Heterocyclic peri-fused CDC7 kinase inhibitors for cancer treatment

Abstract

This application relates to compounds of formula (I), as defined herein, and pharmaceutically acceptable salts thereof. This application also describes pharmaceutical compositions comprising compounds of formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions to inhibit kinase activity and to treat cancer. JPEG2023541047000301.jpg57165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Patent Application No. 63 / 076,721, filed on September 10, 2020, which is incorporated herein by reference in its entirety.

[0002] This application relates to tricyclic and other polycyclic compounds useful for treating proliferative disorders such as cancer. [Background technology]

[0003] Cancer is characterized by the abnormal growth and proliferation of cells. Genomic instability is a characteristic of cancer cells, and high mutation and genomic rearrangement rates result in aggressive and treatment-resistant tumors. See Hanahan and Weinberg, Cell, 144, pp. 646-674 (2011) and McGranahan and Swanton, Cell 168, pp. 613-628 (2017). Dysregulation of DNA replication contributes to genomic instability and tumorigenesis. Eukaryotes divide through a directional, highly regulated, stepwise process (known as the cell cycle). DNA replication is an essential part of this highly regulated stepwise cell cycle, and this tight regulation ensures that DNA replication occurs only once during the S phase with high fidelity.

[0004] During late G1 to S phase, CDC7 kinase (also known as DDK) is activated by binding to its regulatory protein DBF4 (ASK in eukaryotes). This then phosphorylates chromatin-loaded minichromosome maintenance (MCM) 2, 4, and 6 proteins at multiple phosphorylation sites, initiating DNA synthesis. See Jiang, et al., EMBO J., 18, pp. 5703-5713 (1999); Cho, et al., Proc. Natl. Acad. Sci. USA, 103, pp. 11521-11526 (2006); and Masai, et al., J Biol Chem., 281, pp. 39249-39261 (2006). CDC7 kinase plays a crucial role in maintaining the DNA replication fork and DNA damage response pathways. See Yamada, et al., Cell Cycle 13, pp. 1859-1866 (2014). CDC7 is a highly conserved serine / threonine kinase from yeast to humans. Knockdown of CDC7 induces cell death in cancer cells, but not in normal cells where the cell cycle is arrested in the G1 phase via a p53-dependent pathway. The apoptotic response induced in cancer cells by CDC7 depletion is mediated not by p53, but by p38 MAPK. See Montagnoli, et al., Cancer Res., 64, pp. 7110-7116 (2004) and Im and Lee, J. Biol. Chem., 283, pp. 25171-25177 (2008). In addition, upregulation of CDC7 is associated with poor prognosis in various cancer types. For example, see Kulkarni, et al., Clin. Cancer Res., 15, pp. 2417-2425 (2009); Choschzick, et al., Hum. Pathol., 41, pp. 358-365 (2010); Datta, et al., EMBO Rep., 18, pp. 2030-2050 (2017); Cheng, et al., Cancer Lett., 337, 218-225 (2013). [Prior art documents] [Non-Patent Literature]

[0005] [Non-Patent Literature 1] Hanahan and Weinberg, Cell, 144, pp.646-674 (2011) [Non-Patent Literature 2] McGranahan and Swanton, Cell 168, pp.613-628 (2017) [Non-Patent Literature 3] Jiang, et al., EMBO J., 18, pp.5703-5713 (1999); Cho, et al., Proc. Natl. Acad. Sci. U.S.A., 103, pp.11521-11526 (2006) [Non-Patent Literature 4] Masai, et al., J Biol Chem., 281, pp.39249-39261 (2006) [Non-Patent Literature 5] Yamada, et al., Cell Cycle 13, pp.1859-1866 (2014) [Non-Patent Literature 6] Montagnoli, et al., Cancer Res., 64, pp.7110-7116 (2004) [Non-Patent Literature 7] Im and Lee, J. Biol. Chem., 283, pp.25171-25177 (2008) [Non-Patent Literature 8] Kulkarni, et al., Clin. Cancer Res., 15, pp.2417-2425 (2009) [Non-Patent Literature 9] Choschzick, et al., Hum. Pathol., 41, pp.358-365 (2010) [Summary of the Invention] [Means for Solving the Problems]

[0006] It has been found that certain fusion compounds are inhibitors of CDC7 kinase and are useful for the treatment of diseases, for example proliferative diseases such as cancer.

[0007] Accordingly, provided herein is a compound of formula (I):

Chemical Formula

[0008] Also provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0009] Also provided herein is a method of inhibiting mammalian cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0010] Also provided herein is a method of inhibiting CDC7 kinase activity in mammalian cells in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] Also provided herein is a method of treating cancer, comprising administering an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need of cancer treatment.

[0012] Furthermore, methods for treating CDC7-related illnesses or disorders are also provided herein, comprising administering an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need of treatment for a CDC7-related illness or disorder.

[0013] Furthermore, methods for treating cancer and / or inhibiting metastases associated with a particular cancer are also provided herein, comprising administering an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject requiring treatment of cancer and / or inhibition of metastases associated with a particular cancer.

[0014] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer.

[0015] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of CDC7-related diseases or disorders.

[0016] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer and / or in inhibiting metastases associated with certain cancers.

[0017] Compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in inhibiting CDC7 kinase activity are also provided herein.

[0018] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of CDC7-related diseases or disorders.

[0019] Also provided herein are compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals for the treatment of cancer and / or the inhibition of metastases associated with certain cancers.

[0020] Compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals for inhibiting CDC7 kinase activity are also provided herein.

[0021] Compounds of formula (I) as defined herein, or pharmaceutically acceptable salts thereof, for use in the manufacture of pharmaceuticals for the treatment of CDC7-related diseases or disorders are also provided herein.

[0022] Also provided is a method for treating an individual with CDC7-associated cancer, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof before, during, or after administration of other anticancer agents (e.g., a first CDC7 kinase inhibitor or another kinase inhibitor).

[0023] Furthermore, processes for preparing the compound of formula (I) or a pharmaceutically acceptable salt thereof are also provided herein.

[0024] Compounds of formula (I) or pharmaceutically acceptable salts thereof, obtained by processes for preparing compounds as defined herein, are also provided herein.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the invention pertains. Other suitable methods and materials known in the art, as described herein for use in the invention, may also be used. Materials, methods, and examples are illustrative and not intended to limit the scope. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated in their entirety by reference. In the event of any inconsistency, this specification, including its definitions, shall prevail.

[0026] Other features and advantages of the present invention will become apparent from the following detailed description and claims. The present invention provides, for example, the following items: (Item 1) Compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 It is a 5-10 membered heteroaryl compound optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl compounds. Y is -S- or -S(=O)-, Ring A is a C5-C7 cycloalkyl or a 5-7 membered heterocycline. Each R 2 These are independently hydrogen, halogen, hydroxyl, cyano, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and -NR. B R C , C1-C6 alkoxyalkyl, -C(=O)NH-5~10 member heteroaryl, 4~6 member heterocyclyl, 5~10 member heteroaryl, 1~3 independently selected R A Selected from the group consisting of C1-C6 alkyl groups substituted with and C3-C6 cycloalkyl groups optionally substituted with hydroxyl, Two R's 2 Together with the atoms to which they are attached, they form an oxo group; a C3-C6 cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys; or a 3- to 6-membered heterocycline optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. R 3 This is selected from C0-C6 alkyl groups substituted with hydrogen and optionally with 1 to 4 substituents independently selected from the following: (i) Hydroxyl, (ii) Cyano, (iii) halogen, (iv) C3-C6 cycloalkoxy, (v)C(=O)ORF 、 (vi) C1-C6 alkoxy, (vii) A 4-10 member heterocyclyloxy compound substituted with 1-3 independently selected halogens, (viii)-NR B R C 、 (ix) Optionally, hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR B R C , 3-6 membered heterocyclyloxy, and C3-C6 cycloalkyl groups substituted with 1-3 groups independently selected from 3-6 membered heterocyclyl groups optionally substituted with 1-3 C1-C6 alkoxy groups, (x) Optionally, halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NR B R C , C1-C6 alkyl groups substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, and C3-C6 cycloalkoxys, and 3 to 10-membered heterocyclines substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl groups substituted with halogens or hydroxyls, (xi) optionally substituted with cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, optionally substituted with 1-2 substituents independently selected from cyano and hydroxyl, and optionally substituted with 1-3 independently selected R Aで 5-6 member heteroaryls substituted with 1-3 substituents independently selected from substituted 4-10 member heterocyclils, and (xii)-C(=O)-X(where X is -NR) B R C , C1-C6 alkyl, 5-6 member heteroaryl, -NH-5-6 member heteroaryl, -OR E (or a 3-6 member heterocycline optionally substituted with a hydroxyl group), Each R A and R E These are independently halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylamino, 4-6 membered heterocyclyl, or C3-C6 cycloalkyl. Each R B and R C These are independently substituted with hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(=O)-C1-C6 alkyl, optionally C1-C6 alkyl, cyano, halogen, hydroxyl, or C3-C6 cycloalkyl -(C1-C6 alkylene) p -C3-C8 cycloalkyl, 3- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, -C(=O)O-C1-C6 alkyl, or benzyl optionally substituted with C1-C6 alkoxy, or R B and R C Together with the atoms to which they are attached, they form a unified, optionally forming halogens, hydroxyls, cyanos, C1-C6 alkyls, and -NRs. F R G , forming 4-10 membered heterocyclines substituted with 1-3 substituents independently selected from C3-C6 cycloalkoxy, C1-C6 haloalkoxy, and C1-C6 alkoxy, Each p is independently either 0 or 1. m is 0, 1, 2, 3, or 4. R 4 is hydrogen or C1-C6 alkyl, R D This consists of hydrogen, a C1-C6 haloalkyl group, and 1 to 3 independently selected R groups. E A C1-C6 alkyl group substituted with, and 1 to 3 independently selected R groups as optional. E A C3-C6 cycloalkyl group substituted with R, and 1 to 3 independently selected R groups as optional. E A 4-10 member heterocyclyl, C6-C10 aryl, or 1-3 independently selected R substituted with E It is a 5-10 member heteroaryl substituted with, Each R F and R G The compound, or a pharmaceutically acceptable salt thereof, is independently hydrogen or a C1-C6 alkyl group. (Item 2) The compound listed in item 1, wherein Y is -S-. (Item 3) A compound listed in item 1, in which Y is -S(=O)-. (Item 4) A compound described in any one of items 1 to 3, wherein ring A is a 5- to 7-membered heterocycline. (Item 5) A compound described in any one of items 1 to 4, wherein ring A is a 6- to 7-membered monocyclic heterocycline. (Item 6) A compound described in any one of items 1 to 5, wherein ring A contains one oxygen atom. (Item 7) A compound according to any one of items 1 to 3, wherein ring A is a C5-C7 cycloalkyl group. (Item 8) R 1 The compound according to any one of items 1 to 7, wherein the compound is a 5-10 membered heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxyl, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl. (Item 9) R 1 The compound according to any one of items 1 to 8, wherein the compound is a 5-6 member heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl. (Item 10) R 1 The compounds described in any one of items 1 to 9, wherein each is a pyrazole, pyridine, or pyrimidine, each substituted with one to three substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl. (Item 11) R 1 The compounds described in any one of items 1 to 10, wherein each is a pyrazole, pyridine, or pyrimidine, each substituted with a C1-C6 alkyl group. (Item 12) R 1 However, a compound described in any one of items 1 to 11, which is a pyrazole substituted with methyl. (Item 13) R 1 However, each of the compounds listed in any one of items 1 to 11 is a pyridine or pyrimidine, each substituted with methyl. (Item 14) R 1 However, each was substituted with one methyl group.

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[0027] definition As used herein, the term “compound” is intended to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structure described. Compounds identified herein by name or structure as one specific tautomer are intended to include other tautomers unless otherwise specified.

[0028] As used herein, the term “precursor” means a first compound that reacts with one or more chemical transformations to provide a second compound, where the first compound is a precursor to the second compound.

[0029] As used herein, the term “tautomer” refers to a compound whose structure differs significantly in the arrangement of atoms, but which exists in an easily and rapidly equilibrium state. The compounds provided herein may be described as different tautomers, and when a compound has tautomers, all tautomers are intended to be within the scope of the invention. It should be understood that the naming of a compound does not exclude any tautomer. Examples of tautomers are given below. [ka]

[0030] It will be recognized that certain compounds provided herein may contain one or more asymmetric centers and can therefore be prepared and isolated as a mixture of isomers, such as a racemic mixture, or in enantiomerically pure forms.

[0031] The term "halo" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0032] The term "C0-C6 alkyl" refers to saturated linear or branched hydrocarbon chains containing 0, 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. As used herein, "C0" alkyl refers to a bond, for example, R-(C0 alkyl)-R' refers to R-R'.

[0033] The term "C1-C6 haloalkyl" refers to a C1-C6 alkyl as defined herein, substituted with at least one halogen atom independently selected at each occurrence, such as fluorine, chlorine, bromine, and iodine. The halogen atom may be present at any position on the alkyl group. For example, C1-C6 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, e.g., 1-chloroethyl and 2-chloroethyl; trichloroethyl, e.g., 1,2,2-trichloroethyl and 2,2,2-trichloroethyl; fluoroethyl, e.g., 1-fluoromethyl and 2-fluoroethyl; trifluoroethyl, e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl; chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl.

[0034] The term "C1-C6 alkoxy" refers to a C1-C6 alkyl group attached to a molecule via oxygen. This includes moieties such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy, where the alkyl portion may be linear or branched.

[0035] As used herein, the term "cyano" refers to the -CN radical.

[0036] As used herein, the term "hydroxyl" refers to the -OH radical.

[0037] The term "C1-C6 hydroxyalkyl" refers to a C1-C6 alkyl group as defined herein, substituted with one or more hydroxyl radicals. Hydroxyl radicals can be located at any position on the hydrocarbon chain. For example, C1-C6 hydroxyalkyl refers to hydroxymethyl, hydroxyethyl (e.g., 1-hydroxyethyl or 2-hydroxyethyl), and 2-hydroxyisopropyl.

[0038] The term "C1-C6 alkoxyalkyl" refers to a C1-C6 alkyl group substituted with one or more C1-C6 alkoxy groups as defined herein, where the alkoxy group(s) are attached to the alkyl group via oxygen. This includes moieties such as methoxyethyl, ethoxyethyl, or 1,3-dimethoxypropyl, where the alkyl portion of the C1-C6 alkyl or C1-C6 alkoxy may be independently linear or branched.

[0039] As used herein, the term "amino" refers to the -NH2 radical.

[0040] As used herein, the term “aryl” refers to a monocyclic or bicyclic group of 6 to 10 carbon atoms in which at least one ring in the system is aromatic. Non-limiting examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.

[0041] As used herein, the term "heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic group in which at least one ring in the system is aromatic, and one or more carbon atoms in at least one ring in the system are replaced by heteroatoms independently selected from N, O, and S. Non-exclusive examples of heteroaryl groups include furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, sinnoline, and triazine.

[0042] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated monocyclic or bicyclic carbon group having 3 to 10 carbon atoms. Bicyclic cycloalkyl groups include condensed, spiro, and crosslinked ring systems. Non-limiting examples of cyclopropyl groups include cyclopropyl, cyclohexyl, spiro[2.3]hexyl, and bicyclo[1.1.1]pentyl.

[0043] The term “heterocyclyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or bicyclic ring system that is not aromatic and has 3 to 10 ring atoms, with at least one heteroatom selected from N, O, and S within the ring. Bicyclic heterocyclyl groups include condensed, spiro, and bridging ring systems. A heterocyclyl group may be expressed as a “5- to 10-membered heterocyclyl group,” for example, a ring system containing 5, 6, 7, 8, 9, or 10 atoms, with at least one being a heteroatom. For example, there may be one, two, or three, optionally, one or two heteroatoms. A heterocyclyl may further contain one or more carbonyl or thiocarbonyl functional groups, so that the definition may include oxo and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. A heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Examples of heterocyclyl groups include, but are not limited to, 1,3-dioxolane, 1,4-dioxolane, maleimide, succinimide, dioxopiperazine, hydantoin, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidinone, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, azetidine, oxetane, and 2-azaspiro[3.3]heptanyl.

[0044] As used herein, the term "geminal" refers to a substituent atom or group attached to the same atom within a molecule.

[0045] As used herein, the term "vicinal" refers to a substituent atom or group attached to an adjacent atom within a molecule. The stereochemical relationship between the substituent atoms or groups may be cis, trans, undefined, or unresolved.

[0046] As used herein, the term "oxo" refers to a "=O" group attached to a carbon atom.

[0047] Where used herein, the symbol [ka] This depicts the attachment points of an atom or part to the indicated atom or group of the rest of the molecule.

[0048] Compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) include pharmaceutically acceptable salts thereof. In addition, compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts but may be useful as intermediates for preparing and / or purifying compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) and / or for separating enantiomers of compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)). Non-limiting examples of pharmaceutically acceptable salts of compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) include trifluoroacetic acid and its hydrochloride salt.

[0049] Compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or salts thereof may be isolated in the form of solvates, and it will be further recognized that any such solvates are included within the scope of this disclosure. For example, compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) and salts thereof may exist in non-solvated and solvated forms using pharmaceutically acceptable solvents such as water, ethanol, and equivalents.

[0050] In some embodiments, the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) includes the compounds of Examples 1 to 65 and their stereoisomers, as well as pharmaceutically acceptable salts and solvates. In some embodiments, the compounds of Examples 1 to 65 are in free base form. In some embodiments, the compounds of Examples 1 to 65 are in salt form.

[0051] In some embodiments, the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) is prepared as a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is an acid addition salt of the compound. A pharmaceutically acceptable salt can be obtained by reacting the compound with an inorganic acid such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Alternatively, a pharmaceutically acceptable salt can also be obtained by reacting the compound with an organic acid such as an aliphatic or aromatic carboxylic acid or sulfonic acid (e.g., formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid). Furthermore, pharmaceutically acceptable salts can also be obtained by reacting the compound with a base to form salts, such as ammonium salts, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), salts of organic bases (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts with amino acids (e.g., arginine and lysine).

[0052] The term "pharmaceutically acceptable" indicates that a compound, or a salt or composition thereof, is chemically and / or toxicologically compatible with other components of the formulation and / or the subject being treated therewith.

[0053] Protecting groups can be transient substituents that protect potentially reactive functional groups from undesirable chemical transformations. The selection of a particular protecting group to be employed is well within the scope of the skill of those skilled in the art. Several considerations, including but not limited to the functional group being protected, other functionalities present in the molecule, reaction conditions at each step of the synthetic sequence, other protecting groups present in the molecule, the functional group's tolerance to the conditions required to remove the protecting group, and reaction conditions for the thermal decomposition of the compounds provided herein, can determine the selection of a protecting group. The field of protecting group chemistry is examined in (Greene, TW; Wuts, PGMP Rotatory Groups in Organic Synthesis, 2nd ed. Wiley: New York, 1991).

[0054] A nitrogen protecting group can be any transient substituent that protects the amine moiety from undesirable chemical transformations. Examples of moieties formed when such protecting groups are bonded to an amine include, but are not limited to, allylamines, benzylamines (e.g., benzylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine, and tritylamine), acetylamides, trichloroacetamides, trifluoroacetamides, pento-4-enamides, phthalimides, carbamates (e.g., methyl carbamate, t-butyl carbamate, benzyl carbamate, allyl carbamate, 2,2,2-trichloroethyl carbamate, and 9-fluorenylmethyl carbamate), imines, and sulfonamides (e.g., benzenesulfonamide, p-toluenesulfonamide, and p-nitrobenzenesulfonamide).

[0055] An oxygen protecting group can be any transient substituent that protects the hydroxyl moiety from undesirable chemical transformations. Examples of moieties formed when such a protecting group is bonded to a hydroxyl include, but are not limited to, esters (e.g., acetyl, t-butylcarbonyl, and benzoyl), benzyls (e.g., benzyl, p-methoxybenzyl, and 2,4-dimethoxybenzyl, and trityl), carbonates (e.g., methyl carbonate, allyl carbonate, 2,2,2-trichloroethyl carbonate, and benzyl carbonate), ketals, and acetals, as well as ethers.

[0056] The compounds provided herein may also contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. That is, when an atom is referred to in particular with respect to a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)), it includes all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, in either natural abundance or in isotopic enrichment form. For example, when hydrogen is referred to unless otherwise specified, it is, 1 H, 2 H, 3 It is understood to refer to H, or a mixture thereof, and when carbon is mentioned, it refers to, 11 C, 12 C, 13 C, 14 It is understood to refer to C, or a mixture thereof, and when nitrogen is mentioned, it refers to, 13 N, 14 N, 15 It is understood to refer to N, or mixtures thereof, and when oxygen is mentioned, it means, 14 O, 15 O, 16 O, 17 O, 18 It is understood to refer to O, or mixtures thereof, and when fluoro is mentioned, it means 18 F, 19 It is understood to refer to F, or mixtures thereof. For example, in deuterium alkyl and deuterium alkoxy groups, one or more hydrogen atoms are deuterium ( 2It is specifically replaced by H). Since some of the aforementioned isotopes are radioactive, the compounds provided herein also include compounds having one or more isotopes of one or more atoms, including the radioactive compound in which one or more non-radioactive atoms are replaced by one of the radioactively enriched isotopes, and mixtures thereof. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer drugs, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo contrast agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be included within the scope of the invention.

[0057] The ability of the test compound to act as a CDC7 inhibitor can be demonstrated by the biological and computational assays described herein. 50 The values ​​are shown in Tables A and B.

[0058] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) permeability. Such compounds can cross the blood-brain barrier and inhibit CDC7 kinase activity in the brain and / or other CNS structures. In some embodiments, the compounds provided herein can cross the blood-brain barrier in therapeutically effective amounts. For example, treatment of a subject having cancer (e.g., CDC7-related cancers such as CDC7-related brain or CNS cancer) may involve administering the compound to the subject (e.g., orally). In some such embodiments, the compounds provided herein are useful for treating primary or metastatic brain tumors, e.g., CDC7-related primary or metastatic brain tumors.

[0059] In some embodiments, a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof exhibits one or more of the following: high GI absorption, low clearance, and a low likelihood of drug-drug interactions.

[0060] Compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or pharmaceutically acceptable salts thereof are useful for treating diseases and disorders treatable with CDC7 kinase inhibitors, such as CDC7-related cancers, including hematological malignancies and solid tumors.

[0061] As used herein, the terms “to treat” or “treatment” refer to therapeutic or pain-relieving measures. Beneficial or desirable clinical outcomes include, but are not limited to, the whole or partial relief of symptoms associated with a disease or disorder or condition, whether detectable or undetectable; a reduction in the severity of the disease; a stable (i.e., non-worsening) state of the disease; a delay or slowing of disease progression; improvement or relief of symptoms (e.g., one or more symptoms of the disease); and remission (whether partial or whole), whether detectable or undetectable. “Treatment” may also mean an extension of survival compared to expected survival without treatment.

[0062] As used herein, the term “Subject” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented.

[0063] In some embodiments, a subject is identified or diagnosed with a cancer (CDC7-related cancer) (e.g., in a determination using a regulatory-approved (e.g., FDA-approved) assay or kit) involving dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or any of them. In some embodiments, a subject has a tumor (e.g., in a determination using a regulatory-approved assay or kit) that is positive for dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or any of them. A subject may have a tumor(s) (e.g., identified as positive using a regulatory-approved (e.g., FDA-approved) assay or kit) that is positive for dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or any of them. A subject may have a tumor that has dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or any of them (e.g., if the tumor is identified as such using a regulatory-approved (e.g., FDA-approved) kit or assay). In some embodiments, a subject is suspected of having a CDC7-related cancer. In some embodiments, the subject has a clinical record indicating that it has a tumor with dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or any of them (optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. In some embodiments, the subject has been identified or diagnosed with a cancer (CDC7-related cancer) determined to be associated with dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or any of them, based on histological examination.

[0064] As used herein, the term “child subjects” refers to subjects under 21 years of age at the time of diagnosis or treatment. The term “child” can be further divided into various subgroups, including neonates (birth to 1 month of age), infants (1 month to 2 years of age), children (2 years to 12 years of age), and adolescents (12 years to 21 years of age (up to but not including their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WBSaunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, the pediatric subject is from birth to 28 days old, from 29 days old to under 2 years old, from 2 years old to under 12 years old, or from 12 years old to 21 years old (up to but not including the 22nd birthday). In some embodiments, the target age group for children is from birth to 28 days old, from 29 days old to under 1 year old, from 1 month old to under 4 months old, from 3 months old to under 7 months old, from 6 months old to under 1 year old, from 1 year old to under 2 years old, from 2 years old to under 3 years old, from 2 years old to under 7 years old, from 3 years old to under 5 years old, from 5 years old to under 10 years old, from 6 years old to under 13 years old, from 10 years old to under 15 years old, or from 15 years old to under 22 years old.

[0065] In certain embodiments, compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or pharmaceutically acceptable salts thereof are useful for preventing diseases and disorders as defined herein (e.g., autoimmune diseases, inflammatory diseases, and cancer). As used herein, the term “prevent” means preventing the onset, recurrence, or progression of any disease or condition or its symptoms, as described herein.

[0066] As used herein, the term “CDC7-related cancer” refers to cancer associated with, or having with, dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase (also referred herein as the CDC7 kinase protein), or any one of them (e.g., one or more of these) (e.g., any type of dysregulation in the expression, activity, or level of the CDC7 gene, CDC7 kinase, CDC7 kinase domain, or any one of these, as described herein). Non-exclusive examples of CDC7-related cancers are described herein.

[0067] The phrase "dysregulation of expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them" refers to gene mutations (e.g., chromosomal translocations resulting in the expression of a fusion protein including the CDC7 kinase domain and fusion partner; mutations in the CDC7 gene resulting in the expression of a CDC7 protein containing at least one amino acid deletion compared to wild-type CDC7 protein; mutations in the CDC7 gene resulting in the expression of a CDC7 protein having one or more point mutations compared to wild-type CDC7 protein; mutations in the CDC7 gene resulting in the expression of a CDC7 protein having at least one inserted amino acid compared to wild-type CDC7 protein; gene duplication resulting in increased levels of CDC7 protein in cells; or mutations in regulatory sequences (e.g., promoters and / or enhancers) resulting in increased levels of CDC7 protein in cells; alternative splicing versions of CDC7 mRNA resulting in a CDC7 protein having at least one amino acid deletion in the CDC7 protein compared to wild-type CDC7 protein; or increased expression (e.g., increased levels) of wild-type CDC7 kinase in mammalian cells due to abnormal cellular signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells)). As another example, dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or either of them may be a mutation in the CDC7 gene encoding a CDC7 protein that is constitutively active or has increased activity compared to the protein encoded by the CDC7 gene without the mutation. As yet another example, an increase in the copy number of the CDC7 gene may result in overexpression of the CDC7 kinase. For example, dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or either of them may be the result of a gene or chromosomal translocation that leads to the expression of a fusion protein containing a first portion of CDC7 containing the functional kinase domain and a second portion of a partner protein (i.e., not CDC7).In some cases, dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 protein, or any of them may result from a gene translocation between one CDC7 gene and another non-CDC7 gene.

[0068] The term "wild-type" refers to nucleic acids (e.g., CDC7 gene or CDC7 mRNA) or proteins (e.g., CDC7 protein) found in subjects that do not have CDC7-related disease, such as CDC7-related cancer (and optionally, are not at risk of developing CDC7-related disease and / or are not suspected of having CDC7-related disease), or found in cells or tissues from subjects that do not have CDC7-related disease, such as CDC7-related cancer (and optionally, are not at risk of developing CDC7-related disease and / or are not suspected of having CDC7-related disease).

[0069] The term "regulatory agency" refers to a national agency responsible for approving the medical use of drugs. For example, a non-specific example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0070] Provided herein are compounds of formula (I): [ka] The present invention provides a compound of or a pharmaceutically acceptable salt thereof, in which, R 1 It is a 5-10 membered heteroaryl compound optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl compounds. Y is -S- or -S(=O)-, Ring A is a C5-C7 cycloalkyl or a 5-7 membered heterocycline. Each R 2These are independently hydrogen, halogen, hydroxyl, cyano, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and -NR. B R C , C1-C6 alkoxyalkyl, -C(=O)NH-5~10 member heteroaryl, 4~6 member heterocyclyl, 5~10 member heteroaryl, 1~3 independently selected R A Selected from the group consisting of C1-C6 alkyl groups substituted with and optionally hydroxyl-substituted C3-C6 cycloalkyl groups, or Two R's 2 Together with the atoms to which they are attached, they form an oxo group; a C3-C6 cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys; or a 3- to 6-membered heterocycline optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. R 3 This is selected from C0-C6 alkyl groups substituted with hydrogen and optionally with 1 to 4 substituents independently selected from the following: (i) Hydroxyl, (ii) Cyano, (iii) halogen, (iv) C3-C6 cycloalkoxy, (v)C(=O)OR F , (vi) C1-C6 alkoxy, (vii) A 4-10 member heterocyclyloxy compound substituted with 1-3 independently selected halogens, (viii)-NR B R C , (ix) Optionally, hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR B R C, 3-6 membered heterocyclyloxy, and C3-C6 cycloalkyl groups substituted with 1-3 groups independently selected from 3-6 membered heterocyclyl groups optionally substituted with 1-3 C1-C6 alkoxy groups, (x) Optionally, halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NR B R C , C1-C6 alkyl groups substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, and C3-C6 cycloalkoxys, and 3 to 10-membered heterocyclines substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl groups substituted with halogens or hydroxyls, (xi) optionally substituted with cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, optionally substituted with 1-2 substituents independently selected from cyano and hydroxyl, and optionally substituted with 1-3 independently selected R Aで 5-6 member heteroaryls substituted with 1-3 substituents independently selected from substituted 4-10 member heterocyclils, and (xii)-C(=O)-X(where X is -NR) B R C , C1-C6 alkyl, 5-6 member heteroaryl, -NH-5-6 member heteroaryl, -OR E (or a 3-6 member heterocycline optionally substituted with a hydroxyl group), Each R A and R E These are independently halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylamino, 4-6 membered heterocyclyl, or C3-C6 cycloalkyl. Each R B and R CThese are independently substituted with hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(=O)-C1-C6 alkyl, optionally C1-C6 alkyl, cyano, halogen, hydroxyl, or C3-C6 cycloalkyl -(C1-C6 alkylene) p- A C3-C8 cycloalkyl, a 3- to 6-membered heterocyclyl optionally substituted with a C1-C6 alkyl, a -C(=O)O-C1-C6 alkyl, or a benzyl optionally substituted with a C1-C6 alkoxy, or R B and R C Together with the atoms to which they are attached, they form a unified, optionally forming halogens, hydroxyls, cyanos, C1-C6 alkyls, and -NRs. F R G , forming 4-10 membered heterocyclines substituted with 1-3 substituents independently selected from C3-C6 cycloalkoxy, C1-C6 haloalkoxy, and C1-C6 alkoxy, Each p is independently either 0 or 1. m is 0, 1, 2, 3, or 4. R 4 is hydrogen or C1-C6 alkyl, R D This consists of hydrogen, a C1-C6 haloalkyl group, and 1 to 3 independently selected R groups. E A C1-C6 alkyl group substituted with, and 1 to 3 independently selected R groups as optional. E A C3-C6 cycloalkyl group substituted with R, and 1 to 3 independently selected R groups as optional. E A 4-10 member heterocyclyl, C6-C10 aryl, or 1-3 independently selected R substituted with E It is a 5-10 member heteroaryl substituted with, Each R F and R G These are independently hydrogen or a C1-C6 alkyl group.

[0071] In some embodiments, Y is -S-. In some embodiments, Y is -S(=O)-.

[0072] In some embodiments, ring A is a 5- to 7-membered heterocycline. In some embodiments, ring A is a 6- to 7-membered monocyclic heterocycline. In some embodiments, ring A contains one oxygen atom. In some embodiments, ring A contains one nitrogen atom. In some embodiments, ring A contains one oxygen atom and one nitrogen atom. In some embodiments, ring A is a 6-membered heterocycline containing one oxygen atom bonded to a 5-membered ring containing Y. In some embodiments, ring A is a 7-membered heterocycline containing one oxygen atom bonded to a 5-membered ring containing Y. In some embodiments, ring A is tetrahydrofuran, tetrahydropyran, or oxepan.

[0073] In some embodiments, ring A is a C5-C7 cycloalkyl. In some embodiments, ring A is a monocyclic C5-C7 cycloalkyl such as cyclopentyl, cyclohexyl, or cycloheptyl.

[0074] In some embodiments, R 1 R is a 5-10 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxyl, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl. In some embodiments, R 1 This is a 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxyl, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl.

[0075] In some embodiments, R 1 R is a 5-6 member heteroaryl molecule optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl. In some embodiments, R 1This is a 5-6 member heteroaryl substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl.

[0076] In some embodiments, R 1 Each of these is a pyrazole, pyridine, or pyrimidine, each substituted with 1 to 3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl. In some embodiments, R 1 This is a pyrazole, pyridine, or pyrimidine substituted with one substituent selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl.

[0077] In some embodiments, R 1 Each of these is a pyrazole, pyridine, or pyrimidine substituted with a C1-C6 alkyl such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 1 R is a methyl-substituted pyrazole. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 Each is a pyridine or pyrimidine, each substituted with methyl. In some embodiments, R 1 Each of them is substituted with methyl, [ka] That is the case.

[0078] In some embodiments, R 1R is an unsubstituted 5-10 member heteroaryl. In some embodiments, R 1 R is an unsubstituted 5-6 member heteroaryl. In some embodiments, R 1 is a pyrazole. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is pyridine. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is a pyrimidine. In some embodiments, R 1 teeth, [ka] That is the case.

[0079] Several embodiments, each R 2 These are independently halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and -NR. B R C , C1-C6 alkoxyalkyl, -C(=O)NH-5~10 member heteroaryl, 4~6 member heterocyclyl, 5~10 member heteroaryl, 1~3 independently selected R A The group is selected from C1-C6 alkyl groups substituted with hydroxyl, and C3-C6 cycloalkyl groups optionally substituted with hydroxyl.

[0080] Several embodiments, each R 2 Independently, -C(=O)NH-5~10 member heteroaryl 2 Independently, -C(=O)NH-5 member heteroaryl 2Independently, -C(=O)NH-6 member heteroaryl is a six-membered heteroaryl. In some embodiments, each R 2 Independently, -C(=O)NH-10 member heteroaryl. In some embodiments, the heteroaryl group is selected from furan, thiophene, pyrrole, oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, imidazole, isoxazole, isothiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0081] Several embodiments, each R 2 These are independently 4- to 6-membered heterocyclines. In some embodiments, the 4- to 6-membered heterocyclines are linked to formula (I) via carbon atoms. In some embodiments, the 4- to 6-membered heterocyclines are linked to formula (I) via nitrogen atoms. In some embodiments, each R 2 The following are independently selected from morpholine, piperidine, piperazine, pyrrolidine, pyrrolidone, 4-piperidone, azetidine, and oxetane.

[0082] Several embodiments, each R 2 These are independently 5- to 10-membered heteroaryls. In some embodiments, each R 2 Each R is independently a 5-membered heteroaryl. In some embodiments, each R 2 Each R is independently a 6-membered heteroaryl. In some embodiments, each R 2 The following are selected from furan, thiophene, pyrrole, oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, imidazole, isoxazole, isothiazole, thiadiazole, pyridine, pyridazine, pyrimidine, and pyrazine.

[0083] Several embodiments, each R 2R is independently and optionally substituted with a hydroxyl group, which is a C3-C6 cycloalkyl group. In some embodiments, each R 2 These are independently hydroxyl-substituted C3-C6 cycloalkyl groups. In some embodiments, each R 2 These are independently C3-C6 cycloalkyl groups.

[0084] Several embodiments, each R 2 These are 1 to 3 independently selected R components, which are chosen independently and arbitrarily. A It is a C1-C6 alkyl substituted with R. In some embodiments, each R 2 These are independently selected R1, with 1 to 3 independently selected R12. A It is a C1-C6 alkyl substituted with R. In some embodiments, each R 2 These are independently, one R Aで It is a substituted C1-C6 alkyl group. In some embodiments, each R 2 R is independently selected from two or three independently selected R A It is a C1-C6 alkyl group substituted with [a specific compound].

[0085] Several embodiments, each R A R is independently selected from the group consisting of halogens, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkylamino, 4-6 membered heterocyclyl, and C3-C6 cycloalkyl. In some embodiments, each R A R is independently selected from the group consisting of halogens, cyano, hydroxyl, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, C1-C3 alkylamino, 4-6 member heterocyclyl, and C3-C6 cycloalkyl. In some embodiments, each R A This is independently selected from the group consisting of fluoromethyl, methoxy, trifluoromethyl, hydroxymethyl, or hydroxyethyl.

[0086] Several embodiments, each R2 R is independently an unsubstituted C1-C6 alkyl such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, each R 2 It is methyl.

[0087] Several embodiments, each R 2 These are independently halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and -NR. B R C Selected from the group consisting of , and C1-C6 alkoxyalkyl groups.

[0088] Several embodiments, each R 2 R is independently a halogen. In some embodiments, 2 It is fluoro.

[0089] Several embodiments, each R 2 These are independently selected from hydroxy, cyano, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl.

[0090] Several embodiments, each R 2 This is independently of -NR as defined herein. B R C That is the case.

[0091] In some embodiments, two R 2 Together with the atoms to which they are attached, they form an oxo group; a C3-C6 cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys; or a 3- to 6-membered heterocycline group optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys.

[0092] In some embodiments, two R 2These atoms, together with the atoms to which they are attached, form an oxo group.

[0093] In some embodiments, two R 2 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group which is optionally substituted with 1 to 3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. In some embodiments, two R 2 These atoms, together with the atoms to which they are attached, form an unsubstituted C3-C6 cycloalkyl group.

[0094] In some embodiments, two R 2 Together with the atoms to which they are attached, they form a 3-6 membered heterocycline which is optionally substituted with 1-3 substituents independently selected from halogens, cyanos, C1-C6 alkyls, and C1-C6 alkoxys. In some embodiments, two R 2 These, together with the atoms to which they are attached, form an unsubstituted 3- to 6-membered heterocycline.

[0095] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0096] In some embodiments, m is 0.

[0097] In some embodiments, m is 1, and R 2 is an unsubstituted C1-C6 alkyl such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, m is 1 and R 2 It is methyl.

[0098] In some embodiments, m is 1, and R 2 is a halogen. In some embodiments, m is 1 and R 2 It is fluoro.

[0099] In some embodiments, m is 2, and each R 2 These are independently unsubstituted C1-C6 alkyl groups. In some embodiments, m is 2, and each R 2 It is methyl.

[0100] In some embodiments, m is 2, and each R 2 These are, independently, halogens. In some embodiments, m is 2, and each R 2 It is fluoro.

[0101] In some embodiments, m is 2 and R 2 The base is geminal. In some embodiments, R 2 The group is geminal dimethyl. In some embodiments, R 2 The base is a geminal difluoro.

[0102] In some embodiments, R 3 This is selected from C0-C6 alkyl groups substituted with hydrogen and optionally with 1 to 4 substituents independently selected from (i) to (xii) below: (i) Hydroxyl, (ii) Cyano, (iii) halogen, (iv) C3-C6 cycloalkoxy, (v)C(=O)OR F , (vi) C1-C6 alkoxy, (vii) A 4-10 member heterocyclyloxy compound substituted with 1-3 independently selected halogens, (viii)-NR B R C , (ix) Optionally, hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR B R C, 3-6 membered heterocyclyloxy, and C3-C6 cycloalkyl groups substituted with 1-3 groups independently selected from 3-6 membered heterocyclyl groups optionally substituted with 1-3 C1-C6 alkoxy groups, (x) Optionally, halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NR B R C , C1-C6 alkyl groups substituted with 1 to 3 substituents independently selected from halogens, C1-C6 alkoxys, and C3-C6 cycloalkoxys, and 3 to 10-membered heterocyclines substituted with 1 to 4 substituents independently selected from C3-C6 cycloalkyl groups substituted with halogens or hydroxyls, (xi) optionally substituted with cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, optionally substituted with 1-2 substituents independently selected from cyano and hydroxyl, and optionally substituted with 1-3 independently selected R Aで 5-6 member heteroaryls substituted with 1-3 substituents independently selected from substituted 4-10 member heterocyclils, and (xii)-C(=O)-X(where X is -R) B R C , C1-C6 alkyl, 5-6 member heteroaryl, -NH-5~6 member heteroaryl, -OR E (or a 3-6 member heterocycline optionally substituted with a hydroxyl group),

[0103] In some embodiments, R 3 It is hydrogen.

[0104] In some embodiments, R 3 It is an unsubstituted C1-C6 alkyl group.

[0105] In some embodiments, R 3 is a substituted C0-C6 alkyl. In some embodiments, R 3is a C0-C6 alkyl having one substituent selected from (i) to (xii). In some embodiments, R 3 is a C0-C6 alkyl having two substituents independently selected from (i) to (xii). In some embodiments, R 3 is a C0-C6 alkyl having three substituents independently selected from (i) to (xii). In some embodiments, R 3 This is a C0-C6 alkyl having four substituents independently selected from (i) to (xii).

[0106] In some embodiments, R 3 The following are optionally hydroxyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkoxy, and optionally hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR B R C The C0-C6 alkyl group is substituted with 1 to 3 groups independently selected from 3-6 member heterocyclyloxys and C3-C6 cycloalkyls independently selected from 3-6 member heterocyclyls optionally substituted with 1 to 3 C1-C6 alkoxys, and C0-C6 alkyl groups. In some embodiments, R 3 The following are optionally hydroxyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkoxy, and optionally hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR B R C The C0-C6 alkyl group is substituted with 1 to 3 substituents independently selected from 3-6 member heterocyclyloxy groups and C3-C6 cycloalkoxy groups substituted with 3-6 member heterocyclyl groups optionally substituted with 1 to 3 C1-C6 alkoxy groups. In some embodiments, R 3 This is a C0-C6 alkyl group substituted with one or two substituents independently selected optionally from hydroxyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkoxy, and optionally hydroxyl-substituted C3-C6 cycloalkyl groups.

[0107] In some embodiments, R 3 R is a C0-C6 alkyl group substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and optionally hydroxyl-substituted C3-C6 cycloalkyl groups. In some embodiments, R 3 R is a C0-C6 alkyl group substituted with one or two substituents independently selected optionally from hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and optionally hydroxyl-substituted C3-C6 cycloalkyl groups. In some embodiments, R 3 This is a C0-C6 alkyl group that is optionally substituted with one or two substituents independently selected from hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and hydroxyl-substituted C3-C6 cycloalkyl groups.

[0108] In some embodiments, R 3 R is an unsubstituted C1-C6 alkyl such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 It is methyl.

[0109] In some embodiments, R 3 is a hydroxyl-substituted C0-C6 alkyl group. In some embodiments, R 3 R is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, 1-hydroxypropyl, 2-hydroxypropyl, or 3-hydroxypropyl. In some embodiments, R 3 teeth, [ka] That is the case.

[0110] In some embodiments, R 3is a C0-C6 alkyl group substituted with a C3-C6 cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R 3 is a C0-C1 alkyl group substituted with a hydroxyl-substituted C3-C6 cycloalkyl group. In some embodiments, R 3 teeth, [ka] That is the case.

[0111] In some embodiments, R 3 R is a C1-C6 alkyl substituted with hydroxyl and C3-C6 cycloalkyl. In some embodiments, R 3 Each of these is methyl or ethyl, substituted with a hydroxyl and one C3-C6 cycloalkyl group. In some embodiments, R 3 teeth, [ka] That is the case.

[0112] In some embodiments, R 3 is a C1-C6 alkyl substituted with a C3-C6 cycloalkoxy. In some embodiments, R 3 These are methyl or ethyl, each substituted with a C3-C6 cycloalkoxy. In some embodiments, R 3 teeth, [ka] That is the case.

[0113] In some embodiments, R 3 is a C1-C6 alkyl group substituted with one or two C1-C6 alkoxy groups. In some embodiments, R 3 Each of these is ethyl or n-propyl, substituted with one or two C1-C2 alkoxys. In some embodiments, R 3 teeth, [ka] That is the case.

[0114] In some embodiments, R 3 C(=O)-OX 1 It is a C1-C6 alkyl substituted with X. In some embodiments, X 1 is a C1-C6 alkyl such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 These are methyl or ethyl, respectively, substituted with C(=O)-OMe or C(=O)-OEt. In some embodiments, R 3 teeth, [ka] That is the case.

[0115] In some embodiments, R 3 R is a C1-C6 alkyl group substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkoxy, and 3- to 10-membered heterocyclils, where the 3- to 10-membered heterocyclil is optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, hydroxyl, and halogen. In some embodiments, R 3 R is a C1-C6 alkyl group substituted with 1-3 groups independently selected from a 3-10 membered heterocyclil, where the 3-10 membered heterocyclil is optionally substituted with 1-3 substituents selected from C1-C6 alkyl groups, hydroxyls, and halogens. In some embodiments, R 3 is a C1-C6 alkyl substituted with a 3-10 member heterocycline. In some embodiments, R 3 is a C1-C6 alkyl substituted with a hydroxyl-substituted 3- to 10-membered heterocycline. In some embodiments, R 3 is a C1-C6 alkyl substituted with a halogen-substituted 3- to 10-membered heterocycline. In some embodiments, R 3The C1-C6 alkyl group is substituted with a methyl-substituted 3- to 10-membered heterocycline. In some embodiments, the C1-C6 alkyl group is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, the 3- to 10-membered heterocycline is a 4- to 6-membered heterocycline. In some embodiments, the heterocycline group contains one or two nitrogen atoms. In some embodiments, the heterocycline group has a carbon atom via R 3 It is connected to the alkyl group. In some embodiments, the heterocyclyl group is connected to the nitrogen atom via R 3 It is connected to the alkyl group.

[0116] In some embodiments, R 3 Each of these is a C1-C6 alkyl substituted with azetidine, pyrrolidine, pyrrolidinone, or piperidine, each optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, hydroxyl, and halogen. In some embodiments, R 3 Each of these is a C1-C6 alkyl substituted with azetidine, pyrrolidine, pyrrolidine, or piperidine, each substituted with two substituents independently selected from C1-C6 alkyl, hydroxyl, or halogen. In some embodiments, R 3 Each of these is a C1-C6 alkyl substituted with a C1-C6 alkyl, hydroxyl, or halogen, or substituted with azetidine, pyrrolidine, pyrrolidinone, or piperidine. In some embodiments, R 3 This is a C1-C6 alkyl group substituted with azetidine, pyrrolidine, pyrrolidinone, or piperidine.

[0117] In some embodiments, R 3 is a C1-C3 alkyl substituted with azetidine. In some embodiments, R 3 is a C1-C3 alkyl substituted with methyl, fluoro, or hydroxyl-substituted azetidine. In some embodiments, R 3is a C1-C3 alkyl group substituted with pyrrolidine. In some embodiments, R 3 is a C1-C3 alkyl group substituted with a hydroxyl, methyl, or pyrrolidine substituted with one or two fluoropolymers. In some embodiments, R 3 is a C1-C3 alkyl group substituted with pyrrolidinone. In some embodiments, R 3 is a C1-C3 alkyl group substituted with methyl or pyrrolidinone substituted with one or two fluoro groups. In some embodiments, R 3 This is a C1-C3 alkyl group substituted with piperidine.

[0118] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] That is the case.

[0119] In some embodiments, R 3 -NR B R Cで It is a substituted C0-C6 alkyl group. In some embodiments, R B and R CEach of these is independently a benzyl substituted with hydrogen, a C1-C6 alkyl, a C3-C6 cycloalkyl, a C(=O)-C1-C6 alkyl, a C(=O)-C1-C6 alkyl, or a C1-C6 alkoxy. In some embodiments, R B and R C These are, independently, hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C(=O)-C1-C6 alkyl.

[0120] In some embodiments, R B and R C Together with the atoms to which they are attached, they form a unified, optionally forming halogens, hydroxyls, cyanos, C1-C6 alkyls, and -NRs. F R G This forms 4-10 membered heterocyclils substituted with 1-3 substituents independently selected from C3-C6 cycloalkoxys, C1-C6 haloalkoxys, and C1-C6 alkoxys. In some embodiments, the 4-10 membered heterocyclils are bicyclic condensed heterocyclils such as [5,5], [5,6], or [6,6] condensed ring systems.

[0121] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 is a C0-C6 alkyl group substituted with NH2. In some embodiments, R 3 This is NH2 (i.e., the C0-C6 alkyl group is a C0 alkyl group).

[0122] Several embodiments, each R F and R G R is independently hydrogen or a C1-C6 alkyl group. In some embodiments, each R F and R G They are the same. In some embodiments, each R F and R G They are different. In some embodiments, RF and R G One of them is hydrogen, and R F and R G The other is a C1-C6 alkyl group.

[0123] In some embodiments, R 3 is -C(=O)-X 2 And in the formula, X 2 The C1-C6 alkyl or 3-6 membered heterocycline is optionally substituted with a hydroxyl group. In some embodiments, the 3-6 membered heterocycline is azetidine, morpholine, or pyrrolidine.

[0124] In some embodiments, R 3 R is a C1-C6 alkyl group substituted with 1 to 3 substituents independently selected from cyano, hydroxyl, halogen, and C1-C6 alkoxy groups. In some embodiments, R 3 R is a C1-C2 alkyl group substituted with one or two substituents independently selected from cyano, hydroxyl, halogen, and C1-C2 alkoxy groups. In some embodiments, R 3 is a cyano-substituted C1-C6 alkyl. In some embodiments, R 3 teeth, [ka] That is the case.

[0125] In some embodiments, R 3 R is a C1-C6 alkyl group substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkoxy, and 5-6 membered heteroaryl groups. In some embodiments, R 3The 5-C3 alkyl group is substituted with one or two substituents independently selected from hydroxyl, C1-C3 alkoxy, and 5-C3 heteroaryl groups. In some embodiments, the 5-C3 heteroaryl group is optionally substituted with one to three substituents independently selected from cyano, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy groups. In some embodiments, the 5-C3 heteroaryl group is substituted with one to three substituents independently selected from cyano, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy groups. In some embodiments, the 5-C3 heteroaryl group is substituted with one or two substituents independently selected from cyano, hydroxyl, C1-C3 alkyl, and C1-C3 alkoxy groups. In some embodiments, the 5-C3 heteroaryl group is an imidazole, pyrazole, or triazole.

[0126] In some embodiments, a 5-6 member heteroaryl is a cyano-substituted pyrazole. In some embodiments, R 3 teeth, [ka] That is the case.

[0127] In some embodiments, a 5-6 membered heteroaryl is a pyrazole. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] That is the case.

[0128] In some embodiments, the 5-6 member heteroaryl is an imidazole. In some embodiments, R 3 teeth, [ka] That is the case.

[0129] In some embodiments, a 5-6 member heteroaryl is a triazole. In some embodiments, R 3 teeth, [ka] That is the case.

[0130] In some embodiments, R 3 is a C1-C6 alkyl substituted with an unsubstituted 5-6 member heteroaryl. In some embodiments, the 5-6 member heteroaryl is an imidazole. In some embodiments, the 5-6 member heteroaryl is a triazole. In some embodiments, the 5-6 member heteroaryl is [ka] That is the case.

[0131] In some embodiments, each p is 0. In some embodiments, each p is 1. In some embodiments, p appears twice, with one p being 1 and the other p being 0.

[0132] In some embodiments, R 4 is a C1-C6 alkyl such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 It is hydrogen.

[0133] In some embodiments, the compound of formula (I) is the compound of formula (Ia): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 1 This is a 5-membered or 6-membered heteroaryl group optionally substituted with a C1-C6 alkyl group. R 2 m is independently selected from halogens and C1-C6 alkyl groups, and m is 1 or 2.

[0134] In some embodiments, the compound of formula (I) is the compound of formula (Ib): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 1 This is a 5-membered or 6-membered heteroaryl group optionally substituted with a C1-C6 alkyl group. R 2 m is independently selected from halogens and C1-C6 alkyl groups, and m is 1 or 2.

[0135] In some embodiments, m is 2 and R 2 is a geminal difluoro. In some embodiments, m is 2 and R 2 is geminal dimethyl. In some embodiments, m is 1 and R 2 is fluoro. In some embodiments, m is 1 and R 2 It is methyl.

[0136] In some embodiments, the compound of formula (I) is the compound of formula (Ic): [ka] Or any of the above pharmaceutically acceptable salts.

[0137] In some embodiments, R 1 Each of these is a pyrazole, pyridine, or pyrimidine substituted with a C1-C6 alkyl such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 1 R is a methyl-substituted pyrazole. In some embodiments, R 1R is a pyridine substituted with methyl. In some embodiments, R 1 It is a pyrimidine substituted with methyl groups.

[0138] In some embodiments, R 1 is a pyrazole, pyridine, or pyrimidine. In some embodiments, R 1 teeth, [ka] That is the case.

[0139] In some embodiments, R 3 R is a C1-C6 alkyl group substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and optionally hydroxyl-substituted C3-C6 cycloalkyl groups. In some embodiments, R 3 is a C1-C6 alkyl group substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, and optionally hydroxyl-substituted C3-C6 cycloalkyl groups. In some embodiments, R 3 These are hydroxyl-substituted C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, or optionally hydroxyl-substituted C3-C6 cycloalkyl.

[0140] In some embodiments, R 3 R is an unsubstituted C1-C6 alkyl group. In some embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 It is methyl.

[0141] In some embodiments, R 3 is a hydroxyl-substituted C1-C6 alkyl group. In some embodiments, R 3 teeth, [ka] That is the case.

[0142] In some embodiments, R 3 is a C0-C6 alkyl group substituted with a C3-C6 cycloalkyl group optionally substituted with a hydroxyl group. In some embodiments, R 3 is a C1-C6 alkyl group substituted with a hydroxyl-substituted C3-C6 cycloalkyl group. In some embodiments, R 3 R is a methyl molecule substituted with a hydroxyl-substituted C3-C6 cycloalkyl group. In some embodiments, R 3 teeth, [ka] (That is, when the C0-C6 alkyl group is a C0 alkyl group.)

[0143] In some embodiments, R 3 is a C1-C6 alkyl group substituted with one hydroxyl group and one C3-C6 cycloalkyl group. In some embodiments, R 3 Each is methyl or ethyl, substituted with one hydroxyl and one C3-C6 cycloalkyl group. In some embodiments, R 3 Each is methyl or ethyl, substituted with one hydroxyl and cyclopropyl or cyclobutyl. In some embodiments, R 3 teeth, [ka] That is the case.

[0144] In some embodiments, R 3 is a C1-C6 alkyl substituted with a C3-C6 cycloalkoxy. In some embodiments, R 3 teeth, [ka] That is the case.

[0145] In some embodiments, R 3 is a C1-C6 alkyl group substituted with one or two C1-C6 alkoxy groups. In some embodiments, R 3 Each of these is methyl, ethyl, or n-propyl, substituted with one or two C1-C6 alkoxys. In some embodiments, R 3 Each of these is methyl, ethyl, or n-propyl, substituted with one or two methoxy groups. In some embodiments, R 3 teeth, [ka] That is the case.

[0146] In some embodiments, R 3 C(=O)-OX 1 It is a C1-C6 alkyl substituted with X. In some embodiments, X 1 is a C1-C6 alkyl group. In some embodiments, R 3 teeth, [ka] That is the case.

[0147] In some embodiments, R 3 R is a C1-C6 alkyl group substituted with 1-3 3-10 member heterocyclils, where the 3-10 member heterocyclils are optionally substituted with 1-3 substituents selected from C1-C6 alkyl groups, hydroxyls, and halogens. In some embodiments, R 3 is a C1-C6 alkyl substituted with a 3-10 member heterocycline. In some embodiments, R 3 is a C1-C6 alkyl substituted with a hydroxyl-substituted 3- to 10-membered heterocycline. In some embodiments, R 3is a C1-C6 alkyl substituted with a halogen-substituted 3- to 10-membered heterocycline. In some embodiments, R 3 These are C1-C6 alkyl groups substituted with methyl-substituted 3- to 10-membered heterocyclines.

[0148] In some embodiments, R 3 Each of these is a C1-C6 alkyl group that is optionally substituted with a C1-C6 alkyl group, a hydroxyl group, or a halogen group, or substituted with an azetidine, pyrrolidine, or piperidine group.

[0149] In some embodiments, R 3 is a C1-C6 alkyl substituted with azetidine substituted with 1 to 3 substituents independently selected from C1-C6 alkyl, hydroxyl, and halogen. In some embodiments, R 3 is a C1-C6 alkyl substituted with an unsubstituted azetidine. In some embodiments, R 3 teeth, [ka] That is the case.

[0150] In some embodiments, R 3 is a C1-C6 alkyl substituted with an unsubstituted piperidine. In some embodiments, R 3 teeth, [ka] That is the case.

[0151] In some embodiments, R 3 R is a C1-C6 alkyl substituted with pyrrolidine, which is substituted with 1 to 3 substituents independently selected from hydroxyl and halogen. In some embodiments, R 3 is a C1-C6 alkyl group substituted with an unsubstituted pyrrolidine. In some embodiments, R 3 teeth, [ka] That is the case.

[0152] In some embodiments, R 3 -NR B R C It is a C0-C6 alkyl substituted with R. In some embodiments, B and R C These are, independently, hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C(=O)-C1-C6 alkyl. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 is a C0-C6 alkyl group substituted with NH2. In some embodiments, R 3 It is NH2.

[0153] In some embodiments, R 3 is a cyano-substituted C1-C6 alkyl. In some embodiments, R 3 teeth, [ka] That is the case.

[0154] In some embodiments, R 3 This is a C1-C6 alkyl group substituted with 1 to 3 substituents independently selected from C1-C6 alkoxys and 5-6 membered heteroaryls.

[0155] In some embodiments, the 5-6 membered heteroaryl is optionally substituted with 1-3 substituents independently selected from cyano, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy groups.

[0156] In some embodiments, the 5-6 membered heteroaryl is an imidazole, pyrazole, or triazole.

[0157] In some embodiments, the 5-6 membered heteroaryl is an unsubstituted pyrazole. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] That is the case.

[0158] In some embodiments, a 5-6 member heteroaryl is a cyano-substituted pyrazole. In some embodiments, R 3 teeth, [ka] That is the case.

[0159] In some embodiments, the 5-6 member heteroaryl is an unsubstituted imidazole. In some embodiments, R 3 teeth, [ka] That is the case.

[0160] In some embodiments, the 5-6 member heteroaryl is an unsubstituted triazole. In some embodiments, R 3 teeth, [ka] That is the case.

[0161] In some embodiments, the compound is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

[0162] Preparation process For illustrative purposes, general methods and key intermediates for preparing the compounds are shown herein. For a more detailed description of the individual reaction steps, please refer to the Examples section below. Those skilled in the art will understand that the compounds of the present invention can be synthesized using other synthetic routes. Specific starting materials and reagents are depicted in the scheme and discussed below, but other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0163] This specification describes a method for preparing the compound of formula (I), wherein the part of formula (I-iA): [ka] (In the formula, The carbon atom closest to * and the carbon atom closest to ** are ring members of the thiophene in formula (I), (The carbon atom closest to * is bonded to the sulfur ring member of thiophene in formula (I).) A precursor of formula (I) containing is reacted with a compound of formula (int-1) to form a pyridone ring, [ka] (In the formula, R 3’ (This is an unsubstituted C1-C6 alkyl group.) Forming a precursor of formula (I) that includes the part of formula (I-iA'), [ka] The (I-iA') portion of the precursor is reacted with the (I-iA') portion to form the compound of formula (I). [ka] A method is provided which includes forming a part.

[0164] In some embodiments, the reaction of the first precursor of formula (I) including the (I-iA) portion is carried out in the presence of a catalyst. In some embodiments, the catalyst is a rhodium catalyst. In some embodiments, the catalyst is a rhodium(II) catalyst. In some embodiments, the rhodium catalyst is selected from Rh2(OAc)4, Rh2(Oct)4, and (C5(CH3)5RhCl)2Cl2. In some embodiments, the rhodium catalyst is C5(CH3)5RhCl)2Cl2. In some embodiments, the reaction of the first precursor of formula (I) including the (I-iA) portion is carried out in the presence of a base. In some embodiments, the base is an acetate base. In some embodiments, the base is cesium acetate.

[0165] In some embodiments, the (I-iA') moiety is reacted within a precursor containing the (I-iA') moiety to form a compound of formula (I). [ka] Forming a part is R 3’ to R 3 This involves one or more chemical transformations (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 chemical transformations) that result in a methyl group. For example, bromination of a methyl group is followed by substitution of bromine with a nucleophile such as an amine.

[0166] Furthermore, a method for preparing the compound of formula (I), wherein the part of formula (I-iB): [ka] (In the formula, R 3’’ It is an unsubstituted C1-C6 alkyl, The carbon atom closest to * and the carbon atom closest to ** are ring members of the thiophene in formula (I), The carbon atom closest to * is bonded to the sulfur ring member of thiophene in formula (I), The carbon atom closest to **** is a member of the pyridone ring in the compound of formula (I). The precursor of formula (I) containing the (I-iB') portion is reacted in the presence of a base to form a pyridone ring, thereby forming a precursor of formula (I) containing the (I-iB') portion, [ka] The (I-iB') portion of the precursor is reacted with the (I-iB') portion to form the compound of formula (I). [ka] Methods are also provided that include forming parts.

[0167] In some embodiments, the base is a hydride base. In some embodiments, the base is sodium hydride or potassium hydride. In some embodiments, the base is sodium hydride.

[0168] In some embodiments, a precursor of formula (I) containing the (I-iB') portion is reacted to form a compound of formula (I). [ka] Forming the moiety involves removing the 2,4-dimethoxybenzyl group from the ring nitrogen of the moiety of formula (I-iB'), and then R 3’’ to R 3 This includes converting to a compound of formula (I). In some embodiments, a precursor of formula (I) containing the part of formula (I-iB') is reacted to form a compound of formula (I). [ka] Forming a part is R 3’’ to R 3 This includes converting to and then removing the 2,4-dimethoxybenzyl group from the ring nitrogen. In some embodiments, R 3’’ to R 3 Converting to involves one or more chemical transformations (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 chemical transformations). In some embodiments, (R 3’’ to R 3If the conversion involves two or more chemical transformations, the part of formula (I-iB') is reacted to form the compound of formula (I). [ka] Forming a part is (i)R 3’’ to R 3 (ii) performing one or more but not all of the two or more chemical transformations necessary to convert to R 3’’ to R 3 This includes carrying out the remaining chemical transformations necessary to convert it to [the desired state].

[0169] In some embodiments of the method for producing the compound of formula (I), the compound of formula (I) is the compound of formula (I'), [ka] (In the formula, R 1 , R 2 , R 3 , and R 4 This is as defined herein, X 1 (i) any choice of 0, 1, or 2 R 2 (ii) methylene substituted with, or (ii) m optionally R 2 (A C2-C3 alkylene substituted with C2-C3 alkylene, where all carbon atoms in the C2-C3 alkylene are members of ring A.) This method further includes part (I-iiA): [ka] (In the formula, The carbon atom closest to ** is a member of the thiophene ring in the compound of formula (I'), (i) not directly bonded to a sulfur ring member of thiophene, and (ii) also a ring member of the pyridone ring. The carbon atom closest to *** is a member of the thiophene ring in the compound of formula (I'), (i) not directly bonded to a sulfur ring member of thiophene, and (ii) not a ring member of the pyridone ring. The carbon atom closest to **** is a ring member of the pyridone ring in the compound of formula (I'), Q is either H or methyl, X 1 (i) any choice of 0, 1, or 2 R 2 (ii) methylene substituted with, or (ii) m optionally R 2 (A C2-C3 alkylene substituted with C2-C3 alkylene, where all carbon atoms in the C2-C3 alkylene are members of ring A.) A precursor containing is reacted with an acid to form the compound of formula (I'). [ka] This includes forming a part.

[0170] In some embodiments, Q is hydrogen. In some embodiments, Q is methyl.

[0171] In some embodiments, the acid is selected from HCl and HBr. In some embodiments, the acid is aqueous. In some of these embodiments, Q is methyl. In some embodiments, the acid is aqueous HCl. In some embodiments, the acid is aqueous HBr. In some embodiments, the acid is about 48% aqueous HBr.

[0172] In some embodiments, the acid is trimethylsilyl triflate. In some of these embodiments, Q is hydrogen.

[0173] In some embodiments, X 1 is propylene and m is 0. In some embodiments, X 1 is ethylene, m is 1, R 2 It is methyl.

[0174] In some embodiments of the method for producing the compound of formula (I), the compound of formula (I) is the compound of formula (I''), [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , and m are as defined herein.) This method further involves part (I-iiB): [ka] (In the formula, The carbon atom closest to ** is a member of the thiophene ring in the compound of formula (I''), (i) not directly bonded to a sulfur ring member of thiophene, and (ii) also a ring member of the pyridone ring. The carbon atom closest to *** is a member of the thiophene ring in the compound of formula (I'') that is (i) not directly bonded to a sulfur ring member of thiophene, and (ii) not a ring member of the pyridone ring. **** The carbon atom closest to it is a member of the pyridone ring. A precursor containing is reacted in the presence of a ruthenium catalyst to form a precursor containing the (I-iiB') part of formula, [ka] The precursor containing the part of formula (I-iiB') is reacted with the part of formula (I'') [ka] This includes forming a part.

[0175] In some embodiments, the ruthenium catalyst is a ruthenium carbene complex. In some embodiments, the ruthenium carbene complex is selected from benzylidene-bis(tricyclohexylphosphin)-dichlororuthenium and 1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclohexylphosphin)ruthenium, dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphin)ruthenium(II), and [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-isopropoxyphenylmethylene)ruthenium. In some embodiments, the ruthenium carbene complex is [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(o-isopropoxyphenylmethylene)ruthenium.

[0176] In some embodiments, the (I-iiB') portion of a precursor containing the (I-iiB') portion is reacted to produce the (I'') portion. [ka] Forming a moiety involves oxidizing the double bond of ring A, reducing the double bond of ring A, or performing an addition across the double bond of ring A (e.g., addition of HBr or Br2). In some embodiments, the moiety of formula (I-iiB') of a precursor containing the moiety of formula (I'') is reacted to form the moiety of formula (I''). [ka] Forming a part further involves reacting the products of oxidation, reduction, or addition of the double bond of ring A in one or more chemical transformations to form a compound of formula (I'').

[0177] In some embodiments of Embodiment 2, the compound of formula (I) is the compound of formula (I'''), [ka] (In the formula, R 1 , R 3 , and R 4 (As defined herein) This method further involves part (I-iiC): [ka] (In the formula, The carbon atom closest to ** is a member of the thiophene ring in the compound of formula (I'''), (i) not directly bonded to a sulfur ring member of thiophene, and (ii) also a ring member of the pyridone ring. The carbon atom closest to *** is a member of the thiophene ring in the compound of formula (I'''), (i) not directly bonded to a sulfur ring member of thiophene, and (ii) not a ring member of the pyridone ring. Hal 1 (Selected from chloroform, bromoform, and iodine) A precursor containing is reacted in the presence of a catalyst to form a precursor containing the (I-iiC') part of formula, [ka] This includes reacting a precursor containing the (I-iiC') portion to form a precursor containing the (I-iiC'') portion. [ka]

[0178] In some embodiments, a precursor containing the (I-iiC'') portion is a (I) precursor containing the (I-iB) portion.

[0179] In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is tetrakistriphenylphosphinepalladium(0).

[0180] In some embodiments, the reaction of a precursor containing the (I-iiC) portion is carried out in the presence of a base. In some embodiments, the base is a carbonate group. In some embodiments, the carbonate base is sodium carbonate, potassium carbonate, or cesium carbonate. In some embodiments, the carbonate base is potassium carbonate.

[0181] In some embodiments, Hal is chloroform. In some embodiments, Hal is bromoform. In some embodiments, Hal is iodine.

[0182] In any of the above embodiments of the method for producing compounds of formula (I), (I'), (I''), and (I'''), the method further comprises a portion of formula (I-iiiA): [ka] (In the formula, the carbon atoms adjacent to ***** in part (I-iiiA) are members of the thiophene ring of formula (I), (I'), (I''), or (I'''), which are bonded to a sulfur ring member and not to the carbonyl corresponding to the pyridone ring in formula (I), (I'), (I''), or (I'''').) A precursor containing formula Z 2 -R 1 compounds (In the formula, Z 1 and Z 2 One of them is Hal 2 And Z 1 and Z 2 The other side is M, Hal 2 It is selected from the group consisting of iodine, bromo, chloro, and trifluoromethanesulfonate. M is tributylstannyl, trimethylstannyl, -B(OH)2, [ka] Selected from the group consisting of -MgCl, -MgBr, -MgI, -ZnCl, -ZnBr, and -ZnI, R1 (As defined herein) Reacting with to form compounds of formula (I), (I'), (I''), or (I''') [ka] This includes forming a part.

[0183] In some embodiments, Z 1 Hal 2 And Z 2 In some embodiments, Z 1 M is Z 2 Hal 2 That is the case.

[0184] In some embodiments, a precursor containing the portion of formula (I-iiiA) and formula Z 2 -R 1 The reaction with the compound is carried out in the presence of a catalyst, a base, or a salt, and an optional ligand.

[0185] In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is selected from the group consisting of tetrakis(triphenylphosphine)palladium(O), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride-dichloromethane complex, palladium(II) acetate, and tris(dibenzylideneacetone)dipalladium(O). In some embodiments, the palladium catalyst is (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride-dichloromethane complex. In some embodiments, the palladium catalyst is (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride.

[0186] In some embodiments, the ligand is selected from the group consisting of tricyclohexylphosphine, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tri-t-butylphosphine, triisopropylbiphenyl (t-Bu X-Phos), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine, and rac-2-(di-tert-butylphosphino)-1,1'-binaphthyl. For example, the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0187] In some embodiments, the salt or base is selected from the group consisting of copper(I) iodide, cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, and cesium fluoride. For example, the salt or base is sodium carbonate.

[0188] In some embodiments, a precursor containing the portion of formula (I-iiiA) and formula Z 2 -R 1 The reaction with the compound is carried out at a temperature of approximately 40°C to 130°C. For example, a precursor containing the part of formula (I-iiiA) and formula Z 2 -R 1 The reaction with the compound occurs at approximately 50°C to 130°C, 60°C to 130°C, 70°C to 130°C, 80°C to 130°C, 90°C to 130°C, 100°C to 130°C, 110°C to 130°C, 120°C to 130°C, 50°C to 120°C, 50°C to 110°C, and 50°C to 10°C. The tests are conducted at temperatures of 0°C, approximately 50°C to 90°C, approximately 50°C to 80°C, approximately 50°C to 70°C, approximately 50°C to 60°C, approximately 60°C to 120°C, approximately 70°C to 110°C, approximately 80°C to 100°C, approximately 50°C, approximately 60°C, approximately 70°C, approximately 80°C, approximately 90°C, approximately 100°C, approximately 120°C, and approximately 130°C.

[0189] In some embodiments, if any portion of the precursor to be reacted contains one or more NH and / or OH bonds, at least one hydrogen of the one or more NH and / or OH bonds is optionally replaced with a protecting group (e.g., tert-butoxycarbonyl).

[0190] In any embodiment of this specification, unless otherwise specified or unless a particular order of steps is chemically imperative, it should be understood that no particular order of steps is implied or excluded. Furthermore, unless otherwise specified or unless chemically imperative, any precursor may function as an intermediate in the formation of any other precursor.

[0191] In non-limiting exemplary embodiments, a precursor containing the portion of formula (I-iA) is a precursor to a precursor containing the portion of formula (I-iA'), which may be a precursor to a precursor containing the portion of formula (I-iiA), which may be a precursor to a precursor containing the portion of formula (I-iiiA). In another non-limiting example, a precursor containing the portion of formula (I-iiA) is a precursor to a precursor containing the portion of formula (I-iA), which may be a precursor to a precursor containing the portion of formula (I-iA'), which may be a precursor to a precursor containing the portion of formula (I-iiiA). In yet another non-limiting example, a precursor containing the portion of formula (I-iiiA) is a precursor to a precursor containing the portion of formula (I-iA), which may be a precursor to a precursor containing the portion of formula (I-iA'), which may be a precursor to a precursor containing the portion of formula (I-iiA). Further precursor relationships are within the understanding of those skilled in the art.

[0192] Treatment method The present invention provides a method for treating cancer (e.g., CDC7-associated cancer) in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein is a method for treating CDC7-associated cancer in a subject requiring treatment, comprising: a) detecting dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of the thereof in a sample from the subject; and b) administering a therapeutically effective amount of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof. In some embodiments, dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of the thereof comprises one or more fusion proteins.

[0193] In some embodiments of the methods or uses described herein, cancer (e.g., CDC7-associated cancer) is a hematological cancer. In some embodiments of the methods or uses described herein, cancer (e.g., CDC7-associated cancer) is a solid tumor. In some embodiments of the methods or uses described herein, cancer (e.g., CDC7-associated cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer (e.g., sporadic medullary thyroid cancer or hereditary medullary thyroid cancer), differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine neoplasm, lung adenocarcinoma, bronchiolopulmonary carcinoma, multiple endocrine adenoma type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammaryCarcinoma, mammary gland tumors, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuroma of the gastrointestinal mucosa, inflammatory myofibroblastic tumors, or cervical cancer. In some embodiments of the methods or uses described herein, cancer (e.g., CDC7-related cancers) is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adolescent cancer, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, cancer-like tumor, cancer of unknown primary origin, cardiac tumor, cervical cancer, childhood cancer, notochord Tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, site-specific neoplasms, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, ductal carcinoma in situ, embryonic tumors, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal stromal tumor (GIST), Progenitor cell tumors, gestational trophoblastic disease, gliomas, piloriform cell tumors, piloriform cell leukemia, head and neck cancers, thoracic neoplasms, head and neck neoplasms, CNS tumors, primary CNS tumors, cardiac cancer, hepatocellular carcinoma, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancers, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, bone cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma, median duct carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, site-specific neoplasm, neoplasm, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, lung neoplasm, lung cancer, lung neoplasm, respiratory duct neoplasm, bronchogenic carcinoma, bronchial neoplasm, oral cancer, oral cavityCancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasm, pleuroblastoma, pregnancy-related breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colon neoplasm, renal cell carcinoma, CDC7 pineal gland blastoma, rhabdomyosarcoma, salivary gland The following are selected from the group of cancers: liquid gland cancer, sarcoma, Sézary syndrome, skin cancer, Spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell carcinoma of the neck, gastric cancer, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and uCDC7er, cancer of unknown primary origin, uCDC7hral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0194] In some embodiments, hematological cancers (e.g., hematological cancers that are CDC7-associated cancers) include, for example, leukemia, lymphoma (non-Hodgkin lymphoma), Hodgkin's disease (also called Hodgkin lymphoma), and myeloma, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and chronic myelomonocytic leukemia (CMML). The group is selected from the following: chronic neutrophilic leukemia (CNL), acute anaplastic leukemia (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trisystemic myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), and multiple myeloma (MM). Additional examples of hematological malignancies include polycythemia vera (PV), essential thrombocytopenia (ET), and myeloproliferative disorders (MPDs) such as idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological malignancy (e.g., hematological malignancy that is CDC7-associated cancer) is AML or CMML.

[0195] In some embodiments, cancer (e.g., CDC7-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are CDC7-associated cancer) include, for example, thyroid cancer (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal carcinoma, breast cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck tumors, neuroblastoma, and melanoma. See, for example, Nature Reviews Cancer, 2014, 14, 173-186.

[0196] In some embodiments, the cancer is selected from the group consisting of lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglion neuroma of the gastrointestinal mucosa, and cervical cancer.

[0197] In some embodiments, the subject is a human.

[0198] Compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) as well as their pharmaceutically acceptable salts and solvates are also useful for treating CDC7-associated cancers.

[0199] Accordingly, the Specified Publication also provides a method for treating a subject diagnosed or identified as having CDC7-related cancer, for example, any of the exemplary CDC7-related cancers disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof as defined herein. In some embodiments, the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) is selected from Examples 1 to 65.

[0200] Dysregulation of the expression, activity, or level of CDC7 kinase, the CDC7 gene, or any one of them (e.g., one or more) can contribute to tumorigenesis. For example, fusion proteins may have increased kinase activity compared to wild-type CDC7 protein, increased expression (e.g., increased levels) of wild-type CDC7 kinase in mammalian cells may result from abnormal cellular signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to non-cancerous control cells), and CDC7 mRNA splice variants may also lead to CDC7 dysregulation.

[0201] In some embodiments, the compounds provided herein exhibit brain and / or central nervous system (CNS) permeability. Such compounds are capable of crossing the blood-brain barrier and inhibiting CDC7 kinase activity in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in effective amounts. For example, treatment of a subject with cancer (e.g., CDC7-related cancers such as CDC7-related brain or CNS cancer) may include administration of the compound to the subject (e.g., oral administration). In some such embodiments, the compounds provided herein are useful for treating primary brain tumors or metastatic brain tumors. For example, the compound can be used to treat one or more gliomas, such as glioblastoma (also known as glioblastoma multiforme), astrocytoma, oligodendroglioma, ependymoma, and mixed glioma, meningioma, medulloblastoma, ganglioglioma, schwannoma, and craniopharyngioma (see, for example, the tumors listed in Louis, DNet al. Acta Neuropathol 131(6), 803-820 (June 2016)). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the subject has been previously treated with another anticancer agent, for example, another CDC7 inhibitor (e.g., a compound of formula (I) or a compound that is not a multikinase inhibitor). In some embodiments, the brain tumor is a metastatic brain tumor. In some embodiments, the subject has been previously treated with another anticancer agent, for example, another CDC7 inhibitor (e.g., a compound of formula (I) or a compound that is not a multikinase inhibitor).

[0202] In some embodiments of any of the methods or uses described herein, assays used to determine whether a subject has dysregulation of expression, activity, or levels of the CDC7 gene, CDC7 kinase, or any of them, using a sample from the subject, may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is typically carried out using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment. The assay can utilize other detection methods known in the art for detecting dysregulation of expression, activity, or levels of the CDC7 gene, CDC7 kinase, or any of them. In some embodiments, the sample is a biological or biopsy sample from the subject (e.g., a paraffin-embedded biopsy sample). In some embodiments, the subject is a subject suspected of having CDC7-related cancer, a subject with one or more symptoms of CDC7-related cancer, and / or a subject at high risk of developing CDC7-related cancer.

[0203] In some embodiments, dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them can be identified using a liquid biopsy (variably referred to as a fluid biopsy or fluid-phase biopsy). Liquid biopsy methods can be used to detect total tumor volume and / or dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them. Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than conventional methods used to detect total tumor volume and / or dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them at an earlier stage than conventional methods. In some embodiments, biological samples used in liquid biopsies may include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph, cystic fluid, stool, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (using, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of the expression, activity, or levels of the CDC7 gene, CDC7 kinase, or any of them.

[0204] In some embodiments, ctDNA derived from a single gene can be detected using liquid biopsy. In some embodiments, multiple genes (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more, or any number between these) can be detected using liquid biopsy. In some embodiments, ctDNA derived from multiple genes can be detected using any of the various commercially available test panels (e.g., commercially available test panels designed to detect dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them). Liquid biopsy can be used to detect dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them, including, but not limited to, point mutations or single nucleotide variants (SNVs), copy number variants (CNVs), gene fusions (e.g., translocations or rearrangements), insertions, deletions, or any combination thereof. In some embodiments, liquid biopsy can be used to detect germline mutations. In some embodiments, liquid biopsy can be used to detect somatic mutations. In some embodiments, liquid biopsy can be used to detect primary gene mutations (e.g., primary mutations or fusions associated with the early development of a disease, e.g., cancer). In some embodiments, dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them identified using liquid biopsy is also present in cancer cells present in the subject (e.g., in a tumor). In some embodiments, any of the types of dysregulation of the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them described herein can be detected using liquid biopsy. In some embodiments, gene mutations identified via liquid biopsy can be used to identify the subject as a candidate for a specific treatment.For example, the detection of dysregulation in the expression, activity, or level of the CDC7 gene, CDC7 kinase, or any of them in a subject may indicate that the subject would respond to treatment involving the administration of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof.

[0205] Liquid biopsies may be performed multiple times during the diagnostic, monitoring, and / or treatment process to determine one or more clinically relevant parameters, including, but not limited to, disease progression and / or treatment effectiveness. For example, a first liquid biopsy may be performed at a first time point, and a second liquid biopsy may be performed at a second time point during the diagnostic, monitoring, and / or treatment process. In some embodiments, the first time point may be before the subject is diagnosed with the disease (e.g., when the subject is healthy), and the second time point may be after the subject has developed the disease (e.g., the second time point may be used to diagnose the subject with the disease). In some embodiments, the first time point may be before the subject is diagnosed with the disease (e.g., when the subject is healthy), and then the subject is monitored, and the second time point may be after the subject has been monitored. In some embodiments, the first time point may be the time after the subject has been diagnosed with the disease, and thereafter the treatment has been administered to the subject, and the second time point may be the time after the treatment has been administered. In such cases, the second time point may be used to evaluate the effectiveness of the treatment (for example, if the gene mutation detected at the first time point is reduced in abundance or undetectable). In some embodiments, the treatment administered to the subject may include a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the efficacy of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof can be determined by evaluating the allele frequencies of dysregulation of the CDC7 gene in cfDNA obtained from a subject at different time points, e.g., cfDNA obtained from a subject at a first time point and cfDNA obtained from a subject at a second time point, and at least one dose of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof is administered to the subject between the first and second time points. Some embodiments of these methods may further include administering at least one dose of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof to the subject between the first and second time points.For example, the reduction in the allele frequency (AF) of the dysregulated CDC7 gene in cfDNA obtained from the subject at a second time point compared to the allele frequency (AF) of the CDC7 gene in cfDNA obtained from the subject at a first time point (e.g., reduction of 1% to approximately 99%, reduction of 1% to approximately 95%, reduction of 1% to approximately 90%, reduction of 1% to approximately 85%, reduction of 1% to approximately 80%, reduction of 1% to approximately 75%, reduction of 1% to approximately 70%, reduction of 1% to approximately 65%, 1% Reduction of 1% to approximately 60%, reduction of 1% to approximately 55%, reduction of 1% to approximately 50%, reduction of 1% to approximately 45%, reduction of 1% to approximately 40%, reduction of 1% to approximately 35%, reduction of 1% to approximately 30%, reduction of 1% to approximately 25%, reduction of 1% to approximately 20%, reduction of 1% to approximately 15%, reduction of 1% to approximately 10%, reduction of 1% to approximately 5%, reduction of approximately 5% to approximately 99%, reduction of approximately 10% to approximately 99%, reduction of approximately 15% to approximately 99%, approximately 20 Reductions of approximately 99%, 25% to 99%, 30% to 99%, 35% to 99%, 40% to 99%, 45% to 99%, 50% to 99%, 55% to 99%, 60% to 99%, 65% to 99%, 70% to 99%, 75% to 95%, 80% to 99%, 90% to 99%, 95% to 99%, 5% to 10% A reduction of approximately 5% to 25%, 10% to 30%, 20% to 40%, 25% to 50%, 35% to 55%, 40% to 60%, 50% to 75%, 60% to 80%, or 65% to 85% indicates that the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof was effective in the subject. In some embodiments, AF is reduced so that the level falls below the detection limit of the instrument.Alternatively, an increase in the dysregulated allele frequency (AF) of the gene (e.g., the CDC7 gene) in cfDNA obtained from a subject at a second time point, compared to the dysregulated allele frequency (AF) of the CDC7 gene in cfDNA obtained from the subject at a first time point, indicates that the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof was ineffective in the subject. Some embodiments of these methods may further include administering an additional dose of the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof to a subject for whom the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof was determined to be effective. Some embodiments of these methods may further include administering a different treatment (e.g., a treatment that does not involve the administration of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof) to a subject for whom a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof is deemed ineffective.

[0207] In some embodiments, CDC7-associated cancers are high-frequency microsatellite instability (MSI-H) cancers. In other embodiments, CDC7-associated cancers are not high-frequency microsatellite instability (MSI-H) cancers. In some embodiments, the MSI-H status is determined by the detection of a repeating DNA sequence selected from the group consisting of mononucleotide repeat markers, dinucleotide repeat markers, quasi-mononucleotide markers, or any combination thereof.

[0208] In some embodiments, cancer-associated tumors include phenotypes selected from the group consisting of chromosomal instability (CIN), spindle checkpoint assembly abnormalities, mitotic abnormalities, Gl / S checkpoint abnormalities, and combinations thereof. In some embodiments, cancer-associated tumors include mutations in the Wnt signaling pathway. In some embodiments, Wnt signaling pathway mutations are selected from the group consisting of adenomatous polyposis (APC) gene mutations, FAT1 mutations, FAT4 mutations, or any combination thereof.

[0209] In some examples of these methods, the time difference between the first and second time points is approximately 1 day to 1 year, 1 day to 11 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 10 weeks, 1 day to 2 months, 1 day to 6 weeks, 1 day to 1 month, 1 day to 25 days, 1 day to 20 days, 1 day to 15 days, 1 day to 10 days, 1 day to 5 days, 2 days to 1 year, 5 days to 1 year, 10 days to 1 year, 15 days to 1 year, 20 days to 1 year, 25 days to 1 year It could be about 1 year, about 1 month to about 1 year, about 6 weeks to about 1 year, about 2 months to about 1 year, about 3 months to about 1 year, about 4 months to about 1 year, about 5 months to about 1 year, about 6 months to about 1 year, about 7 months to about 1 year, about 8 months to about 1 year, about 9 months to about 1 year, about 10 months to about 1 year, about 11 months to about 1 year, about 1 day to about 7 days, about 1 day to about 14 days, about 5 days to about 10 days, about 5 days to about 20 days, about 10 days to about 20 days, about 15 days to about 1 month, about 15 days to about 2 months, about 1 week to about 1 month, about 2 weeks to about 1 month, about 1 month to about 3 months, about 3 months to about 6 months, about 4 months to about 6 months, about 5 months to about 8 months, or about 7 months to about 9 months. In some embodiments of these methods, subjects may be previously identified as having cancer with a dysregulated CDC7 gene (e.g., any of the examples of dysregulated CDC7 genes described herein). In some embodiments of these methods, subjects may have been previously identified as having any of the types of cancer described herein. In some embodiments of these methods, subjects may have one or more metastases (e.g., one or more brain metastases).

[0210] In some of the embodiments described above, the cfDNA includes ctDNA such as CDC7-related ctDNA. For example, the cfDNA is ctDNA such as CDC7-related ctDNA. In some embodiments, at least a portion of the cfDNA is determined to be CDC7-related ctDNA, and for example, the sequenced and / or quantified amount of the total cfDNA is determined to have CDC7 fusion and / or CDC7 overexpression.

[0211] In the field of medical oncology, it is common practice to treat each target with cancer by using combinations of different forms of treatment. In medical oncology, in addition to the compositions provided herein, other components of such combination therapies or treatments may be, for example, surgery, radiotherapy, and chemotherapeutic agents such as other kinase inhibitors, signaling inhibitors, and / or monoclonal antibodies. For example, surgery may be open surgery or minimally invasive surgery. Compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or pharmaceutically acceptable salts thereof may also be useful as adjuvants in cancer treatment, i.e., they can be used in combination with one or more additional therapies or therapeutic agents, e.g., chemotherapeutic agents that function by the same or different mechanisms of action. In some embodiments, compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or pharmaceutically acceptable salts thereof may be used before the administration of additional therapeutic agents or additional therapies. For example, a patient in need may be administered one or more doses of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof for a period of time, and then undergo at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., tumor volume) before at least partial resection of the tumor. In some embodiments, a patient in need may be administered one or more doses of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof under one or more radiotherapy sessions for a period of time. In some embodiments, treatment with one or more doses of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., tumor volume) before one or more radiotherapy sessions.

[0212] In some embodiments, the subjects have cancer (e.g., locally advanced or metastatic tumors) that is refractory or intolerant to standard therapies (e.g., administration of chemotherapeutic agents) such as a first CDC7 inhibitor or multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine). In some embodiments, the subjects have cancer (e.g., locally advanced or metastatic tumors) that is refractory or intolerant to prior therapies (e.g., administration of chemotherapeutic agents such as a first CDC7 inhibitor or multi-kinase inhibitor, immunotherapy, cell or gene therapy, or radiation (e.g., radioactive iodine)). In some embodiments, the subjects have cancer for which there is no standard therapy (e.g., locally advanced or metastatic tumors). In some embodiments, the subjects are CDC7-kinase inhibitor naive. For example, the subjects are naive to treatment with selective CDC7-kinase inhibitors. In some embodiments, the subjects are not CDC7-kinase inhibitor naive.

[0213] In some embodiments, the subjects have received prior treatment. In some embodiments, subjects with NSCLC (e.g., CDC7-associated NSCLC) have received treatment with platinum-based chemotherapy, PD-1 / PDL-1 immunotherapy, or both, prior to treatment with a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof. In some embodiments, subjects with thyroid cancer (e.g., CDC7-associated thyroid cancer) have received treatment with one or more of sorafenib, lenvatinib, and radioactive iodine prior to treatment with a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof. In some embodiments, subjects with colorectal cancer (e.g., CDC7-associated colorectal cancer) have received treatment with fluoropyrimidine chemotherapy with or without anti-VEGF-targeted therapy or anti-EGFR-targeted therapy prior to treatment with a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof. In some embodiments, subjects with pancreatic cancer (e.g., CDC7-associated pancreatic cancer) have received treatment with one or more of fluoropyrimidine chemotherapy, gemcitabine chemotherapy, and S-1 chemotherapy prior to treatment with a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof. In some embodiments, subjects with breast cancer (e.g., CDC7-associated breast cancer) have received treatment with one or more of the following prior to treatment with a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof: anthracyclines, taxanes, HER2-targeted therapy, and hormone therapy. In some embodiments, subjects with MTC (e.g., CDC7-associated MTC cancer) have received treatment with one or more of the following prior to treatment with a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof: caboxantinib and vandetanib.

[0214] In some embodiments of any of the methods described herein, a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent selected from one or more additional therapeutic or therapeutic agents (e.g., chemotherapeutic agents).

[0215] Non-exclusive examples of additional therapeutic agents include other CDC7-targeted therapies (i.e., primary or secondary CDC7 kinase inhibitors), other kinase inhibitors (receptor tyrosine kinase-targeted therapies (e.g., Trk inhibitors or EGFR inhibitors)), signaling pathway inhibitors, checkpoint inhibitors, apoptotic pathway modulators (e.g., ovataclax), cytotoxic chemotherapy, angiogenesis-targeted therapies, immunotherapy (including immunotherapy), and radiotherapy.

[0216] In some embodiments, the other CDC7-targeted therapeutic agent is a multi-kinase inhibitor exhibiting CDC7 inhibitory activity. In some embodiments, the other CDC7-targeted therapeutic inhibitor is selective for CDC7 kinase. Exemplary CDC7 kinase inhibitors exhibit inhibitory activity (IC) against CDC7 kinase of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 50 nM, less than 25 nM, less than approximately 10 nM, or less than approximately 1 nM, as measured by assays such as those described herein. 50 ) can be shown. In some embodiments, CDC7 kinase inhibitors exhibit inhibitory activity (IC) against CDC7 kinase less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured by assays such as those provided herein. 50 ) can be shown.

[0217] Non-exclusive examples of kinase-targeted therapies (e.g., primary or secondary CDC7 inhibitors) include TAK931, SRA141, and PHA-767491.

[0218] Non-exclusive examples of multikinase inhibitors include alectinib (9-ethyl-6,6-dimethyl-8-[4-(morpholine-4-yl)piperidine-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile), amvatinib (MP470, HPK56) (N-(1,3-benzodioxol-5-ylmethyl)-4-([1]benzoflo[3,2-d]pyrimidine-4-yl)piperazine-1-carbothioamide), apatinib (YN968D1) (N-[4-(1-cyanocyclopentyl)phenyl-2-(4-picolyl)amino-3-nicotinamide methanesulfonate), and cabozantinib (Cometriq XL-184)(N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide), dovitinib (TKI258, GFKI-258, CHIR-258)((3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazine-1-yl)-1,3-dihydrobe [Nzuimidazole-2-ylidene]quinoline-2-one), famitinib (5-[2-(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indole-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-4-one), fedratinib (SAR302503, TG101348) (N- (2-methyl-2-propanyl)-3-{[5-methyl-2-({4-[2-(1-pyrrolidinyl)ethoxy]phenyl}amino)-4-pyrimidinyl]amino}benzenesulfonamide), foCDC7inib (XL880, EXEL-2880, GSK1363089, GSK089) (N1'-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide), fostamantinib (R788) (2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-Dimethyl-4-[(phosphonooxy)methyl]-, sodium salt (1:2)), Iloraceltib (ABT-348) (1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazole-4-yl)thieno[3,2-c]pyridine-3-yl)phenyl)-3-(3-fluorophenyl)urea), Lenvatinib (E7080, Lenvima) (4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline carboxamide), Motesanib (AMG) 706)(N-(3,3-dimethyl-2,3-dihydro-1H-indole-6-yl)-2-[(pyridine-4-ylmethyl)amino]pyridine-3-carboxamide), Nintedanib (3-Z-[1-(4-(N-((4-methyl-piperazine-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methioxycarbonyl-2-indolinone), Ponatinib (AP24534)(3-(2-imidazo[1,2-b]pyridazine-3-ylethinyl)-4-methyl-N -[4-[(4-methylpiperazine-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide), PP242 (torquinib) (2-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl]-1H-indole-5-ol), quizartinib (1-(5-(tert-butyl)isoxazole-3-yl)-3-(4-(7-(2-morpholinoethoxy)benzo[d]imidazo[2,1-b]thiazole-2-yl)phenyl)urea), regorafenib (BAY 73-4506, stivarga) (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate), RXDX-105 (CEP-32496, agerafenib) (1-(3-((6,7-dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropane-2-yl)isoxazole-3-yl)urea), semaxanib (SU5416) ((3Z)-3-[(3,5-dimethyl-1H-pyrrole-2-yl)methylidene]-1,3-dihydro-2H-indole-2-one), citrabatinib (MGCD516, MG516) (N-(3-fluoro-4-{[2-(5-{[(2-methoxyethyl)amino]methyl}-2-pyridinyl)thieno[3,2-b]pyridine-7-yl]oxy}phenyl)-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide), sorafenib (BAY 43-9006)(4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide), vandetanib (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidine-4-yl)methoxy]quinazoline-4-amine), batalanib (PTK787, PTK / ZK, ZK222584)(N-(4-chlorophenyl AD-57(N-[4-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-yl]phenyl]-N'-[3-(trifluoromethyl)phenyl]-urea), AD-80(1-[4-(4-amino-1-propane-2-ylpyrazolo[3,4-d]pyrimidine-3-yl)phenyl]-3-[2-fluoro-5-(trifluoro Methyl(phenyl)urea), AD-81(1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea), ALW-II-41-27(N-(5-((4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl) )Nicotinamide), BPR1K871(1-(3-chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)propoxy)quinazolin-4-yl)amino)ethyl)thiazole-2-yl)urea), CLM3(1-phenethyl-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine), EBI-907(N-(2-chloro-3-(1-cyclopropyl-8-methoxy-3H-pyrazolo[3,4-c]Isoquinoline-7-yl)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide), NVP-AST-487(N-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-N'-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea), NVP-BBT594(BBT594)(5-((6-acetamidopyrimidine-4-yl)oxy)-N-(4-((4-methylpiperazine-1-yl) (Tyl)-3-(trifluoromethyl)phenyl)indoline-1-carboxamide), PD173955(6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidine-7-one), PP2(4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine), PZ-1(N-(5-(tert-butyl)isoxazole-3-yl)-2-(4-(5-(1-methyl-1H-pyrazole (-4-yl)-1H-benzo[d]imidazole-1-yl)phenyl)acetamide), RPI-1(1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene]-H-indole-2-one, (3E)-3-[(4-hydroxyphenyl)methylidene]-5,6-dimethoxy-1H-indole-2-one), SGI-7079(3-[2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-methyl-7H-pyrrolo[2,3-d ]pyrimidine-4-yl]-benzeneacetonitrile), SPP86 (1-isopropyl-3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine), SU4984 (4-[4-[(E)-(2-oxo-1H-indole-3-ylidene)methyl]phenyl]piperazine-1-carbaldehyde), sunitinib (SU11248) (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indole-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide), TG101209 (N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazine-1-yl)phenylamino)pyrimidine-4-ylamino)benzenesulfonamide), Withaferin A ((4β,5β,6β,22R)-4,27-dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-1,26-dione), XL-999 ((Z)-5-((1-ethylpiperidine-4-yl)amino)-3-((3-fluorophenyl)(5-methyl-1H -Imidazole-2-yl)methylene)indoline-2-1), BPR1J373 (5-phenylthiazole-2-ylamine-pyriminide derivative), CG-806 (CG'806), DCC-2157, GTX-186, HG-6-63-01 ((E)-3-(2-(4-chloro-1H-pyrrolo[2,3-b]pyridine-5-yl)vinyl)-N-(4-((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide), SW-01 (cyclobenzaprine hydrochloride), XMD15-44 (N-(4- ((4-ethylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-(pyridine-3-ylethynyl)benzamide (generated from the structure), Y078-DM1 (antibody-drug conjugate composed of CDC7 antibody (Y078) bound to a derivative of the cytotoxic agent mytansin), Y078-DM4 (antibody-drug conjugate composed of CDC7 antibody (Y078) bound to a derivative of the cytotoxic agent mytansin), ITRI-305 (D0N5TB, DIB003599), BLU-667 ((1S,4R)-N-((S)- 1-(6-(4-fluoro-1H-pyrazole-1-yl)pyridine-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazole-3-yl)amino)pyrimidine-2-yl)cyclohexane-1-carboxamide), BLU6864, DS-5010, GSK3179106, GSK3352589, NMS-E668, TAS0286 / HM05, TPX0046, and N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,It contains 6-dihydropyridine-3-yl)-2-fluorophenyl)acetamide.

[0219] Non-exclusive examples of receptor tyrosine kinase (e.g., Trk) targeted therapies include afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, entrectinib, erlotinib, gefitinib, imatinib, lapatinib, restaurtinib, nilotinib, pazopanib, panitumumab, pertuzumab, sunitinib, trastuzumab, 1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidine-3-yl)-3-(4-methyl-3-(2-methylpyrimidine-5-yl)-1-phenyl-1H-pyrazole-5-yl)urea, AG 879, AR-772, AR-786, AR-256, AR-618, AZ-23, AZ623, DS-6051, Go 6976, GNF-5837, GTx-186, GW 441756, LOXO-101, MGCD516, PLX7486, RXDX101, VM-902A, TPX-0005, TSR-011, GNF-4256, N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrole-2-ylmethylene)-1H-indole-6-yl]amino]-4-methylphenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]-urea, AZ623, AZ64, (S)-5-chloro-N2- This includes (1-(5-fluoropyridine-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazole-3-yl)pyrimidine-2,4-diamine, AZD7451, CEP-751, CT327, sunitinib, GNF-8625, and (R)-1-(6-(6-(2-(3-fluorophenyl)pyrrolidine-1-yl)imidazo[1,2-b]pyridazine-3-yl)-[2,4'-b-ipyridine]-2'-yl)piperidine-4-ol.

[0220] Non-exclusive examples of BRAF inhibitors include dabrafenib, vemurafenib (also known as RG7204 or PLX4032), sorafenib tosylate, PLX-4720, GDC-0879, BMS-908662 (Bristol-Meyers Squibb), LGX818 (Novartis), PLX3603 (Hofmann-LaRoche), RAF265 (Novartis), RO5185426 (Hofmann-LaRoche), and GSK2118436 (GlaxoSmithKline). Additional examples of BRAF inhibitors are known in the art.

[0221] In some embodiments, the receptor tyrosine kinase inhibitor is an epidermal growth factor receptor typrosin kinase inhibitor (EGFR). For example, EGFR inhibitors include osimertinib (merelectinib, Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), cetuximab (Erbitux), nesitumumab (Portraza), neratinib (Nerlinx), lapatinib (Tykerb), panitumumab (Vectibix), and vandetanib (Caprelsa).

[0222] In some embodiments, the signaling pathway inhibitors include Ras-Raf-MEK-ERK pathway inhibitors (e.g., binimetinib, selumetinib, encorafenib, sorafenib, trametinib, and vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g., everolimus, rapamycin, perifosin, temsirolimus), and baricitinib. Brigatinib, Capmatinib, Danucertib, Ibrutinib, Milciclib, Quercetin, Regorafenib, Ruxolitinib, Semaxanib, AP32788, BLU285, BLU554, INCB39110, INCB40093, INCB50465, INCB52793, INCB54828, MGCD265, NMS-088, NMS-1286937, PF This includes other kinase inhibitors such as 477736((R)-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazole-4-yl)-6-oxo-1Hpyrrolo[4,3,2-ef][2,3]benzodiazepine-8-yl]-cyclohexaneacetamide), PLX3397, PLX7486, PLX8394, PLX9486, PRN1008, PRN1371, RXDX103, RXDX106, RXDX108, and TG101209(N-tert-butyl-3-(5-methyl-2-(4-(4-methylpiperazine-1-yl)phenylamino)pyrimidine-4-ylamino)benzenesulfonamide).

[0223] Non-exclusive examples of checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pizilizumab, MPDL3208A, MEDI4736, MSB0010718C, BMS-936559, BMS-956559, BMS-935559 (MDX-1105), AMP-224, and pembrolizumab.

[0224] In some embodiments, the cytotoxic chemotherapeutic agent is selected from arsenic trioxide, bleomycin, bendamustine, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

[0225] Non-limited examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.

[0226] In some embodiments, the additional therapy or therapeutic agent may include a histidyl-tRNA synthetase (HRS) polypeptide or an expressible nucleotide encoding an HRS polypeptide.

[0227] The term "immunotherapy" refers to drugs that modulate the immune system. In some embodiments, immunotherapy can increase the expression and / or activity of immune system regulators. In some embodiments, immunotherapy can decrease the expression and / or activity of immune system regulators. In some embodiments, immunotherapy can mobilize and / or enhance the activity of immune cell recruitment.

[0228] In some embodiments, the immunotherapy is cellular immunotherapy (e.g., adoptive T cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is cyplucel-T (APC8015, Provenge®, Plosker (2011) Drugs 71(1):101-108). In some embodiments, the cellular immunotherapy includes cells expressing a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecroucell (Kymriah®).

[0229] In some embodiments, the immunotherapy is antibody therapy (e.g., monoclonal antibodies, conjugated antibodies). In some embodiments, the antibody therapy is bevacizumab (Mvasti®, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera®, Rituxan®), edrecolomab (Panorex), daratumumab (Darzalex®), olaratumumab (Lartruvo®), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), olegovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), tremelimumab (C P-675,206), Ramucirumab (Cyramza®), Ubrituximab (TG-1101), Panitumumab (Vectibix®), Elotuzumab (Empliciti®), Avelumab (Bavencio®), Necitumumab (Portrazza®), Sermutuzumab (UC-961), Ibritumomab These include Zevalin (registered trademark), isatuximab (SAR650984), nimotuzumab, fresolimmab (GC1008), rituximab (INN), mogamulizumab (Poteligeo (registered trademark)), ficratuzumab (AV-299), denosumab (Xgeva (registered trademark)), ganitumab, urerumab, pizilizumab, or amatsuximab.

[0230] In some embodiments, the immunotherapy is an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg®), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), adtrastuzumab emtansine (TDM-1, Kadcyla®), milbetuximab sorabtansine (IMGN853), or anetumablubutansine.

[0231] In some embodiments, the immunotherapy comprises blinatumomab (AMG103, Blincyto®) or midostaurin (Ridapt).

[0232] In some embodiments, the immunotherapy includes a toxin. In some embodiments, the immunotherapy is denileukin difutox (Ontak®).

[0233] In some embodiments, immunotherapy is cytokine therapy. In some embodiments, cytokine therapy is interleukin-2 (IL-2) therapy, interferon-alpha (IFNα) therapy, granulocyte colony-stimulating factor (G-CSF) therapy, interleukin-12 (IL-12) therapy, interleukin-15 (IL-15) therapy, interleukin-7 (IL-7) therapy, or erythropoietin-alpha (EPO) therapy. In some embodiments, IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, IFNα therapy is IntronA® (Roferon-A®). In some embodiments, G-CSF therapy is filgrastim (Neupogen®).

[0234] In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the immunotherapy comprises one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®), or durvalumab (Imfinzi®).

[0235] In some embodiments, the immunotherapy is mRNA-based immunotherapy. In some embodiments, the mRNA-based immunotherapy is CV9104 (see, for example, Rausch et al. (2014) Human Vaccin Immunother 10(11):3146-52 and Kubler et al. (2015) J. Immunother Cancer 3:26).

[0236] In some embodiments, the immunotherapy is Bacillus Calmette-Guérin (BCG) therapy.

[0237] In some embodiments, the immunotherapy is oncolytic virus therapy. In some embodiments, the oncolytic virus therapy is tarimogenra herparepvec (T-VEC, Imlygic®).

[0238] In some embodiments, the immunotherapy is a cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is Gardasil®, Gardasil9®, or Cervarix®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®, Recombivax HB®, or GI-13020 (Tarmogen®). In some embodiments, the cancer vaccine is Twinrix® or Pediarix®. In some embodiments, the cancer vaccine is BiovaxID®, Oncophage®, GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®, Rindopepimut®, CimaVax-EGF, Cipruce-T (APC8024, Neuvenge®), GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlisimut-L (Hepko-V5), DCVAX®, SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac, or viagenpumatucel-L (HS-110).

[0239] In some embodiments, the immunotherapy is a peptide vaccine. In some embodiments, the peptide vaccine is Neripepimut-S (E75) (NeuVax®), IMA901, or SurVaxM (SVN53-67). In some embodiments, the cancer vaccine is an immunogenic, personalized novel antigen vaccine (see, e.g., Ott et al. (2017) Nature 547:217-221, Sahin et al. (2017) Nature 547:222-226). In some embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA-based vaccine is a mammurobin A DNA vaccine (see, e.g., Kim et al. (2016) OncoImmunology 5(2):e1069940).

[0240] In some embodiments, the immunotargeting agent is selected from aldesleukin, interferon alpha-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, and ciplucel-T.

[0241] Non-exclusive examples of radiotherapy include radioactive iodide therapy, external beam radiation, and radium-223 therapy.

[0242] Additional kinase inhibitors include, for example, U.S. Patent Nos. 7,514,446, 7,863,289, 8,026,247, 8,501,756, 8,552,002, 8,815,901, 8,912,204, 9,260,437, 9,273,051, U.S. Publication No. 2015 / 0018336, International Publication No. 2007 / 002325, WO2007 / 002433, WO2008 / 080001, WO2008 / 079906, WO2008 / 079903, WO2008 / 079 909, WO2008 / 080015, WO2009 / 007748, WO2009 / 012283, WO2009 / 143018, WO2009 / 143024, WO2009 / 014637, 2009 / 152083, WO2010 / 111527, WO2012 / 109075, WO2014 / 194127, WO2015 / 112806, WO2007 / 110344, WO2009 / 071480, WO2009 / 118411, WO2010 / 031816, WO2010 / 145998, WO2011 / 092120, W O2012 / 101032, WO2012 / 139930, WO2012 / 143248, WO2012 / 152763, WO2013 / 014039, WO2013 / 102059, WO2013 / 050448, WO2013 / 050446, WO2014 / 01 9908, WO2014 / 072220, WO2014 / 184069, WO2016 / 075224, WO2016 / 081450, WO2016 / 022569, WO2016 / 011141, WO2016 / 011144, WO2016 / 011147, WO20 This includes the documents described in 15 / 191667, WO2012 / 101029, WO2012 / 113774, WO2015 / 191666, WO2015 / 161277, WO2015 / 161274, WO2015 / 108992, WO2015 / 061572, WO2015 / 058129, WO2015 / 057873, WO2015 / 017528, WO / 2015 / 017533, WO2014 / 160521, and WO2014 / 011900, each of which is incorporated herein by reference in its entirety.

[0243] While the genetic basis of tumorigenesis may vary among different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar across all solid tumor types. During the metastasis cascade, cancer cells lose their growth inhibitory response, undergo changes in adhesion, and produce enzymes that can degrade extracellular matrix components. This leads to the detachment of tumor cells from the original tumor, invasion into the circulation through newly formed vascular systems, and migration and spillage of tumor cells to favorable distant sites where they can colonize. Several genes have been identified as metastasis promoters or inhibitors. For example, overexpression of glial cell-derived neurotrophic factor (GDNF) and its CDC7 receptor tyrosine kinase is associated with cancer growth and metastasis. See, for example, Zeng, et al. J. Int. Med. Res. (2008) 36(4): 656-64.

[0244] Accordingly, methods for inhibiting, preventing, supporting the prevention of, or reducing the symptoms of cancer metastasis are also provided herein, comprising administering an effective amount of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject requiring inhibition, prevention, support for prevention, or reduction of the symptoms of cancer metastasis. Such methods may be used in the treatment of one or more cancers described herein. See, for example, U.S. Publication No. 2013 / 0029925; International Publication No. WO2014 / 083567; and U.S. Patent No. 8,568,998. See also Hezam K et al., Rev Neurosci 2018 Jan 26;29:93-98; Gao L, et al., Pancreas 2015 Jan;44:134-143; Ding K et al., J Biol Chem 2014 Jun 6;289:16057-71; and Amit M et al., Oncogene 2017 Jun 8;36:3232-3239. In some embodiments, the cancer is a CDC7-associated cancer. In some embodiments, a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof is used in combination with an additional therapy or another therapeutic agent, which includes chemotherapeutic agents, e.g., kinase inhibitors, e.g., a first or second CDC7 kinase inhibitor. In some embodiments, the additional therapeutic agent is crizotinib. In some embodiments, the additional therapeutic agent is osimertinib. In some embodiments, the subject is administered one or more doses of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (e.g., CDC7-associated lung cancer). In some embodiments, the additional therapeutic agent is a PARP inhibitor (e.g., olaparib). In some embodiments, the additional therapeutic agent is an ATR inhibitor (e.g., ceraracertib). In some embodiments, the additional therapeutic agent is a Wee1 inhibitor (e.g., AZD-1775).In some embodiments, the additional therapeutic agent is an EGFR inhibitor (e.g., lapatinib).

[0245] The term "metastasis" is a technically known term that refers to the formation of an additional tumor (e.g., a solid tumor) in a site distant from the primary tumor in an object, and the additional tumor contains cancer cells that are the same as or similar to those in the primary tumor.

[0246] Furthermore, a method is provided for reducing the risk of metastasis or additional metastasis in subjects having CDC7-related cancer, comprising selecting, identifying, or diagnosing subjects as having CDC7-related cancer, and administering an effective amount of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof to subjects selected, identified, or diagnosed as having CDC7-related cancer. The reduction in the risk of developing metastasis or additional metastasis in subjects with CDC7-associated cancer can be compared to the risk of developing metastasis or additional metastasis in subjects before treatment, or to subjects or populations of subjects with similar or identical CDC7-associated cancer who have not received treatment or have received different treatment. In some embodiments, the additional therapeutic agent is crizotinib. In some embodiments, the additional therapeutic agent is osimertinib. In some embodiments, subjects have been administered one or more doses of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof prior to administration of the pharmaceutical composition. In some embodiments, the cancer is lung cancer (e.g., CDC7-associated lung cancer).

[0247] The phrase "risk of developing metastasis" means the risk that a subject with a primary tumor will develop additional tumors (e.g., solid tumors) at sites distant from the primary tumor over a period of time, and these additional tumors may contain cancer cells identical or similar to those of the primary tumor. Methods for reducing the risk of developing metastasis in subjects with cancer are described herein.

[0248] The phrase "risk of developing additional metastases" means the risk that a subject having a primary tumor and one or more additional tumors at a site distant from the primary tumor (where one or more additional tumors contain the same or similar cancer cells as the primary tumor) will develop one or more further tumors at a site distant from the primary tumor, where the further tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0249] Treatment of cancer patients with multi-kinase inhibitors (MKIs) or target-specific kinase inhibitors (e.g., BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors, RET inhibitors, or RAS inhibitors) may result in dysregulation of the CDC7 gene, CDC7 kinase, or their expression, activity, or levels, and / or resistance to CDC7 inhibitors in the cancer. See, for example, Bhinge et al., Oncotarget 8:27155-27165, 2017; Chang et al., Yonsei Med.J.58:9-18, 2017; and Lopez-Delisle et al., doi:10.1038 / s41388-017-0039-5, Oncogene 2018.

[0250] Treatment of cancer patients with CDC7 inhibitors in combination with multi-kinase inhibitors or target-specific kinase inhibitors (e.g., BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors, RET inhibitors, or RAS inhibitors) may have increased therapeutic efficacy compared to treatment of the same or similar patients with CDC7 inhibitors as monotherapy, or with multi-kinase inhibitors or target-specific kinase inhibitors as monotherapy. For example, see Tang et al., doi:10.1038 / modpathol.2017.109, Mod.Pathol.2017; Andreucci et al., Oncotarget 7:80543-80553, 2017; Nelson-Taylor et al., Mol.Cancer Ther.16:1623-1633, 2017; and Kato et al., Clin.Cancer Res.23:1988-1997, 2017.

[0251] Provided herein is a method for treating a subject having cancer (e.g., any of the cancers described herein) and having previously been administered a multi-kinase inhibitor (MKI) or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, EGFR inhibitor, MEK inhibitor, ALK inhibitor, ROS1 inhibitor, MET inhibitor, aromatase inhibitor, RAF inhibitor, RET inhibitor, or RAS inhibitor) (e.g., as monotherapy), comprising administering to the subject (i) an effective dose of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof, or (ii) an effective amount of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof, and an effective dose of the previously administered MKI inhibitor or the previously administered target-specific kinase inhibitor.

[0252] Provided herein is a method for treating a subject having cancer (e.g., any of the cancers described herein) and who has previously been administered MKI or target-specific kinase inhibitors (e.g., BRAF inhibitors, EGFR inhibitors, MEK inhibitors, ALK inhibitors, ROS1 inhibitors, MET inhibitors, aromatase inhibitors, RAF inhibitors, RET inhibitors, or RAS inhibitors) (e.g., as monotherapy), wherein the subject has cancer cells having dysregulation of the CDC7 gene, CDC7 kinase, or their expression, activity, or levels. The method comprises identifying a target and administering to the identified target an effective dose of (i) a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof, as monotherapy, or (ii) an effective dose of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof, and an effective dose of a previously administered MKI inhibitor or a previously administered target-specific kinase inhibitor.

[0253] Provided herein is a method for treating a subject having cancer (e.g., any of the cancers described herein), comprising administering to the subject an effective dose of MKI or a target-specific kinase inhibitor (e.g., a BRAF inhibitor, EGFR inhibitor, MEK inhibitor, ALK inhibitor, ROS1 inhibitor, MET inhibitor, aromatase inhibitor, RAF inhibitor, RET inhibitor, or RAS inhibitor) (e.g., as monotherapy) for a first period, and thereafter dysregulation of the CDC7 gene, CDC7 kinase, or their expression, activity, or levels. A method comprising: identifying a subject having cancer cells; and administering to the identified subject an effective dose (i) of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof, or (ii) an effective dose of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof, and an effective dose of a previously administered MKI inhibitor or a previously administered target-specific kinase inhibitor.

[0254] Also provided is a method for inhibiting CDC7 kinase activity in mammalian cells, comprising contacting mammalian cells with a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)). In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, and the method comprises administering an effective amount of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof to a subject having mammalian cells having CDC7 kinase activity. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer as described herein. In some embodiments, the mammalian cancer cells are CDC7-associated mammalian cancer cells.

[0255] Also provided are methods for inhibiting CDC7 kinase activity in mammalian cells, comprising contacting mammalian cells with a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)). In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, and the method comprises administering an effective amount of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof to a mammal having mammalian cells having CDC7 kinase activity. In some embodiments, the mammalian cells are mammalian cancer cells. In some embodiments, the mammalian cancer cells are any cancer as described herein. In some embodiments, the mammalian cancer cells are CDC7-associated mammalian cancer cells.

[0256] As used herein, the term “contact” refers to bringing together the indicated portions in an in vitro or in vivo system. For example, “contact” CDC7 kinase with the compound provided herein includes administering the compound provided herein to a subject such as a human having CDC7 kinase activity, as well as introducing the compound provided herein into, for example, mammalian cells or a sample containing a purified preparation containing CDC7 kinase activity.

[0257] Also provided herein are methods for inhibiting the proliferation of mammalian cells in vitro or in vivo, comprising contacting mammalian cells with an effective amount of a compound of formula (I) as defined herein (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0258] A “CDC7 kinase inhibitor” as defined herein includes any compound exhibiting CDC7 inhibitory activity. In some embodiments, the CDC7 kinase inhibitor is selective for CDC7 kinase. Exemplary CDC7 kinase inhibitors exhibit inhibitory activity (IC) against CDC7 kinase at levels less than approximately 1000 nM, less than approximately 500 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 50 nM, less than 25 nM, less than approximately 10 nM, or less than approximately 1 nM, as measured by assays such as those described herein. 50 ) can be shown. In some embodiments, CDC7 kinase inhibitors exhibit inhibitory activity (IC) against CDC7 kinase less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM as measured by assays such as those provided herein. 50 ) can be shown.

[0259] As used herein, “first CDC7 kinase inhibitor” or “first CDC7 inhibitor” is a CDC7 kinase inhibitor as defined herein, but does not contain a compound of formula (I) as defined herein (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof. As used herein, “second CDC7 kinase inhibitor” or “second CDC7 inhibitor” is a CDC7 kinase inhibitor as defined herein, but does not contain a compound of formula (I) as defined herein (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof. When both the first and second CDC7 inhibitors are present in the methods provided herein, the first and second CDC7 kinase inhibitors are different.

[0260] Exemplary first and second CDC7 kinase inhibitors are described herein. In some embodiments, the first or second CDC7 kinase inhibitor may be selected from the group consisting of TAK931, SRA141, and PHA-767491.

[0261] The phrase “effective dose” means that, when administered to a subject in need of such treatment, it is sufficient to (i) treat a CDC7-related disease or disorder (such as CDC7-related cancer), (ii) reduce, improve or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)), or a pharmaceutically acceptable salt thereof that would correspond to such an amount, will vary depending on factors such as the particular compound, the disease and its severity, and the identity of the subject in need of treatment (e.g., body weight), but nevertheless, it can be routinely determined by those skilled in the art.

[0262] When adopted as a pharmaceutical, compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)), including their pharmaceutically acceptable salts, can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical field and can be administered by various routes depending on whether topical or systemic treatment is desired and the area to be treated. Administration may be topical (including transdermal, epidermal, ocular, and mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., intratracheal or intranasal, by inhalation or blowing of powder or aerosol, including by nebulizer), oral, or parenteral. Oral administration may include doses prescribed for once-daily or twice-daily (BID) administration. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intra-abdominal intramuscular or injection or infusion, or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration may take the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, droplets, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and equivalents may be necessary or desirable.

[0263] Also provided herein are pharmaceutical compositions comprising, as an active ingredient, a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients. For example, a pharmaceutical composition prepared using a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions are suitable for topical administration. When preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient, or encapsulated in such a carrier, for example, in the form of a capsule, pouch, paper, or other container. When the excipient acts as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), or ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaging powders. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as tablets or capsules.

[0264] Further provided herein are pharmaceutical compositions containing a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by closely mixing the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier, according to conventional pharmaceutical formulation techniques. The carrier can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral). In some embodiments, the composition is a solid oral composition.

[0265] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in the Handbooks of Pharmaceutical Excipients published by the American Pharmaceutical Association and the British Pharmaceutical Society.

[0266] Methods for formulating pharmaceutical compositions are described in numerous publications, including Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al. and published by Marcel Dekker, Inc.

[0267] When preparing compositions in oral dosage forms, any of the usual pharmaceutical media can be used. Therefore, for liquid oral formulations such as suspensions, elixirs, and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavorings, preservatives, stabilizers, colorants, and equivalents. For solid oral formulations such as powders, capsules, and tablets, suitable carriers and additives include starch, sugars, diluents, granulators, lubricants, binders, disintegrants, and equivalents. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and equivalents. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and equivalents. Solid oral formulations may also be coated with substances such as sugars or enteric-coated to modulate the primary absorption site. For parenteral administration, the carrier is usually composed of sterile water, and other components may be added to increase solubility or shelf life. Injectable suspensions or solutions may also be prepared using aqueous carriers with appropriate additives. The pharmaceutical compositions herein will contain, per dosing unit, e.g., tablet, capsule, powder, injection, teaspoon, and equivalent, the amount of active ingredient necessary to deliver an effective dose as described herein.

[0268] Compositions comprising a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof may be formulated in unit dosage forms, each dose containing about 5 to about 1,000 mg (1 g), more typically about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to a physically distinct unit suitable as a unit dose for human and other subjects, each unit containing a predetermined amount of the active ingredient (i.e., a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof) calculated to produce the desired therapeutic effect in conjunction with a suitable pharmaceutical excipient.

[0269] In some embodiments, the compositions provided herein contain about 5 mg to about 50 mg of the active ingredient. Those skilled in the art will understand that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient.

[0270] In some embodiments, the compositions provided herein contain about 50 mg to about 500 mg of the active ingredient. Those skilled in the art will understand that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient.

[0271] In some embodiments, the compositions provided herein contain about 500 mg to about 1,000 mg of the active ingredient. Those skilled in the art will understand that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0272] The daily dose of a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof can vary over a wide range of 1.0 to 10,000 mg or more per adult per day. For oral administration, the composition is preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250, and 500 milligrams of the active ingredient for symptomatic dose adjustment to the subject being treated. Effective doses of the drug are typically supplied at dose levels of about 0.1 mg / kg body weight to about 1000 mg / kg body weight per day, or any range within that range. Preferably, the range is about 0.5 to about 500 mg / kg body weight per day, or any range within that range. More preferably, it is about 1.0 to about 250 mg / kg body weight per day, or any range within that range. More preferably, it is about 0.1 to about 100 mg / kg body weight per day, or any range within that range. In one example, the range may be about 0.1 to about 50.0 mg / kg body weight per day, or any amount or range within that range. In another example, the range may be about 0.1 to about 15.0 mg / kg body weight per day, or any range within that range. In yet another example, the range may be about 0.5 to about 7.5 mg / kg body weight per day, or any amount or range within that range. A pharmaceutical composition containing a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof may be administered in a dosing regimen of 1 to 4 times per day, or in a once-daily dose.

[0273] Active compounds may be effective across a wide range of doses and are generally administered in pharmaceutically effective amounts. The optimal dose to be administered can be easily determined by those skilled in the art. Therefore, it should be understood that the actual amount of compound administered is usually determined by a physician and will vary according to relevant circumstances, including the method of administration, the actual compound administered, the strength of the formulation, the condition being treated, and the progression of the disease. In addition, factors associated with the specific subject being treated, including the subject's response, age, weight, diet, time of administration, and the severity of the subject's symptoms, may necessitate adjustments to the dosage.

[0274] In some embodiments, the compounds provided herein can be administered in amounts ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compounds provided herein can be administered in amounts ranging from about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, the dosages are approximately 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, or 100 mg / kg. In some embodiments, such administration may be once daily or twice daily (BID).

[0275] In some embodiments, the compounds provided herein may be administered in amounts of about 10 mg twice daily (BID), 20 mg BID, about 40 mg BID, about 60 mg BID, about 80 mg BID, about 120 mg BID, about 160 mg BID, and about 240 mg BID. In some embodiments, each dose is administered at least 6 hours after the previous dose. In some embodiments, each dose is administered at least 12 hours after the previous dose.

[0276] In some embodiments, the compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or their pharmaceutically acceptable salts exhibit pH-dependent solubility at low pH values. Therefore, subjects also being administered proton pump inhibitors (PPIs) and / or antacids may need to adjust the dosage of the compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or their pharmaceutically acceptable salts (e.g., increase the dose of the compounds of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or their pharmaceutically acceptable salts). In some embodiments, the isoform of cytochrome P450 (CYP) that metabolizes a compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or a pharmaceutically acceptable salt thereof is CYP3A4. Therefore, patients receiving drugs that inhibit or induce CYP3A4 may need to adjust the dosage of the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or its pharmaceutically acceptable salt (for example, in the case of a CYP3A4 inducer, increase the dosage of the compound of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or its pharmaceutically acceptable salt, or in the case of a CYP3A4 inhibitor, decrease the dosage of formula (I) (e.g., any one of formulas (Ia), (Ib), (Ic), and (Id)) or its pharmaceutically acceptable salt).

[0277] Those skilled in the art will recognize that both in vivo and in vitro studies using suitable, known, and generally accepted cell and / or animal models predict the ability of a test compound to treat or prevent a given disorder.

[0278] Those skilled in the art will further recognize that human clinical trials, including initial dose-finding and efficacy studies in healthy subjects and / or subjects suffering from a given disorder, can be completed in accordance with methods well known in the clinical and medical fields.

[0279] Provided herein is a pharmaceutical kit useful for the treatment of CDC7-related diseases or disorders, such as cancer, comprising one or more containers containing a pharmaceutical composition comprising an effective amount of the compound provided herein. Such a kit may further include, if desired, one or more of a variety of conventional pharmaceutical kit components, such as containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or labels, indicating the amount of the component to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit. [Examples]

[0280] Materials and methods The compounds provided herein, including the salt thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0281] The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with the starting materials (reactants), intermediates, or products at temperatures ranging from the freezing point to the boiling point of the solvent, for example. A given reaction can be carried out in one solvent or a mixture of one or more solvents. Depending on the specific reaction step, a solvent suitable for that particular reaction step can be selected by those skilled in the art.

[0282] The preparation of compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in Protecting Group Chemistry, 1. stEd.,Oxford University Press,2000,March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,5 th This can be found in Ed., Wiley-Interscience Publication, 2001, and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J. Chem. Educ., 74(11), 1297 (1997).

[0283] The reaction can be monitored according to any preferred method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) The compounds may be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometric methods (e.g., UV-Vis), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Compounds may be purified by those skilled in the art by various methods including high-performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," KFBlom, et al., J. Combi. Chem. 6(6), 874 (2004)), normal-phase silica chromatography, and supercritical fluid chromatography (SFC).

[0284] All solvents and reagents were obtained from commercially available suppliers and used without further purification unless otherwise specified. Anhydrous solvents were purchased and used as supplied. Reactions were monitored by thin-layer chromatography (TLC) and visualized with a UV lamp (254 nm) and KMnO4 staining. NMR spectra were acquired using a Bruker Neo 400M spectrometer operating at 400 MHz. Chemical shifts are reported as parts per million (δ) from tetramethylsilane resonances in the indicated solvent. LC-mass spectra were performed using an Agilent 1260-6125B single quadrupole mass spectrometer with a Welch Biomate column (C18, 2.7 μm, 4.6*50 mm) or a Waters H-Class SQD2 system. Detection was performed by DAD (254 nm, 210 nm, and 280 nm). Chiral HPLC was performed using a Waters acquity UPC2 system with Daicel chiralpak AD-H (5um, 4.6*250mm), Daicel chiralpak OD-H (5um, 4.6*250mm), Daicel chiralpak IG-3 (3um, 4.6*150mm), Chiral Technologies Europe AD-3 (3um, 3.0*150mm), and Trefoil® Technology Trefoil® AMY1 (2.5um, 3.0*150mm) under base-containing conditions. Detection was performed using DAD (254nm). Preparative HPLC was performed using a GILSON Trilution LC system with a Welch XB-C18 column (5um, 21.2*150mm). Flash chromatography was performed using a Biotage Isolera Prime system with a Welch WelFlash flash column (40-63um). Unless otherwise specified, all synthesized compounds have a purity of ≥95%.

[0285] Abbreviation * = Indicates that the amount of solvent or reagent before the asterisk is used in the technique the same number of times as the amount after the asterisk. ℃=Celsius temperature 11H NMR = Proton Nuclear Magnetic Resonance Spectrum Acetic acid (ACOH) Boc2O=tert-butoxycarbonyl anhydride con.=concentration d=double term DCM = Dichloromethane DIAD = Diisopropyl azodicarboxylate DIPEA = N,N-diisopropylethylamine DMF = N,N-dimethylformamide EA = Ethyl acetate ESI = Electrospray Ionization g = grams (multiple grams are possible) h = time (multiple values ​​are possible) HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyluronium) HPLC = High-Performance Liquid Chromatography LCMS = Liquid Chromatography-Mass Spectrum M=mass m / z=mass-to-charge ratio MeCN = Acetonitrile MeOH = methanol MeONa = Sodium Methoxy mg = milligrams (multiple milligrams are allowed) mL = milliliter mmol = millimoles (plural is possible) mol = mole (multiple moles are possible) MS = Mass Spectrum NBS = N-bromosuccinimide obsd. = observed PCy3 = Tricyclohexylphosphine Pd(AcO)2 = Palladium(II) acetate Pd(dppf)Cl2=(1,1'-bis(diphenylphosphin)ferrocene)palladium(II) dichloride PE = Petroleum Ether ppm=parts per million PTSA = paratoluenesulfonic acid rt=room temperature s=singlet t=triplet TBAF = Tetrabutylammonium fluoride TFA = Trifluoroacetic Acid THF = Tetrahydrofuran TLC = Thin-Layer Calculation Trixiephos=rac-2-(di-tert-butylphosphin)-1,1'-binaphthyl

[0286] Example 1: 5-methyl-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Step A: 4-Methoxythiophene-2-carboxylic acid [ka] To a freshly prepared solution of NaOMe (250 mL, 1 M, 2.2 equivalents) in MeOH, methyl 4-bromothiophene-2-carboxylate (26 g, 117.6 mmol, 1 equivalent) and NMP (30 mL) were added under N2 at 0°C. The reaction mixture was heated to 100°C, and CuI (2.2 g, 11.8 mmol, 0.1 equivalent) was added. The mixture was then stirred overnight at 100°C. After most of the methyl 4-methoxythiophene-2-carboxylate had been consumed, the reaction mixture was cooled to 50°C, H2O was added, and stirring was continued for a further 1 hour. The mixture was cooled to room temperature, concentrated, and extracted with Et2O to remove unreacted starting materials. The pH of the aqueous layer was adjusted to 6-7, and it was extracted again with EA. The solvent was removed under vacuum to obtain the crude compound 4-methoxythiophene-2-carboxylic acid (18.0 g) as a yellow oil, which was used in the next step without further purification.

[0287] Step B: 4-Methoxythiophene-2-carboxamide [ka] To a mixture of the crude compound 4-methoxythiophene-2-carboxylic acid (18.0 g, 113.9 mmol, 1 equivalent) in DCM (250 mL), DIPEA (73.7 g, 570.0 mmol, 5.0 equivalents) and HATU (56.4 g, 148.2 mmol, 1.3 equivalents) were added. After stirring at room temperature for 10 minutes, anhydrous NH4Cl (12.2 g, 228.0 mmol, 2 equivalents) was added, and stirring was continued overnight at 38°C. The reaction mixture was quenched with H2O and extracted with DCM. The organic layer was separated, concentrated, and purified by flash chromatography (elution with 0-30% EA in PE) to obtain 4-methoxythiophene-2-carboxamide (17 g) as a white solid. Observed MS: (ESI + ): m / z 157.8 [(M+H) + ].

[0288] Step C: Ethyl 3-methoxy-5-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-4-carboxylate [ka] To a solution of 4-methoxythiophene-2-carboxamide (300 mg, 1.9 mmol, 1.0 equivalent) in DCE (4 mL), CsOAc (183 mg, 0.950 mmol, 0.5 equivalent) and (C5(CH3)5RhCl)2Cl2 (23.5 mg, 2%) were added under N2. The mixture was stirred at room temperature for 5 minutes, and then ethyl 2-diazo-3-oxobutanoate (0.4 mL, 2.85 mmol, 1.50 equivalent) was added dropwise under N2. After stirring at room temperature for 30 minutes, the reaction mixture was heated at 100°C overnight. Once complete, the mixture was cooled to room temperature, diluted with DCM, filtered through a Celite pad, and washed with DCM. The filtrate was concentrated and purified by a flash column eluting 0-50% EA in PE to obtain ethyl 3-methoxy-5-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-4-carboxylate (116 mg) as a yellow solid. Observed MS: (ESI + ): m / z 268.1 [(M+H) + ].

[0289] Step D: Ethyl 7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carboxylate [ka] Ethyl 3-methoxy-5-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-4-carboxylate (30 mg, 0.11 mmol, 1.0 equivalent) was dissolved in POCl3 (2 mL) under N2 and stirred overnight at 105°C. The reaction was quenched with MeOH, filtered, and purified by reverse-phase column (MeOH / H2O = 55%) to obtain ethyl 7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carboxylate (20 mg) as a white solid. Observed MS: (ESI + ): m / z 286 [(M+H) + ].

[0290] Step F: (7-Chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)methanol [ka] To a mixture of ethyl 7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carboxylate (100 mg, 0.35 mmol, 1.0 equivalent) in dry THF (10 mL), LAH (1 mL, 1 M in THF, 2.00 equivalent) was added dropwise under N2 at -78°C. The reaction mixture was immediately heated to 50°C and stirred for 40 minutes. The reaction was quenched with ice water at -78°C (5 drops), and sodium potassium tartrate solution (5 mL) was added with stirring. The mixture was filtered, diluted with H2O, and extracted with DCM. The organic layer was separated, dried over anhydrous Na2SO4, concentrated, and purified by flash column elution of 0-40% EA in PE to obtain (7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)methanol (25 mg) as a white solid. Observed MS: (ESI +): m / z 244 [(M+H) + ].

[0291] Step G: 7-Chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carbaldehyde [ka] (7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)methanol (5 mg, 0.021 mmol, 1.0 equivalent) in DCM (10 mL) was mixed with DMP (17.4 mg, 0.041 mmol, 2.00 equivalent). The reaction mixture was stirred and slowly warmed to room temperature for 2 hours. The reaction was quenched with sodium thiosulfate solution (2 mL). The mixture was filtered, diluted with H2O, extracted with EA, and dried over anhydrous sodium sulfate. The organic layer was concentrated and purified by preparative TLC (EA / PE = 20%) to obtain 7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carbaldehyde (3 mg) as a white solid. Observed MS: (ESI + ): m / z 242 [(M+H) + ].

[0292] Step H: (E)-Ethyl 3-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)acrylate [ka] Triethyl phosphonoacetate (51.0 mg, 0.23 mmol, 1.1 equivalents) was added dropwise to a mixture of t-BuOK (27.8 mg, 0.25 mmol, 1.2 equivalents) in 2 mL of dry THF at -5°C, and the mixture was stirred for 30 minutes. Another 2 mL solution of 7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carbaldehyde (50 mg, 0.21 mmol, 1.0 equivalent) in dry THF was added dropwise, and the mixture was stirred for 30 minutes at -5°C. Once complete, the reaction mixture was poured into ice water, extracted with EA, washed with NaHCO3 and brine, dried over anhydrous sodium sulfate, concentrated, and purified by flash column (EA = 30% in PE) to obtain (E)-ethyl 3-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)acrylate (20 mg) as a green solid. Observed MS: (ESI + ): m / z 312 [(M+H) + ].

[0293] Step I: 3-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)propan-1-ol [ka] (E)-ethyl 3-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)acrylate (86 mg, 0.28 mmol, 1 equivalent) was added to a mixture in PEG400 (5 mL) with NaBH4 (100 mg, 2.45 mmol, 9.0 equivalents). The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction was quenched with 1N HCl and subsequently extracted with EA. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (EA / PE = 1:1) to obtain 3-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)propan-1-ol (45 mg) as a white solid. Observed MS: (ESI + ): m / z 272 [(M+H) + ].

[0294] Step J: 3-Chloro-5-methyl-7,8-dihydro-6H-9-oxa-2-thia-4-azabenzo[cd]azulene [ka] 3-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)propan-1-ol (30 mg, 0.11 mmol, 1.0 equivalent) was added to 48% HBr aqueous solution (3 mL), and the mixture was stirred overnight at 50°C. The reaction was quenched with saturated NaHCO3 aqueous solution to adjust the pH to 6-7. The mixture was extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (EA / PE = 1:1) to obtain 3-chloro-5-methyl-7,8-dihydro-6H-9-oxa-2-thia-4-azabenzo[cd]azulene (15 mg) as a white solid. Observed MS: (ESI + ): m / z 239.95 [(M+H) + ].

[0295] Step K: 5-methyl-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 56 mg, 0.23 mmol, 1.0 equivalent of 3-chloro-5-methyl-7,8-dihydro-6H-9-oxa-2-thia-4-azabenzo[cd]azulene (56 mg, 0.23 mmol, 1.0 equivalent) was mixed with NH4OAc (200 mg, 2.60 mmol, 11.1 equivalents) in an 80% AcOH aqueous solution (5 mL). The reaction mixture was sealed in an autoclave and heated at 210 °C for 40 minutes. After the reaction was complete, the reaction mixture was cooled to room temperature, poured into ice water (10 mL), and extracted with EA (4 x 20 mL). The organic layer was washed with NaHCO3 and brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (EA / PE = 50%) to obtain 5-methyl-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (30 mg) as a white solid. Observed MS: (ESI + ): m / z 221.8 [(M+H)+ ].

[0296] Step L: 1-Bromo-5-methyl-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] To a mixture of 5-methyl-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (10 mg, 0.045 mmol, 1.0 equivalent) in AcOH:DCM (1:1) (15 mL), NBS (6.4 mg, 0.036 mmol, 0.80 equivalent) in AcOH:DCM (1:1) (5 mL) was added at -2°C, and the reaction was stirred at -2°C for 24 hours. The mixture was poured into ice water, extracted with EA, washed with NaHCO3, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (EA / PE = 50%) to obtain 1-bromo-5-methyl-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (3 mg) as a yellow solid. Observed MS: (ESI + ): m / z 299.8 [(M+H) + ].

[0297] Step M: 5-Methyl-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 1-Bromo-5-methyl-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (10 mg, 0.033 mmol, 1.0 equivalent), pyridine-4-ylboronic acid (25.0 mg, 0.20 mmol, 6.00 equivalent), pd(dppf)Cl2 (5.0 mg, 0.007 mmol, 0.20 equivalent), and K2CO3 (27.7 mg, 0.20 mmol, 6.00 equivalent) were dissolved in dioxane:H2O (1:1) (5 mL) and degassed by N2 bubbling for 5 minutes. Next, the reaction mixture was sealed in a tube, stirred at 95°C for 3 hours, filtered, and purified by preparative HPLC to obtain 5-methyl-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (5.0 mg) as a white solid. Observed MS: (ESI + ): m / z 298.8 [(M+H) + ]. 1 H NMR (400 MHz, CDCl3) δ ppm: 10.29 (s, 1H), 8.65 (s, 2H), 7.76 (s, 2H), 4.28-4.45 (m, 2H), 3.04 - 2.88 (m, 2H), 2.37 (s, 3H), 2.24-2.31 (m, 2H).

[0298] Example 2: 6-Methyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] Step A: 7-Chloro-3-methoxy-4-(2-methoxyvinyl)-5-methylthieno[2,3-c]pyridine [ka] To a mixture of t-BuOK (3.3 g, 29.8 mmol, 2.4 equivalents) in 30 mL of dry THF, (methoxymethylene)triphenylphosphan (9.36 g, 27.3 mmol, 2.2 equivalents) was added at -5°C and the mixture was stirred for 30 minutes. A solution of 7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carbaldehyde (3.0 g, 12.4 mmol, 1.0 equivalent) in another 5 mL of dry THF was added dropwise and the mixture was stirred at -5°C for 30 minutes. Once the reaction was complete, the reaction mixture was poured into ice water, extracted with EA, washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous sodium sulfate, concentrated, and purified by flash column (0-15% EA in PE) to obtain 7-chloro-3-methoxy-4-(2-methoxyvinyl)-5-methylthieno[2,3-c]pyridine (1.8 g) as a yellow solid. Observed MS: (ESI + ): m / z 270 [(M+H) + ].

[0299] Step B: 2-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)acetaldehyde [ka] 7-Chloro-3-methoxy-4-(2-methoxyvinyl)-5-methylthieno[2,3-c]pyridine (1.0 g, 3.70 mmol, 1.0 equivalent) was added to 5 mL of 48% HBr aqueous solution and stirred at 70°C for 2 hours. LC-MS indicated that the reaction was complete, and the mixture was quenched with saturated NaHCO3 aqueous solution to adjust the pH to 6-7. The mixture was extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified by flash chromatography to elute 0-40% of EA in PE, yielding 2-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)acetaldehyde (550 mg) as a yellow solid. Observed MS: (ESI + ): m / z 256 [(M+H) + ].

[0300] Step C: 2-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)ethanol [ka] 550 mg, 2.15 mmol, 1.0 equivalent of 2-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)acetaldehyde was added to a mixture of 2-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)acetaldehyde in 20 mL of MeOH at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 40 minutes. LC-MS indicated that the reaction was complete. The mixture was filtered and extracted with EA. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by flash column (EA = 50% PE) to obtain 2-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)ethanol (530 mg) as a yellow solid. Observed MS: (ESI + ): m / z 258 [(M+H) + ].

[0301] Step D: 8-Chloro-6-methyl-4,5-dihydro-3-oxa-1-thia-7-azaacenaphthylene [ka] 2-(7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-yl)ethanol (530 mg, 2.05 mmol, 1.0 equivalent) was added to a 48% HBr aqueous solution (5 mL), and the mixture was stirred at 70°C for 18 hours. When LC-MS indicated that the reaction was complete, the mixture was quenched with a saturated NaHCO3 aqueous solution to adjust the pH to 6-7. The mixture was extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified by flash chromatography to elute 0-20% EA in PE, yielding 8-chloro-6-methyl-4,5-dihydro-3-oxa-1-thia-7-azaacenaphthylene (450 mg) as a yellow solid. Observed MS: (ESI + ): m / z 226 [(M+H) + ].

[0302] Step E: 6-methyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] 8-chloro-6-methyl-4,5-dihydro-3-oxa-1-thia-7-azaacenaphthylene (40 mg, 0.18 mmol, 1.0 equivalent) was mixed in 5 mL of 80% AcOH aqueous solution, to which NH4OAc (126.2 mg, 1.78 mmol, 10.0 equivalent) was added. The reaction mixture was sealed in an autoclave and heated to 210°C for 1.5 hours. After completion, the reaction mixture was cooled to room temperature, poured into ice water, and extracted. The organic layer was washed with NaHCO3 and brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (EA / PE = 50%) to obtain 6-methyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (30 mg) as a yellow solid. Observed MS: (ESI + ): m / z 208 [(M+H) + ].

[0303] Step F: 2-Bromo-6-methyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] 6-methyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (50 mg, 0.24 mmol, 1 equivalent) was dissolved in DCM / MeOH (5 mL, 1:1) and CaCO3 (96 mg, 1 mmol, 4 equivalents) and BTMABr3 (96 mg, 0.24 mmol, 1 equivalent) were added. The tube was covered with aluminum foil to block out light and stirred at -5°C for 1 hour. LC-MS indicated completion of the reaction, although some dibrominated by-products were present. The mixture was quenched with Na2SO3 powder and filtered. The organic filtrate was concentrated and purified by preparative HPLC to obtain 2-bromo-6-methyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (17 mg) as white crystals. Observed MS: (ESI + ): m / z 286.0, 288.0 [(M+H) + ].

[0304] Step G: 6-Methyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] To a solution of 2-bromo-6-methyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (16 mg, 0.05 mmol, 1 equivalent) in dioxane / H2O (2 mL, 3:1), Na2CO3 (18 mg, 0.17 mmol, 3 equivalents), Pd(dppf)Cl2 (8 mg, 0.01 mmol, 0.2 equivalents), and pyridine-4-ylboronic acid (14 mg, 0.11 mmol, 2 equivalents) were added. The mixture was degassed by N2 bubbling for 10 minutes. The reaction mixture was then sealed in a tube and heated in a microwave at 105°C for 1 hour. Once LC-MS indicated the completion of the reaction, the resulting mixture was filtered and purified by preparative HPLC to obtain 6-methyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (1.5 mg) as a white solid. Observed MS: (ESI +): m / z 285.1 [(M+H) + ]. 1 H NMR (400 MHz, DMSO) δ 11.55 (s, 1H), 8.62 (dd, J = 4.6, 1.6 Hz, 2H), 7.75 (dd, J = 4.6, 1.7 Hz, 2H), 4.48 (t, J = 5.6 Hz, 2H), 2.83 (t, J = 5.4 Hz, 1H), 2.21 (s, 3H).

[0305] The following compounds were prepared from the corresponding bromides by the Suzuki reaction using a method similar to that exemplified in Example 2. [Table 2]

[0306] Example 7: (R)-4,6-dimethyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka]

[0307] Example 8: (S)-4,6-dimethyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] Step A: 7-Chloro-3-methoxy-4-(2-methoxyvinyl)-5-methylthieno[2,3-c]pyridine [ka] A solution of (methoxymethyl)triphenylphosphonium bromide (3.85 g, 10 mmol, 0.1 equivalent) in dry THF (100 mL) was degassed three times with N2 at -78°C and refilled. Then, a solution of t-BuOK (11 mL, 1.0 M, 11 mmol, 2.2 equivalents) in THF was added dropwise over 30 minutes. The mixture was then stirred at -78°C for 0.5 hours. Next, 7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carbaldehyde (1.2 g, 5 mmol, 1 equivalent) was added all at once. The mixture was stirred at 0°C for 3 hours and then heated to a maximum of 25°C for a further 3 hours. Upon completion, a saturated NH4Cl solution and siRNA were added at 0°C. The resulting mixture was extracted with siRNA. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluting with PE:Â=1:1) to obtain 7-chloro-3-methoxy-4-(2-methoxyvinyl)-5-methylthieno[2,3-c]pyridine (807 mg) as a yellow solid. Observed MS:(ESI + ): m / z 270.0 [(M+H) + ].

[0308] Step B: 2-(7-chloro-3-hydroxy-5-methylthieno[2,3-c]pyridine-4-yl)acetaldehyde [ka] 7-Chloro-3-methoxy-4-(2-methoxyvinyl)-5-methylthieno[2,3-c]pyridine (807 mg, 3 mmol, 1 equivalent) was dissolved in 40% HBr aqueous solution (20 mL) and stirred at 70°C for 16 hours. After completion, the mixture was concentrated under vacuum. The crude product was recrystallized with PE:siRNA = 1:1 to obtain 2-(7-chloro-3-hydroxy-5-methylthieno[2,3-c]pyridine-4-yl)acetaldehyde (482 mg) as a yellow solid. Observed MS:(ESI + ): m / z 242.0 [(M+H) + ].

[0309] Step C: 7-Chloro-4-(2-hydroxypropyl)-5-methylthieno[2,3-c]pyridine-3-ol [ka] A solution of 2-(7-chloro-3-hydroxy-5-methylthieno[2,3-c]pyridine-4-yl)acetaldehyde (482 mg, 2 mmol, 1 equivalent) in dry THF (100 mL) at 0°C was degassed three times with N2 and repacked. Then, a solution of CH3MgBr (2.7 mL, 3.0 M, 8 mmol, 4 equivalents) in THF was added all at once. The mixture was then stirred at 0°C for 1 hour. After completion, saturated NH4Cl solution and siRNA were added sequentially at 0°C. The resulting mixture was extracted with siRNA. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluting with PE:siRNA = 1:1) to obtain 7-chloro-4-(2-hydroxypropyl)-5-methylthieno[2,3-c]pyridine-3-ol (206 mg) as a yellow solid. Observed MS: (ESI + ): m / z 257.8 [(M+H) + ].

[0310] Step D: 8-Chloro-4,6-dimethyl-4,5-dihydro-3-oxa-1-thia-7-azaacenaphthylene [ka] To a solution of 7-chloro-4-(2-hydroxypropyl)-5-methylthieno[2,3-c]pyridine-3-ol (206 mg, 0.8 mmol, 1 equivalent) in dry DCM (50 mL) at 0°C, TMSOTf (5 mL) was added dropwise over 3 minutes. The mixture was then stirred at 40°C for 16 hours. After completion, the mixture was concentrated under vacuum. The residue was diluted with H2O and basicized with saturated NaHCO3 aqueous solution at 0°C (pH=8). The resulting mixture was extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluting with PE:ethyl = 1:1) to obtain 8-chloro-4,6-dimethyl-4,5-dihydro-3-oxa-1-thia-7-azaacenaphthylene (143 mg) as a yellow solid. Observed MS: (ESI + ): m / z 239.8 [(M+H) + ].

[0311] Step E: 4,6-dimethyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] To a solution of 8-chloro-4,6-dimethyl-4,5-dihydro-3-oxa-1-thia-7-azaacenaphthylene (143 mg, 0.6 mmol, 1 equivalent) in AcOH (10 mL), one drop of water and NH4OAc (231 mg, 3 mmol, 5 equivalents) were sequentially added at room temperature. The mixture was then stirred at 200 °C for 0.5 hours. After completion, the mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with H2O and basicized at 0 °C with a 30 wt% aqueous NH4OH solution (pH=8). The resulting mixture was extracted with DCM:MeOH=1:1. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 4,6-dimethyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (119 mg) as a yellow solid. Observed MS: (ESI + ): m / z 221.8 [(M+H) + ].

[0312] Step F: 2-Bromo-4,6-dimethyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] To a solution of 4,6-dimethyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (119 mg, 0.54 mmol, 1 equivalent) in DCM:MeOH=1:1 (24 mL), BTMABr3 (210 mg, 0.54 mmol, 1 equivalent) was gradually added at 0°C in a tube covered with aluminum foil to block light. The mixture was then stirred under dark conditions at 25°C for 16 hours. After completion, the mixture was diluted with H2O and quenched at 0°C with saturated Na2SO3 solution. The resulting mixture was extracted in DCM:MeOH=1:1. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was recrystallized in a PE:SiO ratio of 1:2 to obtain 2-bromo-4,6-dimethyl-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (120 mg) as a yellow solid. Observed MS:(ESI + ): m / z 300.8 [(M+H) + ].

[0313] Step G: 4,6-dimethyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] A mixture of 2-bromo-6,6-dimethyl-4,5,6,7-tetrahydro-8H-3-oxa-1-thia-5a,7-diazaacenaphthylene-8-one (30 mg, 0.1 mmol, 1 equivalent), pyridine-4-ylboronic acid (24.4 mg, 0.2 mmol, 2 equivalents), Pd(dppf)Cl2 (7.3 mg, 0.01 mmol, 0.1 equivalent), and sodium carbonate (31.8 mg, 0.03 mmol, 3 equivalents) in 1,4-dioxane / H2O=5 / 1 (4 mL) was degassed three times with N2 and refilled. The mixture was then heated to 110°C in a microwave and stirred for 1 hour. The resulting mixture was cooled to room temperature, diluted with DCM / MeOH=10 / 1, filtered through Celite, and concentrated under vacuum. The residue was purified by preparative HPLC (eluting with 0% to 30% MeCN in water and 0.5% FA in water) to obtain 4,6-dimethyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one (5.7 mg, 0.0191 mmol) as a yellow solid. Observed MS: (ESI + ): m / z 298.8 [(M+H) + ]. 1 HNMR (400MHz, DMSO-d6) δ ppm: 11.53 (s, 1H), 8.62 (d, J = 6.1 Hz, 2H), 7.76 (d, J = 6.1 Hz, 2H), 4.36 - 4.58 (m, 1H), 2.94 (dd, J = 15.9, 2.8 Hz, 1H), 2.55 - 2.67 (m, 1H), 2.19 (s, 3H), 1.54 (d, J = 6.2 Hz, (3H) The racemic 4,6-dimethyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one was resolving by chiral SFC to obtain enantiomerically pure (R)-4,6-dimethyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one and (S)-4,6-dimethyl-2-(pyridine-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one. Absolute stereochemistry was randomly assigned to these two compounds.

[0314] Example 9: 4,6-dimethyl-2-(1H-pyrazole-4-yl)-5,7-dihydro-3-oxa-1-thia-7-azaacenaphthylene-8(4H)-one [ka] Example 9 was prepared from the corresponding bromide by the Suzuki reaction, using the same method as illustrated in Examples 7 and 8. Observed MS: (ESI+): m / z [(M+H)+] 288.

[0315] Example 10: (S)-5-((3-hydroxypyrrolidine-1-yl)methyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Step A: 2-Bromo-7-(bromomethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a solution of trideca-1,4(13),7-trien-5-one (100 mg, 452 µl, 1 equivalent) in chloroform (15 mL, 99.8%, ACS reagent), bromine (722 mg, 4.52 mmol, 231.5 µL, 10 equivalents) was added at 0°C. The mixture was warmed to room temperature and stirred for 16 hours. Upon completion, the resulting mixture was diluted with ice / water and quenched with saturated Na2SO3 at 0°C (pH=8). The reaction mixture was stirred at 0°C for 10 minutes. The mixture was extracted with DCM. Crude 2-bromo-7-(bromomethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 in DCM and chloroform] 4,13The combined organic solution containing trideca-1,4(13),7-trien-5-one (173.3 mg) was used in the next step without further purification because the product was unstable. Observed MS: (ESI + ): m / z 377.8 [(M+H) + ].

[0316] Step B: 2-Bromo-7-(bromomethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] (S)-Pyrrolidine-3-ol (362.2 mg, 4.16 mmol, 10 equivalents) in a solution of DCM (10 mL) containing 2-bromo-7-(bromomethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 A solution of trideca-1,4(13),7-trien-5-one (157.5 mg, 0.41 mmol, 52.5 mL) in DCM was added at 0°C. The mixture was then stirred at 25°C for 16 hours. After completion, the mixture was diluted with water and extracted with DCM. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (eluting with 0%-30% MeCN in water and 0.5% FA in water) to obtain (S)-1-bromo-5-((3-hydroxypyrrolidine-1-yl)methyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene 3-one (60 mg) as a yellow solid. Observed MS: (ESI + ): m / z 385.0 [(M+H) + ].

[0317] Step C: (S)-5-((3-hydroxypyrrolidine-1-yl)methyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] A 12 mL mixture of (S)-1-bromo-5-((3-hydroxypyrrolidine-1-yl)methyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (63 mg, 164 umol), pyridine-4-ylboronic acid (60.4 mg, 491.5 umol, 3 equivalents), sodium carbonate (86.82 mg, 819 umol, 3 equivalents), X-Phos (23.4 mg, 49.2 umol, 0.3 equivalents), and Pd(dppf)Cl2 (36.0 mg, 49.2 umol, 0.3 equivalents) in 1,4-dioxane / H2O=5 / 1 was purged three times with argon. Then, it was stirred under MW at 105°C for 2.5 hours. Once completed, the resulting mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by preparative silica TLC (eluting with DCM:MeOH = 10:1) and further purified by preparative HPLC (eluting with 0% to 30% MeCN in water and 0.5% FA in water) to obtain (S)-5-((3-hydroxypyrrolidine-1-yl)methyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (7.5 mg) as a yellow solid. Observed MS: (ESI + ): m / z 354.2 [(M+H) + ]. 1 H NMR (400 MHz, MeOD) δ ppm: 8.57 (dd, J = 4.7, 1.6 Hz, 2H), 8.33 (s, 1H), 7.89 (dd, J = 4.7, 1.6 Hz, 2H), 4.42 - 4.49 (m, 2H), 4.38 - 4.40 (m, 1H), 3.75 (s, 2H), 3.03 - 3.10 (m, 2H), 2.89 - 2.98 (m, 1H), 2.83 (dd, J = 10.0, 5.5 Hz, 1H), 2.69 (dd, J = 10.0, 2.5 Hz, 1H), 2.57 (td, J = 8.7, 6.0 Hz, 1H), 2.16 - 2.33 (m, 3H), 1.75 - 1.82 (m, 1H).

[0318] Example 11: (S)-5-((3-hydroxypyrrolidine-1-yl)methyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] (S)-1-bromo-5-((3-hydroxypyrrolidine-1-yl)methyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (56 mg, 0.15 mmol, 1 equivalent) was suspended in dioxane (10 mL) and then pyrazole-4-boronic acid (32.6 mg, 0.29 mmol, 2 equivalents), potassium carbonate (80.6 mg, 0.58 mmol, 4 equivalents), Pd(dppf)Cl2 (27.8 mg, 0.038 mmol, 0.26 equivalents), and water (2 mL) were added. The mixture was degassed with N2 for 2 minutes. The mixture was stirred under microwave at 105°C for 1 hour. LCMS indicated that the reaction was complete. This was diluted with water and DCM. The organic layer was concentrated, diluted with MeOH, and purified by preparative HPLC to obtain (S)-5-((3-hydroxypyrrolidine-1-yl)methyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (5.6 mg) as a yellow solid. Observed MS: (ESI + ): m / z 373.20 [(M+H) + ]. 1 H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 8.03 (s, 2H), 4.42 (ddd, J = 16.4, 8.4, 4.2 Hz, 3H), 3.86 (d, J = 14.7 Hz, 2H), 3.05 (dd, J = 7.1, 5.1 Hz, 3H), 2.95 (dd, J = 10.5, 5.3 Hz, 1H), 2.86 - 2.67 (m, 2H), 2.28 - 2.16 (m, 3H), 1.84 (dt, J = 13.3, 5.5 Hz, 1H).

[0319] Example 12: 5-(azetidine-1-ylmethyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka]

[0320] Example 13: 5-(azetidine-1-ylmethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Examples 12 and 13 were prepared from the corresponding bromides by the Suzuki reaction in a manner similar to that illustrated in Example 10. Example 12: Observed MS: (ESI + ): m / z [(M+H) + 354. Example 13: Observed MS: (ESI + ): m / z [(M+H) + 343.

[0321] Example 14: tert-butyl((3-oxo-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)carbamate [ka] Step A: tert-butyl((1-bromo-3-oxo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)carbamate [ka] Ammonium hydroxide (900 mg, 28%, 25.7 mmol, 40 equivalents) in acetonitrile (10 mL) is dissolved in CHCl3 and 2-bromo-7-(bromomethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0] from DCM. 4,13 Trideca-1,4(13),7-trien-5-one (240 mg, 0.63 mmol, 1 equivalent) was added at 0°C. The mixture was then warmed to room temperature and stirred for 16 hours. Ditert-butyl dicarbonate (2.76 g, 12.66 mmol, 20 equivalents) was added to the reactant. The mixture was then stirred at room temperature for a further 3 hours. Upon completion, the resulting mixture was diluted with water and extracted by DCM. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluting with PE:siRNA=3:1) to obtain tert-butyl N-[(2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-7-yl)methyl carbamate (55 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 414.8 [(M+H) + ].

[0322] Step B: tert-butyl((3-oxo-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)carbamate [ka] tert-butyl N-[(2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13A mixture of trideca-1,4(13),7-trien-7-yl)methyl carbamate (55 mg, 0.1 mmol, 1 equivalent), pyridine-4-ylboronic acid (37.4 mg, 0.3 mmol, 3 equivalents), sodium carbonate (53.28 mg, 0.5 mmol, 5 equivalents), X-Phos (14.36 mg, 0.3 mmol, 0.3 equivalents), and Pd(dppf)Cl2 (22.1 mg, 0.03 mmol, 0.3 equivalents) in 1,4-dioxane / H2O=5 / 1 (12 mL) was purged three times with argon. The reaction mixture was then stirred under MW at 105 °C for 2.5 hours. After completion, the resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by preparative silica TLC (eluting with DCM:MeOH = 15:1) to obtain the crude product, which was further purified by preparative HPLC (eluting with 0% to 30% MeCN in water and 0.5% FA in water) to obtain tert-butyl((3-oxo-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)carbamate (15 mg) as a yellow solid. Observed MS: (ESI + ): m / z 354.2 [(M+H) + ]. 1 H NMR (400 MHz, DMSO) δ ppm: 11.23 (s, 1H), 8.63 (dd, J = 4.6, 1.6 Hz, 2H), 7.77 (dd, J = 4.6, 1.6 Hz, 2H), 7.19 (s, 1H), 4.39 (t, J = 5.8 Hz, 2H), 4.13 (d, J = 5.4 Hz, 2H), 2.91 -3.02 (m, 2H), 2.12 -2.18 (m, 2H), 1.37 (s, 9H).

[0323] Example 15: 5-(aminomethyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one; hydrochloride [ka] A solution of tert-butyl((3-oxo-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)carbamate (15 mg, 0.036 mmol, 1 equivalent) in DCM (10 mL) was added at 0°C to a solution of hydrogen chloride (4 M, 2 mL) in 1,4-dioxane. The mixture was then stirred at room temperature for 3 hours. After completion, the resulting mixture was concentrated under vacuum, dissolved in water, and washed with DCM. The aqueous layer was freeze-dried to obtain 5-(aminomethyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one hydrochloride (12 mg, 0.0342 mol) as a yellow solid. Observed MS: (ESI + ): m / z 314.0 [(M+H) + ]. 1 H NMR (400 MHz, MeOD) δ ppm: 8.73 (s, 2H), 8.36 (d, J = 5.5 Hz, 2H), 4.54 - 4.62 (m, 2H), 4.24 (s, 2H), 3.15 (dd, J = 7.2, 4.9 Hz, 2H), 2.37 (dt, J = 11.5, 5.8 Hz, 2H).

[0324] Example 16: 5-(((4-methoxybenzyl)amino)methyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Step A: 1-Bromo-5-(((4-methoxybenzyl)amino)methyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] To a solution of 1-bromo-5-(bromomethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one from the previous step in CHCl3 (30 ml) and DCM (60 ml), (4-methoxyphenyl)methaneamine (211 mg, 1.54 mmol, 2.0 equivalents) was added. The mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was then concentrated under vacuum and purified by flash chromatography column (DCM:MeOH=100:3) to obtain 1-bromo-5-(((4-methoxybenzyl)amino)methyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (130 mg) as a yellow oil. Observed MS: (ESI + ): m / z 434.8,436.8 [(M+H) + ].

[0325] Step B: tert-butyl((1-bromo-3-oxo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)(4-methoxybenzyl)carbamate [ka] To a solution of 1-bromo-5-(((4-methoxybenzyl)amino)methyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (120 mg, 0.28 mmol, 1.0 equivalent) in DCM (5 ml), TEA (41.9 mg, 0.41 mmol, 1.5 equivalents) and (Boc)2O (90.5 mg, 0.41 mmol, 1.5 equivalents) were added. The mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was then concentrated under vacuum and purified by flash chromatography column to obtain tert-butyl((1-bromo-3-oxo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)(4-methoxybenzyl)carbamate (70 mg) as a white solid. Observed MS: (ESI+ ): m / z 535.0, 537.0 [(M+H) + ].

[0326] Step C: tert-butyl(4-methoxybenzyl)((3-oxo-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)carbamate [ka] To a solution of tert-butyl((1-bromo-3-oxo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)(4-methoxybenzyl)carbamate (70 mg, 0.13 mmol, 1.0 equivalent) in dioxane / H2O = 10:1 (11 ml), pyridine-4-ylboronic acid (32 mg, 0.26 mmol, 2.0 equivalents) and K2CO3 (54 mg, 0.39 mmol, 3.0 equivalents) were added. The mixture was degassed three times with N2. Then Pd(dppf)Cl2 (29 mg, 0.039 mmol, 0.3 equivalents) was added to the mixture. The mixture was stirred at 80°C for 1 hour under microwave irradiation. LCMS indicated that the reaction was complete. Water was then added to the mixture and extracted with EA. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by preparative TLC to obtain tert-butyl(4-methoxybenzyl)((3-oxo-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)carbamate (50 mg) as a yellow solid. Observed MS: (ESI + ): m / z 534.1 [(M+H) + ].

[0327] Step D: 5-(((4-methoxybenzyl)amino)methyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] To a solution of tert-butyl(4-methoxybenzyl)((3-oxo-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)methyl)carbamate (50 mg, 0.094 mmol, 1.0 equivalent) in MeOH (5 mL), 4 M HCl / dioxane (2 mL) was added. The mixture was stirred at 25 °C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was then concentrated under vacuum and purified by preparative HPLC to obtain 5-(((4-methoxybenzyl)amino)methyl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (16.8 mg) as a white solid. Observed MS: (ESI + ): m / z 434.0 [(M+H) + ]. 1 HNMR (400MHz, DMSO) δ 8.63 (dd, J = 4.6, 1.6 Hz, 2H), 8.19 (s, 1H), 7.77 (dd, J = 4.6, 1.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.41 - 4.34 (m, 2H), 3.72 (s, 3H), 3.64 (d, J = 11.2 Hz, 4H), 2.83 (dd, J = 7.2, 4.9 Hz, 2H), 2.13 (dd, J = 11.9, 5.8 Hz, 2H).

[0328] Example 17: 7-(aminomethyl)-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.04,13]trideca-1,4(13),7-trien-5-one [ka] Example 17 was prepared using the same method as illustrated in Example 15. Observed MS: (ESI+): m / z [(M+H)+] 303.

[0329] The following compounds were prepared using the same method as illustrated in Example 10. [Table 3-1] [Table 3-2]

[0330] Example 26: (S)-1-(1-(3-oxo-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitrile [ka]

[0331] Example 27: (R)-1-(1-(3-oxo-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitrile [ka] Step A: 1-Bromo-5-(1-hydroxyethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 1-Bromo-3-oxo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-carbaldehyde (170 mg, 0.54 mmol) was added dropwise to a solution of CH3MgBr (5.4 mL, 5.4 mmol, 1 M) in THF (20 mL) at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction was quenched with saturated NH4Cl solution and extracted with siRNA. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 1-bromo-5-(1-hydroxyethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (166 mg) as a yellow solid, which was used in the next step without further purification. Observed MS: (ESI + ): m / z 332.3 [(M+H) + ].

[0332] Step B: 1-Bromo-5-(1-chloroethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 1-Bromo-5-(1-hydroxyethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (160 mg, 0.49 mmol) was dissolved in DCM (15 mL) and SOCl2 (577 mg, 4.9 mmol) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under vacuum to obtain 1-bromo-5-(1-chloroethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (150 mg) as a yellow solid, which was used in the next step without further purification. Observed MS: (ESI + ): m / z 348.3[(M+H) + ], 350.3 [(M+2+H) + ].

[0333] Step C: 1-(1-(1-bromo-3-oxo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitri [ka] 1H-pyrazole-4-carbonitrile (400 mg, 4.30 mmol) was added to a solution of 1-bromo-5-(1-chloroethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene 3-one (150 mg, 0.43 mmol) in MeCN (20 mL). The mixture was stirred at 80°C for 16 hours. The mixture was concentrated under vacuum, and the residue was first purified by flash column chromatography (eluting with DCM:MeOH = 20:1), and then by reverse-phase chromatography (eluting with 0% to 40% MeCN in water and 0.5% FA in water) to obtain 1-(1-(1-bromo-3-oxo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitrile (106 mg) as a white solid. Observed MS: (ESI + ): m / z 407.4 [(M+H) + ].

[0334] Step D: 1-(1-(3-oxo-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitriel [ka] 1-(1-(1-bromo-3-oxo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitrile (20 mg, 49.4 umol) in a 1,4-dioxane:H2O=5:1 (3.6 mL) solution, with sodium carbonate (16 mg, 148.0 umol) and cyclopentyl (diphenyl) Phosphan; dichloropalladium; iron(Pd(dppf)Cl2-DCM) (8 mg, 9.9 umol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19 mg, 98.7 umol), and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (7 mg, 14.8 umol) were added. The suspension was degassed with N2 for 10 minutes. The mixture was then sealed in a tube and heated to 105°C in a microwave under N2 for 1.5 hours. Upon completion, H2O was added to the mixture and extracted with ethyl acetate. The organic layer was dried and concentrated under vacuum. The crude product was first purified by preparative silica TLC (eluting with DCM:MeOH = 20:1), and then by preparative HPLC (eluting with 0% to 45% MeCN in water and 0.1% FA in water) to obtain 1-(1-(3-oxo-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitrile (2 mg) as a white solid. Observed MS: (ESI + ): m / z 393.1 [(M+H) + ]. 1 H NMR (400 MHz) δ ppm: 13.20 (s, 1H), 10.97 (s, 1H), 8.73 (s, 1H), 8.23 ​​- 7.79 (m, 3H), 5.96 (q, J = 6.6 Hz, 1H), 4.32 (dt, J = 11.9, 5.8 Hz, 2H), 3.01 (dd, J = 12.8, 5.9 Hz, 2H), 2.15 - 2.09 (m, 2H), 1.89 (d, J = 6.9 Hz, 3H).

[0335] 1-(1-(3-oxo-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitrile (35 mg) was subjected to chiral HPLC (column: AD-H, column size: inner diameter 0.46 cm × length 15 cm, injection: 2 μl, mobile phase: HEP:ETOH (0.1% DEA) = Separation was performed using a 60:40 ratio, flow rate: 0.5 ml, wavelength: UV254 nm, temperature: 25°C, sample solution in ETOH) to obtain (S)-1-(1-(3-oxo-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitrile (5.8 mg) as a white solid. Observed MS: (ESI + ): m / z 393.1 [(M+H) + ]. 1 H NMR (400 MHz, DMSO) δ ppm: 13.17 (s, 1H), 10.95 (s, 1H), 8.73 (s, 1H), 8.01 (d, J = 81.1 Hz, 3H), 5.95 (q, J = 6.9 Hz, 1H), 4.37 - 4.27 (m, 2H), 3.01 (dd, J = 12.9, 6.0 Hz, 2H), 2.16 - 2.07 (m, 2H), 1.89 (d, J = 7.0 Hz, 3H) and (R)-1-(1-(3-oxo-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-5-yl)ethyl)-1H-pyrazole-4-carbonitrile (3.8 mg). Observed MS: (ESI + ): m / z 393.1 [(M+H) + ]. 1¹H NMR (400 MHz, DMSO) δ ppm: δ 13.18 (s, 1H), 10.96 (s, 1H), 8.73 (s, 1H), 8.25 - 7.82 (m, 3H), 5.95 (q, J = 6.9 Hz, 1H), 4.38 - 4.28 (m, 2H), 3.01 (dd, J = 12.8, 6.0 Hz, 2H), 2.17 - 2.07 (m, 2H), 1.89 (d, J = 7.0 Hz, 3H). Absolute stereochemistry was randomly assigned to these two compounds.

[0336] Example 28: 5-(2-hydroxypropan-2-yl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Step A: 5-acetyl-1-bromo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] To a solution of 1-bromo-5-(1-hydroxyethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (340 mg, 1.03 mmol) in DCM (10 mL), des-martin periodinane (1.31 g, 3.09 mmol) was gradually added at 0 °C. The mixture was then stirred at 25 °C for 3 hours. After completion, the mixture was diluted with water (30 mL), quenched with saturated Na₂S₂O₃ (30 mL), and extracted with DCM (30 mL x 3). The combined organic phases were washed with saturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was chromatographed using silica gel column chromography (DCM: i Purified by elution with PrOH=10:1, 7-acetyl-2-bromo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13Trideca-1,4(13),7-trien-5-one (210 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 328.0 [(M+H) + ].

[0337] Step B: 5-Acetyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] A mixture of 5-acetyl-1-bromo-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (63 mg, 192.1 umol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (125 mg, 384.1 umol), sodium carbonate (61 mg, 576.2 umol), Xphos (28 mg, 57.6 umol), and Pd(dppf)Cl2 (42 mg, 57.6 umol) in a 1,4-dioxane:H2O = 5:1 (12 mL) was purged three times with argon. Then, it was stirred under MW at 105°C for 1 hour. Once completed, the resulting mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluting at DCM:MeOH = 10:1) to obtain 7-acetyl-2-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (21 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 446.2 [(M+H) + ].

[0338] Step C: 5-(2-hydroxypropan-2-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 5-acetyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (60 mg, 134.6 ml) was dissolved in THF (15 mL) and methylmagnesium bromide (3 M in ethyl ether, 2.69 mmol, 0.90 mL) was added at 0°C. After addition, the mixture was warmed to room temperature and stirred for 2 hours. Upon completion, the resulting mixture was quenched with saturated NH4Cl at 0°C. The reaction products were extracted with ELISA. The combined organic solution was dried, concentrated, and purified by silica gel column chromatography (eluting with DCM:MeOH = 10:1) to obtain 7-(1-hydroxy-1-methyl-ethyl)-2-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (33 mg) was obtained as a colorless liquid. Observed MS: (ESI + ): m / z 462.2 [(M+H) + ].

[0339] Step D: 5-(2-hydroxypropan-2-yl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 5-(2-hydroxypropan-2-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (45 mg, 97.5 umol) in DCM (5 mL) was mixed with TFA (2 mL) at 0°C. The solution was stirred at room temperature for 1 hour. After completion, the mixture was concentrated and diluted with MeOH. The pH was adjusted to approximately 7 with a 30% NH4OH aqueous solution. This was purified by preparative HPLC to obtain 7-(1-hydroxy-1-methyl-ethyl)-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (11.2 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 331.9 [(M+H) + ]. 1 H NMR (400 MHz, DMSO) δ ppm: 13.18 (s, 1H), 9.73 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 6.12 (s, 1H), 4.30 (t, J = 6.8 Hz, 2H), 3.10 - 2.91 (m, 2H), 2.20 - 1.98 (m, 2H), 1.56 (s, 6H).

[0340] Example 29: 5-(2-hydroxypropan-2-yl)-1-(pyridine-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Example 29 was prepared from the corresponding bromide by the Suzuki reaction, using a method similar to that exemplified in Example 28. Observed MS: (ESI+): m / z [(M+H)+] 343.

[0341] Example 30: (S)-5-(1-(azetidine-1-yl)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka]

[0342] Example 31: (R)-5-(1-(azetidine-1-yl)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Step A: 5-(1-hydroxyethyl)-1-(1-trityl-1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] A mixture of 1-bromo-5-(1-hydroxyethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one (30 mg, 90.8 umol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-trityl-1H-pyrazole (79 mg, 181.7 umol, 2 equivalents), sodium carbonate (39 mg, 363.4 umol, 4 equivalents), Xphos (13 mg, 27.3 umol), and Pd(dppf)Cl2 (20 mg, 27.3 umol) in a 1,4-dioxane:H2O = 5:1 (6 mL) solution was purged three times with argon. The mixture was then stirred under MW at 105°C for 1 hour. Upon completion, the resulting mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluting with DCM:MeOH = 10:1) to obtain 7-(1-hydroxyethyl)-2-(1-tritylpyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13Trideca-1,4(13),7-trien-5-one (34.7 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 560.2 [(M+H) + ].

[0343] Step B: 5-Acetyl-1-(1-trityl-1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 7-(1-hydroxyethyl)-2-(1-tritylpyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a solution of trideca-1,4(13),7-trien-5-one (100 mg, 178.7 umol) in DCM (10 mL), des-martin periodinane (151.57 mg, 357.4 umol) was gradually added at 0°C. The mixture was then stirred at 25°C for 2 hours. After completion, the mixture was diluted with water, quenched with saturated Na2S2O3, and extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to silica preparative TLC (DCM: i Purified by PrOH=10:1, 7-acetyl-2-(1-tritylpyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (63 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 559.2 [(M+H) + ].

[0344] Step C: 5-(1-(azetidine-1-yl)ethyl)-1-(1-trityl-1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 7-Acetyl-2-(1-tritylpyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a solution of trideca-1,4(13),7-trien-5-one (65 mg, 116.6 umol) in MeOH (20 mL), acetic acid (14 mg, 233.1 umol, 2 equivalents), azetidine (67 mg, 1.17 mmol), followed by sodium cyanoborohydride (22 mg, 349.7 umol) was added. The mixture was stirred at room temperature for 2 hours. After completion, the mixture was concentrated, diluted with water, and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica preparative TLC (eluting at DCM:MeOH = 10:1) to obtain 7-[1-(azetidine-1-yl)ethyl]-2-(1-tritylpyrazole-4-yl)-12-oxa-3-thia-6-azatrichro[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (55 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 599.2 [(M+H) + ].

[0345] Step D: 5-(1-(azetidine-1-yl)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 7-[1-(azetidine-1-yl)ethyl]-2-(1-tritylpyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13To a solution of trideca-1,4(13),7-trien-5-one (55 mg, 91.9 umol) in DCM (5 mL), TFA (2 mL) was added at 0°C. The solution was stirred at room temperature for 1 hour. After completion, the mixture was concentrated and diluted with MeOH. The pH was adjusted to approximately 8 with a 30% NH4OH aqueous solution. This was purified by preparative HPLC to obtain 7-[1-(azetidine-1-yl)ethyl]-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (18 mg) was obtained as a pale yellow solid. Observed MS: (ESI + ): m / z 357.2 [(M+H) + ]. 1 ¹H NMR (400 MHz, MeOD) δ ppm: 8.19 - 8.09 (m, 1H), 8.05 (s, 2H), 4.40 (d, J = 6.3 Hz, 2H), 4.21 - 4.03 (m, 1H), 3.64 - 3.45 (m, 4H), 3.21 - 3.06 (m, 1H), 3.06 - 2.94 (m, 1H), 2.34 - 2.14 (m, 4H), 1.30 (d, J = 6.6 Hz, 3H).7-[1-(azetidine-1-yl)ethyl)-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one was subjected to SFC chiral resolution to obtain (S)-5-(1-(azetidine-1-yl)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one and (R)-5-(1-(azetidine-1-yl)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one. The absolute stereochemistry of these two compounds was randomly assigned.

[0346] Examples 32 and 33 were prepared by chiral separation using the intermediate from Example 30. [Table 4]

[0347] Example 34: (5-(1-(cyclobutylamino)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Example 34 was prepared using the same method as illustrated in Example 30. Observed MS:(ESI+): m / z [(M+H)+] 371.

[0348] Example 35: (S)-5-(2-Methoxy-1-(1H-Pyrazole-1-yl)ethyl)-1-(1H-Pyrazole-4-yl)-4,6,7,8-Tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka]

[0349] Example 36: (R)-5-(2-methoxy-1-(1H-pyrazole-1-yl)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Step A: 1-Bromo-5-(oxylan-2-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] A mixture of sodium hydride (26 mg, 636.6 umol, 2 equivalents, 60% purity) and trimethylsulfonium iodide (195 mg, 954.9 umol) in DMSO (5 mL) was stirred at room temperature for 1 hour. Then, bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 A solution of trideca-1,4(13),7-triene-7-carbaldehyde (100 mg, 318.3 ml) in DMSO (10 mL) was added little by little. This was stirred at room temperature for a further 3 hours. Once complete, the mixture was poured into water and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain 2-bromo-7-(oxiran-2-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (70 mg) was obtained. Observed MS: (ESI + ): m / z 328.3 [(M+H) + ].

[0350] Step B: 1-Bromo-5-(1-hydroxy-2-methoxyethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 2-bromo-7-(oxiran-2-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 A mixture of trideca-1,4(13),7-trien-5-one (140 mg, 426.6 ml), NaOMe (5 M, 10 mL), and DMSO (10 mL) was stirred at room temperature for 3 hours. Once complete, the mixture was poured into water and extracted. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse-phase chromatography (eluting with 0%-30% MeCN in water and 0.5% FA in water) to obtain 2-bromo-7-(1-hydroxy-2-methoxyethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13Trideca-1,4(13),7-trien-5-one (80 mg) was obtained as an off-white solid. Observed MS: (ESI + ): m / z 360.0 [(M+H) + ].

[0351] Step C: 1-Bromo-5-(1-chloro-2-methoxyethyl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] Thionyl chloride (105.69 mg, 888.3 umol) is used in 2-bromo-7-(1-hydroxy-2-methoxyethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 [Trideca-1,4(13),7-trien-5-one (32 mg, 88.8 umol) was added at 0°C to a solution in DCM (6 mL). The mixture was warmed to room temperature and stirred for 2 hours. After completion, the mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain 2-bromo-7-(1-chloro-2-methoxyethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (18 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 378.0 [(M+H) + ].

[0352] Step D: 1-Bromo-5-(2-Methoxy-1-(1H-Pyrazole-1-yl)ethyl)-4,6,7,8-Tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 2-Bromo-7-(1-chloro-2-methoxyethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13Trideca-1,4(13),7-trien-5-one (44 mg, 116.2 umol), potassium iodide (97 mg, 581.0 umol), 1H-pyrazole (330 mg, 4.85 mmol), potassium carbonate (110.0 mg, 795.9 umol), and CH3CN (20 mL) were stirred at room temperature for 16 hours. After completion, the mixture was concentrated, diluted with water, and extracted with DCM. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by reverse-phase chromatography (elution with 0%-30% MeCN in water and 0.5% FA in water) to obtain 2-bromo-7-(2-methoxy-1-pyrazole-1-yl-ethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (20 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 410.4 [(M+H) + ].

[0353] Step E: 5-(2-Methoxy-1-(1H-Pyrazole-1-yl)ethyl)-1-(1H-Pyrazole-4-yl)-4,6,7,8-Tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one [ka] 2-bromo-7-(2-methoxy-1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13A mixture of trideca-1,4(13),7-trien-5-one (28 mg, 68.2 umol), 1H-pyrazole-4-ylboronic acid (16 mg, 136.5 umol), sodium carbonate (29 mg, 273.0 umol, 4 equivalents), Xphos (10 mg, 20.5 umol), and Pd(dppf)Cl2 (15 mg, 20.5 umol) in a 1,4-dioxane:H2O ratio of 5:1 (6 mL) was purged three times with argon. This mixture was then stirred under MW at 105°C for 1 hour. After completion, the resulting mixture was cooled to room temperature and concentrated under vacuum. The crude product was first purified by silica gel column chromatography (eluting with DCM:MeOH = 10:1), and then by reverse-phase chromatography (eluting with 0% to 25% MeCN in water and 0.5% FA in water) to obtain 7-(2-methoxy-1-pyrazole-1-ylethyl)-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (6,8 mg) was obtained as an off-white solid. Observed MS: (ESI + ): m / z 398.1 [(M+H) + This racemic product was subjected to SFC chiral resolution to obtain (S)-5-(2-methoxy-1-(1H-pyrazole-1-yl)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one and (R)-5-(2-methoxy-1-(1H-pyrazole-1-yl)ethyl)-1-(1H-pyrazole-4-yl)-4,6,7,8-tetrahydro-3H-9-oxa-2-thia-4-azabenzo[cd]azulene-3-one. The absolute stereochemistry of these two compounds was randomly assigned.

[0354] Compounds were prepared by chiral resolution using the same method as in Examples 35 and 36. [Table 5]

[0355] The following compounds were prepared in the same manner as in Examples 26 and 27. [Table 6]

[0356] Example 43: 10,10-difluoro-7-methyl-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] Step A: 7-Chloro-3-methoxy-5-methyl-4-vinylthieno[2,3-c]pyridine [ka] To a three-necked flask containing methyl(triphenyl)phosphonium bromide (7.79 g, 21.80 mmol) in THF (100 mL), butyllithium (1.6 M, 15.0 mL) was added at -78°C. The mixture was stirred at 0°C for 1 hour. Next, 7-chloro-3-methoxy-5-methylthieno[2,3-c]pyridine-4-carbaldehyde (3.29 g, 10.90 mmol) in THF (100 mL) was added to the mixture at -78°C. The mixture was then warmed to 0°C and stirred at 0°C for 2 hours. After completion, the mixture was quenched with aqueous NH4Cl solution, diluted with water, and extracted with siRNA. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by flash column chromatography (eluting at PE:siRNA=93:7) to obtain 7-chloro-3-methoxy-5-methyl-4-vinyl thieno[2,3-c]pyridine (2.1 g) as a white solid.

[0357] Step B: (S)-2-bromo-7-(hydroxymethyl)-8-((2-(trimethylsilyl)ethoxy)methyl)-4,5,7,8-tetrahydro-3-oxa-1-thia-5a,8-diazabenzo[cd]azulene-9(6H)-one [ka] Tribromoborane (6.27 g, 25.03 mmol, 2.41 mL) was slowly added at 0°C to a flask containing 7-chloro-3-methoxy-5-methyl-4-vinyl-thieno[2,3-c]pyridine (2.1 g, 8.32 mmol) in dry DCM (50 mL). Once complete, the mixture was quenched at 0°C with MeOH. The mixture was stirred at 0°C for 10 minutes. The mixture was then concentrated to obtain the residue. This residue was diluted with  and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7-chloro-5-methyl-4-vinyl-thieno[2,3-c]pyridine-3-ol (1.6 g) as a yellow solid. Observed MS: (ESI + ): m / z 226.3 [(M+H) + ], 228.3 [(M+2+H) + ].

[0358] Step C: 3-(allyloxy)-7-chloro-5-methyl-4-vinylthieno[2,3-c]pyridine [ka] To a flask containing 7-chloro-5-methyl-4-vinylthieno[2,3-c]pyridine-3-ol (1.4 g, 5.83 mmol) in DMF (20 mL), potassium carbonate (2.42 g, 17.49 mmol) and 3-bromopropa-1-ene (705.4 mg, 5.83 mmol, 503.85 μL) were added at 0°C. The mixture was then stirred at room temperature for 2 hours. After completion, it was diluted with RINKAN and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase chromatography (eluting with 0%-45% MeCN in water and 0.1% FA in water) to obtain 3-allyloxy-7-chloro-5-methyl-4-vinylthieno[2,3-c]pyridine (1.1 g) as a yellow solid.

[0359] Step D: 5-Chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13]trideca-1,4(13),5,7,9-pentaene [ka] 3-allyloxy-7-chloro-5-methyl-4-vinylthieno[2,3-c]pyridine (400 mg, 1.51 mmol) was added to a flask containing Hoveyda-Grubbs second-generation catalyst (142 mg, 225.8 mL) and dried DCM (300 mL). The mixture was stirred under N2 protection at 25°C for 5 hours. After completion, it was concentrated and purified by flash column chromatography (eluting at PE:siRNA = 94:6) to obtain 5-chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),5,7,9-pentene (290 mg) was obtained as a white solid.

[0360] Step E: 5-Chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),5,7-tetraene-9,10-diol [ka] 5-chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0] in tert-butanol (30 mL) 4,13To a flask containing trideca-1,4(13),5,7,9-pentaene (300 mg, 1.26 mmol), citric acid (485 mg, 2.52 mmol), 4-methylmorpholine N-oxide in H2O (30 mL) (296 mg, 2.52 mmol), and potassium osmium(VI) dihydrate (23 mg, 63.1 mmol) were added at room temperature. The mixture was stirred at 60°C for 16 hours. After completion, the reaction mixture was quenched by adding saturated Na2SO3 solution. This was stirred at room temperature for 20 minutes. This was then extracted by DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. This was then purified by flash column chromatography (eluting at PE:EA = 30:70) to obtain 5-chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),5,7-tetraene-9,10-diol (245 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 272.3 [(M+H) + ], 274.3 [(M+2+H) + ].

[0361] Step F: 5-Chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),5,7-tetraen-10-one [ka] 5-Chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a three-necked flask containing trideca-1,4(13),5,7-tetraen-9,10-diol (230 mg, 846.5 umol), p-toluenesulfonic acid (73 mg, 423.2 umol) in dry toluene (16 mL) was added. The reaction mixture was heated under reflux for 4 hours. After completion, it was concentrated and purified by flash column chromatography (eluting at DCM:MeOH = 100:1) to obtain 5-chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.04,13 Trideca-1,4(13),5,7-tetraen-10-one (175 mg) was obtained as a pale yellow solid.

[0362] Step G: 5-Chloro-10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]Trideca-1,4(13),5,7-tetraene [ka] 5-chloro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0] in DCM (10 mL) 4,13 To a plastic bottle containing trideca-1,4(13),5,7-tetraen-10-one (50 mg, 197.1 ml), morpholinosulfurtrifluorolide (345 mg, 1.97 mmol) was added at room temperature. This was stirred at room temperature for 24 hours. After completion, the pH was neutralized to 8 with aqueous NaHCO3 solution and extracted by DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the residue. This was then purified by flash column chromatography (eluting with PE:siRNA = 20:1) to obtain 5-chloro-10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),5,7-tetraene (30 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 276.3 [(M+H) + ], 278.3 [(M+2+H) + ].

[0363] Step H: 10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 5-chloro-10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0] in acetic acid (10 mL) 4,13 To a flask containing trideca-1,4(13),5,7-tetraene (52 mg, 188.6 ml), ammonium acetate (140 mg, 1.81 mmol) and H2O (0.1 mL) were added at room temperature. The mixture was then heated to 200 °C. The reaction mixture was stirred at 200 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and concentrated to remove the acetic acid. The residue was diluted with H2O and DCM and basicized to pH=10 with ammonium hydroxide. This was extracted with DCM:MeOH=10:1. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain a solid. This was then recrystallized from PE:EA=30:1 and filtered. The filter cake was collected and 10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (50 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 258.4 [(M+H) + ].

[0364] Step I: 2-bromo-10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0] in DCM (10 mL) 4,13Trideca-1,4(13),7-trien-5-one (50 mg, 194.4 umol) was added to a flask at 0°C with pyridinium tribromide (311 mg, 971.8 umol). The reaction mixture was stirred at 25°C for 24 hours. After completion, it was diluted with DCM, quenched with saturated Na2SO3 solution, and washed with aqueous NaHCO3 solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. This was recrystallized from PE:EA=5:1 to obtain 2-bromo-10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (50 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 336.3 [(M+H) + ], 338.3 [(M+2+H) + ].

[0365] Step J: 10,10-difluoro-7-methyl-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 2-Bromo-10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13[Trideca-1,4(13),7-trien-5-one (45 mg, 133.9 umol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (52.0 mg, 267.7 umol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphan (19 mg, 40.2 umol), sodium carbonate (43 mg, 401.6 umol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.6 mg, 26.8 umol) were mixed with water (1.6 mL) and 1,4-dioxane (8 mL). This mixture was then degassed by bubbling with N2 for 2 minutes. Next, the reaction mixture was sealed in a tube and stirred in a microwave reactor at 105°C for 2.5 hours, and monitored by LC-MS. After completion, it was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the residue. This was purified by flash column chromatography (eluting with DCM:MeOH = 80:1) to obtain the crude product. This was then purified again by reverse-phase chromatography (eluting with 0%~36% MeCN in water and 0.1% FA in water) to obtain 10,10-difluoro-7-methyl-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (18 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 324[(M+H) + ]. 1 H NMR (400 MHz, DMSO) δ ppm: 13.28 (s, 1H), 11.50 (s, 1H), 8.21-7.92 (m, 2H), 4.55-4.48 (t, J=27.2 Hz, 2H), 3.51-3.44 (t, J=31.2 Hz, 2H), 2.23 (s, 3H).

[0366] Example 44: 7-(azetidine-1-ylmethyl)-10,10-difluoro-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.04,13 ]trideca-1,4(13),7-triene-5-one [ka] Step A: 10,10-difluoro-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]Trideca-1,4(13),7-triene-7-carbaldehyde [ka] 10,10-difluoro-7-methyl-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a flask containing trideca-1,4(13),7-trien-5-one (75 mg, 291.5 µl), selenium dioxide (308 mg, 2.77 mmol) was added at room temperature. The reaction mixture was then stirred at 130 °C for 6.5 hours. Upon completion, the mixture was diluted with water and extracted with siRNA. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. This was first purified by C18 column (eluting with 0.1% FA in water, water:MeCN = 50:50) to remove 1-methyl-2-pyrrolidinone. Next, this was concentrated to obtain a residue, which was purified twice by flash column chromatography (eluting at DCM:MeOH=30:1), and then purified by silica preparative TLC (eluting at DCM:MeOH=20:1) to obtain 10,10-difluoro-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-triene-7-carbaldehyde (24 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 272[(M+H) + ].

[0367] Step B: 2-bromo-10,10-difluoro-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]Trideca-1,4(13),7-triene-7-carbaldehyde [ka] 10,10-difluoro-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0] in AcOH (6 mL) 4,13 To a flask containing trideca-1,4(13),7-triene-7-carbaldehyde (60 mg, 221.2 μL), liquid bromide (590 mg, 3.69 mmol, 189.45 μL) was added at 0°C. This was then stirred at room temperature for 3 hours. After completion, this was diluted with DCM and added to saturated sodium sulfite solution, and extracted with DCM:MeOH = 10:1. The organic layer was dried over sodium sulfate, filtered, and then concentrated to obtain 2-bromo-10,10-difluoro-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-triene-7-carbaldehyde (60 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 350 [(M+H) + ], 352 [(M+2+H) + ].

[0368] Step C: 7-(azetidine-1-ylmethyl)-2-bromo-10,10-difluoro-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 2-bromo-10,10-difluoro-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0] in 1,2-dichloroethane (8.5 mL) 4,13To a flask containing trideca-1,4(13),7-triene-7-carbaldehyde (60 mg, 171.4 umol), azetidine (39 mg, 685.4 umol) was added at 20°C. The mixture was stirred at 20°C for 1.5 hours. Then, sodium cyanoboranoid (24 mg, 377 umol) was added to the mixture. The reaction was stirred at 20°C for 15 hours. After the reaction was complete, the mixture was quenched with NaHCO3 solution at 0°C and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the crude product. This was purified by silica preparative TLC (eluting with DCM:MeOH = 20:1) to obtain 7-(azetidine-1-ylmethyl)-2-bromo-10,10-difluoro-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (38 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 391 [(M+H) + ], 393 [(M+2+H) + ].

[0369] Step D: 7-(azetidine-1-ylmethyl)-10,10-difluoro-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 7-(azetidine-1-ylmethyl)-2-bromo-10,10-difluoro-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13[Trideca-1,4(13),7-trien-5-one (44 mg, 102.2 umol), 1H-pyrazole-4-ylboronic acid (35 mg, 306.7 umol), Xphos (39 mg, 81.8 umol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.4 mg, 51.1 umol), and disodium carbonate (44 mg, 409.0 umol) were mixed with 1,4-dioxane:H2O=5:1 (3 mL) at room temperature. This mixture was then degassed by bubbling with N2 for 2 minutes. The reaction mixture was then sealed in a tube and stirred in a microwave reactor at 105°C for 1.5 hours. After completion, the reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the residue. This was purified twice by flash column chromatography (eluting with DCM:MeOH = 10:1), and then a third time by C18 column chromatography (eluting with 0.1% FA in water, water:MeCN = 80:20), to obtain 7-(azetidine-1-ylmethyl)-10,10-difluoro-2-(1H-pyrazole-4-yl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0]. 4,13 Trideca-1,4(13),7-trien-5-one (9 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 379 [(M+H) + ]. 1 H NMR (400 MHz, DMSO) δ ppm: 8.09 (s, 2H), 4.57-4.50 (t, J=27.2 Hz, 2H), 3.70-3.53 (m, 6H), 3.23-3.19 (t, J=14 Hz, 2H), 2.01-1.95 (m, 2H).

[0370] The following compounds were prepared from the corresponding bromides by the Suzuki reaction, using a method similar to that exemplified in Example 28. [Table 7]

[0371] Example 46: (R)-2-(1H-pyrazole-4-yl)-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka]

[0372] Example 47: (S)-2-(1H-pyrazole-4-yl)-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] Step A: Methyl 3-amino-4-hydroxythiophene-2-carboxylate [ka] To a solution of methyl 4-hydroxy-3-nitro-thiophene-2-carboxylate (10.41 g, 49.17 mmol, 1.0 equivalent) in CH3COOH (300.0 mL), iron powder (27.49 g, 491.70 mmol, 10.0 equivalent) was added. The mixture was stirred at 60°C for 2 hours. LC-MS showed complete conversion. The solvent was removed under reduced pressure. The residue was extracted with EA, the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (MeOH / DCM, gradient 0-10%) to obtain methyl 3-amino-4-hydroxy-thiophene-2-carboxylate (7.40 g) as a pale yellow solid. Observed MS: (ESI + ): m / z 174.0 [(M+H) + ].

[0373] Step B: Methyl 3-amino-4-penta-4-enoxythiophene-2-carboxylate [ka] To a solution of methyl 3-amino-4-hydroxythiophene-2-carboxylate (10.0 g, 57.57 mmol, 1.0 equivalent) and 5-bromopenta-1-ene (14.73 g, 97.86 mmol, 1.7 equivalents) in DMF (200.0 mL), K2CO3 (12.04 g, 86.35 mmol, 1.5 equivalents) was added. The mixture was stirred at 80°C for 2 hours. LC-MS showed complete conversion. The solvent was removed under vacuum. The residue was extracted with EA, the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (EA / PE, gradient 0-3%) to obtain methyl 3-amino-4-penta-4-enoxythiophene-2-carboxylate (12.50 g) as a yellow solid. Observed MS: (ESI + ): m / z 242.1 [(M+H) + ].

[0374] Step C: Methyl 3-iodo-4-penta-4-enoxythiophene-2-carboxylate [ka] To a solution of methyl 3-amino-4-penta-4-enoxythiophene-2-carboxylate (11.30 g, 45.42 mmol, 1.0 equivalent) and CH2I2 (24.59 g, 90.85 mmol, 2.0 equivalent) in MeCN (22.0 mL), amyl nitrite (8.06 g, 68.14 mmol, 1.5 equivalent) was added. The mixture was stirred at 60°C for 2 hours. LC-MS showed complete conversion. The solvent was removed under vacuum. The reaction mixture was extracted with EA, the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (EA / PE, gradient 0-3%) to obtain methyl 3-iodo-4-penta-4-enoxythiophene-2-carboxylate (5.28 g) as a yellow oil. Observed MS: (ESI + ): m / z 353.0 [(M+H) + ].

[0375] Step D: Methyl 5-methylene-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylate [ka] To a solution of methyl 3-iodo-4-penta-4-enoxythiophene-2-carboxylate (10.40 g, 28.94 mmol, 1.0 equivalent) in DMF (200.0 mL), Pd(PPh3)4 (5.07 g, 4.34 mmol, 0.15 equivalent) and K2CO3 (6.05 g, 43.41 mmol, 1.5 equivalent) were added. The reaction flask was evacuated and filled with a nitrogen atmosphere. The mixture was then stirred at 100°C for 3 hours. LC-MS showed complete conversion. The solvent was removed under reduced pressure. The residue was extracted with EA, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (EA / PE, gradient 0-3%) to obtain methyl 5-methylene-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylate (3.40 g) as a pale yellow solid. Observed MS: (ESI + ): m / z 225.1 [(M+H) + ].

[0376] Step E: 5-Methylene-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylic acid [ka] Methyl 5-methylene-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylate (3.23 g, 14.13 mmol, 1.0 equivalent) was dissolved in a mixed solvent of H2O (20.0 mL) and MeOH (60.0 mL), to which LiOH (512 mg, 21.19 mmol, 1.0 equivalent) was added. The mixture was stirred at 80°C for 3 hours. LC-MS showed complete conversion. The solvent was removed under vacuum. The residue was adjusted to pH=2 with 1 M aqueous HCl and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude 5-methylene-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylic acid (2.97 g) as a white solid, which was used directly in the next step without further purification. Observed MS: (ESI + ): m / z 211.1 [(M+H) + ].

[0377] Step F: 5-Oxo-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylic acid [ka] To a solution of 5-methylene-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylic acid (2.91 g, 13.70 mmol, 1.0 equivalent) and RuCl3 (62 mg, 0.27 mmol, 0.02 equivalents) in MeCN (90.0 mL), a solution of NaIO4 (8.00 g, 37.0 mmol, 2.7 equivalents) and H2SO4 (2.71 g, 27.40 mmol, 2.0 equivalents) in H2O (90.0 mL) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. LC-MS showed complete conversion. The resulting mixture was extracted with EA, the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude 5-oxo-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylic acid (2.92 g) as a yellow solid, which was used directly in the next step without further purification. Observed MS: (ESI + ): m / z 213.1 [(M+H) + ].

[0378] Step G: Ethyl 2-[(2,4-dimethoxyphenyl)methyl-(5-oxo-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carbonyl)amino]acetate [ka] 5-Oxo-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carboxylic acid (2.42 g, 10.26 mmol, 1.0 equivalent), ethyl 2-[(2,4-dimethoxyphenyl)methylamino]acetate (3.22 g, 12.32 mmol, 1.0 equivalent), and HATU (5.91 g, 15.39 mmol, 1.5 equivalents) were dissolved in DMF (65.0 mL), to which DIPEA (2.68 g, 20.53 mmol, 2.0 equivalents) was added at 0°C. The mixture was stirred at room temperature for 1 hour. LC-MS showed complete conversion. The resulting mixture was quenched with water at 0°C, extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (EA / PE, gradient 0-50%) to obtain ethyl 2-[(2,4-dimethoxyphenyl)methyl-(5-oxo-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carbonyl)-amino]acetate (4.00 g) as a yellow oil. Observed MS: (ESI + ): m / z 447.2 [(M+H) + ].

[0379] Step H: Ethyl 6-[(2,4-dimethoxyphenyl)methyl]-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]Trideca-1,4(13),7-triene-7-carboxylate [ka] To a solution of ethyl 2-[(2,4-dimethoxyphenyl)methyl-(5-oxo-3,4-dihydro-2H-thieno[3,4-b]oxepin-6-carbonyl)amino]acetate (3.50 g, 7.83 mmol, 1.0 equivalent) in DMF (35.0 mL), NaH (313 mg, 7.83 mmol, 60% purity, 1.0 equivalent) was added at 0°C. The mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion. The resulting mixture was added to an aqueous citric acid solution (30.0%) at 0°C. The mixture was extracted with EA, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (EA / PE, gradient 0-50%) to obtain ethyl 6-[(2,4-dimethoxyphenyl)methyl]-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-triene-7-carboxylate (2.15 g) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 430.1 [(M+H) + ].

[0380] Step I: Ethyl 5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]Trideca-1,4(13),7-triene-7-carboxylate [ka] Ethyl 6-[(2,4-dimethoxyphenyl)methyl]-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13A solution of trideca-1,4(13),7-triene-7-carboxylate (2.15 g, 5.01 mmol, 1.0 equivalent) in 4 M HCl / dioxane (68.0 mL, 272.0 mmol, 54.0 equivalents) was stirred at 80°C for 3 hours. LC-MS showed complete conversion. The solvent was removed under vacuum. The mixture was extracted with EA, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (EA / DCM, gradient 0-5%) to obtain ethyl 5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-triene-7-carboxylate (1.10 g, 3.94 mmol, yield 78.6%, purity 100.0%) was obtained as a white solid. Observed MS: (ESI + ): m / z 280.0 [(M+H) + ].

[0381] Step J: Ethyl 2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]Trideca-1,4(13),7-triene-7-carboxylate [ka] Ethyl 5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a solution of trideca-1,4(13),7-triene-7-carboxylate (1.13 g, 3.85 mmol, 1.0 equivalent) in DMF (85.0 mL), NBS (822 mg, 4.62 mmol, 1.2 equivalents) was added at 0°C. The mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion. The resulting mixture was extracted with EA, the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (MeOH / DCM, gradient 0-5%) to obtain ethyl 2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13Trideca-1,4(13),7-triene-7-carboxylate (791 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 357.9 [(M+H) + ].

[0382] Step K: 2-bromo-7-(hydroxymethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] Ethyl 2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a solution of trideca-1,4(13),7-triene-7-carboxylate (1.97 g, 5.50 mmol, 1.0 equivalent) in DCM (250 mL), diisobutylaluminum hydride (10.51 g, 22.0 mmol, 4.0 equivalents) was added at -60°C. The mixture was stirred at -60°C for 1 hour. Then, the mixture was stirred overnight at room temperature. LC-MS showed complete conversion. The reaction mixture was quenched with water, extracted with DCM, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (MeOH / DCM, gradient 0-30%) to obtain crude 2-bromo-7-(hydroxymethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (667 mg) was obtained as a yellow solid and used directly in the next step without further purification. Observed MS: (ESI + ): m / z 317.2[(M+H) + ].

[0383] Step L: 2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]Trideca-1,4(13),7-triene-7-carbaldehyde [ka] 2-Bromo-7-(hydroxymethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a solution of trideca-1,4(13),7-trien-5-one (1.70 g, 5.38 mmol, 1.0 equivalent) in DCM (150.0 mL), des-martin periodinane (4.56 g, 10.75 mmol, 2.0 equivalent) was added. The mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion. The resulting mixture was quenched with water, extracted with DCM, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (MeOH / DCM, gradient 0-30%) to obtain 2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-triene-7-carbaldehyde (368 mg) was obtained as a yellow solid. Observed MS: (ESI + ): m / z 313.1, 315.1 [(M+H) + ].

[0384] Step M: 2-bromo-7-(1-hydroxyethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13To a solution of trideca-1,4(13),7-triene-7-carbaldehyde (580 mg, 1.85 mmol, 1.0 equivalent) in THF (50.0 mL), MeMgBr (2.20 g, 18.46 mmol, 10.0 equivalent) was slowly added at 0°C. The mixture was stirred at 0°C for 1 hour. LC-MS showed complete conversion. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude 2-bromo-7-(1-hydroxyethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (470 mg) was obtained as a brown solid and used directly in the next step without further purification. Observed MS: (ESI + ): m / z 330.0, 332.0 [(M+H) + ].

[0385] Step N: 2-bromo-7-(1-chloroethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 2-Bromo-7-(1-hydroxyethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a solution of trideca-1,4(13),7-trien-5-one (360 mg, 1.09 mmol, 1.0 equivalent) in DCM (50.0 mL), SOCl2 (13.34 g, 109.00 mmol, 100 equivalents) was added at °C. The mixture was stirred at room temperature for 2 hours. LC-MS showed complete conversion. The solvent was removed under reduced pressure. The residue was extracted with EA, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain crude 2-bromo-7-(1-chloroethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13Trideca-1,4(13),7-trien-5-one (390 mg) was obtained as a white solid and used directly in the next step without further purification. Observed MS: (ESI + ): m / z 347.9, 349.9 [(M+H) + ].

[0386] Step O: 2-bromo-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] 2-Bromo-7-(1-chloroethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 To a solution of trideca-1,4(13),7-trien-5-one (150 mg, 0.43 mmol, 1.0 equivalent), 1H-pyrazole (75 mg, 1.08 mmol, 2.5 equivalents), and K2CO3 (224 mg, 1.62 mmol, 3.8 equivalents) in ACN (15.0 mL), KI (79 mg, 0.47 mmol, 1.1 equivalents) was added. The mixture was stirred at room temperature for 16 hours. LC-MS showed complete conversion. The solvent was removed under reduced pressure. The resulting mixture was extracted with EA, the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (MeOH / DCM, gradient 0-5%) to obtain 2-bromo-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (110 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 380.0, 382.0 [(M+H) + ].

[0387] Step P: 2-(1H-pyrazole-4-yl)-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13]trideca-1,4(13),7-triene-5-one [ka] 2-bromo-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (100 mg, 0.26 mmol, 1.0 equivalent) and 1H-pyrazole-4-ylboronic acid (60 mg, 0.53 mmol, 2.0 equivalents) were dissolved in a mixed solvent of H2O (2.5 mL) and DMF (5.0 mL). Xphos (38 mg, 0.08 mmol, 0.3 equivalents), Na2CO3 (84 mg, 0.08 mmol, 3.0 equivalents), and Pd(dppf)Cl2 (65 mg, 0.08 mmol, 0.3 equivalents) were added. The mixture was irradiated in a microwave reactor under a nitrogen atmosphere at 100 °C for 2 hours. LC-MS showed complete conversion. The solvent was removed under reduced pressure. The resulting mixture was extracted with EA, the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography (MeOH / DCM, gradient 0-5%) to obtain 2-(1H-pyrazole-4-yl)-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (42 mg) was obtained as a white solid. Observed MS: (ESI + ): m / z 368.1 [(M+H) + ].

[0388] The racemic product was separated by chiral SFC to obtain (R)-2-(1H-pyrazole-4-yl)-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one was obtained as a white solid. [ka] SFC conditions: Column: AD-H, Column size: Inner diameter 0.46 cm * Length 15 cm, Injection: 2 μl, Mobile phase: HEP:EtOH (0.1% DEA) (60:40), Flow rate: 0.5 ml, Wavelength: UV 254 nm, Temperature: 25°C, EtOH solution. Observed MS: (ESI + ): m / z 368.1 [(M+H) + ]. 1 H NMR (400 MHz, DMSO) δ ppm: 13.17 (s, 1H), 10.74 (s, 1H), 8.04 (s, 1H), 7.98 (d, J = 2.4 Hz, 2H), 7.55 (d, J = 1.9 Hz, 1H), 6.32 (t, J = 2.1 Hz, 1H), 5.91-5.96 (m, 1H), 4.26-4.37 (m, 2H), 3.04-3.11 (m, 1H), 2.94-3.01(m, 1H), 2.07-2.15 (m, 2H), 1.84 (d, J = 7.1 Hz, 3H); and (S)-2-(1H-pyrazole-4-yl)-7-(1-pyrazole-1-ylethyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one was obtained as a white solid. [ka] SFC conditions: Column: AD-H, Column size: Inner diameter 0.46 cm * Length 15 cm, Injection: 2 μl, Mobile phase: HEP:EtOH (0.1% DEA) (60:40), Flow rate: 0.5 ml, Wavelength: UV 254 nm, Temperature: 25°C, EtOH solution. Observed MS: (ESI + ): m / z 368.1 [(M+H) + ]. 1¹H NMR (400 MHz, DMSO-d6) δ ppm: 13.17 (s, 1H), 10.74 (s, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.55 (d, J = 1.9 Hz, 1H), 6.32 (t, J = 2.1 Hz, 1H), 5.91-5.96 (m, 1H), 4.26-4.37 (m, 2H), 3.04-3.11 (m, 1H), 2.94-3.01 (m, 1H), 2.07-2.15 (m, 2H), 1.84 (d, J = 7.1 Hz, 3H). The absolute stereochemistry of these two compounds was randomly assigned.

[0389] The following compounds were prepared in the same manner as illustrated in Examples 26 and 27. [Table 8]

[0390] Example 51: 2-(1H-pyrazole-4-yl)-7-(pyrrolidine-1-carbonyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]-trideca-1,4(13),7-triene-5-one [ka] Step A: 2-bromo-7-(pyrrolidine-1-carbonyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]trideca-1,4(13),7-triene-5-one [ka] Ethyl 2-bromo-5-oxo-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13Trideca-1,4(13),7-triene-7-carboxylate (50 mg, 0.14 mmol, 1 equivalent) was dissolved in pyrrolidine (1.5 mL) at room temperature. The mixture was stirred at 80°C for 2 hours. LC-MS indicated that the reaction was complete. The resulting mixture was concentrated and extracted with EA and H2O. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, DCM:MeOH = 50:1~10:1) to obtain 2-bromo-7-(pyrrolidine-1-carbonyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 Trideca-1,4(13),7-trien-5-one (47 mg) was obtained as a white solid. Observed MS:(ESI+): m / z 383.0, 385.0 [(M+H) + ].

[0391] Step B: 2-(1H-pyrazole-4-yl)-7-(pyrrolidine-1-carbonyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13 ]-trideca-1,4(13),7-triene-5-one [ka] 2-Bromo-7-(pyrrolidine-1-carbonyl)-12-oxa-3-thia-6-azatricyclo[6.4.1.0 4,13To a solution of ]-trideca-1,4(13),7-trien-5-one (42 mg, 0.11 mmol, 1.0 equivalent) in a mixed solvent of DMF (3.0 mL) and H2O (0.6 mL), 1H-pyrazole-4-ylboronic acid (24 mg, 0.22 mmol, 2.0 equivalents), Pd(dppf)Cl2 (18 mg, 0.02 mmol, 0.2 equivalents), X-Phos (16 mg, 0.03 mmol, 0.3 equivalents), and NaHCO3 (9 mg, 0.33 mmol, 3.0 equivalents) were added under N2 at room tempe...

Claims

1. Compounds of formula (Ia), (Ib), (Ic), or (Id): 【Chemistry 264】 or a pharmaceutically acceptable salt thereof, in the formula, R １ These are 5-10 member heteroaryl compounds optionally substituted with C1-C6 alkyl groups. Each R ２ These are independently selected from the group consisting of halogens and C1-C6 alkyl groups. R ３ This is selected from C1-C6 alkyl groups substituted with hydrogen and, optionally, 1 to 4 substituents independently selected from the following: (i) Hydroxyl, (ii) Cyano, (iii) Halogen, (iv) C3-C6 cycloalkoxy, (v)C(=O)OR Ｆ 、 (vi) C1-C6 alkoxy, (vii) A 4-10 member heterocyclyloxy compound substituted with 1-3 independently selected halogens, ())) Ｂ ( Ｃ 、 (ix) Optionally, hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, -NR Ｂ R Ｃ , 3-6 membered heterocyclyloxy, and C3-C6 cycloalkyl groups substituted with 1-3 groups independently selected from 3-6 membered heterocyclyl groups optionally substituted with 1-3 C1-C6 alkoxy groups, (x) 3-10 membered heterocyclyl optionally substituted with 1-4 substituents independently selected from halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -NR Ｂ R Ｃ , C1-C6 alkyl substituted with 1 to 3 substituents independently selected from optionally halogen, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and C3-C6 cycloalkyl optionally substituted with halogen or hydroxyl, (xi) Optionally, a C3-C6 cycloalkyl substituted with cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 1-2 substituents independently selected from cyano and hydroxyl, and optionally, 1-3 independently selected R Ａ 5-6 member heteroaryls substituted with 1-3 substituents independently selected from 4-10 member heterocyclines substituted with, and (xii) - C (= O) - X (where X is -NR Ｂ R Ｃ , C1-C6 alkyl, 5-6 membered heteroaryl, -NH-5-6 membered heteroaryl, -OR Ｅ , or a 3- to 6-membered heterocycline optionally substituted with a hydroxyl group), R ３ This is a C1-C6 alkyl group substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkoxy, and 3- to 10-membered heterocyclils, where the 3- to 10-membered heterocyclil is optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, hydroxyl, halogen, and oxo. Each R Ａ These are independently selected from halogens, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylamino, 4-6 membered heterocyclyl, and C3-C6 cycloalkyl. Each R Ｅ These are independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, 4-6 membered heterocyclyl, and C3-C6 cycloalkyl. Each R Ｂ and R Ｃ These are independently substituted with hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(=O)-C1-C6 alkyl, and optionally C1-C6 alkyl, cyano, halogen, hydroxyl, or C3-C6 cycloalkyl -(C1-C6 alkylene). ｐ -C3-C8 cycloalkyl, 3- to 6-membered heterocyclyl optionally substituted with C1-C6 alkyl, -C(=O)O-C1-C6 alkyl, or benzyl optionally substituted with C1-C6 alkoxy, or R Ｂ and R Ｃ Together with the atoms to which they are attached, they form a unified, optionally forming halogens, hydroxyls, cyanos, C1-C6 alkyls, and -NRs. Ｆ R Ｇ , forming 4-10 membered heterocyclines substituted with 1-3 substituents independently selected from C3-C6 cycloalkoxy, C1-C6 haloalkoxy, and C1-C6 alkoxy, Each p is independently either 0 or 1. m is either 1 or 2. Each R Ｆ and R Ｇ The compound, or a pharmaceutically acceptable salt thereof, is independently hydrogen or a C1-C6 alkyl group.

2. R １ The compound according to claim 1, wherein the compound is a 5-6 member heteroaryl substituted with a C1-C6 alkyl group.

3. R １ The compound according to claim 1, wherein the compound is an unsubstituted 5-6 member heteroaryl.

4. Each R ２ The compound according to any one of claims 1 to 3, wherein the compound is independently a C1-C6 alkyl group.

5. Each R ２ The compound according to any one of claims 1 to 3, wherein the compound is independently a halogen.

6. m is 1, R ２ The compound according to any one of claims 1 to 3, wherein the compound is an unsubstituted C1-C6 alkyl group.

7. m is 2, and each R ２ The compound according to any one of claims 1 to 3, wherein the compound is independently a halogen.

8. R ３ The compound according to any one of claims 1 to 7, wherein the compound is a C1-C6 alkyl group substituted with one to three substituents independently selected from hydroxyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkoxy, and C3-C6 cycloalkyl groups.

9. R ３ The compound according to any one of claims 1 to 7, wherein the C1-C6 alkyl is substituted with 1 to 3 substituents independently selected from hydroxyl, C1-C6 alkoxy, and 3- to 10-membered heterocyclil, and the 3- to 10-membered heterocyclil is optionally substituted with 1 to 3 substituents selected from C1-C6 alkyl, hydroxyl, halogen, and oxo.

10. R ３ The compound according to any one of claims 1 to 7, wherein each is a C1-C6 alkyl substituted with azetidine, pyrrolidine, or piperidine, which is optionally substituted with a C1-C6 alkyl, hydroxyl, or halogen.

11. R ３ but, 【Chemistry 240】 The compound according to any one of claims 1 to 7 or 10.

12. R ３ but, 【Chemistry 241】 The compound according to any one of claims 1 to 7 or 10.

13. R ３ However, -NR Ｂ R Ｃ The compound according to any one of claims 1 to 7, wherein the compound is a C1-C6 alkyl group substituted with [a specific compound].

14. R Ｂ and R Ｃ The compound according to claim 13, wherein each is independently a benzyl substituted with hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C(=O)-C1-C6 alkyl group, a C(=O)-O-C1-C6 alkyl group, or a C1-C6 alkoxy group. 【Request Item 15】 【Table 1-17】 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

17. A composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use in a method of treating cancer in a subject in need thereof, wherein the method is (a) To determine whether the cancer is associated with dysregulation of the CDC7 gene, dysregulation of CDC7 kinase, dysregulation of CDC7 gene expression, or dysregulation of the activity level of CDC7 kinase, (b) If it is determined that the cancer is related to dysregulation of the CDC7 gene, dysregulation of CDC7 kinase, dysregulation of CDC7 gene expression, or dysregulation of the activity level of CDC7 kinase, the subject is administered the composition or the pharmaceutical composition. A composition or pharmaceutical composition containing the following.

18. The composition for use or pharmaceutical composition according to claim 17, wherein the method further comprises administering an additional therapy or therapeutic agent to the subject.

19. The composition for use or pharmaceutical composition according to claim 18, wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutic agents, kinase-targeted therapeutic agents, apoptosis modulators, signaling inhibitors, immunotargeted therapies, and angiogenesis-targeted therapies.

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