HDAC1 / 2 selective inhibitors and uses thereof

Abstract

The invention discloses an HDAC1 / 2 selective inhibitor and application thereof. Specifically, the invention relates to a compound as shown in a general formula (1) and a preparation method thereof, and application of the compound as shown in the general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as HDAC1 / 2 selective inhibitors in preparation of antitumor drugs. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application No. 2023107516937 filed on June 25, 2023. This application cites the entire text of the above Chinese patent application. Technical Field

[0002] The present invention belongs to the field of pharmaceutical chemistry, and more specifically, relates to a class of HDAC1 / 2 selective inhibitors, and a preparation method thereof and the use of the compounds in preparing drugs for treating or preventing cancer. Background Art

[0003] Histone deacetylase (HDAC) is a class of proteases, and its acetylation and deacetylation of histones in chromatin is one of the key links in regulating gene expression. Abnormal gene expression is the molecular biological basis for the occurrence of tumors and some genetic and metabolic diseases. The degree of histone acetylation is coordinated and controlled by histone acetylase (HAT) and histone deacetylase (HDAC). When HDAC is overexpressed and recruited by transcription factors, it will lead to abnormal inhibition of specific genes, thus causing tumors and other diseases.

[0004] HDAC is a large enzyme family, and its members are currently known to have four major categories and 18 different subtypes. Among them, Class I includes four subtypes, HDAC1, 2, 3, and 8; Class II includes six subtypes, HDAC4, 5, 6, 7, 9, and 10 (of which 4, 5, 7, and 9 belong to Ⅱa, and 6 and 10 belong to Ⅱb); Class IV has only one subtype, HDAC11, which has certain homology with the first two categories; Class III includes 7 subtypes, SIRT1-7, and has no structural homology with the first three categories.

[0005] According to published clinical results, although HDAC1, 2, 3 selective inhibitors such as MS275 (Entinostat), cedabenamide (already on the market), CXD101, etc. have significantly less toxic side effects than Pan HDAC inhibitors such as vorinostat, romidepsin, belinostat, and panobinostat, serious adverse reactions were still observed in clinical trials, including hematological adverse reactions, systemic adverse reactions including fatigue and fever, gastrointestinal adverse reactions, metabolic and nutritional system adverse reactions, and other adverse reactions such as dizziness and rash. Summary of the invention

[0006] The present invention provides a series of compounds with high selectivity for HDAC1 / 2, which show excellent efficacy and safety in various in vitro and in vivo evaluation experiments, and are of great clinical significance for improving the efficacy and safety of existing drugs.

[0007] Specifically, the present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0008]

[0009] In the general formula (1):

[0010] X is -NH2 or -OH;

[0011] Cy is (C6-C14)aryl or (5-14 membered)heteroaryl, wherein the (C6-C14)aryl or (5-14 membered)heteroaryl may be independently optionally substituted by 1, 2, 3 or 4 R 4 replace;

[0012] Ring A is (C6-C14)aryl, (5-14 membered)heteroaryl, (C3-C14)cycloalkyl or (3-14 membered)heterocycloalkyl;

[0013] R 1 H, D, halogen;

[0014] R 2 is H, D, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl;

[0015] R 3 H, D, halogen, hydroxyl, 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 、-(CH2) m -NR a C(O)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 -(CH2) m -S(O)(R b )(=NR a ),-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-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, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein the (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, -(C1-C8)alkylene-(5-14-membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 R a replace;

[0016] R 4 H, D, halogen, hydroxyl, amino, cyano, nitro, -OR a 、-NR a R b 、-C(O)R a 、-CO2R a 、-(CH2) m R a 、-(CH2) m CO2Ra 、-(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 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, -(C1-C8) alkylene-(5-14 membered) heteroaryl, wherein the (C1-C8) 8) 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, -(C1-C8) alkylene-(5-14-membered) heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 R c replace;

[0017] R a and R beach 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 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, -(C1-C8) alkylene-(5-14 membered) heteroaryl wherein the (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, -(C1-C8)alkylene-(5-14-membered)heteroaryl may be independently optionally substituted by 1, 2, 3 or 4 R c Replace; or when 2 R a When attached to the same atom, the two R a can form an oxo group; or when 2 R a When attached to the same atom, the two R a Can form a =C(R c )2; or when 2 R b When attached to the same atom, the two R b can form an oxo group; or R a and R b The atoms to which it is attached together form a (5-7 membered) heterocycloalkyl, wherein the (5-7 membered) heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c Substitution; or R attached to different atoms a and R b The atoms to which it is attached together form a (5-7 membered) heterocycloalkyl, wherein the (5-7 membered) heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c replace;

[0018] Ring B is (5-12 membered) heterocycloalkyl;

[0019] R cEach of the following 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 membered) heterocycloalkyl, (C6-C14) aryl, (5-14 membered) heteroaryl, -(C1-C8) alkylene-(C1-C8) alkoxy, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14 membered) heterocycloalkyl, -(C1-C8) alkylene-(C6-C14) aryl, -(C1-C8) alkylene-(5-14 membered) heteroaryl; or when 2 R c When attached to the same atom, the two R c It may form an oxo group, a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group;

[0020] m, n, and p are each independently an integer of 0, 1 or 2.

[0021] In another preferred technical solution, in the compound of the general formula (1), X is -NH2.

[0022] In another preferred technical solution, in the compound of the general formula (1), ring A is (C6-C10)aryl, (5-10 membered)heteroaryl, (C3-C12)cycloalkyl or (3-12 membered)heterocycloalkyl; ring A is preferably phenyl, (5-7 membered)heteroaryl, (C5-C7)cycloalkyl; ring A is more preferably phenyl, pyridyl or cyclohexyl.

[0023] In another preferred technical solution, in the compound of the general formula (1), R 1 For H, D, F, Cl, Br, I; R 1 H, D or F is preferred.

[0024] In another preferred technical solution, in the compound of the 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, (3-6 membered) heterocycloalkyl; R 2 H, D or F is preferred.

[0025] In another preferred technical solution, in the compound of the general formula (1), Cy is (C6-C10) aryl or (5-12 membered) heteroaryl, wherein the (C6-C10) aryl or (5-12 membered) heteroaryl can be independently optionally replaced by 1, 2, 3 or 4 R 4substituted; Cy is preferably phenyl, (5-7 membered) heteroaryl; Cy is more preferably phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl or pyrimidinyl.

[0026] In another preferred technical solution, in the compound of the general formula (1), R 4 H, D, halogen, hydroxyl, 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-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl, wherein the (C1-C 6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C12) cycloalkyl, (3-12 membered) heterocycloalkyl, (C6-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 R c Replacement; R 4 Preferably 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 , (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C7) cycloalkyl, (3-7 membered) heterocycloalkyl; R 4 More preferred is H, D, F, Cl, cyano or (C1-C2) alkyl.

[0027] In another preferred technical solution, in the compound of the general formula (1), R 3 H, D, halogen, hydroxyl, 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 、-(CH2) m -NR a C(O)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-C10)aryl, (5-14-membered)heteroaryl, -(C1-C3)alkylene-(C3-C12)cycloalkyl, -(C1-C3)alkylene-(3-12-membered)heterocycloalkyl, -(C1-C3)alkylene-(C6-C10)aryl, -(C1-C3)alkylene-(5-14-membered)heteroaryl, wherein the (C1-C6)alkylene )alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C12)cycloalkyl, (3-12-membered)heterocycloalkyl, (C6-C10)aryl, (5-14-membered)heteroaryl, -(C1-C3)alkylene-(C3-C12)cycloalkyl, -(C1-C3)alkylene-(3-12-membered)heterocycloalkyl, -(C1-C3)alkylene-(C6-C10)aryl, -(C1-C3)alkylene-(5-14-membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 R a replace.

[0028] In another preferred technical solution, in the compound of the general formula (1), R 3 is a (5-11 membered) heterocycloalkyl group; R 3 Preferably

[0029] wherein q is independently an integer of 1, 2, 3 or 4.

[0030] In another preferred technical solution, in the compound of the general formula (1), R a and R b 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-C12) cycloalkyl, (3-12 membered) heterocycloalkyl, (C6-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl wherein the (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C12) cycloalkyl, (3-12 membered) heterocycloalkyl, (C6-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl may be independently optionally substituted by 1, 2, 3 or 4 R c Replace; or when 2 R a When attached to the same atom, the two R a can form an oxo group; or when 2 R b When attached to the same atom, the two R b can form an oxo group; or R a and R b The atoms to which it is attached together form a (5-7 membered) heterocycloalkyl, wherein the (5-7 membered) heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c replace.

[0031] In another preferred technical solution, in the compound of the general formula (1), R ais -H, -D, (C1-C3) alkyl, -CH2-(5-6 membered) heteroaryl, wherein the (5-6 membered) heteroaryl is optionally substituted by 1, 2, 3 or 4 R c Replacement; R b It is -H, -D, (C1-C3) alkyl.

[0032] In another preferred technical solution, in the compound of the general formula (1), R a -H, -D, -CH3, Wherein o is an integer of 1, 2 or 3; R b It is -H, -D, -CH3.

[0033] In another preferred technical solution, in the compound of the 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-C12) cycloalkyl, (3-12 membered) heterocycloalkyl, (C6-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C1-C6) alkoxy, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl; or when 2 R c When attached to the same atom, the two R c Can form an oxo group; R c Preferred are H, D, halogen, hydroxy, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C3-C7) cycloalkyl, (3-7 membered) heterocycloalkyl.

[0034] In another preferred technical solution, in the compound of the general formula (1), R c It is -H, -D, -CH3.

[0035] In another specific embodiment of the present invention, the compound of formula (1) has one of the compound structures shown in Table 1.

[0036] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and a compound of the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0037] Another object of the present invention is to provide the use of the compound represented by the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above pharmaceutical compositions for preparing drugs for treating, regulating or preventing diseases associated with HDAC1 / 2 inhibitors. The disease is preferably cancer, and the cancer is blood cancer and solid tumor.

[0038] It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0039] Synthesis of compounds

[0040] The following specifically describes the preparation methods of the compounds of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0041] The compounds described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein can be varied. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found 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), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0042] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, the amount of compounds used, reaction temperature, reaction time, etc., are not limited to the following explanation. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by a person skilled in the art. In one aspect, the present invention also provides a method for preparing the compounds, wherein the compounds of formula (1) can be prepared using the following general reaction scheme 1:

[0043] General reaction scheme 1

[0044]

[0045] Among them, A, Cy, R 1 , R 2 , R 3 , R 4 , X, m, and n are as defined above, and PG represents a commonly used amino or hydroxyl protecting group (such as Boc, Cbz, Bz, Fmoc, Bn, etc.). As shown in general reaction scheme 1, compound A1 is subjected to ester hydrolysis to obtain compound A2, A2 is subjected to condensation reaction with raw material B1 to obtain compound A3, and A3 is subjected to conventional deprotection reaction to obtain the target compound (1).

[0046] Further forms of compounds

[0047] "Pharmaceutically acceptable" as used herein refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a material that, when administered to a subject, does not cause undesirable biological effects or interact in a deleterious manner with any of its constituent components.

[0048] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the general formula with an acid or base, wherein the acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1 st Ed., Acids and Bases (Wiley, 2002).

[0049] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystal forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated form is considered to be equivalent to the unsolvated form.

[0050] In other specific embodiments, the compound of formula (1) is prepared in different forms, including but not limited to amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be used as polymorphs. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvents, crystallization rate and storage temperature may cause a single crystal form to dominate.

[0051] In another aspect, the compounds of formula (1) may have chiral centers and / or axial chirality, and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0052] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) and C-14( 14 C). For another example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0053] Unless otherwise specified, any atom of the compounds of the present invention refers to the isotope of the atom in its stable state. Unless otherwise specified, when a site on the molecular structure is selected as "H" or "hydrogen", the site should be understood to have the natural abundance of hydrogen isotopes. Similarly, unless otherwise specified, when a site is selected as "D" or "deuterium", the site should be understood to have a deuterium isotope abundance of at least 3000 times its natural abundance (the natural abundance of deuterium isotopes is 0.015%).

[0054] In the present invention, "isotopic enrichment factor" means the ratio of the isotope to its natural isotope.

[0055] More preferably, the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).

[0056] The term "isotope isomers" refers to different molecules whose structures differ only in their isotopes but are otherwise identical.

[0057] the term

[0058] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and the appended claims, the singular forms "a" and "an" include plural meanings unless otherwise clearly indicated in the text. If not otherwise indicated, conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, if not otherwise indicated, the use of "or" or "and" means "and / or".

[0059] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted by one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, iBu, n Bu or t Bu.

[0060] Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

[0061] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms. Preferably, the lower alkenyl group contains 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl.

[0062] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

[0063] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Preferably, the lower alkynyl group contains 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl.

[0064] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

[0065] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), if the carbocyclic ring contains at least one double bond, then the partially unsaturated cycloalkyl may be referred to as "cycloalkenyl", or if the carbocyclic ring contains at least one triple bond, then the partially unsaturated cycloalkyl may be referred to as "cycloalkynyl". Cycloalkyl may include monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl is monocyclic. In some embodiments, cycloalkyl is monocyclic or bicyclic. The ring-forming carbon atoms of cycloalkyl may be optionally oxidized to form oxo or thio groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl contains 0, 1 or 2 double bonds. In some embodiments, cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl may be fused with aryl, heteroaryl, cycloalkyl and heterocycloalkyl. In some embodiments, cycloalkyl may be fused with aryl, cycloalkyl and heterocycloalkyl. In some embodiments, cycloalkyl can be fused with aryl and heterocycloalkyl. In some embodiments, cycloalkyl can be fused with aryl and cycloalkyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinenyl, norcarbyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, etc.

[0066] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0067] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 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 alkoxy groups, especially alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0068] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, which is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

[0069] Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy include, but are not limited to, phenoxy and naphthoxy.

[0070] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene radicals include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

[0071] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), preferably an aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, more preferably an aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. Heteroaryl is monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, 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,

[0072] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0073] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and phosphorus, preferably a saturated or partially unsaturated ring containing 1-4 heteroatoms selected from oxygen, sulfur or nitrogen, and more preferably a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. If the heterocycloalkyl contains at least one double bond, the partially unsaturated heterocycloalkyl may be referred to as a "heterocycloalkenyl", or if the heterocycloalkyl contains at least one triple bond, the partially unsaturated heterocycloalkyl may be referred to as a "heterocycloalkynyl". Heterocycloalkyl may include a monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring system. In some embodiments, the heterocycloalkyl is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl can be optionally oxidized to form oxo or thio or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O)2, N-oxides, etc.), or nitrogen atoms can be quaternized. Heterocycloalkyl can be connected via ring-forming carbon atoms or ring-forming heteroatoms. In certain embodiments, heterocycloalkyl contains 0 to 3 double bonds. In certain embodiments, heterocycloalkyl contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes a portion (also referred to as partially unsaturated heterocycle) of an aromatic ring having one or more fused to the heterocycloalkyl ring (i.e., sharing a key with it), such as benzo derivatives of piperidine, morpholine, azacycloheptatriene or thienyl, etc. Heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atom, including the ring-forming atom of a fused aromatic ring. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole, oxazolo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactamyl, valerolactamyl, imidazolinyl, hydantoinyl, dioxolanyl, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl, pyridone, 3-pyrrolinyl, thiopyranyl, pyranone, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolyl,

[0074] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0075] Unless otherwise specified, "oxo" means =0; for example, a carbonyl radical substituted with an oxo radical is a "carbonyl radical." ”

[0076] ; The group formed by sulfur being replaced by an oxo group is called "sulfinyl ", the group formed by sulfur being replaced by two oxo groups is called "sulfonyl" ”.

[0077] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0078] Unless otherwise specified, the term "substituted" refers to the case where one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, without exceeding the normal valence of the specified atom. For example, one or more hydrogens of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amido etc. can be replaced by one or more substituents. Wherein the substituent includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent with a further substituent attached to infinity (for example, a substituted aryl with a substituted alkyl itself is replaced by a substituted aryl, which is further replaced by a substituted heteroalkyl, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the substituted aryl is continuously substituted by two other substituted aryls and is limited to the aryl substituted by ((substituted aryl) substituted aryl). Similarly, the above definition does not include unallowed substitution patterns (for example, methyl substituted by 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). This unallowed substitution pattern is well known to those skilled in the art. Whenever used to modify a chemical group, "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes but is not limited to "alkyl aryl". Unless otherwise specified, if a group is described as optionally substituted, any substituent of the group itself is unsubstituted.

[0079] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0080] Unless otherwise specified, it will be understood that the word "comprise", or variations such as "comprises" or "comprising", means the inclusion of stated elements or integers, or groups of elements or integers, but not the exclusion of any other elements or integers, or groups of elements or integers.

[0081] The substituent "-O-CH2-O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:

[0082] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0083] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0084] The term "membered ring" includes any cyclic structure. The term "membered" means the number of backbone atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are five-membered rings.

[0085] The term "fragment" refers to a specific part or functional group of a molecule. A chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.

[0086] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key

[0087] Unless otherwise stated, Indicates a single bond or a double bond.

[0088] Specific pharmaceutical and medical terms

[0089] The term "acceptable," as used herein, means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.

[0090] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a disease or symptom to regress; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom.

[0091] As used herein, a compound or pharmaceutical composition, after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to the administration.

[0092] "Active ingredient" refers to the compounds of the present invention, as well as pharmaceutically acceptable inorganic or organic salts of the compounds of the present invention. The compounds of the present invention may contain one or more asymmetric centers, and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0093] The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), is capable of inducing a desired pharmaceutical and / or physiological response through local and / or systemic effects.

[0094] The term "administered," "administering," or "administration" as used herein refers to directly administering the compound or composition, or administering a prodrug, derivative, or analog of the active compound.

[0095] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate values, the relevant numerical values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean value, depending on the consideration of those skilled in the art. Except for the experimental examples, or unless otherwise explicitly stated, it should be understood that all ranges, quantities, values ​​and percentages used herein (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and the like) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the attached claims are all approximate values ​​and can be changed as needed. At least these numerical parameters should be understood as the number of significant digits indicated and the values ​​obtained using the general rounding method.

[0096] Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as those commonly understood by those skilled in the art. In addition, singular nouns used in this specification include plural forms of the nouns, and plural nouns used also include singular forms of the nouns, unless they conflict with the context.

[0097] Therapeutic Uses

[0098] The present invention provides methods for treating diseases using the compounds of formula (1) or pharmaceutical compositions of the present invention, including but not limited to conditions involving HDAC (eg, cancer).

[0099] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancer is mediated by HDAC. In other embodiments, the cancer is a blood cancer and a solid tumor, wherein the tumor range includes but is not limited to: breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, gastric cancer, blood cancer, lymphoma, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma or intracranial tumor.

[0100] Route of administration

[0101] The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the safe and effective amount range and pharmacologically acceptable excipients or carriers. The "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific circumstances such as the age, condition, and course of treatment of the subject.

[0102] "Pharmaceutically acceptable excipients or carriers" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0103] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0104] Solid dosage forms for oral administration include capsules, tablets, pills, powders 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 with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0105] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0106] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0107] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0108] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0109] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0110] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0111] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 100 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians.

[0112] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features. DETAILED DESCRIPTION

[0113] In the following description, each specific aspect, characteristic and advantage of the above-mentioned compounds, methods and pharmaceutical compositions will be described in detail to make the content of the present invention become very clear. It should be understood that the following detailed description and examples describe specific embodiments and are for reference only. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the application.

[0114] In all embodiments, 1 H-NMR was recorded on a Vian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts were expressed in δ (ppm). The silica gel used for separation was 200-300 mesh unless otherwise specified, and the ratios of the eluents were all by volume.

[0115] The present invention uses the following abbreviations: AcOH represents glacial acetic acid; Boc2O represents di-tert-butyl dicarbonate; CDCl3 represents deuterated chloroform; DCM represents dichloromethane; Diox represents 1,4-dioxane; DIPEA represents diisopropylethylamine; DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide; EA represents ethyl acetate; EtOH represents anhydrous ethanol; Flash represents fast medium pressure preparative chromatography; h represents hour; H2 represents hydrogen; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HCl represents hydrochloric acid; K2CO3 represents anhydrous potassium carbonate, anhydrous potassium phosphate; K3PO4, anhydrous potassium phosphate; LC-MS, liquid chromatography-mass spectrometry; LiOH, lithium hydroxide; LiOH.H2O, lithium hydroxide monohydrate; MeOH, anhydrous methanol; min, minute; mL, milliliter; LC-MS, mass spectrometry; NaBH(OAc)3, sodium triacetoxyborohydride; NMR, nuclear magnetic resonance; Pd(dppf)2Cl2, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Xantphos, 4,5-bis(diphenylphosphino)ferrocene-9,9-dimethylxanthene.

[0116] Example 1 Synthesis of N-(2-amino-5-(5-fluorothiophen-2-yl)phenyl)-4-(1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)benzamide (Compound 12)

[0117]

[0118] Step 1: Synthesis of compound 12-1:

[0119] Add 4-(piperidin-4-yl)benzoic acid methyl ester (6.874g, 31.35mmol), 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (3.892g, 31.35mmol), acetic acid (188mg, 3.135mmol) and DCM (100mL) to a 250mL single-mouth bottle and react at room temperature for 1h. Add NaBH(OAc)3 (13.3g, 62.7mmol) and react at room temperature overnight. After LC-MS detection, add saturated sodium bicarbonate solution to the reaction solution, stir, separate, extract the aqueous phase with DCM, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the product (10.8g, yield: 105%).

[0120] ESI-MS m / z:328.2[M+H] + .

[0121] Step 2: Synthesis of compound 12-2:

[0122] The above compound 12-1 (10.265 g, 31.35 mmol), LiOH.H2O (6.6 g, 156.75 mmol) and MeOH / THF / H2O (30 mL / 30 mL / 10 mL) were added to a 250 mL single-mouth bottle and the temperature was raised to 50°C for 2-3 h. After the reaction was complete as detected by LC-MS, the reaction solution was concentrated to remove the organic solvent, the pH was adjusted to 5-6 with 4N HCl solution, and the system was directly freeze-dried to obtain a white solid crude product (21.4 g, yield: 218%).

[0123] ESI-MS m / z:314.2[M+H] + .

[0124] Step 3: Synthesis of compound 12-3:

[0125] The above compound 12-2 (14.2 g, crude product, 21 mmol), tert-butyl (2-amino-4-bromophenyl)carbamate (4 g, 14 mmol), DIPEA (7.2 g, 56 mmol), HATU (10.6 g, 28 mmol) and DMF (50 mL) were added to a 250 mL single-mouth bottle, and the reaction was allowed to proceed overnight at room temperature. LC-MS detection showed that the reaction was not complete, and the mixture was heated to 80° C. for 2-3 h. After the reaction was complete as detected by LC-MS, water was added to the reaction solution, and EA was extracted three times. The organic phases were combined, washed with saturated sodium chloride, concentrated, and EA / PE (100 mL, 1 / 5) was added to the crude product, stirred at room temperature for 0.5 h, and filtered to obtain an off-white solid product (7.3 g, yield: 90%).

[0126] ESI-MS m / z:582.2[M+H] + .

[0127] Step 4: Synthesis of compound 12-4:

[0128] The above compound 12-3 (530 mg, 0.91 mmol), 2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.09 mmol), K3PO4 (386 mg, 1.82 mmol), Pd(dppf)Cl2 (67 mg, 0.09 mmol) and Diox / H2O (5 mL / 1 mL) were added to a 25 mL single-mouth bottle, and after argon degassing protection, the mixture was heated to 100 ° C for 2 h. After the reaction was complete by LC-MS, the product was purified by Flash column to obtain the product (418 mg, yield: 76%).

[0129] ESI-MS m / z:603.3[M+H] + .

[0130] Step 5: Synthesis of compound 12:

[0131] The above compound 12-4 (418 mg, 0.692 mmol), HCl / Diox (3.5 mL, 14 mmol) and DCM (5 mL) were added to a 25 mL single-mouth bottle and reacted at room temperature for 2 h. After the reaction was complete as detected by LC-MS, the reaction solution was filtered, the solid was dissolved in water, and the pH was adjusted to 8-9 with saturated sodium carbonate, the solid was precipitated, filtered, and the filter cake was dried to obtain an off-white solid product (313 mg, yield: 90%).

[0132] ESI-MS m / z:504.2[M+H] + .

[0133] Similar to the synthesis of compound 12, target compounds 1-46 in Table 1 can be obtained by using different intermediates as raw materials.

[0134] Table 1

[0135]

[0136]

[0137]

[0138]

[0139] The NMR data of some compounds in this patent are listed in Table 2 below:

[0140] Table 2

[0141]

[0142]

[0143]

[0144] Biological Example 1 Test of the Inhibitory Activity of the Compounds of the Invention on HDAC1, 2, 3 Enzymes

[0145] The compounds of the present invention use the FRET method to measure the enzyme inhibitory activity of HDAC1, HDAC2 and HDAC3. HDAC1, HDAC2 and HDAC3 are obtained by purification or directly purchasing a kit.

[0146] Specific method: Add enzyme to 384-well plate, and add reaction buffer to control wells. Add gradient diluted DMSO sample solution to the reaction wells, incubate at room temperature for 15 minutes, then add color developer to terminate the reaction and generate fluorescence. Use EnVision multi-label microplate reader to detect fluorescence intensity (excitation light: 355nM, emission light: 460nM). Read the terminal value after the color development reaches stability. Use GraphPad Prism4 software to calculate the compound inhibition IC compared with DMSO. 50 .

[0147] Table 3 Inhibitory activity of the compounds of the present invention on HDAC1, 2, 3 enzymes (IC 50 ,nM)

[0148]

[0149]

[0150] Note: A stands for IC 50 ≤50nM; B means 50nM <IC 50 ≤500nM; C means 500nM <IC 50 ≤5uM; D represents IC 50 >5uM; Biological Example 2 Inhibition test of Jurkat and 293T cell proliferation by the compounds of the present invention

[0151] 3000 Jurkat or 293T cells / well were seeded in a 96-well plate. After overnight attachment, serial dilutions of the compounds were added. After 72 hours, intracellular ATP levels were tested with CTG. Compared with DMSO, the IC of the compound for inhibiting cell proliferation was calculated. 50 .

[0152] Table 4 Inhibitory activity of the compounds of the present invention on Jukat / 293T cell proliferation (IC 50 ,μM)

[0153] Compound Jukat cells 293T cells Compound Jukat cells 293T cells 1 0.33 2.46 13 0.53 2.51 2 0.56 2.58 14 2.20 16.6 6 0.56 8.08 15 0.13 3.41 7 2.81 >10 17 0.66 >10 8 2.56 >10 18 2.78 >10 10 0.36 2.33 39 0.47 >10 11 0.18 2.48 45 0.45 1.89 12 0.20 1.78 46 2.87 6.6

[0154] Biological Example 3 Determination of the Effect of the Compounds of the Present Invention on the Level of Acetyl Lysine / H3K27 in Cells

[0155] 20,000 Hela cells / well were seeded in a 96-well plate. After overnight attachment, graded dilutions of compounds were added. After 24 hours of treatment, the levels of intracellular acetyl lysine and H3K 27 acetyl lysine were detected by ELISA.

[0156] Table 5 Effects of the compounds of the present invention on the levels of acetyl lysine and H3K 27

[0157]

[0158] Biological Example 4 Metabolic Kinetics Experiment of the Compounds of the Invention in Mice

[0159] CD-1 female mice aged 7 to 10 weeks were selected and intravenously and orally administered with a dose of 1 mg / kg and 10 mg / kg, respectively. The mice were fasted for at least 12 hours before administration and resumed feeding 4 hours after administration. Water was freely available throughout the experiment.

[0160] On the day of the experiment, the animals in the intravenous group were given a single injection of the corresponding compound through the tail vein, and the dosage volume was 10 mL / kg; the animals in the oral group were given a single injection of the corresponding compound by gavage, and the dosage volume was 10 mL / kg. The animals were weighed before administration, and the dosage volume was calculated based on the body weight. The sample collection time was: 0.083, 0.167, 0.5, 1, 2, 4, 8 and 24 h. At each time point, approximately 200 μL of whole blood was collected through the orbital venous plexus and used to prepare plasma for concentration determination 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 linear logarithmic trapezoidal method.

[0161] Table 6 In vivo pharmacokinetic evaluation results of compounds

[0162]

[0163] Biological Example 5 Liver microsomal stability test of the compounds of the present invention

[0164] After incubation of 1 μM compound with 500 mg / mL human, monkey, beagle, rat or mouse liver microsomes and NADPH regeneration system at 37°C for different time periods, the remaining amount of compound was analyzed by LC-MS-MS and T was calculated. 1 / 2 .

[0165] Table 7 Evaluation results of compound stability in human and mouse liver microsomes

[0166]

[0167] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that these are only examples, and various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the protection scope of the present invention is limited by the appended claims.

Claims

1. A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In the general formula (1): X is -NH2 or -OH; Cy is (C6-C14)aryl or (5-14 membered)heteroaryl, wherein the (C6-C14)aryl or (5-14 membered)heteroaryl may be independently optionally substituted by 1, 2, 3 or 4 R 4 replace; Ring A is (C6-C14)aryl, (5-14 membered)heteroaryl, (C3-C14)cycloalkyl or (3-14 membered)heterocycloalkyl; R 1 H, D, 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, (3-6 membered) heterocycloalkyl; R 3 H, D, halogen, hydroxyl, 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 、-(CH2) m -NR a C(O)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 -(CH2) m -S(O)(R b )(=NR a ),-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-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, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein the (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, -(C1-C8)alkylene-(5-14-membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 R a replace; R 4 H, D, halogen, hydroxyl, 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 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, -(C1-C8) alkylene-(5-14 membered) heteroaryl, wherein the (C1-C8) 8) 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, -(C1-C8) alkylene-(5-14-membered) heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 R c replace; R a and R b each 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 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, -(C1-C8) alkylene-(5-14 membered) heteroaryl wherein the (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, -(C1-C8)alkylene-(5-14-membered)heteroaryl may be independently optionally replaced by 1, 2, 3 or 4 R c Replace; or when 2 R a When attached to the same atom, the two R a can form an oxo group; or when 2 R a When attached to the same atom, the two R a Can form a =C(R c )2; or when 2 R b When attached to the same atom, the two R b can form an oxo group; or R a and R b The atoms to which it is attached together form a (5-7 membered) heterocycloalkyl, wherein the (5-7 membered) heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c Substitution; or R attached to different atoms a and R b The atoms to which it is attached together form a (5-7 membered) heterocycloalkyl, wherein the (5-7 membered) heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c replace; Ring B is (5-12 membered) heterocycloalkyl; R c Each of the following 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-membered) heterocycloalkyl, (C6-C14) aryl, (5-14-membered) heteroaryl, -(C1-C8) alkylene-(C1-C8) alkoxy, -(C1-C8) alkylene-(C3-C14) cycloalkyl, -(C1-C8) alkylene-(3-14-membered) heterocycloalkyl, -(C1-C8) alkylene-(C6-C14) aryl, -(C1-C8) alkylene-(5-14-membered) heteroaryl; or when 2 R c When attached to the same atom, the two R c It may form an oxo group, a (C3-C6) cycloalkyl group or a (3-6 membered) heterocycloalkyl group; m, n, and p are each independently an integer of 0, 1 or 2.

2. The compound according to claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), X is -NH2.

3. The compound according to claim 1 or 2, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring A is (C6-C10)aryl, (5-10-membered)heteroaryl, (C3-C12)cycloalkyl or (3-12-membered)heterocycloalkyl; ring A is preferably phenyl, (5-7-membered)heteroaryl, (C5-C7)cycloalkyl; ring A is more preferably phenyl, pyridyl or cyclohexyl.

4. The compound according to any one of claims 1 to 3 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 For H, D, F, Cl, Br, I; R 1 H, D or F is preferred.

5. The compound according to any one of claims 1 to 4 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the 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, (3-6 membered) heterocycloalkyl; R 2 H, D or F is preferred.

6. The compound according to any one of claims 1 to 5 or any of its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Cy is (C6-C10)aryl or (5-12 membered)heteroaryl, wherein the (C6-C10)aryl or (5-12 membered)heteroaryl may be independently optionally replaced by 1, 2, 3 or 4 R 4 substituted; Cy is preferably phenyl, (5-7 membered) heteroaryl; Cy is more preferably phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl or pyrimidinyl.

7. The compound according to claim 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 4 H, D, halogen, hydroxyl, 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-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl, wherein the (C1-C 6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C12) cycloalkyl, (3-12 membered) heterocycloalkyl, (C6-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 R c Replacement; R 4 Preferably 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 , (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C7) cycloalkyl, (3-7 membered) heterocycloalkyl; R 4 More preferred is H, D, F, Cl, cyano or (C1-C2) alkyl.

8. The compound according to any one of claims 1 to 7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 3 H, D, halogen, hydroxyl, 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 、-(CH2) m -NR a C(O)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-C10)aryl, (5-14-membered)heteroaryl, -(C1-C3)alkylene-(C3-C12)cycloalkyl, -(C1-C3)alkylene-(3-12-membered)heterocycloalkyl, -(C1-C3)alkylene-(C6-C10)aryl, -(C1-C3)alkylene-(5-14-membered)heteroaryl, wherein the (C1-C6)alkylene )alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C12)cycloalkyl, (3-12-membered)heterocycloalkyl, (C6-C10)aryl, (5-14-membered)heteroaryl, -(C1-C3)alkylene-(C3-C12)cycloalkyl, -(C1-C3)alkylene-(3-12-membered)heterocycloalkyl, -(C1-C3)alkylene-(C6-C10)aryl, -(C1-C3)alkylene-(5-14-membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 R a replace.

9. The compound according to claim 8 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 3 is a (5-11 membered) heterocycloalkyl group; R 3 Preferably wherein q is independently an integer of 1, 2, 3 or 4.

10. The compound according to any one of claims 1 to 9 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R a and R b 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-C12) cycloalkyl, (3-12 membered) heterocycloalkyl, (C6-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl wherein the (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C12)cycloalkyl, (3-12-membered)heterocycloalkyl, (C6-C10)aryl, (5-14-membered)heteroaryl, -(C1-C3)alkylene-(C3-C12)cycloalkyl, -(C1-C3)alkylene-(3-12-membered)heterocycloalkyl, -(C1-C3)alkylene-(C6-C10)aryl, -(C1-C3)alkylene-(5-14-membered)heteroaryl may be independently optionally substituted by 1, 2, 3 or 4 R c Replace; or when 2 R a When attached to the same atom, the two R a can form an oxo group; or when 2 R b When attached to the same atom, the two R b can form an oxo group; or R a and R b The atoms to which it is attached together form a (5-7 membered) heterocycloalkyl, wherein the (5-7 membered) heterocycloalkyl is independently optionally substituted by 1, 2, 3 or 4 R c replace.

11. The compound according to claim 10 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R a is -H, -D, (C1-C3) alkyl, -CH2-(5-6 membered) heteroaryl, wherein the (5-6 membered) heteroaryl is optionally substituted by 1, 2, 3 or 4 R c Replacement; R b is -H, -D, (C1-C3) alkyl, R b Preferred are -H, -D and -CH3.

12. The compound according to any one of claims 1 to 11 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the 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-C12) cycloalkyl, (3-12 membered) heterocycloalkyl, (C6-C10) aryl, (5-14 membered) heteroaryl, -(C1-C3) alkylene-(C1-C6) alkoxy, -(C1-C3) alkylene-(C3-C12) cycloalkyl, -(C1-C3) alkylene-(3-12 membered) heterocycloalkyl, -(C1-C3) alkylene-(C6-C10) aryl, -(C1-C3) alkylene-(5-14 membered) heteroaryl; or when 2 R c When attached to the same atom, the two R c Can form an oxo group; R c Preferred are H, D, halogen, hydroxy, amino, cyano, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C3-C7) cycloalkyl, (3-7 membered) heterocycloalkyl.

13. The compound according to any one of claims 1 to 12 or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

14. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1 to 13 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

15. Use of the compound according to any one of claims 1 to 13 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 14 in the preparation of drugs for treating, regulating and / or preventing diseases associated with HDAC inhibitors.

16. The use according to claim 15, wherein the disease is cancer, and the cancer is blood cancer and solid tumor, preferably breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, gastric cancer, blood cancer, lymphoma, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma or intracranial tumor.

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