Dual LSD1 / HDAC inhibitor

Abstract

Dual LSD1 / HDAC inhibitor The present disclosure provides compounds of formula (I), analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof. The present disclosure also provides methods for preparing compounds of formula (I), analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers, and pharmaceutically acceptable salts thereof. Compounds of formula (I) modulate MYC or coREST in subjects in need thereof. Compounds of formula (I) inhibit HDAC enzymes or LSD1 enzymes, or both HDAC enzymes and LSD1 enzymes. Compounds of formula (I) are epigenetic regulators with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types.

Description

[Technical field]

[0001] The present disclosure generally relates to the field of pharmaceutical compounds, and more particularly to the compound of formula (I), specifically its enantiomeric form and its related compounds, as an inhibitor of lysine-specific demethylase (LSD1) or histone deacetylase (HDAC), or both LSD1 and HDAC. In particular, the substantially pure enantiomeric form of the compound of formula (I) as a potent LSD1 / HDAC inhibitor for the treatment of disease and / or prevention of symptoms associated therewith. The present disclosure further relates to the LSD1 / HDAC dual inhibitor of the compound of formula (I), which is an epigenetic regulator with a novel mechanism of action that targets MYC amplification in multiple neuroendocrine tumor types. [ka] [Background technology]

[0002] Lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are epigenetic proteins that have been found to be associated with several diseases, including cancer. LSD1 is actively involved in catalyzing the demethylation of histone 3, which controls gene expression. LSD1 has a role in various cellular processes and is involved in embryonic development, cell proliferation and metastasis. Furthermore, the HDAC enzyme family plays a key role in regulating several biological processes, including transcription and cell cycle. Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks et al., J. Natl. Cancer Inst., 2000, 92, 1210-1215; L. Zhang, et.al., Medicinal Research Reviews, 2015, 35, 63-84; PK Agrawala, et.al., HOAJ Biology 2013, 2, 1-8. Other compounds that can inhibit HDAC activity are trichostatin A (TSA), PXDlOl, tropoxin (TPX), sodium butyrate (NaB), sodium valproate (VPA), cyclic hydroxamic acid-containing peptides (CHAP), depsipeptide FK-228, MGCDO103, and MS-275. The above inhibitors can also derepress tumor suppressor genes (e.g., p21wafl / cf l), resulting in antiproliferative effects in vitro and antitumor effects in vivo. Currently, four HDAC inhibitors are FDA approved for the treatment of various cancers: Vorinostat, Istodax, and Belinostat are approved for the treatment of cutaneous T-cell lymphoma, and Panobinostat is approved for the treatment of multiple myeloma.

[0003] Lysine methyltransferases and lysine demethylases are involved in regulating histone methylation. Lysine demethylases (LSD1 and LSD2) are known to remove methyl groups from mono- and dimethylated Lys4 of histone H3 (H3K4me1 / 2) via flavin adenine dinucleotide (FAD)-dependent enzymatic oxidation and release of formaldehyde as a by-product. LSD1-mediated demethylation is not limited to histones, and other non-histone substrates such as p53, STAT3, E2F1 and MYPT1 are also demethylated, leading to altered cellular functions.

[0004] LSD1 is overexpressed in various cancer cells and tissues, including neuroblastoma, prostate cancer, breast cancer, leukemia, lung cancer, and bladder cancer cells. Inhibition of LSD1 by small molecules or RNAi is known to be associated with inhibition of cancer cell growth through modulation of pro-survival gene expression and p53 transcriptional activity. JW Hφjfeldt, et.al., Nature Drug Discovery, 12, 917-930, 2013, Manfred Jung and et.al., Clinical Epigenetics (2016) 8:57, identify novel inhibitors for LSD1 / HDAC.

[0005] Another recent report suggests that crosstalk between LSD1 and HDAC is associated with changes in gene expression leading to growth inhibition and apoptosis (Huang et. al., Carcinogenesis, 34, 1196-1207, 2013). This study and other similar studies suggest that inhibiting both LSD1 and HDAC can exhibit synergistic effects in regulating gene expression and inducing growth inhibition. MYC is considered a master regulator of human cancer because of its key role in regulating the transcription of many cancer-related genes.

[0006] MYC is considered a master regulator of human cancers due to its critical role in regulating the transcription of many cancer-related genes. Dysregulation of MYC expression is a hallmark of several human cancers. MYC amplification has been reported in approximately 15% of all human cancers and is generally associated with poor prognosis and treatment resistance. Several studies have shown that focal amplification of MYC along with RB1 and p53 mutations is a key event in the metastatic process of neuroendocrine tumor progression. Although there are limited options available for direct targeting, transcriptional regulation via epigenetic super-enhancer complexes may be an attractive and viable option to target MYC-driven neuroendocrine cancers. Thus, the treatment of such MYC-amplified cancers represents an attractive target with a high unmet need. Although there are limited options available for direct targeting, transcriptional regulation via epigenetic super-enhancer complexes appears to be an attractive and viable option to target MYC-driven cancers. The epigenetic proteins CREBBP / EP300 and HDACs have been shown to play important roles in MYC transcription.

[0007] Although there are several chemotherapy- and targeted therapy-based drugs for cancer, an effective cure for cancer has yet to be found. Moreover, the development of acquired resistance and disease recurrence remain major problems to be addressed.

[0008] Therefore, there is a need for novel mechanism-based approaches in the treatment of cancers / diseases mediated by LSD1 / HDAC proteins that would have stronger effects on signal transduction pathways and / or affect multiple pathways and mutually exclusive mechanisms in cells. In this regard, there remains a need for dual inhibitors of LSD1 / HDAC that are more effective in treating diseases than treatment with either LSD1 or HDAC inhibitors individually. Summary of the Invention

[0009] In one embodiment of the present disclosure, a compound of formula (I): [ka] [In the formula, Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl; 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R1 is independently hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo, thioxo, -SO2-, amino, hydrazino, formyl, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 7-12 Arylalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, C 6-10 Aryl, C 2-10 Heterocyclyl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 7-12 Arylalkoxy, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy, amino or cyano; Ring B is [ka] and; Y is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl, -CO and -CO-C 2-10 heterocyclyl; 1-6 Heteroaryl, C 2-10 Heterocyclyl and -CO-C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; Here, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy or cyano; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, C 7-12 -arylalkenyl, C 2-12 -Alkylheteroaryl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl, -CONR6-C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR6-C 6-10 Aryl, -NR6-C 1-6 Heteroaryl, -OC 6-10 Aryl, -OC 1-6 Heteroaryl, -CONR6-C 7-12 Alkylaryl, -SO2-C 6-10Aryl, -SO2-C 7-12 Alkylaryl and -NR6SO2-C 7-12 alkylaryl; 2-10 Heterocyclyl, C 2-12 -alkylheteroaryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR6-C 1-6 Heteroaryl and -OC 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R6 is hydrogen or C 1-8 is alkyl; R2 is hydroxy, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 heteroaryl; wherein amino C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 Heteroaryl is independently optionally selected from amino, C 1-8 and optionally substituted with one or more groups selected from alkyl, halogen, hydroxy, or cyano; n is 1 to 4. and its analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers and pharma- ceutically acceptable salts thereof are provided.

[0010] In another embodiment of the present disclosure, a compound of formula (IA): [ka] [In the formula, Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R1 is independently hydrogen, halogen, oxo, C 1-8 Alkyl, C 6-10 Aryl, C 2-10 Heterocyclyl and C 3-6 heteroaryl; 2-10 Heterocyclyl and C 3-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 3-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 optionally substituted by alkyl; Y is C 1-6 Heteroaryl, C 2-10 heterocyclyl and -CO; 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O, or S; 1-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 optionally substituted by alkyl; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R2 is hydroxy or C 6-10 aryl; 6-10aryl is substituted by amino; n is 1 to 4. and its analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers and pharma- ceutically acceptable salts thereof are provided.

[0011] In another aspect of the disclosure, there is provided a process for preparing compounds of formula (I), their analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers and pharma- ceutically acceptable salts thereof, comprising the steps of: Process 1 : reacting compound 1 with an aldehyde or ketone in a protic solvent to give an intermediate imine, which is then reacted with a reducing agent to give intermediate compound 2, or alternatively, reacting compound 1 with an alkyl halide, optionally in the presence of a base, to give intermediate compound 2; Step 2: hydrolysis of intermediate compound 2 with an inorganic base to give the corresponding acid which is then coupled with the respective amine NH2R2 in the presence of an activating agent to give the compound of formula (I), or alternatively, reaction of intermediate compound 2 with NH2R2 and an inorganic base to give the compound of formula (I): [ka] [Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R1 is independently hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo, thioxo, -SO2-, amino, hydrazino, formyl, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 7-12 Arylalkoxy, C 3-8 Cycloalkyl, C3-8 Cycloalkyloxy, C 6-10 Aryl, C 2-10 Heterocyclyl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 7-12 Arylalkoxy, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy, amino or cyano; Ring B is [ka] and; Y is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl, -CO and -CO-C 2-10 heterocyclyl; 1-6 Heteroaryl, C 2-10 Heterocyclyl and -CO-C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; Here, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy or cyano; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, C 7-12 -arylalkenyl, C 2-12 -Alkylheteroaryl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl, -CONR6-C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR6-C 6-10 Aryl, -NR6-C 1-6 Heteroaryl, -OC 6-10 Aryl, -OC 1-6 Heteroaryl, -CONR6-C 7-12 Alkylaryl, -SO2-C 6-10 Aryl, -SO2-C 7-12 Alkylaryl and -NR6SO2-C 7-12 alkylaryl; 2-10 Heterocyclyl, C 2-12 -alkylheteroaryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR6-C 1-6 Heteroaryl and -OC 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R6 is hydrogen or C 1-8 is alkyl; R2 is hydroxy, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6heteroaryl; wherein amino C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 Heteroaryl is independently optionally selected from amino, C 1-8 and n is 1 to 4, optionally substituted by one or more groups selected from alkyl, halogen, hydroxy, or cyano.

[0012] In a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula (I) as described herein and a pharma- ceutically acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0013] In another aspect of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for inhibiting HDAC enzymes or LSD1 enzymes or both LSD1 and HDAC enzymes, or modulating MYC or coREST in a subject in need thereof, comprising a compound of formula (I) as described herein, optionally in combination with one or more other pharmaceutical agents.

[0014] In another aspect of the present disclosure, there is provided a method of treating, preventing, modulating or ameliorating a disease or condition mediated by LSD1 or HDAC or both LSD1 and HDAC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein, optionally together with other clinically relevant immunomodulatory agents or other clinically relevant cytotoxic or non-cytotoxic agents.

[0015] In another aspect of the present disclosure, there is provided a method of treating, preventing, modulating or ameliorating a disease or condition mediated by MYC or coREST in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein, optionally together with other clinically relevant immunomodulatory agents or other clinically relevant cytotoxic or non-cytotoxic agents.

[0016] In another aspect of the present disclosure, there is provided a method of inhibiting both LSD1 and HDAC or a transcriptional cofactor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0017] In a further aspect of the present disclosure, there is provided a method for treating and / or preventing a disease or condition mediated by both LSD1 and HDAC, or a proliferative disorder or cancer, comprising administering to a subject suffering from a condition or a proliferative disorder or cancer mediated by both LSD1 and HDAC a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0018] In another aspect of the present disclosure, there is provided a method for treating and / or preventing a disease or condition mediated by LSD1, or a proliferative disorder or cancer, comprising administering to a subject suffering from a condition or a proliferative disorder or cancer mediated by LSD1 a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0019] In a further embodiment of the present disclosure, there is provided a method for treating and / or preventing an HDAC-mediated disease or condition, or a proliferative disorder or cancer, comprising administering to a subject suffering from an HDAC-mediated condition, or a proliferative disorder, or cancer a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0020] In a further embodiment of the present disclosure, there is provided a method of treating a subject having a tumor, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0021] In a further embodiment of the present disclosure, there is provided a method of treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0022] These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This Summary is provided to introduce some concepts in a simplified form. It is not intended to identify key features or essential features of the disclosure, nor is it intended to be used to limit the scope of the claimed subject matter. [Brief description of the drawings]

[0023] In addition to the features described herein, additional features and modifications will be readily apparent from the following drawings and description of illustrative embodiments, which should be understood to depict exemplary embodiments and are not intended to be limiting in scope.

[0024] [Figure 1] FIG. 1 illustrates Western blot results showing the effect of Example 1, ORY-1001 (an LSD1 inhibitor) and ACY-1215 (an HDAC inhibitor) on c-Myc regulation in erythroid leukemia cells, in accordance with an embodiment of the present disclosure.

[0025] [Diagram 2] FIG. 2 is a line graph showing the effect of Example 1 and docetaxel (standard of care) on mean tumor volume in a prostate cancer xenograft model in accordance with an embodiment of the present disclosure.

[0026] Detailed Description Those skilled in the art will recognize that the present disclosure is subject to variations and modifications other than those specifically described. The present disclosure should be understood to include all such variations and modifications. The present disclosure also includes all such steps, features, compositions and compounds referred to or shown herein, individually or collectively, and any and all combinations of any or more of such steps or features.

[0027] definition For convenience, before further description of the present disclosure, certain terms and examples used herein are collected here.These definitions should be read in light of the remaining parts of the present disclosure and understood by those skilled in the art.Terms used herein have meanings that are recognized and known to those skilled in the art, but for convenience and completeness, certain terms and their meanings are provided below.

[0028] The articles "a", "an" and "the" are used to refer to one or to more than one (ie, to at least one) of the grammatical object of the article.

[0029] The term "or" means "and / or" unless otherwise stated.

[0030] The terms "comprise" and "comprising" are used in an inclusive and open sense, meaning that additional elements may be included. Throughout this specification, unless otherwise required by context, the term "comprise" and variations such as "comprises" and "comprising" are understood to mean the inclusion of the stated elements or steps, or steps of elements or steps, but not the exclusion of other elements or steps, or steps of elements or steps.

[0031] The term "compound(s)" includes compounds disclosed in the present disclosure.

[0032] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0033] In the structural formulas depicted herein and throughout this disclosure, the following terms are given the meanings indicated unless otherwise indicated.

[0034] Additionally, the compounds of formula (I) may be analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers, geometric isomers, or pharma- ceutically acceptable salts and compositions thereof.

[0035] The compounds described herein may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), positional isomers, enantiomers or diastereomers. Thus, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the compounds depicted or identified, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compounds may also exist in several tautomeric forms, including enol forms, keto forms and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the compounds depicted or identified. It is also understood that some isomeric forms, such as diastereomers, enantiomers and geometric isomers, can be separated by those skilled in the art by physical and / or chemical methods.

[0036] The term "enantiomers" refers to two stereoisomers of a compound of formula (I) that are non-superimposable mirror images of one another. Enantiomeric excess refers to the absolute difference between the enantiomers. Enantiomeric excess refers to a chiral compound that contains more of one enantiomer than the other.

[0037] According to the present disclosure, the compounds provided herein include all of the corresponding enantiomers and stereoisomers, i.e., the pure forms of the stereoisomers in terms of geometric isomers, enantiomers, or diastereomers, as well as mixtures of the enantiomeric and stereoisomeric forms of the compounds. Furthermore, mixtures of enantiomers and stereoisomeric forms can be resolved into their pure components by methods known in the art, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization, the use of chiral derivatizing agents, etc. Also, pure enantiomers and stereoisomers can be obtained from reagents in the form of pure enantiomers and stereoisomers by known asymmetric synthesis methods.

[0038] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom.

[0039] Additionally, the term "substituted" or "optionally substituted" means that one or more hydrogen radicals in a given structure are replaced with the radical of a specified substituent, including, but not limited to, halo, oxo, sulfo, sulphido, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, cycloalkyl, heteroaryl, and aliphatic. It is understood that the substituents may be further substituted.

[0040] The term "alkyl" refers to a straight or branched chain aliphatic hydrocarbon group having the specified number of carbon atoms, attached to the remainder of the molecule by a single atom which may be optionally substituted by one or more substituents. Preferred alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, and the like.

[0041] The term "aryl" refers to an optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system having about 6-10 carbon atoms. 10Examples of aryl groups include, but are not limited to, phenyl or naphthyl. Aryl groups may be optionally substituted with one or more suitable groups.

[0042] The term "heterocyclyl" means a heterocyclic ring radical, optionally substituted by one or more substituents. The heterocyclyl ring radical can be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

[0043] Furthermore, the term "heterocyclyl" refers to a stable 2-10 membered ring radical consisting of carbon atoms and one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this disclosure, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. Furthermore, the nitrogen atom may be optionally quaternized; the ring radical may be partially or fully saturated. Preferred heterocyclyl groups include azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, monopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolidinyl, and pyrrolidinyl. aryl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, thienyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, furyl, tetrahydrofuryl, tetrahydropyranyl, chromanyl and isochromanyl.

[0044] The term "heteroaryl", alone or in combination with other terms, refers to a fully unsaturated ring system containing a total of 5-14 ring atoms with at least one carbon atom. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms / groups are independently selected from carbon, oxygen, nitrogen, or sulfur. A heteroaryl may be a single fused ring (monocyclic) or multiple covalently linked rings (bicyclic, tricyclic, or polycyclic). Preferably, a "heteroaryl" is a 5-6 membered ring. The ring may further contain 1-4 heteroatoms selected from N, O, and S, where the N atom may be optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of "heteroaryl" include furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl; benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl. Examples of heteroaryl groups include, but are not limited to, aryl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, a-carbolinyl, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, carbazolyl, dibenzothienyl, acridinyl, and the like. Heteroaryl groups may be optionally further substituted.

[0045] The term "heteroatom" as used herein means a sulfur, nitrogen, or oxygen atom.

[0046] The term "alkylheteroaryl" refers to an alkyl bonded to a heteroaryl group, which may be optionally substituted. For purposes of this disclosure, alkylheteroaryl refers to compounds having in the range of 2-12 carbon atoms, including alkyl groups having 1-6 carbon atoms.

[0047] The term "fused heterocyclyl" refers to a monocyclic or polycyclic ring, and a polycyclic ring system refers to a ring system containing two or more rings, preferably bicyclic or tricyclic rings, which rings may be fused, bridged, spiro, or any combination thereof. As used herein, fused rings means that two rings are connected to each other through two adjacent ring atoms that are common to both rings. The fused rings may be fused by nitrogen or a -CH- group.

[0048] As used herein, the term "bridged ring" means that a ring contains a linker group (C(Rq)2)p-, which links together any two non-adjacent carbon or nitrogen atoms of the ring, where p is 1 or 2 and each p is independently hydrogen or C1-4 alkyl.

[0049] The term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system having about 3 to 8 carbon atoms, optionally substituted by one or more substituents. A polycyclic ring refers to a hydrocarbon system containing two or more ring systems having one or more ring carbon atoms in common, i.e., spiro, fused or bridged structures. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl, bridged cyclic groups or spiro bicyclic groups, such as spiro [4.4] non-2-yl, and the like.

[0050] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen linkage, which may be optionally substituted with one or more substituents. Preferred alkoxy groups include, but are not limited to, -OCH3, -OC2H5, and the like.

[0051] The term "arylalkoxy" refers to a group having an alkyl attached to an alkoxy group. For purposes of this disclosure, an arylalkoxy group has from 7 to 12 carbon atoms.

[0052] The terms "halo" or "halogen", alone or in combination with other terms, mean fluorine, chlorine, bromine, or iodine.

[0053] The term "haloalkoxy" refers to an alkoxy having one or more halogen atoms replacing the hydrogens in the alkoxy group. In the present disclosure, haloalkoxy refers to a compound having 1 to 8 carbon atoms, and examples of haloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OC2H4F, etc.

[0054] The term "cycloalkyloxy" refers to a cycloalkyl group attached through an oxygen linkage in a cycloalkyl molecule, which may be optionally substituted by one or more substituents.

[0055] The term "haloalkyl" refers to an alkyl having one or more halogen atoms. In this disclosure, the term haloalkyl refers to a compound having 1 to 8 carbon atoms, and examples of haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -C2H4F, etc.

[0056] The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and having about 2 to 8 carbon atoms, which may be straight or branched, and which may be optionally substituted by one or more substituents. Preferred alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0057] The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond and ranging from 2 to 8 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0058] The term "alkylaryl" refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents. Preferred alkylaryl groups include, but are not limited to, -CH2-phenyl-, -C2H4-phenyl-, C3H6-phenyl-, and the like.

[0059] The term "alkenylaryl" refers to an alkenyl group directly bonded to an aryl group, which may be optionally substituted by one or more substituents. Preferred alkenylaryl groups include, but are not limited to, -CH=CH-phenyl, -CH2-CH=CH-phenyl, and the like.

[0060] The term "arylalkenyl" refers to an aryl group directly bonded to an alkenyl group, which may be optionally substituted by one or more substituents. Preferred arylalkenyl groups include, but are not limited to, -CH-CH=CH-, -CH-CH=CH-CH-, and the like.

[0061] The term "arylalkynyl" refers to an aryl group directly bonded to an alkynyl group, which may be optionally substituted by one or more substituents. Preferred arylalkenyl groups include, but are not limited to, -CH-ethynyl-, -CH-propynyl-, and the like.

[0062] The term "-CO-alkylaryl" means a carbonyl group directly attached to an alkylaryl group, which may be optionally substituted by one or more substituents. Preferred "-CO-alkylaryl groups" include, but are not limited to, -CO-CH2-phenyl-, -CO-C2H4-phenyl-, and the like.

[0063] The term "-CO-alkenylaryl" means a carbonyl group directly attached to an alkenylaryl group, which may be optionally substituted by one or more substituents. Preferred "-CO-alkenylaryl" groups include, but are not limited to, -CO-CH=CH-phenyl-, -CO-CH2-CH=CH-phenyl-, and the like.

[0064] The term "-CO-heterocyclyl" means a carbonyl group bonded directly through a heteroatom or carbon atom of a heterocyclyl group, which may be optionally substituted by one or more substituents. Preferred "-CO-heterocyclyl" groups include, but are not limited to, -CO-piperazinyl, -CO-N-piperdinyl (meaning bonded through the nitrogen of the piperdinyl group), -CO-C-piperidinyl (meaning bonded through the carbon of the piperdinyl group), and the like.

[0065] The term "cyano" refers to the group -CN.

[0066] The term "oxo" refers to the group ═O.

[0067] The term "amino" refers to the group --NH.

[0068] The term "hydroxy" or "hydroxyl" refers to an --OH group.

[0069] The term "thioxo" refers to the group ═S.

[0070] The term "hydrazino" refers to the group -NH-NH.

[0071] The term "formyl" means [ka] means a group.

[0072] The term "nitro" refers to the group --NO.sub.2.

[0073] The term "nitroso" refers to the group --N.dbd.O.

[0074] The term "azido" refers to the group --N3.

[0075] The term "one or more" as used herein means one to many, and can be 1 to 10. In the present disclosure, the term "one or more groups selected from" means selecting one group or groups from the list. It also means selecting one group or groups of the same or selecting different groups from the list, or a combination of groups.

[0076] It is understood that included within the family of compounds of formula (I) are isomeric forms including diastereomers, enantiomers, tautomers, and mixtures of "E" or "Z" configurational isomers or "E" and "Z" isomers. It is also understood that some isomers, such as diastereomers, enantiomers, and geometric isomers, can be separated by one skilled in the art by physical and / or chemical methods.

[0077] The compounds disclosed herein may exist as single stereoisomers or as mixtures of enantiomers and / or diastereomers. All such single stereoisomers, and mixtures thereof, are intended to be within the scope of the described subject matter.

[0078] The compounds disclosed herein include any isotopes of hydrogen, carbon, oxygen, fluorine, chlorine, iodine, and sulfur that may be incorporated into the compounds, such as 2 H(D), 11 C. 13 C. 15 N, 18 F, 35 S, 36 Cl and 125 I, not limited to. The compounds of the present disclosure, in which atoms are isotopically labeled, can be used in metabolic studies, kinetic studies, and imaging techniques, such as positron emission tomography, used to understand the tissue distribution of drugs. The compounds of the present disclosure, in which hydrogen is replaced by deuterium, can improve the metabolic stability and pharmacokinetic properties of drugs, such as in vivo half-life. 18 F isotopically labeled compounds of the present disclosure may be useful as PET imaging modalities.

[0079] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from the combination of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0080] As used herein, the term "pharmaceutical composition" means a composition containing a therapeutically effective amount of at least one compound of formula (I) or a pharma- ceutically acceptable salt thereof; and a conventional pharma- ceutically acceptable carrier.

[0081] A pharmaceutical composition typically contains about 1% to 99% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof, for example, about 5% to 75%, or about 10% to about 30%. The amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is about 1 mg to about 1000 mg, or about 2.5 mg to about 500 mg, or about 5 mg to about 250 mg, or any range falling within the broader range of 1 mg to 1000 mg, or higher or lower than the aforementioned ranges.

[0082] The term "other pharmaceutical agents" refers to other active pharmaceutical ingredients or agents that may act in combination with a compound of Formula (I) or a pharmaceutical composition of the present disclosure.

[0083] As used herein, the terms "treat," "treating," and "treatment" refer to any treatment of a disease in a mammal, including: (a) inhibiting the disease, i.e., slowing or halting the onset of clinical symptoms; and / or (b) relieving the disease, i.e., causing regression of clinical symptoms; and / or (c) reducing or eliminating the disease and / or its associated symptoms.

[0084] As used herein, the terms "prevent", "preventing" and "prevention" refer to a method of preventing the onset of a disease and / or its associated symptoms or a method of preventing a subject from contracting a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and / or its associated symptoms, as well as reducing a subject's risk of contracting a disease.

[0085] As used herein, the term "subject", which is interchangeable with "patient", means an animal, preferably a mammal, and most preferably a human.

[0086] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I), its analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers, or pharma- ceutically acceptable salts thereof, or a composition comprising a compound of formula (I), its analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers, or pharma- ceutically acceptable salts thereof; effective to produce a desired therapeutic response in a particular patient suffering from a disease or disorder, particularly in diseases or disorders related to cancer. In particular, the term "therapeutically effective amount" includes an amount of a compound of formula (I) or its pharma- ceutically acceptable salts or stereoisomers; that, when administered, is sufficient to induce a positive change in the disease or disorder being treated, or to prevent or alleviate to some extent the onset of one or more symptoms of the disease or disorder being treated in a subject in need thereof. With respect to the therapeutic amount of a compound, it may also be considered, within the scope of sound medical judgment, that the amount of the compound used to treat a subject is low enough to avoid excessive or severe side effects. The therapeutically effective amount of a compound or composition will vary depending on the particular condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of any concurrent treatments, the age and physical condition of the end user, the particular compound or composition used, and the particular pharma- ceutically acceptable carrier employed.

[0087] The phrase "pharmacologically acceptable" means a compound or composition that is physiologically tolerable, generally does not produce an allergic or similar unpleasant reaction, and is generally safe, non-toxic, and biologically or otherwise objectionable, including those that are acceptable for human medical use as well as veterinary use, including, but not limited to, those that do not cause upset stomach or dizziness when administered to a subject.

[0088] Pharmaceutically acceptable salts which form part of this disclosure include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn and ammonium, substituted ammonium salts, aluminum salts, etc.; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamines, thiamine, guanidine, diethanolamine, α-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, etc. Salts also include amino acid salts such as glycine, alanine, cysteine, cysteine, lysine, arginine, phenylalanine, guanidine, etc. Salts may conveniently include acid addition salts such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, fumarates, citrates, succinates, lactates, mesylates, trifluoroacetates, acetates, besylates, propionates, mandelates, hydrobromides, hydrochlorides, palmoates, methanesulfonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarate salts, and the like.

[0089] The terms "histone deacetylase" and "HDAC" are intended to mean any one of a family of enzymes that remove acetyl groups from the ε-amino groups of lysine residues at the N-terminus of histones or tubulin.Unless otherwise specified by context, the term "histone" is meant to refer to any histone protein, including H1, H2A, H2B, H3, H4 and H5, from any species.Human HDAC proteins or gene products include, but are not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10 and HDAC-11.Histone deacetylases can be from protozoan or fungal sources.

[0090] The term "histone deacetylase inhibitor" or "histone deacetylase inhibitor" is used to identify compounds that can interact with histone deacetylase and inhibit its activity, more specifically its enzymatic activity. Inhibiting the enzymatic activity of histone deacetylase means reducing the ability of histone deacetylase to remove acetyl groups from histones or tubulin. Preferably, such inhibition is specific, i.e., the histone deacetylase inhibitor reduces the ability of histone deacetylase to remove acetyl groups from histones or tubulin at a concentration lower than the concentration of inhibitor required to produce any other unrelated biological effect.

[0091] The term "lysine demethylase inhibitor" or "inhibitor of lysine demethylase" is used to identify compounds that can interact with histone demethylase and inhibit its activity, more particularly its enzymatic activity. Inhibiting the enzymatic activity of histone demethylase means reducing the ability of histone demethylase to remove methyl groups from histones. Inhibitors of histone demethylase include removing either mono- or dimethyl- or trimethyl groups from histones. Preferably, such inhibition is specific, i.e., histone demethylase inhibitors reduce the ability of histone demethylase to remove methyl groups from histones at a concentration lower than the concentration of inhibitor required to produce some other unrelated biological effect.

[0092] The term "LSD-1 / HDAC dual inhibitors" are capable of removing acetyl groups from histones or tubulin and removing methyl groups from histones. These inhibitors can inhibit more than one HDAC isozyme, covering all of these isozymes in addition to inhibiting the activity of LSD-1.

[0093] The term dual inhibitor LSD1 / HDAC6 is used to identify compounds that can selectively interact with the HDAC6 enzyme in addition to their enzymatic interaction with LSD-1. Dual inhibitors of LSD-1 / HDAC6 can remove acetyl groups from tubulin and methyl groups from histones.

[0094] The term dual inhibitor LSD1 / HDAC1 is used to identify compounds that can selectively interact with the HDAC1 enzyme in addition to their enzymatic interaction with LSD-1. Dual inhibitors of LSD-1 / HDAC1 can remove acetyl groups from histones and methyl groups from histones.

[0095] The term dual inhibitor LSD1 / HDAC8 is used to identify compounds that can selectively interact with the HDAC8 enzyme in addition to their enzymatic interaction with LSD-1. Dual inhibitors of LSD-1 / HDAC8 can remove acetyl groups from histones and methyl groups from histones.

[0096] The term "MYC" refers to a polymer of amino acid residues disclosed in NCBI Accession No. NP002458.2, and functional homologs, analogs, or fragments thereof; or a nucleic acid sequence encoding an amino acid sequence that is at least 40%-100% identical to the sequence in NCBI Accession No. NP002458.2, or a nucleotide sequence of at least 120 nucleotides that is at least 60%-100% identical or homologously identical to the sequence in NCBI Accession No. NM_002467. The compounds of the present disclosure modulate MYC, which may be further defined as downregulation of MYC RNA and / or degradation of MYC protein. The compounds of the present disclosure also inhibit the transcription factor coREST.

[0097] The term "coREST" refers to a newly identified protein that functions as a corepressor of REST. CoREST is a repressor protein; mutations that inhibit the binding of CoREST to REST also interfere with the repression of REST.

[0098] The term "REST" refers to RE1-silencing transcription factor (REST), also known as neuronal-restrictive silencer factor (NRSF), a transcriptional repressor that acts through epigenetic remodeling to silence target genes.

[0099] The term "immune checkpoint inhibitors" or "immunomodulators" is used to identify any drug or inhibitor that blocks specific proteins made by some types of immune system cells, such as T cells, and some types of cancer cells. These proteins help suppress the immune response and can prevent T cells from killing cancer cells. When these proteins are blocked, the "brakes" on the immune system are released and T cells can more effectively kill cancer cells. Immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM arginase, CD137 (also known as 4-1ββ), ICOS, A2AR, B7-h3, B7-h4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, and PD-L2. The terms "immunomodulatory agent" and "immune checkpoint inhibitor" are used interchangeably throughout the present invention.

[0100] The terms "cytotoxic agent" or "cytotoxic inhibitor" are used to identify any agent or drug that can kill cells, including cancer cells. These agents or inhibitors can stop cancer cells from growing or dividing, causing tumors to shrink.

[0101] The terms "non-cytotoxic agents" or "non-cytotoxic inhibitors" are used to identify agents or inhibitors that do not directly kill cells but affect cellular transport or metabolic functions, ultimately resulting in cell death.

[0102] Once a term is described, it will have the same meaning throughout the patent.

[0103] As mentioned in the background, it can be observed that there is a great need for novel mechanism-based approaches in the treatment of cancers / diseases mediated by LSD1 / HDAC enzymes. It has been surprisingly determined that certain enantiomeric forms of the compound of formula (I) have a significant effect on biological activity compared to its racemic form. Thus, the present disclosure provides enantiomeric forms of the compound of formula (I) that result in unexpected properties. The present disclosure provides substantially pure preparations of highly active specific enantiomeric forms of the compound of formula (I) that have surprisingly higher activity than the racemic forms of said compounds and other related compounds. Furthermore, the compounds of the present disclosure have been found to modulate the MYC gene and / or MYC protein, which are useful in the treatment of various diseases.

[0104] In the practice of this disclosure, a compound of formula (I): [ka] [Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R1 is independently hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo, thioxo, -SO2-, amino, hydrazino, formyl, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 7-12 Arylalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, C 6-10 Aryl, C 2-10 Heterocyclyl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 7-12 Arylalkoxy, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy, amino or cyano; Ring B is [ka] and; Y is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl, -CO and -CO-C 2-10 heterocyclyl; 1-6 Heteroaryl, C 2-10 Heterocyclyl and -CO-C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; Here, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy or cyano; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, C 7-12 -arylalkenyl, C 2-12 -Alkylheteroaryl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl, -CONR6-C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR6-C 6-10 Aryl, -NR6-C 1-6 Heteroaryl, -OC 6-10 Aryl, -OC 1-6 Heteroaryl, -CONR6-C 7-12 Alkylaryl, -SO2-C 6-10 Aryl, -SO2-C 7-12 Alkylaryl and -NR6SO2-C 7-12 alkylaryl; 2-10 Heterocyclyl, C 2-12 -alkylheteroaryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR6-C 1-6 Heteroaryl and -OC 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R6 is hydrogen or C 1-8 is alkyl; R2 is hydroxy, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 heteroaryl; wherein amino C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C1-6 heteroaryl, independently optionally amino, C 1-8 may be substituted by one or more groups selected from alkyl, halogen, hydroxy or cyano; n is 1 to 4. and its analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers and pharma- ceutically acceptable salts thereof are provided.

[0105] In the practice of this disclosure, a compound of formula (IA): [ka] [In the formula, Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R1 is independently hydrogen, halogen, oxo, C 1-8 Alkyl, C 6-10 Aryl, C 2-10 Heterocyclyl and C 3-6 heteroaryl; 2-10 Heterocyclyl and C 3-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 3-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 optionally substituted by alkyl; Y is C 1-6 Heteroaryl, C 2-10 heterocyclyl and -CO; 1-6 Heteroaryl and C 2-10Heterocyclyl has one or more heteroatoms selected from N, O or S, where C 1-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 optionally substituted by alkyl; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R2 is hydroxy or C 6-10 aryl; 6-10 aryl is substituted by amino; n is 1 to 4. and its analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers and pharma- ceutically acceptable salts thereof are provided.

[0106] In the practice of the present disclosure, the compounds of formula (I) disclosed herein, wherein ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O, or S; R1 is independently hydrogen, halogen, hydroxy, nitro, oxo, amino, hydrazino, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aryl, C 2-10 Heterocyclyl and C 1-6heteroaryl; 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, C 6-10 Y is optionally substituted by one or more groups selected from aryl, halogen or hydroxy; 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl, -CO and -CO-C 2-10 heterocyclyl; 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl is independently optionally selected from C 1-8 may be substituted by one or more groups selected from alkyl, oxo, halogen, hydroxy or cyano; Z is 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, C 7-12 -arylalkenyl, C 2-12 -Alkylheteroaryl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl, -CONR6-C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, -CO-C 2-10 heterocyclyl; R2 is selected from the group consisting of hydroxy, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 heteroaryl; wherein aniline, C 6-10 Aryl, Amino C 6-10Aryl and Amino C 1-6 Heteroaryl is independently optionally selected from amino, C 1-6 and n is 1 to 10; optionally substituted with one or more groups selected from alkyl, halogen, hydroxy, or cyano.

[0107] In the practice of the present disclosure, the compounds of formula (I) disclosed herein, wherein ring A is C 6-8 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O, or S; R1 is independently hydrogen, halogen, hydroxy, nitro, oxo, amino, hydrazino, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, C 6-8 Aryl, C 2-10 Heterocyclyl and C 1-6 heteroaryl; 1-8 Alkyl, C 6-8 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-6 Alkyl, C 6-8 Y is optionally substituted by one or more groups selected from aryl, halogen or hydroxy; 1-8 Alkyl, C 6-8 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl, -CO and -CO-C 2-10 heterocyclyl; 1-8 Alkyl, C 6-8 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8Cycloalkyl is independently optionally selected from C 1-6 may be substituted by one or more groups selected from alkyl, oxo, halogen, hydroxy or cyano; Z is 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, C 7-12 -arylalkenyl, C 2-12 -Alkylheteroaryl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl, -CONR6-C 1-8 Alkyl, C 6-8 Aryl, C 1-6 Heteroaryl and -CO-C 2-10 heterocyclyl; R2 is selected from the group consisting of hydroxy, aniline, C 6-8 Aryl, Amino C 6-8 Aryl and Amino C 1-6 heteroaryl; wherein aniline, C 6-8 Aryl, Amino C 6-8 Aryl and Amino C 1-6 Heteroaryl is optionally selected from amino, C 1-6 and n is 1 to 4; and optionally substituted with one or more groups selected from alkyl, halogen, hydroxy, or cyano.

[0108] In the practice of the present disclosure, the compounds of formula (I) disclosed herein, wherein ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O, or S; R is independently hydrogen, halogen, oxo, C 1-8 Alkyl, C 6-10 Aryl, C 2-10 Heterocyclyl and C 3-6heteroaryl; 2-10 Heterocyclyl and C 3-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; 3-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 and Y is optionally substituted by alkyl; 1-6 Heteroaryl, C 2-10 heterocyclyl and -CO; 1-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 and Z is optionally substituted by alkyl; 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl and C 1-6 heteroaryl; R2 is selected from the group consisting of hydroxy or C 6-10 aryl; 6-10 aryl is substituted by amino; and n is 1-4.

[0109] In the practice of the present disclosure, the compounds of formula (I) disclosed herein, wherein ring A is C 6-8 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O, or S; R is independently hydrogen, halogen, oxo, C 1-8 Alkyl, C 6-8 Aryl, C 2-10 Heterocyclyl and C 3-6heteroaryl; 2-10 Heterocyclyl and C 3-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; 3-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 and Z is optionally substituted by alkyl; 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl and C 1-6 heteroaryl; R2 is selected from the group consisting of hydroxy or C 6-8 aryl; 6-8 aryl is substituted by amino; and n is 1-4.

[0110] In the practice of the present disclosure, the compound of formula (I) or (IA) disclosed herein, 6-8 Aryl, C 3-5 Heteroaryl and C 5-9 heterocyclyl, wherein C 3-5 Heteroaryl and C 5-9 Heterocyclyl has one or more heteroatoms selected from N, O, or S; R is independently hydrogen, halogen, oxo, C 1-4 Alkyl, C 6-8 Aryl, C 5-9 Heterocyclyl and C 3-5 heteroaryl; 5-9 Heterocyclyl and C 3-5 Heteroaryl has one or more heteroatoms selected from N, O, or S; 5-9 Heterocyclyl and C 3-5Heteroaryl is independently optionally one or more oxo or C 1-4 and Y is optionally substituted by alkyl; 2-5 Heteroaryl and C 5-9 heterocyclyl; 2-5 Heteroaryl and C 5-9 Heterocyclyl has one or more heteroatoms selected from N, O or S, where C 2-5 Heteroaryl and C 5-9 Heterocyclyl is independently optionally one or more oxo or C 1-4 and Z is optionally substituted by alkyl; 1-4 Alkyl, C 7-9 -Alkylaryl and -CO-C 7-10 alkenylaryl; R2 is selected from the group consisting of hydroxy or C 6-8 aryl; 6-8 aryl is substituted by amino; and n is 1-4.

[0111] In the practice of the present disclosure, there are provided compounds of formula (I) as disclosed herein that act as LSD1 inhibitors or HDAC inhibitors, or both LSD1 / HDAC inhibitors.

[0112] In the practice of the present disclosure, there are provided compounds of formula (I) as disclosed herein that act as epigenetic regulators.

[0113] In the practice of the present disclosure, there are provided compounds of formula (I) as disclosed herein that modulate MYC.

[0114] In the practice of the present disclosure, there are provided compounds of formula (I) as disclosed herein that regulate transcriptional cofactors.

[0115] In the practice of the present disclosure, there are provided compounds of formula (I) as disclosed herein that block neuroendocrine transdifferentiation.

[0116] In practicing the present disclosure: 1. N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide hydrobromide; 2. N-hydroxy-4-((4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide; 3. N-hydroxy-4-(3-(4-((((1R,2S)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 4. N-hydroxy-4-(3-(4-((((1S,2R)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 5. 4-((E)-3-(3-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)azetidin-1-yl)-3-oxoprop-1-en-1-yl)-N-hydroxybenzamide; 6. 4-((E)-3-(3-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)azetidin-1-yl)-3-oxoprop-1-en-1-yl)-N-hydroxybenzamide; 7. N-hydroxy-4-(3-(4-((((1R,2S)-2-(4-(pyrimidin-5-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 8. N-hydroxy-4-(3-(4-((((1S,2R)-2-(4-(pyrimidin-5-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 9. N-hydroxy-4-(3-(4-((((1R,2S)-2-(1,3,3-trimethyl-2-oxoindolin-5-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 10. N-hydroxy-4-(3-(4-((((1S,2R)-2-(1,3,3-trimethyl-2-oxoindolin-5-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 11. N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 12. N-hydroxy-4-((4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 13. N-hydroxy-4-(3-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 14. N-hydroxy-4-(3-(4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 15. N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl) amino)methyl)piperidin-1-yl)propyl)benzamide; 16. N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl) amino)methyl)piperidin-1-yl)propyl)benzamide; 17. N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(1-isopropyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 18. N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(1-isopropyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 19. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 20. N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 21. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl) amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide; 22. N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide; 23. N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 24. N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 25. N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(3,4-difluorophenyl) cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 26. N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(3,4-difluorophenyl) cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 27. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 28. N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 29. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide; and 30. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide, There is provided a compound of formula (I) disclosed herein, selected from the group consisting of:

[0117] In the practice of this disclosure, there is provided a method of preparing a compound of formula (I) disclosed herein, comprising the steps of: Step 1: reacting compound 1 with an aldehyde or ketone in a protic solvent to give an intermediate imine, which is then reacted with a reducing agent to give intermediate compound 2, or alternatively, reacting compound 1 with an alkyl halide, optionally in the presence of a base, to give intermediate compound 2; and Step 2: hydrolysis of intermediate compound 2 with an inorganic base to give the corresponding acid, which is then coupled with the respective amine NH2R2 in the presence of an activating agent to give the compound of formula (I), or alternatively, reaction of intermediate compound 2 with NH2R2 and an inorganic base to give the compound of formula (I): [ka] [Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R1 is independently hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo, thioxo, -SO2-, amino, hydrazino, formyl, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 7-12 Arylalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, C 6-10 Aryl, C 2-10 Heterocyclyl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 7-12 Arylalkoxy, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy, amino or cyano; Ring B is [ka] and; Y is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl, -CO and -CO-C 2-10 heterocyclyl; 1-6 Heteroaryl, C 2-10 Heterocyclyl and -CO-C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; Here, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 cycloalkyl, independently and optionally C 1-8 Alkyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy or cyano; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, C 7-12 -arylalkenyl, C 2-12 -Alkylheteroaryl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl, -CONR6-C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR6-C 6-10 Aryl, -NR6-C 1-6 Heteroaryl, -OC 6-10 Aryl, -OC 1-6 Heteroaryl, -CONR6-C 7-12 Alkylaryl, -SO2-C 6-10Aryl, -SO2-C 7-12 Alkylaryl and -NR6SO2-C 7-12 alkylaryl; 2-10 Heterocyclyl, C 2-12 -alkylheteroaryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR6-C 1-6 Heteroaryl and -OC 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R6 is hydrogen or C 1-8 is alkyl; R2 is hydroxy, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 Heteroaryl; Here, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 Heteroaryl is independently optionally selected from amino, C 1-8 and optionally substituted with one or more groups selected from alkyl, halogen, hydroxy, or cyano; n is 1 to 4. is provided.

[0118] In the practice of the disclosure, there is provided a method for making a compound of formula (I) as disclosed herein, wherein the activating agent is selected from EDCI.HCl (1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), HOBt (1-hydroxybenzotriazole) or (1-propylphosphonic anhydride)T3P / triethylamine; the protic solvent is selected from methanol, ethanol, water or a combination thereof; and the reducing agent is selected from sodium borohydride, lithium borohydride, aluminum borohydride or a combination thereof.

[0119] In the practice of the disclosure, there is provided a method of making a compound of formula (I) disclosed herein, wherein the base is selected from triethylamine, N,N-diisopropylethylamine, potassium carbonate, pyridine, or a combination thereof; and the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, or a combination thereof.

[0120] In the practice of the present disclosure, there is provided a method for preparing a compound of formula (I) as disclosed herein, wherein the protic solvent is selected from methanol, ethanol, water, or a combination thereof; the reducing agent is selected from sodium borohydride, lithium borohydride, aluminum borohydride, or a combination thereof. In another embodiment of the present disclosure, the protic solvent is methanol and the reducing agent is sodium borohydride.

[0121] In the practice of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula (I) disclosed herein and a pharma- ceutically acceptable carrier.

[0122] In the practice of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula (I) as disclosed herein and a pharma- ceutically acceptable carrier, optionally in combination with one or more other pharma- ceutically acceptable carriers.

[0123] In the practice of the present disclosure, there is provided a pharmaceutical composition as disclosed herein, wherein the pharmaceutical composition is in a form selected from the group consisting of a tablet, capsule, powder, syrup, solution, aerosol and suspension.

[0124] In the practice of the present disclosure, there is provided a pharmaceutical composition comprising a compound of formula (I) as disclosed herein, wherein the compound of formula (I) has an enantiomeric excess of greater than 60%, preferably greater than 80%.

[0125] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for inhibiting HDAC enzymes or LSD1 enzymes or both HDAC and LSD1 enzymes, or modulating MYC or coREST in a subject in need thereof, comprising a compound of formula (I) as disclosed herein and a pharma- ceutical acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0126] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for inhibiting HDAC enzymes or LSD1 enzymes, or both HDAC enzymes and LSD1 enzymes, in a subject in need thereof, comprising a compound of formula (I) as disclosed herein and a pharma- ceutically acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0127] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for inhibiting both HDAC and LSD1 enzymes, the pharmaceutical composition comprising a compound of formula (I) as disclosed herein and a pharma- ceutically acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0128] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for inhibiting an HDAC enzyme, the pharmaceutical composition comprising a compound of formula (I) as disclosed herein and a pharma- ceutical acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0129] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for inhibiting the LSD1 enzyme, the pharmaceutical composition comprising a compound of formula (I) as disclosed herein and a pharma- ceutically acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0130] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for modulating MYC or the coREST complex, the pharmaceutical composition comprising a compound of formula (I) as disclosed herein and a pharma- ceutical acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0131] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for modulating the coREST complex, the pharmaceutical composition comprising a compound of formula (I) as disclosed herein, or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0132] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for modulating MYC, the pharmaceutical composition comprising a compound of formula (I) as disclosed herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0133] In the practice of the disclosure, there is provided a compound of formula (I) as disclosed herein for use in the manufacture of a medicament for inhibiting HDAC enzymes, LSD1 enzymes, or both HDAC and LSD1 enzymes, or modulating MYC or coREST in a cell for the treatment of a disease or condition.

[0134] In the practice of the disclosure, a compound according to the present invention is provided which is capable of inhibiting HDAC enzymes, LSD1 enzymes, or both HDAC enzymes and LSD1 enzymes in a cell for treating a disease or condition. Provided herein are compounds of formula (I).

[0135] In the practice of the present disclosure, there is provided a compound of formula (I) as disclosed herein for use in the manufacture of a medicament for inhibiting both HDAC and LSD1 enzymes in a cell for the treatment of a disease or condition.

[0136] In the practice of the present disclosure, there is provided a compound of formula (I) as disclosed herein for use in the manufacture of a medicament for inhibiting HDAC enzymes in a cell for the treatment of a disease or condition.

[0137] In the practice of the present disclosure, there is provided a compound of formula (I) as disclosed herein for use in the manufacture of a medicament for inhibiting the LSD1 enzyme in a cell for treating a disease or condition.

[0138] In the practice of the disclosure, there is provided a compound of formula (I) as disclosed herein for use in the manufacture of a medicament for modulating the MYC or coREST complex in a cell for treating a disease or condition.

[0139] In the practice of the present disclosure, there is provided a compound of formula (I) as disclosed herein for use in the manufacture of a medicament for modulating MYC in a cell for the treatment of a disease or condition.

[0140] In the practice of the disclosure, there is provided a compound of formula (I) as disclosed herein for use in the manufacture of a medicament for modulating a coREST complex in a cell for the treatment of a disease or condition.

[0141] In the practice of the present disclosure, the present invention relates to a method for the treatment of cancer including breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain cancer, schwannoma, clear cell carcinoma, non-small cell lung cancer, small cell lung cancer, liver cancer, liver metastasis, kidney cancer, bile duct cancer, uterine cancer, cervical cancer, ovarian cancer, bladder, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma, vascular fibroma, glioblastoma, sarcoma, neuroendocrine tumor, retinoblastoma, penile cancer, pediatric solid tumors, renal cell carcinoma, pulmonary arterial tumors ... carcinoma), lymphomas, myelomas and leukemias (including, for example, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia), cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM), myeloproliferative neoplasms, MPN), polycythemia vera (PV), myeloproliferative dysplastic syndromes, essential thrombocythemia (ET), essential thrombocythemia and myelofibrosis (MF), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), cancers with specific mutations in the SWI / SNF complex (including but not limited to ARID1A, ARID1B, SMARCA4, SMARCA2), cancers with mutations in specific cancer genes including but not limited to EGFR, KRAS, RET, cancers with differential expression of specific genes including but not limited to LAPTM5, RNASE6, IL-16, APOBEC3 and TYROBP, depression, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia or MYC amplified tumors In one embodiment, there is provided a compound of formula (I) or a pharmaceutical composition disclosed herein for use in the manufacture of a medicament for inhibiting HDAC enzymes, LSD1 enzymes, or both HDAC and LSD1 enzymes in a cell to treat a tumor.

[0142] In the practice of the disclosure, there is provided a compound of formula (I) as disclosed herein for use in the manufacture of a medicament for inhibiting HDAC enzymes, LSD1 enzymes, or both HDAC and LSD1 enzymes in cells to treat multiple myeloma (MM), myeloproliferative neoplasms (MPN), polycythemia vera (PV), myeloproliferative dysplastic syndromes, essential thrombocythemia (ET), essential thrombocythemia, or myelofibrosis (MF).

[0143] In the practice of the disclosure, there is provided the use of a compound of formula (I) or a pharmaceutical composition disclosed herein for treating a condition mediated by LSD1 or HDAC, or both LSD1 and HDAC; treating and / or preventing a proliferative disorder or cancer; or treating cancer together with a clinically relevant cytotoxic or non-cytotoxic agent.

[0144] In the practice of the present disclosure, there is provided a method of inhibiting both SD1 and HDAC or a transcriptional cofactor in a cell in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0145] In the practice of the present disclosure, there is provided a method of inhibiting a transcriptional cofactor in a cell in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0146] In the practice of the present disclosure, there is provided a method of inhibiting both LSD1 and HDAC in a cell in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0147] In the practice of the present disclosure, there is provided a method for treating and / or preventing a disease or condition mediated by both LSD1 and HDAC, or a proliferative disorder or cancer, comprising administering to a subject suffering from a disease or condition mediated by both LSD1 and HDAC, or a proliferative disorder or cancer, a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0148] In the practice of the present disclosure, there is provided a method of treating and / or preventing a disease or condition, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein, together with other clinically relevant immunomodulatory agents.

[0149] In the practice of the disclosure, there is provided a method of treating and / or preventing a disease or condition comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein, together with another clinically relevant immunomodulatory agent, wherein said other clinically relevant immunomodulatory agent is selected from CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2.

[0150] In the practice of the present disclosure, there is provided a method of treating a disease and / or preventing a condition, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein, together with a clinically relevant cytotoxic or non-cytotoxic agent.

[0151] In the practice of the present disclosure, there is provided a method for treating and / or preventing a disease or condition mediated by MYC RNA & MYC protein, comprising administering to a subject suffering from a disease or condition mediated by MYC a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0152] In the practice of the disclosure, there is provided a method of treating and / or preventing a disease or condition comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein, wherein said disease or condition is selected from the group consisting of breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain cancer, schwannoma, clear cell carcinoma, non-small cell lung cancer, small cell lung cancer, liver cancer, liver metastasis, kidney cancer, bile duct cancer, uterine cancer, cervical cancer, ovarian cancer, bladder, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma, glioblastoma, sarcoma, neuroendocrine tumor, retinoblastoma, penile cancer, pediatric solid tumor, renal cell carcinoma, renal cell carcinoma, thyroid cancer ... carcinoma), lymphomas, myelomas and leukemias (including, for example, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia), cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM), myeloproliferative neoplasms, In one embodiment, the cancer is selected from the group consisting of myeloproliferative dysplastic syndromes (MPN), polycythemia vera (PV), myeloproliferative dysplastic syndromes (MDS), essential thrombocythemia (ET), essential thrombocythemia and myelofibrosis (MF), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), cancer with specific mutations in the SWI / SNF complex (including but not limited to ARID1A, ARID1B, SMARCA4, SMARCA2) or cancer with mutations in specific oncogenes EGFR, KRAS, RET, cancer with differential expression of specific genes including LAPTM5, RNASE6, IL-16, APOBEC3 and TYROBP, depression, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia or MYC amplified tumor.

[0153] In the practice of the disclosure, there is provided a method of treating and / or preventing a disease or condition comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein, wherein said disease or condition is selected from multiple myeloma (MM), myeloproliferative neoplasms (MPN), polycythemia vera (PV), myeloproliferative dysplastic syndromes, essential thrombocythemia (ET), essential thrombocythemia, or myelofibrosis (MF).

[0154] In the practice of the disclosure, there is provided the use of a compound of formula (I) or a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating and / or preventing a disease or condition.

[0155] In the practice of the disclosure, there is provided the use of a compound of formula (I) or a pharmaceutical composition disclosed herein for treating a disease or condition mediated by LSD1 or HDAC or both LSD1 and HDAC or MYC or coREST, for treating and / or preventing a proliferative disorder or cancer, or for treating cancer together with a clinically relevant cytotoxic or non-cytotoxic agent.

[0156] In practicing the present disclosure, use of the compounds of formula (I) or pharmaceutical compositions disclosed herein for treating a disease or condition mediated by LSD1 or HDAC or both LSD1 and HDAC, treating and / or preventing a proliferative disorder or cancer, or treating cancer together with a clinically relevant cytotoxic or non-cytotoxic agent is employed.

[0157] In the practice of the disclosure, there is provided use of a compound of formula (I) or a pharmaceutical composition disclosed herein for treating a disease or condition mediated by MYC or coREST, treating and / or preventing a proliferative disorder or cancer; treating cancer together with other clinically relevant cytotoxic or non-cytotoxic agents.

[0158] In the practice of the present disclosure, there is provided a compound of formula (I) or a pharmaceutical composition disclosed herein for treating and / or preventing a disease or condition mediated by MYC.

[0159] In the practice of the present disclosure, there is provided a method of treating and / or preventing a neurodegenerative disease or disorder comprising administering to a patient in need of treatment a therapeutically effective amount of a composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier.

[0160] In the practice of the present disclosure, there is provided a compound of formula (I) for use in the treatment and / or prevention of a neurodegenerative disorder or condition. In a related embodiment, the present disclosure provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment and / or prevention of a neurodegenerative disorder or condition.

[0161] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for inhibiting HDAC enzymes or LSD1 enzymes, or both HDAC enzymes and LSD1 enzymes, comprising a compound of formula (I) as disclosed herein together with a pharma- ceutical acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0162] In the practice of the present disclosure, there is provided a pharmaceutical composition for use in the manufacture of a medicament for modulating MYC, comprising a compound of formula (I) as disclosed herein together with a pharma- ceutical acceptable carrier, optionally in combination with one or more other pharmaceutical agents.

[0163] In the practice of the present disclosure, there is provided a method of treating, preventing, modulating or ameliorating a disease or condition mediated by MYC or coREST or LSD1 or HDAC, or both LSD1 and HDAC, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0164] In the practice of the present disclosure, there is provided a method for treating, preventing, modulating or ameliorating a disease or condition mediated by LSD1 or HDAC or both LSD1 and HDAC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0165] In the practice of the present disclosure, there is provided a method of treating, preventing, modulating or ameliorating a disease or condition associated with MYC or coREST in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0166] In the practice of the present disclosure, there is provided a method of inhibiting both LSD1 and HDAC in a cell in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0167] In the practice of the present disclosure, there is provided a method of inhibiting a transcription cofactor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0168] In the practice of the present disclosure, there is provided a method for treating and / or preventing a disease or condition mediated by both LSD1 and HDAC, or a proliferative disorder or cancer, comprising administering to a subject suffering from a disease or condition mediated by both LSD1 and HDAC, or a proliferative disorder or cancer, a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0169] In the practice of the disclosure, the methods disclosed herein include those comprising administering to the patient a therapeutically effective amount of a therapeutically effective amount of a disease or condition selected from the group consisting of breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain cancer, schwannoma, clear cell carcinoma, non-small cell lung cancer, small cell lung cancer, liver cancer, liver metastasis, kidney cancer, bile duct cancer, uterine cancer, cervical cancer, ovarian cancer, bladder, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma, vascular fibroma, glioblastoma, sarcoma, neuroendocrine tumor, retinoblastoma, penile cancer, pediatric solid tumors, renal cell carcinoma, thyroid cancer ... carcinoma), lymphoma, myeloma, and leukemias including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM), myeloproliferative neoplasms, The present invention provides a method for treating a cancer having a specific mutation in the SWI / SNF complex ARID1A, ARID1B, SMARCA4, SMARCA2, cancer having a mutation in specific cancer genes EGFR, KRAS, RET, cancer with differential expression of specific genes LAPTM5, RNASE6, IL-16, APOBEC3, and TYROBP, depression, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia, or MYC amplified tumor.

[0170] In the practice of the present disclosure, there is provided a method of treating a subject having a tumor, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0171] In the practice of this disclosure, there is provided a method of treating a subject having a tumor as disclosed herein, wherein the tumor is a neuroendocrine tumor, and the neuroendocrine tumor is small cell lung cancer, neuroendocrine prostate cancer, or a MYC amplified tumor.

[0172] In the practice of the present disclosure, there is provided a method of treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition disclosed herein.

[0173] In the practice of this disclosure, there is provided a method of treating a subject having a cancer disclosed herein, wherein the cancer is selected from small cell lung cancer (SCLC), gastric cancer, pancreatic cancer, lung cancer, liver metastasis and breast cancer.

[0174] In the practice of this disclosure, there is provided a method of treating a subject having a cancer as disclosed herein, wherein the cancer has an RB1 mutation.In the practice of this disclosure, there is provided a method of treating a subject having a cancer as disclosed herein, wherein the cancer is breast cancer, and the breast cancer has an RB1 mutation.

[0175] In the practice of the present disclosure, compounds are provided that may be administered in combination therapy by combining a compound of formula (I) with one or more separate agents targeting, but not limited to, DNA methyltransferases, heat shock proteins (e.g., HSP90), kinases, other epigenetic matrix metalloproteinases, and the like.

[0176] "Combination therapy" includes administration of the subject compounds in further combination with other biologically active ingredients (such as, but not limited to, other antineoplastic agents) and non-pharmaceutical therapies (such as, but not limited to, surgery or radiation therapy). The compounds described herein may be preferably used in combination with other pharmacologic active compounds that enhance the effect of the disclosed compounds. The compounds may be administered simultaneously or sequentially with other drug therapies.

[0177] In embodiments of the present disclosure, the subject compounds may be combined with antineoplastic agents that inhibit one or more biological targets (e.g., small molecules, cytotoxic agents, non-cytotoxic agents, monoclonal antibodies, antisense RNA, and fusion proteins). Such combinations may improve therapeutic efficacy over that achieved by either agent alone and may prevent or delay the emergence of resistant variants.

[0178] In the practice of the present disclosure, the subject compounds may be combined with immuno-oncology agents or "immune checkpoint inhibitors" or "immunomodulatory agents" (including, but not limited to, CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1, and PD-L2).

[0179] Although the subject matter has been described in considerable detail with reference to specific implementations thereof, other embodiments are possible, and therefore, the spirit and scope of the disclosure should not be limited to the description of the implementations contained herein. EXAMPLES

[0180] The present disclosure will now be described by way of examples, which are intended to illustrate the operation of the present disclosure and are not intended to be taken as limiting to the scope of the present disclosure.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present disclosure belongs.Although similar or equivalent methods and materials to those disclosed herein can be used in the implementation of the disclosed methods and compositions, exemplary methods, devices and materials are disclosed herein.It should be understood that the present disclosure is not limited to the specific methods and experimental conditions described, since such methods and conditions can be applied.

[0181] General preparation method The following examples provide details regarding the synthesis, activity and application of the compounds of the present disclosure. It should be understood that the following are representative and that the present disclosure is not limited by the details described in these examples.

[0182] Also provided is a process for preparing the compound of formula (I), as shown in Scheme-1 below, where all groups are as defined above. This preparation method is included in WO2017 / 195216, which is incorporated herein by reference.

[0183] The manufacturing process includes the following steps: Process 1 reacting compound 1 with an aldehyde or ketone in a protic solvent to give an intermediate imine, which is then reacted with a reducing agent to give intermediate compound 2, or alternatively, reacting compound 1 with an alkyl halide in the presence / absence of a base to give intermediate compound 2; and Process 2by hydrolyzing intermediate compound 2 with an inorganic base to give the corresponding acid, which is then coupled with an activating agent, such as EDCI.HCl (1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and HOBt (1-hydroxybenzotriazole) or (1-propylphosphonic anhydride)T3P / triethylamine in the presence of the respective amine NH2R2 to give a compound of formula (I); or alternatively, by reacting intermediate compound 2 with NH2R2 and an inorganic base to give a compound of formula (I). [ka]

[0184] Synthesis of intermediate S-amine C-1 and C-2: (1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride and (1S,2R)-2-(4-fluorophenyl)cyclopropanamine hydrochloride [ka] Step 1: 2-((1S,2R)-2-(4-fluorophenyl)cyclopropyl)isoindoline-1,3-dione and 2-((1R,2S)-2-(4-fluorophenyl)cyclopropyl)isoindoline-1,3-dione-B [ka]

[0185] A mixture of 2-(4-fluoro-phenyl)-cyclopropylamine hydrochloride (A, 1.5 g, 7.99 mmol), isobenzofuran-1,3-dione (1.77 g, 11.99 mmol) and diisopropylethylamine (4.27 mL, 23.97 mmol) was heated in a sealed tube at 150° C. for 12 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (3×50 mL). The organic portion was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography to give the racemic product (B, 1.9 g). The racemic product was separated by Chiral Prep. HPLC, Chiralpak IA (250 mm×4.6 mm×5 μm) using 0.1% TFA in solvent to give isomer 1 (0.73 g) and isomer 2 (0.77 g). LC-MS m / z(C 17 H 12 Calculated for FNO2), 281.1; observed 282.2 [M+H] + .

[0186] Step 2: (1R,2S)-2-(4-fluorophenyl)cyclopropanamine [ka] To a stirred solution of 2-[2-(4-fluoro-phenyl)-cyclopropyl]-isoindole-1,3-dione (isomer 2, 0.77 g, 2.73 mmol) in a mixture of dichloromethane and ethanol (12 mL, 5:1) was added hydrazine hydrate (0.41 mL, 8.21 mmol) at room temperature and the resulting mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. Once a precipitate formed, it was filtered and washed with dichloromethane. The filtrate was evaporated to give the product as a yellow oil (0.47 g, 95%). The crude was carried on to the next step without further purification. LC-MS m / z(C9H 10 Calculated for FN), 151.1; Observed 152.2 [M+H] + .

[0187] C-2 (isomer 2): (1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride [ka] To a stirred solution of 2-(4-fluoro-phenyl)-cyclopropylamine (chiral pure, 0.47 g, 2.108 mmol) in dioxane (5 mL) was added HCl in dioxane (2 mL) at 0° C. and the resulting mixture was stirred at room temperature for 2 h. After cooling to room temperature, the solvent was evaporated to give a residue which was triturated with diethyl ether to give the product as an off-white solid (C-2, 0.42 g, 72%). LC-MS m / z (C9H 10 Calculated for FN), 151.1; Observed 152.2 [M+H] + .

[0188] C-1 (Isomer 1): (1S,2R)-2-(4-fluorophenyl)cyclopropanamine hydrochloride [ka] This compound was synthesized from 2-((1S,2R)-2-(4-fluorophenyl)cyclopropyl)isoindoline-1,3-dione (isomer 1) following the same procedure as for the synthesis of (1R,2S)-2-(4-fluorophenyl)cyclopropanamine hydrochloride, and was analyzed by LC-MS m / z (C9H 10 Calculated for FN), 151.1; Observed 152.2 [M+H]+.

[0189] The present disclosure is further exemplified, but not limited, by the following examples illustrating the preparation of compounds according to the invention.

[0190] Example 1: Preparation of N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide hydrobromide [ka] Intermediate 1 was prepared using the chirally pure isomer (1R,2S)-2-phenylcyclopropan-1-amine according to the synthetic method described in PCT patent application WO2017 / 195216.

[0191] Step 1: Synthesis of N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide (2) [ka] To a solution of N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide as a TFA salt (17.0 g, 37.03 mmol) in 10% methanol-dichloromethane (800 mL) was added an aqueous saturated solution of NaHCO3 (200 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the title compound N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide (10.5 g, crude). This crude was used in the next step without further purification.

[0192] Step 2: N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide hydrobromide (Example 1) [ka] To a mixture of N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide (2, 1 eq.) in acetone (20 V) was added hydrobromic acid (1.05 eq, 47% in water) and the reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was cooled to 20° C. and the precipitated solid was filtered, washed with acetone (2 V) and dried under vacuum to give the title product N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide hydrobromide (Example 1, 84.33%) as an off-white solid. 1 HNMR (400 MHz, DMSO-d6): δ 11.22 (bs, 1H), 9.04 (bs, 2H), 7.93 (s, 1H), 7.71 (d, J = 8 Hz, 2H), 7.58 (s, 1H), 7.30-7.18 (m, 5H), 7.12 (d, J = 7.6 Hz, 2H), 5.37 (s, 2H), 4.16 (s, 2H), 2.88-2.86 (m, 1H), 2.43-2.38 (m, 1H), 1.47-1.42 (m, 1H), 1.27-1.24 (m, 1H). LC-MS m / z(C 22 H 21 Calculated for N4O2), 362.17; Observed 363.08 [M+H] + . HPLC purity 98%.

[0193] The following enantiomeric compounds were synthesized as TFA salts using chiral amines according to the synthetic methods described in PCT patent application WO2017 / 195216. The chiral amines were prepared according to the synthetic methods used to prepare intermediates C1 and C2 above.

[0194] Example 2: N-hydroxy-4-((4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide [ka] 1HNMR (400 MHz, DMSO-d6): δ 11.16 (bs, 1H), 9.06 (bs, 3H), 7.87 (s, 1H), 7.70 (d, J = 8 Hz, 2H), 7.54 (s, 1H), 7.31-7.19 (m, 5H), 7.12 LC-MS m / z(C) 21 H 22 Calculate N4O2), 362.17; View 363.2 [M+H] + . HPLC purity 99.8%

[0195] Example 3: N-hydroxy-4-(3-(4-((((1R,2S)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0196] Example 4: N-hydroxy-4-(3-(4-((((1S,2R)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0197] Example 5: 4-((E)-3-(3-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)azetidin-1-yl)-3-oxoprop-1-en-1-yl)-N-hydroxybenzamide

change

[0198] Example 6: 4-((E)-3-(3-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)azetidin-1-yl)-3-oxoprop-1-en-1-yl)-N-hydroxybenzamide [ka] 1 HNMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 9.04 (bs, 1H), 8.90 (bs, 2H), 7.77-7.71 (m, 4H), 7.45 (d, J =15.6 Hz, 1H), 7.25-7.22 (m, 2H), 7.13 (t, J = 8.8 Hz, 2H), 6.74 (d, J =16 Hz, 1H), 4.47-4.40 (m, 1H), 4.10-4.02 (m, 2H), 3.80 (bs, 1H), 3.00-2.93 (m, 2H), 1.44-1.38 (m, 1H), 1.33-1.29 (m, 1H). 2H merged with DMSO water peak, and 1H merged with DMSO residual peak. LC-MS m / z(C 23 H 24 Calculated for FN3O3), 409.18; Observed 410.1 [M+H] + . HPLC purity 98.01%.

[0199] Example 7: N-hydroxy-4-(3-(4-((((1R,2S)-2-(4-(pyrimidin-5-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide [ka] 1HNMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 9.42 (bs, 1H), 9.16 (bs, 2H), 9.11 (bs, 3H), 7. 75 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8 Hz, 2H), 3.52 (d, J = 11.2 Hz, 2H), 3.30-3.18 (m, 1H), 3.10-2.98 (m, 5H), 2.95-2.80 (m, 2H), 2.70-2.62 (m, 2H), 2.55 (bs, 2H), 2.05-1.80 (m, 4H), 1.58-1.50 (m, 1H), 1.46-1.32 (m, 2H). LC-MS m / z(C 29 H 35 N5O2 calculation), 485.27; measured 486.4 [M+H] + . HPLC purity 99.68%.

[0200] Example 8: N-hydroxy-4-(3-(4-((((1S,2R)-2-(4-(pyrimidin-5-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0201] Example 9: N-hydroxy-4-(3-(4-((((1R,2S)-2-(1,3,3-trimethyl-2-oxoindolin-5-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0202] Example 10: N-hydroxy-4-(3-(4-((((1S,2R)-2-(1,3,3-trimethyl-2-oxoindolin-5-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0203] Example 11: N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide

change

[0204] Example 12: N-hydroxy-4-((4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide

change

[0205] Example 13: N-hydroxy-4-(3-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0206] Example 14: N-hydroxy-4-(3-(4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide [ka] 1 HNMR (400 MHz, DMSO-d6): δ 11.13 (bs, 1H), 9.30 (bs, 1H), 8.99 (bs, 2H), 7.68 (d, J = 8 Hz, 2H), 7.32-7.23 (m, 4H), 7.21 (d, J = 7.2 Hz, 1H), 7.18-7.14 (m, 2H), 3.52 (d, J = 12 Hz, 2H), 3.28-3.08 (m, 2H), 3.0-2.8 (m, 6H), 2.65 (bs, 2H), 2.0-1.8 (m, 4H), 1.85-1.62 (m, 1H), 1.48-1.22 (m, 4H). LC-MS m / z (calculated for C25H33N3O2), 407.2; observed 408.2 [M+H]+. HPLC purity 99.72%.

[0207] The following enantiomeric compounds were synthesized as TFA salts using chiral amines according to the synthetic methods described in PCT patent application WO2017 / 195216. The chiral amines were prepared according to the synthetic methods used to prepare intermediates C1 and C2 above.

[0208] Example 15: N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide [ka] 1HNMR (400 MHz, DMSO-d6): δ 9.86 (bs, 1H), 9.49 (bs, 1H), 9.08 (bs, 2H), 7.95 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.25-7.20 (m, 3H), 7.14-7.07 (m, 3H), 6.98 (d, J = 7.6 Hz, 1H), 6.89-6.81 (m, 1H), 3.54 (d, J = 11.6 Hz, 2H), 3.30-3.21 (m, 1H), 3.03 (bs, 4H), 2.93-2.88 (m, 3H), 2.71 (t, J = 6.8 Hz, 2H), 2.06-1.80 (m, 5H), 1.46-1.35 (m, 3H), 1.30-1.25 (m, 1H). LC-MS m / z(C 31 H 37 FN4Oについてcalculated), 500.6; measured 499.4 [MH] + . HPLC purity 99.67%.

[0209] Example 16: N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0210] Example 17: N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(1-isopropyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0211] Example 18: N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(1-isopropyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0212] Example 19: N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide

change

[0213] Example 20: N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide

change

[0214] Example 21: N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide

change

[0215] Example 22: N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide

change

[0216] Example 23: N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0217] Example 24: N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0218] Example 25: N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0219] Example 26: N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide

change

[0220] Example 27: N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide

change

[0221] Example 28: N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide

change

[0222] Example 29: N-(2-aminophenyl)-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide

change

[0223] Example 30: N-(2-aminophenyl)-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide

Chemical Structure

[0224] Example 31: TR-FRET assay of LSD1 (Perkin Elmer) LSD1 enzyme was produced in-house. The LSD1 inhibitor tranylcypromine (TCP) was obtained from Selleckchem. LSD1 enzyme, TCP and biotinylated peptide substrate were diluted in assay buffer immediately before use. 2X inhibitor (10 μL, diluted in assay buffer) or assay buffer and 5 nM enzyme were added to a 96-well plate and incubated at room temperature for 30 min. 5 μL of biotinylated histone H3K4me1 peptide (4X) was added to each well and incubated at room temperature (RT) for 1 h. Stop Solution containing 300 μM tranylcypromine in 1X LANCE Detection Buffer was added to each well and incubated at RT for 5 min. Detection Mix was then prepared containing 2 nM Eu-Ab and 50 nM ULight-streptavidin in 1X LANCE Detection Buffer and added to the reaction mix. This mixture was incubated at room temperature for 1 h. Measurements were performed using a Pherastar reader in TR-FRET mode (excitation: 337 nm, emission: A-665 nm, B-620 nM).

[0225] Example 32: Histone deacetylase assay (BPS Biosciences) Histone deacetylase assays were performed according to the manufacturer's instructions. Briefly, a master mix of assay buffer, 200 uM HDAC substrate (fluorescent HDAC acetylated peptide substrate for class I HDACs (HDAC1, 2, 3) and class 2b HDACs (HDAC6, 10)), and 1% BSA was dispensed at 40 uL per well. Compounds (10X) were diluted in assay buffer and added to each well of a black 96-well plate. For HDAC1 (1.4 ng / μL) and HDAC6 (7 ng / μL), human recombinant enzymes were thawed on ice and 5 μL of enzyme was added per well. Plates were incubated at 37°C for 1 h. Developer solution was then added (50 μL per well) and incubated at room temperature for 10 min. Fluorescence was measured at an excitation wavelength of 350–380 nm and an emission wavelength of 440–480 nm.

[0226] Compounds were tested for enzyme inhibitory activity of LSD1, HDAC1 and HDAC6 as described above. [Table 1]

[0227] From the activity data presented in the above table, it is evident that one enantiomer of a pair exhibited superior potency in LSD1 and HDAC inhibition compared to the other enantiomer.

[0228] Example 33: Western blotting Cell or tissue samples were homogenized in RIPA buffer (150 mM Tris-HCl, 150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS, 0.5 mM PMSF, 1X protease inhibitor cocktail) and 5–10 μg of protein was loaded onto a 10% SDS-PAGE. Proteins were transferred to nitrocellulose membranes and then probed with the respective antibodies. Bands of interest were visualized by chemiluminescence. Antibodies used were acetylated α-tubulin, c-Myc, and vinculin (Figure 1).

[0229] In vivo testing The antitumor activity test of Example 1 was demonstrated in a tumor model against prostate cancer (Pca). A xenograft model was performed in male SCID mice (6-7 weeks old, Vivo Biotech, India [under license from Taconic]) by injecting 5 × 10 IgG into 100 μL of serum-free medium mixed with Matrigel (BD, USA) at a ratio of 1:1. 6 The tumors were developed by subcutaneous injection of 1000 cells of prostate cancer cell line (22RV1). 3 Upon reaching a tumor volume of 1000 mg / kg, mice were randomized into different treatment groups (n=8) to ensure comparable mean tumor volumes in each group. Mice injected with 22RV1 received either dosing vehicle (0.5% methylcellulose) or Example 1 at 25 mg / kg PO; QD, docetaxel at 20 mg / kg IP, QD (Figure 2).

[0230] Dual inhibition of LSD1 / HDAC6 by compounds of formula (I), in contrast to single-target inhibition, was able to effectively downregulate MYC levels and achieve efficacy in in vivo and in vitro MYC amplification models. This novel mechanism increases the potential population of neuroendocrine patients sensitive to the compounds, going beyond the proof-of-principle already established preclinically and clinically with single-target LSD1 inhibitors.

[0231] Inclusion by Reference All publications and patents mentioned herein are herein incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including definitions herein, will control.

[0232] Equivalent While specific embodiments of the subject invention have been described, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the invention, along with such variations, along with its full scope of equivalents, should be determined by reference to the claims and the specification.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R 1 are independently hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo, thioxo, -SO 2 -, amino, hydrazino, formyl, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 7-12 Arylalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, C 6-10 Aryl, C 2-10 Heterocyclyl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 7-12 Arylalkoxy, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy, amino or cyano; Ring B is 【Chemistry 2】 and Here, Y is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl, -CO and -CO-C 2-10 heterocyclyl; 1-6 Heteroaryl, C 2-10 Heterocyclyl and -CO-C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; Here, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy or cyano; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, C 7-12 -arylalkenyl, C 2-12 -Alkylheteroaryl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl, -CONR 6 -C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR 6 -C 6-10 Aryl, -NR 6 -C 1-6 Heteroaryl, -OC 6-10 Aryl, -OC 1-6 Heteroaryl, -CONR 6 -C 7-12 Alkylaryl, -SO 2 -C 6-10 Aryl, -SO 2 -C 7-12 Alkylaryl and -NR 6 SO 2 -C 7-12 alkylaryl; 2-10 Heterocyclyl, C 2-12 -alkylheteroaryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR 6 -C 1-6 Heteroaryl and -OC 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R 6 is hydrogen or C 1-8 is alkyl; R 2 is hydroxy, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 heteroaryl; wherein amino C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 Heteroaryl is independently optionally selected from amino, C 1-8 may be substituted by one or more groups selected from alkyl, halogen, hydroxy or cyano; and n is 1 to 4. and its analogs, tautomeric forms, stereoisomers, enantiomers, diastereomers and pharma- ceutically acceptable salts thereof.

2. Formula (IA): 【Chemistry 3】 [In the formula, Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R 1 are independently hydrogen, halogen, oxo, C 1-8 Alkyl, C 6-10 Aryl, C 2-10 Heterocyclyl and C 3-6 heteroaryl; 2-10 Heterocyclyl and C 3-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 3-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 optionally substituted by alkyl; Y is C 1-6 Heteroaryl, C 2-10 heterocyclyl and -CO; 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O, or S; 1-6 Heteroaryl and C 2-10 Heterocyclyl is independently optionally one or more oxo or C 1-8 optionally substituted by alkyl; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R 2 is hydroxy or C 6-10 aryl; 6-10 The aryl is substituted by amino; and n is 1 to 4.

2. The compound of claim 1 having the structure:

3. Ring A is C 6-8 Aryl, C 3-5 Heteroaryl and C 5-9 heterocyclyl, wherein C 3-5 Heteroaryl and C 5-9 Heterocyclyl has one or more heteroatoms selected from N, O or S; R 1 are independently hydrogen, halogen, oxo, C 1-4 Alkyl, C 6-8 Aryl, C 5-9 Heterocyclyl and C 3-5 heteroaryl; 5-9 Heterocyclyl and C 3-5 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 5-9 Heterocyclyl and C 3-5 Heteroaryl is independently optionally one or more oxo or C 1-4 optionally substituted by alkyl; Y is C 2-5 Heteroaryl and C 5-9 heterocyclyl; 2-5 Heteroaryl and C 5-9 Heterocyclyl has one or more heteroatoms selected from N, O or S, where C 2-5 Heteroaryl and C 5-9 Heterocyclyl is independently optionally one or more oxo or C 1-4 optionally substituted by alkyl; Z is C 1-4 Alkyl, C 7-9 -Alkylaryl and -CO-C 7-10 alkenylaryl; R 2 But hydroxy or C 6-8 aryl; 6-8 The aryl is substituted by amino; and 3. The compound according to claims 1 and 2, wherein n is 1 to 4.

4. 1. N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide hydrobromide; 2. N-hydroxy-4-((4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide; 3. N-hydroxy-4-(3-(4-((((1R,2S)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 4. N-hydroxy-4-(3-(4-((((1S,2R)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 5. 4-((E)-3-(3-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl) azetidin-1-yl)-3-oxoprop-1-en-1-yl)-N-hydroxybenzamide; 6. 4-((E)-3-(3-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl)amino)methyl) azetidin-1-yl)-3-oxoprop-1-en-1-yl)-N-hydroxybenzamide; 7. N-hydroxy-4-(3-(4-((((1R,2S)-2-(4-(pyrimidin-5-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 8. N-hydroxy-4-(3-(4-((((1S,2R)-2-(4-(pyrimidin-5-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 9. N-hydroxy-4-(3-(4-((((1R,2S)-2-(1,3,3-trimethyl-2-oxoindolin-5-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 10. N-hydroxy-4-(3-(4-((((1S,2R)-2-(1,3,3-trimethyl-2-oxoindolin-5-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 11. N-hydroxy-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl) piperidin-1-yl)methyl)benzamide; 12. N-hydroxy-4-((4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl) piperidin-1-yl)methyl)benzamide; 13. N-hydroxy-4-(3-(4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl) piperidin-1-yl)propyl)benzamide; 14. N-hydroxy-4-(3-(4-((((1S,2R)-2-phenylcyclopropyl)amino)methyl) piperidin-1-yl)propyl)benzamide; 15. N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 16. N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 17. N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(1-isopropyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 18. N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(1-isopropyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 19. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 20. N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 21. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide; 22. N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-fluorophenyl)cyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide; 23. N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 24. N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(1-phenyl-1H-pyrazol-4-yl)cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 25. N-(2-aminophenyl)-4-(3-(4-((((1R,2S)-2-(3,4-difluorophenyl) cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 26. N-(2-aminophenyl)-4-(3-(4-((((1S,2R)-2-(3,4-difluorophenyl) cyclopropyl)amino)methyl)piperidin-1-yl)propyl)benzamide; 27. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 28. N-(2-aminophenyl)-4-((4-((((1S,2R)-2-(4-(3,5-dimethylisoxazol-4-yl)phenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzamide; 29. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)methyl)benzamide; and 30. N-(2-aminophenyl)-4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzamide, The compound according to claims 1 to 3, selected from the group consisting of:

5. A process for preparing a compound of formula (I) according to any one of claims 1 to 4, comprising the steps of: Step 1: reacting compound 1 with an aldehyde or ketone in a protic solvent to give an intermediate imine, which is then reacted with a reducing agent to give intermediate compound 2, or alternatively, reacting compound 1 with an alkyl halide, optionally in the presence of a base, to give intermediate compound 2; and Step 2: Intermediate compound 2 is hydrolyzed with an inorganic base to give the corresponding acid, which is then converted to the respective amine NH in the presence of an activating agent. 2 R 2 to give a compound of formula (I), or alternatively, intermediate compound 2 can be coupled with NH 2 R 2 and an inorganic base to obtain a compound of formula (I): 【Chemistry 4】 [Ring A is C 6-10 Aryl, C 1-6 Heteroaryl and C 2-10 heterocyclyl, wherein C 1-6 Heteroaryl and C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; R 1 are independently hydrogen, halogen, hydroxy, nitro, cyano, azido, nitroso, oxo, thioxo, -SO 2 -, amino, hydrazino, formyl, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 7-12 Arylalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkyloxy, C 6-10 Aryl, C 2-10 Heterocyclyl and C 1-6 heteroaryl; 2-10 Heterocyclyl and C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, C 7-12 Arylalkoxy, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy, amino or cyano; Ring B is 【Chemistry 5】 and; Here, Y is C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl, C 3-8 Cycloalkyl, -CO and -CO-C 2-10 heterocyclyl; 1-6 Heteroaryl, C 2-10 Heterocyclyl and -CO-C 2-10 Heterocyclyl has one or more heteroatoms selected from N, O or S; Here, C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, C 2-10 Heterocyclyl and C 3-8 Cycloalkyl is independently optionally selected from C 1-8 Alkyl, oxo, C 3-8 may be substituted by one or more groups selected from cycloalkyl, halogen, hydroxy or cyano; Z is C 1-8 Alkyl, C 2-8 Alkenyl, C 7-12 -Alkylaryl, C 2-10 Heterocyclyl, C 7-12 -arylalkenyl, C 2-12 -Alkylheteroaryl, -CO-C 7-12 Alkylaryl, -CO-C 7-12 Alkenylaryl, -CONR 6 -C 1-8 Alkyl, C 6-10 Aryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR 6 -C 6-10 Aryl, -NR 6 -C 1-6 Heteroaryl, -OC 6-10 Aryl, -OC 1-6 Heteroaryl, -CONR 6 -C 7-12 Alkylaryl, -SO 2 -C 6-10 Aryl, -SO 2 -C 7-12 Alkylaryl and -NR 6 SO 2 -C 7-12 alkylaryl; 2-10 Heterocyclyl, C 2-12 -alkylheteroaryl, C 1-6 Heteroaryl, -CO-C 2-10 Heterocyclyl, -NR 6 -C 1-6 Heteroaryl and -OC 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; R 6 is hydrogen or C 1-8 is alkyl; R 2 is hydroxy, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 heteroaryl; wherein amino C 1-6 Heteroaryl has one or more heteroatoms selected from N, O, or S; Here, aniline, C 6-10 Aryl, Amino C 6-10 Aryl and Amino C 1-6 Heteroaryl is independently optionally selected from amino, C 1-8 may be substituted by one or more groups selected from alkyl, halogen, hydroxy or cyano; and n is 1 to 4.

6. 6. The method of claim 5, wherein the activating agent is selected from EDCI.HCl (1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), HOBt (1-hydroxybenzotriazole) or (1-propylphosphonic anhydride)T3P / triethylamine; the protic solvent is selected from methanol, ethanol, water or a combination thereof; and the reducing agent is selected from sodium borohydride, lithium borohydride, aluminum borohydride or a combination thereof.

7. 6. The method of claim 5, wherein the base is selected from triethylamine, N,N-diisopropylethylamine, potassium carbonate, pyridine, or a combination thereof; and the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, or a combination thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharma- ceutically acceptable carrier, optionally in combination with one or more other pharma- ceutically acceptable carriers.

9. 9. The pharmaceutical composition of claim 8, wherein the composition is in a form selected from the group consisting of a tablet, a capsule, a powder, a syrup, a solution, an aerosol and a suspension.

10. 5. A pharmaceutical composition for use in the manufacture of a medicament for inhibiting HDAC enzyme or LSD1 enzyme, or both LSD1 and HDAC enzymes, or modulating MYC or coREST in a subject in need thereof, comprising a compound according to any one of claims 1 to 4, optionally in combination with one or more other pharmaceutical agents.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, said compound having an enantiomeric excess of more than 60%, preferably more than 80%.

12. 5. A compound according to any one of claims 1 to 4 for use in the manufacture of a medicament for inhibiting HDAC enzymes, LSD1 enzymes, or both HDAC and LSD1 enzymes, or modulating MYC or coREST in a cell for the treatment of a disease or condition.

13. The disease or condition is selected from the group consisting of breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, neurilemmoma, clear cell carcinoma, non-small cell lung cancer, small cell lung cancer, liver cancer, liver metastasis, kidney cancer, bile duct cancer, uterine cancer, cervical cancer, ovarian cancer, bladder, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma, glioblastoma, sarcoma, neuroendocrine tumor, retinoblastoma, penile cancer, pediatric solid tumor, renal cell carcinoma, and the like. carcinoma), lymphoma, myeloma, and leukemias including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM), myeloproliferative neoplasms, 13. The compound according to claim 12, which is selected from the group consisting of myeloproliferative dysplastic syndromes (MPN), polycythemia vera (PV), myeloproliferative dysplastic syndromes (MDS), essential thrombocythemia (ET), essential thrombocythemia and myelofibrosis (MF), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), cancers with specific mutations in the SWI / SNF complexes ARID1A, ARID1B, SMARCA4, SMARCA2, cancers with mutations in specific cancer genes EGFR, KRAS, RET, cancers with differential expression of specific genes LAPTM5, RNASE6, IL-16, APOBEC3 and TYROBP, depression, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia or MYC amplified tumor.

14. A method of treating, preventing, modulating or ameliorating a disease or condition mediated by MYC or coREST or LSD1 or HDAC, or both LSD1 and HDAC, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 8 or 9, optionally together with other clinically relevant immunomodulatory agents or other clinically relevant cytotoxic or non-cytotoxic agents.

15. 15. The method of claim 14, wherein the other clinically relevant immunomodulatory agent is selected from the group consisting of CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2.

16. A method of inhibiting both LSD1 and HDAC or a transcription cofactor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 8 or 9.

17. A method for treating and / or preventing a disease or condition mediated by both LSD1 and HDAC, or a proliferative disorder or cancer, comprising administering to a subject suffering from a disease or condition mediated by both LSD1 and HDAC, or a proliferative disorder or cancer, a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 8 or 9.

18. The disease or condition is selected from the group consisting of breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, neurilemmoma, clear cell carcinoma, non-small cell lung cancer, small cell lung cancer, liver cancer, liver metastasis, kidney cancer, bile duct cancer, uterine cancer, cervical cancer, ovarian cancer, bladder, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma, glioblastoma, sarcoma, neuroendocrine tumor, retinoblastoma, penile cancer, pediatric solid tumor, renal cell carcinoma, and the like. carcinoma), lymphoma, myeloma, and leukemias including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM), myeloproliferative neoplasms, The method according to any one of claims 14, 16 and 17, wherein the cancer is selected from the group consisting of MPN, polycythemia vera (PV), myeloproliferative dysplastic syndrome, essential thrombocythemia (ET), essential thrombocythemia and myelofibrosis (MF), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), cancers with specific mutations in the SWI / SNF complexes ARID1A, ARID1B, SMARCA4, and SMARCA2, cancers with mutations in specific cancer genes EGFR, KRAS, and RET, cancers with differential expression of specific genes LAPTM5, RNASE6, IL-16, APOBEC3, and TYROBP, depression, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia, and MYC amplified tumor.

19. 19. The method of claim 18, wherein the disease or condition is selected from multiple myeloma (MM), myeloproliferative neoplasms (MPN), polycythemia vera (PV), myeloproliferative dysplastic syndromes, essential thrombocythemia (ET), essential thrombocythemia, or myelofibrosis (MF).

20. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 8 or 9 in the manufacture of a medicament for treating and / or preventing a disease or condition.

21. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 8 or 9, optionally in combination with other clinically relevant cytotoxic or non-cytotoxic agents, for the treatment of a disease or condition mediated by LSD1 or HDAC, or both LSD1 and HDAC, or MYC or coREST, for the treatment and / or prevention of a proliferative disorder or cancer, or for the treatment of cancer.

22. The disease or condition is selected from the group consisting of breast cancer, prostate cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, neurilemmoma, clear cell carcinoma, non-small cell lung cancer, small cell lung cancer, liver cancer, liver metastasis, kidney cancer, bile duct cancer, uterine cancer, cervical cancer, ovarian cancer, bladder, skin cancer, hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer, bone tumor, angiofibroma, glioblastoma, sarcoma, neuroendocrine tumor, retinoblastoma, penile cancer, pediatric solid tumor, renal cell carcinoma, and the like. carcinoma), lymphoma, myeloma, and leukemias including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, cutaneous T-cell lymphoma (CTCL), multiple myeloma (MM), myeloproliferative neoplasms, 22. The use according to claims 20 and 21, wherein the cancer is selected from the group consisting of myeloproliferative dysplastic syndromes (MPN), polycythemia vera (PV), myeloproliferative dysplastic syndromes (MDS), essential thrombocythemia (ET), essential thrombocythemia and myelofibrosis (MF), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), cancers with specific mutations in the SWI / SNF complexes ARID1A, ARID1B, SMARCA4, SMARCA2, cancers with mutations in specific cancer genes EGFR, KRAS, RET, cancers with differential expression of specific genes LAPTM5, RNASE6, IL-16, APOBEC3 and TYROBP, depression, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, frontotemporal dementia or MYC amplified tumor.

23. 19. The method of claim 18, wherein the disease or condition is selected from small cell lung cancer (SCLC), gastric cancer, pancreatic cancer, lung cancer, liver metastasis and breast cancer.

24. 19. The method of claim 18, wherein the cancer has an RB1 mutation.

25. A method of treating a subject having a tumor, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 8 or 9.

26. 26. The method of claim 25, wherein the tumor is a neuroendocrine tumor.

27. 27. The method of claim 26, wherein the neuroendocrine tumor is small cell lung cancer, neuroendocrine prostate cancer, or a MYC amplified tumor.

28. A method of treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 8 or 9.

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