)propan-1-ol (5.18 mmol), and 639 mg of KOtBu (5.70 mmol) were used in 15 ml of anhydrous THF. (Since this reaction is exothermic, cooling may be advantageous.) Yield: 2561 mg, yellow solid (crude product). 1 H NMR (400 MHz, DMSO) δ 8.25 (dd, J = 2.6, 0.5 Hz, 1H), 7.87 (dd, J = 8.8, 2.6 Hz, 1H), 6.80 (dd, J = 8.8, 0.5 Hz, 1H), 4.23 (t, J = 6.6 Hz, 2H), 2.36 - 2.25 (m, 6H), 1.88 - 1.79 (m, 2H), 1.51 - 1.43 (m, 4H), 1.40 - 1.32 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 162.4, 147.2, 141.5, 112.8, 111.2, 64.6, 55.1, 54.0, 25.9, 25.6, 24.1. ESI-MS m / z: 299.1 [M+H].

[0223] Scheme 5 1-Phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (TD-327) [ka] A round-bottom flask was charged under an argon atmosphere with a solution of 623 mg of TD-326 (2.30 mmol), 584 mg of B2Pin2 (2.30 mmol), and 1000 mg of KOAc in 12 ml of anhydrous dioxane. A catalytic amount of 5 mol% Pd (dppf)Cl2·DCM (0.12 mmol) was added to the reaction mixture. The reaction mixture was stirred at 90°C for 24 hours until the starting materials were completely consumed and the desired product was shown by HPLC (confirmed by TLC-MS). The product was filtered through SiO2 using 1% DCM / MeOH to obtain the crude product as a brown oily substance. 1 H NMR (200 MHz, CDCl3) δ 8.15 (s, 1H), 8.03 - 7.94 (m, 1H), 7.92 - 7.84 (m, 1H), 7.79 (dd, J = 8.2, 0.8 Hz, 1H), 7.65 - 7.42 (m, 5H), 1.35 (s, 12H). HPLC t ret = 9.06 min. ESI-MS m / z: 375.0 [M+MeOH+Na] + .

[0224] 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-yl)aniline (TD-390, QA) [ka] The procedure was the same as for TD-327, except that 925 mg of TD-346 (3.21 mmol), 802 mg of B2Pin2 (3.18 mmol), 977 mg of KOAc (9.95 mmol), and 5 mol% of Pd(dppf)Cl2 were used in 12 ml of dioxane and reacted overnight at 80°C. Flash chromatography gradient: DCM / MeOH = 0-3.5%. The product was obtained as an oily substance. A small amount of ACN was overlaid on this oily substance and stored at -18°C to initiate crystallization. The product was recovered by filtration and washed with 1.5 ml of cold ACN to obtain colorless crystals (612 mg, 58%). 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.75 - 7.70 (m, 1H), 7.70 - 7.66 (m, 1H), 7.56 (dd, J = 8.1, 0.9 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 5.48 (s, 2H), 1.28 (s, 12H). HPLC t ret = 7.54 min.

[0225] 1-(2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (TD-453, QB) [ka] The same procedure as for TD-327 was followed, except that 795 mg of TD-452 (2.25 mmol), 566 mg of B2Pin2 (2.23 mmol), 685 mg of KOAc (6.98 mmol), and 5 mol% of Pd(dppf)Cl2 were used in 11 ml of dioxane and reacted overnight at 80°C. After the starting materials were completely consumed (HPLC), the brown suspension turned black. The reaction mixture was diluted with DCM and filtered through Celite to obtain a brownish solution. The solvent was removed under reduced pressure, and the crude product (brown solid) was suspended in approximately 3 ml of ACN, recovered by filtration, and washed with the same volume of ACN. Yield: 637 mg, gray solid (71%). 1 H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 7.81 (s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.63 - 7.58 (m, 3H), 6.34 - 6.26 (m, 1H), 2.46 - 2.40 (m, 2H), 2.25 - 2.18 (m, 2H), 1.79 - 1.73 (m, 2H), 1.67 - 1.59 (m, 2H), 1.29 (s, 12H). 13C NMR (101 MHz, DMSO) δ 146.2, 144.5, 141.5, 135.0, 134.1, 133.3, 128.2, 126.2, 125.5, 124.1, 119.5, 116.6, 83.7, 26.6, 25.4, 24.7, 24.5, 22.5, 21.6. HPLC t ret = 12.32 min. ESI-MS m / z: 401.6 [M+H] + .

[0226] 2-Methyl-N-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-yl)phenyl)butanamide (TD-393, QC) [ka] The same procedure as for the preparation of TD-334 was followed, except that 117 mg of TD-390 (0.35 mmol), 114 mg of EDC·HCl (0.60 mmol), and 62 μl of 2-methoxyacetic acid (0.57 mmol) were used. A colorless oil was obtained by flash chromatography using a DCM / MeOH gradient of 0.5-5%, and then treated with n-pentane / diethyl ether and a few drops of acetonitrile. After sonication, the desired product precipitated as colorless needle-shaped crystals. Yield: 68 mg, solid (46%). 1 H NMR (400 MHz, DMSO) δ 10.12 (s, 1H), 8.54 (s, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.81 - 7.72 (m, 2H), 7.64 - 7.53 (m, 3H), 2.48 - 2.40 (m, HPLC t ret = 9.41 min. ESI-MS m / z: 318.5 [MH] - , 454.6 [M+Cl]- , 420.6 [M+H] + , 442.6 [M+Na] + .

[0227] 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-yl)aniline (TD-385, QD) [ka] In a round-bottom flask, 100 mg of TD-319 (0.347 mmol), 87 mg of B2Pin2 (0.344 mmol), and 102 mg (1.04 mmol) of KOAc were dissolved / suspended in 3 ml of anhydrous dioxane under an argon atmosphere. A catalytic amount of 5 mol% Pd(dppf)Cl2·DCM (17 μmol) was added to the reaction mixture. The reaction mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was confirmed by HPLC (confirmed by TLC-MS). The reaction mixture was diluted with EA and filtered through Celite. The brown organic phase was removed under reduced pressure to obtain the crude product as a brown oil. Flash chromatography gradient: DCM / MeOH = 0-5%. Yield: 99 mg, a foamy substance that was not a complete solid (0.295 mmol).

[0228] Another post-treatment: Flash chromatography gradient: DCM / MeOH = 1-1.2%. Acetonitrile was overlaid on the yellow oily product, cooled overnight at -18°C, and the organic phase was filtered / decanted to obtain a highly crystalline white product (54-67%). 1 H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 6.81 - 6.75 (m, 1H), 6.73 - 6.66 (m, J = 6.6 Hz, 2H), 5.57 (s, 2H), 1.29 (s, 12H). 13C NMR (101 MHz, DMSO) δ 150.3, 146.1, 144.3, 136.4, 133.3, 130.4, 128.1, 122.9, 119.4, 116.9, 113.5, 111.0, 108.8, 83.7, 24.6. HPLC t ret = 8.11 min. ESI-MS m / z: 336.3 [M+H] + .

[0229] N-(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-387, QE) [ka] When 71 mg of MsCl (0.62 mmol) was added to a 243 mg solution of anhydrous pyridine (TD-385, 0.55 mmol, 85% purity), the solution turned yellow. HPLC indicated that the starting material had been completely consumed after 2.5 hours. The reaction was stopped with MeOH, and the solvent was removed by distillation under reduced pressure. The crude oil was transferred to a column in liquid form and purified by flash chromatography (DCM / MeOH = 2-6%) to obtain the desired product as a white solid (196 mg, 87%). 1 H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.62 (s, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.44 (s, 1H), 7.42 - 7.32 (m, 2H), 3.13 (s, 3H), 1.30 (s, 12H). HPLC t ret = 8.11 min. ESI-MS m / z: 412.2 [MH] - .

[0230] N-(3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-yl)phenyl)propane-1-sulfonamide (TD-424, QF) [ka] The same procedure as for the preparation of TD-387 was followed, except that 185 mg of TD-385 (0.36 mmol, 69% purity by HPLC) was used in a 5 ml solution of anhydrous pyridine and 74 mg of propane-1-sulfonyl chloride (0.52 mmol). The orange reaction mixture was stirred overnight at ambient temperature until HPLC indicated that the starting materials had been completely consumed. The reaction was stopped with MeOH, and the reaction mixture was poured into a saturated NH4Cl solution. The product was extracted by DCM (four times). The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. HPLC t ret = 8.715 min. (The crude product was used directly in the next reaction without further characterization).

[0231] Inhibitors in Table 1 3-((5-(1-cyclohexyl-1H-benzo[d]imidazole-6-yl)pyridine-2-yl)oxy)-N,N-dimethylpropane-1-amine(TD-228) [ka] Under an argon atmosphere, a solution of 6-bromo-1-cyclohexyl-1H-benzo[d]imidazole (55 mg, 0.18 mmol) in dioxane (2.5 ml) and 97 mg of N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxy)propan-1-amine (Sarkaria, JN; Eshleman, JS; ATM as a target for novel radiosensitizers. Semin Radiat Oncol 2001, 11(4), 316-327. DOI: 10.1053 / srao.2001.26030; obtained from NLM) (0.37 mmol) were mixed with 1.2 ml of 0.5 M K3PO4 aqueous solution. tBu3P Pd G3 (2 mol%) was added, and the reaction mixture was heated at 65°C until TLC indicated that the starting materials were completely consumed. The reaction mixture was diluted with ethyl acetate and saline solution and extracted (three times with ethyl acetate). The crude product was purified by flash chromatography (DCM / MeOH + 2N NH3 = 1-9%). Yield: 40 mg, solid (58%). 1 H NMR (200 MHz, CDCl3) δ 8.41 (d, J = 2.6 Hz, 1H), 8.01 (s, 1H), 7.91 - 7.74 (m, 2H), 7.54 - 7.47 (m, 1H), 7.42 (dd, J = 8.3, 1.5 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 4.45 - 4.15 (m, 3H), 2.63 - 2.41 (m, 2H), 2.36 - 2.18 (m, 8H), 2.11 - 1.69 (m, 7H), 1.65 - 1.28 (m, 3H). 13 C NMR (101 MHz, CDCl3) δ 163.3, 145.5, 143.7, 141.2, 138.0, 134.2, 133.2, 131.0, 121.7, 121.0, 110.9, 108.3, 64.5, 56.6, 55.7, 45.4, 33.5, 27.3, 25.9, 25.6. HPLC ret= 1.73 min. ESI-MS m / z: 379.3 [M+H] + , 401.3 [M+Na] + .

[0232] N,N-dimethyl-3-((5-(1-phenyl-1H-benzo[d]imidazole-6-yl)pyridine-2-yl)oxy)propan-1-amine (TD-225) [ka] The same procedure as for the preparation of TD-228 was followed, except that 50 mg of TD-326 (0.18 mmol), N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxy)propan-1-amine (Sarkaria, JN; Eshleman, JS; ATM as a target for novel radiosensitizers. Semin Radiat Oncol 2001, 11(4), 316-327. DOI: 10.1053 / srao.2001.26030; obtained from NLM) (0.37 mmol), and 1.1 ml of 0.5 M K3PO4 aqueous solution were used. Yield: 55 mg, brownish oily substance (81%). 1 H NMR (200 MHz, CDCl3) δ 8.35 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.5, 2.4 Hz, 1H), 7.65 - 7.40 (m, 7H), 6.77 (d, J = 8.6 Hz, 1H), 4.35 (t, J = 6.5 Hz, 2H), 2.49 - 2.36 (m, 2H), 2.23 (s, 6H), 2.03 - 1.86 (m, 2H). 13C NMR (50 MHz, CDCl3) δ 163.3, 145.3, 143.5, 142.9, 137.8, 136.3, 134.4, 134.2, 130.4, 130.2, 128.3, 124.2, 122.2, 121.0, 110.9, 108.5, 64.5, 56.5, 45.6, 27.5.HPLCt ret = 3.46 min. ESI-MS m / z: 373.2 [M+H] + .

[0233] 1-(2-(dimethylamino)ethyl)-3-(4-(1-phenyl-1H-benzo[d]imidazole-6-yl)phenyl)urea (LS-13) [ka] The procedure was the same as for TD-228 described above, except that 70 mg of TD-326 (0.26 mmol), 94 mg of TD-306 (0.28 mmol), and 205 mg of K3PO4·3H2O (0.673 mmol) were used in dioxane (2 ml) / water (1 ml). The resulting product was extracted by DCM. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. RP-flash chromatography gradient: Water / MeOH = 10-90%. Yield: 32 mg, white solid (31%). 1 H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.56 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.78 - 7.74 (m, 2H), 7.73 - 7.70 (m, 1H), 7.68 - 7.63 (m, 2H), 7.59 - 7.54 (m, 3H), 7.54 - 7.45 (m, 3H), 6.19 (t, J = 5.2 Hz, 1H), 3.22 - 3.15 (m, J = 11.6, 6.0 Hz, 2H), 2.32 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H). 13C NMR (101 MHz, DMSO) δ 155.1, 143.7, 142.9, 140.0, 136.1, 136.0, 133.7, 133.2, 130.1, 127.7, 127.3, 123.8, 121.5, 120.1, 117.8, 107.8, 58.5, 45.0, 37.0.HPLCt ret = 3.76 min. ESI-MS m / z: 400.3 [M+H] + .

[0234] 1-(2-(dimethylamino)ethyl)-1-methyl-3-(4-(1-phenyl-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-336) [ka] The procedure was the same as for TD-307, except that 30 mg of TD-327 (0.094 mmol) and 34 mg of TD-323 (0.112 mmol) were used in 2 ml of dioxane / water (3+1). Stirring was continued overnight at 65°C until the starting materials were completely consumed and the desired product was shown by HPLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 1-7%. A second flash chromatography purification step was performed using reversed-phase C18 silica gel (water / MeOH = 10-100%). Yield: 39 mg, solid (46%). 1 H NMR (400 MHz, DMSO) δ 9.23 (s, 1H), 8.56 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.78 - 7.72 (m, 3H), 7.68 - 7.63 (m, 2H), 7.60 - 7.56 (m, 3H), 7.54 - 7.48 (m, 3H), 3.39 (t, J = 5.9 Hz, 2H), 2.94 (s, 3H), 2.44 (t, J = 5.9 Hz, 2H), 2.23 (s, 6H). 13C NMR (101 MHz, DMSO) δ 155.7, 143.7, 142.9, 140.3, 136.1, 136.0, 133.8, 133.6, 130.2, 127.7, 127.0, 123.8, 121.5, 120.2, 119.4, 107.8, 57.9, 46.7, 45.3, 34.9. HPLC t ret = 3.92 min. ESI-MS m / z: 436.2 [M+Na] + , 468.2 [M+Na+MeOH] + , 412.2 [MH] - .

[0235] 1-(2-(dimethylamino)ethyl)-1,3-dimethyl-3-(4-(1-phenyl-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-348) [ka] The procedure was the same as for TD-307, except that 68 mg of TD-327 (0.214 mmol) and 61 mg of TD-340 (0.194 mmol) were used in dioxane / water (3+1). Stirring was continued overnight at 65°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 1-7%. A second flash chromatography purification step was performed using reversed-phase silica gel (LiChroprep RP-C18, 40-63 μm, solvent: water / MeOH = 10-90%). Yield: 59 mg, oily. Solidified over time (71%). HPLC t ret = min. ESI-MS m / z: [M+H] + . 1H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.78 - 7.74 (m, 3H), 7.68 - 7.63 (m, 4H), 7.59 (dd, J = 8.4, 1.7 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.20 (d, J = 8.7 Hz, 2H), 3.25 (t, J = 6.6 Hz, 2H), 3.09 (s, 3H), 2.60 (s, 3H), 2.27 (t, J = 6.5 Hz, 2H), 2.12 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 160.7, 145.8, 144.0, 143.2, 136.0, 135.8, 135.7, 133.8, 130.3, 128.0, 128.0, 124.0, 122.7, 121.9, 120.4, 108.3, 56.3, 47.1, 45.3, 38.8, 36.1. HPLC t ret = 4.75 min. ESI-MS m / z: 450.4 [M+Na] + , 383.4 [M-NMe2] + , 298.3 [M-C6H 13 N2O] + , 129.2 [MC 20 H 16 N3] + .

[0236] Inhibitors listed in Table 2 1-(2-(dimethylamino)ethyl)-3-(4-(1-(2-fluorophenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (LS-24) [ka] The procedure was the same as for TD-228 described above, except that 69 mg of LS-18 (0.24 mmol), 87 mg of TD-306 (0.26 mmol), and 189 mg of K3PO4·3H2O (0.71 mmol) were used in dioxane (2 ml) / water (1 ml). The resulting product was extracted by DCM. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 2-10%. RP-flash chromatography gradient: Water / MeOH = 10-90%. Yield: 61 mg, white solid (88%). 1 H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.49 (d, J = 1.4 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.65 - 7.52 (m, 5H), 7.51 - 7.44 (m, 4H), 6.11 (t, J = 5.2Hz, 1H), 3.21 - 3.15 (m, J = 11.6, 6.1 Hz, 2H), 2.32 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H). ret = 4.52 min. ESI-MS m / z: 418.3 [M+H] + .

[0237] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(2-methoxyphenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-360) [ka] The procedure was the same as for TD-307, except that 58 mg of TD-354 (0.19 mmol) and 70 mg of TD-306 (0.21 mmol) were used in ml of dioxane / water (3+1). Stirring was continued overnight at 65°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 2.5~10%. A second flash chromatography purification step was performed using reversed-phase C18 silica gel (water / MeOH = 10~100). Yield: 56 mg, solid (69%). 1 H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.34 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.59 - 7.49 (m, 5H), 7.45 (d, J = 8.8 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.18 (td, J = 7.6, 1.1 Hz, 1H), 6.15 (t, J = 5.2 Hz, 1H), 3.80 (s, 3H), 3.21 - 3.13 (m, 2H), 2.32 (t, J = 6.2 Hz, 2H), 2.16 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.2, 153.8, 144.8, 142.1, 139.9, 135.8, 134.9, 133.3, 130.2, 127.7, 127.3, 124.1, 121.2, 121.1, 119.8, 117.9, 113.1, 108.0, 58.6, 55.9, 45.1, 37.0. HPLC t ret = 3.85 min. ESI-MS m / z: 427.4 [MH] - , 385.2 [M-NMe2] + .

[0238] 1-(4-(1-(3-aminophenyl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-432, TD-310) [ka] The procedure was the same as for TD-307, except that 179 mg of TD-385 (0.374 mmol), 107 mg of TD-396 (0.374 mmol), and 398 mg of K3PO4·3H2O (1.49 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. Yield: 138 mg, solid (89%). 1 H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.46 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.59 - 7.51 (m, 3H), 7.48 (d, J = 8.7 Hz, 2H), 7.25 (t, J = 7.9 Hz, 1H), 6.90 - 6.83 (m, 1H), 6.78 (dd, J = 7.7, 1.3 Hz, 1H), 6.67 (dd, J = 8.1, 1.4 Hz, 1H), 6.11 (t, J = 5.2 Hz, 1H), 5.53 (s, 2H), 3.22 - 3.16 (m, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.18 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 150.3, 143.5, 142.9, 139.9, 136.7, 135.9, 133.7, 133.3, 130.5, 127.3, 121.3, 120.1, 117.8, 113.1, 110.4, 108.2, 108.0, 58.5, 45.0, 36.9. HPLC t ret = 2.16 min. ESI-MS m / z: 415.5 [M+H] + , 449.2 [M+Cl] - .

[0239] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(3-methoxyphenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (LS-14) [ka] The procedure was the same as for TD-228 described above, except that 61 mg of LS-11 (0.22 mmol), 61 mg of TD-306 (0.25 mmol), and 160 mg of K3PO4·3H2O (0.670 mmol) were used in dioxane (2 ml) / water (1 ml). The resulting product was extracted by DCM. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. RP-flash chromatography gradient: Water / MeOH = 10-90%. Yield: White solid (15 mg, 39%). 1 H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.56 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.60 - 7.52 (m, 4H), 7.47 (d, J = 8.5 Hz, 2H), 7.35 - 7.28 (m, 2H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H), 6.17 (t, J = 5.0 Hz, 1H), 3.86 (s, 3H), 3.23 - 3.14 (m, J = 11.5, 5.8 Hz, 2H), 2.32 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 160.4, 155.1, 143.8, 142.9, 140.0, 137.1, 136.1, 133.7, 133.2, 131.0, 127.3, 121.5, 120.1, 117.8, 115.8, 113.6, 109.5, 107.9, 58.5, 55.6, 45.1, 37.0. HPLC t ret = 4.61 min. ESI-MS m / z: 430.4 [M+H] + .

[0240] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(4-fluorophenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (LS-10) [ka] The procedure was the same as for TD-228 described above, except that 99 mg of LS-09 (0.34 mmol), 125 mg of TD-306 (0.37 mmol), and 273 mg of K3PO4·3H2O (0.673 mmol) were used in dioxane (2 ml) / water (1 ml). The resulting product was extracted by DCM. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. Yield: 140 mg, white solid (98%). 1 H NMR (200 MHz, DMSO) δ 8.76 (s, 1H), 8.52 (s, 1H), 7.87 - 7.75 (m, 3H), 7.67 (s, 1H), 7.62 - 7.40 (m, 7H), 6.11 (t, J = 5.0 Hz, 1H), 3.25 - 3.11 (m, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (50 MHz, DMSO) δ 161.2 (d, J = 245.0 Hz), 155.1, 143.8, 142.7, 140.0, 136.2, 134.0, 133.2, 132.3 (d, J = 2.6 Hz), 127.3, 126.3 (d, J = 8.7 Hz), 121.5, 120.1, 117.8, 116.9 (d, J = 22.8 Hz), 107.7, 58.5, 45.0, 36.9. HPLC t ret = 3.78 min. ESI-MS m / z: 418.3 [M+H] + .

[0241] 1-(4-(1-(4-aminophenyl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-316) [ka] The procedure was the same as for TD-307 described above, except that 96 mg of TD-314 (0.33 mmol) and 122 mg of TD-306 (0.366 mmol) were used in 4.5 ml of dioxane / water (2+1). Stirring was continued at 70°C for 2.5 hours until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 8.5-10%. Yield: 90 mg, grayish-white (pale pink) solid (65%). 1 H NMR (200 MHz, DMSO) δ 8.75 (s, 1H), 8.34 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.61 - 7.40 (m, 6H), 7.30 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 6.10 (t, J = 5.2 Hz, 1H), 5.45 (s, 2H), 3.25 - 3.11 (m, 2H), 2.32 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (DMSO) δ:155.1, 148.8, 143.9, 142.5, 139.8, 135.6, 134.7, 133.4, 127.2, 125.3, 124.1, 120.9, 119.9, 117.8, 114.4, 107.6, 48.6, 45.0, 36.9.HPLCt ret = 1.57 min. ESI-MS m / z: 415.3 [M+H] + , 449.1 [M+Cl] - .

[0242] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(4-methoxyphenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (LS-07) [ka] The procedure was the same as for TD-228 described above, except that 68 mg of LS-06 (0.22 mmol), 82 mg of TD-306 (0.25 mmol), and 178 mg of K3PO4·3H2O (0.673 mmol) were used in dioxane (2 ml) / water (1 ml). The resulting product was extracted by DCM. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 8-10%. Yield: 70 mg, white solid (75%). 1 H NMR (200 MHz, DMSO) δ 8.76 (s, 1H), 8.46 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.70 - 7.60 (m, 3H), 7.60 - 7.43 (m, 5H), 7.18 (d, J = 8.7 HPLC t ret = 3.62 min. ESI-MS m / z: 420.2 [M+H] + .

[0243] 1-(4-(1-(4-bromophenyl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (FM-992) [ka] At ambient temperature, pyridine (37 μl, 0.46 mmol) was added to a solution of FM-991 (160 mg, 0.440 mmol) in anhydrous DMF (6 ml). Next, phenyl chloroformate (58 μl, 0.46 mmol) was added to this solution, and stirring was continued until TLC indicated that the starting materials were completely consumed. Then, N,N-dimethylethylenediamine (96 μl, 0.88 mmol) was added, and the reaction mixture was heated in an oil bath at 60°C until TLC indicated that the urea product was completely converted (approximately 2 hours). After dilution with Â, the organic phase was washed with water, 2N NaOH (twice), and saline solution, dried over Na2SO4, and the solvent was removed by distillation to dryness. The residue was purified by flash chromatography to obtain the title compound as a white solid (DCM / MeOH + 2N NH3 = 4-10%). 1 H NMR (400 MHz, DMSO) δ 8.81 (br s, 1H), 8.61 (s, 1H), 7.92 - 7.84 (m, 3H), 7.82 - 7.75 (m, 3H), 7.67 - 7.60 (m, 3H), 7.52 (d, J = 8.7 Hz, 2H), 6.15 (t, J = 5.2 Hz, 1H), 3.29 - 3.20 (m, 2H), 2.39 (t, J = 6.2 Hz, 2H), 2.23 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.6, 142.9, 140.0, 136.2, 135.3, 133.6, 133.1, 133.0, 127.3, 125.9, 121.6, 120.3, 120.2, 117.8, 107.8, 58.5, 45.0, 36.9.HPLCt ret = 5.58 min. ESI-MS m / z: 478.6 [M+H] + .

[0244] Inhibitors in Table 3 N-(4-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)acetamide (TD-313) [ka] The procedure was the same as for TD-307, except that 73 mg of TD-312 (0.227 mmol) and 83 mg of TD-306 (0.250 mmol) were used in 3.5 ml of dioxane / water (3+1). The mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. Yield: 62 mg, solid (60%). 1 H NMR (200 MHz, DMSO) δ 10.20 (s, 1H), 8.75 (s, 1H), 8.49 (s, 1H), 7.90 - 7.74 (m, 3H), 7.71 - 7.62 (m, 3H), 7.62 - 7.41 (m, 5H), 6.09 (t, J = 5.1 Hz, 1H), 3.27 - 3.12 (m, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.18 (s, 6H), 2.10 (s, 3H). HPLC t ret = 2.70 min. ESI-MS m / z: 457.3 [M+H], 455.3 [MH]-, 491.3 [M+Cl] - , 479.3 [M+Na] + .

[0245] N-(4-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)isobutylamide (TD-406) [ka] The procedure was the same as for TD-307, except that 54 mg of TD-402 (0.15 mmol) and 50 mg of TD-364 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued overnight at 60°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 1-10%. Yield: 65 mg, solid (89%). 1 H NMR (400 MHz, DMSO) δ 10.09 (s, 1H), 8.75 (s, 1H), 8.48 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.9 Hz, 3H), 7.60 - 7.52 (m, 3H), 7.47 (d, J = 8.7 Hz, 2H), 6.10 (t, J = 5.2 Hz, 1H), 3.23 - 3.14 (m, 2H), 2.70 - 2.59 (m, 1H), 2.33 (t, J = 6.2 Hz, 2H), 2.18 (s, 6H), 1.14 (d, J = 6.8 Hz, 6H). 13 C NMR (101 MHz, DMSO) δ 176.0, 155.6, 144.1, 143.2, 140.4, 139.5, 136.5, 134.5, 133.7, 131.1, 127.8, 124.9, 121.8, 120.7, 120.5, 118.3, 108.2, 59.0, 45.5, 37.4, 35.5, 20.0. HPLC t ret = 5.17 min. ESI-MS m / z: 485.8 [M+H] + , 483.8 [MH] - , 519.9 [M+Cl] - .

[0246] N-(4-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)-2-methylbutanamide (TD-397) [ka] The procedure was the same as for TD-307, except that 56 mg of TD-393 (0.13 mmol) and 38 mg of TD-396 (0.134 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 60°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. Yield: 44 mg, solid (66%). 1 H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 8.48 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.71 - 7.62 (m, 3H), 7.61 - 7.52 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H), 6.09 (t, J = 4.7 Hz, 1H), 3.22 - 3.15 (m, 2H), 2.48 - 2.40 (m, 1H), 2.33 (t, J = 5.9 Hz, 2H), 2.17 (s, 6H), 1.71 - 1.59 (m, 1H), 1.49 - 1.38 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 174.9, 155.1, 143.7, 142.7, 139.9, 138.9, 136.0, 134.0, 133.2, 130.6, 127.3, 124.4, 121.3, 120.3, 120.0, 117.8, 107.7, 58.5, 45.0, 42.2, 36.9, 26.8, 17.4, 11.7. HPLC t ret = 5.61 min. ESI-MS m / z: 499.5 M+H] + , 497.4 [MH] - , 533.6 [M+Cl]- .

[0247] N-(4-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-351) [ka] The procedure was the same as for TD-307 described above, except that 63 mg of TD-349 (0.172 mmol) and 63 mg of TD-306 (0.189 mmol) were used in 7.5 ml of dioxane / water (6 + 1.5). The mixture was stirred overnight at 77°C. TLC confirmed that complete consumption of the starting materials was not observed. Adding more catalyst precursors did not improve the conversion (after 3 hours). The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3. After drying the organic phase and removing the solvent, the crude product was purified by flash chromatography. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 1-10%. Yield: 40 mg, solid (47%). 1 H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 1.2 Hz, 1H), 7.50 - 7.42 (m, 4H), 6.11 (t, J = 5.3 Hz, 1H), 3.22 - 3.16 (m, 2H), 3.09 (s, 3H), 2.35 (t, J = 6.2 Hz, 2H), 2.19 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.7, 142.8, 139.9, 137.9, 136.1, 133.9, 133.2, 131.6, 127.3, 125.0, 121.4, 120.7, 120.1, 117.8, 107.8, 58.5, 45.0, 39.5, 36.9.HPLCt ret= 2.95 min. ESI-MS m / z: 493.3 [M+H] + , 448.2 [M-NMe2] + .

[0248] N-(4-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)cyclopropanesulfonamide (TD-355) [ka] The procedure was the same as for TD-307 described above, except that 70 mg of TD-352 (0.18 mmol) and 65 mg of TD-306 (0.20 mmol) were used in 8 ml of dioxane / water (6+2). The mixture was stirred overnight at 65°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 1-10%. Yield: 69 mg, solid (75%). 1 H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 8.76 (s, 1H), 8.51 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 1.1 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.55 (dd, J = 8.5, 1.6 Hz, 1H), 7.47 (dd, J = 8.7, 1.9 Hz, 4H), 6.11 (t, J = 5.2 Hz, 1H), 3.22 - 3.17 (m, 2H), 2.78 - 2.70 (m, 1H), 2.34 (t, J = 6.1 Hz, 2H), 2.18 (s, 6H), 1.04 - 0.96 (m, 4H). 13C NMR (101 MHz, DMSO) δ 155.0, 143.6, 142.7, 139.9, 137.9, 136.0, 133.9, 133.2, 131.5, 127.3, 124.8, 121.3, 121.1, 120.0, 117.8, 107.7, 58.5, 44.9, 36.9, 29.7, 5.0. HPLC t ret = 3.67 min. ESI-MS m / z: 519.3 [M+H] + , 541.1 [M+Na] + , 474.2 [M-NMe2] + , 431.1 [M-C4H 11 N2] + .

[0249] 1-(4-(1-(4-cyclohexylphenyl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-459) [ka] The procedure was the same as for TD-307, except that 59 mg of TD-458 (0.17 mmol) and 50 mg of TD-396 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 65°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3-9%. The product was dissolved in a small amount of DCM and precipitated with n-pentane. The product was recovered by filtration. Yield: 37 mg, solid (51%). 1H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.52 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.60 - 7.52 (m, 3H), 7.52 - 7.42 (m, 4H), 6.10 (t, J = 5.1 Hz, 1H), 3.22 - 3.14 (m, J = 11.5, 5.9 Hz, 2H), 2.67 - 2.58 (m, 1H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H), 1.90 - 1.78 (m, 4H), 1.73 (d, J = 12.5 Hz, 1H), 1.54 - 1.35 (m, 4H), 1.32 - 1.22 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 155.1, 147.2, 143.8, 142.9, 139.9, 136.0, 133.8, 133.8, 133.2, 128.3, 127.4, 123.7, 121.4, 120.1, 117.8, 107.8, 58.5, 45.0, 43.4, 36.9, 33.9, 26.3, 25.6. HPLC t ret = 7.90 min. ESI-MS m / z: 482.4 [M+H] + , 480.5 [MH] - , 516.4 [M+Cl] - .

[0250] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-454) [ka] The procedure was the same as for TD-307, except that 66 mg of TD-453 (0.17 mmol) and 43 mg of TD-396 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 60°C until the starting materials were completely consumed and the desired product was shown to have formed by TLC (confirmed by TLC-MS). The resulting product was extracted by DCM, and the aqueous phase was diluted with saturated NaHCO3 solution. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-10%. A second flash chromatography purification step was performed using reversed phase C18 silica gel (solvent: water + TEA (0.05 M) / MeOH = 15-100%). Yield: 50 mg, solid (83%) (purity: λ(254 nm) = 93%, λ(230 nm) = 92%). 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.54 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.73 - 7.62 (m, 5H), 7.60 - 7.53 (m, 3H), 7.47 (d, J = 8.6 Hz, 2H), 6.33 - 6.24 (m, 1H), 6.10 (t, J = 5.1 Hz, 1H), 3.22 - 3.15 (m, 2H), 2.47 - 2.40 (m, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.26 - 2.13 (m, 8H), 1.82 - 1.72 (m, 2H), 1.69 - 1.59 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.6, 142.9, 141.1, 139.9, 136.1, 135.0, 134.3, 133.8, 133.2, 127.3, 126.1, 125.3, 123.6, 121.4, 120.1, 117.8, 107.8, 58.5, 45.0, 36.9, 26.6, 25.4, 22.5, 21.6. HPLC t ret = 7.67 min (Method C). ESI-MS m / z: 480.8 [M+H] + .

[0251] Inhibitors in Table 4 N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)acetamide (TD-337) [ka] The procedure was the same as for TD-307 described above, except that 45 mg of TD-334 (0.136 mmol) and 55 mg of TD-306 (0.164 mmol) were used in dioxane / water. Stirring was continued overnight at 65°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH37 ~ 10%. A second flash chromatography purification step was performed using reversed-phase C18 silica gel (water / MeOH = 10 ~ 90). Yield: 22 mg, white solid (35%). 1 H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 8.79 (s, 1H), 8.55 (s, 1H), 8.05 (t, J = 1.8 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.60 - 7.53 (m, 4H), 7.48 (d, J = 8.7 Hz, 2H), 7.41 - 7.37 (m, 1H), 6.15 (t, J = 5.3 Hz, 1H), 3.21 - 3.16 (m, 2H), 2.33 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H), 2.09 (s, 3H). HPLC t ret = 3.49 min. ESI-MS m / z: 457.2 [M+H] + , 479.2 [M+Na] + , 455.2 [MH] - , 491.2 [M+Cl] - .

[0252] 1-(4-(1-(3-acetylphenyl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (LS-35) [ka] The procedure was the same as for TD-228 described above, except that 52 mg of LS-33 (0.17 mmol), 61 mg of TD-306 (0.18 mmol), and 131 mg of K3PO4·3H2O (0.497 mmol) were used in dioxane (2 ml) / water (1 ml). The resulting product was extracted by DCM. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3-10%. RP-flash chromatography gradient: Water / MeOH = 10-90%. Yield: 30 mg, white solid (41%). 1 H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.64 (s, 1H), 8.23 ​​(s, 1H), 8.12 - 8.00 (m, 2H), 7.87 - 7.71 (m, 3H), 7.63 - 7.44 (m, 5H), 6.32 - 6.14 (m, 1H), 3.24 - 3.14 (m, 2H), 2.68 (s, 3H), 2.32 (mf, 2H), 2.16 (s, 6H). HPLC t ret = 3.98 min. ESI-MS m / z: 442.3 [M+H] + .

[0253] N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)ethanesulfonamide (TD-398) [ka] The procedure was the same as for TD-307, except that 55 mg of TD-383 (0.15 mmol) and 48 mg of TD-364 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 60°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 2-10%. Yield: 64 mg, solid (89%). 1 H NMR (400 MHz, DMSO) δ 10.16 (bs, 1H), 8.77 (s, 1H), 8.58 (s, 1H), 7.86 - 7.75 (m, 2H), 7.65 - 7.53 (m, 5H), 7.51 - 7.42 (m, 3H), 7.34 - 7.29 (m, 1H), 6.12 (t, J = 4.6 Hz, 1H), 3.27 - 3.21 (m, 2H), 3.21 - 3.16 (m, 2H), 2.34 (t, J = 5.9 Hz, 2H), 2.18 (s, 6H), 1.24 (t, J = 7.2 Hz, 3H). HPLC t ret = 4.79 min. ESI-MS m / z: 507.6 [M+H] + , 505.6 [MH] - .

[0254] N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)cyclopropanesulfonamide (TD-386) [ka] The procedure was the same as for TD-307, except that 55 mg of TD-382 (0.14 mmol) and 51 mg of TD-306 (0.153 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 60°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-10%. Yield: 54 mg, solid (74%). 1 H NMR (400 MHz, DMSO) δ 9.89 (bs, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 7.84 - 7.77 (m, 2H), 7.63 - 7.56 (m, 5H), 7.50 - 7.45 (m, 3H), 7.37 - 7.32 (m, 1H), 6.11 (t, J = 5.2 Hz, 1H), 3.21 - 3.16 (m, 2H), 2.84 - 2.75 (m, 1H), 2.34 (t, J = 6.2 Hz, 2H), 2.18 (s, 6H), 1.02 - 0.94 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.5, 143.0, 140.0, 140.0, 136.6, 136.2, 133.5, 133.1, 131.1, 127.3, 121.6, 120.3, 118.8, 118.6, 117.9, 114.3, 107.8, 58.5, 45.0, 37.0, 29.8, 5.1. HPLC t ret = 4.86 min. ESI-MS m / z: 519.5 [M+H] + , 517.4 [M+H] - .

[0255] N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)propane-1-sulfonamide (TD-430) [ka] The same procedure as for TD-307 was followed, except that 43 mg of TD-396 (0.15 mmol) and 91 mg of TD-424 (HPLC purity: 58%) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued overnight at 60°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. 1 H NMR (400 MHz, DMSO) δ 10.13 (bs, 1H), 8.75 (s, 1H), 8.58 (s, 1H), 7.84 - 7.76 (m, 2H), 7.64 - 7.55 (m, 5H), 7.48 (d, J = 8.7 Hz, 2H), 7.46 - 7.42 (m, 1H), 7.31 (dd, J = 8.1, 1.2 Hz, 1H), 6.10 (t, J = 5.2 Hz, 1H), 3.24 - 3.16 (m, 4H), 2.34 (t, J = 6.2 Hz, 2H), 2.18 (s, 6H), 1.80 - 1.68 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.4, 142.9, 140.0, 140.0, 136.7, 136.1, 133.4, 133.1, 131.2, 127.2, 121.5, 120.2, 118.2, 117.8, 117.8, 113.4, 107.8, 58.5, 52.8, 45.0, 36.9, 16.9, 12.5. Yield: 45 mg solid (58%). HPLC t ret = 4.65 min. ESI-MS m / z: 521.6 [M+H] + , 519.6 [MH] - .

[0256] (3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)carbamate tert-butyl (TD-307) [ka] In a reaction vial under an argon atmosphere, 80 mg of TD-280 (1.0 mmol), 85 mg of TD-306 (1.2 mmol), and 169 mg of K3PO4·3H2O (0.636 mmol) were suspended / dissolved in 3.6 ml of dioxane / water (3+1). A catalytic amount of tBu3P Pd G3 was added to the reaction mixture. Stirring was continued at 65°C for 3.5 hours until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). The reaction mixture was diluted with EA and washed with 2N NaOH in a separatory funnel. The organic phase was dried over Na2SO4, and the crude product was purified by flash chromatography (DCM / MeOH + 2N NH3 = 5-10%) to obtain 82 mg (75%) of a beige solid. 1 H NMR (200 MHz, DMSO) δ 9.73 (s, 1H), 8.76 (s, 1H), 8.56 (s, 1H), 8.02 - 7.93 (m, 1H), 7.89 - 7.77 (m, 2H), 7.67 - 7.44 (m, 7H), 7.38 - 7.28 (m, 1H), 6.17 - 6.04 (m, 1H), 3.26 - 3.12 (m, J = 4.8 Hz, 2H), 2.33 (t, J = 5.9 Hz, 2H), 2.17 (s, 6H), 1.51 (s, 9H). HPLC t ret = 6.08 min. ESI-MS m / z: 515.8 [M+H] + , 549.6 [M+Cl] - .

[0257] Inhibitors listed in Table 8 N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)-2-fluorophenyl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-420) [ka] The same procedure as for TD-307 was followed, except that 80 mg of TD-387 (0.19 mmol) and 46 mg of 1-(4-bromo-3-fluorophenyl)-3-(2-(dimethylamino)ethyl)urea (Dimitrov, T. et al.) (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued at 70°C for 5 hours until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-10%. Yield: 53 mg, solid (69%). 1 H NMR (400 MHz, DMSO) δ 10.08 (bs, 1H), 8.98 (s, 1H), 8.61 (s, 1H), 7.87 - 7.80 (m, 1H), 7.74 - 7.67 (m, 1H), 7.62 - 7.53 (m, 2H), 7.52 (t, J = 2.0 Hz, 1H), 7.48 - 7.42 (m, 3H), 7.34 - 7.28 (m, 1H), 7.12 (dd, J = 8.5, 2.0 Hz, 1H), 6.19 (t, J = 5.2 Hz, 1H), 3.23 - 3.17 (m, 2H), 3.11 (s, 3H), 2.35 (t, J = 6.2 Hz, 2H), 2.19 (s, 6H). HPLC t ret = 4.60 min. ESI-MS m / z: 511.6 [M+H] + , 509.6 [MH] - .

[0258] N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)-3-fluorophenyl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-416) [ka] The procedure was the same as for TD-307 described above, except that 62 mg of TD-387 (0.15 mmol) and 46 mg of 1-(4-bromo-2-fluorophenyl)-3-(2-(dimethylamino)ethyl)urea (Dimitrov, T. et al.) (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 55-65°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 2-10%. Yield: 48 mg, solid (63%). 1 H NMR (400 MHz, DMSO) δ 10.13 (bs, 1H), 8.71 - 8.45 (m, 2H), 8.23 ​​(t, J = 8.7 Hz, 1H), 7.84 (d, J = 1.0 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.65 - 7.55 (m, 4H), 7.48 (dd, J = 8.1, 1.3 Hz, 2H), 7.31 (dd, J = 8.1, 1.2 Hz, 1H), 6.69 (t, J = 5.2 Hz, 1H), 3.25 - 3.17 (m, 2H), 3.13 (s, 3H), 2.34 (t, J = 6.1 Hz, 2H), 2.18 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.3, 152.4 (d, J = 241.1 Hz), 144.2, 143.7, 140.4, 137.1, 135.3 (d, J = 1.9 Hz), 134.4 (d, J = 7.0 Hz), 134.4, 133.9, 131.6, 128.00 (d, J = 10.5 Hz), 123.21 (d, J = 2.6 Hz), 122.1, 120.84 (d, J = 1.7 Hz), 118.9, 118.7, 114.4, 113.6 (d, J = 20.1 Hz), 108.7, 58.9, 45.5, 40.2, 37.5. HPLC t ret = 4.69 min. ESI-MS m / z: 511.6 [M+H] +, 509.6 [MH] - , 545.5 [M+Cl] - .

[0259] N-(2-(dimethylamino)ethyl)-2-(4-(1-(3-(methylsulfonamide)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)acetamide (TD-477) [ka] The procedure was the same as for TD-307, except that 63 mg of TD-387 (0.15 mmol) and 43 mg of TD-461 (0.15 mmol) were used in 4 ml of dioxane / water (4+1). The mixture was stirred overnight at 65°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. The obtained product was dissolved in a small amount of DCM and diluted with n-pentane until the product precipitated. The final product was recovered by filtration. Yield: 38 mg, solid (52%). 1 H NMR (400 MHz, DMSO) δ 10.13 (bs, 1H), 8.63 (s, 1H), 8.02 (t, J = 5.5 Hz, 1H), 7.88 - 7.82 (m, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.63 - 7.56 (m, 3H), 7.50 - 7.45 (m, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.30 (dd, J = 8.0, 1.5 Hz, 1H), 3.45 (s, 2H), 3.18 - 3.11 (m, 5H), 2.28 (t, J = 6.7 Hz, 2H), 2.14 (s, 6H). HPLC t ret = 4.23 min. ESI-MS m / z: 492.4 [M+H] + , 490.0 [MH] - .

[0260] (4-(1-(3-(methylsulfonamide)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)carbamate 2-(dimethylamino)ethyl (TD-429) [ka] The procedure was the same as for TD-307, except that 43 mg of TD-387 (0.10 mmol) and 68 mg of TD-428 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued at 65°C for 4 hours until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 1-8%. A second flash chromatography purification step was performed using reversed-phase C18 silica gel (water / MeOH = 10-100%). Yield: 14 mg, solid (28%). 1 H NMR (400 MHz, DMSO) δ 10.12 (bs, 1H), 9.76 (s, 1H), 8.60 (s, 1H), 7.85 - 7.80 (m, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.62 - 7.54 (m, 5H), 7.46 (d, J = 7.8 Hz, 1H), 7.30 (dd, J = 8.1, 1.2 Hz, 1H), 4.17 (t, J = 5.7 Hz, 2H), 3.12 (s, 3H), 2.54 - 2.51 (m, 2H), 2.19 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 153.5, 143.6, 143.1, 140.1, 138.5, 136.7, 135.9, 134.6, 133.5, 131.1, 127.4, 121.7, 120.3, 118.6, 118.3, 118.2, 113.9, 108.1, 61.8, 57.6, 45.3, 39.7. HPLC t ret = 3.88 min. ESI-MS m / z: 494.9 [M+H] + , 492.9 [MH] - .

[0261] 4-Methyl-N-(4-(1-(3-(methylsulfonamide)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)piperazine-1-carboxamide (TD-391) [ka] The procedure was the same as for TD-307, except that 55 mg of TD-342 (0.15 mmol) and 57 mg of TD-389 (0.165 mmol) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued at 65°C for 6 hours until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). The solvent was removed by distillation without extraction. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 7-10%. Yield: 61 mg, solid (81%). 1 H NMR (400 MHz, DMSO) δ 10.14 (bs, 1H), 8.65 - 8.55 (m, 2H), 7.86 - 7.78 (m, 2H), 7.66 - 7.54 (m, 7H), 7.48 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 3.49 - 3.42 (m, 4H), 3.13 (s, 3H), 2.37 - 2.28 (m, 4H), 2.21 (s, 3H). HPLC t ret = 4.00 min. ESI-MS m / z: 505.4 [M+H] + , 527.4 [M+Na] + , 503.4 [MH] - , 539.4 [M+Cl] - .

[0262] 4-(dimethylamino)-N-(4-(1-(3-(methylsulfonamide)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)piperidine-1-carboxamide (TD-392) [ka] The procedure was the same as for TD-307, except that 57 mg of TD-342 (0.16 mmol) and 58 mg of TD-373 (0.16 mmol) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued overnight at 60°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). The solvent was removed by distillation without extraction. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 7-10% (not optimal conditions). Since some fractions contained impurities, reverse-phase flash chromatography was performed to purify the desired product (water / MeOH = 10-90%). Yield: 59 mg, solid (73%). 1 H NMR (400 MHz, DMSO) δ 10.08 (bs, 1H), 8.65 - 8.53 (m, 2H), 7.87 - 7.76 (m, 2H), 7.64 - 7.54 (m, 7H), 7.50 - 7.42 (m, 1H), 7.33 - 7.26 (m, 1H), 4.22 - 4.07 (m, 2H), 3.12 (s, 3H), 2.86 - 2.72 (m, 2H), 2.36 - 2.24 (m, 1H), 2.19 (s, 6H), 1.87 - 1.70 (m, 2H), 1.37 - 1.24 (m, 2H). HPLC t ret = 4.16 min. ESI-MS m / z: 533.5 [M+H] + , 555.5 [M+Na] + , 531.5 [MH] - , 567.6 [M+Cl] - .

[0263] 2-(4-methylpiperazine-1-yl)-N-(4-(1-(3-(methylsulfonamide)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)acetamide (TD-542) [ka] The procedure was the same as for TD-307, except that 44 mg of TD-342 (0.12 mmol) and 41 mg of TD-536 (0.115 mmol) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued at 75°C for 8 hours until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. The obtained product was suspended in a small amount of DCM and diluted with n-pentane. The desired product was recovered by filtration. Yield: 39 mg, solid (65%). 1 H NMR (400 MHz, DMSO) δ 10.14 (s, 1H), 9.77 (s, 1H), 8.61 (s, 1H), 7.86 - 7.81 (m, J = 4.8, 3.5 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.63 - 7.56 (m, 3H), 7.50 - 7.44 (m, 1H), 7.33 - 7.28 (m, 1H), 3.13 (s, 5H), 2.60 - 2.50 (m, 4H), 2.39 (s, 4H), 2.18 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 168.3, 143.7, 143.2, 140.0, 137.9, 136.7, 135.8, 135.6, 133.5, 131.1, 127.3, 121.7, 120.3, 119.8, 118.4, 118.2, 113.9, 108.2, 61.8, 54.5, 52.7, 45.7, 39.7. HPLC t ret = 6.78 min. ESI-MS m / z: 519.1 [M+H] + , 517.1 [MH] - , 541.1 [M+Na] + .

[0264] N-(3-(6-(4-(3-(1-methylpyrrolidine-3-yl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-439) [ka] The same procedure as for TD-307 was followed, except that 85 mg of TD-387 (0.21 mmol) and 45 mg of 1-(4-bromophenyl)-3-(1-methylpyrrolidine-3-yl)urea (Dimitrov T. et al.) (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 65°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). The reaction mixture was extracted by DCM (the K3PO4 aqueous phase was diluted with saturated NaHCO3 solution). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. Yield: 36 mg, solid (48%). 1 H NMR (400 MHz, DMSO) δ 10.19 (bs, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 7.84 - 7.78 (m, 2H), 7.62 - 7.56 (m, 5H), 7.47 (d, J = 8.6 Hz, 3H), 7.31 (dd, J = 8.1, 1.2 Hz, 1H), 6.42 (d, J = 7.7 Hz, 1H), 4.19 - 4.10 (m, 1H), 3.13 (s, 3H), 2.75 - 2.64 (m, 1H), 2.61 - 2.53 (m, 1H), 2.44 - 2.39 (m, 1H), 2.34 - 2.25 (m, 4H), 2.22 - 2.12 (m, 1H), 1.58 - 1.48 (m, 1H). 13C NMR (101 MHz, DMSO) δ 154.6, 143.4, 142.9, 139.9, 139.7, 136.7, 136.1, 133.5, 133.2, 131.0, 127.2, 121.5, 120.2, 118.4, 118.1, 117.9, 113.9, 107.8, 62.6, 54.4, 49.0, 41.6, 39.7, 32.6. HPLC t ret = 3.63 min. ESI-MS m / z: 505.8 [M+H] + , 503.8 [MH] - .

[0265] N-(3-(6-(4-(3-(1-methylpiperidine-3-yl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-440) [ka] The same procedure as for TD-307 was followed, except that 85 mg of TD-387 (0.21 mmol) and 47 mg of 1-(4-bromophenyl)-3-(1-methylpiperidine-3-yl)urea (Dimitrov, T. et al.) (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The yellowish reaction mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). The reaction mixture was extracted by DCM (K3PO4 aqueous phase diluted with saturated NaHCO3 solution). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. Yield: 53 mg, solid (68%). 1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.65 - 8.57 (m, 2H), 7.85 - 7.78 (m, 2H), 7.64 - 7.56 (m, 5H), 7.48 (d, J = 8.6 Hz, 3H), 7.31 (dd, J = 8.1, 1.2 Hz, 1H), 6.28 (d, J = 8.1 Hz, 1H), 3.80 - 3.67 (m, 1H), 3.13 (s, 3H), 2.50 (s, 1H), 2.33 - 2.03 (m, 6H), 1.72 - 1.55 (m, 2H), 1.53 - 1.45 (m, 1H), 1.38 - 1.28 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 154.4, 143.5, 142.9, 140.0, 139.9, 136.7, 136.2, 133.5, 133.1, 131.1, 127.3, 121.5, 120.2, 118.4, 118.1, 117.8, 113.9, 107.9, 60.6, 55.2, 46.1, 45.1, 39.7, 29.1, 22.3. HPLC t ret = 3.84 min. ESI-MS m / z: 519.9 [M+H] + , 517.9 [MH] - .

[0266] N-(3-(6-(4-(3-(1-(dimethylamino)propan-2-yl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-441) [ka] The procedure was the same as for TD-307 described above, except that 80 mg of TD-387 (approximately 0.165 mmol, purity approximately 85%) and 45 mg of 1-(4-bromophenyl)-3-(1-(dimethylamino)propan-2-yl)urea (Dimitrov, T. et al.) (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 2-10%. Yield: 52 mg, solid (68%). 1 H NMR (400 MHz, DMSO) δ 10.15 (bs, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 7.85 - 7.77 (m, 2H), 7.64 - 7.55 (m, 5H), 7.51 - 7.45 (m, 3H), 7.34 - 7.27 (m, 1H), 6.00 (d, J = 6.8 Hz, 1H), 3.83 - 3.68 (m, 1H), 3.13 (s, 3H), 2.35 - 2.26 (m, 1H), 2.17 (s, 6H), 2.16 - 2.10 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H). 13 C NMR (101 MHz, DMSO) δ 154.8, 143.5, 142.9, 140.0, 140.0, 136.7, 136.2, 133.5, 133.1, 131.1, 127.2, 121.5, 120.2, 118.4, 118.1, 117.8, 113.9, 107.8, 64.7, 45.4, 43.1, 39.7, 19.7. HPLC t ret = 3.88 min. ESI-MS m / z: 507.8 [M+H] + , 505.8 [MH] - .

[0267] N-(3-(6-(4-(3-(2-(3-fluoroazetidine-1-yl)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-444) [ka] The same procedure as for TD-307 was followed, except that 79 mg of TD-387 (0.16 mmol, 85% purity by HPLC) and 45 mg of 1-(4-bromophenyl)-3-(2-(3-fluoroazetidine-1-yl)ethyl)urea (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 80°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. The resulting product was suspended in a mixture of DCM and n-pentane and recovered by filtration. Yield: 76 mg, solid (97%). 1 H NMR (400 MHz, DMSO) δ 10.13 (bs, 1H), 8.67 (s, 1H), 8.59 (s, 1H), 7.86 - 7.76 (m, 2H), 7.65 - 7.54 (m, 5H), 7.51 - 7.44 (m, 3H), 7.31 (dd, J = 8.1, 1.2 Hz, 1H), 6.11 (t, J = 5.5 Hz, 1H), 5.27 - 5.05 (m, 1H), 3.65 - 3.52 (m, 2H), 3.19 - 3.04 (m, 7H), 2.53 (t, J = 6.1Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 155.0, 143.5, 142.9, 139.9, 139.9, 136.7, 136.2, 133.5, 133.2, 131.1, 127.3, 121.5, 120.2, 118.4, 118.1, 117.9, 113.8, 107.9, 82.84 (d, J = 201.7 Hz), 61.1, 60.9, 58.6, 37.3. HPLC t ret= 3.64 min. ESI-MS m / z: 523.9 [M+H] + .

[0268] N-(3-(6-(4-(3-(2-(3,3-difluoroazetidine-1-yl)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-442) [ka] The same procedure as for TD-307 was followed, except that 80 mg of TD-387 (0.17 mmol, 85% purity by HPLC) and 50 mg of 1-(4-bromophenyl)-3-(2-(3,3-difluoroazetidine-1-yl)ethyl)urea (Dimitrov, T. et al.) (0.15 mmol) were used in 4 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH = 1.5-8%. The resulting product was suspended in a mixture of DCM and n-pentane (1+1) and recovered by filtration. Yield: 60 mg, solid (74%). 1 H NMR (400 MHz, DMSO) δ 10.14 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 7.86 - 7.77 (m, 2H), 7.63 - 7.54 (m, 5H), 7.52 - 7.45 (m, 3H), 7.34 - 7.28 (m, 1H), 6.16 (t, J = 5.4 Hz, 1H), 3.61 (t, J = 12.5 Hz, 4H), 3.16 - 3.08 (m, 5H), 2.63 (t, J = 5.7 Hz, 2H). HPLC t ret = 3.88 min. ESI-MS m / z: 539.8 [MH] - .

[0269] N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-2-methyl-1H-benzo[d]imidazole-1-yl)phenyl)methanesulfonamide (TD-504) [ka] The procedure was the same as for TD-307 described above, except that 42 mg of TD-501 (0.11 mmol) and 37 mg of TD-306 (0.11 mmol) were used in 5 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 10%. Yield: 33 mg, solid (59%). 1 H NMR (400 MHz, DMSO) δ 10.08 (bs, 1H), 8.89 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.53 - 7.44 (m, 5H), 7.39 - 7.32 (m, 4H), 6.33 (s, 1H), 3.32 - 3.27 (m, 2H), 3.12 (s, 3H), 2.69 (s, 2H), 2.46 (d, J = 8.9 Hz, 9H). 13 C NMR (101 MHz, DMSO) δ 155.3, 151.6, 141.5, 139.8, 139.6, 136.3, 136.2, 135.0, 133.4, 131.0, 127.1, 121.7, 121.0, 119.3, 118.8, 118.0, 117.3, 107.1, 57.8, 44.0, 39.8, 35.9, 14.4. HPLC t ret = 2.88 min. ESI-MS m / z: 507.4 [M+H] + , 505.3 [MH] - .

[0270] N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-2-methyl-1H-benzo[d]imidazole-1-yl)phenyl)ethanesulfonamide (TD-545) [ka] The procedure was the same as for TD-307 described above, except that 69 mg of TD-538 (0.18 mmol) and 50 mg of TD-306 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5.5~10% (yield: 63 mg). The obtained product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 50 mg, solid (64%). 1 H NMR (400 MHz, DMSO) δ 10.14 (s, 1H), 8.74 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.52 - 7.47 (m, 3H), 7.44 (d, J = 8.7 Hz, 2H), 7.39 - 7.32 (m, 4H), 6.11 (t, J = 5.1 Hz, 1H), 3.25 - 3.15 (m, 4H), 2.48 (s, 3H), 2.35 (t, J = 6.1 Hz, 2H), 2.19 (s, 6H), 1.23 (t, J = 7.3 Hz, 3H). HPLC t ret = 5.29 min. ESI-MS m / z: 521.3 [M+H] + , 519.3 [MH] - .

[0271] N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-2-methyl-1H-benzo[d]imidazole-1-yl)phenyl)cyclopropanesulfonamide (TD-546) [ka] The procedure was the same as for TD-307 described above, except that 69 mg of TD-539 (0.170 mmol) and 50 mg of TD-306 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 9-10%. The obtained product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 54 mg, colorless solid (68%). 1 H NMR (400 MHz, DMSO) δ 10.08 (bs, 1H), 8.75 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.52 - 7.47 (m, 3H), 7.45 - 7.38 (m, 4H), 7.38 - 7.34 (m, 1H), 7.32 - 7.30 (m, 1H), 6.11 (t, J = 5.2 Hz, 1H), 3.21 - 3.16 (m, 2H), 2.78 (p, J = 6.4 Hz, 1H), 2.48 (s, 3H), 2.35 (t, J = 6.1 Hz, 2H), 2.19 (s, 6H), 0.96 (d, J = 6.3 Hz, 4H). HPLC t ret = 6.55 min. ESI-MS m / z: 533.3 [M+H] + , 531.3 [MH] - .

[0272] N-(3-(5-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-3H-imidazo[4,5-b]pyridine-3-yl)phenyl)methanesulfonamide (TD-512) [ka] The procedure was the same as for TD-307 described above, except that 51 mg of TD-306 (0.153 mmol) and 61 mg of TD-511 (0.165 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 60°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. Yield: 58 mg, solid (77%). 1 H NMR (400 MHz, DMSO) δ 10.15 (bs, 1H), 8.89 - 8.83 (m, 2H), 8.21 (d, J = 8.5 Hz, 1H), 8.11 - 8.06 (m, 3H), 7.90 (d, J = 8.5 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.29 - 7.25 (m, 1H), 6.16 (t, J = 5.2 Hz, 1H), 3.23 - 3.18 (m, J = 11.5, 5.9Hz, 2H), 3.12 (s, 3H), 2.36 (t, J = 6.1 Hz, 2H), 2.20 (s, 6H). HPLC t ret = 5.63 min. ESI-MS m / z: 494.0 [M+H] + , 491.9 [MH] - .

[0273] 2-(3-(dimethylamino)azetidine-1-yl)-N-(4-(3-(3-(methylsulfonamide)phenyl)-3H-imidazo[4,5-b]pyridine-5-yl)phenyl)acetamide (TD-534) [ka] The procedure was the same as for TD-307, except that 58 mg of TD-511 (0.16 mmol) and 54 mg of TD-515 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. Yield: 34 mg, grayish-white solid (44%). 1 H NMR (400 MHz, DMSO) δ 10.18 (bs, 1H), 9.82 (s, 1H), 8.90 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.7 Hz, 2H), 8.13 (t, J = 1.9 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.68 - 7.63 (m, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.29 - 7.24 (m, 1H), 3.54 (t, J = 6.7 Hz, 2H), 3.25 (s, HPLC t ret = 3.67 min (Method C). ESI-MS m / z: 520.3 [M+H] + .

[0274] N-(3-(6-(4-(3-(2-(dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazole-1-yl)phenyl)-N-methylmethanesulfonamide (TD-417) [ka] The procedure was the same as for TD-307, except that 57 mg of TD-410 (0.15 mmol) and 50 mg of TD-364 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 60°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4.5-10%. The resulting product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 55 mg, solid (72%). 1 H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.60 (s, 1H), 7.87 - 7.76 (m, 3H), 7.73 - 7.64 (m, 2H), 7.63 - 7.51 (m, 4H), 7.47 (d, J = 8.5 Hz, 2H), 6.11 (t, J = 5.0 Hz, 1H), 3.35 (s, 3H), 3.23 - 3.16 (m, 2H), 3.05 (s, 3H), 2.34 (t, J = 6.1 Hz, 2H), 2.18 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.6, 143.0, 142.9, 139.9, 136.3, 136.1, 133.6, 133.0, 130.6, 127.2, 124.9, 121.9, 121.5, 121.2, 120.1, 117.8, 107.8, 58.5, 45.0, 37.5, 36.9, 35.3. HPLC t ret = 4.59 min. ESI-MS m / z: 507.8 [M+H] + .

[0275] Compounds of Scheme 6 A) Introduction of sulfonamide at a later stage 6-Nitroindoline-1-carboxylate tert-butyl (TD-543) [ka] To a solution of 5194 mg of 6-nitroindoline (31.66 mmol) in dioxane (40 ml), 6910 mg of Boc2O and a catalytic amount of DMAP (40 mg) were added. The reaction mixture was stirred overnight at room temperature until TLC (PE / DCM = 1 + 1) indicated that the starting materials had been completely consumed. The dioxane was removed by distillation to obtain an oily substance. A small amount of MeOH was overlaid on the oily substance to initiate crystallization. The resulting suspension was stored in a refrigerator. The product was recovered by filtration and washed with a small amount of cold MeOH. Yield: 7464 mg, pale yellow solid (28.24 mmol, 89%). 1 H NMR (400 MHz, DMSO) δ 8.58 - 8.04 (m, 1H), 7.80 (dd, J = 8.2, 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 3.99 (t, J = 8.7 Hz, 2H), 3.17 (t, J = 8.7 Hz, 2H), 1.52 (s, 9H). 13 C NMR (101 MHz, DMSO) δ 151.6, 147.1, 143.7, 140.1, 125.4, 117.7, 108.0, 80.9, 48.0, 27.9, 26.9. HPLC t ret = 11.13 min.

[0276] 6-aminoindoline-1-carboxylate tert-butyl (TD-548) [ka] The same procedure as for the preparation of TD-521 described above was followed, except that 14.01 g of TD-543 (53.01 mmol), 34.65 g of zinc powder, and 28.35 g of NH4Cl were used in 250 ml of MeOH. After workup, an oily substance was obtained, but crystallization could be initiated by rubbing (Note: Since crystallization is highly exothermic, boiling may occur later if solvent remains, so cooling is advantageous). The crude product could be recrystallized in EtOH / EA, and the resulting yellowish crystalline product was washed with a small amount of cold EtOH. Yield: 11.58 g (93%). 1H NMR (400 MHz, DMSO) δ 7.08 (bs, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.13 (dd, J = 7.9, 2.1 Hz, 1H), 4.93 (s, 2H), 3.82 (t, J = 8.5 Hz, 2H), 2.85 (t, J = 8.5 Hz, 2H), 1.49 (s, 9H). HPLC t ret = 7.75 min.

[0277] 6-((5-bromo-2-nitrophenyl)amino)indoline-1-carboxylate tert-butyl (TD-549) [ka] The same procedure as for the preparation of TD-324 described above was followed, except that 4508 mg of 4-bromo-2-fluoro-1-nitrobenzene (20.49 mmol), 4571 mg of TD-548 (19.51 mmol), and 30.7 mmol of triethylamine were used at 65°C. Reaction time: overnight. Solvent for TLC: n-pentane / DCM(1+1). The reaction was stopped by adding cold water, and the product was obtained in the form of a slurry. Crystallization could be initiated by adding MeOH to a portion of the product and rubbing. The obtained solid was added to the mother liquor to obtain a suspension. The obtained product was recovered by filtration. This crude product was suspended in hot MeOH, recovered again by filtration, and air-dried. Yield: 5664 mg, orange solid (67%). 1 H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.75 - 7.46 (m, 1H), 7.32 - 7.07 (m, 2H), 7.02 - 6.95 (m, 1H), 6.89 (dd, J = 7.9, 1.6 Hz, 1H), 3.95 (t, J = 8.6 Hz, 2H), 3.08 (t, J = 8.5 Hz, 2H), 1.47 (s, 9H). HPLC ret = 13.81 min. ESI-MS m / z: 456.1 [M+Na] + .

[0278] 6-(6-bromo-1H-benzo[d]imidazole-1-yl)indoline-1-carboxylate tert-butyl (TD-555) [ka] The same procedure as for the preparation of TD-280 described above was followed, except that 5664 mg of TD-549 (13.04 mmol), 8530 mg of zinc powder, and 7000 mg of NH4Cl were used in approximately 80 ml of MeOH (reaction time: overnight). In step 2, 6.5 ml of triethyl orthoformate (40 mmol) and 250 mg of p-TsOH·H2O (10 mmol%) were used in 150 ml of toluene at 70°C (reaction time: 4.5 hours). Yield: 5295 mg, dark solid (98%). 1 H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 7.91 - 7.57 (m, 3H), 7.46 (dd, J = 8.6, 1.9 Hz, 1H), 7.43 (m, J = 7.9 Hz, 1H), 7.21 (dd, J = 7.9, 2.0 HPLC t ret = 10.82 min.

[0279] 6-bromo-1-(indolin-6-yl)-1H-benzo[d]imidazole (TD-557) [ka] The same procedure as for the preparation of TD-319 was followed, except that 2029 mg of TD-555 (4.90) and 24 ml of HCl-ethanol solution (1.25 mmol) were used in 50 ml of EtOH at 60°C. Workup: The solvent was removed under reduced pressure, and the salt of the product was converted to a free base using saturated NaHCO3 (or 2N NaOH). The product was recovered by filtration or extraction (DCM or EA). Yield: 1455 mg, foamy solid (95%). 1 H NMR (400 MHz, DMSO) δ 8.48 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.6, 1.9 Hz, 1H), 7.22 - 7.17 (m, J = 7.6 Hz, 1H), 6.71 (dd, J = 7.6, 2.0 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 5.93 - 5.87 (m, 1H), 3.53 (td, J = 8.6, 1.5 Hz, 2H), 2.99 (t, J = 8.5Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 154.1, 144.3, 142.8, 134.6, 134.5, 129.0, 125.2, 125.1, 121.6, 115.6, 113.4, 111.8, 103.2, 46.8, 28.7. HPLC t ret = 8.18 min. ESI-MS m / z: 314.2 [M+H] + .

[0280] 5-Bromo-3-(1-(cyclopropylsulfonyl)indoline-6-yl)-3H-imidazo[4,5-b]pyridine (TD-554) [ka] The procedure was the same as for TD-511, except that 473 mg of TD-553 (1.50 mmol) and 295 mg of cyclopropanesulfonyl chloride (2.10 mmol) were used. The dark purple reaction mixture was stirred overnight, and after adding MeOH to stop the reaction, 100 ml of water was added. The fine suspension was filtered through cotton. The product was air-dried and dissolved in DCM / MeOH. The solvent was removed by distillation, and the crude product was purified by flash chromatography (DCM / MeOH = 0-1.3%) to obtain the product as a colorless crystalline solid (260 mg, 41%). 1 H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.39 (dd, J = 8.0, 2.0 Hz, 1H), 4.11 (t, J = 8.5 Hz, 2H), 3.22 (t, J = 8.5 Hz, 2H), 2.96 (tt, J = 8.0, 4.8 Hz, 1H), 1.25 - 1.20 (m, 2H), 1.04 - 0.97 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 146.1, 144.9, 143.0, 135.1, 134.8, 133.7, 131.7, 130.9, 126.3, 122.5, 118.3, 109.2, 50.8, 27.3, 26.3, 4.2. HPLCt ret = 7.70 min.

[0281] B) Direct introduction of sulfonamides 1-(methylsulfonyl)-6-nitroindoline (TD-518) [ka] To an ice-cold solution of 11.5 g of 6-nitroindoline in pyridine (70 ml), 8.13 g of MsCl was added in several portions. After continuous cooling for 20-30 minutes, the reaction mixture changed to a dark red suspension. After HPLC indicated that the starting materials had been completely consumed (usually after about 2 hours), the reaction was stopped with cold water (350 ml). The resulting product was collected by filtration, washed with water, and air-dried to obtain a dark red crystalline solid (16.75 g, 99%). This product can be further purified by suspending it in hot MeOH and collecting it again by filtration. 1 H NMR (400 MHz, DMSO) δ 7.97 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 8.2, 2.2 Hz, 1H), 7.55 - 7.50 (m, J = 8.2 Hz, 1H), 4.06 (t, J = 8.6 Hz, 2H), 3.25 (t, J = 8.5 Hz, 2H), 3.13 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 147.5, 143.1, 140.2, 126.2, 118.8, 107.4, 50.4, 34.9, 27.5. HPLC t ret = 7.66 min.

[0282] 1-(methylsulfonyl)indoline-6-amine (TD-521) [ka] When 888 mg of zinc powder (13 mmol) was slowly added over 5 minutes to an ice-cold MeOH suspension (red) of 329 mg of TD-518 (1.36 mmol) and 726 mg of NH4Cl (13 mmol), the color changed rapidly. After TLC analysis showed that the starting materials had been completely consumed, the reaction was stopped by dilution with EA. This suspension was filtered through Celite. The organic phase was removed by distillation to obtain a brownish crystalline product (260 mg, 90%). 1H NMR (400 MHz, DMSO) δ 6.90 - 6.85 (m, J = 8.0 Hz, 1H), 6.60 (d, J = 1.9 Hz, 1H), 6.23 (dd, J = 8.0, 2.0 Hz, 1H), 5.10 (s, 2H), 3.83 (t, J = 8.3 Hz, 2H), 2.95 - 2.86 (m, 5H). 13 C NMR (101 MHz, DMSO) δ 148.5, 142.7, 125.4, 118.2, 109.2, 99.6, 50.6, 33.6, 26.6. HPLC t ret = 1.87 min. ESI-MS m / z: 213.1 [M+H] + .

[0283] N-(5-bromo-2-nitrophenyl)-1-(methylsulfonyl)indoline-6-amine (TD-522) [ka] The same procedure as for the preparation of TD-324 described above was followed, except that 261 mg of 4-bromo-2-fluoro-1-nitrobenzene (1.19 mmol), 240 mg of TD-521 (mmol), and 0.48 ml of triethylamine were used at 70°C. Reaction time: 48 hours. Yield: 185 mg, yellowish solid (40%). 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.23 - 7.17 (m, 2H), 7.04 - 6.97 (m, 2H), 3.98 (t, J = 8.5 Hz, 2H), 3.13 (t, J = 8.5 Hz, 2H), 3.06 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 143.2, 143.2, 138.0, 132.4, 129.8, 129.3, 128.2, 126.2, 120.5, 119.5, 118.6, 109.8, 50.5, 34.3, 27.0. HPLC tret = 10.60 min. ESI-MS m / z: 434.1 [M+Na] + .

[0284] 6-Bromo-1-(1-(methylsulfonyl)indoline-6-yl)-1H-benzo[d]imidazole (TD-526, (TD-558)) [ka] The same procedure as for the preparation of TD-280 was followed, except that 167 mg of TD-522 (0.405 mmol), 560 mg of zinc powder, 457 mg of NH4Cl, and 30 ml of toluene were used. In step 2, 0.2 ml of triethyl orthoformate (1.2 mmol) and 30 ml of toluene were used. Flash chromatography gradient: DCM / MeOH = 0.5-2.5%. Yield: 154 mg, solid (96%). 1 H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.32 (dd, J = 7.9, 2.0 Hz, 1H), 4.06 (t, J = 8.5 Hz, 2H), 3.22 (t, J = 8.5 Hz, 2H), 3.14 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 144.4, 143.4, 142.8, 134.7, 134.5, 131.9, 126.7, 125.5, 121.7, 118.9, 115.9, 113.4, 108.9, 50.5, 34.8, 27.1. HPLC t ret = 9.99 min. ESI-MS m / z: 414.1 [M+Na] + .

[0285] Another route: Mesylation of TD-557 TD-557 (1427 mg, 4.54 mmol) was dissolved in 15 ml of anhydrous pyridine. 550 mg of MsCl (4.80 mmol) was added over 5 minutes. The reaction was stopped with water, and the product was recovered by filtration. Yield: 1338 mg, 75%.

[0286] 3-(1-(methylsulfonyl)indoline-6-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (TD-636) [ka] The same procedure as for TD-327 was followed, except that 345 mg of TD-556, 321 mg of B2Pin2 (1.26 mmol), and 31 mg of Pd(dppf)Cl2 were used in 10 ml of anhydrous dioxane. After the starting materials were completely converted, the reaction mixture was diluted with approximately 20 ml of DCM and filtered through Celite. The solvent was removed by distillation, and the crude product was obtained as a dark brown oil. Diethyl ether was overlaid on this oil, and PE was gradually added under stirring until the product precipitated. The resulting product was recovered as a gray solid by filtration. Yield: 377 mg (98%). 1 H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.53 - 7.48 (m, 1H), 7.44 - 7.36 (m, 1H), 4.05 (t, J = 7.8 Hz, 2H), 3.27 - 3.16 (m, 5H), 1.31 (s, 12H). HPLC t ret = 5.48 min.

[0287] 1-(methylsulfonyl)-7-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline (TD-675) [ka] The same procedure as for TD-327 was followed, except that 489 mg of TD-635, 279 mg of B2Pin2 (1.10 mmol), and 39 mg of Pd(dppf)Cl2 were used in 9 ml of anhydrous dioxane. After the starting materials were completely converted, the reaction mixture was diluted with DCM and filtered through Celite. The solvent was removed by distillation, and the crude product was obtained as a dark foam. This foam was dissolved in a small amount of DCM and diluted with a small amount of diethyl ether. Upon addition of a small amount of PE, the product precipitated. The obtained product was recovered by filtration and washed with PE. Yield: 490 mg, gray crystalline solid (90%). 1 H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.19 - 8.14 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.1, 2.0 Hz, 1H), 7.40 (d, J = 8.2 Hz, HPLC t ret = 6.21 min. ESI-MS m / z: 453.1 [MH] + .

[0288] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(1-(methylsulfonyl)indoline-6-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-527) [ka] The same procedure as for TD-307 was followed, except that 65 mg of TD-526 (0.17 mmol) and 50 mg of TD-306 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 60°C until TLC indicated (confirmed by TLC-MS) that the starting materials were completely consumed and the desired product had formed. The reaction mixture was poured into a saturated NaHCO3 solution, and the crude product was extracted four times by DCM. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. Yield: 57 mg, solid (73%). 1 H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.58 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.59 - 7.45 (m, 7H), 7.41 - 7.36 (m, 1H), 6.12 (t, J = 4.8 Hz, 1H), 4.07 (t, J = 8.3 Hz, 2H), 3.25 - 3.17 (m, 4H), 3.15 (s, 3H), 2.34 (t, J = 6.0 Hz, 2H), 2.18 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.7, 143.3, 142.8, 140.0, 136.0, 135.3, 133.8, 133.1, 131.4, 127.2, 126.8, 121.4, 120.2, 118.6, 117.9, 108.6, 107.7, 58.5, 50.5, 45.0, 36.9, 34.8, 27.1. HPLC t ret = 6.77 min. ESI-MS m / z: 519.4 [M+H] + .

[0289] 2-(3-(dimethylamino)azetidine-1-yl)-N-(4-(1-(1-(methylsulfonyl)indoline-6-yl)-1H-benzo[d]imidazole-6-yl)phenyl)acetamide (TD-533) [ka] The same procedure as for TD-307 was followed, except that 63 mg of TD-526 (0.16 mmol) and 54 mg of TD-515 (0.15 mmol) were used in 5 ml of dioxane / water (4+1). Stirring was continued overnight at 70°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 5-10%. The obtained product was dissolved in a small amount of DCM and precipitated with n-pentane (recovered by filtration). Yield: 32 mg, solid (39%). 1 H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.60 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.76 - 7.70 (m, 3H), 7.63 (d, J = 8.6 Hz, 2H), 7.59 (dd, J = 8.5, 1.2 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.39 (dd, J = 7.9, 1.6 Hz, 1H), 4.07 (t, J = 8.4 Hz, 2H), 3.53 (t, J = 6.5 Hz, 2H), 3.26 - 3.19 (m, 4H), 3.15 (s, 3H), 2.94 (t, J = 6.8 Hz, 2H), 2.88 - 2.80 (m, 1H), 2.01 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 168.2, 143.9, 143.3, 143.1, 137.9, 135.7, 135.5, 135.2, 133.8, 131.5, 127.1, 126.8, 121.6, 120.3, 119.9, 118.6, 108.6, 108.1, 62.6, 59.5, 56.6, 50.5, 41.7, 34.9, 27.1. HPLC t ret = 3.82 min (Method C). ESI-MS m / z: 545.3 [M+H] + .

[0290] N,N-dimethyl-3-((5-(1-(1-(methylsulfonyl)indoline-6-yl)-1H-benzo[d]imidazole-6-yl)pyridine-2-yl)oxy)propan-1-amine (TD-560) [ka] The same procedure as for TD-307 was followed, except that 62 mg of TD-558 (0.16 mmol) and 46 mg of N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxy)propan-1-amine (Sarkaria, JN; Eshleman, JS ATM as a target for novel radiosensitizers. Semin Radiat Oncol 2001, 11(4), 316-327. DOI: 10.1053 / srao.2001.26030; obtained from NLM) (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was shown to have formed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3-10%. The oily product can be solidified with n-pentane and a small amount of diethyl ether. The product was recovered by filtration. Yield: 40 mg, solid (54%). 1H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 8.6, 2.5 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.59 (dd, J = 8.4, 1.2 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.40 (dd, J = 7.9, 1.7 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 4.31 (t, J = 6.6 Hz, 2H), 4.06 (t, J = 8.5 Hz, 2H), 3.22 (t, J = 8.4 Hz, 2H), 3.15 (s, 3H), 2.35 (t, J = 7.1 Hz, 2H), 2.14 (s, 6H), 1.91 - 1.82 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 162.7, 144.9, 144.0, 143.3, 143.2, 137.9, 135.2, 133.8, 132.8, 131.5, 129.7, 126.8, 121.5, 120.4, 118.6, 110.7, 108.6, 108.3, 64.0, 55.8, 50.5, 45.2, 34.9, 27.1, 26.7. HPLC t ret = 5.76 min. ESI-MS m / z: 492.4 [M+H] + .

[0291] 3-((5-(3-(1-(ethylsulfonyl)indoline-6-yl)-3H-imidazo[4,5-b]pyridine-5-yl)pyridine-2-yl)oxy)-N,N-dimethylpropane-1-amine(TD-679) [ka] The same procedure as for TD-307 was followed, except that 57 mg of TD-657 (0.14 mmol), 79 mg of N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxy)propan-1-amine (Sarkaria, JN; Eshleman, JS ATM as a target for novel radiosensitizers. Semin Radiat Oncol 2001, 11(4), 316-327. DOI: 10.1053 / srao.2001.26030; obtained from NLM) (0.26 mmol), and 146 mg of K2CO3 were used in 2.5 ml of dioxane / water (4+1). Stirring was continued overnight at 70°C until the starting materials were completely consumed and the desired product was shown to have formed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-10%. Yield: 31 mg, white solid (44%). 1 H NMR (400 MHz, DMSO) δ 8.95 (d, J = 2.3 Hz, 1H), 8.90 (s, 1H), 8.47 (dd, J = 8.7, 2.5 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.0, 1.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.34 (t, J = 6.6 Hz, 2H), 4.10 (t, J = 8.6 Hz, 2H), 3.36 (dd, J = 14.7, 7.4 Hz, 2H), 3.23 (t, J = 8.6 Hz, 2H), 2.36 (t, J = 7.1 Hz, 2H), 2.15 (s, 6H), 1.92 - 1.83 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 163.7, 149.3, 146.2, 145.6, 144.4, 143.0, 137.5, 134.7, 134.5, 130.6, 128.8, 128.0, 126.2, 117.0, 115.3, 110.5, 107.9, 64.2, 55.7, 50.5, 45.1, 43.2, 27.1, 26.7, 7.3. HPLC t ret = 5.22 min. ESI-MS m / z: 507.3 [M+H] + , 529.3 [M+Na] + .

[0292] 3-((5-(3-(1-(cyclopropylsulfonyl)indoline-6-yl)-3H-imidazo[4,5-b]pyridine-5-yl)pyridine-2-yl)oxy)-N,N-dimethylpropane-1-amine (TD-641) [ka] The same procedure as for TD-307 was followed, except that 80 mg of TD-554 (0.192 mmol), 49 mg of N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxy)propan-1-amine (Sarkaria, JN; Eshleman, JS ATM as a target for novel radiosensitizers. Semin Radiat Oncol 2001, 11(4), 316-327. DOI: 10.1053 / srao.2001.26030; obtained from NLM) (0.16 mmol), 89 mg of K2CO3 (0.64 mmol), and XPhos Pd G4 were used in 4 ml of dioxane / water (4+1). Stirring was continued overnight at 80°C until the starting materials were completely consumed and the desired product was shown to have formed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 1-4.5%. The product was obtained as a semi-solid. It was stored overnight at -18°C to solidify. Yield: 40 mg, grayish-white solid (48%). 1 H NMR (400 MHz, DMSO) δ 8.95 (d, J = 2.2 Hz, 1H), 8.92 (s, 1H), 8.46 (dd, J = 8.7, 2.4 Hz, 1H), 8.30 - 8.23 ​​(m, 2H), 7.96 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.0, 1.7 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 4.35 (t, J = 6.6 Hz, 2H), 4.12 (t, J = 8.5 Hz, 2H), 3.23 (t, J = 8.4 Hz, 2H), 2.98 - 2.90 (m, 1H), 2.36 (t, J = 7.1 Hz, 2H), 2.15 (s, 6H), 1.92 - 1.83 (m, 2H), 1.20 - 1.14 (m, 2H), 0.99 - 0.92 (m, 2H). 13C NMR (101 MHz, DMSO) δ 163.7, 149.5, 146.2, 145.8, 144.4, 143.1, 137.6, 134.8, 134.6, 130.9, 128.9, 128.0, 126.3, 117.1, 115.5, 110.5, 108.5, 64.2, 55.8, 50.8, 45.2, 27.3, 26.7, 26.3, 4.0. HPLC t ret = 5.75 min. ESI-MS m / z: 519.2 [M+H] + .

[0293] 1-(2-(dimethylamino)ethyl)-3-(4-(3-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline-7-yl)-3H-imidazo[4,5-b]pyridine-5-yl)phenyl)urea (TD-678) [ka] The same procedure as for TD-307 was followed, except that 73 mg of TD-675 (0.16 mmol) and 42 mg of TD-396 (0.15 mmol) were used. The reaction mixture was stirred overnight at 70°C. Flash chromatography gradient: 5-9.2%. Yield after flash chromatography: 57 mg, grayish-white solid (71%). 1H NMR (400 MHz, DMSO) δ 8.87 - 8.79 (m, 2H), 8.35 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.64 (dd, J = 8.2, 2.1 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.3 Hz, 1H), 6.15 (t, J = 5.2 Hz, 1H), 3.82 - 3.76 (m, 2H), 3.23 - 3.15 (m, 5H), 2.90 (t, J = 6.5 Hz, 2H), 2.35 (t, J = 6.1 Hz, 2H), 2.19 (s, 6H), 2.04 - 1.97 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 155.0, 151.8, 146.2, 144.0, 141.4, 137.7, 134.2, 133.4, 131.3, 130.6, 128.5, 128.2, 127.4, 118.1, 117.3, 116.1, 115.2, 58.4, 46.0, 45.0, 38.6, 36.9, 26.3, 21.6. HPLC t ret = 5.28 min. ESI-MS m / z: 534.3 [M+H] + , 532.4 [MH] - .

[0294] 3-((5-(3-(1-(methylsulfonyl)indoline-6-yl)-3H-imidazo[4,5-b]pyridine-5-yl)pyridine-2-yl)oxy)propan-1-ol(TD-642) [ka] The same procedure as for TD-307 was followed, except that 1468 mg of TD-636 (3.00 mmol), 696 mg of TD-636 (3.00 mmol), 1658 mg of K2CO3 (12.00 mmol), and a catalytic amount of XPhos Pd G4 were used in 16 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). The suspension was cooled to room temperature and diluted with cold MeOH. The resulting product was collected by filtration, washed with water, washed with MeOH, and air-dried. Yield: 1264 mg, grayish-white solid (91%). 1 H NMR (400 MHz, DMSO) δ 8.99 - 8.90 (m, 2H), 8.48 (dd, J = 8.7, 2.5 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.0, 1.9 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.57 (t, J = 5.2 Hz, 1H), 4.38 (t, J = 6.5 Hz, 2H), 4.06 (t, J = 8.5 Hz, 2H), 3.60 - 3.54 (m, 2H), 3.21 (t, J = 8.4 Hz, 2H), 3.15 (s, 3H), 1.89 (p, J = 6.4 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 163.8, 149.3, 146.2, 145.6, 144.4, 142.9, 137.5, 134.8, 134.6, 130.8, 128.9, 128.0, 126.3, 117.2, 115.3, 110.6, 108.0, 63.1, 57.4, 50.6, 34.3, 32.0, 27.1. HPLC t ret = 7.19 min. ESI-MS m / z: 488.2 [M+H] + .

[0295] N-methyl-3-((5-(3-(1-(methylsulfonyl)indoline-6-yl)-3H-imidazo[4,5-b]pyridine-5-yl)pyridine-2-yl)oxy)propan-1-amine(TD-674) [ka] The same procedure as for TD-307 was followed, except that 91 mg of TD-636 (0.21 mmol), 37 mg of TD-673 (0.15 mmol), 98 mg of K2CO3 (0.71 mmol), and XPhos Pd G4 were used in 4 ml of dioxane / water (4+1). Stirring was continued overnight at 65°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-10%. The obtained product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 35 mg, grayish solid (49%). 1 H NMR (400 MHz, DMSO) δ 8.96 - 8.90 (m, 2H), 8.47 (dd, J = 8.7, 2.5 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.0, 1.9 Hz, 1H), 7.50 (mf, J = 8.1 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 4.36 (t, J = 6.5 Hz, 2H), 4.06 (t, J = 8.5 Hz, 2H), 3.21 (t, J = 8.5 Hz, 2H), 3.14 (s, 3H), 2.61 (t, J = 6.9 Hz, 2H), 2.28 (s, 3H), 1.87 (p, J = 6.7 Hz, 2H), (NH below water peak). 13C NMR (101 MHz, DMSO) δ 163.8, 149.4, 146.2, 145.6, 144.4, 142.9, 137.5, 134.7, 134.6, 130.8, 128.9, 128.0, 126.2, 117.2, 115.3, 110.6, 108.0, 64.3, 50.6, 48.2, 36.1, 34.4, 28.7, 27.1. HPLC t ret = 4.83 min. ESI-MS m / z: 479.2 [M+H] + .

[0296] N-methyl-3-((5-(3-(1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline-7-yl)-3H-imidazo[4,5-b]pyridine-5-yl)pyridine-2-yl)oxy)propan-1-amine (TD-676) [ka] The procedure was the same as for TD-307 described above, except that 107 mg of TD-675 (0.24 mmol), 50 mg of TD-673 (0.20 mmol), 113 mg of K2CO3 (0.82 mmol), and XPhos Pd G4 were used in 4 ml of dioxane / water (4+1). The mixture was stirred overnight at 65°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-8.2%. The obtained product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 41 mg, grayish solid (42%). 1H NMR (400 MHz, DMSO) δ 8.93 (d, J = 2.3 Hz, 1H), 8.86 (s, 1H), 8.47 (dd, J = 8.7, 2.5 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.2, 2.1 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.37 (t, J = 6.5 Hz, 2H), 3.84 - 3.75 (m, 2H), 3.28 (bs, 1H), 3.16 (s, 3H), 2.90 (t, J = 6.5 Hz, 2H), 2.61 (t, J = 6.9 Hz, 2H), 2.29 (s, 3H), 2.03 - 1.96 (m, 2H), 1.87 (p, J = 6.7 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 163.7, 149.5, 146.2, 145.6, 144.3, 137.6, 137.6, 134.6, 133.3, 130.6, 128.8, 128.2, 128.0, 118.1, 116.1, 115.4, 110.5, 64.2, 48.2, 46.0, 38.4, 36.1, 28.7, 26.3, 21.6. HPLC t ret = 5.18 min. ESI-MS m / z: 493.1 [M+H] + .

[0297] 3-(1-(methylsulfonyl)indoline-6-yl)-5-(6-(3-(pyrroridine-1-yl)propoxy)pyridine-3-yl)-3H-imidazo[4,5-b]pyridine (TD-683) [ka] The same procedure as for TD-307 was followed, except that 97 mg of TD-613 (0.22 mmol), 57 mg of TD-681 (0.20 mmol), 111 mg of K2CO3 (0.80 mmol), and XPhos Pd G4 were used in 5 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3.5-6.5%. The obtained product was suspended in hot MeOH, the suspension was cooled to room temperature, and the product was recovered by filtration. Yield: 22 mg, grayish-white solid (21%). 1 H NMR (400 MHz, DMSO) δ 8.95 - 8.91 (m, 2H), 8.48 (dd, J = 8.7, 2.5 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.0, 1.9 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 4.06 (t, J = 8.5 Hz, 2H), 3.21 (t, J = 8.4 Hz, 2H), 3.14 (s, 3H), 2.55 - 2.51 (m, 2H), 2.46 - 2.39 (m, 4H), 1.91 (p, J = 6.8 Hz, 2H), 1.73 - 1.63 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 163.7, 149.3, 146.2, 145.5, 144.3, 142.9, 137.5, 134.7, 134.6, 130.7, 128.8, 128.0, 126.2, 117.2, 115.3, 110.6, 107.9, 64.3, 53.6, 52.3, 50.5, 34.4, 28.0, 27.0, 23.1. HPLC t ret = 4.40 min. ESI-MS m / z: 519.4 [M+H]+ .

[0298] 3-(1-(methylsulfonyl)indoline-6-yl)-5-(6-(3-(piperidine-1-yl)propoxy)pyridine-3-yl)-3H-imidazo[4,5-b]pyridine (TD-685) [ka] The same procedure as for TD-307 was followed, except that 97 mg of TD-613 (0.22 mmol), 60 mg of TD-681 (0.20 mmol), 111 mg of K2CO3 (0.80 mmol), and XPhos Pd G4 were used in 5 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-7.3%. The obtained product was suspended in hot MeOH, the suspension was cooled to room temperature, and the product was recovered by filtration. Yield: 46 mg, grayish-white solid (43%). 1 H NMR (400 MHz, DMSO) δ 8.98 - 8.88 (m, 2H), 8.48 (dd, J = 8.7, 2.3 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.19 - 8.13 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.34 (t, J = 6.6 Hz, 2H), 4.06 (t, J = 8.4 Hz, 2H), 3.22 (t, J = 8.4 Hz, 2H), 3.14 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 2.36 - 2.27 (m, 4H), 1.94 - 1.84 (m, 2H), 1.53 - 1.45 (m, 4H), 1.41 - 1.33 (m, 2H). HPLC t ret= 4.40 min. ESI-MS m / z: 533.4 [M+H] + .

[0299] 1-(methylsulfonyl)-7-(5-(6-(3-(pyrroridine-1-yl)propoxy)pyridine-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline (TD-684) [ka] The same procedure as for TD-307 was followed, except that 100 mg of TD-675 (0.22 mmol), 57 mg of TD-681 (0.20 mmol), 111 mg of K2CO3 (0.80 mmol), and XPhos Pd G4 were used in 5 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-7.3%. The obtained product was suspended in hot MeOH, the suspension was cooled to room temperature, and the product was recovered by filtration. Yield: 47 mg, grayish-white solid (44%). 1H NMR (400 MHz, DMSO) δ 8.93 (d, J = 2.4 Hz, 1H), 8.86 (s, 1H), 8.47 (dd, J = 8.7, 2.5 Hz, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.2, 2.0 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 3.82 - 3.75 (m, 2H), 3.16 (s, 3H), 2.90 (t, J = 6.5 Hz, 2H), 2.55 - 2.50 (m, 2H), 2.43 (dd, J = 8.3, 3.1 Hz, 4H), 2.04 - 1.96 (m, 2H), 1.95 - 1.87 (m, 2H), 1.73 - 1.62 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 163.7, 149.5, 146.2, 145.6, 144.3, 137.6, 137.6, 134.6, 133.3, 130.6, 128.8, 128.2, 128.1, 118.1, 116.1, 115.4, 110.5, 64.3, 53.6, 52.3, 46.0, 38.4, 28.0, 26.4, 23.1, 21.6. HPLC t ret = 4.71 min. ESI-MS m / z: 533.4 [M+H] + .

[0300] 1-(methylsulfonyl)-7-(5-(6-(3-(piperidine-1-yl)propoxy)pyridine-3-yl)-3H-imidazo[4,5-b]pyridine-3-yl)-1,2,3,4-tetrahydroquinoline (TD-686) [ka] The same procedure as for TD-307 was followed, except that 78 mg of TD-675 (0.22 mmol), 60 mg of TD-682 (0.20 mmol), 111 mg of K2CO3 (0.80 mmol), and XPhos Pd G4 were used in 5 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-7.5%. The obtained product was suspended in hot MeOH, the suspension was cooled to room temperature, and the product was recovered by filtration. Yield: 76 mg, grayish-white solid (70%). 1 H NMR (400 MHz, DMSO) δ 8.95 - 8.91 (m, 1H), 8.86 (s, 1H), 8.47 (dd, J = 8.7, 2.5 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.62 (dd, J = 8.2, 2.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 4.33 (t, J = 6.6 Hz, 2H), 3.83 - 3.75 (m, 2H), 3.16 (s, 3H), 2.89 (t, J = 6.5 Hz, 2H), 2.42 - 2.25 (m, 6H), 2.05 - 1.95 (m, 2H), 1.93 - 1.84 (m, 2H), 1.53 - 1.45 (m, 4H), 1.40 - 1.33 (m, 2H). HPLC t ret = 4.775 min. ESI-MS m / z: 547.5 [M+H] + .

[0301] Biphenyl inhibitors 1-(2-(dimethylamino)ethyl)-3-(4-(1-(2'-fluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-580) [ka] The procedure was the same as for TD-307, except that 65 mg of TD-573 (0.15 mmol) and 42 mg of (2-fluorophenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 80°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. The resulting product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 60 mg, solid (81%). 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.62 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.85 - 7.78 (m, 4H), 7.67 - 7.56 (m, 4H), 7.51 - 7.45 (m, HPLC t ret = 7.09 min. ESI-MS m / z: 494.5 [M+H] + .

[0302] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(3'-fluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-585) [ka] The procedure was the same as for TD-307 described above, except that 65 mg of TD-573 (0.15 mmol) and 42 mg of (3-fluorophenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. The obtained product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 50 mg, colorless solid (68%). 1 H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.62 (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.85 - 7.81 (m, 1H), 7.80 - 7.78 (m, 1H), 7.67 - 7.53 (m, 6H), 7.48 (d, J = 8.7 Hz, 2H), 7.29 - 7.22 (m, 1H), 6.10 (t, J = 5.2 Hz, 1H), 3.22 - 3.16 (m, J = 11.6, 5.9 Hz, 2H), 2.33 (t, J = 6.2 Hz, 2H), 2.18 (s, 6H) (residual (aromatic) impurities in the NMR; was tested anyways, due to >98% HPLC-purity). HPLC t ret = 7.16 min. ESI-MS m / z: 494.4 [M+H] + .

[0303] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-567) [ka] The procedure was the same as for TD-307 described above, except that 62 mg of FM-987 (0.13 mmol) and 24 mg of 4-fluorophenylboronic acid (0.17 mmol) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued overnight at 70°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-10%. Yield: 54 mg, colorless solid (84%). 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.60 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.86 - 7.80 (m, 5H), 7.78 (d, J = 1.2 Hz, 1H), 7.61 - 7.55 (m, 3H), 7.48 (d, J = 8.7 Hz, 2H), 7.34 (t, J = 8.9 Hz, 2H), 6.10 (t, J = 5.2 Hz, 1H), 3.21 - 3.15 (m, J = 11.5, 6.0 Hz, 2H), 2.33 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 162.02 (d, J = 244.9 Hz), 155.0, 143.5, 142.9, 139.9, 138.4, 136.1, 135.50 (d, J = 3.0 Hz), 135.2, 133.7, 133.2, 128.70 (d, J=8.2 Hz), 128.2, 127.2, 124.2, 121.4, 120.1, 117.8, 115.77 (d, J=21.4 Hz), 107.8, 58.5, 44.9, 36.9. t ret = 6.95 min. ESI-MS m / z: 494.2 [M+H] + .

[0304] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(2'-methoxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-581) [ka] The procedure was the same as for TD-307, except that 65 mg of TD-573 (0.15 mmol) and 46 mg of (2-methoxyphenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 80°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. The obtained product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 60 mg, colorless solid (79%). 1 H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.59 (s, 1H), 7.85 - 7.76 (m, 4H), 7.74 (d, J = 8.5 Hz, 2H), 7.62 - 7.54 (m, 3H), 7.48 (d, J = 8.6 Hz, 2H), 7.43 - 7.36 (m, 2H), 7.20 - 7.14 (m, 1H), 7.12 - 7.05 (m, 1H), 6.10 (t, J = 5.2 Hz, 1H), 3.82 (s, 3H), 3.22 - 3.15 (m, J = 11.5, 5.9 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 156.2, 155.1, 143.7, 142.9, 139.9, 137.5, 136.2, 134.6, 133.7, 133.3, 130.8, 130.4, 129.3, 128.6, 127.4, 123.3, 121.5, 120.9, 120.1, 117.8, 111.8, 107.9, 58.5, 55.5, 45.0, 36.9. HPLC tret = 6.97 min. ESI-MS m / z: 506.5 [M+H] + .

[0305] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-582) [ka] The procedure was the same as for TD-307 described above, except that 65 mg of TD-573 (0.15 mmol) and 46 mg of (3-methoxyphenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 80°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. Yield: 49 mg, colorless solid (65%). 1 H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.60 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.87 - 7.81 (m, 3H), 7.80 - 7.76 (m, 1H), 7.62 - 7.55 (m, 3H), 7.48 (d, J = 8.7 Hz, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.37 - 7.28 (m, 2H), 6.99 (dd, J = 8.1, 2.1 Hz, 1H), 6.09 (t, J = 5.2 Hz, 1H), 3.86 (s, 3H), 3.22 - 3.15 (m, J = 11.6, 5.9 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13C NMR (101 MHz, DMSO) δ 159.8, 155.1, 143.7, 142.9, 140.6, 140.0, 139.3, 136.2, 135.3, 133.7, 133.2, 130.1, 128.4, 127.3, 124.1, 121.5, 120.2, 119.0, 117.8, 113.5, 112.2, 107.9, 58.5, 55.2, 45.0, 36.9. HPLC t ret = 7.03 min. ESI-MS m / z: 506.4 [M+H] + .

[0306] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-583) [ka] The procedure was the same as for TD-307 described above, except that 65 mg of TD-573 (0.15 mmol) and 46 mg of (4-methoxyphenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 80°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. Yield: 64 mg, solid (84%). 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.58 (s, 1H), 7.88 (d, J = 8.6 Hz, 2H), 7.84 - 7.78 (m, 3H), 7.78 - 7.76 (m, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.62 - 7.55 (m, 3H), 7.48 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.10 (t, J = 5.2 Hz, 1H), 3.82 (s, 3H), 3.21 - 3.16 (m, J = 11.5, 5.8 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 159.2, 155.1, 143.7, 142.9, 140.0, 139.2, 136.1, 134.6, 133.8, 133.2, 131.4, 127.9, 127.7, 127.3, 124.2, 121.5, 120.1, 117.8, 114.5, 107.9, 58.5, 55.2, 45.0, 36.9. HPLC t ret = 7.03 min. ESI-MS m / z: 506.4 [M+H] + .

[0307] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(3'-nitro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-608) [ka] The procedure was the same as for TD-307, except that 65 mg of TD-573 (0.15 mmol) and 50 mg of (3-nitrophenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 80°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3.5-10%. The yellowish solid was dissolved in a small amount of DCM and precipitated with n-pentane to obtain the product as a pale yellow solid. Yield: 56 mg, solid (72%). 1 H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.64 (s, 1H), 8.55 (t, J = 1.8 Hz, 1H), 8.31 - 8.22 (m, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.86 - 7.77 (m, 3H), 7.64 - 7.55 (m, 3H), 7.48 (d, J = 8.7 Hz, 2H), 6.10 (t, J = 5.2 Hz, 1H), 3.23 - 3.14 (m, J = 11.5, 5.9 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 148.5, 143.7, 143.0, 140.7, 140.0, 137.0, 136.2, 136.2, 133.6, 133.3, 133.1, 130.7, 128.8, 127.4, 124.3, 122.5, 121.6, 121.3, 120.2, 117.8, 107.9, 58.5, 45.0, 36.9.

[0308] 1-(4-(1-(3',4'-difluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-568) [ka] The procedure was the same as for TD-307 described above, except that 62 mg of FM-987 (0.13 mmol) and 27 mg of 3,4-difluorophenylboronic acid (0.17 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was shown to have formed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-10%. Yield: 58 mg, colorless solid (87%). 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.60 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.93 - 7.84 (m, 3H), 7.82 (d, J = 8.4 Hz, 1H), 7.79 - 7.76 (m, 1H), 7.68 - 7.62 (m, 1H), 7.62 - 7.53 (m, 4H), 7.48 (d, J = 8.7 Hz, 2H), 6.10 (t, J = 5.2 Hz, 1H), 3.21 - 3.15 (m, J = 11.6, 5.9 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). HPLC t ret = 7.30 min. ESI-MS m / z: 512.2 [M+H] + , 546.1 [M+Cl] - .

[0309] 1-(4-(1-(2',4'-difluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-576) [ka] The procedure was the same as for TD-307 described above, except that 65 mg of TD-573 (0.15 mmol) and 47 mg of (2,4-difluorophenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 80°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 7-10%. The obtained product was dissolved in a small amount of DCM and precipitated with n-pentane and ethyl acetate. The product was recovered by filtration. Yield: 53 mg, colorless solid (69%). 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.61 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.85 - 7.77 (m, 4H), 7.74 - 7.66 (m, 1H), 7.62 - 7.55 (m, 3H), 7.48 (d, J = 8.6 Hz, 2H), 7.45 - 7.38 (m, 1H), 7.25 (td, J = 8.4, 2.1 Hz, 1H), 6.10 (t, J = 5.1 Hz, 1H), 3.23 - 3.15 (m, J = 11.5, 5.8 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 162.4 (dd, J = 247.4, 12.3 Hz), 159.7 (dd, J = 248.9, 12.4 Hz), 155.6, 144.2, 143.4, 140.5, 136.7, 136.1, 134.1, 134.0 - 133.9 (m), 133.7, 132.4 (dd, J = 9.7, 4.6 Hz), 130.9 (d, J = 2.7 Hz), 127.9, 124.4, 124.4 (dd, J = 13.2, 3.9 Hz), 122.1, 120.7, 118.3, 112.7 (dd, J = 21.1, 3.6 Hz), 108.4, 105.5 - 104.8 (m). HPLC t ret= 7.15 min. ESI-MS m / z: 512.4 [M+H] + .

[0310] 1-(4-(1-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-586) [ka] The procedure was the same as for TD-307 described above, except that 65 mg of TD-573 (0.15 mmol) and 47 mg of (3,5-difluorophenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). The resulting product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 6-10%. Yield: 39 mg, white solid (51%). 1 H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.62 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.63 - 7.53 (m, 5H), 7.48 (d, J = 8.6 Hz, 2H), 7.28 (tt, J = 9.2, 2.0 Hz, 1H), 6.10 (t, J = 5.1 Hz, 1H), 3.21 - 3.15 (m, J = 11.4, 5.8 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). HPLC t ret = 7.30 min. ESI-MS m / z: 512.2 [M+H] + , 546.1 [M+Cl] - .

[0311] 1-(4-(1-(3',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-609) [ka] The procedure was the same as for TD-307, except that 65 mg of TD-573 (0.15 mmol) and 55 mg of (3,5-dimethoxyphenyl)boronic acid (0.30 mmol) were used in 4.2 ml of dioxane / water (3+1). The mixture was stirred overnight at 80°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3.5-10%. The yellowish solid was recrystallized with a small amount of MeOH to obtain the product as a colorless solid. Yield: 42 mg, solid (52%). 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.60 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.86 - 7.81 (m, 3H), 7.79 - 7.77 (m, 1H), 7.61 - 7.56 (m, 3H), 7.47 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 2.2 Hz, 2H), 6.56 (t, J = 2.2 Hz, 1H), 6.10 (t, J = 5.2 Hz, 1H), 3.84 (s, 6H), 3.21 - 3.15 (m, J = 11.6, 6.0 Hz, 2H), 2.32 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H). 13C NMR (101 MHz, DMSO) δ 161.0, 155.1, 143.7, 142.9, 141.3, 140.0, 139.4, 136.2, 135.4, 133.7, 133.2, 128.5, 127.4, 124.1, 121.5, 120.2, 117.8, 107.9, 104.9, 99.8, 58.5, 55.3, 45.0, 36.9. HPLC t ret = 7.30 min. ESI-MS m / z: 535.8 [M+H] + , 533.8 [MH] - , 569.9 [M+Cl] - , 557.8 [M+Na] + .

[0312] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(3',4',5'-trimethoxy-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-665) [ka] The same procedure as for TD-307 was followed, except that 87 mg of TD-574 (0.20 mmol) and 85 mg of (3,4,5-trimethoxyphenyl)boronic acid (0.40 mmol) were used. The reaction mixture was stirred overnight at 70°C. Flash chromatography: DCM / MeOH + 2N NH3. Yield: 94 mg, grayish-white solid (83%). 1 H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 8.59 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.87 - 7.80 (m, 3H), 7.77 (s, 1H), 7.62 - 7.55 (m, 3H), 7.47 (d, J = 8.6 Hz, 2H), 7.02 (s, 2H), 6.09 (t, J = 5.1 Hz, 1H), 3.90 (s, 6H), 3.72 (s, 3H), 3.22 - 3.16 (m, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H).13 C NMR (101 MHz, DMSO) δ 155.2, 153.3, 143.7, 142.9, 139.9, 139.7, 137.5, 136.2, 135.1, 134.9, 133.8, 133.3, 128.4, 127.4, 124.1, 121.5, 120.2, 117.9, 107.9, 104.3, 60.1, 58.4, 56.1, 44.9, 36.8. HPLC t ret = 6.62 min. ESI-MS m / z: 566.9 [M+H] + .

[0313] 1-(4-(3-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-5-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-588) [ka] The procedure was the same as for TD-307 described above, except that 294 mg of TD-306 (0.879 mmol) and 326 mg of TD-566 (1.06 mmol) were used in 17.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 65°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 4-7.5%. The purple product was suspended in cold MeOH and recovered by filtration. Yield: 210 mg, white solid (55%). 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.86 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 6.15 (t, J = 5.2 Hz, 1H), 3.22 - 3.16 (m, 2H), 2.33 (t, J = 6.2 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.0, 151.8, 146.1, 143.9, 141.6, 134.3, 134.3, 131.4, 131.1, 129.5, 128.7, 127.3, 124.4, 117.4, 115.2, 58.5, 45.0, 37.0. HPLCt ret = 6.12 min. ESI-MS m / z: 435.0 [M+H] + , 389.9 [M-NMe2] + , 469.0 [M+Cl] - , 433.0 [MH] - , 318.8 [C5H 12 N2O] - .

[0314] 1-(4-(3-([1,1'-biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-5-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-600) [ka] The procedure was the same as for TD-307, except that 65 mg of TD-588 (0.15 mmol) and 73 mg of phenylboronic acid (0.60 mmol) were used in 3 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3-10%. Yield: 31 mg, solid (43%). 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.87 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.57 - 7.48 (m, 4H), 7.45 - 7.37 (m, 1H), 6.16 (s, 1H), 3.23 - 3.15 (m, J = 11.4, 5.8 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). HPLC t ret = 7.36 min. ESI-MS m / z: 510.9 [M+Cl] - , 474.9 [MH] - , 476.9 [M+H] + .

[0315] 1-(2-(dimethylamino)ethyl)-3-(4-(3-(4'-methoxy-[1,1'-biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-5-yl)phenyl)urea (TD-601) [ka] The same procedure as for TD-307 was followed, except that 65 mg of TD-588 (0.15 mmol) and 68 mg of (4-methoxyphenyl)boronic acid (0.45 mmol) were used in 3 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was confirmed by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3.5-10%. The resulting product still contained impurities after purification by flash chromatography. This product was recrystallized in a small amount of MeOH. The product was recovered by filtration and washed with MeOH. Yield: 40 mg, colorless solid (53%). 1 H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.87 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 8.8 Hz, 2H), 7.96 - 7.85 (m, 3H), 7.74 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.15 (t, J = 5.2 Hz, 1H), 3.82 (s, 3H), 3.24 - 3.15 (m, J = 11.5, 5.9 Hz, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 159.1, 155.0, 151.7, 146.3, 144.0, 141.5, 138.6, 134.3, 134.0, 131.5, 131.3, 128.6, 127.8, 127.3, 127.1, 123.1, 117.4, 115.1, 114.5, 58.5, 55.2, 45.0, 36.9. HPLC t ret = 7.44 min. ESI-MS m / z: 541.0 [M+Cl] - , 505.2 [MH] - , 506.9 [M+H] + .

[0316] 3-((5-(3-(4'-Methoxy-[1,1'-biphenyl]-4-yl)-3H-imidazo[4,5-b]pyridine-5-yl)pyridine-2-yl)oxy)-N,N-dimethylpropane-1-amine (TD-595) [ka] The procedure was the same as for TD-307, except that 61 mg of TD-590 (0.15 mmol) and 28 mg of (4-methoxyphenyl)boronic acid (0.184 mmol) were used in 2.6 ml of dioxane / water (4+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography: DCM / MeOH + 2N NH3 = 1-9%. The obtained product was dissolved in a small amount of DCM, precipitated with n-pentane, and recovered by filtration. Yield: 61 mg, colorless solid (85%). 1 H NMR (400 MHz, DMSO) δ 9.00 - 8.90 (m, 2H), 8.43 (dd, J = 8.7, 2.3 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 1H), 4.34 (t, J = 6.6 Hz, 2H), 3.82 (s, 3H), 2.35 (t, J = 7.1 Hz, 2H), 2.15 (s, 6H), 1.94 - 1.81 (m, 2H). 13C NMR (101 MHz, DMSO) δ 163.7, 159.2, 149.4, 146.4, 145.6, 144.4, 138.7, 137.5, 134.8, 133.9, 131.5, 128.8, 128.0, 127.8, 127.1, 123.2, 115.4, 114.5, 110.7, 64.2, 55.7, 55.2, 45.2, 26.7. HPLC t ret = 7.22 min. ESI-MS m / z: 480.2 [M+H] + .

[0317] Synthesis of hybrid molecules (2-bromo-5-nitrophenyl)(tert-butoxycarbonyl)carbamate tert-butyl (TD-489) [ka] To a solution of 935 mg of 2-bromo-5-nitroaniline (4.31 mmol) in anhydrous dioxane (6 ml), a solution of 2818 mg of Boc2O (12.9 mmol) in anhydrous dioxane (6 ml) was added, and the resulting mixture was added to the aniline. When DMAP (10 mol%) was added to the reaction mixture, it changed to a dark color. After 40 hours, the reaction was controlled by HPLC, and no starting materials were present. The reaction mixture was diluted with ethyl acetate, washed twice with 10% HCl, and washed twice with saturated NaHCO3 solution. The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. The product was purified by flash chromatography using PE / DCM = 70-100%. The product was obtained as a brownish oily substance, but solidified under low pressure. Yield: 1501 mg, solid (84%). 1 H NMR (400 MHz, DMSO) δ 8.41 (d, J = 2.7 Hz, 1H), 8.15 (dd, J = 8.8, 2.7 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 1.36 (s, 18H). 13C NMR (101 MHz, DMSO) δ 149.3, 147.2, 139.5, 133.7, 130.9, 125.2, 124.2, 83.0, 27.4. HPLC t ret = 10.59 min. ESI-MS m / z: 439.2 [M+Na] + , 471.2 [M+MeOH+Na] + , 315.1 [M-C5H9O2] + .

[0318] (tert-butoxycarbonyl)(4-nitro-[1,1'-biphenyl]-2-yl)carbamate tert-butyl (TD-493) [ka] The same procedure as for TD-307 was followed, except that 390 mg of TD-489 (0.94 mmol) and 114 mg of phenylboronic acid (0.94 mmol) were used in 5 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C until the formation of the desired product (confirmed by TLC-MS) and two by-products were observed by TLC. The reaction mixture was diluted with DCM and washed with brine. The organic phase was dried, the solvent was removed under reduced pressure, and the product was purified by flash chromatography. Flash chromatography gradient: PE / DCM = 50-100% (starting materials remained in the product). The product was obtained as an oil. A small amount of MeOH was added to initiate crystallization of the product. Yield: 363 mg, solid (94%). 1 H NMR (400 MHz, DMSO) δ 8.29 (dd, J = 8.5, 2.4 Hz, 1H), 8.27 - 8.24 (m, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.53 - 7.46 (m, 3H), 7.39 - 7.33 (m, 2H), 1.24 (s, 18H). 13HPLC t ret = 10.55 min. ESI-MS m / z: 437.3 [M+Na] + , 469.4 [M+MeOH+Na] + .

[0319] (4-amino-[1,1'-biphenyl]-2-yl)(tert-butoxycarbonyl)carbamate tert-butyl (TD-502) [ka] To a 20 ml MeOH (MeOH) suspension of 617 mg of TD-493 (1.49 mmol) and 797 mg of NH4Cl (14.9 mmol), 1.0 g of zinc powder (approximately 15 mmol) was added. The suspension was stirred until HPLC indicated that the starting materials were completely consumed. The reaction mixture was diluted with DCM and filtered through Celite. The solvent was removed by distillation, and the crude product was purified by flash chromatography (DCM / MeOH = 0-3%). Yield: 1277 mg, brownish solid (86%). 1 H NMR (400 MHz, DMSO) δ 7.36 - 7.31 (m, 2H), 7.27 - 7.22 (m, 3H), 7.04 - 7.00 (m, 1H), 6.60 (dd, J = 8.3, 2.3 Hz, 1H), 6.37 (d, J = 2.3 Hz, 1H), 5.28 (s, 2H), 1.22 (s, 18H). 13 HPLC t ret = 10.45 min. ESI-MS m / z: 407.4 [M+Na] + , 439.4 [M+MeOH+Na]+ .

[0320] (4-((5-bromo-2-nitrophenyl)amino)-[1,1'-biphenyl]-2-yl)(tert-butoxycarbonyl)carbamate tert-butyl (TD-523) [ka] Under an argon atmosphere, a solution of 298 mg of TD-502 (0.775 mmol) in anhydrous THF (14 ml) was stirred, and 34 mg of NaH (0.85 mmol) was added. After 30 minutes, 4-bromo-2-fluoro-1-nitrobenzene (179 mg, 0.814 mmol) was added, and the reaction mixture turned dark purple. The reaction mixture was heated under reflux overnight. The reaction was confirmed by HPLC, and since residual starting material was found, a total of 52 mg of NaH and 93 mg of 4-bromo-2-fluoro-1-nitrobenzene were added until the conversion of the starting material was no longer detectable by HPLC. The reaction was stopped with saturated NH4Cl solution, and the product was extracted by DCM. The organic phase was dried, the solvent was removed, and the product was purified by flash chromatography (PE / DCM = 75-100%). Yield: 257 mg, orange solid (57%). 1 H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.49 - 7.43 (m, 3H), 7.43 - 7.33 (m, 5H), 7.25 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 9.0, 2.0 Hz, 1H), 1.27 (s, 18H). 13 C NMR (101 MHz, DMSO) δ 150.6, 142.8, 138.5, 137.9, 137.4, 136.5, 132.9, 131.2, 129.9, 128.4, 128.3, 128.3, 127.5, 124.7, 124.3, 121.0, 118.5, 82.0, 27.3.HPLCt ret = 14.94 min (Method B). ESI-MS m / z: 582.2 [MH]- , 606.3 [M+Na] + , 638.3 [M+MeOH+Na] + .

[0321] (4-(6-bromo-1H-benzo[d]imidazole-1-yl)-[1,1'-biphenyl]-2-yl)(tert-butoxycarbonyl)carbamate tert-butyl (TD-528) [ka] The same procedure as for the preparation of TD-280 was followed, except that 247 mg of TD-523 (0.422 mmol) was used. The resulting product was purified by flash chromatography (DCM / MeOH = 1-3%). Yield: 182 mg, reddish solid (76%). 1 H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.79 - 7.77 (m, 1H), 7.76 - 7.74 (m, 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.52 - 7.46 (m, 3H), 7.45 - 7.36 (m, 3H), 1.28 (s, 18H). 13 C NMR (101 MHz, DMSO) δ 150.5, 144.1, 142.9, 138.9, 137.8, 137.5, 134.9, 134.2, 131.7, 128.5, 128.3, 127.9, 125.7, 124.3, 123.6, 121.8, 116.0, 113.4, 82.2, 27.4. HPLC t ret = 12.85 min (Method B). ESI-MS m / z: 586.4 [M+Na] + .

[0322] 4-(6-bromo-1H-benzo[d]imidazole-1-yl)-[1,1'-biphenyl]-2-amine (TD-529) [ka] To a solution of TD-528 (176 mg, 0.312 mmol) in EtOH (8 ml), 3 ml of HCl (1.25 M) ethanol solution was added. The reaction mixture was stirred at 50-60°C for 6 hours. The red suspension (containing the white solid) was diluted with Et2O (approximately 10 ml), and the product was obtained by filtration. The white solid was suspended in a saturated NaHCO3 solution, and the free base was extracted twice by DCM. The DCM phase was dried, and the solvent was removed to obtain the product as a brownish solid (93 mg, 82%). 1 H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.53 - 7.47 (m, 4H), 7.46 (dd, J = 8.6, 1.9 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 8.0, 2.2 Hz, 1H), 5.23 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 146.7, 144.1, 142.9, 138.6, 135.4, 134.2, 131.6, 128.9, 128.6, 127.2, 125.4, 125.3, 121.7, 115.8, 113.6, 111.4, 109.3.HPLCt ret = 11.73 min.

[0323] N-(4-(6-bromo-1H-benzo[d]imidazole-1-yl)-[1,1'-biphenyl]-2-yl)methanesulfonamide (TD-530) [ka] TD-529 (88 mg, 0.42 mmol) was dissolved / suspended in 5 ml of anhydrous pyridine. MsCl (20 μl, 0.25 mmol) was added by pipette, and the yellowish solution was stirred at room temperature. To monitor the reaction, HPLC measurement was carried out (after 1.5 h). Since the progress of the conversion was slow, the reaction solution was heated to 50 °C. After 12 h, an additional 22 μl of MsCl (0.28 mmol) was added. After reacting for another 48 h, it was shown that almost complete conversion had occurred, so the reaction was stopped with MeOH. The solvent was distilled off, and the product was purified by flash chromatography (DCM / MeOH = 1.5 - 2.7%) to obtain the desired product as a solid (0.08 g, 75%). 1 H NMR (400 MHz, DMSO) δ 9.24 (s, 1H), 8.69 (s, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.66 (dd, J = 8.2, 2.2 Hz, 1H), 7.58 - 7.55 (m, 1H), 7.54 - 7.47 (m, 5H), 7.46 - 7.41 (m, 1H), 2.87 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 144.2, 142.9, 137.8, 137.1, 135.4, 135.0, 134.2, 132.5, 129.4, 128.5, 127.7, 125.7, 121.8, 121.4, 121.2, 116.1, 113.5, 41.1. HPLC t ret = 8.82 min. ESI-MS m / z: 440.1 [M-H] - .

[0324] N-(4-(6-(4-(3-(2-(Dimethylamino)ethyl)ureido)phenyl)-1H-benzo[d]imidazol-1-yl)-[1,1'-biphenyl]-2-yl)methanesulfonamide (TD-541)

Chemical Structure

[0325] Branching and synthesis paths [ka]

[0326] 4-(6-(4-Nitrophenyl)-1H-benzo[d]imidazol-1-yl)aniline (TD-988) [Chemical Structure] In a 25 mL flask under an argon atmosphere, (4-Nitrophenyl)boronic acid (167 mg, 0.999 mmol) and TD-314 (288 mg, 0.999 mmol) were dissolved in dioxane (18 mL). Next, an aqueous K3PO4 solution (6 mL, 0.5 M) was added via syringe, and the mixture was degassed with argon three times under reduced pressure. A dioxane solution of tBu3P Pd G3 (1.5 mol%) as a stock solution was added, and the degassing operation was repeated. The flask was sealed, and stirring was continued at an oil bath temperature of 70 °C for about 1 hour. After confirming by TLC that the starting materials were completely converted, the reaction mixture was diluted with EA. The organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The solvent was distilled off from the residue by azeotroping several times with DCM to obtain the title compound as a yellow foam. Yield: 330, foam (>99%). 1 H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.27 (s, 2H), 7.99 (s, 2H), 7.91 - 7.60 (m, 3H), 7.33 (s, 2H), 6.77 (s, 2H), 5.47 (br s, 2H). 13 C NMR (101 MHz, DMSO) δ 149.0, 147.4, 146.3, 145.1, 144.1, 134.7, 133.0, 128.1, 125.4, 124.0, 123.8, 121.7, 120.3, 114.3, 109.5. HPLC t ret = 6.89 min. ESI-MS m / z: 329.3 [M-H] - .

[0327] 1-(4-Bromophenyl)-6-(4-nitrophenyl)-1H-benzo[d]imidazole (FM-989) [ka] FM-988 (306 mg, 0.900 mmol) was suspended in 15 ml of semi-saturated HBr aqueous solution, and the resulting suspension was cooled with ice water / water. While stirring this solution, sodium nitrite (70 mg, 1.0 mmol) was added in several portions over 5-10 minutes. After adding the entire amount, stirring was continued for 30 minutes. Separately, a 3M HBr (12 ml) aqueous solution of CuBr was prepared and added dropwise to the above diazonium salt solution. The reaction mixture was stirred for another 30 minutes while cooling, and then heated to ambient temperature. After approximately 1 hour, complete conversion was confirmed by TLC, and the reaction mixture was made basic with 30% wt NaOH under ice cooling. The solid was filtered off, and the filter cake was resuspended in 10% citric acid. The aqueous phase was extracted with 100 ml of siRNA, the organic phase was dried, and the solvent was removed by distillation. The residue was purified by flash chromatography (DCM / MeOH = 1-5%) to obtain the title compound as a yellow solid. Yield: 230 mg, solid (63%). 1 H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 8.28 (d, J = 8.9 Hz, 2H), 8.03 (d, J = 8.9 Hz, 2H), 7.95 (d, J = 1.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.73 (dd, J = 8.5, 1.5 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 147.2, 146.4, 144.8, 144.4, 135.0, 133.7, 133.6, 133.0, 128.3, 126.1, 124.0, 122.3, 120.6, 120.6, 109.7. HPLC t ret = 9.69 min.

[0328] 4-(1-(4-bromophenyl)-1H-benzo[d]imidazole-6-yl)aniline (FM-991) [ka] FM-989 (215 mg, 0.500 mmol) was suspended in a mixed solvent, and then NaOH (218 mg, 5.50 mmol) was added. The resulting mixture was heated until the oil bath temperature reached 50°C, and thiourea dioxide (295 mg, 2.70 mmol) was added all at once as a solid. After about 2 hours, the reaction solution changed to a white suspension, and TLC confirmed that the starting materials had been completely consumed. Water was added, and the suspension was cooled in an ice bath. The solid was isolated by filtration and washed with cold water. The resulting crude product was used in the synthesis without further purification.

[0329] 1-(4-(1-(4-bromophenyl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (FM-992) [ka] At ambient temperature, pyridine (37 μl, 0.46 mmol) was added to a solution of FM-991 (160 mg, 0.440 mmol) in anhydrous DMF (6 ml). Next, phenyl chloroformate (58 μl, 0.46 mmol) was added to this solution, and stirring was continued until TLC indicated that the starting materials had been completely consumed. Then, N,N-dimethylethylenediamine (96 μl, 0.88 mmol) was added, and the reaction mixture was heated in an oil bath at 60°C until TLC indicated that the urea product had been completely converted (approximately 2 hours). After dilution with Â, the organic phase was sequentially washed with water, 2N NaOH (twice), and saline solution, dried over Na2SO4, and the solvent was removed to dryness. The residue was purified by flash chromatography (DCM / MeOH + 2N NH3 = 4-10%) to obtain the title compound as a white solid. 1H NMR (400 MHz, DMSO) δ 8.81 (br s, 1H), 8.61 (s, 1H), 7.92 - 7.84 (m, 3H), 7.82 - 7.75 (m, 3H), 7.67 - 7.60 (m, 3H), 7.52 (d, J = 8.7 Hz, 2H), 6.15 (t, J = 5.2 Hz, 1H), 3.29 - 3.20 (m, 2H), 2.39 (t, J = 6.2 Hz, 2H), 2.23 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.6, 142.9, 140.0, 136.2, 135.3, 133.6, 133.1, 133.0, 127.3, 125.9, 121.6, 120.3, 120.2, 117.8, 107.8, 58.5, 45.0, 36.9.HPLCt ret = 5.58 min. ESI-MS m / z: 478.6 [M+H] + .

[0330] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(4-(furan-2-yl)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (FM-994) [ka] In a screw-cap reaction vial under an argon atmosphere, 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (19 mg, 0.097 mmol) and FM-992 (44 mg, 0.092 mmol) were suspended in dioxane. Next, an aqueous solution of K3PO4 (0.55 ml, 0.28 mmol) was added by syringe, and the mixture was degassed under reduced pressure using argon for 3 cycles. A dioxane solution of tBu3P Pd G3 (1.5 mol%) was added as a stock solution, and the degassing procedure was repeated. The flask was sealed and stirred at an oil bath temperature of 70°C for approximately 1 hour. Since the starting materials were shown to be completely converted by TLC, the reaction mixture was diluted with EA. The organic phase was washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure. The solvent was removed from the residue by distillation while azeotropic several times under DCM to obtain the title compound as a yellow foam. Yield: 38 mg (89%). 1 H NMR (400 MHz, DMSO) δ 8.76 (br s, 1H), 8.59 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.77 (dd, J = 37.0, 21.3 Hz, 5H), 7.62 - 7.52 (m, 3H), 7.47 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 3.2 Hz, 1H), 6.71 - 6.59 (m, 1H), 6.10 (t, J = 5.0 Hz, 1H), 3.24 - 3.12 (m, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 152.2, 143.6, 143.5, 142.9, 140.0, 136.1, 134.8, 133.7, 133.2, 129.6, 127.4, 125.0, 124.3, 121.5, 120.2, 117.8, 112.3, 107.9, 106.7, 58.5, 45.0, 36.9. HPLC t ret = 6.25 min. ESI-MS m / z: 466.6 [M+H] + .

[0331] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(4-(thiophen-2-yl)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (FM-993) [ka] In a screw-cap reaction vial under an argon atmosphere, thiophene-2-ylboronic acid (12 mg, 0.097 mmol) and FM-992 (44 mg, 0.092 mmol) were suspended in dioxane. Next, an aqueous solution of K3PO4 (0.55 ml, 0.28 mmol) was added by syringe, and the mixture was degassed under reduced pressure using argon for 3 cycles. A dioxane solution of tBu3P Pd G3 (1.5 mol%) was added as a stock solution, and the degassing procedure was repeated. The flask was sealed and stirred at an oil bath temperature of 70°C for approximately 1 hour. Since the starting materials were shown to be completely converted by TLC, the reaction mixture was diluted with EA. The organic phase was washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure. The solvent was removed from the residue by distillation while azeotropically mixing several times under DCM to obtain the title compound as a yellow foam. Yield: 29 mg (66%). 1 H NMR (400 MHz, DMSO) δ 8.76 (br s, 1H), 8.60 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.83 - 7.76 (m, 4H), 7.65 - 7.63 (m, 1H), 7.63 - 7.56 (m, 4H), 7.48 (d, J = 8.6 Hz, 2H), 7.19 (dd, J = 5.0, 3.7 Hz, 1H), 6.10 (t, J = 5.2 Hz, 1H), 3.22 - 3.15 (m, 2H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13C NMR (101 MHz, DMSO) δ 155.1, 143.6, 142.9, 142.2, 140.0, 136.2, 135.0, 133.7, 133.1, 133.1, 128.7, 127.4, 126.9, 126.3, 124.4, 124.4, 121.5, 120.2, 117.8, 107.9, 58.5, 45.0, 36.9. HPLC t ret = 6.52 min. ESI-MS m / z: 482.8 [M+H] + .

[0332] [ka]

[0333] 4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)aniline (FM-990) [ka] To a suspension of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (542 mg, 4.00 mmol) in DMF (2 ml), Et3N (0.70 ml, 5.0 mmol) and 4-fluoronitrobenzene (282 mg, 2.00 mmol) were added, and the reaction mixture was heated to an oil bath temperature of 75°C. After approximately 2 hours, complete conversion was shown by TLC, and the mixture was diluted with semi-saturated NH4Cl. The precipitate was collected by filtration and washed with water. The moist filtration cake was suspended in 1 ml of EtOH / water, and then NaOH was added. The reaction mixture was heated to an oil bath temperature of 75°C, and thiourea dioxide (1.08 g, 10.0 mmol) was added in several portions. The yellow suspension changed to a colorless, clear solution, and at this point, complete conversion was shown by TLC. The reaction mixture was poured into saline and extracted with EA. The organic phase was dried with Na2SO4, and the solvent was removed by distillation to dryness. The title compound was obtained as a purple solid. Yield: 310 mg (82%). 1H NMR (400 MHz, DMSO) δ 6.49 (d, J = 8.3 Hz, 2H), 6.38 (d, J = 8.3 Hz, 2H), 4.56 - 4.46 (m, 1H), 4.42 - 4.22 (m, 3H), 3.72 - 3.58 (m, 2H), 3.41 (d, J = 9.0 Hz, 1H), 2.79 (d, J = 9.0 Hz, 1H), 1.89 - 1.81 (m, 1H), 1.81 - 1.69 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 139.3, 139.0, 115.5, 114.3, 75.6, 70.2, 58.7, 57.0, 36.3. HPLC t ret = 1.22 min. ESI-MS m / z: 191.3 [M+H] + .

[0334] 4-Morphorinoaniline (FM-996) [ka] To a suspension of morpholine (348 mg, 4.00 mmol) in DMF (2 ml), Et3N (0.70 ml, 5.0 mmol) and 4-fluoronitrobenzene (282 mg, 2.00 mmol) were added, and the reaction mixture was heated to an oil bath temperature of 75°C. After approximately 2 hours, complete conversion was shown by TLC, and the mixture was diluted with semi-saturated NH4Cl. The precipitate was collected by filtration and washed with water. The moist filtration cake was suspended in 1 ml of EtOH / water, and then NaOH was added. The reaction mixture was heated to an oil bath temperature of 75°C, and thiourea dioxide (1.08 g, 10.0 mmol) was added in several portions. The yellow suspension changed to a colorless, clear solution, and complete conversion was shown by TLC at this point. The reaction mixture was poured into saline and extracted with EA. The organic phase was dried over Na2SO4, and the solvent was removed by distillation to dryness. The title compound was obtained as a purple solid. Yield: 255 mg (72%). 1H NMR (400 MHz, DMSO) δ 6.68 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 8.2 Hz, 1H), 4.58 (br s, 1H), 3.77 - 3.61 (m, 2H), 2.95 - 2.77 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 142.4, 142.3, 117.6, 114.8, 66.3, 50.6. ESI-MS m / z: 179.2 [M+H] + .

[0335] N-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)-5-bromo-2-nitroaniline (FM-995) [ka] FM-990 (330 mg, 1.73 mmol) and 4-bromo-2-fluoronitrobenzene (382 mg, 1.73 mmol) were dissolved in 5 ml of DMA, and then Et3N (0.49 ml, 3.5 mmol) was added. The reaction mixture was heated to an oil bath temperature of 75°C and stirred for 24 hours. Semisaturated NH4Cl was added dropwise to induce precipitation, and the resulting suspension was cooled on ice. The solid was isolated by filtration and washed with added water. The moist filtration cake was resuspended in approximately 2 ml of MeOH and stirred at ambient temperature for 2 hours. The red solid was recovered by filtration, washed with cooled MeOH, and dried under reduced pressure. Yield: 548 mg (81%). 1H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 7.9 Hz, 2H), 6.98 - 6.93 (m, 1H), 6.92 - 6.84 (m, 1H), 6.71 (d, J = 7.9 Hz, 2H), 4.66 - 4.60 (m, 1H), 4.60 - 4.53 (m, 1H), 3.79 - 3.73 (m, 1H), 3.72 - 3.63 (m, 1H), 3.56 - 3.46 (m, 1H), 3.04 - 2.96 (m, 1H), 1.98 - 1.89 (m, 1H), 1.88 - 1.79 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 145.9, 145.1, 130.9, 130.1, 128.1, 127.3, 126.4, 119.2, 117.8, 113.6, 75.6, 71.3, 58.1, 56.8, 36.4. HPLC t ret = 9.75 min.

[0336] 5-Bromo-N-(4-morpholinophenyl)-2-nitroaniline (FM-997) [ka] FM-996 (178 mg, 1.00 mmol) and 4-bromo-2-fluoronitrobenzene (220 mg, 1.00 mmol) were dissolved in 4 ml of DMSO, and then Et3N (0.28 ml, 2.0 mmol) was added. The reaction mixture was heated to 90°C using a heating block and stirred for 2 hours. Semisaturated NH4Cl was added dropwise to induce precipitation, and the resulting suspension was cooled on ice. The solid was isolated by filtration and washed with water. It was dried in a convection oven to obtain the title compound as a sufficiently pure red solid. Yield: 352 mg (93%). 1H NMR (400 MHz, DMSO) δ 9.43 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.21 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 2.0 Hz, 1H), 6.93 (dd, J = 9.1, 2.0 Hz, 1H), 3.81 - 3.70 (m, 4H), 3.21 - 3.10 (m, 4H). 13 C NMR (101 MHz, DMSO) δ 149.5, 144.7, 131.2, 130.1, 129.2, 128.2, 126.8, 119.5, 117.8, 115.8, 66.1, 48.2. ret = 9.59 min.

[0337] 5-Bromo-2-nitro-N-(4-(piperidine-1-yl)phenyl)aniline (FM-1007) [ka] 4-(piperidine-1-yl)aniline (176 mg, 1.00 mmol) and 4-bromo-2-fluoronitrobenzene (220 mg, 1.00 mmol) were dissolved in 4 ml of DMSO, and then Et3N (0.28 ml, 2.0 mmol) was added. The reaction mixture was heated to 90°C using a heating block and stirred for 2 hours. Semisaturated NH4Cl was added dropwise to induce precipitation, and the resulting suspension was cooled on ice. The solid was isolated by filtration and washed with water. It was dried in a convection oven to obtain the title compound as a sufficiently pure red solid. Yield: 325 mg (86%). 1 H NMR (400 MHz, DMSO) δ 9.42 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 7.11 - 6.65 (m, 4H), 3.29 - 2.97 (m, 4H), 1.80 - 1.39 (m, 6H). 13C NMR (101MHz, DMSO) δ 150.1, 144.8, 131.1, 130.1, 128.3, 128.2, 126.8, 119.4, 117.8, 116.4, 49.3, 25.2, 23.8. ret = 10.42 min.

[0338] N-(4-(1H-imidazole-1-yl)phenyl)-5-bromo-2-nitroaniline (FM-1010) [ka] 4-(1H-imidazole-1-yl)aniline (159 mg, 1.00 mmol) and 4-bromo-2-fluoronitrobenzene (220 mg, 1.00 mmol) were dissolved in 4 ml of DMSO, and then Et3N (0.28 ml, 2.0 mmol) was added. The reaction mixture was heated to 90°C using a heating block and stirred for 2 hours. Precipitation was induced by adding semisaturated NH4Cl dropwise, but a tendency for an oily substance to form from the dark-colored DMSO solution was observed. MTBE was added, and the mixture was transferred to a separatory funnel. The organic phase was washed several times (3 times) with water and once with saline solution. After drying with Na2SO4, the solvent was removed by distillation, yielding a sticky residue. This residue was dissolved in 1-2 ml of MeOH and stored frozen until a dark-colored precipitate formed. The solid was isolated by filtration, lightly washed with cold MeOH, and dried under reduced pressure to obtain the title compound as a red crystalline solid. Yield: 130 mg (36%). 1 H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 8.29 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.85 - 7.67 (m, 3H), 7.49 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.12 (s, 1H), 7.05 (dd, J = 9.0, 2.0 Hz, 1H). 13HPLC t ret = 7.35 min.

[0339] (1S,4S)-5-(4-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)-2-oxa-5-azabicyclo[2.2.1]heptane (FM-998) [ka] FM-995 (449 mg, 1.28 mmol) was suspended in 20 ml of THF / MeOH (1+1), and approximately 100 mg of Raney nickel was added to this suspension. The reaction mixture was bubbling with hydrogen for approximately 5 minutes, and the flask was sealed and heated to an oil bath temperature of 50°C. The reaction mixture was stirred under a hydrogen atmosphere until complete conversion was shown by TLC. The catalyst was filtered off and washed with additional solvent. The solvent was removed from the filtrate to obtain a phenylenediamine intermediate as a purple foam. This intermediate was dissolved in 5 ml of toluene, and then triethyl orthoformate (0.42 ml, 3.84 mmol) and p-TsOH·H2O (24 mg, 0.13 mmol) were added. The mixture was heated at an oil bath temperature of 75°C until complete conversion was shown by TLC. The reaction mixture was diluted with ELISA and transferred to a separatory funnel. The organic phase was washed with 1N NaOH and saline solution, dried over Na2SO4, and the solvent was removed by distillation. The residue was purified by flash chromatography to obtain the title substance as a white solid (hexane + Â1 / MeOH(9+1) = 20-80%). Yield: 110 mg (23%). 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.54 - 7.26 (m, 3H), 6.81 (d, J = 7.9 Hz, 2H), 4.78 - 4.50 (m, 2H), 3.79 (d, J = 6.8 Hz, 1H), 3.71 (d, J = 6.8 Hz, 1H), 3.55 (d, J = 9.1 Hz, 1H), 3.04 (d, J = 9.1 Hz, 1H), 1.96 (d, J = 8.9 Hz, 1H), 1.89 (d, J = 8.9 Hz, 1H). 13 C NMR (101 MHz, DMSO) δ 147.0, 144.6, 142.6, 135.1, 125.4, 125.0, 124.1, 121.5, 115.5, 113.5, 113.2, 75.6, 71.4, 58.2, 56.9, 36.4. HPLC t ret = 8.58 min.

[0340] 4-(4-(6-bromo-1H-benzo[d]imidazole-1-yl)phenyl)morpholine (FM-999) [ka] FM-997 (360 mg, 0.95 mmol) was suspended in 15 ml of THF / MeOH (1+1), and approximately 100 mg of Raney nickel was added to this suspension. The reaction mixture was bubbling with hydrogen for approximately 5 minutes, and the flask was sealed and heated to an oil bath temperature of 50°C. The reaction mixture was stirred under a hydrogen atmosphere until complete conversion was shown by TLC. The catalyst was filtered off and washed with additional solvent. The solvent was removed from the filtrate to obtain a phenylenediamine intermediate as a purple foam. This intermediate was dissolved in 5 ml of toluene, and then triethyl orthoformate (0.31 ml, 2.86 mmol) and p-TsOH·H2O (18 mg, 0.10 mmol) were added. The mixture was heated at an oil bath temperature of 75°C until complete conversion was shown by TLC. The reaction mixture was diluted with ELISA and transferred to a separatory funnel. The organic phase was washed with 1N NaOH and saline solution, dried over Na2SO4, and the solvent was removed by distillation. The residue was recrystallized with MeOH to obtain the title compound as a reddish solid. Yield: 220 mg (65%). 1 H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.42 (dd, J = 8.6, 1.9 Hz, 1H), 7.19 - 7.10 (m, 2H), 3.81 - 3.72 (m, 4H), 3.24 - 3.15 (m, 4H). 13 HPLC t ret = 9.51 min.

[0341] 6-Bromo-1-(4-(piperidine-1-yl)phenyl)-1H-benzo[d]imidazole (FM-1009) [ka] FM-1007 (300 mg, 0.800 mmol) was suspended in 15 ml of THF / MeOH (1+1), and approximately 100 mg of Raney nickel was added to this suspension. The reaction mixture was bubbling with hydrogen for approximately 5 minutes, and the flask was sealed and heated to 50°C in an oil bath. The reaction mixture was stirred under a hydrogen atmosphere (overnight) until complete conversion was shown by TLC. The catalyst was filtered off and washed with additional solvent. The filtrate was desoldered to obtain a phenylenediamine intermediate as a purple foam. This intermediate was dissolved in 5 ml of toluene, and then triethyl orthoformate (0.26 ml, 0.25 mmol) and p-TsOH·H2O (15 mg, 0.080 mmol) were added. The mixture was heated to an oil bath temperature of 75°C (approximately 3 hours) until complete conversion was shown by TLC. The reaction mixture was diluted with ELISA and transferred to a separatory funnel. The organic phase was washed with 1N NaOH and saline solution, dried over Na2SO4, and the solvent was removed by distillation. The residue was purified by flash chromatography to obtain the title compound with moderate purity (83% by HPLC). The reddish residue was tritulate with 1 ml of cold MeOH, filtered, and washed with additional MeOH. The residue was dried under reduced pressure to obtain the title compound as a white crystalline solid of sufficient purity. Yield: 193 mg (68%). 1 H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.49 - 7.37 (m, 3H), 7.11 (d, J = 8.9 Hz, 2H), 3.28 - 3.19 (m, 4H), 1.67 - 1.52 (m, 6H). 13 HPLC t ret = 12.10 min.

[0342] 1-(4-(1H-imidazole-1-yl)phenyl)-6-bromo-1H-benzo[d]imidazole (FM-1014) [ka] FM-1010 (105 mg, 0.290 mmol) was suspended in 6 ml of THF / MeOH (1+1), and approximately 50 mg of Raney nickel was added. The reaction mixture was bubbling with hydrogen for approximately 5 minutes, the flask was sealed, and heated to an oil bath temperature of 50°C. The reaction mixture was stirred under a hydrogen atmosphere (overnight) until complete conversion was shown by TLC. The catalyst was filtered off and washed with additional solvent. The filtrate was desoldered to obtain a phenylenediamine intermediate as a purple residue. This intermediate was dissolved in 9 ml of toluene / THF, and then triethyl orthoformate (0.10 ml, 0.88 mmol) and p-TsOH·H2O (6 mg, 0.03 mmol) were added. The mixture was heated to an oil bath temperature of 75°C and intermittently sonicated to obtain a homogeneous mixture. Stirring continued for approximately 6 hours until complete conversion was shown by TLC. The reaction mixture was diluted with Âi and a small amount of MeOH until a clear solution was obtained. The organic phase was washed with 1N NaOH and brine, dried over Na2SO4, and the solvent was removed by distillation. The residue was purified by flash chromatography to obtain the title compound as a purple solid of sufficient purity (approximately 95% by HPLC). Flash chromatography gradient: DCM / MeOH = 2-8%. Yield: 85 mg (86%). 1 H NMR (400 MHz, DMSO) δ 8.64 (s, J = 17.9 Hz, 1H), 8.43 - 8.35 (m, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.89 - 7.82 (m, 3H), 7.78 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 8.6, 1.8 Hz, 1H), 7.21 - 7.14 (m, 1H). HPLC t ret = 5.62 min.

[0343] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(4-(piperidine-1-yl)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-510) [ka] The procedure was the same as for TD-307 described above, except that 56 mg of FM-1009 (0.158 mmol) and 50 mg of TD-306 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 3.5-10%. Yield: 60 mg, solid (83%). 1 H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 8.42 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.57 - 7.49 (m, 5H), 7.46 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.9 Hz, 2H), 6.15 (t, J = 5.2 Hz, 1H), 3.26 - 3.22 (m, 4H), 3.22 - 3.18 (m, 2H), 2.40 (t, J = 5.9 Hz, 2H), 2.23 (s, 6H), 1.67 - 1.61 (m, 4H), 1.60 - 1.54 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 155.1, 150.9, 143.8, 142.7, 139.9, 135.8, 134.3, 133.3, 127.3, 126.3, 124.9, 121.1, 120.0, 117.8, 116.3, 107.6, 58.4, 49.2, 44.8, 36.7, 25.1, 23.9. HPLC2t ret = 4.18 min (Method C). ESI-MS m / z: 517.1 [M+Cl] - , 483.2 [M+H]+ .

[0344] 1-(2-(dimethylamino)ethyl)-3-(4-(1-(4-morpholinophenyl)-1H-benzo[d]imidazole-6-yl)phenyl)urea (TD-505) [ka] The procedure was the same as for TD-307 described above, except that 54 mg of FM-999 (0.15 mmol) and 50 mg of TD-306 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). The mixture was stirred overnight at 70°C. The reaction was stopped with saturated NaHCO3 solution and extracted (3 times) by DCM. Flash chromatography gradient: DCM / MeOH + 2N NH3 = 10%. Yield: 67 mg, solid (92%). 1 H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.43 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.59 - 7.51 (m, 5H), 7.46 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 6.09 (t, J = 5.2 Hz, 1H), 3.84 - 3.73 (m, 4H), 3.24 - 3.15 (m, 6H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 150.5, 143.8, 142.7, 139.9, 135.8, 134.3, 133.3, 127.3, 127.2, 124.9, 121.2, 120.0, 117.8, 115.8, 107.6, 66.1, 58.5, 48.1, 45.0, 36.9. HPLC t ret = 5.30 min. ESI-MS m / z: 485.5 [M+H] + , 519.5 [M+Cl] - .

[0345] 1-(4-(1-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (FM-1000) [ka] In a screw-cap reaction vial under an argon atmosphere, TD-306 (33 mg, 0.10 mmol) and FM-998 (37 mg, 0.10 mmol) were dissolved in 3 ml of dioxane. Next, 0.6 ml of K3PO4 aqueous solution (0.5 M, 0.6 ml) was added by syringe, and the mixture was degassed under reduced pressure using argon for 3 cycles. A dioxane solution of tBu3P Pd G3 (1.0 mg, 1.5 mol%) as a stock solution was added, and the degassing procedure was repeated. The flask was sealed and stirred at 70°C for approximately 1 hour using a heating block. Since the starting materials were shown to be completely converted by TLC, the reaction mixture was diluted with EA. The organic phase was washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography to obtain the title compound as a white solid. Flash chromatography gradient: DCM / MeOH + 2N NH3 (2-8%). Yield: 29 mg (58%). 1H NMR (400 MHz, DMSO) δ 8.75 (br s, 1H), 8.49 - 8.30 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.62 - 7.50 (m, 4H), 7.50 - 7.36 (m, 4H), 6.82 (d, J = 8.8 Hz, 2H), 6.10 (t, J = 5.1 Hz, 1H), 4.70 - 4.57 (m, 2H), 3.79 (d, J = 7.3 Hz, 1H), 3.72 (d, J = 7.3 Hz, 1H), 3.57 - 3.51 (m, 1H), 3.22 - 3.14 (m, 2H), 3.05 (d, J = 9.3 Hz, 1H), 2.33 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H), 1.96 (dd, J = 9.8, 1.6 Hz, 1H), 1.92 - 1.81 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 155.1, 146.8, 143.9, 142.6, 139.9, 135.7, 134.6, 133.3, 127.2, 125.3, 124.7, 121.0, 120.0, 117.8, 113.5, 107.6, 75.6, 71.4, 58.5, 58.1, 56.9, 45.0, 36.9, 36.5. HPLC t ret = 3.50 min. ESI-MS m / z: 497.7 [M+H] + .

[0346] 1-(4-(1-(4-(1H-imidazole-1-yl)phenyl)-1H-benzo[d]imidazole-6-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea (TD-516) [ka] The same protocol as for TD-307 above was carried out, except that 55 mg of FM-1014 (0.16 mmol) and 50 mg of TD-306 (0.15 mmol) were used in 2.5 ml of dioxane / water (4+1). Stirring was continued overnight at 70 °C until the starting materials were completely consumed and the formation of the desired product was indicated by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH + 2N NH3 = 7.5 - 10%. The product obtained was dissolved in a small amount of DCM and precipitated with n-pentane, and recovered by filtration. Yield: 41 mg, purple-tinged white solid (59%) (purity by HPLC: λ(254 nm) >95%, λ(230 nm)>93%). 1 H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 8.60 (s, 1H), 8.39 (s, 1H), 7.97 - 7.91 (m, 4H), 7.90 - 7.86 (m, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.62 - 7.55 (m, 3H), 7.47 (d, J = 8.7 Hz, 2H), 7.20 - 7.14 (m, 1H), 6.10 (t, J = 5.2 Hz, 1H), 3.22 - 3.16 (m, J = 11.5, 5.9 Hz, 2H), 2.34 (t, J = 6.1 Hz, 2H), 2.18 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 155.1, 143.7, 142.8, 140.0, 136.2, 136.1, 135.7, 134.3, 133.8, 133.2, 130.1, 127.3, 125.3, 121.8, 121.5, 120.2, 118.1, 117.8, 107.8, 58.5, 45.0, 36.9. HPLC t ret = 3.94 min. HPLC2t ret = 2.31 min (Method C). ESI-MS m / z: 466.3 [M+H] + .

[0347] [ka]

[0348] 6-(6-(6-fluoropyridine-3-yl)-1H-benzo[d]imidazole-1-yl)indoline-1-carboxylate tert-butyl (TD-564) [ka] The procedure was the same as for TD-307 described above, except that 414 mg of TD-555 (1.00 mmol) and 309 mg of (6-fluoropyridine-3-yl)boronic acid (2.19 mmol) were used in 20 ml of dioxane / water (3+1). The mixture was stirred overnight at 75°C until the starting materials were completely consumed and the desired product was shown by TLC (confirmed by TLC-MS). Flash chromatography gradient: DCM / MeOH = 0-3%. Yield: 405 mg, grayish-white foam (94%). 1 H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.32 (td, J = 8.2, 2.5 Hz, 1H), 8.04 - 7.72 (m, 3H), 7.64 (dd, J = 8.4, 1.7 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.30 (dd, J = 7.9, 2.1 Hz, 1H), 7.26 (dd, J = 8.6, 2.8 Hz, 1H), 4.02 (t, J = 8.7 Hz, 2H), 3.17 (t, J = 8.6 Hz, 2H), 1.48 (bs, 9H). HPLC t ret = 9.65 min. ESI-MS m / z: 453.4 [M+Na] + .

[0349] 6-(6-(6-((1-methylpyrrolidine-3-yl)methoxy)pyridine-3-yl)-1H-benzo[d]imidazole-1-yl)indoline-1-carboxylate tert-butyl (TD-565) [ka] (1-methylpyrrolidine-3-yl)methanol (293 mg, 2.54 mmol) was added to a solution of anhydrous THF (15 ml) with NaH (112 mg, 2.80 mmol, 60 wt%). After 5 minutes, TD-564 (373 mg, 0.867 mmol) was added, and the reaction mixture was heated to 50°C until complete conversion was shown by TLC. The reaction was stopped with MeOH, and the solvent was removed by distillation. The product was purified by flash chromatography using DCM / MeOH + 2N NH3 = 2-10% to obtain an oily substance. Solidification can be induced by adding a small amount of MeOH and then removing the solvent by distillation. Yield: 375, foamy substance (82%). 1 H NMR (400 MHz, DMSO) δ 8.55 (s, 1H), 8.49 - 8.45 (m, 1H), 8.02 (dd, J = 8.6, 2.6 Hz, 1H), 7.98 - 7.71 (m, 3H), 7.58 (dd, J = 8.4, 1.7 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.28 (dd, J = 7.9, 2.0 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 4.23 - 4.12 (m, 2H), 4.01 (t, J = 8.7 Hz, 2H), 3.16 (t, J = 8.6 Hz, 2H), 2.62 - 2.45 (m, 3H), 2.41 - 2.30 (m, 2H), 2.23 (s, 3H), 1.97 - 1.87 (m, 1H), 1.55 - 1.35 (m, 10H). HPLC t ret = 7.14 min. ESI-MS m / z: 526.6 [MH] - .

[0350] 1-(indoline-6-yl)-6-(6-((1-methylpyrrolidine-3-yl)methoxy)pyridine-3-yl)-1H-benzo[d]imidazole (TD-572) [ka] 351 mg of TD-565 (0.668 mmol) was mixed with HCl-ethanol solution (1.25 M, 3.8 ml) and reacted with stirring overnight at 50°C. The solvent was removed by distillation, and the product was purified by flash chromatography using DCM / MeOH + 2N NH3 = 4-10%. Yield: 263 mg, foamy substance (90%). 1 H NMR (400 MHz, DMSO) δ 8.48 - 8.45 (m, 2H), 8.02 (dd, J = 8.6, 2.6 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.73 - 7.71 (m, 1H), 7.55 (dd, J = 8.4, 1.7 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.88 (dd, J = 8.6, 0.5 Hz, 1H), 6.79 (dd, J = 7.6, 2.0 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 5.88 - 5.83 (m, 1H), 4.24 - 4.12 (m, 2H), 3.53 (td, J = 8.7, 1.1 Hz, 2H), 2.99 (t, J = 8.5 Hz, 2H), 2.62 - 2.51 (m, 3H), 2.46 - 2.34 (m, 2H), 2.26 (s, 3H), 2.00 - 1.88 (m, 1H), 1.56 - 1.46 (m, 1H). 13 C NMR (101 MHz, DMSO) δ 162.6, 154.1, 144.8, 143.9, 143.2, 138.0, 135.0, 133.9, 132.6, 130.0, 128.7, 125.1, 121.3, 120.3, 111.8, 110.6, 108.5, 103.3, 68.8, 59.0, 55.3, 46.8, 41.7, 36.8, 28.7, 27.6. HPLC t ret = 3.27 min. ESI-MS m / z: 426.4 [M+H] + .

[0351] 6-(6-((1-methylpyrrolidine-3-yl)methoxy)pyridine-3-yl)-1-(1-(methylsulfonyl)indoline-6-yl)-1H-benzo[d]imidazole (TD-577) [ka] 64 mg of TD-572 (0.15 mmol) was dissolved in 3 ml of anhydrous pyridine, to which 27 mg of MsCl (0.236 mmol) was added. The bright orange reaction mixture (later changing to dark purple) was stirred overnight at room temperature until HPLC confirmed that the starting materials were completely consumed. The solvent was removed, and the resulting crude product was purified by flash chromatography (DCM / MeOH + 2N NH3 = 6-10%). Yield: 32 mg, yellow foam (42%). 1 H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 8.49 - 8.45 (m, 1H), 8.02 (dd, J = 8.6, 2.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 1.2 Hz, 1H), 7.59 (dd, J = 8.4, 1.7 Hz, 1H), 7.53 - 7.49 (m, 2H), 7.40 (dd, J = 7.9, 2.0 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.24 - 4.13 (m, 2H), 4.06 (t, J = 8.5 Hz, 2H), 3.22 (t, J = 8.5 Hz, 2H), 3.15 (s, 3H), 2.63 - 2.45 (m, 3H), 2.43 - 2.33 (m, 2H), 2.24 (s, 3H), 1.98 - 1.89 (m, 1H), 1.54 - 1.46 (m, 1H). 13C NMR (101 MHz, DMSO) δ 162.7, 144.8, 144.0, 143.3, 143.3, 137.9, 135.2, 133.8, 132.8, 131.5, 129.8, 126.8, 121.5, 120.4, 118.6, 110.6, 108.6, 108.3, 68.9, 59.1, 55.4, 50.5, 41.8, 36.9, 34.9, 27.6, 27.1. HPLC t ret = 4.52 min. ESI-MS m / z: 504.5 [M+H] + .

[0352] 3-((5-(3-(1-(methylsulfonyl)indoline-6-yl)-3H-imidazo[4,5-b]pyridine-5-yl)pyridine-2-yl)oxy)propan-1-amine(TD-659) [ka] Step 1: The same procedure as for TD-307 was followed, except that 1026 mg of TD-556 (2.30 mmol, 88% purity by HPLC), 268 mg of (6-fluoropyridine-3-yl)boronic acid (2.61 mmol), and 1443 mg of K2CO3 were used in 18 ml of dioxane / water (4+1). The reaction mixture was stirred overnight at 75°C. The resulting product was purified by flash chromatography (DCM / MeOH = 0-1.3%). The product was suspended in MeOH and recovered by filtration. Yield: 815 mg white solid (86%). Step 2: 40 mg of 3-aminopropan-1-ol (0.532 mmol) and 60 mg of KOtBu (0.532 mmol) were stirred in 5 ml of anhydrous THF. 109 mg of the product obtained in Step 1 (0.266 mmol) was added, and the mixture was heated to 50°C until TLC indicated that the starting materials had been completely consumed. The solvent was removed by distillation, and the crude product was purified by flash chromatography (DCM / MeOH + 2N NH3 = 2-8.5%). Yield: 71 mg, solid (57%). 1H NMR (400 MHz, DMSO) δ 8.93 (d, J = 2.3 Hz, 1H), 8.92 (s, 1H), 8.47 (dd, J = 8.7, 2.5 Hz, 1H), 8.26 ...

Claims

1. General formula (Ia) or general formula (Ib): 【Chemistry 1】 (In the formula, X 1 and X 3 These are independently selected from N and CH, X 2 C is, R 1 , R 2 and R 3 Each is independently selected from H and a substituted or unsubstituted alkyl group. R 4 teeth, 【Chemistry 2】 and (In the formula, Z 1 is, independently of each other, H, F, Cl, Br, I, -N(R 7 )(R 8 ), -N(COR 7 )(R 8 ), -N(SO 2 R 7 )(R 8 ), -O(R 7 ), -CO(R 7 ), -COO(R 7 ), -SO 2 (R 7 ), a substituted or unsubstituted alkyl, a substituted or unsubstituted ring, a substituted or unsubstituted heterocycle, a substituted or unsubstituted condensed ring, and a substituted or unsubstituted condensed heterocycle, and is selected from Z 2 is H or -SO 2 (R 7 ) and R 7 and R 8 Each of these is independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted rings, substituted or unsubstituted heterocycles, substituted or unsubstituted fused rings, and substituted or unsubstituted fused heterocycles. n is either 1 or 2), A is 【Transformation 3】 That is (In the formula, Z 3 These are selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted ring groups, substituted or unsubstituted heterocycles, substituted or unsubstituted fused ring groups, substituted or unsubstituted fused heterocycles, and combinations thereof. Z 4 (It is either H or F) The compound represented by, or its stereoisomers, enantiomers, tautomers, prodrugs and / or pharmaceutically acceptable salts.

2. R 1 and R 2 However, all of them are H, R 3 However, it is H or methyl, and / or A is the following a) to e): a) 4-anilinyl, 2-(4-(7-methyl-3-oxohexahydroimidazo[1,5-a]pyrazine-2(3H)-yl)phenyl), 4-(hydroxymethyl)phenyl, 2-(2-(dimethylamino)ethyl)-1H-benzo[d]imidazole-5-yl, 6-(3-hydroxypropoxy)pyridine-3-yl, or 1-(3-(dimethylamino)propyl)-1H-pyrazole-4-yl; b) B, a residue of general formula (II) 【Chemistry 4】 (In the formula, X is CR a Or it is N, R a is either H, or a substituted or unsubstituted alkyl group, or is absent. R c is H, methyl or methylene, R b and R d It is either H or F, V 1 NH, N-CH 3 Or CH 2 And, V 2 NH, N-CH 3 Or it is O, R a If not, then B is X=C and V 1 It forms a fused ring with =N, creating a substituted indoline. R c If C is a methylene group, then C is a ring that forms a substituted pyrrolidine ring or a substituted piperidine ring, or D is a ring that forms a substituted difluoroazetidine or a substituted monofluoroazetidine. n is 0, 1, or 2); c) Residues of general formula (III) 【Transformation 5】 (In the formula, X is either N or CH. R is a substituted or unsubstituted alkyl, a substituted or unsubstituted benzyl, or N(R) 1 )(R 2 ) d) Residues of general formula (IV) 【Transformation 6】 (In the formula, X is CH, CR a Or it is N, R a H is either a substituted or unsubstituted alkyl group, or it is absent. Q is O, S, or N. F may be a condensed ring that forms a substituted benzimidazole. R 5 and R 6 These are independently selected from H and methyl, R 5 and R 6 These may together form unsubstituted or substituted pyrrolidines, or unsubstituted or substituted piperidines. n is 0, 1, or 2); e) Residues of general formula (V) 【Transformation 7】 (In the formula, R is either methyl or methylene. (If R is a methylene group, then I is a ring that forms a substituted azetidine, or J is a ring that forms a substituted piperazine); and f) Residues in the following equation 【Transformation 8】 A compound according to claim 1, selected from the following.

3. X 1 However, N is, X 2 However, C is, X 3 However, it is CH or N, R 1 , R 2 and R 3 However, each of them is H, R 4 but, 【Chemistry 9】 and (In the formula, Z 1 is, -N(SO 2 R 7 )(R 8 ) and R 7 and R 8 These are H and unsubstituted C, respectively, independently. 1 -C 5 Alkyl and unsubstituted C 1 -C 5 Selected from cycloalkyl, preferably R 7 and R 8 However, each is independently selected from H, methyl, ethyl, and cyclopropyl, Z 2 is, -SO 2 (R 7 ) and), A 【Chemistry 10】 That is (In the formula, X 4 is N or CH, V 1 is O or NH, preferably O. V 2 CH 2 , NH or 3-(1-methylpyrrolidine), V 3 CH 2 or CO, V 4 is hydroxyl or -N(R 7 )(R 8 ) and R 7 and R 8 These may combine to form a ring, forming a substituted pyrrolidine or substituted piperidine. n is 0, 1, or 2. The compound according to any one of the preceding claims.

4. X 1 However, N is, X 2 However, C is, X 3 However, it is CH or N, R 1 and R 2 However, each of them is H, R 3 is H or unsubstituted C 1 -C 5 is alkyl, preferably H or methyl, R 4 However, the substituted ring, 2-R-phenyl, 3-R-phenyl, 4-R-phenyl, or 【Chemistry 11】 And, R is selected from F, Cl, Br, I, -O(unsubstituted C 1 -C 5 -alkyl), -NH 2 -, -NHSO 2 (unsubstituted C 1 -C 5 -alkyl), unsubstituted or substituted rings, and unsubstituted or substituted heterocycles, and preferably, when R 4 is 3-R-phenyl, R is -NHSO 2 (unsubstituted C 1 -C 5 -alkyl), or when R 4 is 4-R-phenyl, R is selected from unsubstituted or substituted rings, and unsubstituted or substituted heterocycles, n is 1 or 2, Z 2 However, -SO 2 (Unsubstituted C 1 -C 5 It is alkyl, A 【Chemistry 12】 That is (In the formula, X 4 and X 5 Each is independently selected from CH, CF, and N, preferably X 4 and X 5 However, each is CH, V 1 and V 2 Each is independently selected from NH, S, and O. V 3 CH 2 or CO, V 4 is -N(R 7 )(R 8 ), substituted 1-azetidine, substituted 2-pyrrolidine, substituted 3-pyrrolidine, or unsubstituted 1-piperidine, R 7 and R 8 These are independently selected from H and methyl, V 5 (CH 2 ) n or (CHCH 3 ) n (where n is 0, 1, or 2) The compound according to claim 1 or 2.

5. In the compound of formula (Ia) above, X 1 N is X 2 C is X 3 Is it CH or X 1 and X 3 N is X 2 The compound according to any one of the preceding claims, wherein is C, or the compound of formula (Ia) is the compound of formula (IIb).

6. R 4 but, 【Chemistry 13】 Selected from (In the formula, R is an unsubstituted alkyl or unsubstituted cycloalkyl, preferably methyl, ethyl, or cyclopropyl, or 3-R 9 - or 4-R 9 -phenyl, R 9 teeth, 【Chemistry 14】 (It is) The compound according to any one of the preceding claims.

7. A 【Chemistry 15】 The compound according to any one of the preceding claims.

8. (a) The compound has the general formula (VIa): 【Chemistry 16】 (In the formula, R is, 【Chemistry 17】 (is) Do you have it? (b) The compound is of general formula (VIb): [Chemistry 18] (In the formula, R is, 【Chemistry 19】 (is) Do you have it? (c) The compound has the general formula (VIc): 【Chemistry 20】 (In the formula, R is, 【Chemistry 21】 (is) Do you have it? (d) The compound has the general formula (VId): 【Chemistry 22】 (In the formula, R 1 teeth, 【Chemistry 23】 And, X is CH, R 2 teeth, 【Chemistry 24】 is; or R 1 teeth, 【Chemistry 25】 And, X is N, R 2 teeth, 【Chemistry 26】 (is) Do you have it? (e) The compound is of general formula (VIe): 【Chemistry 27】 (In the formula, R is, 【Chemistry 28】 (is) Do you have it? (f) The compound has the general formula (VIf): 【Chemistry 29】 (In the formula, R 1 is Me, Et or cPr, X is CH, R 2 is Me, and R 3 teeth, 【Transformation 30】 Is it; R 1 is Me, X is N, and R 2 H is R 3 teeth, 【Chemistry 31】 is; or R 1 is Me, X is N, and R 2 H is R 3 teeth, 【Chemistry 32】 (is) Do you have it? (g) The compound is of general formula (VIg): 【Transformation 33】 (In the formula, R 1 teeth, 【Transformation 34】 And, X is CH, R 2 teeth, 【Chemistry 35】 Is it; R 1 teeth, 【Transformation 36】 And, X is CH, R 2 teeth, 【Chemistry 37】 Is it; R 1 teeth, 【Transformation 38】 And, X is N, R 2 teeth, 【Chemistry 39】 is; or R 1 teeth, 【Chemistry 40】 And, X is N, R 2 teeth, 【Chemistry 41】 (is) Having; or (h) The compound has the general formula (VIh): 【Chemistry 42】 (In the formula, R 1 teeth, 【Chemistry 43】 And, R 2 teeth, 【Chemistry 44】 is; or R 1 teeth, 【Chemistry 45】 And, R 2 teeth, 【Chemistry 46】 (is) A compound according to any one of the preceding claims, having the following characteristics.

9. The aforementioned compound, 【Chemistry 47】 【change】 The compound according to any one of claims 1, 2, and 4 to 8.

10. The aforementioned compound, 【Chemistry 48】 【change】 【change】 The compound according to any one of claims 1 to 3 and 5 to 8.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, a prodrug, a biologically active metabolite, a solvate, or a stereoisomer thereof, and which may also comprise an inert carrier and / or one or more other therapeutic agents.

12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, prodrug, biologically active metabolite, solvate or stereoisomer thereof, or a composition according to claim 11, for use in the treatment of a disease, preferably the disease being an ATM kinase-mediated disease.

13. The compound according to claim 12, wherein the disease is cancer, preferably selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer.

14. A method for treating a disease in which intervention on ATM kinase, preferably inhibition, control, and modulation of ATM kinase, is beneficial, in humans or warm-blooded animals or mammals requiring treatment of such a disease, A method comprising the step of administering to a human or warm-blooded or mammalian animal in need of the aforementioned treatment a therapeutically effective amount of the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, prodrug, biologically active metabolite, solvate or stereoisomer thereof, or the composition according to claim 11.

15. The method according to claim 14, wherein the disease is cancer, preferably selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, hepatocellular carcinoma, small cell lung cancer, and non-small cell lung cancer.

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