Inhibitors of CDK8 and CDK19

Abstract

The present invention relates to compounds according to Formula I and their use as CDK8 and / or CDK19 inhibitors. # imgabs0 #

Description

Technical Field

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

[0002] CDK8 and its homologue CDK19 (collectively referred to as "Mediator kinases") are cyclin-dependent kinases that are considered key rheostats in cellular homeostasis and developmental programming. CDK8 and CDK19 are integrated in a mutually exclusive manner as part of a 4-protein complex (called the Mediator Kinase Module). This module reversibly associates with Mediator, a 26-subunit protein complex that regulates RNA polymerase II-mediated gene expression. As part of this complex, Mediator kinases are involved in a variety of processes such as developmental signaling, metabolic homeostasis, and innate immunity. In recent years, dysregulation of Mediator kinase module proteins, including CDK8 / 19, has been implicated in the development of different human diseases and, in particular, cancer. Summary of the invention

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

[0004]

[0005] in:

[0006] R1 to R4 are each independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy and optionally substituted amino;

[0007] R5 and R6 are each independently selected from:

[0008] hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, and optionally substituted heteroaryl;

[0009] -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted cycloalkyl), -CO-(L) n -(optionally substituted heterocyclic group), -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),

[0010] wherein each L is independently selected from optionally substituted alkylene, (O-alkylene) w , optionally substituted heteroarylene, O and NH,

[0011] n is selected from 0, 1 and 2, and

[0012] w is selected from 1, 2 and 3; and

[0013] -SO2-(optionally substituted alkyl), -SO2-(optionally substituted cycloalkyl), -SO2-(optionally substituted heterocyclyl), -SO2-(optionally substituted alkoxy), -SO2-(optionally substituted aryl), -SO2-(optionally substituted heteroaryl) and -SO2-(optionally substituted amino);

[0014] Provided that the compound is not any of the following:

[0015]

[0016] Preferably, R1 to R4 are each independently selected from hydrogen and halogen, preferably hydrogen and fluorine.

[0017] Preferably, R1 is hydrogen.

[0018] Preferably, R2 is hydrogen or halogen, preferably hydrogen or fluorine.

[0019] Preferably, R3 is hydrogen.

[0020] Preferably, R4 is hydrogen.

[0021] Preferably, R5 and R6 are each independently selected from hydrogen, optionally substituted alkyl, -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclic group), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino) and -CO-(L) n -CO-(optionally substituted amino).

[0022] Preferably, R5 is hydrogen.

[0023] Preferably, R6 is selected from optionally substituted alkyl, -CO-(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclic group), -CO-(optionally substituted heteroaryl group), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino) and -CO-(L) n -CO-(optionally substituted amino).

[0024] Preferably, R6 is selected from:

[0025] Optionally substituted C1-C 12 alkyl;

[0026] -CO-(optionally substituted C1-C 12 alkyl);

[0027] -CO-(L) n -(optionally substituted azetidinyl), -CO-(L) n -(optionally substituted oxetane), -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 quinuclidine), -CO-(L) n -(optionally substituted morpholinyl), -CO-(L) n -(optionally substituted heterochromatic group), -CO-(L) n -(optionally substituted chromanyl), -CO-(L) n -(optionally substituted pyrazolidinyl), -CO-(L) n -(optionally substituted pyrazolyl), -CO-(L) n -(optionally substituted tetronoyl) and -CO-(L) n -(optionally substituted tetramoyl);

[0028] -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 furanyl), -CO-(optionally substituted benzofuranyl), -CO-(optionally substituted isobenzofuranyl), -CO-(optionally substituted chromenyl), -CO-(optionally substituted xanthene), -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 pyridinyl), -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 quinazolinyl), -CO-(optionally substituted cinnolinyl), -CO-(optionally substituted pteridinyl), -CO-(optionally substituted carbazolyl), -CO-(optionally substituted β-carbolinyl), -CO-(optionally substituted phenanthridinyl), -CO-(optionally substituted acridinyl), -CO-(optionally substituted perylenediazolephenyl) ), -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-oxindolyl), and -CO-(optionally substituted 2-oxobenzimidazolyl);

[0029] -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 furanyl), -CO-(L) n -(optionally substituted benzofuranyl), -CO-(L) n -(optionally substituted isobenzofuranyl), -CO-(L) n -(optionally substituted chromene), -CO-(L) n -(optionally substituted xanthene), -CO-(L) n -(optionally substituted thiophenoxane), -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 triazine), -CO-(L) n -(optionally substituted tetrazinyl), -CO-(L) n -(optionally substituted indolizinyl), -CO-(L) n -(optionally substituted isoindole), -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 quinazolinyl), -CO-(L) n -(optionally substituted cinnolinyl), -CO-(L) n -(optionally substituted pteridinyl), -CO-(L) n -(optionally substituted carbazolyl), -CO-(L) n -(optionally substituted β-carbolyl), -CO-(L) n -(optionally substituted phenanthridinyl), -CO-(L) n -(optionally substituted acridinyl), -CO-(L) n -(optionally substituted perylene), -CO-(L) n -(optionally substituted phenanthroline), -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-oxindolyl) and -CO-(L) n -(optionally substituted 2-oxobenzimidazolyl);

[0030] -CO-(L) n -((C1-C 12 alkyl)amino); and

[0031] -CO-(L) n -CO-(di(C1-C 12 alkyl)amino).

[0032] Preferably, R6 is selected from:

[0033] Optionally substituted C1-C6 alkyl;

[0034] -CO-(optionally substituted C1-C6 alkyl);

[0035] -CO-(L) n -(optionally substituted oxetane);

[0036] -CO-(optionally substituted imidazolyl);

[0037] -CO-(L) n -(optionally substituted pyrazinyl);

[0038] -CO-(L) n -(optionally substituted pyrimidinyl);

[0039] -CO-(L) n -(di(C1-C6 alkyl)amino); and

[0040] -CO-(L) n -CO-(di(C1-C6 alkyl)amino).

[0041] Preferably, R6 is selected from:

[0042] Optionally substituted C1-C4 alkyl;

[0043] -CO-(optionally substituted C1-C4 alkyl);

[0044] -CO-(L) n -(optionally substituted oxetanyl), wherein the oxetanyl group has the following structure:

[0045]

[0046] Where * indicates CO or (L) n and R', if present, represents one or more optional substituents;

[0047] -CO-(optionally substituted imidazolyl), wherein the imidazolyl group has the following structure:

[0048]

[0049] wherein * represents the point of attachment to CO, and R', if present, represents one or more optional substituents;

[0050] -CO-(L) n -(optionally substituted pyrazinyl), wherein the pyrazinyl group has the structure:

[0051]

[0052] Where * indicates CO or (L) n and R', if present, represents one or more optional substituents;

[0053] -CO-(L) n-(optionally substituted pyrimidinyl), wherein the pyrimidinyl group has the structure:

[0054]

[0055] Where * indicates CO or (L) n and R', if present, represents one or more optional substituents;

[0056] -CO-(L) n -(di(C1-C4alkyl)amino); and

[0057] -CO-(L) n -CO-(di(C1-C4alkyl)amino).

[0058] Preferably, each L is independently selected from optionally substituted alkylene and optionally substituted heteroarylene.

[0059] Preferably, each L is independently selected from an optionally substituted C1-C 12 an alkylene group and an optionally substituted imidazolylene group.

[0060] Preferably, n is 0 or 2.

[0061] Preferably, n is 0.

[0062] Preferably, (L) n is (optionally substituted heteroarylene)-(optionally substituted alkylene).

[0063] Preferably, (L) n Selected from: (optionally substituted thienyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzo[b]thienylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted naphtho[2,3-b]thienylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted thianthrenyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted furanyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzofuranylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted isobenzofuranyl)-(optionally substituted C1-C 12 (optionally substituted chromene)-(optionally substituted C1-C 12 alkylene), (optionally substituted xanthene)-(optionally substituted C1-C 12 alkylene), (optionally substituted thienylene)-(optionally substituted C1-C12 alkylene), (optionally substituted pyrrolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted imidazolyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted triazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted tetrazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyridylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrimidinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyridazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted triazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted tetrazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted indolizinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoindoleyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted 3H-indolyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted indolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted indazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted purinylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted 4H-quinolizinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoquinolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted quinolinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phthalazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted naphthyridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted quinazolinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted cinnolinyl)-(optionally substituted C1-C 12(C1-C2-alkylene), (optionally substituted pteridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted carbazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted β-carbolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenanthridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted acridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted perylene diazaphenyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenanthroline)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isothiazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenothiazinylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoxazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted furazanyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenoxazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazolo[1,5-α]pyrimidinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted 1,2-benzisoxazol-3-ylidene)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzimidazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted 2-oxindolylene)-(optionally substituted C1-C 12 alkylene) and (optionally substituted 2-oxobenzimidazolyl)-(optionally substituted C1-C 12 alkylene).

[0064] Preferably, (L) n It is (optionally substituted imidazolylene)-(optionally substituted C1-C6 alkylene).

[0065] Preferably, (L) n Selected from:

[0066]

[0067] wherein ** represents the point of connection to the CO group on the left, and *** represents the point of connection to the optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted heterocyclyl group, optionally substituted alkoxy group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted amino group or CO-(optionally substituted amino) group.

[0068] Preferably, the compound is selected from compounds 1 to 10:

[0069]

[0070] Preferably, the compound is compound 11:

[0071]

[0072] Preferably, the compound is not any of the following:

[0073]

[0074] 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:

[0075]

[0076] wherein R1 to R6 are as defined herein.

[0077] According to another aspect of the present invention, there is provided a dosage form comprising a composition as defined herein.

[0078] 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:

[0079]

[0080] wherein R1 to R6 are as defined herein; or a composition as defined herein; or a dosage form as defined herein; for use in treating a disease modulated by CDK8 and / or CDK19.

[0081] Preferably, the disease modulated by CDK8 and / or CDK19 is cancer.

[0082] 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 adenocarcinoma) and uterine cancer (e.g. uterine corpus endometrial carcinoma).

[0083] 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:

[0084]

[0085] wherein R1 to R6 are as defined herein; or a composition as defined herein; or a dosage form as defined herein; use in the manufacture of a medicament for treating a disease regulated by CDK8 and / or CDK19, preferably wherein the disease is as defined herein.

[0086] According to another aspect of the present invention, there is provided: a method for treating a disease regulated by CDK8 and / or CDK19 in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0087]

[0088] wherein R1 to R6 are as defined herein; or a composition as defined herein; or a dosage form as defined herein; preferably wherein the disease is as defined herein.

[0089] According to another aspect of the present invention, there is provided: a kit comprising a compound according to formula I or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0090]

[0091] wherein R1 to R6 are as defined herein; or a composition as defined herein; or a dosage form as defined herein; and instructions for using the compound, composition or dosage form in the treatment of a disease modulated by CDK8 and / or CDK19, preferably wherein the disease is as defined herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] The invention is further described in the following non-limiting drawings.

[0093] Figure 1 The predicted binding mode of compound 5 at the CDK8 active site (PDB ID: 4F6U) is shown. For clarity, only the amino acid residues surrounding the ligand are shown. The docking pose is depicted, while hydrogen bonds and π-π stacking interactions are indicated with dashed lines.

[0094] Figure 2 A magnified view of the binding pocket is shown, highlighting the key interactions between compound 5 and CDK8. DETAILED DESCRIPTION

[0095] The following applies to all aspects of the invention.

[0096] General Chemical Definition

[0097] As used herein, the term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine, or iodine.

[0098] As used herein, the term "alkyl" refers to straight and branched chain groups of up to twelve carbons. For example, an alkyl group can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 12 The limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups. Preferably, as used herein, the term "alkyl" may refer to a straight or branched chain group comprising one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms." alkyl optionally substituted " groups may include substituents as described below for the term "optionally substituted". For example, "alkyl optionally substituted " groups may include "haloalkyl" groups.

[0099] As used herein, the term "haloalkyl" refers to straight and branched chain groups of up to twelve carbon atoms containing at least one halogen atom. For example, a haloalkyl group may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Preferably, as used herein, the term "haloalkyl" may refer to a straight or branched chain group containing one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms and containing at least one halogen atom.

[0100] For example, a "haloalkyl" group can be a fluoroalkyl or a perfluoroalkyl group.

[0101] Preferably, the "haloalkyl" group may be a C1-C6 fluoroalkyl group or a C1-C6 perfluoroalkyl group.

[0102] Even more preferably, the "haloalkyl" group may be a C1-C4 fluoroalkyl group or a C1-C4 perfluoroalkyl group. For example, the "haloalkyl" group may include difluoromethyl, trifluoromethyl or pentafluoroethyl.

[0103] As used herein, the term "cycloalkyl" refers to an alkyl group comprising a closed ring comprising 3 to 8 carbon atoms (e.g., 3 to 6 carbon atoms). For example, the cycloalkyl group can contain 3, 4, 5, 6, 7 or 8 carbon atoms. The limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, (cyclohexyl) methyl and (cyclohexyl) ethyl. "Optionally substituted cycloalkyl" groups can include substituents as described below for the term "optionally substituted".

[0104] As used herein, the term "heterocyclyl" refers to a saturated or partially saturated 3 to 7-membered monocyclic or 7 to 10-membered bicyclic system consisting of carbon atoms and one to four heteroatoms independently selected from O, N and S, wherein nitrogen and sulfur heteroatoms may be optionally oxidized, nitrogen may be optionally quaternized, and includes any bicyclic group wherein any one of the rings defined above is fused to a benzene ring, and wherein if the resulting compound is stable, the ring may be substituted on carbon or nitrogen atoms. Non-limiting examples of common saturated or partially saturated heterocyclic groups include azetinyl, oxetane, tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tert-butyl and tert-butyl aminoacyl groups. An "optionally substituted heterocyclyl" group may include substituents as described hereinbelow for the term "optionally substituted".

[0105] As used herein, the term "alkoxy" refers to an alkyl group as defined herein that is attached to the parent molecular moiety by 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, "alkoxy" itself as used herein or as a part for another group can refer to a straight or branched group comprising one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms that are attached to the parent molecular moiety by an oxygen atom. The non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy." alkoxy optionally substituted " group can include a substituent as described below for term "optionally substituted". For example, " alkoxy optionally substituted " group can include a "haloalkoxy " group.

[0106] As used herein, the term "haloalkoxy" refers to a linear and branched chain group of up to twelve carbon atoms that contains at least one halogen atom and is 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" by itself or as part of another group can refer to a linear or branched chain group containing one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms, containing at least one halogen atom and attached to the parent molecular moiety through an oxygen atom.

[0107] For example, a "haloalkoxy" group can be a fluoroalkoxy or a perfluoroalkoxy.

[0108] Preferably, the "haloalkoxy" group may be a C1-C6 fluoroalkoxy group or a C1-C6 perfluoroalkoxy group.

[0109] Even more preferably, the "haloalkoxy" group may be a C1-C4 fluoroalkoxy group or a C1-C4 perfluoroalkoxy group. For example, the "haloalkoxy" group may include difluoromethoxy, trifluoromethoxy or pentafluoroethoxy.

[0110] As used herein, the term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms in the ring. Common aryl groups include C6-C 14 Aryl, such as C6-C 10 Aryl. C6-C 14 Non-limiting examples of aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. An "optionally substituted aryl" group may include substituents as described below for the term "optionally substituted".

[0111] As used herein, the term "heteroaryl" refers to an 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 heteroaryl groups include thienyl (thiophenyl), benzo [b] thienyl, naphtho [2,3-b] thienyl, thianthrenyl, furyl (furanyl), benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, thienyl, pyrrolyl (including but not limited to 2H-pyrrolyl), imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl (pyridinyl) (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, Pyridazinyl, triazinyl, tetrazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perylene, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, pyrazolo[1,5-α]pyrimidinyl (including but not limited to pyrazolo[1,5-α]pyrimidin-3-yl), 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindolyl and 2-oxobenzimidazolyl. In the case where the heteroaryl group contains a nitrogen atom in the ring, such a nitrogen atom may be in the form of an N-oxide, such as pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide. An "optionally substituted heteroaryl" group may include the substituents described below for the term "optionally substituted".

[0112] As used herein, the term "amino" refers to a group -NR'2, wherein R' is hydrogen or an optional substituent. An "optionally substituted amino" group may include substituents described below for the term "optionally substituted".

[0113] As used herein, the term "alkylene" refers to divalent straight and branched chain groups of up to twelve carbon atoms. For example, an alkylene group can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 12The limiting examples of alkylidene groups include methylene, ethylene, propylene, isopropylene, butylidene, sec-butylidene, tert-butylidene, sub-3-pentyl, hexylidene and octylidene. Preferably, as used herein, the term "alkylidene" may refer to a divalent straight or branched chain group comprising one to eight carbon atoms, more preferably one to six carbon atoms and even more preferably one to four carbon atoms. An "optionally substituted alkylidene" group may include a substituent described below for the term "optionally substituted".

[0114] As used herein, the term "heteroarylene" refers to a divalent aromatic group having 5 to 14 ring atoms (eg, 5 to 10 ring atoms) and containing carbon atoms and 1, 2, or 3 oxygen, nitrogen, or sulfur heteroatoms. Examples of heteroarylene groups include thioenylene (thiophenlene), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (furanylene), benzofuranylene, isobenzofuranylene, chromenylene, xanthenylene, thiophenoxylene, pyrrolylene (including but not limited to 2H-pyrrolylene), imidazolylene, pyrazolylene, triazolylene, tetrazolylene, pyridylene (pyridinylene) (including but not limited to 2-pyridylene, 3-pyridylene and 4-pyridylene), pyrazinylene, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolyl, phenanthridinyl, acridinyl, naphthylidene Azaphenyl, phenanthroline, phenazine, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, pyrazolo[1,5-α]pyrimidinyl (including but not limited to pyrazolo[1,5-α]pyrimidinyl-3-ylidene), 1,2-benzisoxazole-3-ylidene, benzimidazolyl, sub-2-oxindolyl and sub-2-oxobenzimidazolyl. In the case where the sub-heteroaryl group contains a nitrogen atom in the ring, such a nitrogen atom can be in the form of an N-oxide, such as pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide. "Optionally substituted sub-heteroaryl" may include substituents described below for the term "optionally substituted".

[0115] As described herein, compounds may contain "optionally substituted" moieties. Typically, the term "substituted" (whether or not beginning with the term "optionally") means that one or more hydrogen atoms of the designated moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a designated group, the substituent may be the same or different at each position. The combination of substituents contemplated by the present invention is preferably those combinations that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not undergo substantial changes when subjected to conditions that allow it to be produced, detected, and in certain embodiments, recovered, purified, and used for one or more purposes disclosed herein.

[0116] For example, as used herein, the term "optionally substituted" may refer to when 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.

[0117] Preferably, as used herein, the term "optionally substituted" may refer to when 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.

[0118] More preferably, as used herein, the term "optionally substituted" may refer to when at least one substituent is selected from oxo, hydroxy, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3 to 10 membered heterocyclyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CO-(C1-C6 alkyl), -CO-(C1-C6 alkoxy), amino, 5 to 14 membered aryl and 5-14 membered heteroaryl.

[0119] The conjugates of the present invention may be provided in the form of "salts". As used herein, the term "salt" refers to salts of compounds as described herein derived from suitable inorganic and organic acids and bases. Examples of salts of basic groups include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as trifluoroacetic acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, 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, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-C4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, further salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates.

[0120] Some compounds of the present disclosure may exist in non-solvated forms as well as solvated forms (including hydrated forms). "Hydrate" refers to a complex formed by a combination of water molecules and molecules or ions of a solute. "Solvate" refers to a complex formed by a combination of solvent molecules and molecules or ions of a solute. The solvent may be an organic compound, an inorganic compound, or a mixture of the two. 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. Typically, solvated forms are equivalent to non-solvated forms and are encompassed within the scope of the present disclosure. Some compounds of the present disclosure may exist as solid materials (e.g., a variety of crystals or amorphous forms). Typically, all physical forms are equivalent for the purposes contemplated by the present disclosure and are intended to be included within the scope of the present disclosure.

[0121] "Tautomer" refers to a compound resulting from the phenomenon in which a proton of one atom of a molecule moves to another atom (see Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992)). Tautomer also refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. Examples include keto-enol tautomers such as acetone / propene-2-ol, imine-enamine tautomers, etc., ring-chain tautomers such as glucose / 2,3,4,5,6-pentahydroxy-hexanal, etc., tautomeric forms of heteroaryl groups containing -N=C(H)-NH- ring atom arrangements such as pyrazole, imidazole, benzimidazole, triazole and tetrazole. In the case where a compound contains, for example, a ketone or oxime group or an aromatic moiety, the phenomenon of tautomerism ("tautomerism") may occur. The compounds described herein may have one or more tautomers, and therefore include various isomers. Those skilled in the art will recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.

[0122] "Isomers" refer to compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or in the arrangement of their atoms in space. Isomers whose atoms are arranged differently in space are called "stereoisomers". "Stereoisomers" and "these stereoisomers" refer to compounds that exist in different stereoisomeric forms if the compound has one or more asymmetric centers or has double bonds with asymmetric substitutions, and therefore they can occur as single stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, then a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described by the R and S ordering rules of Cahn and Prelog, or described and designated as right-handed or left-handed (i.e., (+) or (-)-isomers, respectively) by the way in which the molecule rotates the plane of polarized light. Chiral compounds can exist as single enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture". Unless otherwise indicated, descriptions are intended to include single stereoisomers as well as mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 6th edition J. March, John Wiley and Sons, New York, 2007), which differ in the chirality of one or more stereocenters.

[0123] The present disclosure also encompasses isotopically labeled compounds of the present disclosure, which are identical to the compounds described herein, but differ in the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from that usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 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 125I. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen or its isotopes such as deuterium (D) or tritium ( 3 H). Certain isotopically labeled compounds of the present disclosure (e.g., with ( 3 H) and 14 C-labeled compounds) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) and fluorine-18 (i.e. 18 F) isotopes are useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e. 2 H)) may offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in certain circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those described herein (providing that an isotopically labeled reagent is substituted for a non-isotopically labeled reagent).

[0124] Compound

[0125] In another embodiment of the present invention, provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0126]

[0127] Compounds according to formula I have been shown to exhibit high binding affinity to CDK8 and / or CDK19. Therefore, compounds according to formula I can be advantageously used to treat diseases regulated by CDK8 and / or CDK19. Without wishing to be bound by theory, it is speculated that the presence of the benzisothiazole and piperidine rings helps the compounds according to formula I to bind deeply into the binding pockets of CDK8 and CDK19 (e.g. Figure 1 and 2 ), resulting in high binding affinity.

[0128] In formula I, R1 is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy and optionally substituted amino.

[0129] Preferably, R1 can be selected from hydrogen, hydroxy, halogen, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 an alkoxy group and an optionally substituted amino group.

[0130] More preferably, R1 may be selected from hydrogen and halogen.

[0131] Even more preferably, R1 may be selected from hydrogen and fluorine.

[0132] Even more preferably, R1 may be hydrogen.

[0133] In formula I, R2 is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy and optionally substituted amino.

[0134] Preferably, R2 can be selected from hydrogen, hydroxy, halogen, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 an alkoxy group and an optionally substituted amino group.

[0135] More preferably, R2 may be selected from hydrogen and halogen.

[0136] Even more preferably, R2 may be selected from hydrogen and fluorine.

[0137] Still even more preferably, R2 may be hydrogen.

[0138] In formula I, R3 is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy and optionally substituted amino.

[0139] Preferably, R3 can be selected from hydrogen, hydroxy, halogen, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 an alkoxy group and an optionally substituted amino group.

[0140] More preferably, R3 may be selected from hydrogen and halogen.

[0141] Even more preferably, R3 may be selected from hydrogen and fluorine.

[0142] Still even more preferably, R3 may be hydrogen.

[0143] In formula I, R4 is selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy and optionally substituted amino.

[0144] Preferably, R4 can be selected from hydrogen, hydroxy, halogen, optionally substituted C1-C 12 Alkyl, optionally substituted C1-C 12 an alkoxy group and an optionally substituted amino group.

[0145] More preferably, R4 may be selected from hydrogen and halogen.

[0146] Even more preferably, R4 may be selected from hydrogen and fluorine.

[0147] Still even more preferably, R4 may be hydrogen.

[0148] In Formula I, R5 is selected from:

[0149] hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, and optionally substituted heteroaryl;

[0150] -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted cycloalkyl), -CO-(L) n -(optionally substituted heterocyclic group), -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),

[0151] wherein each L is independently selected from optionally substituted alkylene, (O-alkylene) w , optionally substituted heteroarylene, O and NH,

[0152] n is selected from 0, 1 and 2, and

[0153] w is selected from 1, 2 and 3; and

[0154] -SO2-(optionally substituted alkyl), -SO2-(optionally substituted cycloalkyl), -SO2-(optionally substituted heterocyclyl), -SO2-(optionally substituted alkoxy), -SO2-(optionally substituted aryl), -SO2-(optionally substituted heteroaryl) and -SO2-(optionally substituted amino).

[0155] Preferably, R5 can be selected from hydrogen, optionally substituted alkyl, -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclic group), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino) and -CO-(L) n -CO-(optionally substituted amino).

[0156] More preferably, R5 may be hydrogen.

[0157] In Formula I, R6 is selected from:

[0158] hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aryl, and optionally substituted heteroaryl;

[0159] -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted cycloalkyl), -CO-(L) n -(optionally substituted heterocyclic group), -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),

[0160] wherein each L is independently selected from optionally substituted alkylene, (O-alkylene) w , optionally substituted heteroarylene, O and NH,

[0161] n is selected from 0, 1 and 2, and

[0162] w is selected from 1, 2 and 3; and

[0163] -SO2-(optionally substituted alkyl), -SO2-(optionally substituted cycloalkyl), -SO2-(optionally substituted heterocyclyl), -SO2-(optionally substituted alkoxy), -SO2-(optionally substituted aryl), -SO2-(optionally substituted heteroaryl) and -SO2-(optionally substituted amino).

[0164] Preferably, R6 can be selected from hydrogen, optionally substituted alkyl, -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclic group), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino) and -CO-(L) n -CO-(optionally substituted amino).

[0165] More preferably, R6 can be selected from:

[0166] Optionally substituted C1-C 12 alkyl;

[0167] -CO-(optionally substituted C1-C 12 alkyl);

[0168] -CO-(L) n -(optionally substituted azetidinyl), -CO-(L) n-(optionally substituted oxetane), -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 quinuclidine), -CO-(L) n -(optionally substituted morpholinyl), -CO-(L) n -(optionally substituted heterochromatic group), -CO-(L) n -(optionally substituted chromanyl), -CO-(L) n -(optionally substituted pyrazolidinyl), -CO-(L) n -(optionally substituted pyrazolyl), -CO-(L) n -(optionally substituted tert-butyl) and -CO-(L) n -(optionally substituted aminoacyl);

[0169] -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 furanyl), -CO-(optionally substituted benzofuranyl), -CO-(optionally substituted isobenzofuranyl), -CO-(optionally substituted chromenyl), -CO-(optionally substituted xanthene), -CO-(optionally substituted thiophenoxanyl), -CO-(optionally substituted pyrrolyl), -CO-(optionally substituted imidazolyl), -CO-(optionally substituted pyrazolyl ), -CO-(optionally substituted triazolyl), -CO-(optionally substituted tetrazolyl), -CO-(optionally substituted pyridinyl), -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 purine yl), -CO-(optionally substituted 4H-quinolizinyl), -CO-(optionally substituted isoquinolyl), -CO-(optionally substituted quinolyl), -CO-(optionally substituted phthalazinyl), -CO-(optionally substituted naphthyridinyl), -CO-(optionally substituted quinazolinyl), -CO-(optionally substituted cinnolinyl), -CO-(optionally substituted pteridinyl), -CO-(optionally substituted carbazolyl), -CO-(optionally substituted β-carbolinyl), -CO-(optionally substituted phenanthridinyl), -CO-(optionally substituted acridinyl), -CO-(optionally substituted perimelinyl), -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-oxindolyl), and -CO-(optionally substituted 2-oxobenzimidazolyl);

[0170] -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 furanyl), -CO-(L) n -(optionally substituted benzofuranyl), -CO-(L) n -(optionally substituted isobenzofuranyl), -CO-(L) n -(optionally substituted chromene), -CO-(L) n -(optionally substituted xanthene), -CO-(L) n -(optionally substituted thiophenoxane), -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 triazine), -CO-(L) n -(optionally substituted tetrazinyl), -CO-(L) n -(optionally substituted indolizinyl), -CO-(L) n -(optionally substituted isoindole), -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 quinazolinyl), -CO-(L) n-(optionally substituted cinnolinyl), -CO-(L) n -(optionally substituted pteridinyl), -CO-(L) n -(optionally substituted carbazolyl), -CO-(L) n -(optionally substituted β-carbolyl), -CO-(L) n -(optionally substituted phenanthridinyl), -CO-(L) n -(optionally substituted acridinyl), -CO-(L) n -(optionally substituted perylene), -CO-(L) n -(optionally substituted phenanthroline), -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-oxindolyl) and -CO-(L) n -(optionally substituted 2-oxobenzimidazolyl);

[0171] -CO-(L) n -((C1-C 12 alkyl)amino); and

[0172] -CO-(L) n -CO-(di(C1-C 12 alkyl)amino).

[0173] Even more preferably, R6 may be selected from:

[0174] Optionally substituted C1-C6 alkyl;

[0175] -CO-(optionally substituted C1-C6 alkyl);

[0176] -CO-(L) n -(optionally substituted oxetane);

[0177] -CO-(optionally substituted imidazolyl);

[0178] -CO-(L) n -(optionally substituted pyrazinyl);

[0179] -CO-(L) n -(optionally substituted pyrimidinyl);

[0180] -CO-(L) n -(di(C1-C6 alkyl)amino); and

[0181] -CO-(L) n -CO-(di(C1-C6 alkyl)amino).

[0182] For example, R6 can be selected from:

[0183] Optionally substituted C1-C6 alkyl;

[0184] -CO-(optionally substituted C1-C6 alkyl);

[0185] -CO-(L) n -(optionally substituted oxetane);

[0186] -CO-(optionally substituted imidazolyl);

[0187] -CO-(L) n -(optionally substituted pyrazinyl);

[0188] -CO-(L) n -(di(C1-C6 alkyl)amino); and

[0189] -CO-(L) n -CO-(di(C1-C6 alkyl)amino).

[0190] Even more preferably, R6 may be selected from:

[0191] Optionally substituted C1-C4 alkyl;

[0192] -CO-(optionally substituted C1-C4 alkyl);

[0193] -CO-(L) n -(optionally substituted oxetanyl), wherein the oxetanyl group has the following structure:

[0194]

[0195] Where * indicates CO or (L) n nand R', if present, represents one or more optional substituents;

[0196] -CO-(optionally substituted imidazolyl), wherein the imidazolyl group has the following structure:

[0197]

[0198] wherein * represents the point of attachment to CO, and R', if present, represents one or more optional substituents;

[0199] -CO-(L) n -(optionally substituted pyrazinyl), wherein the pyrazinyl group has the structure:

[0200]

[0201] Where * indicates CO or (L) n and R', if present, represents one or more optional substituents;

[0202] -CO-(L) n -(optionally substituted pyrimidinyl), wherein the pyrimidinyl group has the structure:

[0203]

[0204] Where * indicates CO or (L) n and R', if present, represents one or more optional substituents;

[0205] -CO-(L) n -(di(C1-C4alkyl)amino); and

[0206] -CO-(L) n -CO-(di(C1-C4alkyl)amino).

[0207] For example, R6 can be selected from:

[0208] Optionally substituted C1-C4 alkyl;

[0209] -CO-(optionally substituted C1-C4 alkyl);

[0210] -CO-(L) n -(optionally substituted oxetanyl), wherein the oxetanyl group has the following structure:

[0211]

[0212] Where * indicates CO or (L) nand R', if present, represents one or more optional substituents;

[0213] -CO-(optionally substituted imidazolyl), wherein the imidazolyl group has the following structure:

[0214]

[0215] wherein * represents the point of attachment to CO, and R', if present, represents one or more optional substituents;

[0216] -CO-(L) n -(optionally substituted pyrazinyl), wherein the pyrazinyl group has the structure:

[0217]

[0218] Where * indicates CO or (L) n and R', if present, represents one or more optional substituents;

[0219] -CO-(L) n -(di(C1-C4alkyl)amino); and

[0220] -CO-(L) n -CO-(di(C1-C4alkyl)amino).

[0221] In formula I, preferably each L may be independently selected from optionally substituted alkylene and optionally substituted heteroarylene. Preferably, when n is 2, then the first L group is different from the second L group.

[0222] More preferably, each L can be independently selected from an optionally substituted C1-C 12 an alkylene group and an optionally substituted imidazolylene group.

[0223] Even more preferably, each L may be independently selected from an optionally substituted C1-C6 alkylene group and an optionally substituted imidazolylene group.

[0224] Even more preferably, each L may be independently selected from optionally substituted C1-C4 alkylene and optionally substituted imidazolylene.

[0225] In formula I, n may be preferably 0 or 2.

[0226] In a preferred embodiment, n may be 0. In other words, in (L) n The groups on either side of the moiety are connected by a direct bond.

[0227] In another preferred embodiment, n may be 2.

[0228] Preferably, (L) n It may be (optionally substituted heteroarylene)-(optionally substituted alkylene).

[0229] More preferably, (L) n It can be (optionally substituted heteroarylene)-(optionally substituted C1-C 12 alkylene).

[0230] Even more preferably, (L) n can be selected from (optionally substituted thienyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzo[b]thienylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted naphtho[2,3-b]thienylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted thianthrenyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted furanyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzofuranylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted isobenzofuranyl)-(optionally substituted C1-C 12 (optionally substituted chromene)-(optionally substituted C1-C 12 alkylene), (optionally substituted xanthene)-(optionally substituted C1-C 12 alkylene), (optionally substituted thienylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrrolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted imidazolyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted triazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted tetrazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyridylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrimidinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyridazinyl)-(optionally substituted C1-C 12alkylene), (optionally substituted triazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted tetrazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted indolizinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoindoleyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted 3H-indolyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted indolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted indazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted purinylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted 4H-quinolizinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoquinolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted quinolinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phthalazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted naphthyridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted quinazolinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted cinnolinyl)-(optionally substituted C1-C 12 (C1-C2-alkylene), (optionally substituted pteridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted carbazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted β-carbolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenanthridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted acridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted perylene diazaphenyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenanthroline)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isothiazolylene)-(optionally substituted C1-C 12alkylene), (optionally substituted phenothiazinylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoxazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted furazanyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenoxazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazolo[1,5-α]pyrimidinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted 1,2-benzisoxazol-3-ylidene)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzimidazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted 2-oxindolylene)-(optionally substituted C1-C 12 alkylene) and (optionally substituted 2-oxobenzimidazolyl)-(optionally substituted C1-C 12 alkylene).

[0231] Even more preferably, (L) n It may be (optionally substituted imidazolylene)-(optionally substituted C1-C6 alkylene).

[0232] Most preferably, wherein (L) n Can be selected from:

[0233]

[0234] wherein ** represents the point of connection to the CO group on the left, and *** represents the point of connection to the optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted heterocyclyl group, optionally substituted alkoxy group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted amino group or CO-(optionally substituted amino) group.

[0235] The compound according to Formula I can be selected from Compounds 1 to 10, but the compounds provided herein are not necessarily limited thereto:

[0236]

[0237] The compound according to Formula I may be Compound 11, but the compounds provided herein are not necessarily limited thereto:

[0238]

[0239] In embodiments involving compounds of Formula I, the compound is not any of the following:

[0240]

[0241] In further embodiments involving compounds of Formula I, the compound may not be any of the following:

[0242]

[0243] Composition

[0244] In another embodiment of the present invention, provided herein is a composition comprising a compound according to Formula I or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient:

[0245]

[0246] wherein R1 to R6 are as defined herein.

[0247] In embodiments involving compositions comprising a compound of Formula I, the compound may not be any of the following:

[0248]

[0249]

[0250] However, the compositions provided herein are not necessarily limited thereto.

[0251] In further embodiments involving compositions comprising a compound of Formula I, the compound may not be any of the following:

[0252]

[0253] However, the compositions provided herein are not necessarily limited thereto.

[0254] Pharmaceutical carriers or excipients may include fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers and surfactants, which may be selected to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose or sucrose, various types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, etc. Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solutions, glucose solutions, Hank's solutions, Ringer's solutions, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, etc. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, microcrystalline cellulose, carboxymethyl cellulose, croscarmellose sodium, 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, castor oil mineral oil, polyethylene glycol (e.g., PEG 400 or PEG 4000-8000), polyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, divinylbenzene methacrylate copolymer, docusate sodium (sodium docusate), cyclodextrins (e.g., 2-hydroxypropyl-δ-cyclodextrin), polysorbates (e.g., polysorbate 80), cetrimide, TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, di-fatty acid esters of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan esters ), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters such as sorbitan fatty acid esters 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, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrose, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, etc.

[0255] In some embodiments, oral administration can be used. Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. The compounds of Formula I described herein can be combined with solid excipients, the resulting mixture is optionally ground, and the mixture of particles is processed after adding suitable adjuvants (if desired) to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous, alcoholic or oily solutions), etc. Suitable excipients are particularly fillers such as sugars, including lactose, glucose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methyl-cellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable oils and animal oils, such as sunflower oil, olive oil or cod liver oil. Oral pharmaceutical preparations may also contain disintegrants, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid, or salts thereof 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 flavorings, such as mint, wintergreen oil or cherry flavoring; or dyes or pigments, which may be used to identify or characterize different doses or combinations. A dragee core with a suitable coating is also provided. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.

[0256] Pharmaceutical preparations that can be used orally include push-in capsules made of gelatin ("gelcaps"), and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-in capsules can contain the active ingredient in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient, such as a compound of Formula I, can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or a liquid polyethylene glycol.

[0257] In some embodiments, injection (parenteral administration) can be used, such as intramuscular, intravenous, intraperitoneal and / or subcutaneous injection. The compound of formula I described herein for injection can be prepared in a sterile liquid solution, preferably in a physiologically compatible buffer or solution (such as saline solution, 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 oil). The solution can also contain preservatives, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In addition, the compound of formula I described herein can be configured in solid form (including, for example, lyophilized form) and redissolved or suspended before use.

[0258] In some embodiments, transmucosal, topical or transdermal administration can be used. In such preparations of the compounds of formula I described herein, penetrants suitable for the barrier to be penetrated are used. Such penetrants are generally known in the art, and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents can be used to facilitate penetration. Transmucosal administration can be carried out, for example, by nasal sprays or suppositories (rectal or vaginal). The compositions of the compounds of formula I described herein for topical administration can be formulated as oils, creams, lotions, ointments, etc. by selecting appropriate carriers known in the art. Suitable carriers include vegetable oils or mineral oils, white vaseline (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C 12 ). In some embodiments, the carrier is selected so that the active ingredient is soluble. If necessary, emulsifiers, stabilizers, moisturizers and antioxidants and agents that impart color or fragrance may also be included. Creams for topical application are preferably prepared from a mixture of mineral oil, self-emulsifying beeswax and water, in which the active ingredient dissolved in a small amount of solvent (e.g., oil) is mixed. In addition, transdermal administration may include a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art. When administered in the form of a transdermal delivery system, dosage administration will be continuous, rather than intermittent throughout the administration regimen.

[0259] In some embodiments, the compound of formula I or its composition is administered as an inhalant. The compound of formula I described herein can be formulated as a dry powder or a suitable solution, suspension or aerosol. Powders and solutions can be formulated with suitable additives known in the art. For example, powders can include suitable powder bases such as lactose or starch, and solutions can include 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 sprays, pumps, nebulizers or sprayers.

[0260] Dosage form

[0261] In another embodiment of the present invention, provided herein is a dosage form comprising the composition described herein.

[0262] The dosage form may be a unit dose or single dose form, such as a single dose pill, capsule, or the like.

[0263] Medical Uses

[0264] In another embodiment of the present invention, provided herein is a compound according to Formula I or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0265]

[0266] wherein R1 to R6 are as defined herein; or a composition as defined herein; or a dosage form as defined herein; for use in treating a disease modulated by CDK8 and / or CDK19.

[0267] In another embodiment of the present invention, provided herein is a compound according to Formula I or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0268]

[0269] wherein R1 to R6 are as defined herein; or a composition as defined herein; or a dosage form as defined herein; for use in the manufacture of a medicament for treating a disease regulated by CDK8 and / or CDK19.

[0270] In another embodiment of the present invention, provided herein is: a method for treating a disease regulated by CDK8 and / or CDK19 in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound according to Formula I or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0271]

[0272] wherein R1 to R6 are as defined herein; or a composition as defined herein; or a dosage form as defined herein.

[0273] In embodiments involving a compound as described herein (or a composition as described herein, or a dosage form as described herein) for use in treatment, use of a compound (or a composition as described herein, or a dosage form as described herein) in a medicament for use in treatment with a device as described herein, or a method of treatment as described herein, the compound may not be any of the following:

[0274]

[0275]

[0276] However, the compounds (or compositions / dosage forms) for use in treatment, the use of the compounds (or compositions / dosage forms) in the manufacture of a medicament for treatment, or the methods of treatment as provided herein are not necessarily limited thereto.

[0277] In further embodiments relating to a compound as described herein (or a composition as described herein, or a dosage form as described herein) for use in treatment, the use of a compound (or a composition as described herein, or a dosage form as described herein) in the manufacture of a medicament for treatment as described herein, or a method of treatment as described herein, the compound may not be any of the following:

[0278]

[0279] However, the compounds (or compositions / dosage forms) for use in treatment, the use of the compounds (or compositions / dosage forms) in the manufacture of a medicament for treatment, or the methods of treatment as provided herein are not necessarily limited thereto.

[0280] Preferably, the disease modulated by CDK8 and / or CDK19 is cancer.

[0281] 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. liver 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 adenocarcinoma) and uterine cancer (e.g. uterine corpus endometrial carcinoma). It has been demonstrated in the literature that expression of CDK8 and / or CDK19 generally leads to shorter patient survival in a large number of cancer types (see, for example, Roninson et al., Cells 2019, 8, 821). Therefore, without wishing to be bound by theory, it is speculated that inhibition of CDK8 and CDK19 (e.g., by administering a compound according to Formula I) will limit the downstream effects caused by the expression of CDK8 and CDK19, and thereby allow the treatment of a large number of cancer types.

[0282] As used herein, the terms "treat" and "treatment" and similar terms refer to the administration of a material (e.g., any one or more compounds described herein) in an amount effective to prevent, alleviate or ameliorate one or more symptoms (i.e., indications) of a disease or condition and / or prolong the survival of the subject being treated.

[0283] In some cases, one or more compounds as described herein may be used in combination with one or more pharmaceutically active compounds (eg, in a composition as described herein).

[0284] As used herein, the term "therapeutically effective" or "effective amount" means that the compound of Formula I or the amount of the compound is sufficient or effective to prevent, alleviate or improve one or more symptoms of the disease, disorder or medical condition being treated and / or prolong the survival of the treated subject when administered. The therapeutically effective amount will vary according to the compound, disease, disorder or condition and its severity and the age, weight, etc. of the mammal to be treated. In general, the satisfactory results obtained in the subject indicate that the daily dose is about 0.1 to about 10g / kg of the subject's body weight. In some embodiments, the range of daily dose is about 0.10 to 10.0mg / kg body weight, about 1.0 to 3.0mg / kg body weight, about 3 to 10mg / kg body weight, about 3 to 150mg / kg body weight, about 3 to 100mg / kg body weight, about 10 to 100mg / kg body weight, about 10 to 150mg / kg body weight or about 150 to 1000mg / kg body weight. The dosage can be conveniently applied, for example, in a split dose or sustained release form up to four times a day.

[0285] As used herein, the term "modulating" or "modulate" refers to the effect of changing a biological activity, especially a biological activity associated with a particular biological molecule. For example, an inhibitor of a particular biological molecule modulates the activity of a biological molecule (e.g., an enzyme) by reducing the activity of the biological molecule (e.g., an enzyme). Such activity is typically measured in terms of the inhibitory concentration (IC) of the compound for the inhibitor (relative to, e.g., the enzyme). 50 ) or pK d To express.

[0286] As used herein, the term "subject" refers to a living organism that is treated with a compound as described herein, including but not limited to any mammal such as humans, other primates, sport animals, animals of commercial interest (such as cattle), farm animals (such as horses), or pets (such as dogs and cats).

[0287] As used herein, the term "administer" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration to a subject, or implantation of a slow release device (e.g., a mini-osmotic pump) into a subject. Administration is performed by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Other modes of delivery include, but are not limited to, use of liposome preparations, intravenous infusions, transdermal patches, etc.).

[0288] The compounds for use herein are typically used for the treatment of human subjects. However, they may also be used to treat similar or identical indications in other animal subjects. The compounds of Formula I described herein may be administered by various routes, including injection (i.e., parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalation. Such dosage forms allow the compound to reach the target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that delay the compound or composition from exerting its effect. Techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21 st Found in: Lippincott, Williams and Wilkins, Philadelphia, PA, 2005.

[0289] Reagent test kit

[0290] In another embodiment of the present invention, provided herein is a kit comprising a compound according to Formula I or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof:

[0291]

[0292] wherein R1 to R6 are as defined herein; or a composition as described herein; or a dosage form as described herein; and instructions for using the compound, composition or dosage form in the treatment of a disease modulated by CDK8 and / or CDK19.

[0293] In embodiments relating to a kit as described herein, the compound may not be any of the following:

[0294]

[0295]

[0296] However, the kits provided herein are not necessarily limited thereto.

[0297] In other embodiments involving the kit as described herein, the compound may not be any of the following:

[0298]

[0299] However, the kits provided herein are not necessarily limited thereto.

[0300] The invention is further described in the following non-limiting examples.

[0301] Example

[0302] Synthesis Example

[0303] General Procedure

[0304] General procedure for amide formation 1:

[0305] In a round-bottomed flask, acid or corresponding carboxylate (1.2 equivalents), amine (1 equivalent), EtN (1 mL) and DMF (10 mL) were loaded. HATU (1.2 equivalents) was then added and the mixture was stirred at RT for 4 h. The reaction was diluted with H2O (30 mL) and extracted with EtOAc (x 3). Organics were merged and washed with H2O (x 3). Organics were then dried with Na2SO4, filtered, and evaporated to obtain residue. The crude material was purified by flash silica column chromatography to obtain the relevant amides.

[0306] Synthetic routes for intermediates

[0307]

[0308]

[0309] Intermediate 1 – benzo[c]isothiazol-3(1H)-one (Int-1):

[0310]

[0311] A solution of potassium hydroxide (8.90 g, 159 mmol, 1.3 eq) in methanol (150 mL) was purged with hydrogen sulfide gas for 30 min while stirring the solution at room temperature. Hexahydro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (20.0 g, 123 mmol, 1 eq) was added in portions and stirred for another 10 min. The reaction mixture was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give a yellow solid. The yellow solid was then suspended in water (75.0 mL) and treated with 30% aqueous hydrogen peroxide (20.0 mL) while maintaining the temperature below 40 ° C. After stirring for another 1 h, the reaction mixture was filtered and the filtrate was adjusted to about pH-6 with 2N HCl. The compound was extracted with ethyl acetate and washed with brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remaining crude compound was triturated with hexanes to give [benzo[c]isothiazol-3(1H)-one] (10.0 g) as an off-white solid. The crude compound was used without further purification.

[0312] MS m / z 150.2[MH] + .

[0313] Intermediate 2-3-chlorobenzo[c]isothiazole (Int-2):

[0314]

[0315] POCl3 (4.93 mL, 52.9 mmol, 2 eq) was added dropwise to a mixture of benzo [c] isothiazol-3 (1H) -one (intermediate 1; 4.00 g, 26.5 mmol, 1 eq) in pyridine (2.00 mL, 26.5 mmol, 1 eq) at 10 °C, and the reaction mixture was stirred at 130 °C for 2 h. After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (20% EtOAc / hexane, gradient elution) to give 3-chlorobenzo [c] isothiazole (2.80 g, 62% yield) as a yellow liquid.

[0316] 1 H NMR (400MHz, DMSO-d6) δ7.73 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.45-7.41 (m, 1H), 7.28-7.24 (m, 1H).

[0317] Intermediate 3-tert-butyl (1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (Int-3):

[0318]

[0319] K2CO3 (7.30g, 53.2mmol, 2 equivalents) is added to a solution of tert-butyl piperidin-4-ylcarbamate (5.30g, 26.6mmol, 1 equivalent) in DMSO (10mL). Thereto, 3-chlorobenzo [c] isothiazole (intermediate 2; 4.50g, 26.6mmol, 1 equivalent) is added and the reaction is heated at 90 ° C for 16h. After completion, the reaction mixture is quenched with ice-cold water and extracted with ethyl acetate. The organic layer is washed with brine, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound is purified by silica column chromatography (50% EtOAc / hexane, gradient elution) to obtain tert-butyl (1- (benzo [c] isothiazole-3-yl) piperidin-4-yl) carbamate (6.00g, 68%) as a light yellow jelly.

[0320] 1 H NMR (400MHz, CDCl3) δ7.61-7.56(m,2H),7.30-7.25(m,1H),6.98-6.94(m,1H),4.60(m,1H) ,3.83-3.73(m,2H),3.19-3.14(m,2H),2.14-2.11(m,2H),1.75-1.68(m,2H),1.45(s,9H).

[0321] MS m / z 334.16[M+H] +

[0322] Intermediate 4 – 1-(Benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (Int-4):

[0323]

[0324] A 4M HCl solution of tert-butyl (1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (Intermediate 3; 6.00 g, 18.0 mmol, 1 eq.) in dioxane (60.0 mL) was stirred at room temperature for 2 h. After completion, the solvent was evaporated and the residue was triturated with diethyl ether to give 1-(benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (4.00 g, 95%) as an off-white solid.

[0325] 1H NMR (400MHz, CDCl3) δ8.35(m,3H),7.87(d,J=8.8Hz,1H),7.48(d,J=8.8Hz,1H),7.38-7.34(m,1H),7.03-6 .99(m,1H),3.96-3.93(m,2H),3.38-3.34(m,1H),3.27-3.21(m,2H),2.13-2.10(m,2H),1.88-1.83(m,2H).

[0326] MS m / z 234.16[M+H] + .

[0327] Intermediate 5-4-methylbenzenesulfonic acid oxetan-3-ylmethyl ester (Int-5):

[0328]

[0329] TEA (4.80mL, 34.0mmol, 2 equivalents) was added to a stirred solution of oxetane-3-ylmethanol (1.50g, 17.0mmol, 1 equivalent) in DCM (30.0mL) at 0°C, and the reaction was stirred for 10min. TsCl (4.80g, 25.5mmol, 1.5 equivalents) was added in batches and the reaction mixture was stirred at RT for 4h. After completion, the reaction mixture was diluted with DCM and washed with water, followed by brine washing. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-methylbenzenesulfonic acid oxetane-3-ylmethyl ester (3.80g), which was a light yellow jelly. The crude compound was used without further purification.

[0330] MS m / z 243.20[M+H] + .

[0331] Intermediate 6 – 1-(Oxetane-3-ylmethyl)-1H-imidazole-4-carboxylic acid ethyl ester (Int-6):

[0332]

[0333] To a stirred solution of 1H-imidazole-4-carboxylic acid ethyl ester (2.60 g, 18.5 mmol, 1 eq.) in MeCN (50.0 mL) was added CsCO (10.0 g, 30.9 mmol, 1.70 eq.), and the reaction was stirred at RT for 10 min. 4-methylbenzenesulfonic acid oxetanes-3-ylmethyl ester (intermediate 5; 5.00 g, 20.6 mmol, 1.1 eq.) was added, and the reaction mixture was stirred at 50 ° C for 16 h. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (5% MeOH / DCM) to give 1-(oxetanes-3-ylmethyl)-1H-imidazole-4-carboxylic acid ethyl ester (2.50 g, 58%) as a light yellow liquid.

[0334] 1 H NMR (400MHz, CDCl3) δ7.72(s,1H),7.59(s,1H),4.78(t,J=6.7Hz,2H),4.61(d,J=7.5 Hz, 2H), 4.40 (t, J = 6Hz, 2H), 4.33-4.23 (m, 2H), 3.50-3.43 (m, 1H), 1.37-1.33 (m, 3H).

[0335] MS m / z 211.18[M+H] + .

[0336] The structures of the desired compounds were confirmed by NOE NMR experiments.

[0337] Intermediate 7 – 1-(Oxetane-3-ylmethyl)-1H-imidazole-4-carboxylic acid, sodium salt (Int-7):

[0338]

[0339] To 1- (oxetanes -3- ylmethyl) -1H- imidazoles -4- ethyl formate (1.90g, 9.04mmol, 1 equivalent) in THF-H in a stirred solution of O (1: 1) (30.0mL), NaOH (362mg, 9.04mmol, 1 equivalent) was added and the reaction mixture was stirred at RT for 14h. After completion, the reaction mixture was concentrated under reduced pressure and the remaining aqueous layer was washed with ethyl acetate, then freeze-dried to obtain 1- (oxetanes -3- ylmethyl) -1H- imidazoles -4- sodium formate (1.50g), which was a white solid. The crude compound was used without further purification.

[0340] Intermediate 8 – 1-(2-(dimethylamino)-2-oxoethyl)-1H-imidazole-4-carboxylic acid ethyl ester (Int-8):

[0341]

[0342] Methyl 4-imidazolecarboxylate (0.25 g, 1.98 mmol), cesium carbonate (775 mg, 2.38 mmol) and 2-bromo-N,N-dimethylacetamide (394.9 mg, 2.38 mmol) were reacted in MeCN (7.9 mL) following the same procedure as Intermediate 6. After purification and separation of the regioisomers, methyl 1-[2-(dimethylamino)-2-oxo-ethyl]imidazole-4-carboxylate (0.214 g, 1.01 mmol) was obtained in 51% yield as a white solid.

[0343] 1 H NMR (400MHz, DMSO-d6): δ7.76(s,1H),7.62(s,1H),5.05(s,2H),3.74(s,3H),3.01(s,3H),2.86(s,3H).

[0344] MS m / z 212[M+H] + .

[0345] Intermediate 9 – 1-(2-(Dimethylamino)-2-oxoethyl)-1H-imidazole-4-carboxylic acid, sodium salt (Int-9):

[0346]

[0347] Following the same procedure as Intermediate 7, methyl 1-[2-(dimethylamino)-2-oxo-ethyl]imidazole-4-carboxylate (231 mg, 1.09 mmol), methanol (4.37 mL) and water (1.16 mL) were added. NaOH (91.8 mg, 2.19 mmol) was added and the resulting solution was stirred at RT overnight. The crude compound was used without further purification.

[0348] Intermediate 10 – 1-(Pyrazin-2-ylmethyl)-1H-imidazole-4-carboxylic acid ethyl ester (Int-10):

[0349]

[0350] Following the same procedure as Intermediate 6; ethyl 4-imidazolecarboxylate (0.24 g, 1.90 mmol), cesium carbonate (744 mg, 2.28 mmol) and MeCN (7.61 mL). 2-(Chloromethyl)pyrazine (293.6 mg, 2.28 mmol) was added dropwise. After purification and separation of the regioisomers; methyl 1-(pyrazin-2-ylmethyl)imidazole-4-carboxylate (164 mg, 0.75 mmol) was obtained in 39.5% yield.

[0351] 1H NMR (400MHz, CDCl3) δ8.59(s,2H),8.52(s,1H),7.72(s,1H),7.67(s,1H),5.29(s,2H),3.88(s,3H).

[0352] Intermediate 11 – 1-(Pyrazin-2-ylmethyl)-1H-imidazole-4-carboxylic acid, sodium salt (Int-11):

[0353]

[0354] Following the same procedure as Intermediate 7, methyl 1-(pyrazine-2-ylmethyl)imidazole-4-carboxylate (148 mg, 0.68 mmol), methanol (2.71 mL) and water (0.72 mL) were added. NaOH (56.9 mg, 1.36 mmol) was added and the resulting solution was stirred overnight at RT. 1-(pyrazine-2-ylmethyl)imidazole-4-carboxylic acid (138 mg, 0.68 mmol) was obtained in 99.6% yield. The crude compound was used without further purification.

[0355] 1 H NMR (400MHz, DMSO) δ9.33 (s, 1H), 8.82 (s, 1H), 8.66 (d, J = 2.1Hz, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 5.71 (s, 2H).

[0356] MS m / z 205[M+H] +

[0357] Intermediate 12 – 1-(2-(Dimethylamino)-ethyl)-1H-imidazole-4-carboxylic acid, sodium salt (Int-12):

[0358]

[0359] Methyl 4-imidazolecarboxylate (0.28 g, 1.98 mmol), cesium carbonate and 2-bromo-N,N-dimethylethan-1-amine were reacted in MeCN in the same manner as Intermediate 6. After purification and separation of the regioisomers, methyl 1-[2-(dimethylamino)-2-oxo-ethyl]imidazole-4-carboxylate (0.08 g) was obtained.

[0360] Then, methyl 1-[2-(dimethylamino)-ethyl]imidazole-4-carboxylate (80 mg, 1.09 mmol) was hydrolyzed in the same manner as Intermediate 7 to give the desired product as a sodium salt, 70 mg. The crude compound was used without further purification.

[0361] Intermediate 13 – 5-Fluorobenzo[c]isothiazol-3(1H)-one (Int-13):

[0362]

[0363] A solution of potassium hydroxide (20.0 g, 359 mmol, 1.3 eq) in methanol (850 mL) was stirred at room temperature while purging with hydrogen sulfide gas for 30 min. 6-Fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (50.0 g, 276 mmol, 1 eq) was added in portions and stirred for another 10 min. The reaction mixture was dried over sodium sulfate and evaporated under reduced pressure to give a yellow solid. The yellow solid was then suspended in water (150 mL) and treated with 15% hydrogen peroxide (93.0 mL, 2.76 mol, 10 eq) while maintaining the temperature at 40 ° C. After stirring for another 1 h, the reaction mixture was filtered and the filtrate was adjusted to about pH-6 with 2N HCl. The compound was extracted with ethyl acetate and washed with brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remaining crude compound was triturated with hexanes to afford 5-fluorobenzo[c]isothiazol-3(1H)-one (20.0 g, 42%) as a light yellow solid.

[0364] 1 H NMR (400MHz, DMSO-d6): δ9.89(brs,1H),7.54-7.50(m,1H),7.40-7.37(m,2H).

[0365] MS m / z 169.9[M+H] + .

[0366] Intermediate 14 – 3-Chloro-5-fluorobenzo[c]isothiazole (Int-14):

[0367]

[0368] At 10 ℃, POCl (24.0mL, 264mmol, 2 equivalents) was added dropwise to a mixture of 5-fluorobenzo [c] isothiazole-3 (1H) -one (20.0g, 132mmol, 1 equivalent) in pyridine (10.5mL, 119mmol, 0.9 equivalents), and the reaction was stirred at 130 ℃ for 2h. After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography (20% EtOAc / hexane, gradient elution) to obtain 3- chloro-5-fluorobenzo [c] isothiazole (16.0g, 64%) as an off-white solid.

[0369] 1 H NMR (400MHz, CDCl3): δ7.74-7.70(m,2H),7.29-7.23(m,2H).

[0370] Intermediate 15 – tert-butyl (1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (Int-15):

[0371]

[0372] To a stirred solution of tert-butyl piperidin-4-ylcarbamate (2.30 g, 11.7 mmol, 1.1 eq) in DMSO (15.0 mL) was added KCO (3.70 g, 26.6 mmol, 2.5 eq) and the reaction was stirred at RT for 15 min. A solution of 3-chloro-5-fluorobenzo[c]isothiazole (intermediate 14; 2.00 g, 11.0 mmol, 1 eq) in DMSO (5.00 mL) was added and the reaction was stirred at 90 ° C for 16 h. After completion, the reaction mixture was diluted with ethyl acetate and washed with ice-cold water followed by brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (50% EtOAc / hexanes, gradient elution) to give tert-butyl (1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (2.50 g, 67%) as a light yellow solid.

[0373] 1 H NMR (400MHz, DMSO-d6): δ7.58-7.50(m,2H),7.31-7.26(m,1H),6.96(brs,1H),3.77-3.74(m, 2H),3.54-3.52(m,1H),3.16-3.11(m,2H),1.8-1.87(m,2H),1.68-1.65(m,2H),1.40(s,9H).

[0374] MS m / z 352.0[M+H] +

[0375] Intermediate 16 – 1-(5-Fluorobenzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (Int-16):

[0376]

[0377] To a solution of tert-butyl (1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (Intermediate 15; 2.50 g, 7.44 mmol, 1 eq) in dioxane (25.0 mL) was added 4M HCl in dioxane (25.0 mL) and the reaction was stirred at RT for 3 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to give 1-(5-fluoro-2,1-benzothiazol-3-yl)piperidin-4-amine hydrochloride (1.5 g, 80%) as a yellow solid.

[0378] 1H NMR (400MHz, DMSO-d6): δ8.26(m,3H),7.64-7.61(m,1H),7.56-7.52(m,1H),7.33-7.29(m,1H),3.8 8-3.85(m,2H),3.32-3.20(m,1H),3.17-3.12(t,J=12Hz,2H),2.10-2.07(m,2H),1.90-1.81(m,2H).

[0379] MS m / z 252.18[M+H] + .

[0380] Synthesis Example 1 – 1-(Benzo[c]isothiazol-3-yl)-N-methylpiperidin-4-amine (1):

[0381]

[0382] 3- chloro-2,1-benzothiazole (100mg, 0.5895mmol) and N- methyl-N- (4-piperidinyl) carbamic acid tert-butyl ester (151.6mg, 0.7074mmol) are combined in a sealed tube and heated to 125 ° C, while stirring overnight. Cool to rt and dilute with DCM, and the DCM solution is washed with saturated NaHCO3 aqueous solution. Each layer is separated by a phase separator. Volatiles are removed from the organic layer. Purified by preparative LCMS, and then volatiles are evaporated from the fraction containing the product to obtain N- [1- (2,1-benzothiazole-3-yl) -4-piperidinyl] -N- methyl - tert-butyl carbamate (104.3mg, 0.285mmol), 48.4% yield.

[0383] Trifluoroacetic acid (372.25 mg, 3.2648 mmol) was added to a solution of N-[1-(2,1-benzothiazol-3-yl)-4-piperidinyl]-N-methyl-tert-butyl carbamate (41.1 mg, 0.1183 mmol) in DCM (1 mL), and the reaction was stirred at room temperature for 30 min. The reaction mixture was poured onto an SCX cartridge, washed with methanol, and then the product was eluted with 2M NH3 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.

[0384] 1H NMR (500MHz, DMSO-d6) δ7.81(d,J=8.8Hz,1H),7.46–7.41(m,1H),7.30(ddd,J=8.9,6.4,1.1Hz,1H),6.95(ddd,J=8.8,6.4,1.0Hz,1H),3.81( dt,J=12.3,3.8Hz,2H),3.22–3.15(m,2H),2.61(ddd,J=13.4,9.6,3.9Hz,1H),2.32(s,3H),1.99(dd,J=13.1,3.6Hz,2H),1.59–1.49(m,2H).

[0385] MS m / z 248[M+H] +

[0386] Synthesis Example 2 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)acetamide (2):

[0387]

[0388] 3-Chloro-2,1-benzothiazole (Intermediate 2; 100.0 mg, 0.6 mmol), N-(4-piperidinyl)acetamide (100.6 mg, 0.7 mmol) and sodium tert-butoxide (85.0 mg, 0.9 mmol) were suspended in toluene (2 mL). The mixture was degassed under vacuum and then flushed with nitrogen, and then Pd(PtBu3)2 (15.1 mg, 3.0·10 -2 mmol) and the mixture was heated to 100 °C overnight. The reaction mixture was cooled to room temperature, diluted with DCM and filtered through a celite cartridge. The crude product was purified by reverse phase HPLC to give N-(1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)acetamide (18.8 mg, 11%).

[0389] 1 H NMR(500MHz,DMSO)7.93(1H,d,J=7.5Hz),7.82(1H,d,J=8.7Hz),7.46(1H,d,J=9.0Hz),7.32(1H,ddd,J=1.1,6.4,9 .0Hz),6.99-6.96(1H,m),3.88-3.80(3H,m),3.28-3.22(2H,m),1.97-1.91(2H,m),1.83(3H,s),1.72-1.63(2H,m).

[0390] MS m / z 276.1179[M+H] + .

[0391] Synthesis Example 3 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-methyl-1H-imidazole-4-carboxamide(3)：

[0392]

[0393] To a suspension of 1-methyl-1H-4-carboxylic acid (100 mg, 0.79 mmol) in DCM (5 mL) was added oxalyl chloride (0.11 mL, 1.35 mmol) and a catalytic amount of DMF (10 μL). After 1 h, the sample was quenched with methanol and the volatiles were evaporated to give 1-methylimidazole-4-carbonyl chloride (115 mg, 0.79 mmol).

[0394] 1-(2,1-benzothiazol-3-yl)piperidin-4-amine (206mg, 0.79mmol) was suspended in DCM (5mL) and DIPEA (0.32mL, 2.38mmol) was added. This mixture was added to crude 1-methylimidazole-4-carbonyl chloride (115mg, 0.79mmol), and DMF (0.5mL) was added to the reaction mixture. After 1.5h, the reaction was quenched by adding saturated NaHCO3 aqueous solution (30mL), and the product was extracted into DCM (30mL). The organic matter was dried (phase separator) and evaporated. The crude product was purified by silica chromatography (0-10% MeOH in DCM) gradient elution) and then purified by reverse phase HPLC to obtain N-(1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-methyl-1H-imidazole-4-carboxamide (100mg, 36%).

[0395] 1 H NMR (500MHz, d6-DMSO): δ7.86-7.81(2H,m),7.66-7.64(2H,m),7.46(1H,d,J=9.0Hz),7.32(1H,dd,J=6.3,8.9Hz),6.9 8(1H,dd,J=6.4,8.7Hz),4.11-4.02(1H,m),3.90(2H,d,J=12.4Hz),3.29(2H,s),3.28-3.22(2H,m),1.97-1.91(5H,m).

[0396] MS m / z 342.1[M+H] + .

[0397] Synthesis Example 4 - N-(1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)-1-methyl-1H-imidazole-4-carboxylate Amine (4):

[0398]

[0399] The flask containing 1-methyl isophthalic acid (1.48g, 11.74mmol) is sealed and purged with nitrogen (x 3).DCM (46mL) is added and the flask is cooled to 0 ° C.Then oxalyl chloride (1.04mL, 12.32mmol) is slowly added, followed by dropwise addition of DMF (9.1 μL, 0.12mmol). Once gas evolution has stopped, the flask is removed from an ice bath and stirred at RT for 1h.Then the acyl chloride suspension is concentrated in a vacuum to obtain a light brown solid.

[0400] To a separate flask was added 1-(5-fluoro-2,1-benzothiazol-3-yl)piperidin-4-amine; dihydrochloride (3.84 g, 11.85 mmol) and the flask was sealed and purged with nitrogen (x 3).DCM (47 mL) was added and the flask was cooled to 0°C.

[0401] The flask that will be equipped with acyl chlorides will be purged with nitrogen (x 3) again and add DCM (66mL), then add NEt3 (6.7mL, 48.12mmol).Then at 0 ℃ acyl chloride solution is dropwise added in this amine.The flask that will be equipped with acyl chlorides will be washed out with the DCM (26mL) of another part, and it is added in this amine.After completing adding, reaction is moved out from ice bath and stirred overnight at RT.Reaction is directly evaporated on silica gel and purified by silica column chromatography, the 0-20%7M methanol ammonia wash-out that is used in DCM obtains yellow solid.This material is 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-piperidinyl]-1-methyl-imidazole-4-carboxamide (2.58 g, 58%) as a yellow solid.

[0402] 1 H NMR(500MHz,d6-DMSO)δ7.82(d,J=8.4Hz,1H),7.65(s,1H),7.63(d,J=1.2Hz,1H),7.58(dd,J=10.4,2.5Hz,1H),7.52(dd,J=9.6,5.2Hz,1H) ,7.29(ddd,J=9.7,8.4,2.6Hz,1H),4.04(dd,J=15.1,7.0Hz,1H),3.83(d,J=12.5Hz,2H),3.69(s,3H),3.23–3.16(m,2H),1.96–1.87(m,4H).

[0403] MS m / z 360[M+H] + .

[0404] Synthesis Example 5 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(pyrazin-2-ylmethyl)-1H-imidazole Oxazole-4-carboxamide (5):

[0405]

[0406] Prepared as described in General Procedure 1 from 1-(benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (93 mg, 0.4 mmol) and 1-(pyrazin-2-ylmethyl)-1H-imidazole-4-carboxylic acid (130 mg, 0.5 mmol) in 34% yield.

[0407] 1 H NMR (400MHz, d6-DMSO) δ8.67(s,1H),8.63(s,2H),7.96(d,J=8.4Hz,1H),7.86(d,J=0.8Hz,1H),7.82(d,J=8.8Hz,1H),7.77(s,1H),7.45(d,J=8 .8Hz,1H),7.33–7.29(m,1H),6.99–6.95(m,1H),5.45(s,2H),4.09–4.0 3(m,1H),3.89(d,J=12.4Hz,2H),3.26–3.20(m,2H),1.96–1.90(m,4H).

[0408] MS m / z 420[M+H] + .

[0409] Synthesis Example 6 - N-(1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(pyrazin-2-ylmethyl)-1H- Imidazole-4-carboxamide (6):

[0410]

[0411] Prepared as described in General Procedure 1 from 1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (40 mg, 0.16 mmol) and 1-(pyrazin-2-ylmethyl)-1H-imidazole-4-carboxylic acid (130 mg, 0.5 mmol) in 78% yield.

[0412] 1H NMR(400MHz,d6-DMSO)δ8.67(s,1H),8.62(s,2H),7.89(d,J=8.3Hz,1H),7.8 5(d,J=1.0Hz,1H),7.75(d,J=1.0Hz,1H),7.58(dd,J=10.3,2.5Hz,1H),7.52 (dd,J=9.6,5.1Hz,1H),7.29(ddd,J=9.7,8.5,2.5Hz,1H),5.45(s,2H),4.09 –3.97(m,1H),3.83(d,J=12.7Hz,2H),3.24–3.10(m,2H),1.95–1.86(m,4H).

[0413] MS m / z 438[M+H] + .

[0414] Synthesis Example 7 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(2-(dimethylamino)-2-oxo Ethyl)-1H-imidazole-4-carboxamide (7):

[0415]

[0416] Prepared as described in General Procedure 1 from 1-(benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (93 mg, 0.4 mmol) and 1-(2-(dimethylamino)-2-oxoethyl)-1H-imidazole-4-carboxylic acid (130 mg, 0.5 mmol) in 31% yield.

[0417] 1 H NMR (400MHz, d6-DMSO) δ7.92(d,J=8.4Hz,1H),7.83(d,J=8.8Hz,1H),7.59(d,J=1.2Hz,1H)),7.55(d,J=1.2Hz,1H),7.45(d,J=8.8Hz,1H),7.33–7.2 9(m,1H),6.99–6.95(m,1H),5.04(s,2H),4.10–4.04(m,1H),3.90(d,J=12 .4Hz,2H),3.27–3.21(m,2H),3.02(s,3H),2.86(s,3H),2.00–1.91(m,4H).

[0418] MS m / z 413[M+H] + .

[0419] Synthesis Example 8 – 1-(2-(dimethylamino)-2-oxoethyl)-N-(1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin pyridine-4-yl)-1H-imidazole-4-carboxamide (8):

[0420]

[0421] Prepared as described in General Procedure 1 from 1-(5-fluorobenzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (40 mg, 0.16 mmol) and 1-(2-(dimethylamino)-2-oxoethyl)-1H-imidazole-4-carboxylic acid (38 mg, 0.19 mmol) in 25% yield.

[0422] 1 H NMR (400MHz, CDCl3) δ7.58–7.53(m,2H),7.46(d,J=1.0Hz,1H),7.22(dd,J=9.6,2.4 Hz,1H),7.15(ddd,J=10.7,8.3,2.5Hz,1H),7.08(d,J=7.9Hz,1H),4.79(s,2H),4.2 8–4.15(m,1H),3.80(dt,J=12.9,3.1Hz,2H),3.21(td,J=12.5,2.5Hz,2H),3.09(s, 3H), 3.02 (s, 3H), 2.22 (dd, J=13.1, 2.7Hz, 2H), 1.89 (ddd, J=24.1, 11.3, 4.0Hz, 2H).

[0423] MS m / z 431[M+H] + .

[0424] Synthesis Example 9 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(2-(dimethylamino)ethyl)- 1H-imidazole-4-carboxamide (9):

[0425]

[0426] Prepared as described in General Procedure 1 from 1-(benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (93 mg, 0.4 mmol) and 1-(2-(dimethylamino)-2-oxoethyl)-1H-imidazole-4-carboxylic acid (130 mg, 0.5 mmol) in 43% yield.

[0427] 1 H NMR (400MHz, CDCl3) δ7.63–7.53(m,3H),7.46(s,1H),7.33–7.27(m,1H),6.99(t,J=7.6Hz,1H),6.52–6.42(m,1H),4.41(t,J=6.4Hz ,2H),4.22–4.18(m,1H),3.92(d,J=12.4Hz,2H)3.24(t,J=12.0Hz,2H),2.68(t,J=6.0Hz,2H),2.26–2.09(m,8H),1.91–1.83(m,2H).

[0428] MS m / z 399[M+H] + .

[0429] Synthesis Example 10 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(oxetane-3-ylmethyl)- 1H-imidazole-4-carboxamide (10):

[0430]

[0431] Prepared as described in General Procedure 1 from 1-(benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (93 mg, 0.4 mmol) and 1-(oxetan-3-ylmethyl)-1H-imidazole-4-carboxylic acid, sodium salt (Intermediate 7; 130 mg, 0.5 mmol) in 49% yield.

[0432] 1 H NMR(400MHz,d6-DMSO)δ7.93(d,J=8.4Hz,1H),7.82(d,J=8.4Hz,1H),7.78( d,J=0.8Hz,1H),7.74(s,1H),7.46(d,J=7.2Hz,1H),7.33–7.29(m,1H),6.99 –6.95(m,1H),4.64–4.60(m,2H),4.37–4.31(m,4H),4.13–4.02(m,1H)3.89 (d,J=12.0Hz,2H),3.44–3.38(m,1H),3.26–3.20(m,2H),2.01–1.83(m,4H).

[0433] MS m / z 398[M+H] + .

[0434] Synthesis Example 11 - N-(1-(Benzo[c]isothiazol-3-yl)piperidin-4-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole Oxazole-4-carboxamide (11):

[0435]

[0436] To 2-nitrobenzoic acid (5g, 29.9mmol) in DMF (50mL) solution, add TEA (6g, 59.3mmol), piperidin-4-yl tert-butyl carbamate (7.2g, 35.9mmol) and HATU (17g, 44.7mmol). The reaction is stirred overnight at RT. The reaction mixture is diluted with H o and extracted with EA (x 2). Organic matter is washed with salt water and dried over sodium sulfate. The organic phase is concentrated and the residue is purified by column chromatography to obtain tert-butyl (1- (2-nitrobenzoyl) piperidin-4-yl) carbamate (10.3g, 98%), which is a white solid.

[0437] MS theoretical value: 349.16; MS experimental value 294.1 [M+H-C4H8] +

[0438] To a flask was added tert-butyl (1-(2-nitrobenzoyl)piperidin-4-yl)carbamate (10.3 g, 29.5 mmol) and Pd / C (2 g). MeOH (150 mL) was added and the mixture was stirred at room temperature overnight 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.

[0439] MS theoretical value: 319.19; MS experimental value: 320.2 [M+H] +

[0440] To (1-(2-aminobenzoyl)piperidin-4-yl)t-butyl carbamate (9.3g, 29.1mmol) and NaHCO (4.9g, 58.3mmol) in a mixture of THF (200mL), P2S5 (9g, 40.5mmol) was added. The reaction was allowed to reach 60°C for 3h under an argon atmosphere. H2O was added and the mixture was extracted with EA (x2). 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 obtain (1-(2-aminophenylthiocarbonyl)piperidin-4-yl)t-butyl carbamate (5.3g, 54%), which was a yellow oil.

[0441] MS theoretical value: 335.17; MS experimental value: 336.0 [M+H] +

[0442] In flask, add (1-(2-aminophenylthiocarbonyl) piperidin-4-yl) tert-butyl carbamate (5.3g, 15.8mmol) and THF (60mL).Add NBS (2.8g, 15.8mmol) dropwise and stir the reaction for 15min.Then react with H o dilute and extract with EA (x 3).Organic matter is dried over sodium sulfate.The organic phase is concentrated and residue is purified by column chromatography to obtain (1-(benzo [c] isothiazole-3-yl) piperidin-4-yl) tert-butyl carbamate (4.1g, 76%), which is a yellow solid.

[0443] MS theoretical value: 333.15; MS experimental value: 334.0 [M+H] +

[0444] To a flask was added tert-butyl (1-(benzo[c]isothiazol-3-yl)piperidin-4-yl)carbamate (4.1 g, 12 mmol) and HCl (4M in MeOH, 30 mL, 120 mmol). The mixture was stirred at RT overnight. The residue was concentrated in vacuo to give 1-(benzo[c]isothiazol-3-yl)piperidin-4-amine hydrochloride (2.8 g, 80%) as a yellow solid.

[0445] MS theoretical value: 233.10; MS experimental value 234.2 [M+H] +

[0446] To a flask was 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 allowed to reach 50 °C and stirred overnight. The reaction mixture was filtered, concentrated in vacuo and purified by column chromatography to give ethyl 1-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxylate (301 mg, 43%) as a colorless oil.

[0447] To a flask was 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 RT for 5 h. HCl (1 M in H2O) was added to bring the pH to ~5. The mixture was concentrated in vacuo to give crude 1-(pyrimidin-2-ylmethyl)-1H-imidazole-4-carboxylic acid, which was used without further purification.

[0448] 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), NEt3 (1 mL), and DMF (10 mL) were added to a flask. HATU (198 mg, 0.5 mmol) was added and the reaction was stirred at RT for 4 h. The reaction was diluted with H2O and extracted with EA (x 3). The organics were combined, washed with H2O (x3), dried over Na2SO4, 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.

[0449] 1H NMR(400MHz,d6-DMSO)δ8.80(d,J=4.8Hz,2H),7.96(d,J=8.4Hz,1H),7.84-7.81(m,2H),7.73(d,J=1.6Hz,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=12.4Hz,2H),3.28-3.21(m,2H),1.99-1.92(m,4H).

[0450] MS theoretical value: 419.15; MS experimental value 420.0 [M+H] +

[0451] Examples 1 to 11 - CDK8 and CDK19 inhibition data

[0452] Compounds 1 to 11 were tested for their in vitro binding activity to CDK8 and CDK19. The results are provided in Table 1.

[0453] Kinase assay: A kinase-tagged T7 phage strain was prepared in an E. coli host derived from a BL21 strain. E. coli was grown to logarithmic phase and 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 labeled with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands at room temperature for 30 minutes to generate affinity resins for kinase assays. The ligand-tagged beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific binding. Binding reactions were assembled by assembling the kinase, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6mM DTT). Test compounds were prepared as 111X stock solutions in 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds used for Kd measurements were distributed in 100% DMSO by acoustic transfer (contactless dispensing). Compounds were then diluted directly into the assay to a final concentration of 0.9% DMSO. All reactions were performed in polypropylene 384-well plates. Each well had a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour, and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1xPBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated for 30 minutes at room temperature with shaking. The kinase concentration in the eluate was measured by qPCR.

[0454] Compound treatment: 11-point 3-fold serial dilutions of each test compound were prepared at 100x final test concentration in 100% DMSO and subsequently diluted to 1x in the assay (final DMSO concentration = 1%). Most Kds were determined using compound top concentration = 30,000 nM. If the initial Kd determined was < 0.5 nM (lowest concentration tested), the measurement was repeated using serial dilutions starting with a lower top concentration. A Kd value reported as 40,000 nM indicates that the Kd was determined to be > 30,000 nM.

[0455] Binding constant: The binding constant (Kd) was calculated using the Hill equation using a standard dose-response curve:

[0456]

[0457] Set the Hill slope to -1.

[0458] The curves were fitted using a nonlinear least squares fit using the Levenberg-Marquardt algorithm.

[0459] Table 1 – CDK8 / CDK19 inhibition data

[0460]

[0461] Each of compounds 1 to 11 has a micromolar (pKd of 4 to 6) to nanomolar (pKd of 7 to 9) binding affinity to CDK8 and CDK19, indicating that these compounds bind strongly to CDK8 and CDK19. Without wishing to be bound by theory, it is speculated that the presence of the benzisothiazole and piperidine rings helps the compounds according to Formula I bind deeply into the binding pockets of CDK8 and CDK19 (see Example 12), resulting in high binding affinity.

[0462] Both CDK8 and CDK19 are involved in various types of cancer. It has been confirmed that the expression of CDK8 and / or CDK19 generally leads to shorter patient survival in a large number of cancer types (see, for example, Roninson et al., Cells 2019, 8, 821).

[0463] Compounds 1 to 11 have been shown to bind strongly to both CDK8 and CDK 19. Without wishing to be bound by theory, it is speculated that inhibition of CDK8 and CDK19 limits downstream effects caused by the expression of CDK8 and CDK19 and thereby allows for the treatment of a wide range of cancer types.

[0464] Example 12 - Docking studies

[0465] 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 Protein preparation wizard tool ( Release 2020-2). Solvent molecules and residues defined as heteroatoms in the PDB were removed, while hydrogen atoms and missing side chain residues were added to the protein structure. PROPKA was used at pH 7.0 to assign protonation states and optimize hydrogen bonding networks. Finally, the OPLS3e force field with default settings was used to perform a constrained energy minimization step. The LigPrep tool ( The compound structures were prepared using Epik at pH 7.0±1.0 to generate possible tautomers and stereoisomers, and the OPLS3e force field was used for energy minimization.

[0466] Docking studies: To gain insight into the binding mode, Kit( Release 2020-2) to perform docking studies. The receptor grid generation tool was used to generate a grid box for the protein prepared above (PDBID: 4F6U); the co-crystallized inhibitor was selected as the center of the grid and The cube is defined as the inner box. During docking, the “penalize non-planar conformations” option for amides was turned on, allowing a total of 20 poses per ligand to undergo the post-docking minimization step, while a maximum of ten docked poses were output for each ligand; all other settings were kept at default values. The described protocol was first evaluated by redocking and was able to reproduce the binding mode of the cocrystal inhibitor as observed in the X-ray structure (PDBID: 4F6U), with a root mean square deviation (RMSD, heavy atoms) of 1.0 when the highest scoring pose was used.

[0467] If you can Figure 1 and Figure 2 As seen in Figure 1, the benzothiazole and piperidine rings are deeply bound within the binding pocket of CDK8. In particular, the nitrogen atom on the benzisothiazole ring forms a key hydrogen bonding interaction with Ala-100. Other key bonding interactions, such as those with Asp-173 and His-149, are also shown.

Claims

1. A compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: in: R1 to R4 are each independently selected from hydrogen, hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy and optionally substituted amino; R5 and R6 are each independently selected from: 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 heterocyclic group), -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 selected from optionally substituted alkylene, (O-alkylene) w , optionally substituted heteroarylene, O and NH, n is selected from 0, 1 and 2, and w is selected from 1, 2 and 3; and -SO2-(optionally substituted alkyl), -SO2-(optionally substituted cycloalkyl), -SO2-(optionally substituted heterocyclyl), -SO2-(optionally substituted alkoxy), -SO2-(optionally substituted aryl), -SO2-(optionally substituted heteroaryl) and -SO2-(optionally substituted amino); Provided that the compound is not any of the following:

2. The compound according to claim 1, wherein R1 to R4 are each independently selected from hydrogen and halogen, preferably hydrogen and fluorine.

3. A compound according to claim 1 or claim 2, wherein R1 is hydrogen.

4. A compound according to any one of claims 1 to 3, wherein R2 is hydrogen or halogen, preferably hydrogen or fluorine.

5. A compound according to any one of claims 1 to 4, wherein R3 is hydrogen.

6. A compound according to any one of claims 1 to 5, wherein R4 is hydrogen.

7. A compound according to any one of claims 1 to 6, wherein R5 and R6 are each independently selected from hydrogen, optionally substituted alkyl, -CO-(L) n -(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclic group), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino) and -CO-(L) n -CO-(optionally substituted amino).

8. A compound according to any one of claims 1 to 7, wherein R5 is hydrogen.

9. A compound according to any one of claims 1 to 8, wherein R6 is selected from optionally substituted alkyl, -CO-(optionally substituted alkyl), -CO-(L) n -(optionally substituted heterocyclic group), -CO-(optionally substituted heteroaryl group), -CO-(L) n -(optionally substituted heteroaryl), -CO-(L) n -(optionally substituted amino) and -CO-(L) n -CO-(optionally substituted amino).

10. The compound according to claim 9, wherein R6 is selected from: Optionally substituted C1-C 12 alkyl; -CO-(optionally substituted C1-C 12 alkyl); -CO-(L) n -(optionally substituted azetidinyl), -CO-(L) n -(optionally substituted oxetane), -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 quinuclidine), -CO-(L) n -(optionally substituted morpholinyl), -CO-(L) n -(optionally substituted heterochromatic group), -CO-(L) n -(optionally substituted chromanyl), -CO-(L) n -(optionally substituted pyrazolidinyl), -CO-(L) n -(optionally substituted pyrazolyl), -CO-(L) n -(optionally substituted tert-butyl) and -CO-(L) n -(optionally substituted aminoacyl); -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 furanyl), -CO-(optionally substituted benzofuranyl), -CO-(optionally substituted isobenzofuranyl), -CO-(optionally substituted chromenyl), -CO-(optionally substituted xanthene), -CO-(optionally substituted thiophenoxanyl), -CO-(optionally substituted pyrrolyl), -CO-(optionally substituted imidazolyl), -CO-(optionally substituted pyrazolyl ), -CO-(optionally substituted triazolyl), -CO-(optionally substituted tetrazolyl), -CO-(optionally substituted pyridinyl), -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 purine yl), -CO-(optionally substituted 4H-quinolizinyl), -CO-(optionally substituted isoquinolyl), -CO-(optionally substituted quinolyl), -CO-(optionally substituted phthalazinyl), -CO-(optionally substituted naphthyridinyl), -CO-(optionally substituted quinazolinyl), -CO-(optionally substituted cinnolinyl), -CO-(optionally substituted pteridinyl), -CO-(optionally substituted carbazolyl), -CO-(optionally substituted β-carbolinyl), -CO-(optionally substituted phenanthridinyl), -CO-(optionally substituted acridinyl), -CO-(optionally substituted perimelinyl), -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-oxindolyl), 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 furanyl), -CO-(L) n -(optionally substituted benzofuranyl), -CO-(L) n -(optionally substituted isobenzofuranyl), -CO-(L) n -(optionally substituted chromene), -CO-(L) n -(optionally substituted xanthene), -CO-(L) n -(optionally substituted thiophenoxane), -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 triazine), -CO-(L) n -(optionally substituted tetrazinyl), -CO-(L) n -(optionally substituted indolizinyl), -CO-(L) n -(optionally substituted isoindole), -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 quinazolinyl), -CO-(L) n -(optionally substituted cinnolinyl), -CO-(L) n -(optionally substituted pteridinyl), -CO-(L) n -(optionally substituted carbazolyl), -CO-(L) n -(optionally substituted β-carbolyl), -CO-(L) n -(optionally substituted phenanthridinyl), -CO-(L) n -(optionally substituted acridinyl), -CO-(L) n -(optionally substituted perylene), -CO-(L) n -(optionally substituted phenanthroline), -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-oxindolyl) and -CO-(L) n -(optionally substituted 2-oxobenzimidazolyl); -CO-(L) n -((C1-C 12 alkyl)amino); and -CO-(L) n -CO-(di(C1-C 12 alkyl)amino).

11. The compound according to claim 10, wherein R6 is selected from: Optionally substituted C1-C6 alkyl; -CO-(optionally substituted C1-C6 alkyl); -CO-(L) n -(optionally substituted oxetane); -CO-(optionally substituted imidazolyl); -CO-(L) n -(optionally substituted pyrazinyl); -CO-(L) n -(optionally substituted pyrimidinyl); -CO-(L) n -(di(C1-C6 alkyl)amino); and -CO-(L) n -CO-(di(C1-C6 alkyl)amino).

12. The compound according to claim 11, wherein R6 is selected from: Optionally substituted C1-C4 alkyl; -CO-(optionally substituted C1-C4 alkyl); -CO-(L) n -(optionally substituted oxetanyl), wherein the oxetanyl group has the structure: Where * indicates CO or (L) n and R', if present, represents one or more optional substituents; -CO-(optionally substituted imidazolyl), wherein the imidazolyl group has the following structure: wherein * represents the point of attachment to CO, and R', if present, represents one or more optional substituents; -CO-(L) n -(optionally substituted pyrazinyl), wherein the pyrazinyl group has the structure: Where * indicates CO or (L) n and R', if present, represents one or more optional substituents; -CO-(L) n -(optionally substituted pyrimidinyl), wherein the pyrimidinyl group has the structure: Where * indicates CO or (L) n and R', if present, represents one or more optional substituents; -CO-(L) n -(di(C1-C4alkyl)amino); and -CO-(L) n -CO-(di(C1-C4alkyl)amino).

13. A compound according to any one of claims 1 to 12, wherein each L is independently selected from optionally substituted alkylene and optionally substituted heteroarylene.

14. The compound according to claim 13, wherein each L is independently selected from optionally substituted C1-C 12 an alkylene group and an optionally substituted imidazolylene group.

15. The compound according to any one of claims 1 to 14, wherein n is 0 or 2. The compound according to claim 15 , wherein n is 0.

17. A compound according to any one of claims 1 to 15, wherein (L) n is (optionally substituted heteroarylene)-(optionally substituted alkylene).

18. The compound according to claim 17, wherein (L) n Selected from: (optionally substituted thienyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzo[b]thienylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted naphtho[2,3-b]thienylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted thianthrenyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted furanyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzofuranylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted isobenzofuranyl)-(optionally substituted C1-C 12 (optionally substituted chromene)-(optionally substituted C1-C 12 alkylene), (optionally substituted xanthene)-(optionally substituted C1-C 12 alkylene), (optionally substituted thienylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrrolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted imidazolyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted triazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted tetrazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyridylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrimidinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyridazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted triazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted tetrazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted indolizinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoindoleyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted 3H-indolyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted indolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted indazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted purinylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted 4H-quinolizinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoquinolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted quinolinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phthalazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted naphthyridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted quinazolinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted cinnolinyl)-(optionally substituted C1-C 12 (C1-C2-alkylene), (optionally substituted pteridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted carbazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted β-carbolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenanthridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted acridinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted perylene diazaphenyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenanthroline)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted isothiazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenothiazinylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted isoxazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted furazanyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted phenoxazinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted pyrazolo[1,5-α]pyrimidinyl)-(optionally substituted C1-C 12 alkylene), (optionally substituted 1,2-benzisoxazol-3-ylidene)-(optionally substituted C1-C 12 alkylene), (optionally substituted benzimidazolylene)-(optionally substituted C1-C 12 alkylene), (optionally substituted 2-oxindolylene)-(optionally substituted C1-C 12 alkylene) and (optionally substituted 2-oxobenzimidazolyl)-(optionally substituted C1-C 12 alkylene).

19. The compound according to claim 18, wherein (L) n It is (optionally substituted imidazolylene)-(optionally substituted C1-C6 alkylene).

20. The compound according to claim 19, wherein (L) n Selected from: wherein ** represents the point of connection to the CO group on the left, and *** represents the point of connection to the optionally substituted alkyl group, the optionally substituted cycloalkyl group, the optionally substituted heterocyclyl group, the optionally substituted alkoxy group, the optionally substituted aryl group, the optionally substituted heteroaryl group, the optionally substituted amino group or the CO-(optionally substituted amino) group.

21. The compound according to claim 1, wherein the compound is selected from compounds 1 to 10:

22. The compound according to claim 1, wherein the compound is compound 11:

23. A compound according to any one of claims 1 to 22, with the proviso that the compound is not any of the following:

24. A composition comprising a compound according to formula I or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient: wherein R1 to R6 are as defined in any one of claims 1 to 23.

25. A dosage form comprising the composition according to claim 24.

26. A compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: wherein R1 to R6 are as defined in any one of claims 1 to 23; or a composition according to claim 24; or a dosage form according to claim 25; for use in treating a disease regulated by CDK8 and / or CDK19; Preferably wherein the disease modulated by CDK8 and / or CDK19 is cancer; More preferably, the cancer is selected from the group consisting of 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. liver 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 adenocarcinoma) and uterine cancer (e.g. uterine corpus endometrial carcinoma).

27. A kit comprising a compound according to formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: wherein R1 to R6 are as defined in any one of claims 1 to 23; or a composition according to claim 24; or a dosage form according to claim 25; and instructions for using the compound, the composition or the dosage form in the treatment of a disease regulated by CDK8 and / or CDK19; Preferably wherein the disease modulated by CDK8 and / or CDK19 is cancer; More preferably, the cancer is selected from the group consisting of 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. liver 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 adenocarcinoma) and uterine cancer (e.g. uterine corpus endometrial carcinoma).

Images