Inhibitors of CDK8 and CDK19

Abstract

The present invention relates to compounds of formula I and their use as CDK8 and / or CDK19 inhibitors. 【Chemical 1】 TIFF2025516353000084.tif5748

Description

Technical Field

[0001] The present invention relates to compounds of formula I and their use as CDK8 and / or CDK19 inhibitors.

Background Art

[0002] CDK8 and its paralog CDK19, collectively referred to as "mediator kinases", are cyclin-dependent kinases that have been implicated as important rheostats in cell homeostasis and developmental programming. CDK8 and CDK19 are mutually exclusively incorporated as part of a 4-protein complex called the mediator kinase module. This module reversibly binds to mediator, a 26-subunit protein complex that regulates RNA polymerase II-mediated gene expression. As part of this complex, mediator kinases have been associated with diverse processes such as developmental signaling, metabolic homeostasis, and innate immunity. In recent years, dysregulation of mediator kinase module proteins, including CDK8 / 19, has been associated with the development of various human diseases, particularly cancer.

Summary of the Invention

[0003] According to an aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

Chemical Formula

[0004]

Chemical formula

[0005] Preferably, R 1 ~R 4 is independently selected from hydrogen and halogen, preferably hydrogen and fluoro. Preferably, R 1 is hydrogen. Preferably, R 2 is hydrogen or halogen, preferably hydrogen or fluoro. Preferably, R 3 is hydrogen. Preferably, R 4 is hydrogen. Preferably, R 5 and R 6 are independently selected from hydrogen, optionally substituted alkyl, -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclyl), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino), and -CO-(L) n -CO-(optionally substituted amino).

[0006] Preferably, R 5 is hydrogen. Preferably, R 6 is optionally substituted alkyl, -CO-(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclyl), -CO-(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino), and -CO-(L) n -CO-(optionally substituted amino).

[0007] Preferably, R 6 is optionally substituted C 1-C 12 Alkyl; -CO-(optionally substituted C 1 -C 12 alkyl); -CO-(L) n -(optionally substituted azetidinyl), -CO-(L) n -(optionally substituted oxetanyl), -CO-(L) n -(optionally substituted tetrahydrofuranyl), -CO-(L) n -(optionally substituted pyranyl), -CO-(L) n -(optionally substituted piperidinyl), -CO-(L) n -(optionally substituted piperazinyl), -CO-(L) n -(optionally substituted pyrrolidinyl), -CO-(L) n -(optionally substituted imidazolidinyl), -CO-(L) n -(optionally substituted imidazolinyl), -CO-(L) n -(optionally substituted indolinyl), -CO-(L) n -(optionally substituted isoindolinyl), -CO-(L) n -(optionally substituted quinuclidinyl), -CO-(L) n -(optionally substituted morpholinyl), -CO-(L) n -(optionally substituted isochromanyl), -CO-(L) n -(optionally substituted chromanyl), -CO-(L) n -(optionally substituted pyrazolidinyl), -CO-(L) n -(optionally substituted pyrazolinyl), -CO-(L) n -(optionally substituted tetronoyl), and -CO-(L) n -(optionally substituted tetramoyl); -CO-(optionally substituted thienyl), -CO-(optionally substituted benzo[b]thienyl), -CO-(optionally substituted naphtho[2,3-b]thienyl), -CO-(optionally substituted thianthrenyl), -CO-(optionally substituted furyl), -CO-(optionally substituted benzofuranyl), -CO-(optionally substituted isobenzofuranyl), -CO-(optionally substituted chromenyl), -CO-(optionally substituted xanthenyl), -CO-(optionally substituted phenoxanthiinyl), -CO-(optionally substituted pyrrolyl), -CO-(optionally substituted imidazolyl), -CO-(optionally substituted pyrazolyl), -CO-(optionally substituted triazolyl), -CO-(optionally substituted tetrazolyl), -CO-(optionally substituted pyridyl), -CO-(optionally substituted pyrazinyl), -CO-(optionally substituted pyrimidinyl), -CO-(optionally substituted pyridazinyl), -CO-(optionally substituted triazinyl), -CO-(optionally substituted tetrazinyl), -CO-(optionally substituted indolizinyl), -CO-(optionally substituted isoindolyl), -CO-(optionally substituted 3H-indolyl), -CO-(optionally substituted indolyl), -CO-(optionally substituted indazolyl), -CO-(optionally substituted purinyl), -CO-(optionally substituted 4H-quinolizinyl), -CO-(optionally substituted isoquinolyl), -CO-(optionally substituted quinolyl), -CO-(optionally substituted phthalazinyl), -CO-(optionally substituted naphthyridinyl), -CO-(optionally substituted quinozalinyl), -CO-(optionally substituted cinnolinyl), -CO-(optionally substituted pteridinyl), -CO-(optionally substituted carbazolyl), -CO-(optionally substituted β-carbolinyl), -CO-(optionally substituted phenanthridinyl), -CO-(optionally substituted acrindinyl), -CO-(optionally substituted perimidinyl)-CO-(optionally substituted phenanthrolinyl), -CO-(optionally substituted phenazinyl), -CO-(optionally substituted isothiazolyl), -CO-(optionally substituted phenothiazinyl), -CO-(optionally substituted isoxazolyl), -CO-(optionally substituted phthalazinyl), -CO-(optionally substituted phenoxazinyl), -CO-(optionally substituted pyrazolo[1,5-α]pyrimidinyl), -CO-(optionally substituted 1,2-benzisoxazol-3-yl), -CO-(optionally substituted benzimidazolyl), -CO-(optionally substituted 2-oxyindolyl), and -CO-(optionally substituted 2-oxobenzimidazolyl); -CO-(L) n -(optionally substituted thienyl), -CO-(L) n -(optionally substituted benzo[b]thienyl), -CO-(L) n -(optionally substituted naphtho[2,3-b]thienyl), -CO-(L) n -(optionally substituted thianthrenyl), -CO-(L) n -(optionally substituted furyl), -CO-(L) n -(optionally substituted benzofuranyl), -CO-(L) n -(optionally substituted isobenzofuranyl), -CO-(L) n -(optionally substituted chromenyl), -CO-(L) n -(optionally substituted xanthenyl), -CO-(L) n -(optionally substituted phenoxanthiinyl), -CO-(L) n -(optionally substituted pyrrolyl), -CO-(L) n -(optionally substituted imidazolyl), -CO-(L) n -(optionally substituted pyrazolyl), -CO-(L) n -(optionally substituted triazolyl), -CO-(L) n -(optionally substituted tetrazolyl), -CO-(L) n-(optionally substituted pyridyl), -CO-(L) n -(optionally substituted pyrazinyl), -CO-(L) n -(optionally substituted pyrimidinyl), -CO-(L) n -(optionally substituted pyridazinyl), -CO-(L) n -(optionally substituted triazinyl), -CO-(L) n -(optionally substituted tetrazinyl), -CO-(L) n -(optionally substituted indolizinyl), -CO-(L) n -(optionally substituted isoindolyl), -CO-(L) n -(optionally substituted 3H-indolyl), -CO-(L) n -(optionally substituted indolyl), -CO-(L) n -(optionally substituted indazolyl), -CO-(L) n -(optionally substituted purinyl), -CO-(L) n -(optionally substituted 4H-quinolizinyl), -CO-(L) n -(optionally substituted isoquinolyl), -CO-(L) n -(optionally substituted quinolyl), -CO-(L) n -(optionally substituted phthalazinyl), -CO-(L) n -(optionally substituted naphthyridinyl), -CO-(L) n -(optionally substituted quinoxalinyl), -CO-(L) n -(optionally substituted cinnolinyl), -CO-(L) n -(optionally substituted pteridinyl), -CO-(L) n -(optionally substituted carbazolyl), -CO-(L) n -(optionally substituted β-carbolinyl), -CO-(L) n -(optionally substituted phenanthridinyl), -CO-(L) n -(optionally substituted acrindinyl), -CO-(L) n-(optionally substituted perimidinyl), -CO-(L) n -(optionally substituted phenanthrolinyl), -CO-(L) n -(optionally substituted phenazinyl), -CO-(L) n -(optionally substituted isothiazolyl), -CO-(L) n -(optionally substituted phenothiazinyl), -CO-(L) n -(optionally substituted isoxazolyl), -CO-(L) n -(optionally substituted furazanyl), -CO-(L) n -(optionally substituted phenoxazinyl), -CO-(L) n -(optionally substituted pyrazolo[1,5-α]pyrimidinyl), -CO-(L) n -(optionally substituted 1,2-benzisoxazol-3-yl), -CO-(L) n -(optionally substituted benzimidazolyl), -CO-(L) n -(optionally substituted 2-oxyindolyl), and -CO-(L) n -(optionally substituted 2-oxobenzimidazolyl); -CO-(L) n -(di(C 1 -C 12 alkyl)amino); and -CO-(L) n -CO-(di(C 1 -C 12 alkyl)amino) is selected from.

[0008] Preferably, R 6 is optionally substituted C 1 -C 6 alkyl; -CO-(optionally substituted C 1 -C 6 alkyl); -CO-(L) n -(optionally substituted oxetanyl); -CO-(optionally substituted imidazolyl); -CO-(L) n -(optionally substituted pyrazinyl); -CO-(L) n -(optionally substituted pyrimidinyl); -CO-(L) n -(di(C 1 -C 6 alkyl)amino); and -CO-(L) n -CO-(di(C 1 -C 6 alkyl)amino) selected from the following. Preferably, R 6 is optionally substituted C 1 -C 4 alkyl; -CO-(optionally substituted C 1 -C 4 alkyl); -CO-(L) n -(optionally substituted oxetanyl) (wherein the oxetanyl group has the following structure

[0009]

Chemical formula

Chemical formula

[0010]

Chemical formula

[0011] Preferably, each L is independently selected from optionally substituted alkylene and optionally substituted heteroarylene. Preferably, each L is independently selected from optionally substituted C 1 -C 12 alkylene and optionally substituted imidazolylene. Preferably, n is 0 or 2. Preferably, n is 0. Preferably, (L) n is (optionally substituted heteroarylene)-(optionally substituted alkylene).

[0012] Preferably, (L) n is (optionally substituted thienylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted benzo[b]thienylene)-(optionally substituted C 1 -C12 (alkylene), (optionally substituted naphtho[2,3-b]thienylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted thianthrenylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted furylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted benzofuranylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted isobenzofuranylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted chromenylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted xanthenylenylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted phenoxanthiinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrrolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted imidazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted triazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted tetrazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyridylene)-(optionally substituted C 1 -C 12(alkylene), (optionally substituted pyrazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrimidinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyridazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted triazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted tetrazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted indolizinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted isoindolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted 3H-indolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted indolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted indazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted purinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted 4H-quinolizinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted isoquinolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted quinolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted phthalazinylene)-(optionally substituted C 1 -C12 (alkylene), (optionally substituted naphthyridinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted quinoxalinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted cinnolinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted pteridinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted carbazolylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted β-carbolinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted phenanthridinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted acrindinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted perimidinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted phenanthrolinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted phenazinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted isothiazolylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted phenothiazinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted isoxazolylene)-(optionally substituted C 1 -C 12(alkylene), (optionally substituted phthalanylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted phenoxazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrazolo[1,5-α]pyrimidinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted 1,2-benzisoxazol-3-yl)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted benzimidazolyl)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted 2-oxoindolyl)-(optionally substituted C 1 -C 12 (alkylene), and (optionally substituted 2-oxobenzimidazolyl)-(optionally substituted C 1 -C 12 is selected from (alkylene).

[0013] Preferably, (L) n is (optionally substituted imidazolyl)-(optionally substituted C 1 -C 6 (alkylene). Preferably, (L) n is [Chemical formula] is selected from. (In the formula, ** represents the connection point to the remaining CO group, and *** represents the connection point to an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted amino group, or a CO-(optionally substituted amino) group)

[0014] Preferably, the compound is selected from Compounds 1 to 10.

Chem.

[0015] Preferably, the compound is Compound 11.

Chem.

[0016] Preferably, the compound is not any of the following.

Chem.

[0017] According to another aspect of the present invention, there is provided a composition comprising a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

Chem.

[0018] According to another aspect of the present invention, there is provided a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof; or the composition as defined herein; or the dosage form as defined herein for use in the treatment of a disease modulated by CDK8 and / or CDK19.

Chem.

[0019] Preferably, the disease modulated by CDK8 and / or CDK19 is cancer. Preferably, the cancer is selected from leukemia (e.g., acute myeloid leukemia), bladder cancer (e.g., bladder carcinoma), breast cancer, colon cancer, skin cancer (e.g., cutaneous melanoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), glioblastoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma of the kidney), liver cancer (e.g., liver cancer, hepatocellular carcinoma), brain cancer (e.g., low-grade glioma), lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma), ovarian cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), adrenal cancer (e.g., pheochromocytoma), paraganglioma, prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer (e.g., rectal adenocarcinoma), sarcoma, stomach cancer (e.g., gastric adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor), thyroid cancer (e.g., thyroid carcinoma), and uterine cancer (e.g., endometrial carcinoma of the uterine body).

[0020] According to another aspect of the present invention, use in the manufacture of a medicament for treating a disease modulated by CDK8 and / or CDK19 of a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof; or a composition as defined herein; or a dosage form as defined herein,

Chemical formula

[0021] According to another aspect of the present invention, a method of treating a disease in a patient in need of treatment of a disease modulated by CDK8 and / or CDK19, comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof; or a composition as defined herein; or a dosage form as defined herein,

Chemical formula

[0022] According to another aspect of the present invention, there is provided a kit comprising instructions for use of a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof; or a composition as defined herein; or a dosage form as defined herein; and the use of the compound, composition or dosage form in the treatment of a disease modulated by CDK8 and / or CDK19,

Chemical Formula

Brief Description of the Drawings

[0023]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0024] The following applies to all aspects of the present invention. General Chemical Definitions As used herein, the terms "halo" or "halogen" refer to any group of fluorine, chlorine, bromine or iodine. In this specification, the term "alkyl" refers to both straight-chain and branched-chain groups having up to 12 carbon atoms. For example, an alkyl group can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. C 1 -C 12 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl groups. Preferably, in this specification, the term "alkyl" can refer to a straight-chain or branched-chain group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. A "optionally substituted alkyl" group can contain substituents as described below for the term "optionally substituted". For example, an "optionally substituted alkyl" group can include a "haloalkyl" group.

[0025] In this specification, the term "haloalkyl" refers to both straight-chain and branched-chain groups having up to 12 carbon atoms and containing at least one halogen atom. For example, a haloalkyl group can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Preferably, in this specification, the term "haloalkyl" can refer to a straight-chain or branched-chain group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms and containing at least one halogen atom. For example, a "haloalkyl" group can be a fluoroalkyl group or a perfluoroalkyl group. Preferably, a "haloalkyl" group is C 1 -C 6 a fluoroalkyl group, or C 1 -C 6 a perfluoroalkyl group.

[0026] Even more preferably, a "haloalkyl" group is C 1 -C 4 a fluoroalkyl group, or C 1 -C4 It can be a perfluoroalkyl group. For example, as the "haloalkyl" group, difluoromethyl, trifluoromethyl or pentafluoroethyl can be mentioned. In this specification, the term "cycloalkyl" refers to an alkyl group containing a closed ring having 3 to 8 carbon atoms, for example 3 to 6 carbon atoms. For example, the cycloalkyl group can contain 3, 4, 5, 6, 7 or 8 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (cyclohexyl)methyl, and (cyclohexyl)ethyl. The "optionally substituted cycloalkyl" group can contain substituents described below for the term "optionally substituted".

[0027] In this specification, the term "heterocyclyl" consists of carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of O, N, and S, the nitrogen and sulfur heteroatoms may be oxidized, and the nitrogen may be quaternized, and refers to a saturated or partially saturated 3- to 7-membered monocyclic ring system or 7- to 10-membered bicyclic ring system, and includes any bicyclic group in which any of the rings defined above is condensed to a benzene ring, and the ring may be substituted on a carbon or nitrogen atom as long as the resulting compound is stable. Non-limiting examples of common saturated or partially saturated heterocyclyl groups include azetidinyl, oxetanyl, tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups. The "optionally substituted heterocyclyl" group can contain substituents described below for the term "optionally substituted". As used herein, the term "alkoxy" refers to an alkyl group as defined herein that is attached to the parent molecular moiety through an oxygen atom. For example, an alkoxy group can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Preferably, as used herein, "alkoxy" can refer to a straight-chain or branched-chain group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms, which is attached to the parent molecular moiety through an oxygen atom, either by itself or as part of another group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. A "optionally substituted alkoxy" group can contain substituents as described below for the term "optionally substituted". For example, a "haloalkoxy" group can be mentioned as an example of an "optionally substituted alkoxy" group.

[0028] As used herein, the term "haloalkoxy" refers to both straight-chain and branched-chain groups having up to 12 carbon atoms that contain at least one halogen atom and are attached to the parent molecular moiety through an oxygen atom. For example, a haloalkoxy group can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Preferably, as used herein, the term "haloalkoxy" can refer to a straight-chain or branched-chain group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms, which contains at least one halogen atom and is attached to the parent molecular moiety through an oxygen atom, either by itself or as part of another group. For example, a "haloalkoxy" group can be a fluoroalkoxy or perfluoroalkoxy group.

[0029] Preferably, a "haloalkoxy" group is a 1 -C 6 fluoroalkoxy group, or a 1 -C 6 perfluoroalkoxy group. More preferably, the "haloalkoxy" group is C 1 -C 4 a fluoroalkoxy group, or C 1 -C 4 a perfluoroalkoxy group. For example, examples of the "haloalkoxy" group include difluoromethoxy, trifluoromethoxy, or pentafluoroethoxy. In this specification, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms in the ring. General aryl groups include C 6 -C 14 aryl, for example C 6 -C 10 aryl. C 6 -C 14 Non-limiting examples of the aryl group include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylylenyl, and fluorenyl groups. The "optionally substituted aryl" group can include substituents as described below for the term "optionally substituted".

[0030] As used herein, the term "heteroaryl" refers to an aromatic group having from 5 to 14 ring atoms (e.g., from 5 to 10 ring atoms) and containing carbon atoms and 1, 2, or 3 oxygen, nitrogen, or sulfur heteroatoms. Examples of heteroaryl groups include, but are not limited to, thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl (including, but not limited to, 2H-pyrrolyl), imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl (including, but not limited to, 2-pyridyl, 3-pyridyl, and 4-pyridyl; pyridinyl), pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, pyrazolo[1,5-α]pyrimidin-3-yl (pyrazolo[1,5-α]pyrimidinyl, including, but not limited to), 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxoindolyl, and 2-oxobenzimidazolyl. When a heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom can take the form of an N-oxide, e.g., N-oxide pyridyl, N-oxide pyrazinyl, and N-oxide pyrimidinyl. The term "optionally substituted heteroaryl" group can include substituents as described below for the term "optionally substituted".

[0031] As used herein, the term "amino" refers to -NR’ 2The term "group (wherein R' is hydrogen or an optional substituent)" is meant. The term "optionally substituted amino" group can include substituents as described hereinafter for the term "optionally substituted". As used herein, the term "alkylene" refers to both straight-chain and branched-chain divalent groups having up to 12 carbon atoms. For example, an alkylene group can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. C 1 -C 12 Non-limiting examples of alkylene groups include methylene, ethylene, propylene, isopropylene, butylene, sec-butylene, tert-butylene, 3-pentylene, hexylene, and octylene groups. Preferably, as used herein, the term "alkylene" can refer to a straight-chain or branched-chain divalent group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. The term "optionally substituted alkylene" group can include substituents as described hereinafter for the term "optionally substituted".

[0032] As used herein, the term "heteroarylene" refers to a divalent aromatic group having 5 to 14 ring atoms (e.g., 5 to 10 ring atoms) and containing carbon atoms and 1, 2, or 3 oxygen, nitrogen, or sulfur heteroatoms. Examples of heteroarylene groups include, but are not limited to, thienylene (thiophenylene), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (furanylene), benzofuranylene, isobenzofuranylene, chromenylene, xanthenylene, phenoxanthiinylene, pyrrolylene (including, but not limited to, 2H-pyrrolylene), imidazolylene, pyrazolylene, triazolylene, tetrazolylene, pyridylene (including, but not limited to, 2-pyridylene, 3-pyridylene, and 4-pyridylene), pyrazinylene, pyrimidinylene, pyridazinylene, triazinylene, tetrazinylene, indolizinylene, isoindolylene, 3H-indolylene, indolylene, indazolylene, purinylene, 4H-quinolizinylene, isoquinolylene, quinolylene, phthalazinylene, naphthyridinylene, quinozalinylene, cinnolinylene, pteridinylene, carbazolylene, β-carbolinylene, phenanthridinylene, acrindinylene, perimidinylene, phenanthrolinylene, phenazinylene, isothiazolylene, phenothiazinylene, isoxazolylene, furazanylene, phenoxazinylene, pyrazolo[1,5-α]pyrimidinylene (including, but not limited to, pyrazolo[1,5-α]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzimidazolylene, 2-oxyindolylene, and 2-oxobenzimidazolylene. When a heteroarylene group contains a nitrogen atom in the ring, such nitrogen atoms can take the form of N-oxides, such as N-oxide pyridylene, N-oxide pyrazinylene, and N-oxide pyrimidinylene. The term "optionally substituted heteroarylene" group can include substituents as described hereinafter for the term "optionally substituted".

[0033] As described herein, a compound can include a "optionally substituted" moiety. Generally, the term "substituted", whether or not followed by the term "optionally", means replacing one or more hydrogen atoms of the designated moiety with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at any substitutable position of the group, and when more than one position of a given structure can be substituted with more than one substituent selected from the designated groups, the substituents can be the same or different at any position. The combinations of substituents contemplated by the present invention are preferably combinations that form stable or chemically suitable compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when placed in a state that enables their generation, detection, and in some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0034] For example, as used herein, the term "optionally substituted" can refer to the case where at least one substituent is selected from the non-limiting examples such as oxo, hydroxy, halogen, cyano, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, haloalkoxy, -CO-(optionally substituted alkyl), -CO-(optionally substituted alkoxy), optionally substituted amino, optionally substituted aryl, and optionally substituted heteroaryl. Preferably, as used herein, the term "optionally substituted" can refer to the case where at least one substituent is selected from oxo, hydroxy, halogen, cyano, alkyl, haloalkyl, cycloalkyl, heterocyclyl, alkoxy, haloalkoxy, -CO-(alkyl), -CO-(alkoxy), amino, aryl, and heteroaryl.

[0035] More preferably, in this specification, the term "optionally substituted" means that at least one substituent is selected from oxo, hydroxy, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, 3- to 10-membered heterocyclyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CO-(C 1 -C 6 alkyl), -CO-(C 1 -C 6 alkoxy), amino, 5- to 14-membered aryl and 5- to 14-membered heteroaryl.

[0036] The conjugate of the present invention can be provided in the form of a "salt". As used herein, the term "salt" refers to salts of the compounds described herein derived from suitable inorganic and organic acids and bases. Examples of salts of basic groups include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as trifluoroacetic acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or those formed by using other methods used in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1 -C 4 alkyl) 4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkylsulfonates and arylsulfonates where appropriate.

[0037] Some compounds of the present disclosure can exist in solvated forms, including non-solvated forms and hydrate forms. "Hydrate" refers to a complex formed by the combination of water molecules with molecules or ions of a solute. "Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvates are intended to include hydrates. Some examples of solvents include, but are not limited to, methanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. In general, solvated forms are equal to non-solvated forms and are included within the scope of the present disclosure. Some compounds of the present disclosure can exist, for example, as multiple crystalline or amorphous solid materials. In general, all physical forms are equivalent in the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0038] "Tautomers" mean compounds generated by the phenomenon in which a proton of an atom in a molecule moves to another atom (see Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992)). Tautomers also refer to one of two or more structural isomers that exist in an equilibrium state and can be easily converted from one isomeric form to another. Examples include keto-enol tautomers such as acetone / propen-2-ol, imine-enamine tautomers, ring-chain tautomers such as glucose / 2,3,4,5,6-pentahydroxy-hexanal, and tautomeric forms of heteroaryl groups containing -N=C(H)-NH-ring atom sequences such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. When a compound contains, for example, a keto or oxime group or an aromatic moiety, isomerism of the tautomers ("tautomerism") may occur. The compounds described herein can have one or more tautomers and can thus include various isomers. One of ordinary skill in the art should recognize that other tautomeric ring atom sequences may be possible. All such isomeric forms of these compounds are expressly included in this disclosure.

[0039] "Isomers" means compounds having the same molecular formula but differing in the nature or sequence of their atomic bonds or the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". "Stereoisomers" refer to compounds that exist as different stereoisomers when they have one or more chiral centers or double bonds with asymmetric substitution and can thus be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has a chiral center, for example, when the chiral center is bonded to four different groups, a pair of enantiomers can be considered. Enantiomers can be characterized by the absolute configuration of their chiral centers, described by the Cahn and Prelog R- and S-rank rules, or designated as dextrorotatory or levorotatory ((+) or (-)-isomers respectively) by the manner in which the molecule rotates the plane of polarization. Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture". Unless otherwise indicated, the description is intended to include individual stereoisomers and mixtures. Methods for determining stereochemistry and methods for separating stereoisomers with different chirality at one or more stereocenters are well known in the art (see the discussion in Chapter 4 of Advanced Organic Chemistry, 6th edition J. March, John Wiley and Sons, New York, 2007).

[0040] This disclosure also encompasses isotope-labeled compounds of this disclosure that are identical to those recited herein except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H (deuterium, D), 3 H (tritium),11 C 13 C 14 C 15 N 18 F 31 P 32 P 35 S 36 Cl, and 125 I are included, but not limited to these. Unless otherwise specified, when the position is specifically designated as "H" or "hydrogen", the position is hydrogen with its natural abundance isotope composition, or its isotopes, such as deuterium (D) or tritium ( 3 H). It is understood to have. Some isotope-labeled compounds of the present disclosure (e.g., 3 compounds labeled with H and 14 C) are useful in compound and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) and fluorine-18 (i.e., 18 F) isotopes are useful for their ease of preparation and detection. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., 2 H), can result in some therapeutic advantages (e.g., increased in vivo half-life or reduced required dose) due to increased metabolic stability, and is therefore sometimes preferred in some situations. The isotope-labeled compounds of the present disclosure can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents according to procedures similar to those described herein.

[0041] Compound In another embodiment of the invention, a compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof is provided herein.

Chemical formula

[0042] In formula I, R 1 is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted amino. Preferably, R 1 is selected from hydrogen, hydroxy, halogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 -C 12 alkoxy, and optionally substituted amino. More preferably, R 1 is selected from hydrogen and halogen. Even more preferably, R 1 is selected from hydrogen and fluoro. Even more preferably, R 1 can be hydrogen. In formula I, R 2 is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted amino. Preferably, R 2 is selected from hydrogen, hydroxy, halogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 -C 12 alkoxy, and optionally substituted amino.

[0043] More preferably, R 2may be selected from hydrogen and halogen. Even more preferably, R 2 may be selected from hydrogen and fluoro. Even more preferably, R 2 can be hydrogen. In formula I, R 3 is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted amino. Preferably, R 3 is selected from hydrogen, hydroxy, halogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 -C 12 alkoxy, and optionally substituted amino. More preferably, R 3 may be selected from hydrogen and halogen. Even more preferably, R 3 may be selected from hydrogen and fluoro. Even more preferably, R 3 can be hydrogen.

[0044] In formula I, R 4 is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted amino. Preferably, R 4 is selected from hydrogen, hydroxy, halogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 1 -C 12 alkoxy, and optionally substituted amino. More preferably, R 4 may be selected from hydrogen and halogen. Even more preferably, R 4 may be selected from hydrogen and fluoro. Even more preferably, R 4can be hydrogen.

[0045] In formula I, R 5 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, and optionally substituted heteroaryl; -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted cycloalkyl), -CO-(L) n -(optionally substituted heterocyclyl), -CO-(L) n -(optionally substituted alkoxy), -CO-(L) n -(optionally substituted aryl), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino), and -CO-(L) n -CO-(optionally substituted amino) (wherein each L is independently optionally substituted alkylene, (O-alkylene) w , optionally substituted heteroarylene, O and NH, n is selected from 0, 1 and 2, w is selected from 1, 2 and 3); and -SO 2 -(optionally substituted alkyl), -SO 2 -(optionally substituted cycloalkyl), -SO 2 -(optionally substituted heterocyclyl), -SO 2 -(optionally substituted alkoxy), -SO 2 -(optionally substituted aryl), -SO 2 -(optionally substituted heteroaryl), and -SO 2 -(optionally substituted amino) selected from. Preferably, R 5is hydrogen, optionally substituted alkyl, -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclyl), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino), and -CO-(L) n -CO-(optionally substituted amino). More preferably, R 5 can be hydrogen.

[0046] In formula I, R 6 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, and optionally substituted heteroaryl; -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted cycloalkyl), -CO-(L) n -(optionally substituted heterocyclyl), -CO-(L) n -(optionally substituted alkoxy), -CO-(L) n -(optionally substituted aryl), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino), and -CO-(L) n -CO-(optionally substituted amino) (wherein each L is independently optionally substituted alkylene, (O-alkylene) w optionally substituted heteroarylene, O and NH, n is selected from 0, 1 and 2, w is selected from 1, 2 and 3); and -SO 2 -(optionally substituted alkyl), -SO2 -(optionally substituted cycloalkyl), -SO 2 -(optionally substituted heterocyclyl), -SO 2 -(optionally substituted alkoxy), -SO 2 -optionally substituted aryl), -SO 2 -(optionally substituted heteroaryl), and -SO 2 -optionally substituted amino) selected from the group consisting of

[0047] Preferably, R 6 is hydrogen, optionally substituted alkyl, -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclyl), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino), and -CO-(L) n -CO-(optionally substituted amino).

[0048] More preferably, R 6 is optionally substituted C 1 -C 12 alkyl; -CO-(optionally substituted C 1 -C 12 alkyl); -CO-(L) n -(optionally substituted azetidinyl), -CO-(L) n -(optionally substituted oxetanyl), -CO-(L) n -(optionally substituted tetrahydrofuranyl), -CO-(L) n -(optionally substituted pyranyl), -CO-(L) n -(optionally substituted piperidinyl), -CO-(L) n -(optionally substituted piperazinyl), -CO-(L) n -(optionally substituted pyrrolidinyl), -CO-(L)n -(optionally substituted imidazolidinyl), -CO-(L) n -(optionally substituted imidazolinyl), -CO-(L) n -(optionally substituted indolinyl), -CO-(L) n -(optionally substituted isoindolinyl), -CO-(L) n -(optionally substituted quinuclidinyl), -CO-(L) n -(optionally substituted morpholinyl), -CO-(L) n -(optionally substituted isochromanyl), -CO-(L) n -(optionally substituted chromanyl), -CO-(L) n -(optionally substituted pyrazolidinyl), -CO-(L) n -(optionally substituted pyrazolinyl), -CO-(L) n -(optionally substituted tetronoyl), and -CO-(L) n -(optionally substituted tetramoyl); -CO-(optionally substituted thienyl), -CO-(optionally substituted benzo[b]thienyl), -CO-(optionally substituted naphtho[2,3-b]thienyl), -CO-(optionally substituted thianthrenyl), -CO-(optionally substituted furyl), -CO-(optionally substituted benzofuranyl), -CO-(optionally substituted isobenzofuranyl), -CO-(optionally substituted chromenyl), -CO-(optionally substituted xanthenyl), -CO-(optionally substituted phenoxanthiinyl), -CO-(optionally substituted pyrrolyl), -CO-(optionally substituted imidazolyl), -CO-(optionally substituted pyrazolyl), -CO-(optionally substituted triazolyl), -CO-(optionally substituted tetrazolyl), -CO-(optionally substituted pyridyl), -CO-(optionally substituted pyrazinyl), -CO-(optionally substituted pyrimidinyl), -CO-(optionally substituted pyridazinyl), -CO-(optionally substituted triazinyl), -CO-(optionally substituted tetrazinyl), -CO-(optionally substituted indolizinyl), -CO-(optionally substituted isoindolyl), -CO-(optionally substituted 3H-indolyl), -CO-(optionally substituted indolyl), -CO-(optionally substituted indazolyl), -CO-(optionally substituted purinyl), -CO-(optionally substituted 4H-quinolizinyl), -CO-(optionally substituted isoquinolyl), -CO-(optionally substituted quinolyl), -CO-(optionally substituted phthalazinyl), -CO-(optionally substituted naphthyridinyl), -CO-(optionally substituted quinozalinyl), -CO-(optionally substituted cinnolinyl), -CO-(optionally substituted pteridinyl), -CO-(optionally substituted carbazolyl), -CO-(optionally substituted β-carbolinyl), -CO-(optionally substituted phenanthridinyl), -CO-(optionally substituted acrindinyl), -CO-(optionally substituted perimidinyl)-CO-(optionally substituted phenanthrolinyl), -CO-(optionally substituted phenazinyl), -CO-(optionally substituted isothiazolyl), -CO-(optionally substituted phenothiazinyl), -CO-(optionally substituted isoxazolyl), -CO-(optionally substituted furazanyl), -CO-(optionally substituted phenoxazinyl), -CO-(optionally substituted pyrazolo[1,5-α]pyrimidinyl), -CO-(optionally substituted 1,2-benzisoxazol-3-yl), -CO-(optionally substituted benzimidazolyl), -CO-(optionally substituted 2-oxyindolyl), and -CO-(optionally substituted 2-oxobenzimidazolyl);, -CO-(L) n -(optionally substituted thienyl), -CO-(L) n -(optionally substituted benzo[b]thienyl), -CO-(L) n -(optionally substituted naphtho[2,3-b]thienyl), -CO-(L) n -(optionally substituted thianthrenyl), -CO-(L) n -(optionally substituted furyl), -CO-(L) n -(optionally substituted benzofuranyl), -CO-(L) n -(optionally substituted isobenzofuranyl), -CO-(L) n -(optionally substituted chromenyl), -CO-(L) n -(optionally substituted xanthenyl), -CO-(L) n -(optionally substituted phenoxanthiinyl), -CO-(L) n -(optionally substituted pyrrolyl), -CO-(L) n -(optionally substituted imidazolyl), -CO-(L) n -(optionally substituted pyrazolyl), -CO-(L) n -(optionally substituted triazolyl), -CO-(L) n -(optionally substituted tetrazolyl), -CO-(L) n-(optionally substituted pyridyl), -CO-(L) n -(optionally substituted pyrazinyl), -CO-(L) n -(optionally substituted pyrimidinyl), -CO-(L) n -(optionally substituted pyridazinyl), -CO-(L) n -(optionally substituted triazinyl), -CO-(L) n -(optionally substituted tetrazinyl), -CO-(L) n -(optionally substituted indolizinyl), -CO-(L) n -(optionally substituted isoindolyl), -CO-(L) n -(optionally substituted 3H-indolyl), -CO-(L) n -(optionally substituted indolyl), -CO-(L) n -(optionally substituted indazolyl), -CO-(L) n -(optionally substituted purinyl), -CO-(L) n -(optionally substituted 4H-quinolizinyl), -CO-(L) n -(optionally substituted isoquinolyl), -CO-(L) n -(optionally substituted quinolyl), -CO-(L) n -(optionally substituted phthalazinyl), -CO-(L) n -(optionally substituted naphthyridinyl), -CO-(L) n -(optionally substituted quinoxalinyl), -CO-(L) n -(optionally substituted cinnolinyl), -CO-(L) n -(optionally substituted pteridinyl), -CO-(L) n -(optionally substituted carbazolyl), -CO-(L) n -(optionally substituted β-carbolinyl), -CO-(L) n -(optionally substituted phenanthridinyl), -CO-(L) n -(optionally substituted acrindinyl), -CO-(L) n-(optionally substituted perimidinyl), -CO-(L) n -(optionally substituted phenanthrolinyl), -CO-(L) n -(optionally substituted phenazinyl), -CO-(L) n -(optionally substituted isothiazolyl), -CO-(L) n -(optionally substituted phenothiazinyl), -CO-(L) n -(optionally substituted isoxazolyl), -CO-(L) n -(optionally substituted furazanyl), -CO-(L) n -(optionally substituted phenoxazinyl), -CO-(L) n -(optionally substituted pyrazolo[1,5-α]pyrimidinyl), -CO-(L) n -(optionally substituted 1,2-benzisoxazol-3-yl), -CO-(L) n -(optionally substituted benzimidazolyl), -CO-(L) n -(optionally substituted 2-oxyindolyl), and -CO-(L) n -(optionally substituted 2-oxobenzimidazolyl); -CO-(L) n -(di(C 1 -C 12 alkyl)amino); and -CO-(L) n -CO-(di(C 1 -C 12 alkyl)amino) may be selected from.

[0049] Even more preferably, R 6 is optionally substituted C 1 -C 6 alkyl; -CO-(optionally substituted C 1 -C 6 alkyl); -CO-(L) n -(optionally substituted oxetanyl); -CO-(optionally substituted imidazolyl); -CO-(L) n -(optionally substituted pyrazinyl); -CO-(L) n -(optionally substituted pyrimidinyl); -CO-(L) n -(di(C 1 -C 6 alkyl)amino); and -CO-(L) n -CO-(di(C 1 -C 6 alkyl)amino) may be selected from. For example, R 6 is optionally substituted C 1 -C 6 alkyl; -CO-(optionally substituted C 1 -C 6 alkyl); -CO-(L) n -(optionally substituted oxetanyl); -CO-(optionally substituted imidazolyl); -CO-(L) n -(optionally substituted pyrazinyl); -CO-(L) n -(di(C 1 -C 6 alkyl)amino); and -CO-(L) n -CO-(di(C 1 -C 6 alkyl)amino) may be selected from.

[0050] Even more preferably, R 6 is optionally substituted C 1 -C 4 alkyl; -CO-(optionally substituted C 1 -C 4 alkyl); -CO-(L) n-(optionally substituted oxetanyl) (wherein the oxetanyl group has the following structure

Chemical formula

[0051]

Chemical formula

[0052]

Chemical formula

Chemical formula

[0053] For example, R 6 is Optionally substituted C 1 -C 4 alkyl; -CO-(optionally substituted C 1 -C 4 alkyl); -CO-(L) n -(optionally substituted oxetanyl) (wherein the oxetanyl group has the following structure

Chemical formula

[0054]

Chemical formula

Chemical formula

[0055] In formula I, preferably, each L is independently selected from optionally substituted alkylene and optionally substituted heteroarylene. When n is 2, the first L group is preferably different from the second L group. More preferably, each L is independently selected from optionally substituted C 1 -C 12 alkylene and optionally substituted imidazolylene. Even more preferably, each L is independently selected from optionally substituted C 1 -C 6 alkylene and optionally substituted imidazolylene. Even more preferably, each L is independently selected from optionally substituted C 1 -C 4 alkylene and optionally substituted imidazolylene. In formula I, preferably, n can be 0 or 2.

[0056] In a preferred embodiment, n can be 0. In other words, the groups on both sides of the (L) n moiety are linked by direct bonds. In another preferred embodiment, n can be 2. Preferably, (L) n can be (optionally substituted heteroarylene)-(optionally substituted alkylene). More preferably, (L) n can be (optionally substituted heteroarylene)-(optionally substituted C 1 -C 12 alkylene).

[0057] Even more preferably, (L) n is (optionally substituted thienylene)-(optionally substituted C 1 -C 12(alkylene), (optionally substituted benzo[b]thienylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted naphtho[2,3-b]thienylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted thianthrenylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted furylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted benzofuranylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted isobenzofuranylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted chromenylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted xanthenylenylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted phenoxanthiinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrrolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted imidazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted triazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted tetrazolylene)-(optionally substituted C 1 -C 12(alkylene), (optionally substituted pyridylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrimidinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyridazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted triazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted tetrazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted indolizinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted isoindolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted 3H-indolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted indolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted indazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted purinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted 4H-quinolizinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted isoquinolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted quinolylene)-(optionally substituted C 1 -C12 (alkylene), (optionally substituted phthalazinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted naphthyridinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted quinoxalinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted cinnolinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted pteridinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted carbazolylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted β-carbolinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted phenanthridinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted acrindinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted perimidinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted phenanthrolinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted phenazinylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted isothiazolylene)-(optionally substituted C 1 -C 12 alkylene), (optionally substituted phenothiazinylene)-(optionally substituted C 1 -C 12(alkylene), (optionally substituted isoxazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted furazanylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted phenoxazinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted pyrazolo[1,5-α]pyrimidinylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted 1,2-benzisoxazol-3-yl)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted benzimidazolylene)-(optionally substituted C 1 -C 12 (alkylene), (optionally substituted 2-oxyindolylene)-(optionally substituted C 1 -C 12 (alkylene), and (optionally substituted 2-oxobenzimidazolylene)-(optionally substituted C 1 -C 12 alkylene) can be selected from.

[0058] More preferably, (L) n is (optionally substituted imidazolylene)-(optionally substituted C 1 -C 6 alkylene). Most preferably, in the formula, (L) n is

Chemical formula

[0059] The compound according to formula I can be selected from Compounds 1 to 10, but the compounds described herein are not necessarily

Chemical Structure

[0060] The compound according to formula I can be Compound 11, but the compounds described herein are not necessarily

Chemical Structure

[0061] In an embodiment regarding the compound of formula I, the compound is not any of the following.

Chemical Structure

[0062] In another embodiment regarding the compound of formula I, the compound may not be any of the following.

Chemical Structure

[0063] Composition In another embodiment of the present invention, a composition comprising a compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient is provided herein. [Chemistry] (wherein, R 1 ~R 6 is as defined herein)

[0064] In embodiments relating to compositions comprising a compound of Formula I, the compound may not be any of the following. [Chemistry] However, the compositions provided herein are not necessarily limited thereto.

[0065] In another embodiment relating to compositions comprising a compound of Formula I, the compound may not be any of the following. [Chemistry] However, the compositions provided herein are not necessarily limited thereto.

[0066] Pharmaceutically acceptable carriers or excipients can include fillers, binders, disintegrants, fluidizing agents, lubricants, complexing agents, solubilizing agents, and surfactants that can be selected to facilitate the administration of the compound by a specific route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, etc. Carriers can also include physiologically compatible liquids as solvents or for suspensions, such as sterile solutions of water for injection (WFI), physiological saline, dextrose solutions, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycol, liquid paraffin, etc. Excipients can include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macro - crystalline cellulose, carboxymethyl cellulose, cross - linked sodium carboxymethyl cellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, Stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, sesame seed oil, mineral oil, polyethylene glycol (e.g., PEG 400 or PEG(4000 - 8000), polyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylic acid divinylbenzene copolymer, doxate sodium, cyclodextrin (e.g., 2-hydroxypropyl-δ-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, di-fatty acid ester of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween (registered trademark)), polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, such as sorbitan fatty acid ester derived from fatty acids such as oleic acid, stearic acid or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or spray-dried lactose, sucrose, fructose, calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, dextrate, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrose (polydextrosem), chitosan, gelatin, HPMC (hydroxypropylmethylcellulose), HPC (hydroxypropylcellulose), hydroxyethylcellulose, etc. can also be mentioned.

[0067] In some embodiments, oral administration can be used. Pharmaceutical formulations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid formulations such as syrups, elixirs, and concentrated drops. The compounds of Formula I described herein may be combined with solid excipients, the resulting mixture may be pulverized, and if desired, the mixture of granules may be processed after adding suitable auxiliaries, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (for example, aqueous, alcoholic, or oily solutions), etc. can be obtained. Suitable excipients include, in particular, sugars such as lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose (CMC), and / or polyvinyl pyrrolidone (PVP: povidone); fillers such as oily excipients including vegetable and animal oils such as sunflower oil, olive oil, or cod liver oil. Formulations for oral administration can also include disintegrants such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid, or their salts such as sodium alginate; lubricants such as talc or magnesium stearate; plasticizers such as glycerol or sorbitol; sweeteners such as sucrose, fructose, lactose, or aspartame; natural or artificial flavoring agents such as peppermint, wintergreen oil, or cherry flavoring; or dyes or pigments that can be used for the identification or characterization of different dosages or combinations. Sugar-coated tablet cores with suitable coatings are also provided. For this purpose, for example, sugar concentrates may also be used that may include gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

[0068] Pharmaceutical formulations that can be used orally include push-fit capsule preparations made of gelatin ("gel caps"), as well as sealed soft capsule preparations made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsule preparation can contain the active ingredient admixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally admixed with a stabilizer. In the soft capsule preparation, the active ingredient such as the compound of formula I can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, injection (parenteral administration), such as intramuscular, intravenous, intraperitoneal, and / or subcutaneous injection, can be used. The compound of formula I described herein for injection can be formulated in a sterile liquid solution, preferably in a physiologically compatible buffer or solution such as physiological saline, Hank's solution, or Ringer's solution. Dispersions can also be prepared in non-aqueous solutions such as glycerol, propylene glycol, ethanol, liquid polyethylene glycol, triacetin, and vegetable oils. The solution can also contain preservatives such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal. Furthermore, the compound of formula I described herein can be formulated in a solid form, such as a lyophilized form, and redissolved or resuspended before use.

[0069] In some embodiments, transmucosal, topical, or transdermal administration can be used. In such formulations of the compounds of Formula I described herein, penetration enhancers suitable for the barriers encountered during permeation are used. Such penetration enhancers are generally known in the art and include, for example, bile salts and fusidic acid derivatives in the case of transmucosal administration. Further, detergents can be used to enhance permeation. For example, transmucosal administration can be effected through nasal sprays or (rectal or vaginal) suppositories. Compositions of the compounds of Formula I described herein for topical administration can be formulated as oils, creams, lotions, ointments, etc. by selecting suitable carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched-chain fats or oils, animal fats, and high molecular weight alcohols (C 12 greater than). In some embodiments, a carrier is selected such that the active ingredient can dissolve. If desired, emulsifiers, stabilizers, wetting agents, and antioxidants can also be included, as well as agents that impart color or fragrance. Creams for topical application are preferably formulated from a mixture of mineral oil, self-emulsifying wax, and water, in which the active ingredient dissolved in a small amount of solvent (e.g., oil) is incorporated. Additionally, administration by transdermal means can include transdermal patches or dressings such as bandages impregnated with the active ingredient and optionally one or more carriers or diluents known in the art. For administration in the form of a transdermal delivery system, the dosage administration is continuous rather than intermittent over the entire dosing schedule.

[0070] In some embodiments, the compound of formula I, or a composition thereof, is administered as an inhalant. The compounds of formula I described herein can be formulated as dry powders or as suitable solutions, suspensions, or aerosols. The powders and solutions can be formulated using suitable additives known in the art. For example, the powder can contain a suitable powder base such as lactose or starch, and the solution can contain propylene glycol, sterile water, ethanol, sodium chloride, and other additives such as acids, alkalis, and buffer salts. Such solutions or suspensions can be administered by inhalation via a spray, pump, nebulizer, or atomizer, etc.

[0071] Dosage form In another embodiment of the present invention, dosage forms containing the compositions described herein are provided herein. The dosage form can be in the form of a unit dose or a single administration, such as a single administration pill, capsule, etc. Medical use In another embodiment of the present invention, a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, for use in the treatment of a disease modulated by CDK8 and / or CDK19

[0072]

Chemical formula

[0073] In another embodiment of the present invention, a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease modulated by CDK8 and / or CDK19

Chemical formula

[0074] In another embodiment of the invention, a method of treating a disease in a patient in need of treatment of a disease modulated by CDK8 and / or CDK19, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof

Chemical formula

[0075] In embodiments relating to the compounds described herein (or the compositions or dosage forms described herein) for use in treatment, the use of the compounds (or the compositions or dosage forms described herein) in the manufacture of a medicament for treatment, or the methods of treatment described herein, the compound may not be any of the following.

[0076]

Chemical formula

[0077] In another embodiment related to the use of a compound (or a composition or dosage form described herein) for use in a treatment, the use of a compound (or a composition or dosage form described herein) in the manufacture of a medicament for treatment, or the treatment method described herein, the compound may not be any of the following.

[0078]

Chemical formula

[0079] More preferably, the cancer is selected from leukemia (e.g., acute myeloid leukemia), bladder cancer (e.g., bladder carcinoma), breast cancer, colon cancer, skin cancer (e.g., cutaneous melanoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), glioblastoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma of the kidney), liver cancer (e.g., liver cancer, hepatocellular carcinoma), brain cancer (e.g., low-grade glioma), lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma), ovarian cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), adrenal cancer (e.g., pheochromocytoma), paraganglioma, prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer (e.g., rectal adenocarcinoma), sarcoma, stomach cancer (e.g., gastric adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor), thyroid cancer (e.g., thyroid carcinoma), and uterine cancer (e.g., endometrial carcinoma of the uterine corpus). The expression of CDK8 and / or CDK19 has generally been shown in the literature to be associated with shorter patient survival in several cancer types (see, e.g., Roninson et al. in Cells 2019, 8, 821). Thus, without wishing to be bound by a particular theory, it is hypothesized that inhibition of CDK8 and CDK19 (e.g., by administration of a compound according to Formula I) limits downstream effects resulting from the expression of CDK8 and CDK19, thereby enabling treatment of several cancer types.

[0080] As used herein, the terms “treating” and “treatment” and similar terms refer to an amount of a material, e.g., administration of any one or more of the compounds described herein, that is effective to prevent, reduce, or ameliorate a disease or condition, i.e., one or more symptoms of a disorder, and / or to extend the survival of a subject being treated. In some cases, one or more of the compounds described herein may be used in combination with one or more pharmaceutically active compounds (e.g., in the compositions described herein). As used herein, the terms "therapeutically effective" or "effective amount" indicate that when the compound of formula I or the amount of the compound of formula I administered is sufficient or effective to prevent, reduce, or ameliorate one or more symptoms of a disease, disorder, or pathological condition being treated and / or to extend the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disease, disorder or condition and their severity, and the age, weight, etc. of the mammalian subject being treated. In general, satisfactory results in a subject are shown to be obtained with a daily dosage of about 0.1 to about 10 g per kg of body weight of the subject. In some embodiments, the daily dosage is in the range of about 0.10 to 10.0 mg / kg body weight, about 1.0 to 3.0 mg / kg body weight, about 3 to 10 mg / kg body weight, about 3 to 150 mg / kg body weight, about 3 to 100 mg / kg body weight, about 10 to 100 mg / kg body weight, about 10 to 150 mg / kg body weight, or about 150 to 1000 mg / kg body weight. The dosage can be conveniently administered, for example, in divided doses up to four times a day or in the form of a sustained release.

[0081] As used herein, the terms "modulate" or "modulating" refer to the effect of changing a biological activity, particularly a biological activity associated with a specific biomolecule. For example, an inhibitor of a specific biomolecule modulates the activity of that biomolecule, such as an enzyme, by reducing the activity of the biomolecule such as an enzyme. Such activity is typically indicated, for example, by the inhibitory concentration (IC 50 ) or pK d of the compound for an inhibitor of an enzyme. As used herein, the term "subject" refers to any mammalian body treated with the compounds described herein, including but not limited to humans, other primates, sport animals, animals of commercial interest such as cattle, livestock such as horses, or pet animals such as dogs and cats. As used herein, the term "administering" refers to oral administration to a subject, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or implantation of a sustained release device, such as a mini-osmotic pump. Administration is effected by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) routes. Parenteral administration includes, for example, intravenous, intramuscular, arteriolar, intracutaneous, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery modes include, but are not limited to, the use of liposomal formulations, intravenous infusions, transdermal patches, etc.).

[0082] The compounds for use herein are typically used in the treatment of human subjects. However, they can also be used to treat similar or identical indications in other animal subjects. The compounds of formula I described herein can be administered by a variety of routes, including injection (i.e., parenteral injection, including intravenous, intraperitoneal, subcutaneous, and intramuscular injection), oral, transdermal, transmucosal, rectal, or inhalation. Such dosage forms enable the compound to reach the target cells. Other factors are well known in the art and include considerations such as toxicity and dosage form that would prevent the compound or composition from exerting its effect. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005. Kit In another embodiment of the invention, a compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof

[0083] [Chemical formula] (wherein R 1 ~R 6as defined herein); or a composition described herein; or a dosage form described herein; and a kit is provided herein that includes instructions for use of a compound, composition or dosage form in the treatment of a disease modulated by CDK8 and / or CDK19.

[0084] In embodiments relating to the kits described herein, the compound may not be any of the following.

Chemical formula

[0085] In another embodiment relating to the kits described herein, the compound may not be any of the following.

Chemical formula

Examples

[0086] (Synthesis Example) General Procedure General Procedure 1 for Amide Formation: Into a round-bottom flask, an acid or the corresponding carboxylate salt (1.2 equivalents), an amine (1 equivalent), Et 3 N (1 mL) and DMF (10 mL) were charged. Then, HATU (1.2 equivalents) was added and the mixture was stirred at room temperature for 4 hours. The reaction was diluted with H 2 O (30 mL) and extracted with EtOAc (3 times). The organics were combined and washed with H 2 O (3 times). Then, the organics were washed with Na 2 SO 4It was dehydrated, filtered, and evaporated to obtain a residue. The crude material was purified by flash silica column chromatography to obtain the relevant amide.

[0087] Synthetic route of the intermediate

Chem.

[0088] Intermediate 1-benz[c]isothiazol-3(1H)-one (Int-1):

Chem.

[0089] Intermediate 2-3-chlorobenz[c]isothiazole (Int-2):

Chem.

[0090] Intermediate 3 - Tert-butyl (1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (Int-3):

Chemical Structure

[0091] Intermediate 4 - 1 - (benzo[c]isothiazol - 3 - yl)piperidin - 4 - amine hydrochloride (Int - 4):

Chemical Structure

[0092] Intermediate 5-oxetan-3-ylmethyl 4-methylbenzenesulfonate (Int-5):

Chem.

[0093] Intermediate 6-ethyl 1-(oxetan-3-ylmethyl)-1H-imidazole-4-carboxylate (Int-6):

Chem.

[0094] Intermediate 7 - Sodium 1-(oxetan - 3 - ylmethyl)-1H - imidazole - 4 - carboxylate (Int - 7):

Chem.

[0095] Intermediate 8 - Ethyl 1-(2-(dimethylamino)-2 - oxoethyl)-1H - imidazole - 4 - carboxylate (Int - 8):

Chem.

[0096] Intermediate 9 - Sodium 1-(2-(dimethylamino)-2-oxoethyl)-1H-imidazole-4-carboxylate (Int-9):

Chemical formula

[0097] Intermediate 10 - Ethyl 1-(pyrazin-2-ylmethyl)-1H-imidazole-4-carboxylate (Int-10):

Chemical formula

[0098] Intermediate 11 - Sodium 1-(pyrazin-2-ylmethyl)-1H-imidazole-4-carboxylate (Int-11):

Chemical Structure

[0099] Sodium 1-(2-(dimethylamino)ethyl)-1H-imidazole-4-carboxylate (Int-12):

Chem.

[0100] 5-Fluorobenzo[c]isothiazol-3(1H)-one (Int-13):

Chem.

[0101] Intermediate 14 - 3-Chloro-5-fluorobenzo[c]isothiazole (Int-14):

Chemical Structure

[0102] Intermediate 15 - Tert-butyl (1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (Int-15):

Chemical Structure

[0103] Intermediate 16 - 1-(5-Fluorobenzothieno[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (Int-16):

Chemical Structure

[0104] Synthesis Example 1 - 1-(Benzo[c]isothiazol-3-yl)-N-methylpiperidin-4-amine (1):

Chemical Structure

[0105] Trifluoroacetic acid (372.25 mg, 3.2648 mmol) was added to a solution of tert-butyl N-[1-(2,1-benzothiazol-3-yl)-4-piperidyl]-N-methyl-carbamate (41.1 mg, 0.1183 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured onto an SCX cartridge, washed through with methanol, and then the product was eluted with 2M NH 3 in MeOH. The volatiles were evaporated to give 1-(2,1-benzothiazol-3-yl)-N-methyl-piperidin-4-amine (27 mg, 88%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J = 8.8 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.30 (ddd, J = 8.9, 6.4, 1.1 Hz, 1H), 6.95 (ddd, J = 8.8, 6.4, 1.0 Hz, 1H), 3.81 (dt, J = 12.3, 3.8 Hz, 2H), 3.22 - 3.15 (m, 2H), 2.61 (ddd, J = 13.4, 9.6, 3.9 Hz, 1H), 2.32 (s, 3H), 1.99 (dd, J = 13.1, 3.6 Hz, 2H), 1.59 - 1.49 (m, 2H). MS m / z 248 [M+H] +

[0106] Synthesis Example 2 - N-(1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)acetamide (2):

Chemical formula

[0107] Synthesis Example 3 - N-(1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-methyl-1H-imidazole-4-carboxamide (3):

Chemical Structure

[0108] 1-(2,1-Benzothiazol-3-yl)piperidin-4-amine (206 mg, 0.79 mmol) was suspended in DCM (5 mL), and DIPEA (0.32 mL, 2.38 mmol) was added. This mixture was added to crude 1-methylimidazole-4-carbonyl chloride (115 mg, 0.79 mmol), and DMF (0.5 mL) was added to the reaction mixture. After 1.5 hours, the reaction was quenched by adding saturated aqueous NaHCO 3 (30 mL), and the product was extracted with DCM (30 mL). The organic matter was dried (phase separator) and evaporated. The crude product was purified by silica chromatography (0 - 10% MeOH / DCM gradient elution), and then by reverse-phase HPLC to give N-(1-(benzothiazol-3-yl)piperidin-4-yl)-1-methyl-1H-imidazole-4-carboxamide (100 mg, 36%). 1 H NMR (500 MHz, d 6 -DMSO): δ 7.86 - 7.81 (2H, m), 7.66 - 7.64 (2H, m), 7.46 (1H, d, J = 9.0 Hz), 7.32 (1H, dd, J = 6.3, 8.9 Hz), 6.98 (1H, dd, J = 6.4, 8.7 Hz), 4.11 - 4.02 (1H, m), 3.90 (2H, d, J = 12.4 Hz), 3.29 (2H, s), 3.28 - 3.22 (2H, m), 1.97 - 1.91 (5H, m). MS m / z 342.1 [M+H] + .

[0109] Synthesis Example 4 - N-(1-(5-Fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)-1-methyl-1H-imidazole-4-carboxamide (4):

Chemical Structure

[0110] In a separate flask, 1-(5-fluoro-2,1-benzothiazol-3-yl)piperidin-4-amine; dihydrochloride (3.84 g, 11.85 mmol) was added, the flask was sealed and purged with nitrogen (3 times). DCM (47 mL) was added and the flask was cooled to 0 °C.

[0111] The flask containing the acid chloride was purged with nitrogen again (3 times), DCM (66 mL) was added, and then NEt 3(6.7 mL, 48.12 mmol) was added. Subsequently, the acid chloride solution was added dropwise to the amine at 0 °C. The flask containing the acid chloride was rinsed out with another portion of DCM (26 mL), and this was added to the amine. After the addition was complete, the reaction mixture was removed from the ice bath and stirred overnight at room temperature. The reaction mixture was evaporated directly onto silica gel and purified by silica column chromatography eluting with 0 - 20% methanol in ammonia in DCM to give a yellow solid. The material was suspended in diethyl ether and methanol and filtered. The solid material was then dissolved in DCM (30 mL), washed with water (30 mL), dried over anhydrous sodium sulfate, and evaporated to give N-[1-(5-fluoro-2,1-benzothiazol-3-yl)-4-piperidyl]-1-methyl-imidazole-4-carboxamide (2.58 g, 58%) as a yellow solid. 1 1H NMR (500 MHz, d6-DMSO) δ 7.82 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.58 (dd, J = 10.4, 2.5 Hz, 1H), 7.52 (dd, J = 9.6, 5.2 Hz, 1H), 7.29 (ddd, J = 9.7, 8.4, 2.6 Hz, 1H), 4.04 (dd, J = 15.1, 7.0 Hz, 1H), 3.83 (d, J = 12.5 Hz, 2H), 3.69 (s, 3H), 3.23 - 3.16 (m, 2H), 1.96 - 1.87 (m, 4H). MS m / z 360 [M+H] + .

[0112] Synthesis Example 5 - N-(1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(pyrazin-2-ylmethyl)-1H-imidazole-4-carboxamide (5):

Chemical Structure

[0113] Synthesis Example 6 - N-(1-(5-Fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(pyrazin-2-ylmethyl)-1H-imidazole-4-carboxamide (6):

Chemical Structure

[0114] Synthesis Example 7 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(2-(dimethylamino)-2-oxoethyl)-1H-imidazole-4-carboxamide (7):

Chemical Structure

[0115] Synthesis Example 8-1-(2-(Dimethylamino)-2-oxoethyl)-N-(1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)-1H-imidazole-4-carboxamide (8):

Chemical Structure

[0116] Synthesis Example 9 - N-(1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(2-(dimethylamino)ethyl)-1H-imidazole-4-carboxamide (9):

Chemical Structure

[0117] Synthesis Example 10 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(oxetan-3-ylmethyl)-1H-imidazole-4-carboxamide (10):

Chem.

[0118] Synthesis Example 11 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxamide (11):

Chemical formula

[0119] ​To a flask, tert-butyl (1-(2-nitrobenzoyl)piperidin-4-yl)carbamate (10.3 g, 29.5 mmol) and Pd / C (2 g) were added. MeOH (150 mL) was added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The solution was then concentrated and the residue was purified by column chromatography to give tert-butyl (1-(2-aminobenzoyl)piperidin-4-yl)carbamate (9.3 g, 98%) as a colorless oil. MS calculated: 319.19; MS found: 320.2 [M+H] +

[0120] To a mixture of tert-butyl (1-(2-aminobenzoyl)piperidin-4-yl)carbamate (9.3 g, 29.1 mmol) and NaHCO 3 (4.9 g, 58.3 mmol) in THF (200 mL) was added P 2 S 5 (9 g, 40.5 mmol). The reaction was allowed to reach 60 °C for 3 h under an argon atmosphere. H 2 O was added and the mixture was extracted with EA (twice). The organic matter was washed with brine and dried over sodium sulfate. The organic phase was concentrated and the residue was purified by column chromatography to give tert-butyl (1-(2-aminophenylcarbonothioyl)piperidin-4-yl)carbamate (5.3 g, 54%) as a yellow oil. MS calculated: 335.17; MS found: 336.0 [M+H] +

[0121] To a flask, tert-butyl (1-(2-aminophenylcarbonothioyl)piperidin-4-yl)carbamate (5.3 g, 15.8 mmol) and THF (60 mL) were added. NBS (2.8 g, 15.8 mmol) was added portionwise and the reaction was stirred for 15 min. Then the reaction was H 2It was diluted with O and extracted with EA (3 times). The organic matter was dehydrated with sodium sulfate. The organic phase was concentrated, and the residue was purified by column chromatography to obtain tert-butyl (1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (4.1 g, 76%) as a yellow solid. MS calculated value: 333.15; MS measured value: 334.0 [M+H] + To a flask were added tert-butyl (1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (4.1 g, 12 mmol) and HCl (4M HCl in MeOH, 30 mL, 120 mmol). The mixture was stirred overnight at room temperature. The residue was concentrated in vacuo to obtain 1-(benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (2.8 g, 80%) as a yellow solid. MS calculated value: 233.10; MS measured value: 234.2 [M+H] +

[0122] To a flask were added ethyl 1H-imidazole-4-carboxylate (420 mg, 3.0 mmol), 2-(bromomethyl)pyrimidine (0.4 mL, 3.6 mmol), and MeCN (20 mL). The reaction was brought to 50 °C and stirred overnight. The reaction mixture was filtered, concentrated in vacuo, and purified by column chromatography to obtain ethyl 1-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxylate (301 mg, 43%) as a colorless oil. To a flask were added ethyl 1-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxylate (110 mg, 0.48 mmol), NaOH (38 mg, 0.96 mmol), and MeOH (10 mL). The reaction was stirred at room temperature for 5 hours. HCl (1M HCl in 2 H2O) was added to bring the pH to about 5. The mixture was concentrated in vacuo to obtain crude 1-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxylic acid. It was used without further purification.

[0123] To a flask, 1-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxylic acid (crude, 130 mg), 1-(benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (93 mg, 0.4 mmol), NEt 3 (1 mL), and DMF (10 mL) were added. HATU (198 mg, 0.5 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction was diluted with H 2 O and extracted with EA (3 times). The organics were combined, washed with H 2 O (3 times), dehydrated over Na 2 SO 4 and filtered and evaporated. The residue was purified by column chromatography to give N-(1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxamide (Compound 11) (25 mg, 26%) as a yellow solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.80 (d, J = 4.8 Hz, 2H), 7.96 (d, J = 8.4 Hz, 1 H), 7.84-7.81 (m, 2H), 7.73 (d, J = 1.6 Hz, 1H), 7.48-7.45 (m, 2H), 7.34-7.29 (m, 1H), 6.99-6.95 (m, 1H), 5.53 (s, 2H), 4.11-4.05 (m, 1H), 3.90 (d, J = 12.4 Hz, 2H), 3.28-3.21 (m, 2H), 1.99-1.92 (m, 4H). MS calculated: 419.15; MS found 420.0 [M+H] +

[0124] (Examples 1 - 11) - CDK8 and CDK19 Inhibition Data Compounds 1 - 11 were tested for their in vitro binding activities against CDK8 and CDK19. These results are presented in Table 1. Kinase assay: Kinase-tagged T7 phage strains were prepared in an Escherichia coli (E. coli) host derived from the BL21 strain. The E. coli was grown to the logarithmic phase, infected with T7 phage, and incubated at 32 °C with shaking until lysis. The lysate was centrifuged and filtered to remove cell debris. The remaining kinase was produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to prepare an affinity resin for the kinase assay. The ligand-bound beads were blocked with excess biotin and washed with a blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween20, 1 mM DTT) to remove unbound ligand and reduce non-specific binding. The binding reaction was assembled by combining the kinase, ligand-bound affinity beads, and test compound in 1× binding buffer (20% SeaBlock, 0.17× PBS, 0.05% Tween20, 6 mM DTT). The test compound was prepared as an 111× stock in 100% DMSO. An 11-point three-fold dilution series of the compound was used with three DMSO control points to determine the Kd. All compounds for Kd measurement were dispensed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compound was then directly diluted into the assay such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plates. The final volume of each was 0.02 mL. The assay plates were incubated at room temperature for 1 hour with shaking, and the affinity beads were washed with wash buffer (1× PBS, 0.05% Tween20). The beads were then resuspended in elution buffer (1× PBS, 0.05% Tween20, 0.5 μM of non-biotinylated affinity ligand) and incubated at room temperature for 30 minutes with shaking. The kinase concentration in the eluate was measured by qPCR.

[0125] Compound Handling: An 11-point three-fold serial dilution of each test compound was prepared in 100% DMSO at 100× the final test concentration and subsequently diluted to 1× in the assay (final DMSO concentration = 1%). Most Kd values were determined using a compound highest concentration of 30,000 nM. If the initial Kd determined was <0.5 nM (the lowest concentration tested), the measurement was repeated using a serial dilution starting at a lower highest concentration. A Kd value reported as 40,000 nM indicates that the Kd was determined to be >30,000 nM. Binding Constant: The binding constant (Kd) was calculated using Hill's equation with a standard dose-response curve. [Number] The Hill slope was set to -1.

[0126] The curve was fitted using non-linear least squares fitting with the Levenberg-Marquardt algorithm. [Table 1]

[0127] Each of Compounds 1 - 11 has a micromolar (pKd of 4 - 6) to nanomolar (pKd of 7 - 9) binding affinity for CDK8 and CDK19, and thus these compounds are shown to bind strongly to CDK8 and CDK19. Without wishing to be bound by a particular theory, the presence of the benzisothiazole and piperidine rings is hypothesized to assist the compounds of Formula I in binding deeply into the binding pockets of CDK8 and CDK19 (see Example 12), resulting in a high binding affinity. Both CDK8 and CDK19 are associated with several types of cancer. The expression of CDK8 and / or CDK19 has generally been shown in the literature to be associated with reduced patient survival in several cancer types (see, for example, Roninson et al. in Cells 2019, 8, 821). Compounds 1-11 were shown to bind strongly to both CDK8 and CDK19. Without wishing to be bound by a particular theory, it is hypothesized that inhibition of CDK8 and CDK19 limits downstream effects resulting from the expression of CDK8 and CDK19, thereby enabling the treatment of several cancer types.

[0128] (Example 12)-Docking Study Protein and ligand setup: The crystal structure of CDK8 was retrieved from the Protein Data Bank (PDB ID: 4F6U, retrieved from https: / / doi.org / 10.1073 / pnas.1305378110) and prepared using Schrödinger's Protein Preparation Wizard tool (Schrödinger release 2020-2). Solvent molecules and residues defined as heteroatoms in the PDB were removed, and hydrogen atoms and missing side chain residues were added to the protein structure. The protonation state was specified using PROPKA at pH 7.0, and the hydrogen bond network was optimized. Finally, a constrained energy minimization step was performed using the OPLS3e force field with default settings. The compound structures were prepared using Schrödinger’s LigPrep tool (Schrödinger release 2020-2). Possible tautomers and stereoisomers were generated using Epik at pH 7.0 ± 1.0 and used for energy minimization with the OPLS3e force field.

[0129] Docking study: To gain insights into the binding mode, docking studies were performed using the Glide Standard Precision (SP) mode of Schrödinger Suite (Schrödinger Release 2020-2). Prior to docking, a grid box for the above-prepared protein (PDB ID: 4F6U) was created using the Schrödinger's Receptor Grid Generation tool. The co-crystallized inhibitor was selected as the center of the grid, and a 10 Å cube was defined as the inner box. During docking, "penalize any 'non-planar conformations' of amides" was turned on, and a total of 20 poses per ligand were subjected to the post-docking minimization step, and a maximum of 10 docking poses were output for each ligand. All other settings were kept as default. The described protocol was first evaluated by re-docking, and when using the highest-scoring pose, the binding mode of the co-crystallized inhibitor observed in the X-ray structure (PDB ID: 4F6U) could be reproduced with a root mean square deviation (RMSD, heavy atoms) of 0.46 Å.

[0130] As seen in Figures 1 and 2, the benzothiazole ring and the piperidine ring bind deeply within the binding pocket of CDK8. In particular, the nitrogen atom on the benzisothiazole ring forms an important hydrogen bond interaction with Ala-100. Other important binding interactions with Asp-173, His-149, etc. are also shown.

Claims

1. Compounds according to formula I, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof. 【Chemistry 1】 (In the formula, R 1 ~R 4 Each is independently selected from hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted amino. R 5 and R 6 Each is independent of the others. Hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, and optionally substituted heteroaryl; -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted cycloalkyl), -CO-(L) n -(optionally substituted heterocyclyl), -CO-(L) n -(optionally substituted alkoxy), -CO-(L) n -(optionally substituted aryl), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino), and -CO-(L) n -CO-(optionally substituted amino) (In the formula, L is independently an alkylene that may be substituted, (O-alkylene) w , selected from heteroarylenes, O and NH, which may be substituted, n is selected from 0, 1, and 2. w is selected from 1, 2 and 3); and -SO 2 - (optionally substituted alkyl), -SO 2 - (Optionally substituted cycloalkyl), -SO 2 - (may be substituted heterocyclyl), -SO 2 - (Optionally substituted alkoxy), -SO 2 - (Aryl that may be substituted), -SO 2 - (may be substituted heteroaryls), and -SO 2 - (Amino that may be substituted) Selected from the following, provided that the compound is not one of the following: 【Chemistry 2】 【change】

2. R 1 ~R 4 The compound according to claim 1, wherein each of the elements is independently selected from hydrogen and halogen, preferably hydrogen and fluoro.

3. R 1 The compound according to claim 1, wherein the compound is hydrogen.

4. R 2 The compound according to claim 1, wherein R3 is hydrogen or halogen, preferably hydrogen or fluoro, and / or R4 is hydrogen.

5. R 5 and R 6 Each of these independently consists of hydrogen, an optionally substituted alkyl group, and -CO-(L) n - (optionally substituted alkyl), -CO-(L) n - (may be substituted heterocyclyl), -CO-(L) n - (may be substituted heteroaryl), -CO-(L) n - (optionally substituted amino acids), and -CO-(L) n The compound according to claim 1, selected from -CO- (an optionally substituted amino).

6. R 5 The compound according to claim 1, wherein the compound is hydrogen.

7. R 6 However, substituted alkyl, -CO-(substituted alkyl), -CO-(L) n - (may be substituted heterocyclyl), -CO- (may be substituted heteroaryl), -CO-(L) n - (may be substituted heteroaryl), -CO-(L) n - (optionally substituted amino acids), and -CO-(L) n Selected from -CO- (optional substituted amino acids), at will R 6, substituted C1-C12 alkyl groups; -CO- (may be substituted C1-C12 alkyl); -CO-(L)n-(optionally substituted azethinyl), -CO-(L)n-(optionally substituted oxetanyl), -CO-(L)n-(optionally substituted tetrahydrofuranyl), -CO-(L)n-(optionally substituted pyranyl), -CO-(L)n-(optionally substituted piperidinyl), -CO-(L)n-(optionally substituted piperazinyl), -CO-(L)n-(optionally substituted pyrrolidinyl), -CO-(L)n-(optionally substituted imidazolidinyl), -CO-(L)n-(optionally substituted imidazolinyl), -CO-(L)n-(optionally substituted indolinyl), -CO-(L)n-(optionally substituted isoindolinyl), -CO-(L)n-(optionally substituted quinuclidinyl), -CO-(L)n-(optionally substituted morpholinyl), -CO-(L)n - (optionally substituted isochromanil), -CO-(L)n- (optionally substituted chromanil), -CO-(L)n- (optionally substituted pyrazolidinil), -CO-(L)n- (optionally substituted pyrazolinil), -CO-(L)n- (optionally substituted tetronoyl), and -CO-(L)n- (optionally substituted tetramoyl); -CO- (optionally substituted thienyl), -CO- (optionally substituted benzo[b]thienyl), -CO- (optionally substituted naphtho[2,3-b]thienyl), -CO- (optionally substituted thianthrenyl), -CO- (optionally substituted furyl), -CO- (optionally substituted benzofuranyl), -CO- (optionally substituted isobenzofuranyl), -CO- (optionally substituted clomenyl), -CO- (optionally substituted xanthenyl), -CO- (optionally substituted phenoxathinyl (ph (enoxanthiinyl)), -CO- (optionally substituted pyrrolyl), -CO- (optionally substituted imidazolyl), -CO- (optionally substituted pyrazolyl), -CO- (optionally substituted triazolyl), -CO- (optionally substituted tetrazolyl), -CO- (optionally substituted pyridyl), -CO- (optionally substituted pyrazinyl), -CO- (optionally substituted pyrimidinyl), -CO- (optionally substituted pyridazinyl), -CO- (optionally substituted triazinyl), -CO- ( (Optionally substituted tetradinyl), -CO- (optionally substituted indolidinyl), -CO- (optionally substituted isoindolyl), -CO- (optionally substituted 3H-indolyl), -CO- (optionally substituted indolyl), -CO- (optionally substituted indazolyl), -CO- (optionally substituted prinyl), -CO- (optionally substituted 4H-quinolidinyl), -CO- (optionally substituted isoquinolyl), -CO- (optionally substituted quinolyl), -CO- (optionally substituted phthalate) Dinyl), -CO- (optionally substituted naphthilidinyl), -CO- (optionally substituted quinoxalinyl), -CO- (optionally substituted synnorinyl), -CO- (optionally substituted pteridinyl), -CO- (optionally substituted carbazolyl), -CO- (optionally substituted β-carbolinyl), -CO- (optionally substituted phenantridinyl), -CO- (optionally substituted acridinyl), -CO- (optionally substituted perimidinyl),-CO- (optionally substituted phenanthrolinyl), -CO- (optionally substituted phenazinyl), -CO- (optionally substituted isothiazolyl), -CO- (optionally substituted phenothiazinyl), -CO- (optionally substituted isoxazolyl), -CO- (optionally substituted fluzanyl), -CO- (optionally substituted phenoxazinyl), -CO- (optionally substituted pyrazolo[1,5-α]pyrimidinyl), -CO- (optionally substituted 1,2-benzoisoxazole-3-yl), -CO- (optionally substituted benzimidazolyl), -CO- (optionally substituted 2-oxyindolyl), and -CO- (optionally substituted 2-oxobenzoimidazolyl); -CO-(L)n-(optionally substituted thienyl), -CO-(L)n-(optionally substituted benzo[b]thienyl), -CO-(L)n-(optionally substituted naphtho[2,3-b]thienyl), -CO-(L)n-(optionally substituted thianthrenyl), -CO-(L)n-(optionally substituted furyl), -CO-(L)n-(optionally substituted benzofuranyl), -CO-(L)n-(optionally substituted isobenzofuranyl), -CO-(L)n-(optionally substituted clomenyl), -CO-(L)n-(optionally substituted xanthenyl), -CO-(L)n-(optionally substituted phenoxathiinyl), -CO-(L)n-(optionally substituted pyrrolyl), -CO-(L)n - (optionally substituted imidazolyl), -CO-(L) n - (optionally substituted pyrazolyl), -CO-(L) n - (optionally substituted triazolyl), -CO-(L) n - (optionally substituted tetrazolyl), -CO-(L) n - (optionally substituted pyridyl), -CO-(L) n - (optionally substituted pyrazinyl), -CO-(L) n - (optionally substituted pyrimidinyl), -CO-(L) n - (optionally substituted pyridazinyl), -CO-(L) n - (optionally substituted triazinyl), -CO-(L) n - (optionally substituted tetradinyl), -CO-(L) n - (optionally substituted indolidinyl), -CO-(L) n - (optionally substituted isoindolyl), -CO-(L) n - (optionally substituted 3H-indolyl), -CO-(L) n - (optionally substituted indolyl), -CO-(L) n - (optionally substituted indazolyl), -CO-(L) n - (optionally substituted prinyl), -CO-(L) n - (optionally substituted 4H-quinolidinyl), -CO-(L) n - (optionally substituted isoquinolyl), -CO-(L) n - (optionally substituted quinolyl), -CO-(L) n - (optionally substituted phthalazinyl), -CO-(L) n - (optionally substituted naphthilidinyl), -CO-(L) n-(optionally substituted quinoxalinyl), -CO-(L) n -(optionally substituted synnorinyl), -CO-(L) n -(optionally substituted pteridinyl), -CO-(L) n -(optionally substituted carbazolyl), -CO-(L) n -(optionally substituted β-carbolinyl), -CO-(L) n -(optionally substituted phenanthrolinyl), -CO-(L) n -(optionally substituted acrindinyl), -CO-(L) n -(optionally substituted perimidinyl), -CO-(L) n -(optionally substituted phenanthrolinyl), -CO-(L) n -(optionally substituted phenadinyl), -CO-(L) n -(optionally substituted isothiazolyl), -CO-(L) n -(optionally substituted phenothiazinyl), -CO-(L) n - (optionally substituted isoxazolyl), -CO-(L)n- (optionally substituted fluzanyl), -CO-(L)n- (optionally substituted phenoxadinyl), -CO-(L)n- (optionally substituted pyrazolo[1,5-α]pyrimidinyl), -CO-(L)n- (optionally substituted 1,2-benzoisoxazole-3-yl), -CO-(L)n- (optionally substituted benzimidazolyl), -CO-(L)n- (optionally substituted 2-oxyindolyl), and -CO-(L)n- (optionally substituted 2-oxobenzoimidazolyl); -CO-(L)n-(di(C1-C12 alkyl)amino); and -CO-(L)n-CO-(di(C1-C12 alkyl)amino) Selected from, Furthermore, optionally, R 6, substituted C1-C6 alkyl groups; -CO- (may be substituted C1-C6 alkyl); -CO-(L)n-(optional oxetanyl); -CO- (imidazolyl may be substituted); -CO-(L)n-(optionally substituted pyrazinyl); -CO-(L)n-(optional pyrimidinyl substitution); -CO-(L)n-(di(C1-C6 alkyl)amino); and -CO-(L)n-CO-(di(C1-C6 alkyl)amino) Selected from, Furthermore, optionally, R 6, substituted C1-C4 alkyl; -CO- (may be substituted C1-C4 alkyl); -CO-(L)n-(optionally substituted oxetanyl) (wherein the formula the oxetanyl group has the following structure) 【Transformation 3】 (In the formula, * represents a linkage point to CO or (L)n, and R' represents one or more optional substituents, if any)); -CO- (optionally substituted imidazolyl) (wherein the formula the imidazolyl group has the following structure) 【Chemistry 4】 (In the formula, * represents a linkage point to CO, and R' represents one or more optional substituents, if any)); -CO-(L)n-(optionally substituted pyrazinyl) (wherein the pyrazinyl group has the following structure) 【Transformation 5】 (In the formula, * represents a linkage point to CO or (L)n, and R' represents one or more optional substituents, if any)); -CO-(L)n-(optionally substituted pyrimidinyl) (wherein the pyrimidinyl group has the following structure) 【Transformation 6】 (In the formula, * represents a linkage point to CO or (L)n, and R' represents one or more optional substituents, if any)); -CO-(L)n-(di(C1-C4 alkyl)amino); and -CO-(L)n-CO-(di(C1-C4 alkyl)amino) Selected from, The compound according to claim 1.

8. L is independently selected from optionally substituted alkylenes and optionally substituted heteroarylenes. Optionally, The compound according to claim 1, wherein each L is independently selected from optionally substituted C1-C12 alkylenes and optionally substituted imidazolyenes.

9. The compound according to claim 1, wherein n is 0 or 2, and optionally n is 0.

10. (L) n However, it is (a heteroarylene that may be substituted) - (a alkylene that may be substituted), and optionally, (L) n is (optionally substituted thienylene)-(optionally substituted C1-C12 alkylene), (optionally substituted benzo[b]thienylene)-(optionally substituted C1-C12 alkylene), (optionally substituted naphtho[2,3-b]thienylene)-(optionally substituted C1-C12 alkylene), (optionally substituted thiantrenylene)-(optionally substituted C1-C12 alkylene), (optionally substituted furylene)-(optionally substituted C1-C12 alkylene), (optionally substituted benzofuranylene)-(optionally substituted C1-C12 alkylene), (optionally substituted isobenzofuranylene)-(optionally substituted C1-C12 alkylene), (optionally substituted chromenylene)-(optionally substituted C1-C12 Alkylene), (optionally substituted xantheylene)-(optionally substituted C1-C12 alkylene), (optionally substituted phenoxathienylene)-(optionally substituted C1-C12 alkylene), (optionally substituted pyrrolylene)-(optionally substituted C1-C12 alkylene), (optionally substituted imidazoylene)-(optionally substituted C1-C12 alkylene), (optionally substituted pyrazolylene)-(optionally substituted C1-C12 alkylene), (optionally substituted triazolylene)-(optionally substituted C1-C12 alkylene), (optionally substituted tetrazoylene)-(optionally substituted C1-C12 alkylene), (optionally substituted pyridylene)-(optionally substituted C1-C12 Alkylene), (optionally substituted pyrazinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted pyrimidinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted pyridadinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted triazinylene)-(optionally substituted C1-C12Alkylene), (optionally substituted tetradinylene) - (optionally substituted C1-C12 alkylene), (optionally substituted indolidinelene) - (optionally substituted C1-C12 alkylene), (optionally substituted isoidomidrylene) - (optionally substituted C1-C12 alkylene), (optionally substituted 3H-indolylene) - (optionally substituted C1-C12 alkylene), (optionally substituted indolylene) - (optionally substituted C1-C12 alkylene), (optionally substituted indazoylene) - (optionally substituted C1-C12 alkylene), (optionally substituted prinylene) - (optionally substituted C1-C12 alkylene), (optionally substituted 4H-quinolidinylene) - (optionally substituted C1-C12 alkylene), (optionally substituted isoquinolylene) - (optionally substituted C1 -C12 alkylene), (optionally substituted quinolylene)-(optionally substituted C1-C12 alkylene), (optionally substituted phthalazine)-(optionally substituted C1-C12 alkylene), (optionally substituted naphthylidinerene)-(optionally substituted C1-C12 alkylene), (optionally substituted quinoxalinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted synnolinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted pteridinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted carbazoylene)-(optionally substituted C1-C12 alkylene), (optionally substituted β-carbolinylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenanthridinerene) - (optionally substituted C1-C12 alkylene), (optionally substituted acrindinylene) - (optionally substituted C1-C12 alkylene), (optionally substituted perimidinylene) - (optionally substituted C1-C12Alkylene), (optionally substituted phenanthrolinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted phenadinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted isothiazolylene)-(optionally substituted C1-C12 alkylene), (optionally substituted phenothiazinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted isoxazolylene)-(optionally substituted C1-C12 alkylene), (optionally substituted fluzanylene)-(optionally substituted C1-C12 alkylene), (optionally substituted phenoxadinylene)-(optionally substituted C1-C12 alkylene), (optionally substituted pyrazolo[1,5-α]pyrimidinylene)-(optionally substituted C1-C12 Selected from alkylene), (optionally substituted 1,2-benzoisoxazole-3-ylene)-(optionally substituted C1-C12 alkylene), (optionally substituted benzimidazoylene)-(optionally substituted C1-C12 alkylene), (optionally substituted 2-oxyindolylene)-(optionally substituted C1-C12 alkylene), and (optionally substituted 2-oxobenzoimidazoylene)-(optionally substituted C1-C12 alkylene), Furthermore, optionally, (L) n is (a substituted imidazoylene) - (a substituted C1-C6 alkylene), Furthermore, optionally, (L) n is, 【Transformation 7】 The compound according to claim 1, selected from (wherein ** represents a linking point to the remaining CO group, and *** represents a linking point to an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted amino group, or a CO-(optionally substituted amino) group).

11. A compound according to claim 1, selected from compounds 1 to 11. 【Transformation 8】 【change】

12. A pharmaceutical composition comprising a compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. 【Chemistry 11】 (In the formula, R 1 ~R 6 (As defined in claim 1)

13. A dosage form comprising the pharmaceutical composition described in claim 12.

14. Use in the manufacture of a medicament for the treatment of a disease modulated by CDK8 and / or CDK19, of a compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof; or the pharmaceutical composition according to claim 12; or the dosage form according to claim 13, 【Chemistry 12】 (In the formula, R 1 ~R 6 (As defined in claim 1) Preferably, the disease modulated by CDK8 and / or CDK19 is cancer. More preferably, the cancer is selected from leukemia (e.g., acute myeloid leukemia), bladder cancer (e.g., bladder cancer), breast cancer, colon cancer, skin cancer (e.g., cutaneous melanoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), glioblastoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), brain cancer (e.g., low-grade glioma), lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma), ovarian cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), adrenal cancer (e.g., pheochromocytoma), paraganglioma, prostate cancer (e.g., prostate adenocarcinoma), rectal cancer (e.g., rectal adenocarcinoma), sarcoma, gastric cancer (e.g., gastric adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor), thyroid cancer (e.g., thyroid cancer), and uterine cancer (e.g., endometrial cancer of the uterine body). The aforementioned use.

15. A kit comprising a compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof; or the composition according to claim 12; or the dosage form according to claim 13; and instructions for the use of the compound, pharmaceutical composition or dosage form in the treatment of a disease modulated by CDK8 and / or CDK19, 【Chemistry 13】 (In the formula, R 1 ~R 6 (As defined in claim 1) Preferably, the disease modulated by CDK8 and / or CDK19 is cancer. More preferably, the cancer is selected from leukemia (e.g., acute myeloid leukemia), bladder cancer (e.g., bladder cancer), breast cancer, colon cancer, skin cancer (e.g., cutaneous melanoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), glioblastoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), brain cancer (e.g., low-grade glioma), lung cancer (e.g., lung adenocarcinoma, lung squamous cell carcinoma), ovarian cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), adrenal cancer (e.g., pheochromocytoma), paraganglioma, prostate cancer (e.g., prostate adenocarcinoma), rectal cancer (e.g., rectal adenocarcinoma), sarcoma, gastric cancer (e.g., gastric adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor), thyroid cancer (e.g., thyroid cancer), and uterine cancer (e.g., endometrial cancer of the uterine body).

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