HDAC1 / 2 selective inhibitors and their use

Abstract

This invention relates to HDAC1 / 2 selective inhibitors and their use. Specifically, the invention relates to compounds represented by general formula (1) and methods for preparing them, as well as the use of compounds represented by general formula (1) and their isomers, crystals, pharmaceutically acceptable salts, hydrates, or solvates as HDAC1 / 2 selective inhibitors in the preparation of antitumor drugs. [Formula 1] TIFF2026517492000048.tif29168

Description

[Technical Field]

[0001] This application claims priority to China Patent Application No. 202310547297.2, filed on 15 May 2023, which are incorporated herein by reference in their entirety.

[0002] This disclosure relates to the field of pharmaceutical chemistry, and more particularly to a group of HDAC1 / 2 selective inhibitors, methods for preparing the same, and the use of such compounds in the preparation of pharmaceuticals for the treatment or prevention of cancer. [Background technology]

[0003] Histone deacetylases (HDACs) are a type of protease whose histone acetylation and chromatin deacetylation are crucial processes in regulating gene expression. Abnormal gene expression is a molecular biological basis for the development of tumors and certain hereditary and metabolic diseases. Histone acetylation levels are coordinately regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Overexpression of HDACs and recruitment by transcription factors can lead to abnormal repression of specific genes, potentially inducing tumors and other diseases.

[0004] HDACs constitute a large enzyme family, with 18 known subtypes currently classified into four major classes. Class I has four subtypes: HDAC1, HDAC2, HDAC3, and HDAC8. Class II has six subtypes: HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10. Of these, HDAC4, HDAC5, HDAC7, and HDAC9 belong to Class IIa, while HDAC6 and HDAC10 belong to Class IIb. Class IV has only one subtype, HDAC11, which shows some homology to the aforementioned two classes. Class III has seven subtypes (SIRT1 to SIRT7) and does not structurally homologous to the previous three classes.

[0005] Published clinical results indicate that while HDAC1, HDAC2, and HDAC3 selective inhibitors such as MS275 (entinostat), chidamide (marketed), and CXD101 have significantly lower toxicity and side effects compared to pan-HDAC inhibitors such as vorinostat, romidepsin, bellinostat, and panobinostat, serious adverse reactions have still been observed in clinical trials. These adverse reactions include hematological adverse reactions, systemic adverse reactions (including fatigue and fever), gastrointestinal adverse reactions, metabolic and nutritional adverse reactions, and other adverse reactions such as dizziness and rash. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] (overview) This disclosure provides a group of compounds exhibiting high selectivity for HDAC1 / 2. These compounds demonstrate excellent efficacy and safety in various in vitro and in vivo evaluation experiments and have significant clinical implications for improving the efficacy and safety of existing drugs. [Means for solving the problem]

[0007] Specifically, the present invention provides compounds of general formula (1), their isomers, their crystals, pharmaceutically acceptable salts thereof, their hydrates, or their solvates. [ka] (In general formula (1), X is either -NH2 or -OH; Cy is a (C6-C14) aryl or (5-14 membered) heteroaryl, where each (C6-C14) aryl or (5-14 membered) heteroaryl independently has 1, 2, 3, or 4 R 5 It may be arbitrarily replaced with; Ring A is (C6-C14) aryl, (5-14 member) heteroaryl, (C3-C14) cycloalkyl, or (3-14 member) heterocycloalkyl; R 1 is H, D, or halogen; R 2 is H, D, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 member) heterocycloalkyl; R 3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 member) heterocycloalkyl, where the (C1-C6) alkyl, the (C1-C6) alkoxy, the (C1-C6) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C6) cycloalkyl, or the (3-6 member) heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R a ; R 4 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 member) heterocycloalkyl, where the (C1-C6) alkyl, the (C1-C6) alkoxy, the (C1-C6) haloalkyl, the (C2-C4) alkenyl, the (C2-C4) alkynyl, the (C3-C6) cycloalkyl, or the (3-6 member) heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R b ; Alternatively, R 3 and R 4 together with the S atom to which they are attached form a (3-16 member) heterocycloalkyl, where the (3-16 member) heterocycloalkyl are each independently optionally substituted with 1, 2, 3, or 4 R6 It may be arbitrarily replaced with; R 5 H, D, halogen, hydroxy, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO2R a ,-(CH2) m R a ,-(CH2) m CO2R a ,-(CH2) m -CONR a R b , -S(O) p R a , -S(O) p NR a R b ,-CONR a R b -C(=NR a )-NR a R b , -NR a COR b ,-CR a CONR a R b , -NR a CO2R a , -NR a S(O) p NR a R b , -NR a S(O) p R a ,-P(O) p R a R b, (C1~C8)alkyl, (C1~C8)alkoxy, (C1~C8)haloalkyl, (C2~C8)alkenyl, (C2~C8)alkynyl, (C3~C14)cycloalkyl, (3~14 member)heterocycloalkyl, (C6~C14)aryl, (5~14 member)heteroaryl, -(C1~C8)alkylene-(C3~C14)cycloalkyl, -(C1~C8)alkylene-(3~14 member)heterocycloalkyl, -(C1~C8)alkylene-(C6~C14)aryl, or -(C1~C8)alkylene-(5~14 member)heteroaryl, where the (C1~C8)alkyl, the (C1~ C8) alkoxy, the (C1~C8) haloalkyl, the (C2~C8) alkenyl, the (C2~C8) alkynyl, the (C3~C14) cycloalkyl, the (3~14 member) heterocycloalkyl, the (C6~C14) aryl, the (5~14 member) heteroaryl, the -(C1~C8) alkylene-(C3~C14) cycloalkyl, the -(C1~C8) alkylene-(3~14 member) heterocycloalkyl, the -(C1~C8) alkylene-(C6~C14) aryl, or the -(C1~C8) alkylene-(5~14 member) heteroaryl each independently has 1, 2, 3, or 4 R c It may be arbitrarily replaced with; R 6 H, D, halogen, hydroxy, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO2R a ,-(CH2) m R a ,-(CH2) m CO2R a ,-(CH2) m -CONR a R b , -S(O) p R a , -S(O) p NR a R b ,-CONR a R b -C(=NR a )-NR a Rb 、 -NR a COR b 、 -CR a CONR a R b 、 -NR a CO2R a 、 -NR a S(O) p NR a R b 、 -NR a S(O) p R a 、 -P(O) p R a R b 、 (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, -(C1-C8) alkylene-(C6-C14) aryl, or -(C1-C8) alkylene-(5-14 member) heteroaryl, wherein the (C1-C8) alkyl, the (C1-C8) alkoxy, the (C1-C8) haloalkyl, the (C2-C8) alkenyl, the (C2-C8) alkynyl, the (C3-C14) cycloalkyl, the (3-14 member) heterocycloalkyl, the (C6-C14) aryl, the (5-14 member) heteroaryl, the -(C1-C8) alkylene-(C3-C14) cycloalkyl, the -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, the -(C1-C8) alkylene-(C6-C14) aryl, or the -(C1-C8) alkylene-(5-14 member) heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R c ; or, when two R 6 are bonded to the same atom, the two R 6 may together with the atom to which they are bonded form one oxo group, a (C3-C6) cycloalkyl group, or a (3-6 member) heterocycloalkyl group; R a and R b each independently represents -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, or -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, the (C1-C8)alkoxy, the (C1-C8)haloalkyl, the (C2-C8)alkenyl, the (C2-C8)alkynyl, the (C3-C14)cycloalkyl, the (3-14-membered)heterocycloalkyl, the (C6-C14)aryl, the (5-14-membered)heteroaryl, the -(C1-C8)alkylene-(C3-C14)cycloalkyl, the -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, the -(C1-C8)alkylene-(C6-C14)aryl, or the -(C1-C8)alkylene-(5-14-membered)heteroaryl are each independently optionally substituted with 1, 2, 3, or 4 R c groups; or when two R a groups are attached to the same atom, the two R a groups may together form one oxo group; or when two R b groups are attached to the same atom, the two R b groups may together form one oxo group; or R a and R b attached to the same atom together with the atom to which they are attached may form one (5-7-membered)heterocycloalkyl group or (C3-C9)cycloalkyl group, wherein the (5-7-membered)heterocycloalkyl group or the (C3-C9)cycloalkyl group is each independently optionally substituted with 1, 2, 3, or 4 R cIt may be arbitrarily replaced with; R c is -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1~C8)alkyl, (C1~C8)alkoxy, (C1~C8)haloalkyl, (C2~C8)alkenyl, (C2~C8)alkynyl, (C3~C14)cycloalkyl, (3~14 member)heterocycloalkyl, (C6~C14)aryl, (5~14 member)heteroaryl, -(C1~C8)alkylene-(C1~C8)alkoxy, -(C1~C8)alkylene-(C3~C14)cycloalkyl, -(C1~C8)alkylene-(3~14 member)heterocycloalkyl, -(C1~C8)alkylene-(C6~C14)aryl, or -(C1~C8)alkylene-(5~14 member)heteroaryl; or two R c If the two R atoms are bonded to the same atom, c This may form one oxo group, a (C3-C6) cycloalkyl group, or a (3-6 membered) heterocycloalkyl group; m, n, and p are integers of 0, 1, or 2.

[0008] In another preferred embodiment, in general formula (1), X is -NH2 or -OH, and preferably X is -NH2.

[0009] In another preferred embodiment, in general formula (1), ring A is a (C6-C10)aryl, a (5-10 membered) heteroaryl, a (C3-C12) cycloalkyl, or a (3-12 membered) heterocycloalkyl, preferably ring A is a phenyl, a (5-7 membered) heteroaryl, or a (C5-C7) cycloalkyl, and more preferably ring A is a phenyl, pyridinyl, or cyclohexyl.

[0010] In another preferred embodiment, in general formula (1), Cy is a (C6-C10)aryl or a (5-12 membered) heteroaryl, where the (C6-C10)aryl or the (5-12 membered) heteroaryl each independently has 1, 2, 3, or 4 R 5The following can be optionally substituted, and preferably Cy is phenyl or a (5-7 membered) heteroaryl.

[0011] In another preferred embodiment, in general formula (1), Cy is phenyl or a (5-6 membered) heteroaryl, preferably, [ka] That is the case.

[0012] In another preferred embodiment, in general formula (1), R 5 H, D, halogen, hydroxy, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO2R a ,-(CH2) m R a ,-(CH2) m CO2R a ,-(CH2) m CONR a R b , -S(O) p R a , -S(O) p NR a R b ,-CONR a R b -C(=NR a )-NR a R b , -NR a COR b ,-CR a CONR a R b , -NR a CO2R a , -NR a S(O) p NR a R b , -NR a S(O) p R a ,-P(O) p R a R b, (C1~C6)alkyl, (C1~C6)alkoxy, (C1~C6)haloalkyl, (C2~C6)alkenyl, (C2~C6)alkynyl, (C3~C12)cycloalkyl, (3~12-membered)heterocycloalkyl, (C6~C14)aryl, (5~14-membered)heteroaryl, -(C1~C6)alkylene-(C3~C14)cycloalkyl, -(C1~C6)alkylene-(3~14-membered)heterocycloalkyl, -(C1~C6)alkylene-(C6~C14)aryl, or -(C1~C6)alkylene-(5~14-membered)heteroaryl, where the (C1~C6)alkyl, the (C1~ C6) alkoxy, the (C1~C6) haloalkyl, the (C2~C6) alkenyl, the (C2~C6) alkynyl, the (C3~C12) cycloalkyl, the (3~12-membered) heterocycloalkyl, the (C6~C14) aryl, the (5~14-membered) heteroaryl, the -(C1~C6) alkylene-(C3~C14) cycloalkyl, the -(C1~C6) alkylene-(3~14-membered) heterocycloalkyl, the -(C1~C6) alkylene-(C6~C14) aryl, or the -(C1~C6) alkylene-(5~14-membered) heteroaryl each independently contains 1, 2, 3, or 4 R c It may be optionally replaced with R 5 H, D, halogen, hydroxy, amino, cyano, nitro, -OR a , -NR a R b ,-CONR a R b ,-P(O) p R a R b , -S(O) p R a These are (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C7) cycloalkyl, or (3-7 member) heterocycloalkyl.

[0013] In another preferred embodiment, in general formula (1), R 5is H, D, F, Cl, -CN, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, or (C3-C6)cycloalkyl, preferably R 5 These are H, D, F, Cl, -CN, -CH3, -CF3, -OCH3, or [ka] That is the case.

[0014] In another preferred embodiment, in general formula (1), R 1 is H, D, F, Cl, Br, or I, preferably R 1 It is H, D, or F.

[0015] In another preferred embodiment, in general formula (1), R 2 is H, D, F, Cl, Br, I, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl, preferably R 2 It is H, D, or F.

[0016] In another preferred embodiment, in general formula (1), R 3 The (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl, where the (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl each independently has 1, 2, 3, or 4 R a It may be optionally replaced with R 3is a (C1-C4) alkyl, a (C1-C4) alkoxy, or a (C1-C4) haloalkyl, more preferably R 3 These are methyl, ethyl, or methoxymethyl.

[0017] In another preferred embodiment, in general formula (1), R 4 The R is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, or (3-6 membered)heterocycloalkyl, where the (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, or (3-6 membered)heterocycloalkyl each independently has 1, 2, 3, or 4 R b It may be optionally replaced with R 4 is a (C1-C4) alkyl, a (C1-C4) alkoxy, or a (C1-C4) haloalkyl, more preferably R 4 These are methyl, ethyl, or methoxymethyl.

[0018] In another preferred embodiment, in general formula (1), R 3 and R 4 These, together with the S atoms bonded to them, form a (3-14 member) heterocycloalkyl group, and each of these (3-14 member) heterocycloalkyl groups independently has 1, 2, 3, or 4 R atoms. 6 It may be replaced as needed.

[0019] In another preferred embodiment, in general formula (1), R 3 and R 4These, together with the S atoms bonded to them, form a (4-6 member) monocyclic heterocycloalkyl group containing one or two atoms optionally selected from N, S, and O, or a (7-9 member) bicyclic spiroheterocycloalkyl group containing one or two atoms optionally selected from N, S, and O, where the (4-6 member) monocyclic heterocycloalkyl group or the (7-9 member) bicyclic spiroheterocycloalkyl group each independently contains 1, 2, 3, or 4 R atoms. 6 It may be replaced as needed.

[0020] In another preferred embodiment, in general formula (1), R 6 H, D, halogen, hydroxy, amino, cyano, nitro, -OR a , -NR a R b , -C(O)R a , -CO2R a ,-(CH2) m R a ,-(CH2) m CO2R a ,-(CH2) m CONR a R b , -S(O) p R a , -S(O) p NR a R b ,-CONR a R b -C(=NR a )-NR a R b , -NR a COR b ,-CR a CONR a R b , -NR a CO2R a , -NR a S(O) p NR a R b , -NR a S(O) p R a ,-P(O) p R a R b, (C1~C6)alkyl, (C1~C6)alkoxy, (C1~C6)haloalkyl, (C2~C6)alkenyl, (C2~C6)alkynyl, (C3~C14)cycloalkyl, (3~14 member)heterocycloalkyl, (C6~C14)aryl, (5~14 member)heteroaryl, -(C1~C6)alkylene-(C3~C14)cycloalkyl, -(C1~C6)alkylene-(3~14 member)heterocycloalkyl, -(C1~C6)alkylene-(C6~C14)aryl, or -(C1~C6)alkylene-(5~14 member)heteroaryl, where the (C1~C6)alkyl, the (C1~ C6) alkoxy, the (C1~C6) haloalkyl, the (C2~C6) alkenyl, the (C2~C6) alkynyl, the (C3~C14) cycloalkyl, the (3~14 member) heterocycloalkyl, the (C6~C14) aryl, the (5~14 member) heteroaryl, the -(C1~C6) alkylene-(C3~C14) cycloalkyl, the -(C1~C6) alkylene-(3~14 member) heterocycloalkyl, the -(C1~C6) alkylene-(C6~C14) aryl, or the -(C1~C6) alkylene-(5~14 member) heteroaryl each independently has 1, 2, 3, or 4 R c It may be optionally replaced with; preferably, R 6 H, D, halogen, hydroxy, amino, cyano, -OR a , -NR a R b The (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, -(C1-C4) alkylene-(C3-C7) cycloalkyl, -(C1-C4) alkylene-(3-7 member) heterocycloalkyl, or -(C1-C4) alkylene-(5-7 member) heteroaryl, where the (C1-C4) alkyl, the (C1-C4) alkoxy, the (C1-C4) haloalkyl, the -(C1-C4) alkylene-(C3-C7) cycloalkyl, the -(C1-C4) alkylene-(3-7 member) heterocycloalkyl, or the -(C1-C4) alkylene-(5-7 member) heteroaryl each independently has 1, 2, 3, or 4 R cIt may be arbitrarily substituted with; or two R 6 If the two R atoms are bonded to the same atom, 6 These atoms, together with the atoms bonded to them, may form one oxo group.

[0021] In another preferred embodiment, in general formula (1), R 6 These are H, D, F, Cl, hydroxy, amino, cyano, methyl, ethyl, -NH(CH3), -N(CH3)2, -CD3, -C(O)CH3, or [ka] That is the case.

[0022] In another preferred embodiment, in general formula (1), R a and R bEach of these is independently -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1~C6)alkyl, (C1~C6)alkoxy, (C1~C6)haloalkyl, (C2~C6)alkenyl, (C2~C6)alkynyl, (C3~C14)cycloalkyl, (3~14 member)heterocycloalkyl, (C6~C14)aryl, (5~14 member)heteroaryl, -(C1~C6)alkylene-(C3~C14)cycloalkyl, -(C1~C6)alkylene-(3~14 member)heterocycloalkyl, -(C1~C6)alkylene-(C6~C14)aryl, or -(C1~C6)alkylene-(5~14 member)heteroaryl, where, Each of the following (C1-C6) alkyls, (C1-C6) alkoxys, (C1-C6) haloalkyls, (C2-C6) alkenyls, (C2-C6) alkynyls, (C3-C14) cycloalkyls, (3-14 member) heterocycloalkyls, (C6-C14) aryls, (5-14 member) heteroaryls, -(C1-C6) alkylene-(C3-C14) cycloalkyls, -(C1-C6) alkylene-(3-14 member) heterocycloalkyls, -(C1-C6) alkylene-(C6-C14) aryls, or -(C1-C6) alkylene-(5-14 member) heteroaryls independently contains 1, 2, 3, or 4 R c It may be arbitrarily substituted with; or two R a If the two R atoms are bonded to the same atom, a It may form one oxo group; or two R groups b If the two R atoms are bonded to the same atom, b It may form one oxo group; preferably, R a and R bEach of these is independently H, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C3-C7) cycloalkyl, (3-7 member) heterocycloalkyl, (C6-C10) aryl, or (5-7 member) heteroaryl, where the (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C3-C7) cycloalkyl, (3-7 member) heterocycloalkyl, (C6-C10) aryl, or (5-7 member) heteroaryl each independently has 1, 2, 3, or 4 R c It may be replaced as needed.

[0023] In another preferred embodiment, in general formula (1), R bonded to the same atom a and R b Together with the atoms bonded to them, these form one (5-7 member) heterocycloalkyl group or (C3-C9) cycloalkyl group, where each (5-7 member) heterocycloalkyl group or (C3-C9) cycloalkyl group independently has 1, 2, 3, or 4 R atoms. c It is arbitrarily replaced.

[0024] In another preferred embodiment, in general formula (1), R c is -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1~C6)alkyl, (C1~C6)alkoxy, (C1~C6)haloalkyl, (C2~C6)alkenyl, (C2~C6)alkynyl, (C3~C14)cycloalkyl, (3~14 member)heterocycloalkyl, (C6~C14)aryl, (5~14 member)heteroaryl, -(C1~C6)alkylene-(C1~C8)alkoxy, -(C1~C6)alkylene-(C3~C14)cycloalkyl, -(C1~C6)alkylene-(3~14 member)heterocycloalkyl, -(C1~C6)alkylene-(C6~C14)aryl, or -(C1~C6)alkylene-(5~14 member)heteroaryl; or two R c If the two R atoms are bonded to the same atom, cIt may form one oxo group; preferably, R c These are H, D, halogen, hydroxy, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C3-C7) cycloalkyl, or (3-7 member) heterocycloalkyl.

[0025] In various embodiments of the present invention, the compound of general formula (1) has the following structure: [ka] [ka] [ka] Take one of them.

[0026] The present invention further intends to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and as an active ingredient, a compound of general formula (1) of the present invention or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate or its solvate.

[0027] The present invention further intends to provide the use of a compound of general formula (1) of the present invention, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate or solvate, or the above-mentioned pharmaceutical composition, in the preparation of a pharmacopoeia for treating, modulating or preventing a disease associated with HDAC1 / 2, wherein the disease is preferably cancer, and the cancer is hematological or solid tumor. [Modes for carrying out the invention]

[0028] The above general description and the following detailed description of the present invention are both illustrative and descriptive, and should be understood as being intended to provide a further description of the claimed invention.

[0029] (Synthesis of compounds)

[0030] Methods for preparing the compound of general formula (1) of this disclosure are described below in detail, but these specific methods do not limit the disclosure in any way.

[0031] The compound of formula (1) above can be synthesized using standard synthetic techniques, well-known techniques, combined with the methods described herein. Furthermore, the solvent, temperature, and other reaction conditions described herein may vary. The starting materials for the synthesis of the compound may be obtained by synthesis or may be commercially available. The compound described herein and other related compounds with different substituents are described in March, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANICSYNTHESIS, 3 rd The compounds can be synthesized using well-known techniques and starting materials, including the method found in Ed., (Wiley 1999). General methods for preparing the compounds can be modified by using appropriate reagents and conditions for introducing various groups into the molecular formulas described herein.

[0032] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, and reaction time, are not limited to those described below. Furthermore, the compounds of this disclosure may be easily prepared by any combination of various synthesis methods described herein or known in the art, and such combinations can be readily determined by those skilled in the art to whom this disclosure relates. In one embodiment, this disclosure further provides a method for preparing a compound of general formula (1) using the following general reaction schemes 1 to 3.

[0033] General reaction scheme 1 [ka]

[0034] A, Cy, R 1 , R 2 , R 3 , R 4 X, m, and n are as defined above, and PG represents a commonly used amine group or hydroxyl protecting group (e.g., Boc, Cbz, Bz, Fmoc, or Bn). As shown in General Reaction Scheme 1, compound A1 and starting material A2 are subjected to a condensation reaction to obtain compound A3, and A3 is subjected to a coupling reaction and a conventional deprotection reaction to obtain the target compound (1).

[0035] General reaction scheme 2 [ka]

[0036] A, Cy, R 1 , R 2 , R 3 , R 4 X, m, and n are as defined above, and PG represents a commonly used amine group or hydroxyl protecting group (e.g., Boc, Cbz, Bz, Fmoc, or Bn). As shown in General Reaction Scheme 2, compound B1 is subjected to a coupling reaction to obtain compound B2, and compound B2 and starting material A1 are subjected to a condensation reaction and a conventional deprotection reaction to obtain the target compound (1).

[0037] General reaction scheme 3 [ka]

[0038] A, Cy, R 1 , R 2 , R 3 , R 4X, m, and n are as defined above, PG represents a commonly used amine group or hydroxyl protecting group (e.g., Boc, Cbz, Bz, Fmoc, or Bn), and Y represents a leaving group such as Br, I, or OTf. As shown in General Reaction Scheme 3, compound C1 and starting material C2 are subjected to a condensation reaction to obtain the target compound C3, and compound C3 and compound C4 are subjected to a coupling reaction and a conventional deprotection reaction to obtain the target compound (1).

[0039] Further forms of compounds

[0040] In this specification, "pharmaceutically acceptable" means a relatively non-toxic substance, such as a carrier or diluent, that does not cause the loss of biological activity or properties in a compound. For example, when a substance is administered to an individual, the substance does not cause undesirable biological effects or harmful interactions with any of its components.

[0041] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism receiving the administration, nor does it eliminate the biological activity and properties of the compound. In certain specific embodiments, the pharmaceutically acceptable salt is obtained by reacting the compound of the general formula with an acid or a base, where the acid or base is as defined in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 1 st Examples include, but are not limited to, those listed in Ed., (Wiley, 2002).

[0042] It should be understood that pharmaceutically acceptable salts include solvated or crystalline forms, particularly solvates or polymorphs. Solvates are formed selectively upon crystallization in pharmaceutically acceptable solvents such as water and ethanol, containing stoichiometric or nonstoichiometric amounts of solvent. Hydrates are formed when the solvent is water, and alkoxides are formed when the solvent is ethanol. Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, the organic solvents used including, but not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds described herein may exist in either a non-solvated or solvated form. Generally, the solvated form is considered equivalent to the non-solvated form for the purposes of the compounds and methods provided herein.

[0043] In other specific examples, compounds of general formula (1) may be prepared in different forms, including but not limited to amorphous, pulverized, and nanoparticle forms. Furthermore, compounds of general formula (1) may include crystalline forms and may be polymorphs. Polymorphs contain different lattice arrangements of the same elements of the compound. Polymorphs generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystalline forms, optical properties, electrical properties, stability, and solubility. A single dominant crystalline form may result from various factors such as the recrystallization solvent, crystallization rate, and storage temperature.

[0044] In another embodiment, compounds of general formula (1) may have chiral centers and / or axial chirality, and thus may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomer compounds, single diastereomers, and cis-trans isomers. Each chiral center or axial chirality independently produces two optical isomers, and all possible optical isomers, diastereomer mixtures, and pure or partially pure compounds are included in the scope of this disclosure. This disclosure means that it includes all such isomers of these compounds.

[0045] The compounds of this disclosure may contain unnatural proportions of atomic isotopes in one or more of the atoms constituting such compounds. For example, the compound may contain tritium ( 3 H), Iodine-125( 125 I) and C-14 ( 14 They can be labeled with radioactive isotopes such as ¹¹C). As another example, deuterated compounds can be formed by substituting a hydrogen atom with deuterium. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated pharmaceuticals, deuterated pharmaceuticals generally have advantages such as reduced toxicity and side effects, improved drug stability, enhanced potency, and extended in vivo half-life of the drug. All isotopic variations of the compounds of this disclosure, whether radioactive or not, are included in the scope of this disclosure.

[0046] Any atom of a compound in this disclosure refers to an isotope of the atom in the stable state of the compound, unless otherwise specified. Unless otherwise specified, when a site in the molecular structure is selected as "H" or "hydrogen", that site should be understood to have the natural abundance of the hydrogen isotope. Similarly, unless otherwise specified, when a site is selected as "D" or "deuterium", that site should be understood to have a deuterium isotope abundance at least 3000 times the natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0047] More preferably, each deuterated site of the deuterated compound of this disclosure has a deuterium atom abundance of at least 3500 times its natural abundance (deuterium atom enrichment of 52.2%). More preferably, the deuterium atom abundance is at least 4500 times its natural abundance (deuterium atom enrichment of 67.5%). More preferably, the deuterium atom abundance is at least 5000 times its natural abundance (deuterium atom enrichment of 75%). More preferably, the deuterium atom abundance is at least 6000 times its natural abundance (deuterium atom enrichment of 90%). More preferably, the deuterium atom abundance is at least 6333 times its natural abundance (deuterium atom enrichment of 95%). More preferably, the deuterium atom abundance is at least 6466.7 times its natural abundance (deuterium atom enrichment of 97%). More preferably, the deuterium atom abundance is at least 6600 times its natural abundance (deuterium atom enrichment of 99%). More preferably, the deuterium atom abundance is at least 6633.3 times that of the natural abundance (deuterium atom enrichment of 99.5%).

[0048] Explanation of terms

[0049] Unless otherwise specified, terms used herein, including those used in this specification and in the claims, are defined as follows: Note that in this specification and in the appended claims, the singular forms “a” and “an” have plural meanings unless otherwise specified. Unless otherwise specified, conventional methods of mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. In this specification, “or” or “and” means “and / or” unless otherwise specified.

[0050] Unless otherwise specified, “alkyl” refers to saturated aliphatic hydrocarbon groups having linear and branched groups containing 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl, are preferred. As used herein, “alkyl” includes unsubstituted alkyl and substituted alkyl groups, in particular alkyl groups substituted with one or more halogens. Preferred alkyl groups are CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu, and t Selected from Bu.

[0051] Unless otherwise specified, "alkylene" refers to the divalent alkyl group as defined above. Examples of alkylenes include, but are not limited to, methylene and ethylene.

[0052] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon double bond, including a linear or branched group containing 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl, are preferred. Lower alkenyl groups containing 1 to 2 carbon atoms are even more preferred.

[0053] Unless otherwise specified, "alkenylene" refers to the divalent alkenyl as defined above.

[0054] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group having a carbon-carbon triple bond, including linear and branched groups containing 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl, are preferred. Lower alkynyl groups containing 1 to 2 carbon atoms are even more preferred.

[0055] Unless otherwise specified, "alkynylene" refers to the divalent alkynyl as defined above.

[0056] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), preferably a non-aromatic hydrocarbon ring system containing 3 to 14 ring carbon atoms (C 3~14 It is a cycloalkyl. In some embodiments, the cycloalkyl has 3 to 10 ring carbon atoms (C 3~10 (Cycloalkyl). In some embodiments, the cycloalkyl has 3 to 8 ring carbon atoms (C 3~8 (Cycloalkyl). In some embodiments, the cycloalkyl has 3 to 7 ring carbon atoms (C 3~7 (Cycloalkyl). In some embodiments, the cycloalkyl has 3 to 6 ring carbon atoms (C 3~6 (Cycloalkyl). In some embodiments, the cycloalkyl has 4 to 6 ring carbon atoms (C 4~6 (Cycloalkyl). In some embodiments, the cycloalkyl has 5-6 ring carbon atoms (C 5~6 (Cycloalkyl). In some embodiments, the cycloalkyl has 5 to 10 ring carbon atoms (C 5~10 Cycloalkyl). In the case of cycloalkyls, partially unsaturated cycloalkyls may be called "cycloalkenyls" if the carbocyclic ring contains at least one double bond, or "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. Cycloalkyls may contain monocyclic or polycyclic groups (e.g., having two, three, or four fused rings) and spiro rings. In some embodiments, cycloalkyls are monocyclic. In some embodiments, cycloalkyls are bicyclic. In some embodiments, cycloalkyls are monocyclic or bicyclic. In some embodiments, cycloalkyls are tricyclic. The ring carbon atoms of cycloalkyls may optionally be oxidized to form oxo or thio groups. Cycloalkyls further contain cycloalkylenes. In some embodiments, cycloalkyls contain zero, one, or two double bonds. In some embodiments, cycloalkyls contain one or two double bonds (partially unsaturated cycloalkyls). In some embodiments, cycloalkyls may be condensed with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, the cycloalkyl may be condensed with aryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl may be condensed with aryl and heterocycloalkyl. In some embodiments, the cycloalkyl may be condensed with aryl and cycloalkyl. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, and bicyclo[2.1.1]hexyl.

[0057] Unless otherwise specified, "cycloalkylene" refers to the divalent cycloalkyl group as defined above.

[0058] Unless otherwise specified, "alkoxy" refers to an alkyl group that is bonded to the rest of the molecule via an ether oxygen atom. Typical alkoxy groups have 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxys, in particular alkoxys substituted with one or more halogens. Preferred alkoxys include OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO, and t- Selected from BuO.

[0059] Unless otherwise specified, "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group. For example, a monocyclic aryl ring can be condensed with one or more carbocyclic aromatic groups. Examples of aryls include, but are not limited to, phenyl, naphthyl, and phenanthryl.

[0060] Unless otherwise specified, "aryloxy" refers to an aryl group that is bonded to the rest of the molecule via an ether oxygen atom. Examples of aryloxys include, but are not limited to, phenoxy and naphthoxy.

[0061] Unless otherwise specified, "arylene" refers to the divalent aryl compounds defined above. Examples of arylenes include, but are not limited to, phenylene, naphthylene, and phenanthrylene.

[0062] Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms independently selected from O, N, and S, preferably 1, 2, 3, or 4 heteroatoms. Preferably, the heteroaryl is a 5-14 membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen. More preferably, the heteroaryl is a 5-9 membered aromatic group containing 1-2 heteroatoms optionally selected from oxygen, sulfur, and nitrogen. More preferably, the heteroaryl is a 5-6 membered ring aromatic group containing 1-3 heteroatoms optionally selected from oxygen, sulfur, and nitrogen. The heteroaryl can be monocyclic or polycyclic. A monocyclic heteroaryl is preferably a 5-6 membered aromatic group containing 1-3 heteroatoms optionally selected from oxygen, nitrogen, and sulfur. More preferably, a monocyclic heteroaryl is a 5-6 membered aromatic group containing 1-2 heteroatoms optionally selected from oxygen, nitrogen, and sulfur. More preferably, the monocyclic heteroaryl is a 5-6 membered aromatic group containing one heteroatom optionally selected from oxygen, nitrogen, and sulfur. In some embodiments, the monocyclic heteroaryl ring is condensed with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryls include pyridyl, pyridadinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanil, thienyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranil, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, [ka] These include, but are not limited to, the following:

[0063] Unless otherwise specified, "heteroarylene" refers to the divalent heteroaryl as defined above.

[0064] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of its ring structure and has at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and selenium. A heterocycloalkyl is preferably a saturated or partially unsaturated ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and more preferably a saturated or partially unsaturated ring containing 1 to 2 heteroatoms selected from oxygen, sulfur, and nitrogen. In some embodiments, a heterocycloalkyl is a 5 to 8-membered non-aromatic ring containing a ring carbon atom and 1 to 4 ring heteroatoms, each heteroatom independently optionally selected from nitrogen, oxygen, or sulfur (5 to 8-membered heterocycloalkyl). A heterocycloalkyl is a 5 to 6-membered non-aromatic ring containing a ring carbon atom and 1 to 4 ring heteroatoms, each heteroatom independently optionally selected from nitrogen, oxygen, and sulfur (5 to 6-membered heterocycloalkyl). In some embodiments, a 5- to 6-membered heterocycloalkyl group contains 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocycloalkyl group contains 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocycloalkyl group contains 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Partially unsaturated heterocycloalkyl groups may be called "heterocycloalkenyls" if the heterocycloalkyl group contains at least one double bond, and may be called "heterocycloalkynyls" if the heterocycloalkyl group contains at least one triple bond. Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridging rings) systems. In some embodiments, a heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.The ring carbon atoms and heteroatoms of a heterocycloalkyl group may optionally be oxidized to form an oxo group, a thio group, or other oxidative bonds (e.g., C(O), S(O), C(S), or S(O)2, and N-oxides), or the nitrogen atom may be quaternized. Heterocycloalkyl groups may be bonded via ring carbon atoms or ring heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. The definition of a heterocycloalkyl group also includes benzo derivatives that have one or more aromatic rings fused (i.e., sharing a bond) to a heterocycloalkyl ring (also called a partially unsaturated heterocycle), such as piperidine, morpholine, azepine, and thienyl. Heterocycloalkyl groups containing fused aromatic rings may be bonded via any ring atoms containing the ring atoms of the fused aromatic ring. Examples of heterocycloalkyls include azetidinyl, azepinyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazo[ 4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinonyl, hydantoinyl, dioxolanil, phthalimidyl, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinil, thiopyranil, pyronyl, tetrahydrothienyl, 2-azaspiro[3,3]heptanil, indolinyl. [ka] These include, but are not limited to, the following:

[0065] Unless otherwise specified, "heterocycloalkylene" refers to the divalent heterocycloalkyl group as defined above.

[0066] Unless otherwise specified, "heterocyclic spirocycloalkyl" refers to a polycyclic hydrocarbyl formed by sharing one carbon atom (called a spiro atom) between two or more saturated or partially unsaturated monocyclic rings, where one or more (e.g., 1, 2, or 3) ring atoms are nitrogen, oxygen, and S(O). pThe heteroatom is selected from (wherein p is an integer of 0, 1, or 2), and the remaining ring atoms are carbon atoms. If the heteroatom is a nitrogen atom, the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or other substituents already defined herein). Each monocyclic ring may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Depending on the number of spiroatoms shared between the rings, the spiroheterocyclyl may be a monospiroheterocyclyl, a dispiroheterocyclyl, or a polyspiroheterocyclyl. The term "(5-15 member) heterocyclic spirocycloalkyl" refers to a heterocyclic spirocycloalkyl having 5-15 ring atoms, where the monocyclic rings sharing the spiroatoms are 3-8 member monocyclic rings, and at least one monocyclic ring is a heterocycloalkyl ring. A heterocyclic spirocycloalkyl having 6 to 18 ring atoms, of which 1 to 3 are heteroatoms (6 to 18 members), is preferred. A heterocyclic spirocycloalkyl having 7 to 15 ring atoms, of which 1 to 3 are heteroatoms (7 to 15 members), is more preferred. A 9-membered (4-membered monocyclic (heterocyclyl) ring / 6-membered monocyclic (heterocyclyl) ring, 5-membered monocyclic (heterocyclyl) ring / 5-membered monocyclic (heterocyclyl) ring) monospiroheterocyclyl, a 10-membered (5-membered monocyclic (heterocyclyl) ring / 6-membered monocyclic (heterocyclyl) ring) monospiroheterocyclyl, or an 11-membered (6-membered monocyclic (heterocyclyl) ring / 6-membered monocyclic (heterocyclyl) ring) monospiroheterocyclyl is most preferred. Specific examples of heterocyclic spirocycloalkyls include: [ka] These include, but are not limited to, the following:

[0067] Unless otherwise specified, "oxo" means =O. For example, a group formed when one carbon atom is substituted with one oxo atom is called a "carbonyl." [ka] The group formed when sulfur is substituted with one oxo is called "sulfinyl". [ka] The group formed when sulfur is substituted with two oxos is called "sulfonyl". [ka] That is the case.

[0068] Unless otherwise specified, "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" (or "halogenated") preceding a group name indicates that the group is partially or completely halogenated, i.e., substituted with F, Cl, Br, or I, preferably in any combination of F or Cl.

[0069] Unless otherwise specified, the term “substituted” means that one or more hydrogen atoms on a given atom or group are substituted with one or more substituents other than hydrogen, to the extent that the valence of the given atom does not exceed its normal valence. For example, one or more hydrogen atoms in alkyl, alkylene, alkenyl, alkynyl, hydroxy, amino, etc., may be substituted with one or more substituents. Examples of such substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxy, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. The definition of “substituted” does not include similar indeterminate structures obtained by defining substituents that are infinitely further bonded (e.g., a substituted aryl with a substituted alkyl is itself substituted with a substituted aryl, and that substituted aryl is further substituted with a substituted heteroalkyl). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl with two other substituted aryls is limited to a substituted aryl substituted with ((substituted aryl) substituted substituted aryl). Similarly, the above definition does not include unacceptable substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, “substituted” may refer to other chemical groups as defined herein. For example, the term “substituted aryl” includes, but is not limited to, “alkylaryl.” Unless otherwise specified, when a group is described as optionally substituted, the substituents of that group themselves are not substituted.

[0070] "Optional" or "optional" means that the event or situation described thereafter may occur, but is not necessarily to occur, and that description includes both cases in which the event or situation occurs and cases in which it does not occur.

[0071] Unless otherwise specified, "acyl" refers to -C(=O)-R, where R is selected from optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocycloalkyl.

[0072] Unless otherwise specified, the word "comprise," or its variations such as "comprises" or "comprising," refers to the inclusion of a specified element or integer, or group of elements or integers, but does not exclude other elements or integers, or groups of elements or integers.

[0073] The substituent "-O-CH2-O-" means that two oxygen atoms in the substituent are bonded to two adjacent carbon atoms in the heterocycloalkyl, aryl, or heteroaryl group, for example as follows: [ka]

[0074] If the linker group number is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0075] If one of the variables is selected from chemical bonds, it means that the two groups linked by this variable are directly linked. For example, if L in XLY represents a chemical bond, it actually means that the structure is XY.

[0076] The term "membered ring" includes any cyclic structure. The term "member" refers to the number of back-chain atoms that form the ring. For example, cyclohexyl, pyridinyl, pyranyl, and thiopyranyl are 6-membered rings, while cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.

[0077] The term "part" refers to a specific part or functional group of a molecule. A chemical part is generally considered to refer to a chemical substance that is contained within or bonded to a molecule.

[0078] The term “isomer” refers to any tautomer, stereoisomer, atropisomer, isotopeisomer, enantiomer, or diastereomer of the compounds of this disclosure. The compounds of this disclosure may have one or more chiral centers or double bonds and therefore exist in the form of stereoisomers, e.g., double bond isomers (i.e., E / Z geometric isomers), or diastereomers (i.e., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Accordingly, the compounds of this disclosure encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, as well as mixtures of enantiomers and stereoisomers, e.g., racemates. Mixtures of enantiomers and stereoisomers of the compounds disclosed herein can be decomposed into their constituent enantiomers or stereoisomers by well-known methods such as chiral gas chromatography and chiral high-performance liquid chromatography, as well as by the form of chiral salt complexes or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0079] The term "isotopic isomer" refers to distinct molecules whose structure differs only due to their isotopic composition, with the rest of their structure being identical.

[0080] Specific pharmaceutical and medical terms

[0081] As used herein, the term “acceptable” means that the formulation ingredient or active ingredient does not have an unduly adverse effect on the health of the general subject being treated.

[0082] As used herein, the terms “treatment,” “treatment course,” and “therapy” include alleviating, inhibiting, or improving the symptoms or condition of a disease; inhibiting the development of complications; improving or preventing an underlying metabolic syndrome; inhibiting the development of a disease or symptom (e.g., controlling the progression of a disease or condition); alleviating a disease or symptom; regressing a disease or symptom; alleviating complications caused by a disease or symptom; or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, may improve a disease, symptom, or condition, particularly by improving the severity of the disease, delaying its onset, slowing its progression, or shortening its duration. A fixed or single dose, or a continuous or intermittent dose, may be caused by or related to the administration.

[0083] "Active ingredient" refers to the compound of general formula (1) and a pharmaceutically acceptable inorganic or organic salt of the compound of general formula (1). The compounds of this disclosure may contain one or more chiral centers (chiral centers or axial chiral centers) and may therefore exist in the form of racemates, racemic mixtures, single enantiomers, diastereomer compounds, and single diastereomers. The possible chiral centers may exist depending on the properties of various substituents on the molecule. Each of these chiral centers independently produces two optical isomers, and all possible optical isomers, diastereomer mixtures, and pure or partially pure compounds are within the scope of this disclosure. This disclosure means that it includes all such isomeric forms of these compounds.

[0084] In this specification, terms such as “compound,” “composition,” “drug,” or “pharmaceutical or medicinal product” are used interchangeably and all refer to compounds or compositions that, when administered to an organism (human or animal), can induce a desired pharmacological and / or physiological response through local and / or systemic effects.

[0085] The terms “administered, administered, or given” in this specification mean the direct administration of a compound or composition, or the administration of a prodrug, derivative, analogue, etc., of an active compound.

[0086] While the numerical ranges and parameters defining the broad scope of this disclosure are approximations, relevant values ​​shown in specific embodiments are shown herein as accurately as possible. However, any numerical value inherently includes a standard deviation that inevitably arises from certain test methods. Here, “approximately” generally means that the actual numerical value is within a specific numerical value or range of ±10%, 5%, 1%, or 0.5%. Alternatively, the term “approximately” indicates that the actual numerical value is within the acceptable standard error of the mean, as those skilled in the art would understand. Except for experimental examples or unless otherwise specified, all ranges, quantities, values, and percentages used herein (e.g., to describe quantities of substance, lengths of time, temperatures, operating conditions, proportions of quantities, etc.) are understood to be modified by the term “approximately.” Thus, unless otherwise specified, all numerical parameters described herein and in the appended claims are approximations that may vary as desired. At a minimum, these numerical parameters should be interpreted as numerical values ​​obtained using the indicated significant figures or conventional rounding rules.

[0087] Unless otherwise defined herein, scientific and technical terms used herein have the same meanings as those generally understood by those skilled in the art. Furthermore, singular nouns used herein include their plural forms unless inconsistent with the context, and plural nouns used include their singular forms.

[0088] therapeutic use

[0089] The present invention provides a method for treating diseases, including but not limited to HDAC enzyme-related conditions (e.g., cancer), using a compound of general formula (1) or a pharmaceutical composition of the present invention.

[0090] In some embodiments, a method for treating cancer is provided, the method comprising administering an effective amount of any of the aforementioned pharmaceutical compositions containing a compound of general formula (1) to an individual in need. In some embodiments, the cancer is mediated by a relevant HDAC enzyme. In some embodiments, the compounds of the Disclosure are used in combination with an immune checkpoint inhibitor. In some embodiments, the compounds of the Disclosure are used in combination with a PD-1 or PD-L1 inhibitor. In some embodiments, the compounds of the Disclosure are used in combination with a PD-1 antibody. In some embodiments, the compounds of the Disclosure are used in combination with a PD-L1 antibody. In some embodiments, the compounds of the Disclosure are used in combination with a VEGF / VEGFR inhibitor. In some embodiments, the compounds of the Disclosure are used in combination with an immune checkpoint inhibitor and a VEGF / VEGFR inhibitor. In some embodiments, the compounds of the Disclosure are used in combination with a PD-1 inhibitor and a VEGF / VEGFR inhibitor. In some embodiments, the compounds of the Disclosure are used in combination with a PD-1 antibody and a VEGF / VEGFR inhibitor. PD-1 antibodies include, but are not limited to, nivolumab, pembrolizumab, tripalimab, cintilimab, camrelizumab, tislerizumab, penprimab, zinbererimab, serpullimab, pukotenlimab, pidilizumab, semiprimab, spartalizumab, AMG404, RN888, mAbl5, MEDI-0680, BGB-108, spartalizumab, IBI-308, mDX-400, SHR-1210, PF-06801591, PDR-001, GB-226, and STI-1110, as well as biosimilars, biobetters, and bioequivalences of these inhibitors. PD-L1 antibodies include, but are not limited to, durvalumab, atezolizumab, emvafolimab, sugemalimab, avelumab, BMS-936559, AMP-714, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, KY-1003, and biosimilars, biobetters, and bioequivalences of these inhibitors.VEGF / VEGFR inhibitors include, but are not limited to, bevacizumab, ranibizumab, ramucirumab, sorafenib, axitinib, apatinib, sunitinib, regorafenib, vandetanib, pazopanib, lenvatinib, cabozantinib, ponatinib, aflibercept, and fluquintinib. In other embodiments, the cancers include breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, gastric cancer, leukemia, lymphoma, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma, or intracranial tumors.

[0091] Route of administration

[0092] The compounds of this disclosure and their pharmaceutically acceptable salts can be made into various formulations comprising a safe and effective amount of the compound of this disclosure or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient or carrier, where “safe and effective amount” means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the person being treated.

[0093] "Pharmacopoeia-acceptable excipients or carriers" means one or more compatible solid or liquid fillers or gels that are suitable for human use and must be of sufficient purity and low toxicity. "Compatibility" as used herein means that the components of the composition can be mixed with the compounds of this disclosure without significantly reducing the pharmaceutically active properties of the compounds. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, fragrances, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0094] The compounds of this disclosure may be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0095] Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or any of the following components: (a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders such as paraffin; (f) absorption enhancers such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may further contain a buffering agent.

[0096] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. These may contain opacifying agents, and the active compound or compound in such compositions may be released with delay in specific parts of the gastrointestinal tract. Examples of embedding components that can be used include polymers and waxes. If necessary, the active compound may form microcapsules with one or more of the above excipients.

[0097] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof, which are commonly used in the art.

[0098] In addition to such inert diluents, the composition may further contain adjuvants such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0099] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar, or mixtures thereof.

[0100] Parenteral injection compositions may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injection solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0101] Dosage forms for topical administration of the compounds of this disclosure include ointments, powders, patches, sprays, and inhalants. The active ingredients are mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or sprays as required.

[0102] The compounds of this disclosure may be administered alone or in combination with other pharmaceutically acceptable compounds. When the pharmaceutical compositions of the present invention are used, a safe and effective amount of the compounds of this disclosure is administered to the mammal to be treated (such as a human), where the dose is a pharmaceutically effective dose. For a 60 kg human, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, factors such as the route of administration and the patient's health condition are also taken into consideration when determining the specific dose, but these are well known to those skilled in the art.

[0103] The features described herein, or the features described in the embodiments, can be combined in any way. All features disclosed herein can be used in any composition, and various features disclosed herein can be replaced with any alternative features that serve the same, equivalent, or similar purpose. Accordingly, unless otherwise specified, the features disclosed herein are merely general examples of equivalent or similar features. [Examples]

[0104] (Detailed explanation)

[0105] Various specific embodiments, features, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions are described in detail below, which will make the contents of this disclosure very clear. Please understand that the following detailed description and examples describe specific examples for reference purposes only. After reading the description of this disclosure, those skilled in the art can make various changes or modifications to the invention, and such equivalents also fall within the scope of this application as defined herein.

[0106] In all embodiments, 1 ¹H-NMR spectra were recorded using a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts are expressed as δ (ppm). Unless otherwise specified, 200-300 mesh silica gel was used for separation, and the ratio of the eluent was expressed as a volume ratio.

[0107] The following abbreviations are used in this disclosure: AcOH is glacial acetic acid; Boc2O is di-tert-butyl dicarbonate; CDCl3 is deuterated chloroform; CD3I is deuterated iodomethane; Cs2CO3 is cesium carbonate; DCM is dichloromethane; DCE is 1,2-dichloroethane; Diox is 1,4-dioxane; DIPEA is diisopropylethylamine; DMSO is dimethyl sulfoxide; DMAP is 4-dimethylaminopyridine; DMF is N,N-dimethylformamide; EA is ethyl acetate; EtOH is anhydrous ethanol; Flash is flash preparative medium-pressure liquid chromatography; h is time; H2 is hydrogen; HATU is O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HCl is hydrochloric acid; K2CO3 is anhydrous potassium carbonate K3PO4 represents anhydrous potassium phosphate; LC-MS represents liquid chromatography-mass spectrometry; LiOH represents lithium hydroxide; LiOH.H2O represents lithium hydroxide monohydrate; MeOH represents anhydrous methanol; min represents minute; mL represents milliliter; LC-MS represents mass spectrometry; NaBH(OAc)3 represents sodium triacetoxyborohydride; NMR represents nuclear magnetic resonance; NH4OAc represents ammonium acetate; Pd / C represents palladium carbon; Pd(dppf)2Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; Pd(OAc)2 represents palladium acetate; TFA represents trifluoroacetic acid; THF represents tetrahydrofuran; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Zn represents zinc powder.

[0108] Preparation Example 1: Synthesis of 4-((dimethylsulfinylidene)amino)benzoic acid (S1-1) [ka]

[0109] Synthesis of S1-1a: Methyl 4-bromobenzoate (21.5 g, 100.0 mmol), Xantphos (5.78 g, 10 mmol), Cs2CO3 (81.5 g, 250.0 mmol), Diox (500 mL), and dimethyl sulfoximine (10.23 g, 110.0 mmol) were added to a 1 L necked flask. The mixture was purged with argon, and then Pd(OAc)2 (1.13 g, 5.0 mmol) was added. The mixture was heated to 100 °C and stirred under an argon atmosphere for 8 hours. After the completion of the reaction was detected by LC-MS, the mixture was cooled and filtered. The filtrate cake was rinsed with EA (approximately 100 mL). The filtrate was concentrated. Water (200 mL) and EA (200 mL) were added to the residue. The resulting mixture was stirred and liquid-phase separation was performed. The organic phase was washed with saturated sodium chloride solution and concentrated. The residue was purified by column chromatography to obtain a light brown oily product (19.3 g, yield: 85%). ESI-MS m / z: 228.1 [M+H] + .

[0110] Synthesis of S1-1: The above compound S1-1a (19.3 g, 85.02 mmol), THF (300 mL), MeOH (100 mL), water (100 mL), and lithium hydroxide monohydrate (14.28 g, 340.0 mmol) were added to a 1 L necked flask, and the mixed solution was stirred at room temperature for 20 hours. After the completion of the reaction was detected by LC-MS, the mixed solution was concentrated to about one-third of its volume, and the pH was adjusted to 2-3 with 2N HCl. The mixture was extracted twice with EA (200 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an off-white solid product (15.2 g, yield: 83.9%). ESI-MS m / z: 214.1 [M+H] + .

[0111] Preparation Example 2: 4-((4-methyl-1-oxo-1λ 6 Synthesis of thiomorpholine-1-imine)amino)benzoic acid (S1-2) [ka]

[0112] Synthesis of S1-2a: N-Boc-thiomorpholine (1 g, 4.22 mmol), EtOH (20 mL), ammonium acetate (1.3 g, 16.88 mmol), and iodobenzene diacetate (4.07 g, 12.66 mmol) were added to a 100 mL necked flask. The mixture was purged with argon and stirred at room temperature for 20 hours. After LC-MS detected completion of the reaction, the mixture was concentrated. Water (50 mL) and EA (50 mL) were added to the residue. The resulting mixture was stirred and liquid-phase separation was performed. The organic phase was then washed with saturated sodium chloride solution and concentrated. The residue was purified by column chromatography to obtain a light brown oily product (925 mg, yield: 81.8%). ESI-MS m / z: 269.1 [M+H] + .

[0113] Synthesis of S1-2b: Methyl 4-bromobenzoate (741 mg, 3.45 mmol), Xantphos (279 mg, 0.5 mmol), Cs2CO3 (2.81 g, 8.62 mmol), Diox (20 mL), and S1-2a (925 mg, 3.45 mmol) were added to a 1 L necked flask. The mixture was purged with argon, and then Pd(OAc)2 (113 mg, 0.5 mmol) was added. The mixture was heated to 100 °C and stirred under an argon atmosphere for 4 hours. After the completion of the reaction was detected by LC-MS, the mixture was cooled and filtered. The filtrate cake was rinsed with EA (approximately 20 mL), and the filtrate was concentrated. Water (30 mL) and EA (30 mL) were added to the residue. The resulting mixture was stirred, and liquid-phase separation was performed. The organic phase was washed with saturated sodium chloride solution and concentrated. The residue was purified by column chromatography to obtain a light brown oily product (1.05 g, yield: 75.6%). ESI-MS m / z: 403.1 [M+H] + .

[0114] Synthesis of S1-2c: The above compound S1-2b (900 mg, 2.24 mmol), MeOH (10 mL), and 10% Pd / C (100 mg) were added to a 250 mL necked flask. The mixed solution was purged three times with hydrogen and then stirred at room temperature under atmospheric pressure for 20 hours. After confirmation of the completion of the reaction by LC-MS, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain an off-white solid product (624 mg, yield: 100%). ESI-MS m / z: 269.1 [M+H] + .

[0115] Synthesis of S1-2d: The above compound S1-2c (104 mg, crude product, 0.373 mmol), DCE (5 mL), AcOH (30 mg, 0.5 mmol), and paraformaldehyde (16 mg, 0.533 mmol) were added to a 50 mL necked flask. The mixed solution was stirred at room temperature for 30 minutes, after which NaBH(OAc)3 (158 mg, 0.746 mmol) was added. The mixed solution was stirred at room temperature for 20 hours. After the completion of the reaction was detected by LC-MS, DCM (10 mL) and water (10 mL) were added to the system. The resulting mixture was stirred, liquid phase separation was performed, and the aqueous phase was extracted with DCM (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. ESI-MS m / z: 283.1 [M+H] + .

[0116] S1-2 synthesis: The above compound S1-2d (126 mg, crude product, 0.373 mmol), THF (5 mL), MeOH (2 mL), water (2 mL), and lithium hydroxide monohydrate (155 mg, 3.7 mmol) were added to a 50 mL necked flask. The mixed solution was stirred at room temperature for 2 hours. After the completion of the reaction was detected by LC-MS, the mixed solution was concentrated, the residue was purified by flash, and then freeze-dried to obtain an off-white solid product (76 mg, yield 75.9%). ESI-MS m / z: 269.1 [M+H] + .

[0117] Preparation Example 3: 4-((4-methyl-d3-1-oxo-1λ 6 Synthesis of thiomorpholine-1-imine)amino)benzoic acid (S1-3) [ka]

[0118] Synthesis of S1-3a: The above compound S1-2c (104 mg, crude product, 0.373 mmol), DMF (5 mL), K2CO3 (155 mg, 1.12 mmol), and CD3I (60 mg, 0.448 mmol) were added to a 25 mL necked flask. The mixed solution was stirred at room temperature for 2 hours. After the completion of the reaction was detected by LC-MS, EA (10 mL) and water (10 mL) were added to the system. The resulting mixture was stirred, and after liquid-phase separation, the aqueous phase was extracted with EA (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (156 mg). ESI-MS m / z: 286.1 [M+H] + .

[0119] Synthesis of S1-3: The above compound S1-3a (156 mg, crude product, 0.373 mmol), THF (5 mL), MeOH (2 mL), water (2 mL), and lithium hydroxide monohydrate (155 mg, 3.7 mmol) were added to a 25 mL necked flask. The mixed solution was stirred at room temperature for 2 hours. After the completion of the reaction was detected by LC-MS, the mixed solution was concentrated, the residue was purified by flash, and lyophilized to obtain an off-white solid product (57 mg, yield: 56.3%). ESI-MS m / z: 272.1 [M+H] + .

[0120] Following the synthesis methods for intermediates S1-1, S1-2, and S1-3, the target intermediates S1-4 to S1-23 shown in Table 1 were obtained using different starting materials.

[0121] [Table 1]

[0122] Example 1: N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-((dimethyl(oxo)-1λ 6 Synthesis of sulfanylidene (amino)benzamide (compound 1) [ka] [ka]

[0123] Step 1: Synthesis of Compound 1-1 tert-butyl(2-amino-4-bromophenyl)carbamate (5.0 g, 17.42 mmol), DIPEA (3.37 g, 26.13 mmol), S1-1 (3.71 g, 17.42 mmol), HATU (9.92 g, 26.13 mmol), and DMF (100 mL) were added to a 500 mL necked flask. The mixture was purged with argon and stirred at room temperature for 20 hours. After LC-MS detected completion of the reaction, water (200 mL) was added to the mixture to stop the reaction, and the resulting mixture was extracted twice with EA (100 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain a white solid product (7.22 g, yield: 86.0%). ESI-MS m / z: 482.1 [M+H] + .

[0124] Step 2: Synthesis of Compound 1-2: Compound 1-1 (100 mg, 0.207 mmol), K3PO4 (110 mg, 0.52 mmol), Diox / H2O (5 mL / 1 mL), 4-fluorophenylboronic acid (35 mg, 0.25 mmol), and Pd(dppf)2Cl2 (14 mg) were added to a 100 mL necked flask. The mixed solution was purged with argon and heated to 100 °C and stirred for 2 hours. After the completion of the reaction was detected by LC-MS, the mixed solution was concentrated. The residue was purified by flash to obtain a light brown oily product (56 mg, yield: 54.4%). ESI-MS m / z: 498.2 [M+H] + .

[0125] Step 3: Synthesis of Compound 1: Compounds 1-2 (56 mg, 0.113 mmol), DCM (5 mL), and TFA (0.5 mL) were added to a 25 mL necked flask. The mixed solution was stirred at room temperature for 2 hours. After the completion of the reaction was detected by LC-MS, the system was concentrated, the residue was purified by flash, and then lyophilized to obtain an off-white solid product (33 mg, yield: 73.5%). ESI-MS m / z: 398.1 [M+H] + .

[0126] Following the synthesis method of compound 1, target compounds 2 to 139 shown in Table 2 were obtained using different intermediates.

[0127] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

Table 2-6

[0128] Some of the nuclear magnetic resonance data of the compounds of the present disclosure are shown in Table 3 below.

[0129]

Table 3

[0130] Biological Example 1: Assay of the inhibitory activity of the compounds of the present disclosure against various subtypes of HDAC enzymes For the compounds of the present disclosure, the enzyme inhibitory activity against various subtypes of HDAC enzymes was assayed using the FRET method. Various subtypes of HDAC enzymes were obtained by purification or direct purchase of assay kits. The specific method is as follows: The enzyme was added to a 384-well plate, and the reaction buffer was added to the control wells. The stepwise diluted DMSO sample solution was added to the reaction wells, and the plate was incubated at room temperature for 15 minutes. Then, the color developer was added to stop the reaction and generate fluorescence. The fluorescence intensity was measured using an EnVision multi-label microplate reader (excitation: 355 nM, fluorescence: 460 nM). After the color development was stable, the endpoint value was read. Compared with DMSO, using GraphPad Prism4 software, the inhibitory IC 50 of the compound was calculated.

[0131]

Table 4

[0132] A indicates that the IC 50 is less than 500 nM. B indicates that the IC 50 is between 500 nM and 5 μM. C indicates that the IC 50 is greater than 5 μM.

[0133] [Table 5]

[0134] ++++ is IC 50 This indicates that it is 30nM or less. +++ indicates IC 50 This indicates that the current is greater than 30 nM and less than or equal to 300 nM. ++ indicates IC 50 This indicates that the value is greater than 300 nM and less than or equal to 3 μM. + indicates IC 50 This indicates that the concentration exceeds 3 μM.

[0135] [Table 6]

[0136] The reference compound is N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-4-(S-methylsulfonamide)benzamide. ND means not detected.

[0137] Biological Example 2: Assay of inhibition of Jurkat cell and 293T cell proliferation by the compounds of the present disclosure. Jurkat cells or 293T cells were seeded at 3000 cells / well in 96-well plates. After overnight adherent culture, the compound, serially diluted with DMSO, was added. After 72 hours, intracellular ATP levels were measured by CTG. IC of cell proliferation inhibition by the compound was assessed. 50 This was calculated in comparison to the DMSO group.

[0138] [Table 7]

[0139] Biological Example 3: Measurement of intracellular acetyllysine / H3K27-acetyllysine levels using the disclosed compound. HeLa cells were seeded in a 96-well plate at 20,000 cells / well. After overnight adherent culture, the serially diluted compounds were added. After 24 hours of treatment, the levels of acetyl lysine and H3K27 acetyl lysine in the cells were quantified by ELISA.

[0140]

Table 8

[0141] Biological Example 4: Pharmacokinetic Experiment of the Compounds of the Present Disclosure in Mice CD-1 female mice aged 7 - 10 weeks were intravenously and orally administered at doses of 1 mg / kg and 10 mg / kg, respectively. The mice were fasted for more than 12 hours before administration, fed after 4 hours of administration, and allowed to drink water freely during the experiment. On the day of the experiment, the animals in the intravenous administration group were injected once via the tail vein with the corresponding compound at a dose of 10 mL / kg, and the animals in the oral administration group were administered once via intragastric injection with the corresponding compound at a dose of 10 mL / kg. The body weight of the animals was measured before administration, and the dosage was calculated according to the body weight. The sample collection time points were 0.083 hours, 0.167 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. Approximately 200 μL of whole blood was collected from the orbital venous plexus at each time point and used for plasma preparation for concentration measurement by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). The plasma concentration was processed using the non-compartmental model of Winnolin pharmacokinetic software, and the pharmacokinetic parameters were calculated using the logarithmic linear trapezoidal method. The results are shown in Table 13 below.

[0142]

Table 9

[0143] Biological Example 5: Assay of the Stability of the Compounds of the Present Disclosure in Liver Microsomes A 1 μM compound was incubated with 500 mg / mL liver microsomes derived from humans, monkeys, beagles, rats, or mice at 37°C for various durations in the presence of an NADPH regeneration system. The remaining amount of the compound was then analyzed using LC-MS-MS. 1 / 2 The result was calculated.

[0144] [Table 10]

[0145] As can be seen from the results in the table above, the stability of the compounds disclosed in human liver microsomes was superior to that of the reference compounds.

[0146] Biological Example 6: In vivo efficacy experiment of the compounds disclosed herein in the MC-38 model Female C57BL6N mice (6 weeks old, 18-22g) were provided by Vital River Laboratory Animal Technology Co. Ltd. (China), and mice that had been quarantined and acclimatized for one week were used. All animals were housed in a room at 23±2℃ and 50±5% relative humidity, with artificial lighting from 08:00 to 20:00 daily, and the air was changed 13-18 times per hour.

[0147] Mouse colon cancer MC38 cells were cultured in a 37°C / 5% CO2 incubator using 1640 medium containing 10% fetal bovine serum, following the conventional method. After subculturing, cells were harvested when the desired volume was reached. 2 × 10 6 Individual MC38 cells were subcutaneously injected into the right side of a C57BL6N mouse to induce tumor formation. The tumor was approximately 100 mm. 3 After growth, the animals were randomly divided into groups and administered the treatment. Tumor volume was measured with calipers on days 3, 7, 10, 14, 17, and 21 after administration. The tumor growth inhibitory effect of the compound was evaluated using the tumor growth inhibition rate (TGI) = 1 - (tumor volume on day 28 of the treatment group - tumor volume on day 1 of the treatment group) / (tumor volume on day 28 of the control group - tumor volume on day 1 of the control group). The toxicity of the compound was evaluated based on the body weight and condition of the mice.

[0148] The groups are as follows: 1) Solvent control group, 2) PD-1+Reg group, 3) Compound 1 group, 4) Reference compound group, 5) Compound 1 (10 mg / kg) and PD-1+Reg combination group, 6) Compound 1 (30 mg / kg) and PD-1+Reg combination group, 7) Compound 1 (90 mg / kg) and PD-1+Reg combination group, 8) Reference compound (10 mg / kg) and PD-1+Reg combination group, 9) Reference compound (30 mg / kg) and PD-1+Reg combination group, 10) Reference compound (90 mg / kg) and PD-1+Reg combination group (6 mice in each group). The results are shown in Table 11 below.

[0149] [Table 11]

[0150] Note: Reg represents regorafenib, PD-1 represents anti-PD-1 antibody, IV represents intravenous administration, PO represents oral administration, QD represents once daily administration, QW represents once weekly administration, CR represents complete remission (tumor completely disappears after completion of the administration cycle), PR represents partial response (tumor volume reduction exceeds 30% of the initial volume at completion of the administration cycle), SD represents disease stability (tumor volume reduction or growth does not exceed 30% of the initial volume at completion of the administration cycle), died represents the mouse dying before completion of the administration cycle, and the duration of administration. * In the first treatment plan, the drug is administered once daily (QD) for 10 consecutive days, followed by a 16-day rest period, and then once weekly (QW) administration, with the drug being administered only on days 1 and 8.

[0151] As can be seen from the results of the in vivo experiments described above, the compounds disclosed herein exhibit remarkable inhibitory effects on the MC-38 in vivo tumor model, either as monotherapy or in combination with PD-1 and Reg. Specifically, in the group treated with compound 1 as monotherapy, complete tumor regression was achieved in 83.3% (5 / 6) of mice. On the other hand, in the triple combination therapy of compound 1 + PD-1 + Reg, complete tumor regression was achieved in 83.3% (5 / 6) of mice in the low-dose group and in 100% (5 / 5) of mice in the high-dose group. Compared to the reference compound, both the monotherapy and triple combination therapy showed a clear advantage in suppressing tumor growth at equivalent doses.

[0152] Biological Example 7: In vivo efficacy experiment of the compounds of this disclosure in the CT-26 model Female BALB / c mice (6 weeks old, 18-22g) were provided by Vital River Laboratory Animal Technology Co. Ltd. (China), and mice that had been quarantined and acclimatized for one week were used. All animals were housed in a room at 23±2℃ and 50±5% relative humidity, with artificial lighting from 08:00 to 20:00 daily, and the air was changed 13-18 times per hour.

[0153] Mouse colon cancer CT-26 cells were cultured using 1640 medium containing 10% fetal bovine serum in a 37°C, 5% CO2 incubator using the conventional method. After subculturing, cells were harvested when the desired volume was reached. 2 × 10 5 CT-26 cells were subcutaneously injected into the right side of BALB / c mice to induce tumor formation. The tumor was approximately 100 mm. 3 After growth, the animals were randomly divided into groups and administered the compound. Tumor volume was measured with calipers on days 3, 7, 10, 14, 17, and 21 after administration. The tumor growth inhibitory effect of the compound was evaluated using the tumor growth inhibition rate (TGI) = 1 - (tumor volume on day 28 of the administered group - tumor volume on day 1 of the administered group) / (tumor volume on day 28 of the control group - tumor volume on day 1 of the control group). The toxicity of the compound was evaluated based on the body weight and condition of the mice.

[0154] The groups are as follows: 1) Solvent control group, 2) PD-1+Reg group, 3) Compound 1-A (30 mg / kg) group, 4) Compound 1-B (90 mg / kg) group, 5) Reference compound-A (30 mg / kg) group, 6) Reference compound-B (90 mg / kg) group, 7) Compound 1 (10 mg / kg) and PD-1+Reg combination group, 8) Compound 1 (30 mg / kg) and PD-1+Reg combination group, 9) Compound 1 (90 mg / kg) and PD-1+Reg combination group, 10) Reference compound (10 mg / kg) and PD-1+Reg combination group, 11) Reference compound (30 mg / kg) and PD-1+Reg combination group, 12) Control drug (90 mg / kg) and PD-1+Reg combination group (6 mice in each group). The results are shown in Table 12 below.

[0155] [Table 12]

[0156] Note: Reg represents regorafenib, PD-1 represents anti-PD-1 antibody, IV represents administration by intravenous injection, PO represents oral administration, QD represents administration once daily, QW represents administration once weekly, CR represents complete remission (tumor completely disappears after completion of the treatment cycle), PR represents partial response (tumor volume reduction of more than 30% compared to the initial volume at completion of the treatment cycle), SD represents stable disease (tumor volume reduction or growth not exceeding 30% compared to the initial volume at completion of the treatment cycle), the treatment period is once daily (QD) for 14 consecutive days, and once weekly (QW) administration is administered only on days 1 and 8.

[0157] As can be seen from the results of the in vivo experiments described above, the compounds of this disclosure showed relatively good inhibitory effects on the CT-26 in vivo tumor model when administered in combination with PD-1 and Reg. Among these, significant tumor reduction was observed in 50% (3 / 6) of mice in group 7, 66.7% (4 / 6) in group 8, and 83.3% (5 / 6) in group 9. At equivalent doses, the combination of the three compounds of this disclosure showed superior efficacy compared to the reference compound.

[0158] Biological Example 8: Tumor cell killing effect of the compounds of this disclosure via PBMCs OVCAR3 cells were seeded at 4000 cells / well in 96-well plates. After overnight adherent culture, serially diluted compounds were added and incubated for a further 72 hours. OVCAR3 cells were stained with Calcein AM, and then PBMCs were added. The cells were cultured for a further 1-4 hours, washed with PBS, and then the tumor cell count was measured. EC of compounds in promoting cell death 50 This was calculated based on DMSO.

[0159] Biological Example 9. PD-L1 Expression Assay in Cells Using the Compounds of the Disclosure MD-MBA231 cells were seeded at 3000 cells / well in 96-well plates. After overnight adherent culture, serially diluted compounds were added. After 72 hours of treatment, PD-L1 expression on the cell surface was detected by ELISA.

[0160] While specific embodiments of this disclosure have been described above, those skilled in the art will understand that these embodiments are merely illustrative and that many changes or modifications can be made to them without departing from the principles and spirit of this disclosure.

Claims

1. Compounds represented by general formula (1), their isomers, their crystals, their pharmaceutically acceptable salts, their hydrates, or their solvates. 【Chemistry 1】 (In general formula (1), X is -NH ２ or -OH; Cy is a (C6-C14) aryl or (5-14 membered) heteroaryl, where each (C6-C14) aryl or (5-14 membered) heteroaryl independently has 1, 2, 3, or 4 R ５ It may be arbitrarily replaced with; Ring A is a (C6-C14) aryl, a (5-14 membered) heteroaryl, a (C3-C14) cycloalkyl, or a (3-14 membered) heterocycloalkyl; R １ is H, D, or halogen; R ２ These are H, D, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 member) heterocycloalkyl; R ３ The (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl, where the (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl each independently has 1, 2, 3, or 4 R ａ It may be arbitrarily replaced with; R ４ The (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl, where the (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl each independently has 1, 2, 3, or 4 R ｂ It may be arbitrarily replaced with; Alternatively, R ３ and R ４ together with the S atoms attached thereto form a (3- to 16-membered) heterocycloalkyl, wherein said (3- to 16-membered) heterocycloalkyl is each independently optionally substituted with 1, 2, 3, or 4 R ６ ; and may be optionally substituted; R ５ H, D, halogen, hydroxy, amino, cyano, nitro, -OR ａ , -NR ａ R ｂ , -C(O)R ａ , -CO ２ R ａ ,-(CH ２ ) ｍ R ａ ,-(CH ２ ) ｍ CO ２ R ａ ,-(CH ２ ) ｍ -CONR ａ R ｂ , -S(O) ｐ R ａ , -S(O) ｐ NR ａ R ｂ , -CONR ａ R ｂ , -C(=NR ａ ) - NR ａ R ｂ , -NR ａ COR ｂ , -CR ａ CONR ａ R ｂ , -NR ａ CO ２ R ａ , -NR ａ S(O) ｐ NR ａ R ｂ , -NR ａ S(O) ｐ R ａ , -P(O) ｐ R ａ R ｂ , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, -(C1-C8) alkylene-(C6-C14) aryl, or -(C1-C8) alkylene-(5-14 member) heteroaryl, where the (C1-C8) alkyl, the (C1- C8) alkoxy, the (C1-C8) haloalkyl, the (C2-C8) alkenyl, the (C2-C8) alkynyl, the (C3-C14) cycloalkyl, the (3-14 member) heterocycloalkyl, the (C6-C14) aryl, the (5-14 member) heteroaryl, the -(C1-C8) alkylene-(C3-C14) cycloalkyl, the -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, the -(C1-C8) alkylene-(C6-C14) aryl, or the -(C1-C8) alkylene-(5-14 member) heteroaryl each independently has 1, 2, 3, or 4 R ｃ It may be arbitrarily replaced with; R ６ is H, D, halogen, hydroxy, amino, cyano, nitro, -OR ａ , -NR ａ R ｂ , -C(O)R ａ , -CO ２ R ａ , -(CH ２ ) ｍ R ａ , -(CH ２ ) ｍ CO ２ R ａ , -(CH ２ ) ｍ -CONR ａ R ｂ , -S(O) ｐ R ａ , -S(O) ｐ NR ａ R ｂ , -CONR ａ R ｂ , -C(=NR ａ )-NR ａ R ｂ , -NR ａ COR ｂ , -CR ａ CONR ａ R ｂ , -NR ａ CO ２ R ａ , -NR ａ S(O) ｐ NR ａ R ｂ , -NR ａ S(O) ｐ R ａ , -P(O) ｐ R ａ R ｂ , (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, -(C1-C8) alkylene-(C6-C14) aryl, or -(C1-C8) alkylene-(5-14 member) heteroaryl, where the (C1-C8) alkyl, the (C1- C8) alkoxy, the (C1-C8) haloalkyl, the (C2-C8) alkenyl, the (C2-C8) alkynyl, the (C3-C14) cycloalkyl, the (3-14 member) heterocycloalkyl, the (C6-C14) aryl, the (5-14 member) heteroaryl, the -(C1-C8) alkylene-(C3-C14) cycloalkyl, the -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, the -(C1-C8) alkylene-(C6-C14) aryl, or the -(C1-C8) alkylene-(5-14 member) heteroaryl each independently has 1, 2, 3, or 4 R ｃ It may be arbitrarily substituted with; or two R ６ If the two R atoms are bonded to the same atom, then the two R atoms ６ These may form an oxo group, a (C3-C6) cycloalkyl group, or a (3-6 membered) heterocycloalkyl group together with the atoms to which they are bonded; R ａ and R ｂ Each of these is independently -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, -(C1-C8) alkylene-(C6-C14) aryl, or -(C1-C8) alkylene-(5-14 member) heteroaryl, where, The (C1-C8) alkyl, the (C1-C8) alkoxy, the (C1-C8) haloalkyl, the (C2-C8) alkenyl, the (C2-C8) alkynyl, the (C3-C14) cycloalkyl, the (3-14 member) heterocycloalkyl, the (C6-C14) aryl, the (5-14 member) heteroaryl, the -(C1-C8) alkylene-(C3-C14) cycloalkyl, the -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, the -(C1-C8) alkylene-(C6-C14) aryl, or the -(C1-C8) alkylene-(5-14 member) heteroaryl each independently contains 1, 2, 3, or 4 R ｃ It may be arbitrarily substituted with; or two R ａ If the two R atoms are bonded to the same atom, then the two R atoms ａ It may form one oxo group; or two R groups ｂ If the two R atoms are bonded to the same atom, then the two R atoms ｂ It may form one oxo group; or it may be bonded to the same atom. ａ and R ｂ Together with the atoms bonded to them, these form one (5-7 member) heterocycloalkyl group or (C3-C9) cycloalkyl group, where each (5-7 member) heterocycloalkyl group or (C3-C9) cycloalkyl group independently has 1, 2, 3, or 4 R atoms. ｃ It may be arbitrarily replaced with; R ｃ is -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1-C8) alkyl, (C1-C8) alkoxy, (C1-C8) haloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C8) alkylene-(C1-C8) alkoxy, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14 member) heterocycloalkyl, -(C1-C8) alkylene-(C6-C14) aryl, or -(C1-C8) alkylene-(5-14 member) heteroaryl; or two R ｃ If the two R atoms are bonded to the same atom, then the two R atoms ｃ This may form one oxo group, a (C3-C6) cycloalkyl group, or a (3-6 membered) heterocycloalkyl group; m, n, and p are integers of 0, 1, or 2.

2. In general formula (1), X is -NH ２ Or -OH, preferably X is -NH ２ The compound described in claim 1, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate, or its solvate.

3. The compound according to claim 1 or 2, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, in general formula (1), wherein ring A is a (C6-C10) aryl, a (5-10 membered) heteroaryl, a (C3-C12) cycloalkyl, or a (3-12 membered) heterocycloalkyl, preferably ring A is a phenyl, a (5-7 membered) heteroaryl, or a (C5-C7) cycloalkyl, and more preferably ring A is a phenyl, a pyridinyl, or a cyclohexyl.

4. In general formula (1), Cy is a (C6-C10) aryl or a (5-12 membered) heteroaryl, where each of the (C6-C10) aryl or (5-12 membered) heteroaryl independently has 1, 2, 3, or 4 R ５ The compound according to any one of claims 1 to 3, or an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted, preferably, Cy is phenyl or a (5-7 membered) heteroaryl.

5. In general formula (1), Cy is phenyl or a (5-6 membered) heteroaryl, preferably, 【Chemistry 2】 The compound according to claim 4, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate, or its solvate.

6. In general formula (1), R ５ However, H, D, halogen, hydroxy, amino, cyano, nitro, -OR ａ , -NR ａ R ｂ , -C(O)R ａ , -CO ２ R ａ ,-(CH ２ ) ｍ R ａ ,-(CH ２ ) ｍ CO ２ R ａ ,-(CH ２ ) ｍ CONR ａ R ｂ , -S(O) ｐ R ａ , -S(O) ｐ NR ａ R ｂ , -CONR ａ R ｂ , -C(=NR ａ ) - NR ａ R ｂ , -NR ａ COR ｂ , -CR ａ CONR ａ R ｂ , -NR ａ CO ２ R ａ , -NR ａ S(O) ｐ NR ａ R ｂ , -NR ａ S(O) ｐ R ａ , -P(O) ｐ R ａ R ｂ , (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C12) cycloalkyl, (3-12 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C6) alkylene-(C3-C14) cycloalkyl, -(C1-C6) alkylene-(3-14 member) heterocycloalkyl, -(C1-C6) alkylene-(C6-C14) aryl, or -(C1-C6) alkylene-(5-14 member) heteroaryl, where the (C1-C6) alkyl, the (C1- C6) alkoxy, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C12) cycloalkyl, the (3-12 member) heterocycloalkyl, the (C6-C14) aryl, the (5-14 member) heteroaryl, the -(C1-C6) alkylene-(C3-C14) cycloalkyl, the -(C1-C6) alkylene-(3-14 member) heterocycloalkyl, the -(C1-C6) alkylene-(C6-C14) aryl, or the -(C1-C6) alkylene-(5-14 member) heteroaryl each independently has 1, 2, 3, or 4 R ｃ It may be optionally replaced with R ５ However, H, D, halogen, hydroxy, amino, cyano, nitro, -OR ａ , -NR ａ R ｂ , -CONR ａ R ｂ , -P(O) ｐ R ａ R ｂ , -S(O) ｐ R ａ The compound according to claim 4 or 5, which is (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C7) cycloalkyl, or (3-7 membered) heterocycloalkyl, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

7. In general formula (1), R ５ However, the elements are H, D, F, Cl, -CN, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, or (C3-C6) cycloalkyl, preferably R ５ is H, D, F, Cl, -CN, -CH ３ , -CF ３ , -OCH ３ ,or 【Transformation 3】 The compound according to claim 6, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate, or its solvate.

8. In general formula (1), R １ However, it is H, D, F, Cl, Br, or I, preferably R １ A compound according to any one of claims 1 to 7, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, wherein the compound is H, D, or F.

9. In general formula (1), R ２ The elements are H, D, F, Cl, Br, I, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl, preferably R ２ A compound according to any one of claims 1 to 8, wherein the compound is H, D, or F, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

10. In general formula (1), R ３ However, the (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl, where the (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl each independently has 1, 2, 3, or 4 R ａ It may be optionally replaced with R ３ However, R is (C1-C4)alkyl, (C1-C4)alkoxy, or (C1-C4)haloalkyl, and more preferably R ３ The compound according to any one of claims 1 to 9, wherein the compound is methyl, ethyl, or methoxymethyl, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

11. In general formula (1), R ４ However, the (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl, where the (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, or (3-6 membered) heterocycloalkyl each independently has 1, 2, 3, or 4 R ｂ It may be optionally replaced with R ４ However, R is (C1-C4)alkyl, (C1-C4)alkoxy, or (C1-C4)haloalkyl, and more preferably R ４ The compound according to any one of claims 1 to 10, wherein the compound is methyl, ethyl, or methoxymethyl, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.

12. In general formula (1), R ３ and R ４ However, together with the S atoms bonded to them, they form a (3-14 member) heterocycloalkyl group, and each of these (3-14 member) heterocycloalkyl groups independently has 1, 2, 3, or 4 R atoms. ６ A compound according to any one of claims 1 to 9, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with.

13. In general formula (1), R ３ and R ４ However, together with the S atoms bonded to them, they form a (4-6 member) monocyclic heterocycloalkyl group containing one or two atoms arbitrarily selected from N, S, and O, or a (7-9 member) bicyclic spiroheterocycloalkyl group containing one or two atoms arbitrarily selected from N, S, and O, where the (4-6 member) monocyclic heterocycloalkyl group or the (7-9 member) bicyclic spiroheterocycloalkyl group each independently contains 1, 2, 3, or 4 R atoms. ６ The compound according to claim 12, or its isomer, crystals thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with.

14. In general formula (1), R ６ However, H, D, halogen, hydroxy, amino, cyano, nitro, -OR ａ , -NR ａ R ｂ , -C(O)R ａ , -CO ２ R ａ ,-(CH ２ ) ｍ R ａ ,-(CH ２ ) ｍ CO ２ R ａ ,-(CH ２ ) ｍ CONR ａ R ｂ , -S(O) ｐ R ａ , -S(O) ｐ NR ａ R ｂ , -CONR ａ R ｂ , -C(=NR ａ ) - NR ａ R ｂ , -NR ａ COR ｂ , -CR ａ CONR ａ R ｂ , -NR ａ CO ２ R ａ , -NR ａ S(O) ｐ NR ａ R ｂ , -NR ａ S(O) ｐ R ａ , -P(O) ｐ R ａ R ｂ , (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C6) alkylene-(C3-C14) cycloalkyl, -(C1-C6) alkylene-(3-14 member) heterocycloalkyl, -(C1-C6) alkylene-(C6-C14) aryl, or -(C1-C6) alkylene-(5-14 member) heteroaryl, where the (C1-C6) alkyl, the (C1- C6) alkoxy, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C14) cycloalkyl, the (3-14 member) heterocycloalkyl, the (C6-C14) aryl, the (5-14 member) heteroaryl, the -(C1-C6) alkylene-(C3-C14) cycloalkyl, the -(C1-C6) alkylene-(3-14 member) heterocycloalkyl, the -(C1-C6) alkylene-(C6-C14) aryl, or the -(C1-C6) alkylene-(5-14 member) heteroaryl each independently has 1, 2, 3, or 4 R ｃ It may be optionally replaced with; preferably, R ６ However, H, D, halogen, hydroxy, amino, cyano, -OR ａ , -NR ａ R ｂ , (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, -(C1-C4) alkylene-(C3-C7) cycloalkyl, -(C1-C4) alkylene-(3-7 member) heterocycloalkyl, or -(C1-C4) alkylene-(5-7 member) heteroaryl, where the (C1-C4) alkyl, the (C1-C4) alkoxy, the (C1-C4) haloalkyl, the -(C1-C4) alkylene-(C3-C7) cycloalkyl, the -(C1-C4) alkylene-(3-7 member) heterocycloalkyl, or the -(C1-C4) alkylene-(5-7 member) heteroaryl each independently has 1, 2, 3, or 4 R ｃ It may be arbitrarily substituted with; or two R ６ If the two R atoms are bonded to the same atom, then the two R atoms ６ The compound according to claim 12 or 13, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may form one oxo group together with the atoms to which they are bonded.

15. In general formula (1), R ６ However, H, D, F, Cl, hydroxy, amino, cyano, methyl, ethyl, -NH(CH ３ ), -N(CH ３ ) ２ , -CD ３ , -C(O)CH ３ ,or 【Chemistry 4】 The compound according to claim 14, or its isomer, its crystals, its pharmaceutically acceptable salt, its hydrate, or its solvate.

16. In general formula (1), R ａ and R ｂ However, each is independently -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C6) alkylene-(C3-C14) cycloalkyl, -(C1-C6) alkylene-(3-14 member) heterocycloalkyl, -(C1-C6) alkylene-(C6-C14) aryl, or -(C1-C6) alkylene-(5-14 member) heteroaryl, where, The (C1-C6) alkyl, the (C1-C6) alkoxy, the (C1-C6) haloalkyl, the (C2-C6) alkenyl, the (C2-C6) alkynyl, the (C3-C14) cycloalkyl, the (3-14 member) heterocycloalkyl, the (C6-C14) aryl, the (5-14 member) heteroaryl, the -(C1-C6) alkylene-(C3-C14) cycloalkyl, the -(C1-C6) alkylene-(3-14 member) heterocycloalkyl, the -(C1-C6) alkylene-(C6-C14) aryl, or the -(C1-C6) alkylene-(5-14 member) heteroaryl each independently contains 1, 2, 3, or 4 R ｃ It may be arbitrarily substituted with; or two R ａ If the two R atoms are bonded to the same atom, then the two R atoms ａ It may form one oxo group; or two R groups ｂ If the two R atoms are bonded to the same atom, then the two R atoms ｂ It may form one oxo group; preferably, R ａ and R ｂ Each of these is independently H, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C3-C7) cycloalkyl, (3-7 member) heterocycloalkyl, (C6-C10) aryl, or (5-7 member) heteroaryl, where the (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C3-C7) cycloalkyl, (3-7 member) heterocycloalkyl, (C6-C10) aryl, or (5-7 member) heteroaryl each independently has 1, 2, 3, or 4 R ｃ A compound according to any one of claims 1 to 15, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which may be optionally substituted with.

17. In general formula (1), R bonded to the same atom ａ and R ｂ However, together with the atoms bonded to them, they form one (5-7 member) heterocycloalkyl group or (C3-C9) cycloalkyl group, where the (5-7 member) heterocycloalkyl group or the (C3-C9) cycloalkyl group each independently has 1, 2, 3, or 4 R atoms. ｃ A compound according to any one of claims 1 to 15, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, which is optionally substituted with.

18. In general formula (1), R ｃ However, -H, -D, halogen, hydroxy, amino, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (3-14 member) heterocycloalkyl, (C6-C14) aryl, (5-14 member) heteroaryl, -(C1-C6) alkylene-(C1-C8) alkoxy, -(C1-C6) alkylene-(C3-C14) cycloalkyl, -(C1-C6) alkylene-(3-14 member) heterocycloalkyl, -(C1-C6) alkylene-(C6-C14) aryl, or -(C1-C6) alkylene-(5-14 member) heteroaryl; or two R ｃ If the two R atoms are bonded to the same atom, then the two R atoms ｃ It may form one oxo group; preferably, R ｃ The compound according to any one of claims 1 to 17, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, wherein is H, D, halogen, hydroxy, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C3-C7) cycloalkyl, or (3-7 membered) heterocycloalkyl.

19. The compound has the following structure: 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 A compound according to any one of claims 1 to 18, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, having one of the above.

20. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and as an active ingredient, a compound or its isomer, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, as described in any one of claims 1 to 19.

21. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and as an active ingredient, a therapeutically effective amount of a compound or its isomer, crystalline form thereof, a pharmaceutically acceptable salt thereof, hydrate thereof, or solvate thereof, and a therapeutically effective amount of an immune checkpoint inhibitor.

22. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and as an active ingredient, a therapeutically effective amount of a compound or its isomer according to any one of claims 1 to 19, its crystals, a pharmaceutically acceptable salt thereof, its hydrate or solvate, a therapeutically effective amount of an immune checkpoint inhibitor, and a therapeutically effective amount of a VEGFR inhibitor.

23. Use of a compound according to any one of claims 1 to 19, or an isomer thereof, a crystalline form thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a pharmaceutical composition according to claims 20 to 22, in the preparation of a pharmaceutical for treating, modulating, and / or preventing HDAC inhibitor-related diseases.

24. The use according to claim 23, wherein the disease is cancer, and the cancer is a blood cancer or a solid tumor.

25. The use according to claim 24, wherein the cancer includes breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, leukemia, lymphoma, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma, or intracranial tumor.

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