Novel compounds as pkmyt1 inhibitors and uses thereof

Abstract

Disclosed are compounds useful as inhibitors of PKMYT1, or pharmaceutically acceptable salts, stereoisomers or isotope variants thereof, pharmaceutical compositions comprising them and their use in the treatment of PKMYT1-related diseases or disorders, such as cancer.

Description

[0001] Cross-references

[0002] This patent application claims the benefit of International Application No. PCT / CN2023 / 119295, filed on September 18, 2023, the entire contents of which are incorporated herein by reference.

[0003] background

[0004] DNA is constantly subjected to endogenous damage (such as stalled replication forks and reactive oxygen species) and exogenous damage (UV radiation, ionizing radiation, and chemicals), which can lead to DNA damage. As a result, cells have developed complex mechanisms to defend against these harmful events, which would otherwise disrupt genome integrity and lead to genomically unstable diseases such as tumors. To maintain genome integrity, two checkpoints in the cell cycle provide efficient repair of DNA damage, one of which is the WEE kinase family. The WEE kinase family consists of three members: WEE1, PKMYT1, and the less important WEE1B. PKMYT1 acts as a negative regulator of the cell cycle by inhibiting the CDK1-cyclin B complex. As a core regulator of the cell cycle, CDK1 is essential for cells to enter mitosis, meaning that PKMYT1 can be expected to act as a tumor suppressor by preventing CDK1 activation. Studies have shown that PKMYT1 deficiency interferes with the G2-M checkpoint, causing cells to enter mitosis prematurely, leading to the accumulation of genetic disorders caused by unrepaired DNA damage, and ultimately resulting in apoptosis or mitotic catastrophe. However, co-inhibition of WEE1 and PKMYT1 leads to strong cytotoxicity. Therefore, PKMYT1 is a promising target for anticancer therapy. Furthermore, PKMYT1 is involved in many cancer types, including gastric cancer, non-small cell lung cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, and colorectal cancer, where overexpression of PKMYT1 is often associated with poor prognosis and disease progression. Therefore, selectively targeting PKMYT1 with small molecules offers new opportunities for cancer therapy.

[0005] Overview

[0006] This article discloses novel compounds as PKMYT1 inhibitors. As a result, the disclosed compounds are particularly useful in regulating PKMYT1, and thus particularly useful in treating PKMYT1-related diseases and conditions.

[0007] In one aspect, this disclosure provides compounds of formula (V) or pharmaceutically acceptable salts thereof:

[0008] Formula (V), as disclosed herein.

[0009] In one aspect, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0010] Formula (I), as disclosed herein.

[0011] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the compound has formula (Ia):

[0012] Formula (Ia), as disclosed herein.

[0013] This document also discloses pharmaceutical compositions comprising the compounds disclosed herein (e.g., compounds of formula (V), (I), (Ia) or listed in Table 1 or 2) or their pharmaceutically acceptable salts or stereoisomers and pharmaceutically acceptable excipients.

[0014] This document also discloses methods for treating cancer in individuals in need, comprising administering to an individual a compound disclosed herein (e.g., a compound of formula (V), (I), (Ia) or a compound listed in Table 1 or 2) or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition disclosed herein.

[0015] This document also discloses a method for modulating PKMYT1 in an individual, which includes administering to the individual a compound disclosed herein (e.g., a compound of formula (V), (I), (Ia) or a compound listed in Table 1 or 2) or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition disclosed herein.

[0016] This document also discloses a method for inhibiting PKMYT1 in an individual, the method comprising administering to the individual a compound disclosed herein (e.g., a compound of formula (V), (I), (Ia) or a compound listed in Table 1 or 2) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the individual has cancer. In some embodiments, the cancer depends on PKMYT1 activity. In some embodiments, the cancer overexpresses CCNE1. In some embodiments, the cancer has an inactivating mutation in the FBXW7 gene. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, gastric cancer, or uterine cancer.

[0017] This document also discloses pharmaceutical compositions for treating PKMYT1-related diseases or conditions, comprising compounds disclosed herein (e.g., compounds of formula (V), (I), (Ia) or compounds listed in Table 1 or 2) or pharmaceutically acceptable salts or stereoisomers thereof and pharmaceutically acceptable excipients.

[0018] This document also discloses the use of the compounds disclosed herein (e.g., compounds of formula (V), (I), (Ia) or compounds listed in Table 1 or 2) or pharmaceutically acceptable salts or stereoisomers thereof, or pharmaceutical compositions disclosed herein, in the preparation of a medicament for treating PKMYT1-related diseases or conditions such as cancer.

[0019] A medicine box for treating PKMYT1-related diseases or conditions such as cancer, comprising a compound disclosed herein (e.g., a compound of formula (V), (I), (Ia) or a compound listed in Table 1 or 2) or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition disclosed herein, a container, and optionally a packaging insert or label indicating treatment of said disease or condition.

[0020] By incorporating references

[0021] All publications, patents and patent applications listed in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference.

[0022] Detailed description

[0023] definition

[0024] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the disclosed technology can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, the word “comprising” and its variations such as “including” and “containing” throughout the following specification and claims shall be interpreted in an open, inclusive sense, meaning “including but not limited to”. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0025] Throughout this specification, references to "some embodiments" or "implementation" mean that a particular feature, structure, or characteristic associated with that embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Additionally, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural referent unless the content clearly indicates otherwise. It should also be noted that the terms "or" or "or" are generally used to include "and / or" unless the content clearly indicates otherwise.

[0026] Unless otherwise indicated, the following terms as used herein have the following meanings.

[0027] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally as defined therein. Additionally, general principles of organic chemistry and descriptions of specific functional group components and reactivity are found in the following references: Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March, March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004; the entire contents of each are incorporated herein by reference.

[0028] Linking substituents are described in various parts of this disclosure. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", then "alkyl" should be understood to mean a linked alkylene group.

[0029] When a substituent is shown as a bond passing through two atoms in the linking ring, the substituent can bond to any atom in the ring. When a substituent is listed without specifying the atoms through which such a substituent bonds with the remainder of a compound of a given general formula, the substituent can bond to any atom in that general formula. Combinations of substituents and / or variables are permitted, provided that only such combinations produce a stable compound.

[0030] When any variable (e.g., R) i When a group appears more than once in any component or general formula of a compound, its definition for each occurrence is independent of its definition for any other occurrence. Thus, for example, if the group is shown as being surrounded by 0-2 R... i In the case of partial substitution, the group can optionally be replaced by up to two R groups. i Partial replacement, and R i Each time it appears, it is selected independently from R. i The definition of [the compound]. Furthermore, combinations of substituents and / or variables are permitted, provided that only such combinations produce a stable compound.

[0031] As used in this article, the term "C" i -C j "C" represents a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point in between, where j is greater than i. For example, C1-C6 represents a range of 1-6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some implementations, the term "C" is used to indicate the range of carbon atoms. 1-12 "Indicates 1-12, especially 1-10, especially 1-8, especially 1-6, especially 1-5, especially 1-4, especially 1-3 or especially 1-2 carbon atoms.

[0032] "Oxytochemical" refers to the compound oxygen (O).

[0033] Whether used as part of another term or independently, "amino" refers to the -NR group. a R b , where R a and R b The group is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl or other suitable organic groups, and each of these groups may optionally be substituted.

[0034] Whether used as part of another term or independently, "hydroxyl group" refers to -OH.

[0035] Whether used as part of another term or independently, "alkyl" refers to a straight-chain or branched monovalent group of a saturated hydrocarbon having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups, such as heptyl, octyl, etc. Wherever it appears in this document, numerical ranges such as "C1-C6 alkyl" or "C1-6 alkyl" refer to alkyl groups that can be composed of 1, 2, 3, 4, 5, or 6 carbon atoms. However, this definition also covers the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group is C1- 10 Alkyl group. In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C1-5 alkyl. In some embodiments, the alkyl group is C1-4 alkyl. In some embodiments, the alkyl group is C1-3 alkyl. Unless otherwise stated in this specification, the alkyl group may optionally be substituted, for example, substituted by one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group is optionally substituted by one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted by one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with a halogen.

[0036] An alkylidenyl group is a divalent group formed from an alkane by removing two hydrogen atoms from the same carbon atom. Its free valence is the double bond attached to the rest of the molecule. For example, in the following compounds:

[0037] The alkyl subunits are enclosed in boxes as indicated by arrows.

[0038] Whether used as part of another term or independently, "alkenyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group can be in cis or trans configuration, or, regarding the double bond... E or Z The configuration, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Wherever it appears herein, numerical ranges such as “C2-C6 alkenyl” or “C2-6 alkenyl” mean that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms; however, this definition also covers the occurrence of the term “alkenyl” where no numerical range is specified. Unless otherwise expressly stated in this specification, the alkenyl group may optionally be substituted, for example, by one or more substituents such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with a halogen.

[0039] Whether used as part of another term or independently, "alkynyl" refers to a straight-chain or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Wherever it appears herein, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" refer to an alkynyl group that can be composed of 2, 3, 4, 5, or 6 carbon atoms; however, this definition also covers the occurrence of the term "alkynyl" where no numerical range is specified. Unless otherwise expressly stated in this specification, the alkynyl group may optionally be substituted, for example, by one or more substituents such as oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted with one or more substituents, such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with one or more substituents, such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0040] Whether used as part of another term or independently, "alkoxy" refers to the formula -OR a The group, wherein R a Alkyl groups are defined as such. Wherever they appear herein, numerical ranges such as “C1-C6 alkoxy” or “C1-6 alkoxy” refer to alkyl groups that can consist of 1, 2, 3, 4, 5, or 6 carbon atoms; however, this definition also covers the occurrence of the term “alkoxy” where no numerical range is specified. In some embodiments, the alkoxy group is C1- 10Alkoxy group. In some embodiments, the alkoxy group is C1-6 alkoxy. In some embodiments, the alkoxy group is C1-5 alkoxy. In some embodiments, the alkoxy group is C1-4 alkoxy. In some embodiments, the alkyl group is C1-3 alkoxy. In some embodiments, the alkyl group is C1-2 alkoxy. In some embodiments, the alkyl group is methoxy. Unless otherwise expressly stated in this specification, the alkoxy group may optionally be substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted by halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted by halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted by halogen.

[0041] Whether used as part of another term or independently, "aryl" refers to a group derived from a hydrocarbon ring system comprising 6-30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) ring system, which can include fused (e.g., fused with a cycloalkyl, heterocyclic, or heteroaryl ring, wherein the aryl group is bonded by aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is 6- to 10-membered aryl. In some embodiments, the aryl group is 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, naphthylene, phenanthrylene, anthracene, azurite, benzene, phenanthrylene, fluorene, as-indacene, s-indacene, indene, indene, naphthalene, phenalene, pleiadene, pyrene, and triphenylene[9,10]. Unless otherwise expressly stated in this specification, aryl groups may optionally be substituted, for example, by one or more substituents such as halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted with one or more substituents, such as halogens, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with one or more substituents, such as halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with a halogen.

[0042] "Aminoalkyl" refers to an alkyl group as defined above, which is substituted with one or more amino groups. In some embodiments, the alkyl group is substituted with one amino group. In some embodiments, the alkyl group is substituted with one, two, or three amino groups. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0043] Whether used as part of another term or independently, "cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (e.g., fused with a heterocyclic alkyl ring or another cycloalkyl ring), spirocyclic, or bridged ring systems. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated. Representative cycloalkyl groups include, but are not limited to, those having 3-15 carbon atoms (C3-C4). 15 cycloalkyl groups, 3-10 carbon atoms (C3-C4) 10 Cycloalkyl groups are 3-8 carbon atoms (C3-C8 cycloalkyl), 3-6 carbon atoms (C3-C6 cycloalkyl), 3-5 carbon atoms (C3-C5 cycloalkyl), or 3-4 carbon atoms (C3-C4 cycloalkyl). Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethylbicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in this specification, the cycloalkyl group is optionally substituted, for example, by one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted by a halogen.

[0044] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine.

[0045] "Halogenated alkyl" refers to an alkyl group as defined above, which is substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0046] "Hydroxyalkyl" refers to an alkyl group as defined above, which is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0047] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise expressly stated in this specification, heteroalkyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with halogen.

[0048] "Heteroalkenyl" refers to an alkenyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The heteroalkenyl group is attached to the rest of the molecule at the carbon atom of the heteroalkenyl group. In one aspect, the heteroalkenyl group is a C2-C6 heteroalkenyl group, wherein the heteroalkenyl group consists of 2-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, wherein the heteroalkenyl group is attached to the rest of the molecule at the carbon atom of the heteroalkenyl group. Examples of such heteroalkenyl groups are, for example, -CH=CHOCH3, -CH=CHOCH2CH2OCH3, -CH2CH2OCH=CHOCH3, -C(=CH2)OCH3, -CH=NCH3, -CH2N=CH2, -CH=CHNHCH3, or -CH=CHN(CH3)2. Unless otherwise expressly stated in this specification, the heteroalkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkenyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkenyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkenyl group is optionally substituted with halogen.

[0049] "Hydynyl" refers to an ynyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The ynylyl group is attached to the rest of the molecule at the carbon atom of the ynylyl group. In one aspect, the ynylyl group is a C2-C6 ynylyl group, wherein the ynylyl group consists of 2-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, wherein the ynylyl group is attached to the rest of the molecule at the carbon atom of the ynylyl group. Examples of such ynylyl groups are, for example, -C≡COCH3, -C≡COCH2CH2OCH3, -CH2CH2OC≡COCH3, -C≡C-NHCH3, or -C≡CN(CH3)2. Unless otherwise expressly stated in this specification, the xylenyl group is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the xylenyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the xylenyl group is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the xylenyl group is optionally substituted by halogen.

[0050] Whether used as part of another term or independently, "heterocyclic alkyl" refers to a 3- to 24-membered or fully saturated cyclic group comprising 2-23 carbon atoms and 1-8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises 1-3 nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises 1 nitrogen atom. In some embodiments, the heterocyclic alkyl comprises 1 nitrogen atom and 1 oxygen atom. Unless otherwise expressly stated in this specification, heterocyclic alkyl groups can be monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) ring systems, which may include fused (e.g., fused with a cycloalkyl group or another heterocyclic alkyl group), spirocyclic, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms on the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, those having 2-15 carbon atoms (C2-C4). 15 Heterocyclic alkyl groups, 2-10 carbon atoms (C2-C4) 10Heterocyclic alkyl groups with 2-8 carbon atoms (C2-C8 heterocyclic alkyl groups), 2-7 carbon atoms (C2-C7 heterocyclic alkyl groups), 2-6 carbon atoms (C2-C6 heterocyclic alkyl groups), 2-5 carbon atoms (C2-C5 heterocyclic alkyl groups), or 2-4 carbon atoms (C2-C4 heterocyclic alkyl groups). Examples of such heterocyclic alkyl groups include, but are not limited to, azirropropyl, azirrobutyl, oxacyclobutyl, dioxacyclopentyl, thienyl[1,3]dithiohexyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidyl, oxazolyl, piperidinyl, piperazine, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazolyl, tetra Hydrofuranyl, trithiohexyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl group has 2-10 carbons on the ring. It should be understood that when referring to the number of carbon atoms on a heterocycloalkyl group, the number of carbon atoms on the heterocycloalkyl group is different from the total number of atoms (including heteroatoms) constituting the heterocycloalkyl group (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group. Unless otherwise expressly stated in this specification, the heterocyclic alkyl group may optionally be substituted as described below, for example, substituted by one or more substituents, such as oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, the heterocyclic alkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group is optionally substituted with one or more substituents, such as halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted with a halogen.

[0051] Whether used as part of another term or independently, "heteroaryl" refers to a 5- to 14-membered cyclic group comprising 1-13 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group comprises 1-3 nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 nitrogen atom. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (e.g., fused with a cycloalkyl, heterocycloalkyl, or aryl ring) or bridged ring system; and the nitrogen, carbon, or sulfur atoms on the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azatriyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxyl, benzonaphthuronyl, benzooxazolyl, benzodioxolyl, benzodioxenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenylyl, dibenzo[b][1,4]dioxepinyl, 1,4-benzodioxylyl, benzonaphthuronyl, benzooxazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzo[b][1,4]dioxylyl, benzo[b][1,4]naphthuronylyl, benzo[b][1,2-a]pyridylyl, carbazole, cenylylyl, dibenzo[b][1,4]dioxepinyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]dioxylylylyl, benzo[b][1,4]naphthuronyl ... Furanyl, dibenzothiopheneyl, furanyl, furanyl, furanoneyl, isothiazolyl, imidazolyl, indazole, indoleyl, isoindoleyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthidyl, oxadiazolyl, 2-oxoazapyryl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide The following are listed: 1-oxypyridazinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purineyl, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thiophenyl). It should be understood that any ring system satisfying Hückel's rule is considered an aromatic ring.Therefore, "heteroaryl" also includes both tautomers, such as hydroxypyridinyl and pyridoneyl, hydroxypyrimidinyl and pyrimidoneyl, hydroxypyrazinyl and pyrazinoneyl, and hydroxytriazinyl and triazinoneyl or their polycyclic systems. Unless otherwise expressly stated in this specification, heteroaryl groups may optionally be substituted, for example, by one or more substituents, such as halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the heteroaryl group is optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN, -CF3, -OH, or -OMe. In some implementations, the heteroaryl group is optionally replaced by a halogen.

[0052] The terms "cycloalkyl-alkyl" or "alkyl-cycloalkyl," used interchangeably herein, whether as part of another term or independently, refer to an alkyl group in which one carbon atom of an alkyl group is substituted by a cycloalkyl group or in which one carbon atom of a cycloalkyl group is substituted by an alkyl group. A cycloalkyl-alkyl group can be bonded to the remainder of the compound by either the cycloalkyl moiety or the alkyl moiety. Unless otherwise expressly stated in this specification, both the cycloalkyl moiety and the alkyl moiety of a cycloalkyl-alkyl group may optionally be substituted by one or more groups as described above.

[0053] The terms “heterocyclic alkyl-alkyl” or “alkyl-heterocyclic alkyl”, used interchangeably herein, whether as part of another term or used independently, refer to an alkyl group in which any carbon atom of an alkyl group is replaced by a heterocyclic alkyl group, or in which any carbon atom or heteroatom of a heterocyclic alkyl group is replaced by an alkyl group. A heterocyclic alkyl-alkyl group may be bonded to the remainder of the compound by either the heterocyclic alkyl moiety or the alkyl moiety. Unless expressly stated otherwise in this specification, both the heterocyclic alkyl moiety and the alkyl moiety of a heterocyclic alkyl-alkyl group may optionally be replaced by one or more groups as described above.

[0054] The terms “arylalkyl” or “alkylaryl”, used interchangeably herein, whether as part of another term or independently, refer to an alkyl group in which an alkyl group is substituted with an aryl group at any carbon atom or an aryl group in which an aryl group is substituted with an alkyl group at any carbon atom. An arylalkyl group may be bonded to the remainder of the compound by either the aryl moiety or the alkyl moiety. Unless expressly stated otherwise in this specification, both the aryl and alkyl moieties of an arylalkyl group may optionally be substituted with one or more groups as described above.

[0055] The terms “heteroarylalkyl” or “alkylheteroaryl”, used interchangeably herein, whether as part of another term or independently, refer to an alkyl group in which any carbon atom of an alkyl group is replaced by a heteroaryl group, or a heteroaryl group in which any carbon atom or heteroatom of a heteroaryl group is replaced by an alkyl group. A heteroarylalkyl group may be bonded to the remainder of the compound by either the heteroaryl moiety or the alkyl moiety. Unless expressly stated otherwise in this specification, both the heteroaryl moiety and the alkyl moiety of a heteroarylalkyl group may optionally be substituted with one or more groups as described above.

[0056] The terms “partially saturated” or “partially unsaturated” refer to groups that include at least one double or triple bond and are intended to cover a ring with multiple unsaturated sites, but are not intended to include aromatic (i.e., completely unsaturated) parts.

[0057] When two atoms are directly connected by a single bond (e.g., a single, double, or triple bond), these two atoms are "adjacent" to each other. When two atoms are connected by one or more other atoms and two or more bonds (e.g., single, double, or triple bonds), these two atoms are not adjacent or are "non-adjacent". For example, in the following hexane, carbon atom 1 and carbon atom 2 or carbon atom 1 and carbon atom 6 are "adjacent" atoms; while carbon atom 1 and carbon atom 3, carbon atom 1 and carbon atom 4, or carbon atom 1 and carbon atom 5 are "non-adjacent" atoms.

[0058]

[0059] Hexane with indicated carbon atom numbers

[0060] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes instances where said event or situation occurs and instances where said event or situation does not occur. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between full substitution and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any spatially impractical and / or synthetically infeasible substitution or substitution pattern. Therefore, any substituent described should generally be understood to have a molecular weight of at most about 1,000 Daltons, and more typically, at most about 500 Daltons.

[0061] The term "one or more" when referring to optional substituents means that the subject group is optionally substituted by one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted by one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted by one, two, or three substituents. In some embodiments, the subject group is optionally substituted by one or two substituents. In some embodiments, the subject group is optionally substituted by one substituent. In some embodiments, the subject group is optionally substituted by two substituents.

[0062] "Effective dose" or "therapeutic effective dose" refers to the amount of compound administered to a mammalian individual to effectively produce the desired therapeutic effect, as part of a single dose or a series of doses.

[0063] As used herein, the term “treatment” includes relieving, reducing or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing a disease or condition to subside, relieving the condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0064] As used in this article, “PKMYT1-related disease or condition” or “PKMYT1-mediated disease or condition” refers to any disease or other harmful condition in which PKMYT1 or its mutants are known or suspected to play a role.

[0065] compound

[0066] This article describes compounds or pharmaceutically acceptable salts thereof for regulating PKMYT1 (e.g., inhibiting PKMYT1) and thereby for treating PKMYT1-related diseases and conditions.

[0067] In one respect, this paper provides compounds of formula (V):

[0068]

[0069] Formula (V)

[0070] Or its pharmaceutically acceptable salt, wherein:

[0071] Each of X, Y, and Z is independently N or C;

[0072] Each It can be a single bond or a double bond;

[0073] Ring A can be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0074] Q is N or CR Q ;

[0075] R Q It can be H, OH or NH2;

[0076] Or R Q and R 1 Together with the atoms to which they are attached, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted with one or more R groups;

[0077] Or R Q and R 7 Together with the atoms to which they are attached, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted with one or more R groups;

[0078] Each R A Independently halogen, cyano, oxo, -OR a -SR a -SO2R a -N(R) b )2、-C(O)OR b -C(O)N(R) b )2、-SO2N(R b 2. Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0079] Or two adjacent R A Together with the atoms to which they are attached, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted with one or more R groups;

[0080] R 6 For oxygenation;

[0081] R 1 and R 2 Each of them is independently hydrogen, halogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0082] R 3 Hydrogen, halogen, cyano, -NO2, -OR a -SR a -N(R) b )2、-C(O)Ra -C(O)OR a -C(O)N(R) b 2. Alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more R;

[0083] R 4 Hydrogen, halogen, cyano, -OR a -SR a -N(R) b )2、-C(O)R a -C(O)OR a -C(O)N(R) b 2. Alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted by one or more R;

[0084] R 5 -C(O)NH(R) a -C(O)R a or -SO2R a ;

[0085] R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -N(R) b )2、-C(O)R a -C(O)OR b -C(O)N(R) b 2. C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0086] Each R is independently halogenated, cyanoated, oxo-, or -OR. a -SR a -SO2R a -N(R) b )2、-C(O)N(R b )2、-SO2N(R b 2. Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted by one or more R'.

[0087] Each R' is independently halogenated, cyano, oxo, or -OR. a -SR a -SO2R a -N(R) b )2、-C(O)N(R b )2、-SO2N(R b 2. Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0088] Each R A Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0089] Each R b Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0090] Or two Rs b Together with the atoms they are attached to, they form heterocyclic alkyl groups; and

[0091] n is an integer between 0 and 8.

[0092] In some implementations, Q is N. In some implementations, for In some implementation schemes, for , , , or .

[0093] In some implementations, Q is CR Q And R Q and R 1 Together with the atoms they are attached to, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each optionally substituted with one or more R groups. In some embodiments, Q is CR. Q And R Q and R 1 Together with the atoms they are attached to, they form C 5-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each optionally substituted with one or more R. In some embodiments, Q is CR. Q And R Q and R 1Together with the atoms to which they are attached, they form 5- to 6-membered heterocyclic alkyl groups or 5- to 6-membered heteroaryl groups, each optionally substituted with one or more R groups. In some embodiments, Q is CR. Q And R Q and R 1 Together with the atoms they are attached to, they form a pyrazol group, wherein the pyrazol group is optionally substituted with one or more R atoms. In some embodiments, for , , , or In some implementation schemes, for , , , , , , , , , , , , , , , or In some implementation schemes, for .

[0094] In some implementations, Q is CR Q And R Q and R 7 Together with the atoms they are attached to, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each optionally substituted with one or more R groups. In some embodiments, Q is CR. Q And R Q and R 7 Together with the atoms they are attached to, they form C 5-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, each optionally substituted with one or more R. In some embodiments, Q is CR. Q And R Q and R 7 Together with the atoms to which they are attached, they form 5- to 6-membered heterocyclic alkyl groups or 5- to 6-membered heteroaryl groups, each optionally substituted with one or more R groups. In some embodiments, Q is CR. Q And R Q and R 7 Together with the atoms they are attached to, they form a pyrazol group, wherein the pyrazol group is optionally substituted with one or more R atoms. In some embodiments, for , , or In some implementation schemes, for .

[0095] In some implementations, Q is CR Q And R Q For OH. In some implementations, yes In some implementation schemes, for , , , , or .

[0096] In some implementations, Q is CR Q And R Q For NH2. In some implementations, for In some implementation schemes, for , , or .

[0097] In some implementation schemes, R 7 It is hydrogen or halogen. In some implementations, R 7 It is hydrogen or F. In some implementations, R 7 It is hydrogen.

[0098] In one respect, this paper provides compounds of formula (I):

[0099]

[0100] Formula (I)

[0101] Or its pharmaceutically acceptable salt, wherein:

[0102] Each of X, Y, and Z is independently N or C;

[0103] Each It can be a single bond or a double bond;

[0104] Ring A can be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0105] Each R A Independently halogen, cyano, oxo, -OR a -SR a-SO2R a -N(R) b )2、-C(O)OR b -C(O)N(R) b )2、-SO2N(R b 2. Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0106] Or two adjacent R A Together with the atoms to which they are attached, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted with one or more R groups;

[0107] R 6 For oxygenation;

[0108] R 1 and R 2 Each of them is independently hydrogen, halogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R;

[0109] R 3 Hydrogen, halogen, cyano, -NO2, -OR a -SR a -N(R) b )2、-C(O)R a -C(O)OR a -C(O)N(R) b 2. Alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more R;

[0110] R 4 Hydrogen, halogen, cyano, -OR a -SR a -N(R) b )2、-C(O)R a -C(O)OR a -C(O)N(R) b2. Alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, ynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted by one or more R;

[0111] R 5 -C(O)NH(R) a -C(O)R a or -SO2R a ;

[0112] Each R is independently halogenated, cyanoated, oxo-, or -OR. a -SR a -SO2R a -N(R) b )2、-C(O)N(R b )2、-SO2N(R b 2. Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted by one or more R'.

[0113] Each R' is independently halogenated, cyano, oxo, or -OR. a -SR a -SO2R a -N(R) b )2、-C(O)N(R b )2、-SO2N(R b 2. Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0114] Each R A Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0115] Each R b Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

[0116] Or two Rs b Together with the atoms they are attached to, they form heterocyclic alkyl groups; and

[0117] n is an integer between 0 and 8.

[0118] In some implementation schemes,

[0119] X is C, Y is C, and Z is C;

[0120] X is C, Y is C, and Z is N;

[0121] X is N, Y is C, and Z is C;

[0122] X is N, Y is C, and Z is N;

[0123] X is C, Y is N, and Z is C;

[0124] X is C, Y is N, and Z is N;

[0125] X is N, Y is N, and Z is C; or

[0126] X is N, Y is N, and Z is N.

[0127] In some implementation schemes,

[0128] X is C, Y is C, and Z is N;

[0129] X is N, Y is C, and Z is N;

[0130] X is C, Y is N, and Z is C; or

[0131] X is N, Y is C, and Z is C.

[0132] In some implementation schemes, for , , , or .

[0133] In some embodiments, ring A is a heterocyclic alkyl or heteroaryl group. In some embodiments, ring A is a heterocyclic alkyl or heteroaryl group containing at least one nitrogen atom.

[0134] In some embodiments, ring A is a 5- to 10-membered heterocyclic alkyl, 5- to 9-membered heterocyclic alkyl, 5- to 8-membered heterocyclic alkyl, 6- to 8-membered heterocyclic alkyl, or 6- to 7-membered heterocyclic alkyl. In some embodiments, ring A is a 10-membered heterocyclic alkyl, 9-membered heterocyclic alkyl, 8-membered heterocyclic alkyl, 7-membered heterocyclic alkyl, 6-membered heterocyclic alkyl, or 5-membered heterocyclic alkyl. In some embodiments, ring A is a 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8-membered heteroaryl, or 6- to 7-membered heteroaryl. In some embodiments, ring A is a 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl.

[0135] In some embodiments, ring A is a 6-membered heterocyclic alkyl group. In some embodiments, ring A is a 6-membered heteroaryl group.

[0136] In some implementation schemes, for , , , , , , , , , , , , , , , , , , , , , , , , or ,in

[0137] R A1 R A2 and R A3 Each of them is independently hydrogen or independently selected from R A ;

[0138] Or R A1 and R A2 When they are adjacent to each other, they together with the atoms to which they are attached form cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, each of which is optionally substituted by one or more R groups;

[0139] Or R A1 and R A3 When they are adjacent to each other, they together with the atoms to which they are attached form cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, each of which is optionally substituted by one or more R groups;

[0140] Or R A2 and R A3 When they are adjacent to each other, they together with the atoms to which they are attached form cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, each of which is optionally substituted by one or more R groups;

[0141] Or two Rs A2 Together with the same atom to which it is attached, they form cycloalkyl or heterocycloalkyl groups, each of which is optionally substituted by one or more R groups;

[0142] Or two Rs A3Together with the same atom to which it is attached, they form cycloalkyl or heteroalkyl groups, each of which is optionally substituted by one or more R atoms.

[0143] In some implementation schemes, R A1 R A2 and R A3 Each of these elements is independently hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R.

[0144] In some implementation schemes, R A1 and R A2 Together with the atoms to which they are attached, they form 5- to 6-membered heterocyclic alkyl or 5- to 6-membered heteroaryl groups, each of which is optionally substituted with one or more R groups.

[0145] In some implementation schemes, R A2 and R A3 Together with the atoms they are attached to, they form C 5-6 Cycloalkyl, 5- to 6-membered heterocycloalkyl, C6 aryl or 5- to 6-membered heteroaryl, each optionally substituted with one or more R.

[0146] In some implementations, each R A Independently for -OR a Hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more (e.g. two or three, etc.) R.

[0147] In some implementations, one or more R A C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl, each of which is optionally substituted with one or more R.

[0148] In some implementations, one or more R A C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl or C 2-3 Alkenyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A It is C6-alken, C5-alken, C4-alken, C3-alken, or C2-alken, each of which is optionally substituted by one or more (e.g., two or three, etc.) R.

[0149] In some implementations, one or more R A C 2-6 alkynyl group, C 2-5 alkynyl group, C 2-4 alkynyl or C 2-3 The alkynyl groups are optionally substituted with one or more R groups. In some embodiments, one or more R groups are substituted with one or more R groups. A It is a C6 ynyl, C5 ynyl, C4 ynyl, C3 ynyl or C2 ynyl, each of which is optionally substituted by one or more (e.g., two or three, etc.) R.

[0150] In some implementations, one or more R A C 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2 The alkyl halogroups are optionally substituted with one or more R groups. In some embodiments, one or more R groups are substituted with one or more R groups. A It is a C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl or C1 haloalkyl, each of which is optionally substituted by one or more (e.g. two or three, etc.) R.

[0151] In some implementations, one or more R A C 1-6 Hydroxyalkyl, C 1-5 Hydroxyalkyl, C 1-4 Hydroxyalkyl, C 1-3 Hydroxyalkyl or C 1-2 The hydroxyalkyl groups are optionally substituted with one or more R groups. In some embodiments, one or more R groups are... A It is a C6 hydroxyalkyl, C5 hydroxyalkyl, C4 hydroxyalkyl, C3 hydroxyalkyl, C2 hydroxyalkyl or C1 hydroxyalkyl, each of which is optionally substituted with one or more R.

[0152] In some implementations, one or more RA C 1-6 aminoalkyl, C 1-5 aminoalkyl, C 1-4 aminoalkyl, C 1-3 aminoalkyl or C 1-2 The aminoalkyl group is optionally substituted with one or more R. In some embodiments, one or more R A It is a C6 aminoalkyl, C5 aminoalkyl, C4 aminoalkyl, C3 aminoalkyl, C2 aminoalkyl or C1 aminoalkyl, each of which is optionally substituted by one or more (e.g. two or three, etc.) R.

[0153] In some implementations, one or more R A It is a C1-6 alkoxy, C1-5 alkoxy, C1-4 alkoxy, C1-3 alkoxy, or C1-2 alkoxy, each optionally substituted with one or more R. In some embodiments, one or more R A It is a C6 alkoxy, C5 alkoxy, C4 alkoxy, C3 alkoxy, C2 alkoxy, or C1 alkoxy, each of which is optionally substituted with one or more (e.g., two or three, etc.) R.

[0154] In some implementations, one or more R A Cycloalkyl-C 1-6 Alkyl, cycloalkyl-C 1-5 Alkyl, cycloalkyl-C 1-4 Alkyl, cycloalkyl-C 1-3 Alkyl or cycloalkyl-C 1-2 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A The alkyl group is a cycloalkyl-C6 alkyl, cycloalkyl-C5 alkyl, cycloalkyl-C4 alkyl, cycloalkyl-C3 alkyl, cycloalkyl-C2 alkyl, or cycloalkyl-C1 alkyl group, each optionally substituted with one or more R groups. In some embodiments, one or more R groups are... A C 3-10 cycloalkyl-C 1-6 Alkyl, C 3-9 cycloalkyl-C 1-6 Alkyl, C 3-8 cycloalkyl-C 1-6 Alkyl, C 3-7 cycloalkyl-C 1-6 Alkyl or C 3-6 cycloalkyl-C 1-6 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A C 3-10 cycloalkyl-C1 alkyl, C 3-9 cycloalkyl-C1 alkyl, C3-8 cycloalkyl-C1 alkyl, C 3-7 cycloalkyl-C1 alkyl or C 3-6 Cycloalkyl-C1 alkyl, each of which is optionally substituted with one or more (e.g., two or three, etc.) R.

[0155] In some implementations, one or more R A Heterocyclic alkyl-C 1-6 Alkyl, heterocyclic alkyl-C 1-5 Alkyl, heterocyclic alkyl-C 1-4 Alkyl, heterocyclic alkyl-C 1-3 Alkyl or heterocyclic alkyl-C 1-2 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A The alkyl group is a heterocyclic alkyl-C6 alkyl, heterocyclic alkyl-C5 alkyl, heterocyclic alkyl-C4 alkyl, heterocyclic alkyl-C3 alkyl, heterocyclic alkyl-C2 alkyl, or heterocyclic alkyl-C1 alkyl, each optionally substituted with one or more R. In some embodiments, one or more R A 4- to 10-membered heterocyclic alkyl-C 1-6 Alkyl, 4- to 9-membered heterocyclic alkyl-C 1-6 Alkyl, 4- to 8-membered heterocyclic alkyl-C 1-6 Alkyl, 4- to 7-membered heterocyclic alkyl-C 1-6 Alkyl or 4- to 6-membered heterocyclic alkyl-C 1-6 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A It is a 4- to 10-membered heterocyclic alkyl-C1 alkyl, a 4- to 9-membered heterocyclic alkyl-C1 alkyl, a 4- to 8-membered heterocyclic alkyl-C1 alkyl, a 4- to 7-membered heterocyclic alkyl-C1 alkyl, or a 4- to 6-membered heterocyclic alkyl-C1 alkyl, each optionally substituted with one or more (e.g., two or three, etc.) R.

[0156] In some implementations, one or more R A For aryl-C 1-6 Alkyl, aryl-C 1-5 Alkyl, aryl-C 1-4 Alkyl, aryl-C 1-3 Alkyl or aryl-C 1-2 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A It is an aryl-C6 alkyl, aryl-C5 alkyl, aryl-C4 alkyl, aryl-C3 alkyl, aryl-C2 alkyl, or aryl-C1 alkyl, each optionally substituted with one or more R. In some embodiments, one or more R A C6-12 Aryl-C 1-6 Alkyl, C 6-11 Aryl-C 1-6 Alkyl, C 6-10 Aryl-C 1-6 Alkyl, C 6-9 Aryl-C 1-6 Alkyl or C 6-8 Aryl-C 1-6 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A C 6-12 Aryl-C1 alkyl, C 6-11 Aryl-C1 alkyl, C 6-10 Aryl-C1 alkyl, C 6-9 aryl-C1 alkyl or C 6-8 Aryl-C1 alkyl groups, each optionally substituted with one or more (e.g., two or three, etc.) R.

[0157] In some implementations, one or more R A For heteroaryl-C 1-6 Alkyl, heteroaryl-C 1-5 Alkyl, heteroaryl-C 1-4 Alkyl, heteroaryl-C 1-3 Alkyl or heteroaryl-C 1-2 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A The alkyl group is a heteroaryl-C6 alkyl, heteroaryl-C5 alkyl, heteroaryl-C4 alkyl, heteroaryl-C3 alkyl, heteroaryl-C2 alkyl, or heteroaryl-C1 alkyl group, each optionally substituted with one or more R groups. In some embodiments, one or more R groups are... A 5- to 10-membered heteroaryl-C 1-6 Alkyl, 5- to 9-membered heteroaryl-C 1-6 Alkyl, 5- to 8-membered heteroaryl-C 1-6 Alkyl, 6- to 8-membered heteroaryl-C 1-6 Alkyl or 6- to 7-membered heteroaryl-C 1-6 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A It is a 5- to 10-membered heteroaryl-C1 alkyl, a 5- to 9-membered heteroaryl-C1 alkyl, a 5- to 8-membered heteroaryl-C1 alkyl, a 6- to 8-membered heteroaryl-C1 alkyl, or a 6- to 7-membered heteroaryl-C1 alkyl, each optionally substituted with one or more (e.g., two or three, etc.) R.

[0158] In some implementations, one or more R A C3-10 cycloalkyl, C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl or C 3-5 Cycloalkyl groups, each optionally substituted with one or more R groups. In some embodiments, one or more R groups... A C 10 Cycloalkyl, C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl or C3 cycloalkyl, each optionally substituted with one or more (e.g. two or three, etc.) R.

[0159] In some implementations, one or more R A The alkyl group is a 4- to 10-membered heterocyclic alkyl group, a 4- to 9-membered heterocyclic alkyl group, a 4- to 8-membered heterocyclic alkyl group, a 5- to 8-membered heterocyclic alkyl group, a 5- to 8-membered heterocyclic alkyl group, or a 5- to 7-membered heterocyclic alkyl group, each optionally substituted with one or more R groups. In some embodiments, one or more R groups are... A It is a 10-membered heterocyclic alkyl, 9-membered heterocyclic alkyl, 8-membered heterocyclic alkyl, 7-membered heterocyclic alkyl, 6-membered heterocyclic alkyl, 5-membered heterocyclic alkyl or 4-membered heterocyclic alkyl, each optionally substituted by one or more (e.g. two or three, etc.) R.

[0160] In some implementations, one or more R A The R is a 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8-membered heteroaryl, or 6- to 7-membered heteroaryl, each optionally substituted with one or more Rs. In some embodiments, one or more Rs A It is a 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl or 5-membered heteroaryl, each of which is optionally replaced by one or more (e.g., two or three, etc.) R.

[0161] In some implementations, one or more R A C 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl or C 6-8 Aryl groups, each optionally replaced by one or more R groups. In some embodiments, one or more R groups... A C 12 Aryl, C 11 Aryl, C 10 Aryl, C9 aryl, C8 aryl, C7 aryl or C6 aryl, each optionally substituted by one or more (e.g. two or three, etc.) R.

[0162] In some implementations, one or more R A Independently for -OR a In some implementations, R a C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R a It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments, R a C 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2 Halogenated alkyl groups. In some embodiments, R a It is a C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl or C1 haloalkyl.

[0163] In some implementations, one or more R A -OC 1-6 Alkyl, -OC 1-5 Alkyl, -OC 1-4 Alkyl, -OC 1-3 Alkyl or -OC 1-2 Alkyl group. In some embodiments, one or more R... A It can be -O-C6 alkyl, -O-C5 alkyl, -O-C4 alkyl, -O-C3 alkyl, -O-C2 alkyl or -O-C1 alkyl.

[0164] In some implementations, one or more R A -OC 1-6 Halogenated alkyl groups, -OC 1-5 Halogenated alkyl groups, -OC 1-4 Halogenated alkyl groups, -OC 1-3 Halogenated alkyl or -OC 1-2 Halogenated alkyl groups. In some embodiments, one or more R groups... A It can be -O-C6 haloalkyl, -O-C5 haloalkyl, -O-C4 haloalkyl, -O-C3 haloalkyl, -O-C2 haloalkyl or -O-C1 haloalkyl.

[0165] In some embodiments, each R is independently a halogen, hydroxyl, cyano, alkyl, oxo, or alkylene group, wherein the alkyl and alkylene groups are independently and optionally substituted by one or more R's. In some embodiments, each R is independently -F, hydroxyl, cyano, -CH3, or oxo. In some embodiments, each R is an alkylene group, wherein the alkylene group is independently and optionally substituted by a halogen, -OR, or hydroxyl group. a Or 5- to 6-membered heterocyclic alkyl substitution.

[0166] In some implementations, each R A Independently, -CH3, -CH2CH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CHF2, -CH2CH2F, -OCH3, -OCF3, -OCH2F, -OCHF2, -OCH2CH3, -OCH2CF3, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0167] In some implementation schemes, R 1 Alkyl groups optionally substituted with one or more R. In some embodiments, R 1 C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, R groups are... 1 It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl, each of which is optionally substituted with one or more R.

[0168] In some implementation schemes, R 1 It is -CH3.

[0169] In some implementation schemes, R 2 Alkyl groups optionally substituted with one or more R. In some embodiments, R 2 C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl groups, each optionally substituted with one or more R groups. In some embodiments, R groups are... 2 It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl, each of which is optionally substituted with one or more R.

[0170] In some implementation schemes, R 2 It is -CH3.

[0171] In some implementation schemes, R 3 It is hydrogen or halogen. In some implementations, R 3 It can be hydrogen or -F.

[0172] In some implementation schemes, R 4 -N(R) b 2. In some implementations, each R b Independently hydrogen or alkyl. In some embodiments, each R is... b Independently hydrogen, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, each R b It is hydrogen. In some implementations, R 4 It is -NH2.

[0173] In some implementation schemes, R 5 -C(O)NH(R) a In some implementations, R a It is hydrogen or alkyl. In some embodiments, R a For hydrogen, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group. In some embodiments, R a It is hydrogen. In some implementations, R 5 It is -C(O)NH2.

[0174] In some implementations, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some implementations, n is 0, 1, 2, 3, 4, or 5. In some implementations, n is 0, 1, or 2.

[0175] In some embodiments, the compounds provided herein have formula (Ia):

[0176]

[0177] Equation (Ia),

[0178] Among them, rings A, X, Y, Z, and R 1 -R 6 R A And n is as defined in this article.

[0179] In some embodiments of the compounds disclosed herein, R, R 1 R 2 R 3 R 4 R 5 R A R a and R b One or more of the groups contain deuterium in a percentage higher than the natural abundance of deuterium.

[0180] In some embodiments of the compounds disclosed herein, one or more of the following groups are present. 1 H is replaced by one or more deuterium atoms: R, R 1 R 2 R 3 R 4 R 5 R A R a and R b .

[0181] In some embodiments of the compounds disclosed herein, R, R 1 R 2 R 3 R 4 R 5 R A R a and R bThe abundance of deuterium in each of them is independently calculated as at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% in molar terms.

[0182] In some embodiments of the compounds disclosed herein, one or more rings A 1 H is replaced by one or more deuterium atoms.

[0183] This document focuses on any combination of the groups described above, representing different variables. Throughout this specification, those skilled in the art will select the groups and their substituents to provide stable moieties and compounds.

[0184] In some embodiments, this disclosure provides a compound selected from any of the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[0185] Table 1 Exemplary Compounds

[0186]

[0187] In some embodiments, this disclosure provides a compound selected from any of the compounds in Table 2 or a pharmaceutically acceptable salt thereof.

[0188] Table 2 Exemplary Compounds

[0189]

[0190]

[0191]

[0192]

[0193] In some implementations, the compounds disclosed herein are not , or .

[0194] Other forms of the compounds disclosed herein

[0195] Isomers / stereoisomers

[0196] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis (cis, syn, zusammen (Z)), trans (trans, anti, entgegen (E)) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers produced by a single preparation step, combination or interconversion can be used in the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereoisomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereoisomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized for separation. In some embodiments, the diastereoisomers are separated by chiral chromatography or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers and the resolving agent are subsequently recovered by any practical method that does not cause racemization.

[0197] Isotope-labeled compounds

[0198] Unless otherwise indicated, the compounds described herein may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, designated as 1 H (protium), 2 H (deuterium) and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium can provide some therapeutic advantages, such as increased in vivo half-life and / or exposure, or can provide compounds for studying in vivo drug elimination and metabolic pathways.

[0199] For example, the compounds described herein can be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes selected from deuterium (… 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Isotopes. In some embodiments, the compounds described herein are artificially enriched with one or more isotopes selected from... 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br、 131 I and 125 I. In some embodiments, the abundance of enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0200] In some embodiments, the compound is deuterated at at least one position. In some embodiments, the compounds disclosed herein have some or all of these deuterated positions. 2 H atom substitution 1 H atoms. In some embodiments, each hydrogen atom in the compounds disclosed herein is independently [a specific type of hydrogen atom]. 1 H, 2 H (D) or 3 H(T). In some embodiments, one or more hydrogen atoms of the compound disclosed herein are 2 H (deuterium or D).

[0201] Methods for synthesizing deuterium-containing compounds are known in the art, and by way of non-limiting example only, include the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997 and the following synthetic methods. For example, deuterium-substituted compounds can be synthesized using various methods, as described in the following literature: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0202] Deuterated raw materials are readily available and can be synthesized using the methods described herein to provide the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0203] Pharmaceutically acceptable salts

[0204] In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0205] In some embodiments, the compounds described herein have acidic or basic groups, and thus can react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final separation and purification of the compounds disclosed herein, or by reacting the purified compounds in their free form with a suitable acid or base and separating the resulting salts.

[0206] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic acids, organic acids, or inorganic bases, including acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconate, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucono-heptanoates, glycerophosphates, glycolates, hemisulfates, heptasulfates, heptasulfates, hexyn-1,6-dicitates, hydroxybenzoates, and gamma-hydroxybutyrates. Hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0207] Furthermore, the compounds described herein can be prepared into pharmaceutically acceptable salts by reacting the compounds in their free base form with pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, etc. Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids (e.g., oxalic acid), while not pharmaceutically acceptable on their own, may be used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0208] In some embodiments, the compounds comprising free acid groups described herein react with suitable bases, such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations, or with ammonia or with pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include bases or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1-4 Alkyl)4, etc.

[0209] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization yields products soluble or dispersible in water or oil.

[0210] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternaries of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained via this quaternization.

[0211] tautomer

[0212] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can interconvert through hydrogen atom migration, accompanied by the conversion of single bonds and adjacent double bonds. In bond arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomer forms of the compounds disclosed herein are considered. The exact proportions of tautomers depend on a variety of factors, including temperature, solvent, and pH.

[0213] Treatment

[0214] In another aspect, this disclosure relates to a method of treating an individual with a PKMYT1-related disease or condition, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (V), (I), or (Ia) as provided herein, or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof, attributable to the PKMYT1 inhibitory activity of the compounds of this disclosure. In some embodiments, the compounds of this disclosure are selective PKMYT1 inhibitors.

[0215] As used herein, the term "individual in need" refers to an individual who has a PKMYT1-related disease or condition, or an individual whose risk of developing a PKMYT1-related disease or condition is increased compared to the majority of the population. In some embodiments, the individual 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.

[0216] PKMYT1 is a potentially important cancer target because it is essential in many cancer cells. Overexpression of PKMYT1 has been observed in various cancers, including hepatocellular carcinoma and clear cell renal cell carcinoma. Downregulation of PKMYT1 has minimal effect in undisturbed cells but a more pronounced effect in cells exposed to DNA damage. Furthermore, cells exhibiting high levels of replication stress, in addition to G1 checkpoint regulation defects, may be particularly sensitive to loss of PKMYT1 function because these cells tend to prematurely enter mitosis, where damage to genomic material leads to mitotic catastrophe. PKMYT1 inhibitors, regulators of the G2-M transition, have been found particularly useful in treating tumors (e.g., cancers) carrying CCNE1 amplification or FBXW7 loss-of-function mutations using synthetic lethal therapy strategies. Cancers carrying CCNE1 amplification can include, for example, uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, endometrial cancer, etc. Cancers carrying FBXW7 loss-of-function mutations can include, for example, uterine cancer, colorectal cancer, breast cancer, lung cancer, and esophageal cancer, etc. In addition, PKMYT1 is involved in non-small cell lung cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, etc.

[0217] In some implementations, PKMYT1-related diseases or conditions are tumors, particularly advanced solid tumors. In some implementations, PKMYT1-related diseases or conditions are selected from uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer (e.g., non-small cell lung cancer), endometrial cancer, colorectal cancer, hepatocellular carcinoma, glioblastoma, neuroblastoma, etc.

[0218] The methods for treating PKMYT1-related diseases or conditions described herein can be used as monotherapy. As used herein, the term "monotherapy" refers to the administration of a single active or therapeutic pharmaceutical compound to an individual in need. In some embodiments, monotherapy involves administering to an individual in need of such treatment a therapeutically effective amount of one of the compounds of this disclosure or a pharmaceutically acceptable salt, stereoisomer, or isotopic variant thereof.

[0219] Depending on the specific disease or condition to be treated, the methods for treating PKMYT1-related diseases or conditions described herein may also involve combination therapy with one or more additional therapeutic agents besides the compound of formula (V), (I), or (Ia), such as an anticancer agent as a second therapeutic agent. In some embodiments, non-limiting examples of additional therapeutic agents may include additional PKMYT1 inhibitors. In some embodiments, one or more additional therapeutic agents may be selected from: cytotoxic agents; antimetabolites; alkylating agents; anthracyclines; antibiotics; antimitotic agents; hormone therapy; signal transduction inhibitors; gene expression regulators; apoptosis inducers; angiogenesis inhibitors; immunotherapeutic agents; DNA damage repair inhibitors; or combinations thereof.

[0220] In another aspect, this disclosure provides a method for treating cancer in an individual in need, the method comprising administering to the individual a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition disclosed herein.

[0221] In another aspect, this disclosure provides a method for modulating PKMYT1 in an individual, the method comprising administering to the individual a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition disclosed herein.

[0222] In another aspect, this disclosure provides a method for inhibiting PKMYT1 in an individual, the method comprising administering to the individual a compound disclosed herein or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition disclosed herein.

[0223] In some embodiments, the individual has cancer. In some embodiments, the cancer depends on the activity of PKMYT1. In some embodiments, the cancer overexpresses CCNE1. In some embodiments, the cancer has an inactivating mutation in the FBXW7 gene. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, gastric cancer, or uterine cancer.

[0224] In another aspect, this disclosure provides pharmaceutical compositions for treating PKMYT1-related diseases or conditions, comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

[0225] In another aspect, this disclosure provides for the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, in the preparation of medicaments for the treatment of cancer.

[0226] In another aspect, this disclosure provides a medicine box for treating cancer, comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein, a container, and optionally a packaging insert or label indicating treatment of said disease or condition.

[0227] Dosage

[0228] In some embodiments, a composition comprising the compounds described herein is administered for therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or disorder in an amount sufficient to cure or at least partially alleviate at least one symptom of the disease or disorder. The effective amount for this purpose depends on the severity and duration of the disease or condition, prior therapy, the patient's health status, weight, and response to the medication, as well as the judgment of the attending physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0229] Application route

[0230] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0231] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection into an organ, typically in the form of a reservoir preparation or a sustained-release formulation. In specific embodiments, long-acting formulations are administered via implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in the form of a targeted drug delivery system, such as liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by it. In other embodiments, the compounds described herein are provided as immediate-release formulations, extended-release formulations, or intermediate-release formulations.

[0232] Pharmaceutical Compositions / Formulations

[0233] In accordance with standard pharmaceutical practice, the compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as a pharmaceutical composition to an individual in need. In some embodiments, the compounds described herein are administered to animals.

[0234] On the other hand, this document provides pharmaceutical compositions comprising the compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in the following references: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., editors, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the contents of which are incorporated herein by reference.

[0235] Example

[0236] For illustrative purposes, the following examples are included. The examples provided herein describe the compounds disclosed herein and the synthesis of intermediates for the preparation of the compounds. However, it should be understood that these examples are not limiting of this disclosure, but merely suggestive of methods for implementing this disclosure. Those skilled in the art will recognize that the described chemical reactions can be readily applied to the preparation of many other compounds of this disclosure, and alternative methods for preparing the compounds of this disclosure are considered within the scope of this disclosure. For example, the synthesis of non-exemplary compounds according to this disclosure can be successfully carried out by variations obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art besides those described above, and / or by conventional variations of the reaction conditions. Furthermore, those skilled in the art will understand that the individual steps or batches of steps of the compounds described herein can be combined. Alternatively, other reactions disclosed herein or known in the art are considered suitable for the preparation of other compounds of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure, but rather as specified in the appended claims.

[0237] Example 1: Synthesis of an exemplary compound

[0238] Example 1.1:

[0239]

[0240] Step 1: Preparation of compounds 1-2

[0241] To a solution of compound 1-1 (3.70 g, 19.68 mmol) in THF (10 mL), TBAF (78.7 mL, 78.72 mmol) and CH3I (2.45 mL, 39.36 mmol) were added. The mixture was stirred at 60 °C for 16 h. The mixture was cooled to rt, diluted with EA (100 mL), and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give compound 1-2 (3.50 g, 88.0%). LCMS: 204.0 [M+H] + ; 1 H NMR (400MHz, CDCl3): δ 6.72 (d, J = 4.0 Hz, 1H), 6.23 (s, 1H), 3.48 (s, 3H), 2.34 (s, 3H).

[0242] Step 2: Preparation of compounds 1-3

[0243] NCS (726.96 mg, 5.444 mmol) was added to a solution of compounds 1-2 (1.0 g, 4.949 mmol) in DMF (10 mL). The mixture was stirred at 45 °C for 16 h. The reaction mixture was diluted with EA (100 mL) and washed with brine (100 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compounds 1-3 (1.00 g, 85.4%). LCMS: 237.9 [M+H] + .

[0244] Step 3: Preparation of compounds 1-5

[0245] Compounds 1-4 (352 mg, 2.326 mmol), XantPhos Pd G3 (240.6 mg, 0.254 mmol), and Cs2CO3 (2.07 g, 6.343 mmol) were added to a solution of compounds 1-3 (500 mg, 2.114 mmol) in dioxane (10 mL). The mixture was stirred at 110 °C for 16 h and cooled to rt. The mixture was diluted with EA (100 mL) and water (30 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give compounds 1-5 (230 mg, 35.5%). LCMS: 307.1 [M+H] + .

[0246] Step 4: Preparation of compounds 1-7

[0247] NaH (46 mg, 1.147 mmol) was added to a solution of compounds 1-6 (75.79 mg, 1.147 mmol) in DMF (3 mL) at 0 °C. The mixture was stirred for 0.5 h. Then CuI (4.9 mg, 0.026 mmol) and methyl[(1 S ,2 S [2-(methylamino)cyclohexyl]amine (7.42 mg, 0.052 mmol) and compounds 1-5 (160 mg, 0.522 mmol). The mixture was stirred in a microwave at 150 °C for 1 h. The mixture was quenched with water (10 mL) and extracted with EA (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative-TLC to give compounds 1-7. LCMS: 337.1 [M+H] + .

[0248] Step 5: Preparation of compounds 1-8

[0249] A mixture of compounds 1-7 (50 mg, 0.149 mmol) in H₂SO₄ (2 mL) was stirred at 15 °C for 0.5 h. The mixture was quenched with ice-water (15 mL) and alkalized to pH ~8 with 2 M NaOH. The mixture was extracted with DCM (20 mL × 3). The organic layers were combined, dried over Na₂SO₄, and concentrated to dryness. The residue was purified by preparative-TLC to give compounds 1-8. LCMS: 355.1 [M+H] + .

[0250] Step 6: Preparation of Compound 1

[0251] BBr3 (0.3 µL, 0.027 mmol) was added to a solution of compounds 1-8 (90 mg, 0.277 mmol) in DCM (1 mL). The mixture was stirred at 15 °C for 2 h. The reaction was quenched with MeOH (1 mL). The mixture was concentrated and purified by preparative-HPLC to give compound 1. LCMS: 341.0 [M+H] + .

[0252] 1 H NMR (400 MHz, DMSO- d 6): δ 10.33 (s, 1H), 9.63 (s, 1H), 7.09 (t, J =7.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.64 (s, 1H), 6.45 (s, 1H), 6.27 (s,1H), 5.67 (s, 1H), 3.49 (s, 3H), 2.30 (s, 3H), 1.78 (s, 3H), 1.69 (s, 3H).

[0253] Example 1.2

[0254]

[0255] Step 1: Preparation of Compound 2-2

[0256] Compound 2-1 (2.28 g, 26.593 mmol), Cu(OAc)₂ (2.42 g, 13.296 mmol), pyridine (5.35 mL, 66.482 mmol), and KHMDS (13.3 mL, 13.296 mmol) were added to a solution of compound 1-1 (2.50 g, 13.296 mmol) in toluene (50 mL). The reaction mixture was stirred overnight at 100 °C under an O₂ atmosphere. The mixture was cooled to rt and diluted with DCM and water. The organic layer was separated, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 2-2 (1.70 g, 56.1%). LCMS: 230.1 [M+H] + .

[0257] Step 2: Preparation of Compound 2

[0258] Compound 2 was prepared from compound 2-2 (1.50 g, 6.576 mmol) in a similar manner to the synthesis of compound 1, and the isomers were separated by SFC. Instrumentation: Waters SFC 150; Column: Daicelchiralcel® OZ, 250. 25 mm × 10 µm; Conditions: 45% MeOH (+0.1% 7.0 mol / L ammonia in MeOH solution) and 55% CO2; Flow rate: 80 mL / min; RT = 2.671 min (for the other enantiomer, RT = 4.589 min). LCMS: 367.3 [M+H] + .

[0259] 1 H NMR (400 MHz, DMSO- d 6): δ 10.26 (s, 1H), 9.63 (s, 1H), 7.09 (d, J =8.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.63 (s, 1H), 6.42 (s, 2H), 5.61 (s,1H), 2.95–2.79 (m, 1H), 2.38 (s, 3H), 1.78 (s, 3H), 1.69 (s, 3H), 1.17–1.12(m, 2H), 0.85–0.81 (m, 2H).

[0260] Example 1.3

[0261]

[0262] Step 1: Preparation of compound 3-2

[0263] LDA (245.40 mL, 490.798 mmol) was added to a solution of compound 3-1 (50 g, 306.748 mmol) in THF (2 L) at -78 °C. The mixture was stirred at -78 °C for 0.5 h. Then I2 (217.7 g, 490.798 mmol) in THF (500 mL) was added, and the mixture was stirred at -78 °C for 1 h. The reaction was quenched in an ice bath with NH4Cl (saturated aqueous solution, 2 L), and extracted with EA (2 L × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 3-2 (25 g, 28.2%). 1H NMR (400 MHz, DMSO-) d 6): δ 2.54 (s, 3H).

[0264] Step 2: Preparation of compound 3-3

[0265] LiHMDS (1.0 M, 263.07 mL) was added to a solution of compounds 3-2 (38 g, 131.533 mmol) and 1-4 (19.9 g, 131.533 mmol) in THF (1.5 L) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. The mixture was quenched with NH4Cl (saturated aqueous solution, 1 L) in an ice bath and extracted with EA (500 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 3-3 (11.5 g, 21.7%). LCMS: 404.0 [M+H] + .

[0266] 1 H NMR (400 MHz, CDCl3): δ 7.08 (d, J = 8.4 Hz, 1H), 6.81–6.77 (m,2H), 3.84 (s, 3H), 2.36 (s, 3H), 2.13 (s, 3H), 2.06 (s, 3H).

[0267] Step 3: Preparation of compounds 3-4

[0268] NaH (123.9 mg, 3.097 mmol) was added to a solution of compounds 1-6 (245.7 mg, 3.717 mmol) in DME (15 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then, compounds 3-3 (500 mg, 1.239 mmol) and XantPhos Pd G3 (176.2 mg, 0.186 mmol) were added. The mixture was stirred at 130 °C under N2 for 3 h. The mixture was quenched with H2O (50 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compounds 3-4 (70.4 mg, 33.7%). LCMS: 342.1 [M+H] + .

[0269] 1H NMR (400 MHz, DMSO- d 6 ): δ 7.49 (s, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 2.42 (s, 3H), 1.80 (s, 3H), 1.71 (s, 3H).

[0270] Step 4: Preparation of compounds 3-5

[0271] To a solution of compounds 3-4 (500 mg, 1.463 mmol) in AcOH (10 mL), NaOAc (959.7 mg, 11.704 mmol) was added. The mixture was stirred at 100 °C for 24 h. The reaction mixture was carefully added to ice-water (30 mL) with stirring, and the pH was adjusted to ~8 with NaOH (4 M aqueous solution). The mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compounds 3-5. LCMS: 324.0 [M+H] + .

[0272] Step 4: Preparation of compounds 3-6

[0273] Racemic compounds 3-5 were separated by SFC to yield compounds 3-6. Instrumentation: Waters SFC150; Column: Daicelchiralpak® AS, 250 25 mm 10 µm; Conditions: 25% EtOH (+0.1% 7.0 mol / L ammonia in MeOH solution) with supercritical CO2; Flow rate: 120 mL / min; RT = 1.654 min (for the other enantiomer, RT = 2.534 min). LCMS: 324.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ): δ 12.10 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.06 (d, J= 8.4 Hz, 1H), 6.39 (s, 2H), 3.83 (s, 3H), 2.17 (s, 3H), 1.82 (s, 3H), 1.72 (s, 3H).

[0274] Step 5: Preparation of compounds 3-7

[0275] Fluoroiodomethane (297 mg, 1.856 mmol) was added to a solution of compounds 3-6 (500 mg, 1.546 mmol) in ACN (10 mL) and Cs₂CO₃ (756 mg, 2.319 mmol). The mixture was stirred at rt for 2 h. The mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to give compounds 3-7. LCMS: 356.2 [M+H] + .

[0276] 1 H NMR (400 MHz, DMSO- d 6): δ 7.23 (d, J = 8.4 Hz, 1H), 7.09 (d, J =8.4 Hz, 1H), 6.59 (s, 2H), 6.17 (d, J = 52.0 Hz, 1H), 3.84 (s, 3H), 2.45 (s, 3H), 1.84 (s, 3H), 1.74 (s, 3H)

[0277] Step 6: Preparation of Compound 3

[0278] Compound 3 was synthesized from compounds 3-7 (900 mg, 2.53 mmol) in a similar manner to that used for compound 1. LCMS: 360.2 [M+H] + .

[0279] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.59 (s, 1H), 9.14 (s, 1H), 7.06 (d, J =8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.54 (s, 2H), 6.23 (d, J= 52.0 Hz, 2H), 2.49 (s, 3H), 1.80 (s, 3H), 1.71 (s, 3H).

[0280] Example 1.4

[0281]

[0282] Step 1: Preparation of compound 4-2

[0283] MeI (46.1 mg, 0.325 mmol) was added to a solution of compounds 3-6 (70 mg, 0.216 mmol) and Cs₂CO₃ (141.0 mg, 0.433 mmol) in CH₃CN (4 mL). The mixture was stirred at rt for 2 h. The mixture was diluted with H₂O (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 4-2 (50 mg, 68.5%). LCMS: 338.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.22 (d, J = 8.4 Hz, 1H), 7.07 (d, J =8.4 Hz, 1H), 6.44 (s, 2H), 3.83 (s, 3H), 3.47 (s, 3H), 2.37 (s, 3H), 1.82 (s, 3H), 1.73 (s, 3H).

[0284] Step 2: Preparation of Compound 4

[0285] Compound 4 was synthesized from compound 4-2 (40 mg, 0.119 mmol) in a similar manner to that used for compound 1. LCMS: 342.2 [M+H] + .

[0286] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.54 (s, 1H), 9.50 (s, 1H), 7.05 (d, J =8.4 Hz, 1H), 6.90 (d, J= 8.4 Hz, 1H), 6.75 (s, 1H), 6.45 (s, 2H), 3.52 (s, 3H), 2.40 (s, 3H), 1.78 (s, 3H), 1.69 (s, 3H).

[0287] Example 1.5

[0288]

[0289] Step 1: Preparation of Compound 5-2

[0290] Compound 5-1 (129.2 mg, 0.557 mmol) and Cs₂CO₃ (181.3 mg, 0.557 mmol) were added to a solution of compound 3-6 (150 mg, 0.464 mmol) in ACN (8 mL). The mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 5-2 (90 mg, 47.9%). LCMS: 406.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6): δ 7.22 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.59 (s, 2H), 5.05 (q, J = 8.0 Hz, 2H), 3.83(s, 3H), 2.43 (s, 3H), 1.83 (s, 3H), 1.74 (s, 3H).

[0291] Step 2: Preparation of Compound 5

[0292] Compound 5 was synthesized from compound 5-2 (80 mg, 0.197 mmol) in a similar manner to that used for compound 1. LCMS: 410.3 [M+H] + .

[0293] 1 H NMR (400 MHz, DMSO- d 6): δ 9.56 (s, 1H), 9.16 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.55 (s, 2H), 5.05 (q, J = 8.0 Hz, 2H), 2.47 (s, 3H), 1.79 (s, 3H), 1.71 (s, 3H).

[0294] Example 1.6

[0295]

[0296] Step 1: Preparation of Compound 6-2

[0297] Compound 6-1 (119.2 mg, 0.557 mmol) and Cs₂CO₃ (181.3 mg, 0.557 mmol) were added to a solution of compound 3-6 (150 mg, 0.464 mmol) in ACN (8 mL). The mixture was stirred at rt for 2 h. The mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 6-2 (75 mg, 41.7%). LCMS: 388.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.22 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.55 (s, 2H), 6.50–6.20 (m, 1H), 4.52–4.44 (m, 2H), 3.84 (s, 3H), 2.41 (s, 3H), 1.83 (s, 3H), 1.74 (s, 3H).

[0298] Step 2: Preparation of Compound 6

[0299] Compound 6 was synthesized from compound 6-2 (65 mg, 0.168 mmol) in a similar manner to that used for compound 1. LCMS: 392.2 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6): δ 9.62 (s, 1H), 9.25 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 2.8 Hz,1H), 6.52 (s, 2H), 6.40–6.24 (m, 1H), 4.57–4.49 (m, 2H), 2.45 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H).

[0300] Example 1.7

[0301]

[0302] Step 1: Preparation of Compound 7-2

[0303] To a solution of compound 3-6 (150 mg, 0.464 mmol) in DMF (5 mL), iodoethane (86.8 mg, 0.557 mmol) and Cs₂CO₃ (181.3 mg, 0.557 mmol) were added. The mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 7-2 (90 mg, 55.2%). LCMS: 352.1 [M+H] + .

[0304] 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.21 (d, J = 8.4 Hz, 1H), 7.07 (d, J =8.4 Hz, 1H), 6.43 (s, 2H), 4.06–4.01 (m, 2H), 3.83 (s, 3H), 2.41 (s, 3H), 1.82 (s, 3H), 1.73 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H).

[0305] Step 2: Preparation of Compound 7

[0306] Compound 7 was synthesized from compound 7-2 (70 mg, 0.199 mmol) in a similar manner to that used for compound 1. LCMS: 356.2 [M+H] + .

[0307] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.57 (s, 1H), 9.49 (s, 1H), 7.05 (d, J =8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 3.2 Hz, 1H), 6.46 (s,2H), 4.08 (q, J = 8.0 Hz, 2H), 2.45 (s, 3H), 1.78 (s, 3H), 1.69 (s, 3H), 1.25(t, J = 8.0 Hz, 3H).

[0308] Example 1.8

[0309]

[0310] Step 1: Preparation of Compound 8-2

[0311] Cs₂CO₃ (181.3 mg, 0.557 mmol) was added to a solution of compounds 3-6 (150 mg, 0.464 mmol) and 8-1 (112.2 mg, 0.928 mmol) in DMF (5 mL). The solution was stirred at rt for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 8-2 (70 mg, 41.5%). LCMS: 364.0 [M+H] + .

[0312] 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.24 (d, J = 8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.48 (s, 2H), 5.98–5.89 (m, 1H), 5.18 (dd, J = 10.4, 0.8 Hz,1H), 5.11–4.94 (m, 1H), 4.69 (d, J = 4.8 Hz, 2H), 3.84 (s, 3H), 2.36 (s, 3H), 1.84 (s, 3H), 1.74 (s, 3H).

[0313] Step 2: Preparation of Compound 8

[0314] Compound 8 was synthesized from compound 8-2 (80 mg, 0.220 mmol) in a similar manner to that used for compound 1. LCMS: 368.2 [M+H] + .

[0315] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.57 (s, 1H), 9.42 (d, J = 3.2 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 3.2 Hz, 1H), 6.49 (s, 2H), 5.98–5.91 (m, 1H), 5.19 (dd, J = 10.4, 1.2 Hz, 1H), 5.00 (dd, J = 17.2, 1.2 Hz, 1H), 4.73 (d, J = 5.2 Hz, 2H), 2.40 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H).

[0316] Example 1.9

[0317]

[0318] Step 1: Preparation of Compound 9-1

[0319] A solution of compounds 3-6 (150 mg, 0.464 mmol) in H₂SO₄ (5 mL) was stirred at 40 °C for 1 h. The reaction mixture was carefully added to ice-water (20 mL) with stirring, and the pH was adjusted to ~8 with NaOH (4 M aqueous solution). The mixture was extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 9-1 (150 mg, 94.7%). LCMS: 342.3 [M+H] + .

[0320] 1 H NMR (400 MHz, DMSO- d 6 ): δ 12.28 (s, 1H), 9.46 (s, 1H), 7.23 (d, J =8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 6.41 (s, 2H), 3.84 (s, 3H), 2.21 (s, 3H), 1.83 (s, 3H), 1.73 (s, 3H).

[0321] Step 2: Preparation of compound 9-3

[0322] K₂CO₃ (182.2 mg, 1.318 mmol) was added to a solution of compound 9-1 (150 mg, 0.439 mmol) and compound 9-2 (79.0 mg, 0.659 mmol) in DMF (1 mL). The solution was stirred at 50 °C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 9-3. LCMS: 381.3 [M+H] + .

[0323] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.14 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.91 (s, 1H), 6.61 (s, 2H), 5.22 (s, 2H), 3.85 (s,3H), 2.50 (s, 3H), 1.85 (s, 3H), 1.75 (s, 3H).

[0324] Step 3: Preparation of Compound 9

[0325] Compound 9 was synthesized from compound 9-3 (60 mg, 0.158 mmol) in a similar manner to that used for compound 1. LCMS: 367.0 [M+H] + .

[0326] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.58 (s, 1H), 9.12 (s, 1H), 7.06 (d, J =8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.56 (s, 2H), 5.20 (s,2H), 2.51 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H).

[0327] Example 1.10

[0328]

[0329] Step 1: Preparation of Compound 10-2

[0330] Compound 10-1 (61.6 mg, 0.322 mmol) and Cs₂CO₃ (286.5 mg, 0.879 mmol) were added to a solution of compound 9-1 (100 mg, 0.293 mmol) in DMF (2 mL). The mixture was stirred at rt under N₂ for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to give compound 10-2 (90 mg, 81.0%). LCMS: 380.0 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.31 (d,J = 2.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 2.8 Hz,1H), 6.56 (s, 2H), 4.94 (d, J = 2.0 Hz, 2H), 3.84 (s, 3H), 3.38 (t, J = 2.0Hz, 1H), 2.52 (s, 3H), 1.84 (s, 3H), 1.74 (s, 3H).

[0331] Step 2: Preparation of Compound 10

[0332] Compound 10 was synthesized from compound 10-2 (40 mg, 0.105 mmol) in a similar manner to that used for compound 1. LCMS: 366.2 [M+H] + .

[0333] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.57 (s, 1H), 9.31 (d, J = 2.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.8 Hz, 1H), 6.51 (s, 2H), 4.94 (d, J = 2.0 Hz, 2H), 3.38 (t, J = 2.0 Hz, 1H), 2.52 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H).

[0334] Example 1.11

[0335]

[0336] Step 1: Preparation of Compound 11-2

[0337] Compound 11-1 (86.3 mg, 0.474 mmol) and Cs₂CO₃ (154.4 mg, 0.474 mmol) were added to a solution of compound 9-1 (135 mg, 0.395 mmol) in DMF (3 mL). The mixture was stirred at rt under a N₂ atmosphere for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give compound 11-2 (90 mg, 57.5%). LCMS: 396.2 [M+H] + .

[0338] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.49 (d, J = 3.2 Hz, 1H), 7.24 (d, J =8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 3.2 Hz, 1H), 6.51 (s,2H), 4.00 (d, J = 6.8 Hz, 2H), 3.84 (s, 3H), 2.48 (s, 3H), 1.84 (s, 3H), 1.74(s, 3H), 1.24–1.19 (m, 1H), 0.57–0.37 (m, 4H).

[0339] Step 2: Preparation of Compound 11

[0340] Compound 11 was synthesized from compound 11-2 (110 mg, 0.278 mmol) in a similar manner to that used for compound 1. LCMS: 382.2 [M+H] + .

[0341] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.57 (s, 1H), 9.48 (d, J = 3.2 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 6.47 (s, 2H), 4.00 (d, J = 6.8 Hz, 2H), 1.79 (s, 3H), 1.70 (s, 3H), 1.25–1.21(m, 1H), 0.65–0.35 (m, 4H).

[0342] Example 1.12

[0343]

[0344] Step 1: Preparation of Compound 12-2

[0345] A mixture of compound 9-1 (50 mg, 0.146 mmol), compound 12-1 (38.4 mg, 0.161 mmol), and Cs₂CO₃ (143.1 mg, 0.439 mmol) in DMF (1 mL) was stirred at 50 °C for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by preparative-TLC to give compound 12-2 (50 mg, 68.5%). LCMS: 500.3 [M+H] + .

[0346] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.59 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.92 (s, 1H), 6.62 (s, 2H), 4.32 (t, J = 4.8 Hz, 2H), 4.04 (t, J = 4.8 Hz, 2H), 3.98 (s, 3H), 2.61 (s, 3H), 1.97 (s, 3H), 1.87(s, 3H), 0.88 (s, 9H), 0.00 (s, 6H).

[0347] Step 2: Preparation of Compound 12

[0348] Compound 12 was synthesized from compound 12-2 (50 mg, 0.100 mmol) in a similar manner to that used for compound 1. LCMS: 372.2 [M+H] + .

[0349] 1 H NMR (400 MHz, DMSO- d 6 ): δ 9.54 (s, 1H), 9.48 (s, 1H), 7.05 (d, J =8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.45 (s, 2H), 4.96 (s,1H), 4.11 (t, J = 5.4 Hz, 2H), 3.70 (t, J = 5.4 Hz, 2H), 2.49 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H).

[0350] Other compounds disclosed herein can be synthesized using similar methods, with modified conditions and different raw materials.

[0351] Example 2: Biological assay

[0352] Example 2.1: PKMYT1 HTRF Measurement

[0353] Serial dilutions of the test compound were performed using Echo, with final concentrations varying between 10 µM and 0.5 nM. Plates were filled by adding 5 µL / well of enzyme solution to each well containing the test compound. The plates were centrifuged at 1000 rpm for 1 min and incubated at 25 °C for 15 min. Then, 5 µL / well of tracer solution (Tracer 178) was added to initiate the reaction, and the plate was incubated at 25 °C for 60 min. Next, 5 μL of GST-Tb was added to the plate, and the plate was centrifuged at 1000 rpm for 1 min and incubated at 25 °C for 15 min. The plate was read on an Envision display.

[0354] Example 2.2: WEE1 ADP-Glo ​​Measurement

[0355] Serial dilutions of the test compound were performed using Echo, with final concentrations varying between 10 µM and 0.5 nM. The plates were filled by adding 5 µL / well of enzyme solution to each well containing the test compound. The plates were centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 15 minutes. Then, 5 µL / well of substrate solution was added to initiate the reaction, and the plates were incubated at 25°C for 60 minutes. Next, 10 μL of the kinase assay reagent was added to the plate, and the plate was centrifuged at 1000 rpm for 1 minute and incubated at 25°C for 60 minutes. The US LUM in RLU form was read from the plate using Envision.

[0356] The data for Examples 2.1 and 2.2 are shown in Table 3, where "A" represents IC. 50 Less than or equal to 10 nM; "B" indicates IC 50 Greater than 10 nM, but less than or equal to 50 nM; "C" indicates IC 50 Greater than 50 nM, but less than or equal to 500 nM; "D" indicates IC 50 Greater than 500 nM, but less than or equal to 5000 nM; "E" indicates IC 50 Greater than 5000 nM; and “NT” indicates untested.

[0357] Table 3

[0358]

[0359] Other compounds disclosed in this paper also showed PKMYT1 inhibitory activity.

Claims

1. Compounds of formula (I): Equation (V), Or its pharmaceutically acceptable salt, wherein: Each of X, Y, and Z is independently N or C; Each It can be a single bond or a double bond; Ring A can be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Q is N or CR Q ; R Q is H, OH or NH2; or R Q and R 1 together with the atoms on which they are attached form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; or R Q and R 7 Together with the atoms to which they are attached, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted by one or more R groups; Each R A Independently halogen, cyano, oxo, -OR a -SR a -SO2R a -N(R) b )2、-C(O)OR b -C(O)N(R) b )2、-SO2N(R b 2. Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R; Or two adjacent R A Together with the atoms to which they are attached, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted by one or more R groups; R 6 For oxygenation; R 1 and R 2 Each of them is independently hydrogen, halogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R; R 3 Hydrogen, halogen, cyano, -NO2, -OR a -SR a -N(R) b )2、-C(O)R a -C(O)OR a -C(O)N(R) b 2. Alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more R; R 4 Hydrogen, halogen, cyano, -OR a -SR a -N(R) b )2、-C(O)R a -C(O)OR a -C(O)N(R) b 2. Alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted by one or more R; R 5 -C(O)NH(R) a -C(O)R a or -SO2R a ; R 7 Hydrogen, halogen, -CN, -NO2, -OH, -OR a -N(R) b )2、-C(O)R a -C(O)OR b -C(O)N(R) b 2. C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl, wherein the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R; Each R is independently halogenated, cyano, oxo, or -OR. a -SR a -SO2R a -N(R) b )2、-C(O)N(R b )2、-SO2N(R b 2. Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted by one or more R'. Each R' is independently halogenated, cyano, oxo, or -OR. a -SR a -SO2R a -N(R) b )2、-C(O)N(R b )2、-SO2N(R b 2. Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R A Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R b Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Or two Rs b Together with the atoms they are attached to, they form heterocyclic alkyl groups; and n is an integer between 0 and 8.

2. Compounds of formula (I): Formula (I), Or its pharmaceutically acceptable salt, wherein: Each of X, Y, and Z is independently N or C; Each It can be a single bond or a double bond; Ring A can be cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R A Independently halogen, cyano, oxo, -OR a -SR a -SO2R a -N(R) b )2、-C(O)OR b -C(O)N(R) b )2、-SO2N(R b 2. Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R; Or two adjacent R A Together with the atoms to which they are attached, they form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups, each of which is optionally substituted by one or more R groups; R 6 For oxygenation; R 1 and R 2 Each of them is independently hydrogen, halogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more R; R 3 Hydrogen, halogen, cyano, -NO2, -OR a -SR a -N(R) b )2、-C(O)R a -C(O)OR a -C(O)N(R) b 2. Alkyl, alkenyl, ynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, ynyl, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more R; R 4 Hydrogen, halogen, cyano, -OR a -SR a -N(R) b )2、-C(O)R a -C(O)OR a -C(O)N(R) b 2. Alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted by one or more R; R 5 -C(O)NH(R) a -C(O)R a or -SO2R a ; Each R is independently halogenated, cyano, oxo, or -OR. a -SR a -SO2R a -N(R) b )2、-C(O)N(R b )2、-SO2N(R b 2. Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are independently and optionally substituted by one or more R'. Each R' is independently halogenated, cyano, oxo, or -OR. a -SR a -SO2R a -N(R) b )2、-C(O)N(R b )2、-SO2N(R b 2. Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R A Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R b Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Or two Rs b Together with the atoms they are attached to, they form heterocyclic alkyl groups; and n is an integer between 0 and 8.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, X is C, Y is C, and Z is N; X is N, Y is C, and Z is N; X is C, Y is N, and Z is C; or X is N, Y is C, and Z is C.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, for , , , or .

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein ring A is a heterocyclic alkyl or heteroaryl group.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered heterocyclic alkyl or a 6-membered heteroaryl.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein... for , , , , , , , , , , , , , , , , , , , , , , , , or ,in R A1 R A2 and R A3 Each of them is independently hydrogen or independently selected from R A ; or R A1 and R A2 When they are adjacent to each other, they together with the atoms to which they are attached form cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, each of which is optionally substituted by one or more R groups; or R A1 and R A3 When they are adjacent to each other, they together with the atoms to which they are attached form cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, each of which is optionally substituted by one or more R groups; or R A2 and R A3 When they are adjacent to each other, they together with the atoms to which they are attached form cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, each of which is optionally substituted by one or more R groups; Or two Rs A2 Together with the same atom to which it is attached, they form cycloalkyl or heterocycloalkyl groups, each of which is optionally substituted by one or more R groups; Or two Rs A3 Together with the same atom to which it is attached, they form cycloalkyl or heteroalkyl groups, each of which is optionally substituted by one or more R atoms.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, each R A Independently, it is hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more R.

9. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein each R A Independently for -OR a Alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl-alkyl-, heterocycloalkyl-alkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more R.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein each R is independently a halogen, hydroxyl, cyano, alkyl, oxo, or alkylene group, wherein the alkyl and alkylene groups are optionally substituted by one or more R'.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein each R A Independently, -CH3, -CH2CH3, -CF3, -CH2F, -CHF2, -CH2CF3, -CH2CH2F, -CH2CHF2, -OCH3, -OCF3, -OCH2F, -OCHF2, -OCH2CH3, -OCH2CF3, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

12. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R 1 Alkyl groups optionally substituted with one or more R.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1 It is -CH3.

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein R 2 Alkyl groups optionally substituted with one or more R.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 2 It is -CH3.

16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen or halogen.

17. The compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R 4 -N(R) b )2.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein each R b It is hydrogen.

19. The compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, wherein R 5 -C(O)NH(R) a ).

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R a It is hydrogen.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia): Formula (Ia).

22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the compounds listed in Table 1 or Table 2.

23. A pharmaceutical composition comprising a compound of any one of claims 1-22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

24. A method of treating cancer in an individual in need, the method comprising administering to the individual a compound of any one of claims 1-22 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition of claim 23.

25. A method for regulating PKMYT1 in an individual, the method comprising administering to the individual a compound of any one of claims 1-22 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition of claim 23.

26. A method for inhibiting PKMYT1 in an individual, the method comprising administering to the individual a compound of any one of claims 1-22 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition of claim 23.

27. The method of claim 25 or 26, wherein the individual suffers from cancer.

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