Stereoisomers of pyrazoloquinazoline compounds, deuterated derivatives and uses thereof

Abstract

The present disclosure provides a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, wherein R 1 and R 2 As described herein, may be used as PLK1 inhibitors, and also provided are pharmaceutical compositions containing same and uses in the treatment of diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, such as cancer. JPEG2026504095000078.jpg46147

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Chinese Patent Application No. 202310083163.X filed on January 17, 2023, and Chinese Patent Application No. 202310430237.2 filed on April 20, 2023, the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present disclosure relates to stereoisomers, deuterated derivatives, or stereoisomeric deuterated derivatives of pyrazoloquinazoline compounds, or pharmaceutically acceptable salts or solvates thereof. The present disclosure further relates to pharmaceutical compositions containing one or more of such stereoisomers and derivatives or pharmaceutically acceptable salts or solvates thereof as active ingredients. The present disclosure further relates to such stereoisomers and derivatives or pharmaceutically acceptable salts or solvates thereof, and to uses of such stereoisomers and derivatives or pharmaceutically acceptable salts or solvates thereof as Polo-like kinase inhibitors. [Background technology]

[0003] Mammalian polo-like kinases (PLKs) comprise a family of five serine / threonine kinases (PLKs 1-5) with distinct functions and expression patterns in mammalian cells. Most PLKs contain a C-terminal polo-box domain (PBD) for substrate recognition and an N-terminal kinase domain for substrate phosphorylation. PLK1 is the most extensively studied PLK family member and plays an important role in cell cycle progression, particularly in the G2-M checkpoint, mitosis, and cytokinesis. PLK1 activity is tightly regulated by binding to other phosphorylation scaffold proteins during cell cycle progression.

[0004] To date, PLK1 has been widely studied as an attractive target in cancer therapy, and several small molecule PLK1 inhibitors have been developed over the past decade. These include solid tumors such as pancreatic, breast, and prostate cancers, as well as liquid tumors such as leukemia and lymphoma. While PLK1 inhibitors have demonstrated antitumor activity in preclinical cancer models and initial promising results in clinical trials, dose-limiting toxicity has prevented satisfactory therapeutic efficacy to date (Translational Oncology Volume 16, February 2022, 101332). Among the ATP-competitive inhibitors primarily targeting PLK1 in clinical development, onvansertib (NMS-P937, NMS1286937) is highly selective and shows promising prospects for clinical development. However, oral absorption and bioavailability of most onvansertib derivatives (Bioorg Med Chem Lett. 2011 May 15;21(10):2969-74, Bioorg Med Chem Lett. 2010 Nov 15;20(22):6489-94) in mice have been reported to be very low. Furthermore, according to literature (Mol Cancer Ther;11(4) April 2012, Supplementary table S4), the absorption and bioavailability of onvansertib vary significantly and are inconsistent between species, posing a significant challenge to the development of selective PLK1 inhibitors.

[0005] The project team members of this study unexpectedly discovered that stereocyclization, deuteration, and a combination of stereocyclization and deuteration in onvansertib N-methylpiperazine could effectively adjust its oral absorption, bioavailability, tissue distribution, and other parameters. Multiple animal studies have shown that the modified molecule has lower toxicity and better efficacy than onvansertib, providing a wider range of effective molecule options for different types of diseases. Summary of the Invention

[0006] The present disclosure discloses stereoisomers, deuterated derivatives, or stereoisomeric deuterated derivatives of pyrazoloquinazoline compounds, or pharmaceutically acceptable salts or solvates thereof, as Polo-like kinase inhibitors. Accordingly, the compounds of the present disclosure are particularly suited to targeting PLK1 and may be used in the treatment of diseases and conditions caused by dysregulated PLK1 activity and / or diseases and conditions associated with PLK1, including, but not limited to, leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis.

[0007] In one aspect, the present disclosure provides a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I):

[0008] [ka] or a pharmaceutically acceptable salt or solvate thereof, where R 1 and R 2 are each independently hydrogen, deuterium, deuterated or non-deuterated C 1-6 alkyl group, or R 1 and R 2 form a 5-membered heterocyclic ring together with the N atom and C atom bonded thereto,

[0009] [ka] is optionally substituted with one or more deuterium atoms.

[0010] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of Formula (I) described herein, or a pharmaceutically acceptable salt, solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0011] In another aspect, the present disclosure relates to a method of treating diseases and conditions caused by dysregulated PLK1 activity and / or diseases and conditions associated with PLK1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of Formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0012] In yet another aspect, the present disclosure relates to a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate thereof, for use in treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0013] In yet another aspect, the present disclosure relates to the use of a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) described herein, or a pharmaceutically acceptable salt, solvate thereof, in the manufacture of a medicament for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0014] In yet another aspect, the present disclosure relates to a kit for treating diseases and conditions caused by dysregulated PLK1 activity and / or diseases and conditions associated with PLK1, the kit comprising a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient, a container, and a package insert or label indicating any treatment.

[0015] Diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 include, but are not limited to, leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis. [Brief explanation of the drawings]

[0016] [Figure 1] The IC50 values ​​of the growth inhibitory effects of the compounds of the examples of the present disclosure and the positive control compound on the growth of a pancreatic cancer cell line (PSN1) are shown, where A is CPD02 of the present disclosure, B is CPD03 of the present disclosure, C is the positive control compound NMS-P937, D is CPD04 of the present disclosure, and E is CPD06 of the present disclosure. [Figure 2] 1 shows a graph of tumor growth in a HCT116 subcutaneously implanted tumor mouse model after initiation of treatment with compounds of the present disclosure. [Figure 3] 1 shows the weight change curves of experimental animals in a HCT116 subcutaneously implanted tumor mouse model after initiation of treatment with compounds of the present disclosure. [Figure 4] 1 shows a graph of tumor growth in a BxPC-3 subcutaneously implanted tumor mouse model after initiation of treatment with compounds of the present disclosure. [Figure 5] 1 shows the weight change curves of experimental animals in a BxPC-3 subcutaneously implanted tumor mouse model after initiation of treatment with compounds of the present disclosure. [Figure 6] 1 shows a graph of tumor growth in a PSN1 subcutaneous tumor mouse model after initiation of treatment with compounds of the present disclosure. [Figure 7] 1 shows the weight change curves of experimental animals in a PSN1 subcutaneously implanted tumor mouse model after initiation of treatment with compounds of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0017] Some embodiments are described in detail below, examples of which are illustrated in the accompanying specific embodiments. While the listed embodiments are described, it should be understood that they are not intended to limit the disclosure to these embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present disclosure, as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that could be used to implement the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated documents and similar materials differ from or contradict this disclosure in any respect, including, but not limited to, defined terms, term usage, described techniques, etc., the present disclosure controls.

[0018] It will be appreciated that certain features of the present disclosure may, for clarity, be described in the context of a single embodiment, or may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure that are, for brevity, described in the context of a single embodiment, may also be provided alone or in any suitable subcombination.

[0019] This specification provides the following:

[0020] Item 1 Stereoisomers, deuterated derivatives or stereoisomeric deuterated derivatives of compounds of formula (I):

[0021] [ka] or a pharmaceutically acceptable salt or solvate thereof, where R 1 and R 2 are each independently hydrogen, deuterium, deuterated or non-deuterated C 1-6 alkyl group, or R 1 and R 2 form an optionally substituted deuterated or non-deuterated 5-membered heterocycle together with the N atom and C atom bound thereto,

[0022] [ka] is optionally substituted with one or more deuterium atoms.

[0023] Item 2 In the stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound according to item 1, or a pharmaceutically acceptable salt or solvate thereof, R 1 is deuterated or non-deuterated C 1-6 an alkyl group, preferably a methyl group or a deuterated methyl group, more preferably a fully deuterated methyl group; R 2 is hydrogen or deuterium.

[0024] Item 3 In the stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of item 1, or a pharmaceutically acceptable salt or solvate thereof, R 1 and R 2 form, together with the N atom and C atom bonded thereto, an optionally substituted 5-membered heterocycle as shown below,

[0025] [ka] wherein the 5-membered heterocycle is optionally substituted with 1 to 7 deuterium atoms.

[0026] Item 4 In the stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of item 3, or a pharmaceutically acceptable salt or solvate thereof, R 1 and R 2 together with the N atom and C atom bound thereto, form an optionally substituted 5-membered heterocycle selected from the following:

[0027] [ka] wherein the 5-membered heterocycle is optionally substituted with 1 to 7 deuterium atoms.

[0028] Item 5 In the stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to any one of the above, or a pharmaceutically acceptable salt or solvate thereof,

[0029] [ka] is optionally substituted with 1 to 8 deuterium atoms.

[0030] Item 6 In the stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to item 1, or a pharmaceutically acceptable salt or solvate thereof, the stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) is

[0031] [ka] Item 7 A pharmaceutical composition comprising a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) according to any one of items 1 to 6, or a pharmaceutically acceptable salt, solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0032] Item 8 A method for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) described in any one of items 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

[0033] Item 9In the method described in item 8, the diseases and pathological conditions caused by dysregulation of PLK1 activity and / or diseases and pathological conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma and sepsis.

[0034] Item 10 The stereoisomers, deuterated derivatives or stereoisomeric deuterated derivatives of the compounds of formula (I) according to any one of items 1 to 6, or pharmaceutically acceptable salts, solvates thereof, are used to treat diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0035] Item 11 Item 10: In the stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, the diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma and sepsis.

[0036] Item 12 Use of a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) according to any one of items 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0037] Item 13In the use of item 12, the diseases and pathological conditions caused by dysregulation of PLK1 activity and / or diseases and pathological conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma and sepsis.

[0038] Item 14 A kit for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, said kit comprising: A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to item 7; A container and and a package insert or label for indicating any treatment.

[0039] Item 15 In the kit described in Item 14, the diseases and pathological conditions caused by dysregulation of PLK1 activity and / or diseases and pathological conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma and sepsis.

[0040] definition Terms used but not defined herein have their ordinary meanings, and those meanings will be construed independently at each occurrence. However, unless otherwise stated, the following definitions apply throughout this specification and claims.

[0041] As used herein, the terms "comprises" and "comprises" are intended to specify the presence of said features, wholes, components or steps, but do not exclude the presence or addition of one or more other features, wholes, components, steps or groups thereof.

[0042] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, and the Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described in these documents. In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modem Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0043] Unless otherwise stated, all ranges cited herein are inclusive.

[0044] When a series of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C 1-6 ” is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 is intended to encompass.

[0045] When any variable occurs more than one time in any constituent or in Formula (I), or any other formula depicting and describing compounds of this disclosure, its definition on each occurrence shall be construed independently of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0046] As used herein, the term "deuterated" refers to one or more hydrogens on a compound or group being replaced with deuterium. When a compound or group is deuterated, one, two, three, or more hydrogen atoms on the compound or group may be replaced with deuterium; once all hydrogen atoms on a compound or group have been replaced with deuterium, the compound or group may be referred to as a "fully deuterated compound or group."

[0047] In some embodiments, the deuterium isotope abundance at the deuterated position is greater than the natural deuterium isotope abundance (0.015%), preferably 50% greater, more preferably 60% greater, 70% greater, 80% greater, 90% greater, 95% greater, 96% greater, 97% greater, 98% greater, 99% greater, 99.5% greater, or 100% greater.

[0048] In some cases, for example, when "hydrogen" and "deuterium" appear as parallel alternatives in the description, or when "hydrogen" appears to be substituted with "deuterium" in the description, the term "hydrogen" refers to the hydrogen isotope " 1 hydrogen( 1 H), and the term "deuterium" refers to the hydrogen isotope " 2 hydrogen( 2 It is understood that a compound represented by a symbol "H") represents "H" or that a position in the compound where hydrogen is present at various isotopic natural abundances is substituted with deuterium present at greater than the natural deuterium isotopic abundance (e.g., where the deuterium abundance is 50% greater, 60% greater, 70% greater, 80% greater, 90% greater, 95% greater, 96% greater, 97% greater, 98% greater, 99% greater, 99.5% greater, or 100%).

[0049] In some embodiments,

[0050] [ka] When is optionally substituted with one deuterium, the deuterium can be substituted on any ring carbon atom.

[0051] [ka] When is optionally substituted with two or more deuterium atoms, these two or more deuterium atoms may be substituted on the same ring carbon atom or on different ring carbon atoms.

[0052] In some embodiments, R 2 If is hydrogen,

[0053] [ka] In this case, R 2 Hydrogens on ring carbon atoms, including may be replaced with 1 to 8 deuteriums, for example 1, 2, 3, 4, 5, 6, 7, or 8 deuteriums. These deuteriums may be replaced on the same or different ring carbon atoms.

[0054] In some embodiments, R 1 is a non-deuterated methyl group, and R 2 If is hydrogen,

[0055] [ka] In this case, R 2 At least one hydrogen on a ring carbon atom, including: is replaced with deuterium, for example, 1, 2, 3, 4, 5, 6, 7, or 8 deuteriums. The deuteriums can be replaced on the same or different ring carbon atoms.

[0056] In a preferred embodiment, optionally deuterated

[0057] [ka] Selected from R 1 is optionally non-deuterated, e.g., a non-deuterated methyl group, or deuterated, e.g., a fully deuterated methyl group, e.g.,

[0058] [ka] is.

[0059] In some embodiments,

[0060] [ka] or its stereoisomers

[0061] [ka]

[0033] When the ring structure is fused ring structure, one or more deuterium atoms may be substituted on any ring carbon atom, and when two or more deuterium atoms are present, the two or more deuterium atoms may be substituted on the same ring carbon atom or on different ring carbon atoms. In some embodiments, when two or more deuterium atoms are present, the two or more deuterium atoms may be substituted on one ring of the fused ring structure or on both rings of the fused ring structure. In some embodiments, one or more deuterium atoms may be substituted on a carbon atom shared by the two rings of the fused ring structure.

[0062] In a preferred embodiment, optionally deuterated

[0063] [ka] is selected from.

[0064] In some embodiments,

[0065] [ka] As used herein, the term "alkyl group" refers to a straight or branched chain saturated hydrocarbon group. i-j The term "alkyl group" refers to an alkyl group having i to j carbon atoms. Unless otherwise specified, an alkyl group can contain 1 to 10 carbon atoms. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, e.g., 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, neopentyl, and the like.

[0066] As used herein, the term "deuterated alkyl group" refers to a substituent obtained by replacing one or more hydrogen atoms on an alkyl group with deuterium. When an alkyl group is deuterated, one, two, three, or more hydrogen atoms on the alkyl group may be replaced with deuterium; when all hydrogen atoms on the alkyl group are replaced with deuterium, the alkyl group may be referred to as a "fully deuterated alkyl group." In some embodiments, non-limiting examples of deuterated alkyls include deuterated methyl, e.g., monodeuterated methyl, dideuterated methyl, trideuterated methyl (fully deuterated methyl), monodeuterated ethyl, dideuterated ethyl, trideuterated ethyl, tetradeuterated ethyl, pentadeuterated ethyl (fully deuterated ethyl), and the like.

[0067] As used herein, the term "cycloalkyl group" refers to non-aromatic, saturated monocyclic and polycyclic ring systems in which all ring atoms are carbon. Unless otherwise specified, cycloalkyl groups contain from 3 to 10 ring carbon atoms (i.e., C 3-10In some embodiments, the cycloalkyl group may include 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6 ring carbon atoms, etc. In particular, the cycloalkyl group may be monocyclic or bicyclic. Optionally, bicyclic cycloalkyl groups may include fused, spiro, and bridged cycloalkyl structures.

[0068] In another aspect, cycloalkyl rings in which one, two, or three heteroatoms are substituted for ring carbon atoms are also included. Such groups, referred to as "heterocyclic groups" or "heterocycles," refer to cycloalkyl groups as defined above, but containing at least one heteroatom selected from N, O, and S as a ring atom. Unless otherwise specified, heterocyclic groups may contain 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclic groups). In some embodiments, heterocyclic groups may contain 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, etc. ring atoms. In particular, heterocyclic groups may be monocyclic or bicyclic. Optionally, bicyclic heterocyclic groups may include fused, spiro, and bridged heterocyclic structures. Non-limiting examples of heterocyclic groups include oxiranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, pyrrolidinyl, and morpholinyl. Heterocyclic groups may also be described using the number of carbon atoms, for example, C 3-6 A heterocyclic group refers to a heterocyclic group containing 3 to 6 ring carbon atoms and can contain at least one heteroatom, for example, 1, 2, or 3 heteroatoms, as a ring atom. In some embodiments, a heterocyclic group or heterocycle contains 1 or 2 heteroatoms as ring atoms. In some embodiments, a heterocyclic group can be monocyclic or bicyclic, for example, fused bicyclic and spiro bicyclic. In the context of this disclosure, the terms "heterocyclic group" and "heterocycle" can be used interchangeably.

[0069] As used herein, the term "deuterated heterocyclic group" refers to a substituent obtained by replacing one or more hydrogen atoms on a heterocyclic group with deuterium. When a heterocyclic group is deuterated, one, two, three, or more hydrogen atoms on the heterocyclic group may be replaced with deuterium; when all hydrogen atoms on a heterocyclic group are replaced with deuterium, the heterocyclic group may be referred to as a "fully deuterated heterocyclic group."

[0070] As used herein, the term "halogenated" or "halogen" refers to fluoride, chloride, bromide, and iodide. In some embodiments, non-limiting examples of halides include fluoride, chloride, bromide, and more particularly fluoride and chloride.

[0071] As used herein, the term "heteroatom" refers to nitrogen (N), oxygen (O), sulfur (S), and unless otherwise specified, can include any oxidized form of nitrogen and sulfur, and any quaternized form of a basic nitrogen.

[0072] As used herein, the term "substituted," when referring to a chemical group, means that the chemical group has one or more hydrogen atoms and that heteroatom is removed or replaced with a substituent. As used herein, the term "substituent" has the ordinary meaning known in the art and refers to a chemical moiety that is covalently bonded to a parent group or, where appropriate, fused to a parent group. It may be understood that substitution of a given atom is limited by the valence of the atom. It is understood that a substituent can be further substituted.

[0073] In Formula (I) or any embodiment thereof, when a moiety is described as being "optionally" substituted, this means that Formula (I) or an embodiment thereof includes compounds substituted with the indicated substituent on that moiety, as well as compounds that do not include the indicated substituent on that moiety (i.e., compounds in which that moiety is unsubstituted).

[0074] The compounds provided herein are described with reference to general formulas and specific compounds. Additionally, the compounds of the present disclosure may exist in various different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, pharmaceutically acceptable salts, tautomers, stereoisomers, racemic mixtures, positional isomers, prodrugs, solvated forms, different crystalline or polycrystalline forms, and active metabolites.

[0075] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acid / base form of the particular compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include salts formed with inorganic and organic bases or acids. When compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes their corresponding pharmaceutically acceptable salts. Thus, compounds of the present disclosure that contain acidic groups (e.g., carboxyl groups) may exist in the form of salts and may be used in accordance with the present disclosure, for example, as alkali metal salts, alkaline earth metal salts, aluminum salts, or ammonium salts. Further non-limiting examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids). For example, these salts can be readily obtained by reacting a compound having an acidic group with a suitable base (e.g., lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide). Other base salts of the compounds of the present disclosure include, but are not limited to, copper(I), copper(II), iron(II), iron(III), manganese(II), and zinc salts. The compounds of the present disclosure can contain one or more basic groups, e.g., groups that can be protonated, and can exist in the form of salts and can be used in accordance with the present disclosure in the form of addition salts with inorganic or organic acids.Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, pamoic acid, mandelic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid, or aspartic acid, as well as other acids known to those skilled in the art. The salts formed are, inter alia, hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate (mesylate), toluenesulfonate, carbonate, bicarbonate, formate, acetate, sulfoacetate, trifluoromethanesulfonate, oxalate, malonate, maleate, succinate, tartrate, malate, pamoate, mandelate, fumarate, lactate, citrate, glutarate, stearate, aspartate, and glutamate. Additionally, the stoichiometry of the salts formed from the compounds of the present disclosure may be an integer or non-integer multiple of 1.

[0076] Compounds of the present disclosure that contain basic nitrogen groups include, for example, C groups such as methyl, ethyl, isopropyl, and tert-butyl chloride, bromine, and iodine. 1-4 Alkyl halides, such as di-C alkyl esters, such as dimethyl sulfate, diethyl ester, and dipentyl ester 1-4 C alkyl sulfates, such as decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides 10-18 Alkyl halides and aryl bromides such as benzyl chloride and phenethyl C 1-4 It can be quaternized using reagents such as alkyl halides.

[0077] When the compounds of the present disclosure contain both acidic and basic groups in the molecule, the present disclosure also encompasses internal salts or betaines (zwitterions) in addition to the above salt forms. The corresponding salts may be obtained by conventional methods known to those skilled in the art, such as by contacting them with an organic or inorganic acid or base in a solvent or dispersion medium, or by anion or cation exchange with other salts. The present disclosure also encompasses all salts of the compounds of the present disclosure, which, although not directly applicable to drugs due to their poor physiological compatibility, may be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts. For a review of more suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0078] The compound of formula (I) and its pharmaceutically acceptable salts can exist in unsolvated and solvated forms. As used herein, the term "solvate" refers to a molecular complex comprising a stereoisomer, deuterated derivative, or stereoisomeric deuterated derivative of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules. For example, when the solvent is water, the term "hydrate" is used.

[0079] The compounds of formula (I) may have one or more chiral (asymmetric) centers. The present disclosure encompasses all stereoisomers of the compounds of formula (I). The asymmetric centers present in the compounds of formula (I) may have either the (R) or (S) configuration, independently of one another. When the bonds at the chiral carbons in the structural formulas of the present disclosure are depicted as linear, or when the names of the compounds are depicted without the (R) or (S) chiral name of the chiral carbon, it should be understood that both the (R) and (S) configurations of each chiral carbon, and each enantiomeric or diastereomeric isomer and mixtures thereof, are encompassed by the formula or name. The production of a specific stereoisomer or mixture thereof may be identified in instances where such a stereoisomer or mixture is obtained, but this does not limit the inclusion of all stereoisomers and mixtures thereof within the scope of the present disclosure. When a bond at a chiral carbon in a structural formula of the present disclosure is depicted as a solid or dashed triangular line, or when a compound name is depicted in the presence of an (R) or (S) chiral name at the chiral carbon, it is understood that the compound represented by the structural formula or name at that time has a specific configuration at the chiral carbon position and is distinguished from other stereoisomers, enantiomeric isomers, diastereomeric isomers, or mixtures thereof.

[0080] The present disclosure includes all possible enantiomeric and diastereomeric isomers, as well as mixtures of two or more stereoisomers, for example, mixtures of enantiomeric and / or diastereomeric isomers in all proportions. Accordingly, enantiomeric isomers include the pure enantiomeric isomer forms (levorotatory and dextrorotatory enantiomers) of the subject matter of the present disclosure, racemic forms, and mixtures of the two enantiomers in all proportions. In the case of cis / trans isomers, the present disclosure includes the cis form, the trans form, and mixtures of these forms in all proportions. If necessary, single stereoisomers can be prepared by separation and mixing using conventional methods (e.g., chromatography or crystallization, use of stereochemically uniform synthetic starting materials, stereoselective synthesis). Optionally, derivatization can be performed before separating the stereoisomers. Separation of stereoisomeric mixtures can be performed at an intermediate stage during the synthesis of the compound of Formula (I) or on the final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereocenter of known configuration. Optionally, absolute stereochemistry may be determined by vibrational circular dichroism (VCD) spectroscopy.

[0081] Unless otherwise stated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, in other words, compounds in which one or more atoms are replaced with an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly occurring in nature. Such compounds are referred to as "isotopic variants." The present disclosure is intended to include all pharmaceutically acceptable isotopic variants of compounds of Formula (I). Examples of isotopes suitable for inclusion in compounds of the present disclosure include, for example, 2 H (i.e., D, deuterium) and 3 isotopes of hydrogen, such as H (i.e., deuterium), 11 C. 13 C and 14 Carbon such as C, e.g. 36 Chlorine such as Cl, e.g. 18 Fluorine such as F, e.g. 123 I and125 Iodine such as I, e.g. 13 N and 15 Nitrogen such as N, e.g. 15 O. 17 O and 18 Oxygen such as O, e.g. 32 Phosphorus, such as P, and e.g. 35 Certain isotopic variations of the compounds of formula (I), for example those doped with a radioactive isotope, may be used in drug and / or substrate tissue distribution studies. In particular, substitution with a heavier isotope (deuterium ( 2 Compounds that differ in the depicted structure only in the replacement of hydrogen by H or D) may offer certain therapeutic advantages due to requirements such as greater metabolic stability, increased in vivo half-life, reduced dosage, etc., and therefore may be used in some specific cases. Isotopic variants of compounds of formula (I) may generally be prepared by synthesis using conventional techniques known to those skilled in the art or methods analogous to those described in the accompanying examples, and using the appropriate isotopically labeled reagent in place of the unlabeled reagent previously used.

[0082] When describing the structure of a compound herein, in the structural formula shown, a hydrogen atom is represented by D (i.e. 2 Unless otherwise specified (H), the hydrogen at that position is generally assumed to be the hydrogen isotope " 1 hydrogen( 1 It is understood that hydrogen atoms in the depicted structures may exist in the form of D (i.e., H) or in the form with natural isotopic abundance in the natural state. 2 When specified as hydrogen, the hydrogen at that position is the hydrogen isotope " 2 hydrogen( 2 It is understood that deuterium may be present in the form of "H, D, deuterium" or in a form where deuterium is present in a greater than natural deuterium isotope abundance (e.g., 50% greater, 60% greater, 70% greater, 80% greater, 90% greater, 95% greater, 96% greater, 97% greater, 98% greater, 99% greater, 99.5% greater, or 100% greater deuterium abundance).

[0083] Pharmaceutically acceptable solvates in accordance with the present disclosure may include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0084] One way of implementing the present disclosure is to administer a compound of formula (I) in the form of a prodrug. Thus, some derivatives of the compound of formula (I) may have little or no pharmacological activity themselves, but upon administration into or onto the body, they are converted to a compound of formula (I) with the desired activity, for example, by hydrolytic cleavage, particularly hydrolytic cleavage promoted by esterases or peptidases. Such derivatives are called "prodrugs." For details regarding the use of prodrugs, see, for example, T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series, and E. B. Roche (Ed.), "Bioreversible Carriers in Drug Design," Pergamon Press, 1987, American Pharmaceutical Association. Further reference may be made to Nature Reviews / Drug Discovery, 2008, 7, 355, and Current Opinion in Drug Discovery and Development, 2007, 10, 550.

[0085] Prodrugs according to the present disclosure may be prepared, for example, by replacing appropriate functional groups present in compounds of formula (I) with specific moieties known to those skilled in the art, such as the "promoieties" described in H. Bundgaard, "Design of Prodrugs", Elsevier, 1985 and YM Choi-Sledeski and C.G. Wermuth, "Designing Prodrugs and Bioprecursors", Practice of Medicinal Chemistry, 4th Edition, Chapter 28, 657-696, Elsevier, 2015. Thus, prodrugs according to the present disclosure may include, but are not limited to, (a) an ester or amide derivative of a carboxylic acid, if present, in a compound of formula (I); (b) an amide, imine, carbamate, or amine derivative of an amino group, if present, in a compound of formula (I); (c) an oxime or imine derivative of a carbonyl group, if present, in a compound of formula (I); or (d) a methyl group, primary alcohol group, or aldehyde group, if present, that can be metabolically oxidized to a carboxylic acid in a compound of formula (I).

[0086] The references to compounds of formula (I) include the compounds themselves and prodrugs thereof. The present disclosure includes compounds of formula (I), as well as pharmaceutically acceptable salts of such compounds, and pharmaceutically acceptable solvates of said compounds and salts.

[0087] Use and Administration The compounds of the present disclosure (stereoisomers, deuterated derivatives, or stereoisomeric deuterated derivatives of the compound of Formula (I))—or pharmaceutically acceptable salts, solvates thereof, including mixtures thereof in all proportions—can be used as drugs. They have been found to exhibit pharmacological activity inhibiting PLK1. Due to this activity, it is hypothesized that the compounds of the present disclosure can prevent or reverse dysregulation of PLK1 activity. By preventing dysregulation of PLK1 activity, they can act as tumor suppressors. In addition to preventing or reversing dysregulation of PLK1 activity, the pharmacological activity of the compounds of the present disclosure can also be utilized in other pathophysiological situations in which inhibition of PLK1 is beneficial.

[0088] Therefore, the compounds of the present disclosure as PLK1 inhibitors are particularly applicable to the treatment of diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, such as cancer, including, but not limited to, cancers such as leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis, etc. Without wishing to be bound by any particular theory or explanation, it can be hypothesized that these compounds may achieve this purpose by acting directly on cancer cells and / or indirectly modulating the immune system's response to tumors.

[0089] The compounds of the present disclosure may be administered in an amount effective for treating the diseases or conditions described herein. The compounds of the present disclosure may be administered as the compounds themselves, or optionally as a pharmaceutically acceptable salt. For purposes of administration and dosage, the compounds of the present disclosure themselves (stereoisomers, deuterated derivatives, or stereoisomeric deuterated derivatives of the compounds of Formula (I)) or pharmaceutically acceptable salts, solvates thereof are referred to as compounds of the present disclosure.

[0090] The compounds of the present disclosure are administered by any suitable route, in the form of a pharmaceutical composition appropriate for such route, and in a dose effective for the intended treatment. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.

[0091] As used herein, the term "administration" refers to the absorption, ingestion, injection, inhalation, implantation, or other introduction of a compound of the present disclosure or a pharmaceutical composition thereof. The term "treatment" refers to the reversal of, alleviation of, delaying the onset of, or inhibiting the progression of a "pathological condition" (e.g., a disease, illness, or condition, or one or more signs or symptoms thereof) described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of a disease or condition have appeared or been observed. In other embodiments, treatment can be administered even in the absence of signs or symptoms of a disease or condition. For example, susceptible individuals are treated before symptoms appear (e.g., based on a history of symptoms and / or genetic or other susceptibility factors). Treatment can continue after symptoms have disappeared, for example, to delay or prevent recurrence. As used herein, the terms "disease," "illness," "condition," and "pathological condition" may be used interchangeably.

[0092] Those skilled in the art can determine the dosage level to be administered through routine experimentation. The dosage regimen for the compounds of the present disclosure and / or compositions containing the compounds is based on various factors, including the type, age, weight, sex, and medical condition of the patient, the severity of the condition, the route of administration, and the activity of the particular compound used. Thus, dosage regimens can vary widely. For example, dosage levels for the compounds of the present disclosure may range from about 0.001 to about 100 mg / kg (i.e., mg / kg body weight) per day. In some embodiments, the total daily dosage of the compounds of the present disclosure may range from about 0.001 to about 10 mg / kg, in single or divided doses. It is not uncommon for the administration of the compounds of the present disclosure to be repeated multiple times per day.

[0093] Pharmaceutical Composition In some aspects, the present disclosure relates to pharmaceutical compositions comprising a stereoisomer, deuterated derivative, or stereoisomeric deuterated derivative of a compound of Formula (I) described herein, or a pharmaceutically acceptable salt, solvate thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0094] As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and can be used to prepare a pharmaceutical composition, including carriers or excipients that are acceptable for veterinary and human pharmaceutical use. As used herein, a pharmaceutically acceptable carrier or excipient includes one or more such carriers or excipients. The specific carrier or excipient used will depend on the application and purpose of the compound of the present disclosure. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. To achieve better function of the drug (i.e., the compounds or pharmaceutical compositions provided herein) or to facilitate the manufacture of a pharmaceutical formulation (i.e., a drug product), one or more of buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives may also be included.

[0095] The compositions of the present disclosure may be formulated in multiple forms, including, for example, liquid, semi-solid and solid dosage forms, such as injectable and infusible solutions, dispersions or suspensions, tablets, pills, powders, liposomes, suppositories, etc. The dosage form depends on the intended route of administration and therapeutic application.

[0096] The pharmaceutical compositions of the present disclosure may be prepared by any known pharmaceutical technique (e.g., effective formulation and administration procedures). The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. For example, pharmaceutical formulations are discussed in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients, 3rd ed., American Pharmaceutical Association, Washington, 1999.

[0097] In yet another aspect, the present disclosure relates to a kit for treating diseases and conditions caused by dysregulated PLK1 activity and / or diseases and conditions associated with PLK1, the kit comprising a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof, a container, and a package insert or label indicating an optional treatment.

[0098] Treatment method In yet another aspect, the present disclosure relates to a method of treating diseases and conditions caused by dysregulated PLK1 activity and / or diseases and conditions associated with PLK1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0099] As used herein, the term "subject in need" refers to a subject suffering from a disease or condition caused by dysregulation of PLK1 activity and / or a disease or condition associated with PLK1, or a subject at increased risk for developing a disease or condition associated with PLK1 compared to the population at large. In some embodiments, the subject is a warm-blooded animal. In some embodiments, the warm-blooded animal is a mammal. In some embodiments, the warm-blooded animal is a human.

[0100] As used herein, the term "diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1" refers to diseases and conditions resulting from dysregulation of PLK1 activity, any pathophysiological condition in which inhibition of PLK1 is beneficial. In some embodiments, the diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are cancers. In some embodiments, the diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis.

[0101] In yet another aspect, the present disclosure relates to a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate thereof, for use in treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0102] In yet another aspect, the present disclosure relates to the use of a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) described herein, or a pharmaceutically acceptable salt, solvate thereof, in the manufacture of a medicament for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1.

[0103] synthesis The compounds of the present disclosure may be prepared by the general and specific methods described below, using common knowledge of one skilled in the art of synthetic organic chemistry, as described in standard reference texts such as Barton and Ollis (eds.), General Organic Chemistry, Elsevier, Richard Larock, General Organic Transformations: A Guide to Introducing Functional Groups, John Wiley and Sons, and Compendium of Organic Synthesis Methods, Volumes I-XII, Wiley-Interscience.

[0104] The schemes described below are intended to provide a general description of methods for preparing compounds of the present disclosure. Some compounds of the present disclosure may contain single or multiple chiral centers, having the stereochemical designation (R) or (S). It will be apparent to those skilled in the art that all synthetic transformations can be carried out in a similar manner, regardless of whether the material is enantiomerically enriched or racemic. Furthermore, characterization of the desired optically active material may be carried out at any desired stage of the procedure using well-known methods, as described herein and in the chemical literature.

[0105] Example In order to more fully illustrate the present disclosure, the following examples are provided. The examples described herein are intended to illustrate the compounds, methods, and compositions described herein, and should not be construed in any way as limiting the scope thereof.

[0106] During the synthetic processes, it may be necessary and / or desirable to protect any sensitive or reactive groups on any of the molecules concerned. This may be achieved by conventional protecting groups such as those described in T.W. Greene and P.G.M. Hutts, Protective Groups in Organic Synthesis, 4th Edition, John Wiley and Sons. The protecting groups are optionally removed at a convenient subsequent stage using methods well known in the art.

[0107] The compounds of the present disclosure may be easily prepared using readily available starting materials, reagents, and conventional synthetic procedures according to the following reaction schemes and examples or modifications thereof. Variants known to those skilled in the art but not specifically mentioned may also be used in these reactions. Furthermore, other methods for preparing the compounds of the present disclosure will be apparent to those skilled in the art according to the reaction schemes and examples described herein. Unless otherwise specified, all variables are as defined above. Generally, in chemical procedures, all reagents and starting materials are available from commercial suppliers or can be easily prepared by those skilled in the art.

[0108] Exemplary compounds are shown in Table 1.

[0109] [Table 1-1]

[0110] [Table 1-2] Preparation of intermediates

[0111] [ka] Step 1, Synthesis of Compound 2 Compound 1 (40.0 g, 408.2 mmol, 1.0 eq) was dissolved in EtOH (40 mL) at room temperature, and p-toluenesulfonic acid (PTSA) (7.0 g, 40.8 mmol, 0.1 eq) was added. The mixture was refluxed with stirring overnight. After TLC confirmed that no compound 1 remained, the mixture was concentrated. The residue was dissolved in EtOAc (200 mL), washed with saturated sodium bicarbonate solution (100 mL × 3), NaSO, and concentrated to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100:1) to give compound 2 (30.0 g, 60.1%) as a yellow oil. 1HNMR (300MHz, DMSO-d6): δ ppm5.98(t, J=4.5Hz, 1H), 3.67(q, J=6.9Hz, 2H), 2.46-2.24(m, 4H), 1.95-1.77(m, 2H), 1.22(t, J=6.9Hz, 3H). LCMS:141.1([M+H] + ).

[0112] Step 2, synthesis of compound 4 Compound 2 (20.0 g, 142.7 mmol, 1.0 eq) was dissolved in THF (250 mL) and protected with nitrogen gas. LiHMDS (171 mL, 171.2 mmol, 1.2 eq, 1 M in THF) was added dropwise at -50 °C. After the addition was complete, the mixture was stirred at this temperature for 30 min. The mixture was then maintained at -50 °C and compound 3 (22.2 mL, 157.0 mmol, 1.1 eq) was added dropwise. After the addition was complete, the mixture was returned to room temperature and stirred overnight. After LC-MS confirmed the complete disappearance of compound 2, the pH was adjusted to 4 with 1 N HCl (approximately 180 mL) in an ice-water bath. The mixture was extracted three times with ethyl acetate (300 mL each time). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give a residue, which was further purified by column chromatography to give compound 4 (20.0 g, 58.3%) as a yellow oil. 1 H NMR (300MHz, CDCl3):δ ppm14.93(s, 1H), 5.88(d, J=4.8Hz, 1H), 4.34(q, J=6.9Hz, 2H), 3.82(q, J= 6.9Hz, 2H), 2.89(t, J=6.9H, 2H), 2.40(q, J=5.1Hz, 2H), 1.50-1.32(m, 6H).

[0113] Step 3, Synthesis of Compound 5 Compound 4 (20.0 g, 83.3 mmol, 1.0 eq) was dissolved in acetic acid (200 mL), and 2-hydroxyethylhydrazine (6.3 g, 83.3 mmol, 1.0 eq) was added while stirring at room temperature. Stirring was continued at room temperature for 2 hours until the complete disappearance of compound 4 was confirmed by LCMS. The reaction mixture was concentrated, and the residue was dissolved in 500 mL of ethyl acetate. The mixture was washed three times with water, saturated sodium bicarbonate solution, and saturated brine. After drying over anhydrous sodium sulfate, the drying agent was removed by filtration and the solvent was removed by rotary evaporation to give pale yellow compound 5 (16.0 g, 76.2%). 1 H NMR (300MHz, DMSO-d6):δ ppm4.86(t, J=5.7Hz, 1H), 4.54(t, J=5.7Hz, 2H), 4.29(q, J=6.9Hz, 2H), 3.72(q, J=5.7Hz, 2 H), 2.93(t, J=6.0Hz, 2H), 2.62-2.42(m, 2H), 2.13-1.95(m, 2H), 1.30(t, J=7.2Hz, 3H) were obtained. LCMS:253.1([M+H] + ).

[0114] In step 4, synthesis of intermediate Int-A Compound 5 (20.0 g, 79.3 mmol, 1.0 eq) was dissolved in DMF (180 mL), compound 6 (48.3 g, 237.9 mmol, 3.0 eq) was added, and the mixture was stirred at 60° C. for 2 hours. After the complete disappearance of compound 5 was monitored by LCMS, the mixture was cooled to room temperature, the reaction solution was poured into 1000 mL of water, and extracted six times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the drying agent was filtered off, and the solvent was removed by rotary evaporation to give pale yellow intermediate Int-A (13.0 g, 66.7%) without further purification. 1H NMR (300MHz, DMSO-d6): δppm7.48(s, 1H), 4.84(brs, 1H), 4.60(t, J=6.0Hz, 2H), 4.27(q, J=7.2Hz, 2 H), 3.78-3.65 (m, 2H), 3.11 (s, 6H), 2.96-2.86 (m, 2H), 2.86-2.76 (m, 2H), 1.29 (t, J=7.2Hz, 3H) were obtained.

[0115] In step 5, synthesis of intermediate A1 Intermediate Int-A (6.0 g, 0.7 mmol, 1.0 eq) was dissolved in DMF (60 mL) and compound 7 (4.7 g, 48.8 mmol, 2.5 eq) was added. Under N2 protection, the mixture was reacted at 110 °C for 12 hours. The reaction was monitored by LCMS until no INT-A remained. The mixture was cooled to room temperature, poured into 180 mL of water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed by rotary evaporation. The product was purified by column chromatography to give a pale yellow intermediate (3.6 g, 60.8%). 1 H NMR (400MHz, CDCl3):δ ppm8.20(s, 1H), 5.10(s, 2H), 4.93(t, J=4.8Hz, 2H), 4.42(q, J=7.2Hz, 2H), 4.13(t , J=4.8Hz, 2H), 3.06(t, J=7.6Hz, 2H), 2.81(t, J=7.6Hz, 2H), 1.40(t, J=7.2Hz, 3H). LCMS:304.1([M+H] + ).

[0116] In step 6, synthesis of intermediate A2 Intermediate A1 (4.0 g, 13.2 mmol, 1.0 eq) was dissolved in DME (320 mL) and CsI (6.9 g, 26.4 mmol, 2.0 eq), I2 (3.3 g, 13.2 mmol, 1.0 eq), CuI (1.0 g, 5.3 mmol, 0.4 eq), and isoamyl nitrite (4.6 g, 39.6 mmol, 3.0 eq) were added. The reaction mixture was heated at 80 °C for 3 h, then cooled to room temperature. A white solid precipitated. The white solid was filtered and dissolved in 200 mL of dichloromethane. The solution was washed once each with aqueous ammonia, sodium thiosulfate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was removed by rotary evaporation to give the crude product. This crude product was purified by column chromatography to give yellow intermediate A2 (2.0 g, 36.6%). 1 H NMR (400MHz, CDCl3):δ ppm8.30(s, 1H), 4.92(t, J=4.8Hz, 2H), 4.42(q, J=7.2Hz, 2H), 4.14(t, J=4.8 Hz, 2H), 3.15 (t, J=7.2Hz, 2H), 2.94 (t, J=8.0Hz, 2H), 1.41 (t, J=7.2Hz, 3H). LCMS:415.1([M+H] + ).

[0117] Synthesis of intermediate A4

[0118] [ka] HOBT (4.0 g, 29.6 mmol, 1.0 eq) was dissolved in methanol (40 mL), and aqueous ammonia (2.4 mL) was added. The mixture was stirred at room temperature for 5 hours to precipitate a solid. The solid was filtered to obtain a white solid, which was washed with petroleum ether and then dried to obtain Intermediate A4 (3.6 g, 79.9%).

[0119] Synthesis of intermediate A8

[0120] [ka] In Step 1, A7 ((R)-tert-butyl hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate-1,1,4,4-d4) is synthesized.

[0121] A6 (12 g, 77.4 mmol) was dissolved in a mixture of CD3OD (25 mL) and DCM (500 mL) and heated to reflux for 8 h. The solvent was then removed by rotary evaporation. The residue was redissolved in CD3OD (25 mL) and DCM (500 mL) and refluxed for 8 h. The solvent was then removed to give a white solid. The solid was dissolved in THF (200 mL) and added with LiAlD4 (8.13 g, 193.5 mmol) at room temperature. The mixture was refluxed for 1 h, cooled to 0 °C, and added with DCM (500 mL), water (8.13 mL), and 15% NaOH (8.13 mL). (Boc)2O (33.75 g, 154.9 mmol) and TEA (23.46 g, 232.2 mmol) were added to the reaction mixture, which was stirred at room temperature for 8 hours. The insoluble matter was filtered off, and the filtrate was concentrated and purified by silica gel column chromatography to give the crude product A7 (12.7 g, 71%) as a brown oil. LCMS: 231.2 [M+H] + .

[0122] In step 2, synthesis of A8 The above intermediate A7 was dissolved in MeOH (10 mL), and dioxane hydrochloride solution (4N, 10 mL) was added, reacted at room temperature for 16 hours, and the solvent was removed to give crude product A8 (1.26 g) without further purification.

[0123] Synthesis Example 1. Synthesis of Compounds CPD02 and CPD03

[0124] [ka] Step 1, Synthesis of Compound 6 A mixture of Intermediate A3 (550.0 mg, 1.9 mmol, 1.0 eq), X-phos (190.7 mg, 0.4 mmol, 0.2 eq), (R)-octahydropyrrolo[1,2-A]pyrazine (718 mg, 5.7 mmol, 3 eq), and Cs2CO3 (1.2 g, 3.8 mmol, 2.0 eq) was added to 1,4-dioxane (55 mL). Pd2(dba)3 (183.1 mg, 0.2 mmol, 0.1 eq) was added at room temperature. The reaction mixture was purged with N2 three times and heated to 90 °C under N2 protection for 6 h. The reaction mixture was cooled to room temperature, concentrated, and then 15 mL of water was added. The mixture was extracted three times with dichloromethane. The organic phase was washed three times with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was removed by rotary evaporation to give the crude product, which was purified by column chromatography to give a pale yellow solid compound 6 (370 mg, 58.1%). LCMS: 332.1 ([M+H] + ).

[0125] Step 2, Synthesis of Compound 7 Compound 6 (370.0 mg, 1.1 mmol, 1.0 eq) was dissolved in ethyl acetate (7.4 mL) and Pd / C (148.0 mg, 40% wt) was added. The reaction was carried out overnight at room temperature under H protection, the catalyst was filtered, and the mixture was concentrated to give crude compound 7 (300 mg), which was used directly in the next reaction without further purification. LCMS: 302.7 ([M+H] + ).

[0126] Step 3, Synthesis of Compound 8 In a glove box, to a mixture of Intermediate A2 (120.0 mg, 0.29 mmol, 1.0 eq), Compound 7 (174.6 mg, 0.58 mmol, 2.0 eq), K2CO3 (120.1 mg, 0.87 mmol, 3.0 eq), BINAP (72.2 mg, 0.12 mmol, 0.4 eq), and Pd(OAc)2 (9.7 mg, 0.06 mmol, 0.2 eq) was added DMF (2 mL). The mixture was then reacted under N2 protection at 120 °C for 4 h. The reaction was monitored by LCMS until Intermediate A2 was completely reacted. The reaction temperature was then returned to room temperature, water (10 mL) was added, and the mixture was extracted three times with EtOAc. The organic phase was washed three times with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off and the solvent was removed by rotary evaporation to give the crude product, which was purified by column chromatography to give a brown oil, Compound 8 (100 mg, 58.7%). LCMS: 588.2 ([M+H] + ).

[0127] Step 4, Synthesis of Compound 9 Compound 8 (100 mg, 0.17 mmol, 1.0 eq) was dissolved in MeOH (1 mL), THF (1 mL), and HO (1 mL). KOH (19.0 mg, 0.34 mmol, 2.0 eq) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was added with 5 mL of water and extracted three times with ethyl acetate. The aqueous phase was lyophilized to give crude compound 9 (80 mg) as a gray color. LCMS: 560.2 ([M-K+H+H]+, acidic signal).

[0128] Step 5, Synthesis of Compound CPD02 Compound 9 (80 mg, 0.14 mmol, 1.0 eq) was dissolved in DMF (2 mL), and EDCI (80.2 mg, 0.42 mmol, 3.0 eq) and Intermediate A4 (63.8 mg, 0.42 mmol, 3.0 eq) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was monitored by HPLC until the compound 9 was no longer present. 10 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the solvent was removed by rotary evaporation to give the crude product. This crude product was purified by preparative HPLC (mobile phase: acetonitrile, 0.1% formic acid, 5%-35% water) and lyophilized to give CPD02 (10.0 mg, 10.5% yield for two steps). 1 H NMR (400MHz, DMSO-d6):δ ppm8.85(s, 1H), 8.33(s, 1H), 7.43(s, 1H), 7.31-7.23(m, 3H), 6.80(dd, J=9.2, 2 .1Hz, 1H), 4.62(t, J=5.2Hz, 2H), 3.76(d, J=9.6Hz, 1H), 3.70-3.58(m, 3H), 3.10- 2.90(m, 4H), 2.85-2.69(m, 3H), 2.42(t, J=10.4Hz, 1H), 2.21(td, J=11.2, 3.2Hz, 1H), 2.13-1.95(m, 2H), 1.90-1.76(m, 1H), 1.76-1.60(m, 2H), 1.45-1.27(m, 1H). LCMS:559.1([M+H] + ).

[0129] The synthesis of compound CPD03 is similar to that of CPD02, and the structural spectrum is 1H NMR (300 MHz, DMSO-d): δ ppm8.86(brs, 1H), 8.34(s, 1H), 7.44(s, 1H), 7.29-7.15(m, 3H), 6.80(dd, J=9.1, 2.9Hz, 1H), 4.66-4.54(m, 3H), 3.80-3.70(m, 1H), 3.68-3.54( m, 3H), 3.08-2.93(m, 4H), 2.83-2.69(m, 3H), 2.31-2.22(m, 1H), 2.22-2 .14(m, 1H), 2.09-1.96(m, 2H), 1.86-1.64(m, 3H), 1.43-1.29(m, 1H). LCMS: 559.3 ([M+H] + ).

[0130] Synthesis Example 2. Synthesis of Compound CPD04

[0131] [ka] Step 1: Composition of A10 5-Bromo-2-trifluoromethoxyaniline A9 (10.0 g, 39.0 mmol) was dissolved in EtOH (30 mL) and added dropwise to a solution containing cyanamide (3.28 g, 78 mmol), EtOH (10 mL), and HO (2 mL). A mixture of 37% HCl (6.5 mL) and EtOH (20 mL) was added dropwise to the mixture and refluxed for 5 days. The reaction mixture was cooled to room temperature, concentrated, diluted with water, and diluted with 1N NaOH until the reaction mixture became alkaline. The mixture was extracted several times with ethyl acetate, dried over sodium sulfate, and concentrated to give A10 (3.2 g, 27%).

[0132] Step 2, Synthesis of Intermediate 10 A10 (29.3 g, 98.3 mmol, 1.2 eq) was dissolved in DMF (400 mL), and a DMF solution (200 mL) of intermediate INT-A (24 g, 81.9 mmol, 1.0 eq) was added. The reaction mixture was reacted at 110 °C for 16 hours, then cooled to room temperature, poured into ice water, and the insoluble matter was filtered to give compound 10 (21.2 g, 50%) as a white solid. LCMS: 528.2, 530.2 ([M+H] + ).

[0133] Step 3, Synthesis of intermediate compound 11 Compound 10 (21.2 g, 40.1 mmol, 1.0 eq) was dissolved in THF (500 mL), and NH4Cl (6.44 g, 120 mmol, 3.0 eq) and LiHMDS (240 mmol, 6.0 eq) were added and stirred at room temperature for 30 min. The solvent was removed by rotary evaporation, and the residue was washed with water and dried to give compound 11 (16.8 g, 81.8%) as a white solid. LCMS: 513.1, 515.1 ([M+H] + ).

[0134] Step 4, Synthesis of CPD04 To a mixture of compound 11 (2.0 g, 3.9 mmol, 1.0 eq), Intermediate A8 (1.26 g, 6.25 mmol, 1.6 eq), Pd2(dba)3 (285 mg, 0.312 mmol, 0.08 eq), and Davephos (123 mg, 0.312 mmol, 0.08 eq), THF (100 mL) and LiHMDSLi (40 mL, 40 mmol) were added. The mixture was reacted at 100 °C for 2 h. Water was added to quench the reaction, and the reaction solution was extracted with EtOAc (50 mL × 3). The organic phases were combined, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to give the desired product, CPD04 (1 g, 45.6%), as a white solid. LCMS: 563.3 ([M+H] + . 1 H NMR (400MHz, Methanol-d4) δ 8.30(s, 1H), 7.57(d, 1H), 7.26(dd, 1H), 6.85(dd, 1H), 4.79(t, 2H), 3.84(t, 2H), 3.69(d, 1H), 3.47(dt, 1H), 3.23(d, 1H), 3.07(q, 3H), 2.88(t, 2H), 2.20(dt, 1H), 2.14-2.05(m, 2H), 1.97(s, 1H), 1.85(q, 1H).

[0135] Synthesis Example 3. Synthesis of Compound CPD06

[0136] [ka] To a mixture of compound 11 (2.0 g, 3.9 mmol, 1.0 eq), N-methylpiperazine-2,2,3,3,5,5,6,6-D8 hydrochloride (1.13 g, 6.25 mmol, 1.6 eq), Pd2(dba)3 (285 mg, 0.312 mmol, 0.08 eq), and Davephos (123 mg, 0.312 mmol, 0.08 eq) was added THF (100 mL) and LiHMDS (40 mL, 40 mmol). The mixture was reacted at 100 °C for 2 h. The reaction was quenched by adding water, and the reaction mixture was extracted with EtOAc (50 mL × 3). The organic phases were combined, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to give the desired product, CPD06 (1 g, 47.4%), as a white solid. LCMS: 541.3 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ ppm8.92(s, 1H), 8.34(s, 1H), 7.45(bs, 1H), 7.27-7.21(m, 3H), 6.80(dd, 1) H), 4.62(q, 3H), 3.62(q, 2H), 2.97(t, 2H), 2.79(t, 2H), 2.49-2.32(m, 3H).

[0137] Test Example 1. Pharmacokinetic studies in mice The purpose of this study was to investigate the pharmacokinetic properties of compounds of the present disclosure after intravenous (IV) and oral administration (PO) in female CD1 mice. Plasma samples were collected at 0, 0.083, 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration to the mice. Plasma drug concentrations at each time point were detected by LC-MS / MS, and relevant pharmacokinetic parameters were calculated using WinNonlin software.

[0138] 1.1. Test materials 1.1.1 Information on the reagents and equipment used in this example is as follows:

[0139] [Table 2]

[0140] [Table 3] 1.1.2 Test animals: Female CD1 mice used in the experiments were purchased from Speifuku Laboratory Animal Technology Co., Ltd., aged 6-8 weeks and weighing 20-30 g. They were housed in a controlled environment (temperature set at 20-25°C, relative humidity set at 40-70%). They were maintained on a 12-hour light / 12-hour dark cycle unless interrupted by a study-related event.

[0141] 1.2. Testing steps 1.2.1 Preparation of experimental compound solutions The positive control compound used in this example is NMS-P937, whose structural formula is as follows:

[0142] [ka] The compound solutions were prepared in a clean bench and used immediately after preparation. They were mixed uniformly before use to ensure the uniformity of the formulation. The specific compound preparation methods are shown in the following table:

[0143] [Table 4]

[0144] [Table 5] 1.2.2 Administration method Administration method: IV Solvent composition: 10% DMSO + 90% (20% SBE-β-CD)

[0145] [Table 6] Administration method: PO Solvent composition: 10% DMSO + 90% (20% SBE-β-CD)

[0146] [Table 7] Solvent ratio: 0.5%MC+1%Tween-20

[0147] [Table 8] 1.2.3 Drug administration and blood sample collection schedule Before the experiment, the animals were randomly divided into groups. The mice were fasted for 12 hours before administration and allowed to eat freely again 4 hours after administration. The animal group allocation and blood sampling time points are shown in the table below.

[0148] [Table 9] All blood samples were transferred to plastic microcentrifuge tubes containing anticoagulant (EDTA-K2) and centrifuged at 4000 g for 5 min at 4°C, the supernatant was transferred to microcentrifuge tubes without anticoagulant, and the plasma was stored in a refrigerator at −75 ± 15°C for detection.

[0149] 1.3. Data and Results The collected blood samples were purified by HPLC and analyzed with mass spectrometry detection to obtain plasma concentration-time curves of the compounds of the present disclosure.

[0150] Here, for compounds CPD02 and CPD03, a Waters ACQUITY HPLC system was used, and the HPLC purification conditions were as follows:

[0151] [Table 10] Here, for compounds CPD04 and CPD06, an HPLC apparatus AB SHIMADZU LC-30AD was used, and the HPLC purification conditions were as follows:

[0152] [Table 11] Pharmacokinetic parameters were estimated by non-compartmental modeling (calculated using Phoenix WinNonlin software). IV pharmacokinetic parameters included CL, T 1 / 2 , C0, AUC, MRT, Vss, and PO pharmacokinetic parameters include T 1 / 2 , T max , C max , AUC, MRT, etc.

[0153] The formula for calculating bioavailability F is as follows:

[0154]

number

[0155] [Table 12] Table 10. Pharmacokinetic parameters of intravenous administration in SD mice

[0156] [Table 13] As can be seen from the pharmacokinetic data, the compounds of the present disclosure have suitable half-lives in mice, and the oral bioavailability of the stereodesigned R-configured molecule CPD02 is significantly higher than that of the S-configured molecule CPD03 and higher than that of NMS-P937. Furthermore, the bioavailability of the deuterated compounds is significantly higher than that of the non-deuterated compounds (CPD04 vs. CPD02, CPD06 vs. NMS-P937).

[0157] Test Example 2. Growth inhibitory activity against cell line PSN1 2.1. Test materials The reagents and equipment used in this example are listed below:

[0158] [Table 14]

[0159] [Table 15]

[0160] [Table 16]

[0161] [Table 17] 2.2 Test Method Day 0: Seeding on plates a) Adherent cells require digestion and centrifugation, whereas suspension cells can be centrifuged directly.

[0162] b) Suspend in complete medium and count using an automated cell counter.

[0163] c) PSN1 cells were seeded at 6000 cells per well and the cell suspension was diluted to the required density.

[0164] d) 100 μL of cells were seeded into each well and incubated overnight at 37°C in a 5% CO2 incubator to stabilize and balance the cells.

[0165] Day 1: Compound preparation and addition a) Compounds were prepared in DMSO to a concentration 200 times the final concentration.

[0166] b) 200x compounds were diluted in complete medium to 3x the final concentration.

[0167] c) 50 μL of compound was added to each well, and the same volume of culture medium was added to the control wells. The wells were incubated at 37°C, 5% CO₂ The cells were cultured in a CO2 incubator for 72 hours.

[0168] Day 4: Detection a) The cell plate and CTG reagent were equilibrated to room temperature.

[0169] b) 30 μL of CellTiter-Glo® Reagent was added to each well.

[0170] c) Allowed to stand at room temperature for 15 minutes.

[0171] d) Detected by ELISA device. Data analysis 1) Using GraphPad Prism 8 to calculate IC 50 was calculated.

[0172] 2)%Inh=(1-(Raw data-Mean min ) / (Mean max -Mean min ))×100.

[0173] 3) Mean max are positive control wells to which only cells and the same volume of culture medium are added.

[0174] 4) Mean min are negative control wells receiving culture medium only.

[0175] 5) Raw data is the sum of the signal values ​​of the compound wells, and if two wells overlap, they are designated as Raw1 and Raw2.

[0176] 2.3 Test Results Half-inhibitory concentration IC of compounds of the present disclosure on PSN1 cell proliferation 50 is shown in Table 16.

[0177] [Table 18] Table 16. IC of compounds of the present disclosure against PSN1 cell proliferation 50 The results of the cell proliferation inhibition test showed that the compounds of the present disclosure exhibited significant inhibitory effects on the proliferation of pancreatic cancer cell line (PSN1), and the sensitivity of the stereochemically designed R-configuration molecule CPD02 was higher than that of the S-configuration molecule CPD03. No significant difference was observed in the biological activity (PSN1) between the deuterated and non-deuterated compounds (CPD04 vs. CPD02, CPD06 vs. NMS-P937).

[0178] Test Example 3. Evaluation of metabolic stability of liver microsomes 3.1. Test Materials The materials used in this example are listed in Tables 17-19 below:

[0179] [Table 19]

[0180] [Table 20]

[0181] [Table 21] 3.2. Test Method 3.2.1 Preparation of reagents

[0182] [Table 22] 3.2.2 Experimental procedures 1) A 0.6289 mg / ml microsome solution was prepared in PBS.

[0183] 2) 318 μL of 0.6289 mg / mL microsome solution was added to each well of a 96-well incubation plate.

[0184] 3) Add 40 μL of 10 mM NADPH solution and 40 μL of 20 mM UDPGA solution to the incubation plate. For negative samples, add 80 μL of PBS (100 mM, pH = 7.4) solution, vortex at 800 rpm for 10 seconds, and pre-incubate in a 37 °C water bath for 10 minutes.

[0185] 4) After pre-incubation, 2 μL of a control drug or test compound was added to each well to initiate the reaction, which was then allowed to proceed in a water bath at 37° C. at 60 rpm.

[0186] 5) After 0.5, 15, 30, 45, and 60 minutes, 50 μL of the reaction mixture per well was removed and added to 200 μL of cold methanol solution containing an internal standard to terminate the reaction.

[0187] 6) The mixture was mixed evenly and centrifuged at 4°C and 4000 rpm for 30 minutes.

[0188] 7) 100 μL of the supernatant was taken and mixed uniformly with 100 μL of ultrapure water for liquid mass spectrometry.

[0189] *Internal standards: 50nM alprazolam, 50nM labetalol, and 100nM ketoprofen 3.2.3 Data Processing When the internal standard method is used, the remaining percentage is calculated from the ratio of the sample peak area to the internal standard peak area (the ratio of the sample peak area to the internal standard peak area after 0.5 minutes is 100%).

[0190] The natural logarithm of the percentage remaining is plotted against incubation time, and the slope of the line is the elimination rate constant (k).

[0191] t12min=-0.693k

[0192]

number

[0193] [Table 23-1]

[0194] [Table 23-2] Conclusion: The compounds of the present disclosure have moderate in vitro clearance values. Test Example 4. Evaluation of permeability of test substance and transporter substrate test 4.1. Test Materials 4.1.1 Compound information

[0195] [Table 24] 4.1.2 Positive Control Information

[0196] [Table 25] 4.2. Test Method 4.2.1 Caco-2 cell culture a) 50 μL and 25 mL of cell culture medium were added to the upper and lower chambers of each well of a Transwell plate, respectively.

[0197] b) Transwell plates were pre-incubated at 37°C, 5% CO2 for 1 hour before seeding the cells.

[0198] c) Density 2×10 5 50 μL of the cell suspension at 1000 cells / mL was seeded in the upper chamber and cultured in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity for 14 to 21 days, with the medium changed every 2 days.

[0199] d) Cell culture medium was changed every other day for 7 days, and then changed daily after 7 days.

[0200] e) Electrical resistance (TEER) on the monolayer was measured using EVOM3.

[0201] 4.2.2 ABBA measurement process a) Transwell plates were washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4) and then incubated at 37°C for 30 minutes.

[0202] b) A 1 mM DMSO stock solution of the test compound was prepared and diluted 200-fold with buffer (pH 7.2-7.4) to 5 μM.

[0203] c) From side A to side B: Add 75 µL of 5 µM working solution to the upper chamber and 235 µL of HBSS (10 mM HEPES, pH 7.4) to the lower chamber.

[0204] d) From B to A side: 235 µL of 5 µM working solution was added to the lower chamber and 75 µL of HBSS (10 mM HEPES, pH 7.4) was added to the upper chamber.

[0205] e) 50 μL of the 5 μM working solution was transferred to a sample plate containing 200 μL of pre-chilled methanol internal standard samples as the zero point.

[0206] f) Incubated for 2 hours at 37°C, 5% CO2, and 95% relative humidity.

[0207] g) After 2 hours of incubation, 50 μL was transferred from each well to a sample plate containing 200 μL of methanol internal standard.

[0208] h) The sample plate was centrifuged at 4000 rpm for 30 minutes.

[0209] i) 100 μL of the supernatant was transferred to an assay plate containing 100 μL of water, centrifuged for 10 minutes, and then subjected to LC-MS / MS analysis.

[0210] 4.2.3 Data analysis Apparent permeability coefficient (Papp, cm / s) and efflux ratio were calculated using Microsoft Excel.

[0211]

number

[0212] [Table 26] 4.4 Test results The permeability results of compounds of the present disclosure in Caco-2 cells are shown in Table 21.

[0213] [Table 27] Test Example 5. Solubility Test Evaluation of Test Substances 5.1. Test materials

[0214] [Table 28] 5.2. Test Method 5.2.1 Preparation of the buffer 7.098 g of NaHPO (solution A) was weighed and dissolved in 500 mL of ultrapure water and sonicated. 3.40 g of KHPO (solution B) was weighed and dissolved in 250 mL of ultrapure water and sonicated. Solution B was slowly added dropwise to solution A, and the pH was adjusted to 7.40 ± 0.05.

[0215] 5.2.2 Test operation a) Weigh approximately 1.0 mg of compound into three separate 1.5 mL glass vials (one vial will be used to prepare the standard solution, and the other two vials will be used for solubility testing).

[0216] b) Add an appropriate volume (approximately 1000 μL) of assay buffer to each vial of solubility sample to achieve a final concentration of 1 mg / mL.

[0217] c) A PTFE-encapsulated stainless steel stick stirrer was placed in each vial and the vials were sealed with PTFE / SIL silicone stoppers.

[0218] d) Solubility The sample plate was transferred to a Thermomixer Comfort plate shaker and shaken at 1100 rpm and 25°C for 24 hours.

[0219] e) After 24 hours, the stir bar was removed using a magnet.

[0220] f) 200 μL of sample was pipetted onto a filter plate, filtered and the filtrate was collected.

[0221] g) 10 μL of the filtered sample and 10 μL of DMSO were added to 980 μL of methanol, and the mixture was further diluted 10-fold with methanol:water (1:1) to be used as the filtered sample for LC-MS / MS analysis.

[0222] h) For the standard sample, DMSO was added to a final concentration of 1.0 mg / mL. The sample was shaken at 1100 rpm at 25°C for 5 minutes.

[0223] i) 10 μL of 1 mg / mL DMSO sample and 10 μL of buffer were added to 980 μL of methanol, which was then diluted 10-fold with methanol:water (1:1) and used as the filtered sample for LC-MS / MS analysis.

[0224] 5.2.3 Data Processing The solubility was calculated using Excel.

[0225]

number

[0226] [Table 29] 5.4. Test Results The compounds of the present disclosure have solubility comparable to that of NMS-P937.

[0227] Test Example 6. Pharmacodynamic study of compounds against colorectal cancer in mice 6.1. Test materials Balb / c nude mouse, SPF grade, female, age 6~8w, weight 16~20g, Sigaifu (Beijing) Biotechnology Co., Ltd. HCT116 cells were purchased from ATCC.

[0228] The reagents and equipment used in the in vivo efficacy studies are listed in Tables 23 and 24.

[0229] [Table 30]

[0230] [Table 31] 6.2. Test Method 6.2.1 Cell culture HCT116 cells were cultured in RPMI-1640 medium containing 10% inactivated fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin, and 2 mM glutamine in a 5% CO2 incubator at 37°C. The cells were subcultured in vials until they reached saturation. Tumor cells in the logarithmic growth phase were used for inoculation of tumors in vivo.

[0231] 6.2.2 Tumor cell inoculation and grouping Tumor cells were washed twice with PBS and the cell concentration was adjusted to 5 × 10 7 The tumor cells were adjusted to 100 μl / mouse, i.e., 5 × 10 cells / ml, and resuspended. The cells were then injected into the right flank of the experimental animals at 100 μl / mouse, i.e., 5 × 10 cells / ml. 6 The tumors were subcutaneously inoculated into mice. The average tumor volume was 100-150 mm. 3 Once the tumors had grown to 100 mg / kg, they were divided into groups according to tumor volume and administered. There were a total of 7 groups, with 8 mice per group. The specific administration schedule is shown in Table 25. The first day of administration was designated as PG-D0.

[0232] [Table 32] Note: The dose is 10 μl / g. Po: Intragastric administration. qd: Once daily for 10 consecutive days. 6.2.3 Dose Adjustment or Suspension During the administration period, the health condition of the animals will be closely monitored, and administration will be suspended if any of the following situations occur:

[0233] 1) If the animal's weight falls below 85% of the weight at the start of drug treatment, administration will be stopped and continued after the weight has recovered to 90% of the weight at the start of drug treatment.

[0234] 2) If the animal shows progressive behavioral retardation or abnormalities (such as hypothermia, difficulty breathing, diarrhea, hunched posture, convulsions, etc.) after administration, continue administration after the animal's behavior and general condition have returned to normal.

[0235] 6.2.4 Humane endpoints for experimental animals During an experiment, animals should be euthanized using CO2 if any of the following situations occur: 1) The animal appears to be behaving abnormally or paralyzed and is unable to eat or drink on its own.

[0236] 2) If the animal loses more than 20% of its weight at the start of drug treatment, the veterinarian determines that this will have a significant impact on the welfare of the animal and / or the normal conduct of the experiment.

[0237] 6.2.5 Euthanasia of Experimental Animals At the end of the experiment or when a humane endpoint is achieved, animals are euthanized using CO2.

[0238] 6.2.6 Detection indicators General Observations After dividing into groups, the animals are observed once a day until the end of the experiment, and the observations include, but are not limited to, tumor inoculation site, mental state of the animals, feeding, and exercise status.

[0239] Weight detection After group division, the mice are weighed using an electronic balance every 3 days until the end of the experiment.

[0240] Tumor volume After dividing the mice into groups, the major and minor diameters of the tumors were measured every three days using electronic calipers until the end of the experiment. The calculation formula was: volume (TV) = 0.5 × major diameter × minor diameter. 2 is.

[0241] Tumor imaging After the experiment is completed, the mice are euthanized, the tumors are excised, and the excised tumors from the control and test groups are left in an orderly manner and photographed.

[0242] 6.2.7 Drug Evaluation Index Tumor growth inhibition rate (TGI) TV (%) Tumor growth inhibition rate (%)=(1-T / C)×100% T / C = mean RTV of treatment group / mean RTV of control group RTV is the relative tumor volume, ie, the ratio of the tumor volume after administration to the tumor volume before administration.

[0243] A tumor growth inhibition rate of ≥ 30% and p < 0.05 was considered statistically significant.

[0244] Tumor weight inhibition rate TGITw (%) Tumor weight suppression rate (%)=(1-T / C)×100% T / C = mean TW of treatment group / mean TW of control group TW is the tumor weight.

[0245] A tumor weight inhibition rate of ≥ 30% and p < 0.05 was considered statistically significant.

[0246] 6.2.8 Statistical analysis Statistical analysis of tumor volume and tumor weight was performed using Graphpad Prism 8 statistical software applying One-Way ANOVA test (when variances are homogeneous), with p<0.05 considered to be significant.

[0247] 6.3 Test Results 6.3.1 Tumor-inhibitory effects of test drugs in a mouse model with subcutaneously transplanted HCT116 tumors As shown in Figure 2, mice were orally administered PG-D22 for 10 days. Compared with the vehicle group, the 60 mg / kg CPD04 group, 30 mg / kg and 60 mg / kg CPD06, and NMS-P937 groups were able to significantly inhibit tumor growth in mice. The tumor-inhibitory effects of CPD04, CPD06, and NMS-P937 groups were dose-dependent, and the tumor growth inhibition rate (TGI) of each group was significantly higher. TV ) are shown in Table 26.

[0248] [Table 33] 6.3.2 Safety of Test Drugs in the HCT116 Subcutaneous Tumor Mouse Model As shown in Figure 3, during the treatment period, three mice in the NMS-P937 60 mg / kg group died due to the effects of PG-D12 and PG-D16, respectively. The weight of the mice in the NMS-P937 group fluctuated greatly, and the weight loss was thought to be due to the low tolerance of tumor-bearing mice to NMS-P937. After the administration was stopped, the symptoms of some animals did not improve in a timely manner and led to death. In other groups, the weight loss during the treatment period was less than 10%.

[0249] 6.4. Test Conclusions As mentioned above, in the HCT116 subcutaneous tumor mouse model, CPD04, CPD06, and NMS-P937 treatment groups inhibited tumor growth in a dose-dependent manner. The CPD06 60 mg / kg treatment group showed a significantly superior tumor growth inhibitory effect compared to the other treatment groups, and TGI TV The toxicity was also significantly superior to that of NMS-P937 at the same dose (3 out of 8 mice died in the NMS-P937 group at the same dose).

[0250] Test Example 7. Pharmacodynamic study of compounds against pancreatic cancer in mice 7.1. Test Materials The pancreatic cancer cell line BxPC-3 was purchased from ATCC, and other experimental materials and equipment were the same as in Example 9. 7.2. Test Method The dosing schedule is shown in Table 27, and other test methods are the same as in Example 9.

[0251] [Table 34] 7.3 Test Results 7.3.1 Antitumor Effect of Test Drugs in BxPC-3 Subcutaneously Xenografted Tumor Mouse Model As shown in Figure 4, after 10 days of oral administration to mice, each treatment group was able to significantly (p<0.0001) inhibit tumor growth in mice compared with the vehicle group at the end of the experiment. Different doses of CPD06 showed a dose-dependent effect on the inhibition of pancreatic tumors, and the tumor growth inhibition rate (TGI) of each group was significantly higher. TV ) are shown in Table 28.

[0252] [Table 35] 7.3.2 Safety of Test Drugs in the BxPC-3 Subcutaneous Tumor Mouse Model As shown in Figure 5, during the treatment period, two mice in the NMS-P937 60 mg / kg group died due to the effects of PG-D9 and PG-D19, respectively. The weight of the mice in the NMS-P937 group fluctuated greatly, and the weight loss was thought to be due to the low tolerance of tumor-bearing mice to NMS-P937. After administration was stopped, some animals' symptoms did not improve in a timely manner and they died. In the other groups, the weight remained relatively stable during the treatment period, with a loss of less than 10%, and their weight recovered quickly after administration was stopped.

[0253] 7.4. Test Conclusions As mentioned above, in the BxPC-3 subcutaneous tumor-implanted mouse model, each CPD06 administration group inhibited tumor growth in mice in a dose-dependent manner. The CPD06 60 mg / kg administration group showed a significantly superior tumor growth inhibitory effect compared to the other treatment groups, and TGI TV The efficacy was significantly superior to that of NMS-P937 at the same dose, and the toxicity was significantly superior to that of the NMS-P937 group at the same dose. No obvious toxic symptoms were observed during the treatment period in CPD06, but in the NMS-P937 group at the same dose, 2 out of 8 mice died.

[0254] Test Example 8. Pharmacodynamic study of compounds against pancreatic cancer in mice 8.1. Test Materials M-NSG mouse, SPF grade, female, age 6~8w, weight 16~20g, Shanghai Southern Model Biological Science and Technology Co., Ltd.

[0255] PSN1 cells were purchased from ATCC.

[0256] The equipment used in the in vivo efficacy studies is shown in Table 29.

[0257] [Table 36] 8.2. Test Method 8.2.1 Preparation of the drug

[0258] [Table 37] 8.2.2 Cell culture PSN1 cells were cultured in an incubator at 37°C with 5% CO2 in RPMI-1640 culture medium containing 10% inactivated fetal bovine serum. When cells reached growth saturation every 2–3 days, they were subcultured by distributing them onto dishes.

[0259] 8.2.3 Tumor cell inoculation and grouping 8.2.3.1 PSN1 cells in the logarithmic growth phase were harvested and resuspended in PBS. The cell suspension was then subcutaneously inoculated into the right flank of M-NSG mice using a 1 mL syringe (cell number inoculated: 5E6 / mouse + 30% M). The mice were observed every other day for survival and subcutaneous tumor formation.

[0260] 8.2.3.2 On the day of group allocation, mice were placed in groups with a mean tumor volume (approximately 190 mm 3 ) and mice were divided into 8 groups according to their weight, with 8 mice in each group.

[0261] The treatments were administered according to the grouping plan in 8.2.3.3. All treatments were administered intragastrically at a dose of 10 mL / kg, once a day for a total of six doses. The mice's hair and condition were observed twice a week, and their body weight and tumor size were recorded to calculate the TGI%.

[0262] 8.2.3.4 Test Animal Groups The average tumor volume was approximately 190 mm 3 When the tumor volume reached 1000 mg / kg, mice with medium tumor volume were selected and placed into groups. The animals were assigned to experimental groups according to tumor volume and mouse weight, with 8 animals in each group. The administration began the day after the grouping. The specific administration schedule is shown in the table below:

[0263] [Table 38] 8.2.4 Calculation formula Tumor volume (TV) TV=1 / 2×a×b2 Here, a represents the long diameter of the tumor, and b represents the short diameter of the tumor.

[0264] Relative tumor volume (RTV) RTV=V t / Vinitial ×100(%) where V initial When administering to groups (i.e., d inital ) is the tumor volume measured at 1000 mcg / s, and V t is the tumor volume at each measurement.

[0265] Relative tumor proliferation rate T / C (%) T / C(%)=(T RTV / C RTV )×100% where T RTV represents the relative tumor volume of the treatment group, and C RTV represents the relative tumor volume in the vehicle group.

[0266] Tumor volume inhibition rate (TGI) TGI = [1-(TV t -TV initial ) / (CV t -CV initial )] × 100% Here, TV t represents the tumor volume of the treatment group at each measurement, and TV initial represents the tumor volume of the treatment group when administered in groups, and CV t represents the tumor volume of the control group at each measurement, and CV initial represents the tumor volume of the control group when administered in separate groups.

[0267] 8.2.5 Animal Weight Change Rate (BWC) Weight change rate = (BW final -BW initial ) / BW initial ×100% Here, BW initial represents the body weight of the animals at the time of group dosing, and BW final represents the body weight of the animal at each measurement.

[0268] 8.2.6 Data Analysis The original data measured and observed should be recorded. Analysis was performed based on the original data, and the analysis results were expressed as mean ± standard error ((Mean ± SEM). The difference in tumor volume between the control group and the treatment group was analyzed by T-test, with P<0.05 indicating a statistically significant difference.

[0269] 8.3 Test Results 8.3.1 Tumor-inhibitory effects of test drugs in a PSN1 subcutaneous tumor-implanted mouse model As shown in Figure 6, mice were orally administered with NMS-P937 for 6 days. At the end of the study (day 31), each treatment group significantly (p<0.0001) inhibited tumor growth in mice compared with the vehicle group. However, the NMS-P937 60 mg / kg group showed a significant decrease in body weight and half of the mice died, so the TGI could not be calculated. Therefore, the tumor growth inhibition rate (TGI) of each group was calculated. TV ) are shown in Table 30.

[0270] [Table 39] 8.3.2 Safety of Test Drugs in the PSN1 Subcutaneous Tumor Mouse Model As shown in Figure 7, during the treatment period, four mice in the NMS-P937 60 mg / kg group died on days 27 and 31, respectively. At the end of the study, only two mice in the NMS-P937 60 mg / kg group had slightly recovered their body weight. This weight loss was likely due to the tumor-bearing mice's low tolerance to NMS-P937. In the CPD06 60 mg / kg group, no mice died, and weight loss did not exceed 15% during the treatment period. After treatment was stopped, the mice regained their body weight. In the CPD04 90 mg / kg group, no mice died, and no weight loss was observed.

[0271] 8.4. Test Conclusions As mentioned above, CPD06 60mg / kg and CPD04 90mg / kg significantly inhibited tumor growth in the PSN1 subcutaneous tumor transplant mouse model. The CPD06 60mg / kg group showed significantly better tumor growth inhibition effects than the other treatment groups, and TGI TV The toxicity of NMS-P937 at 60 mg / kg in severely immunodeficient mice was much stronger than that of CPD06 at 60 mg / kg and CPD04 at 90 mg / kg, with 4 of 8 mice dying in the NMS-P937 60 mg / kg group.

[0272] The foregoing description merely illustrates the principles of the present disclosure. Moreover, since numerous modifications and changes will be apparent to those skilled in the art, it is not desired to limit the disclosure to the exact structures and processes described above. Accordingly, all suitable modifications and equivalents may be deemed to be included within the scope of the present disclosure as defined by the appended claims.

[0273] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety into this disclosure.

Claims

1. Stereoisomers, deuterated derivatives or stereoisomeric deuterated derivatives of compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, Here, R １ and R ２ are each independently hydrogen, deuterium, deuterated or non-deuterated C １－６ alkyl group, or R １ and R ２ form an optionally substituted deuterated or non-deuterated 5-membered heterocycle together with the N atom and C atom bonded thereto, 【Chemistry 2】 is optionally substituted with one or more deuterium atoms; A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, characterized in that:

2. R １ is deuterated or non-deuterated C １－６ an alkyl group, preferably a methyl group or a deuterated methyl group, more preferably a fully deuterated methyl group; and / or R ２ is hydrogen or deuterium, A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. R １ and R ２ form an optionally substituted 5-membered heterocycle shown below together with the N atom and C atom bonded thereto, 【Transformation 3】 wherein the 5-membered heterocycle is optionally substituted with 1 to 7 deuterium atoms. A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. R １ and R ２ together with the N atom and C atom bonded thereto form an optionally substituted 5-membered heterocycle selected from the following: 【Chemistry 4】 wherein the 5-membered heterocycle is optionally substituted with 1 to 7 deuterium atoms. A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 5】 【Chemistry 5】 is optionally substituted with 1 to 8 deuterium atoms; A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to any one of the above, or a pharmaceutically acceptable salt or solvate thereof.

6. The stereoisomers, deuterated derivatives or stereoisomeric deuterated derivatives of the compounds of formula (I) are 【Transformation 6】 Selected from: A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition comprising a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate thereof, and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition comprising:

8. 10. A method for treating diseases and conditions caused by dysregulated PLK1 activity and / or diseases and conditions associated with PLK1 in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

10. A method for treating diseases and conditions caused by dysregulated PLK1 activity and / or diseases and conditions associated with PLK1 in a subject in need thereof, comprising:

9. The diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma and sepsis.

9. A method for treating diseases and conditions caused by dysregulated PLK1 activity and / or diseases and conditions associated with PLK1 in a subject in need thereof according to claim 8.

10. used to treat diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

11. The diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma, and sepsis. A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, as described in claim 10.

12. 10. Use of a stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of a compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, comprising 1. A use characterized by:

13. The diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma and sepsis.

13. The use according to claim 12.

14. 1. A kit for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, said kit comprising: A stereoisomer, deuterated derivative or stereoisomeric deuterated derivative of the compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 7; A container and and a package insert or label indicating any treatment.

10. A kit for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1, comprising:

15. The diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 are selected from the group consisting of leukemia, lymphoma, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, colorectal cancer, liver cancer, gastric cancer, esophageal cancer, melanoma, multiple myeloma and sepsis. A kit for treating diseases and conditions caused by dysregulation of PLK1 activity and / or diseases and conditions associated with PLK1 according to claim 14.

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