Imidazolo[1,2-a]pyrazine or pyrazolo[1,5-a]pyrimidine derivatives and uses thereof

Abstract

The invention provides an imidazo[1,2-a]pyrazine or pyrazolo[1,5-a]pyrimidine derivative and its use. The compound is a compound represented by formula (I) or a stereoisomer, tautomer, deuterated product, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (I). #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to imidazo[1,2-a]pyrazine or pyrazolo[1,5-a]pyrimidine derivatives as LSD1 inhibitors and uses thereof. Background Art

[0002] Histone lysine-specific demethylase 1 (LSD1) is a member of the monoamine oxidase family. It catalyzes demethylation reactions using flavin adenine dinucleotide (FAD) as a cofactor. LSD1 can catalyze the demethylation of H3K4me1 / 2 and H3K9me1 / 2, thereby regulating gene transcription.

[0003] Under normal physiological conditions, the epigenetic system in cells regulates physiological processes such as cell self-renewal, differentiation, and proliferation. However, in the physiological processes of various cancers, this system becomes dysregulated, thereby promoting physiological processes such as cancer cell proliferation.

[0004] LSD1 has been found to be dysregulated and overexpressed in a variety of cancers, including acute myeloid leukemia, small cell lung cancer, breast cancer, and colorectal cancer. This is particularly true for cancers that exhibit differentiation arrest. LSD1 knockout has been shown to induce differentiation and inhibit proliferation in various cancer subtypes. Therefore, LSD1 inhibitors have great potential for clinical treatment of various cancers.

[0005] Early studies of LSD1 inhibitors generally possessed a phenylcypromine structure, covalently binding to flavin adenine dinucleotide (FAD) within the LSD1 aminooxidase domain (AO) pocket, thereby irreversibly inhibiting the enzyme. However, due to the critical role of LSD1 in hematopoiesis and embryonic stem cells, irreversible LSD1 inhibitors may exhibit target-related toxicity. Currently, at least five irreversible LSD1 inhibitors (including INCB-59872, Bomedemstat, GSK-2879552, ladademstat, and vafidemstat) have entered clinical trials, alone or in combination with other drugs, for the treatment of cancers such as small cell lung cancer and acute myeloid leukemia. As previously mentioned, irreversible LSD1 inhibitors covalently bind to FAD, potentially affecting embryonic stem cell and hematopoietic function, leading to target-related side effects.

[0006] The potential advantages of reversible LSD1 inhibitors in terms of phenotype and safety make them a hot topic of current research in this field. Summary of the Invention

[0007] This application is based on the inventor's discovery and understanding of the following facts and problems:

[0008] The present invention provides a reversible LSD1 inhibitor with a novel structure, which has higher LSD1 inhibitory activity and lower hERG inhibitory activity.

[0009] The present invention provides a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, deuterated product, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I).

[0010]

[0011] wherein X is C, N or O;

[0012] X1, X2, X3, and X4 are independently selected from C or N, provided that X1 and X2 are different, X1 and X4 are different, and X2 and X3 are different;

[0013] R1 and R2 are each independently H, deuterium, C 1-6 Alkyl, C 3-12 Carbocyclic group, C 3-12 Carbocyclyl-C 1-4 Alkylene, heterocyclic group composed of 3-12 atoms, (heterocyclic group composed of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms, (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, or R1, R1 and the X to which they are attached, together form C 3-12 A carbon ring or a heterocycle consisting of 3-12 atoms, wherein the C 1-6 Alkyl, C 3-12 Carbocyclic group, C 3-12 Carbocyclyl-C 1-4 Alkylene, heterocyclic group composed of 3-12 atoms, (heterocyclic group composed of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms, (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, or R1, R2 and the X to which they are attached, together form C 3-12The carbocyclic ring or heterocyclic ring composed of 3-12 atoms is independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R's;

[0014] R3 is C 6-10 Aryl or heteroaryl composed of 5-10 atoms, wherein the C 6-10 Aryl and heteroaryl consisting of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R";

[0015] R4 is H, deuterium, F, Cl, Br, CN, NO2, -OR a 、-NR b R c 、C 1-6 alkyl;

[0016] Each R', R" is independently H, deuterium, F, Cl, Br, CN, NO2, =O, -OR a 、-NR b R c 、-S(=O)2R a 、C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, Br, CN, =O, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c ;

[0017] R a 、R b 、R c are independently H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, heterocyclic group consisting of 3-6 atoms or R b 、R c Together with the nitrogen atom to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms, wherein the C 1-6 The alkyl group and the heterocyclic ring of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, CN, OH, NH2, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino.

[0018] In other embodiments, the present invention relates to stereoisomers, tautomers, deuterated forms, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of compounds having the structure represented by formula (II) or (III),

[0019]

[0020] Among them, ring A is C 3-6 A carbocyclic ring or a heterocyclic ring composed of 3-6 atoms;

[0021] Ring B is a bridged ring composed of 6 to 8 atoms;

[0022] m is 0, 1, 2, 3, 4 or 5;

[0023] X, X1, X2, X3, X4, R3, R4, and R' have the same meanings as described in the present invention.

[0024] In other embodiments, the present invention relates to stereoisomers, tautomers, deuterated forms, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of compounds having structures represented by formula (IV), formula (V), formula (VI) or formula (VII).

[0025]

[0026] wherein X5 is empty or C, X6 and X7 are independently selected from C or N, and X8 is O, S, C or N;

[0027] n is 0, 1, 2, 3 or 4;

[0028] X, X1, X2, X3, X4, R1, R2, R4, and R″ have the same definitions as those described in the present invention.

[0029] In other embodiments, the present invention relates to stereoisomers, tautomers, deuterated forms, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof of compounds having the structure represented by formula (VIII) or formula (IX):

[0030]

[0031] Among them, ring A is C 3-6 A carbocyclic ring or a heterocyclic ring composed of 3-6 atoms;

[0032] Ring B is a bridged ring composed of 6 to 8 atoms;

[0033] m is 0, 1, 2, 3, 4 or 5;

[0034] n is 1, 2, 3 or 4;

[0035] R″ is C 1-6 Alkyl, C 3-8 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-8 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c ;

[0036] X, X1, X2, X3, X4, R4, and R' have the same definitions as described in the present invention.

[0037] In other embodiments, the present invention relates to stereoisomers, tautomers, deuterated forms, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof of compounds having the structure represented by formula (X) or formula (XI):

[0038]

[0039] Among them, ring A is C 3-6 A carbocyclic ring or a heterocyclic ring composed of 3-6 atoms;

[0040] Ring B is a bridged ring composed of 6 to 8 atoms;

[0041] m is 0, 1, 2, 3, 4 or 5;

[0042] n is 0, 1, 2, 3 or 4.

[0043] X, X1, X2, X3, X4, R4, R' and R" have the same definitions as described in the present invention.

[0044] In other embodiments, X is N.

[0045] In other embodiments, R1 and R2 are each independently H, deuterium, C 1-6 Alkyl, C 3-6 Carbocyclic group, C 3-6 Carbocyclyl-C 1-4 Alkylene, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms)-C 1-4 Alkylene, C 6-8 Aryl, C6-8 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-8 atoms, (heteroaryl composed of 5-8 atoms)-C 1-4 Alkylene, or R1, R2 and the X to which they are attached, together form C 3-8 A carbon ring or a heterocycle consisting of 3-8 atoms, wherein the C 1-6 Alkyl, C 3-6 Carbocyclic group, C 3-6 Carbocyclyl-C 1-4 Alkylene, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms)-C 1-4 Alkylene, C 6-8 Aryl, C 6-8 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-8 atoms, (heteroaryl composed of 5-8 atoms)-C 1-4 Alkylene, or R1, R2 and the X to which they are attached, together form C 3-8 The carbocyclic ring or heterocyclic ring composed of 3 to 8 atoms is independently unsubstituted or substituted with 1, 2 or 3 R's.

[0046] In other embodiments, R3 is C 6-9 Aryl or heteroaryl consisting of 5 to 9 atoms, wherein the C 6-9 Aryl and heteroaryl groups of 5 to 9 atoms are each independently unsubstituted or substituted with 1 or 2 R".

[0047] In other embodiments, R4 is H, deuterium, F, Cl, Br, CN, NO2, -OH, -NH2, or C 1-3 alkyl.

[0048] In other embodiments, each R' is independently H, deuterium, F, Cl, Br, CN, NO2, =O, -OR a 、-NR b R c 、-S(=O)OR a 、C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, Br, CN, =O, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6Haloalkyl or -CO-NR b R c .

[0049] In other embodiments, each R" is independently H, deuterium, F, Cl, Br, CN, NO2, =O, -OR a 、-NR b R c 、-S(=O)OR a 、C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, Br, CN, =O, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

[0050] In other embodiments, R" is C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

[0051] In other embodiments, R1 and R2 are each independently H, deuterium, C 1-6 Alkyl, C 3-6 Carbocyclic group, heterocyclic group composed of 3-6 atoms or R1, R2 and X connected to them together form C 3-8 A carbon ring or a heterocycle consisting of 3-8 atoms, wherein the C 1-6 Alkyl, C 3-6 Carbocyclic group, heterocyclic group composed of 3-6 atoms, or R1, R2 and X connected to them together form C 3-8 The carbocyclic ring or heterocyclic ring composed of 3 to 8 atoms is independently unsubstituted or substituted with 1, 2 or 3 R's.

[0052] In other embodiments, R3 is phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiyl, wherein the phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiyl are each independently unsubstituted or substituted with 1 or 2 R".

[0053] In other embodiments, R4 is F, Cl, or Br.

[0054] In other embodiments, each R' is independently H, deuterium, F, Cl, Br, -NR b R c .

[0055] In other embodiments, each R" is independently H, deuterium, F, Cl, Br, CN, NO2, =O, -OR a 、-NR b R c 、C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

[0056] In other embodiments, R" is C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1 or 2 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NRb R c .

[0057] In other embodiments, R a 、R b 、R c are independently H, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C 1-3 Haloalkyl, heterocyclic group consisting of 3-6 atoms or R b 、R c Together with the nitrogen atom to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms, wherein the methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl and the heterocyclic ring consisting of 3 to 6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 substituents, and the substituents are independently selected from deuterium, F, Cl, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino.

[0058] In other embodiments, the present invention relates to a pharmaceutical composition comprising an effective amount of the aforementioned compound.

[0059] In other embodiments, the pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

[0060] In other embodiments, the pharmaceutical composition further comprises one or more therapeutic agents, wherein the therapeutic agents are selected from other anti-tumor drugs.

[0061] In other embodiments, the therapeutic agent is an antimitotic drug, an alkylating agent, an antimetabolite drug, a topoisomerase inhibitor, an estrogen receptor modulator, an androgen receptor modulator, a small molecule inhibitor targeting protein kinase, or an antibody drug targeting protein kinase.

[0062] In other embodiments, the anti-mitotic drug is paclitaxel or vincristine.

[0063] In other embodiments, the alkylating agent is cisplatin, oxaliplatin, carboplatin, or cyclophosphamide.

[0064] In other embodiments, the antimetabolite drug is gemcitabine, 5-fluorouracil, or methotrexate.

[0065] In other embodiments, the topoisomerase inhibitor is epipodophyllotoxin, etoposide, topotecan, or camptothecin.

[0066] In other embodiments, the estrogen receptor modulator is tamoxifen or fulvestrant.

[0067] In other embodiments, the androgen receptor modulator is bicalutamide.

[0068] In other embodiments, the small molecule inhibitor targeting protein kinase is dasatinib, bosutinib, gefitinib, erlotinib, lapatinib, imatinib, nilotinib, sorafenib, tipifarnib, sunitinib, or axitinib.

[0069] In other embodiments, the antibody drug targeting protein kinase is trastuzumab, panitumumab, or cetuximab.

[0070] In other embodiments, the present invention relates to the use of the aforementioned compound or pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to prevent, manage, treat or alleviate a disease associated with LSD1 overexpression or overactivity in a patient.

[0071] In other embodiments, the disease associated with LSD1 overexpression is a tumor.

[0072] In other embodiments, the tumor is papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer, or non-Hodgkin's lymphoma.

[0073] In other embodiments, the present invention relates to the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicament for inhibiting LSD1.

[0074] Unless otherwise specified, the present invention includes all stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention.

[0075] In some embodiments, the salts are pharmaceutically acceptable salts.The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith.

[0076] The compounds of the present invention also include salts thereof, which are not necessarily pharmaceutically acceptable salts but are intermediates useful for preparing and / or purifying the compounds of the present invention and / or for separating enantiomers of the compounds of the present invention.

[0077] The compounds of the present invention, including their salts, may also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); Therefore, the present invention also includes their solvated and unsolvated forms.

[0078] Alternatively, the compounds of the invention may contain several asymmetric centers or may be present as racemic mixtures as generally described herein. The invention further encompasses racemic mixtures, partially racemic mixtures, and the isolated enantiomers and diastereomers thereof.

[0079] The compounds of the present invention may exist in the form of one of possible isomers, rotamers, atropisomers, tautomers or a mixture thereof. The present invention may further include a mixture of isomers, rotamers, atropisomers and tautomers of the compounds of the present invention, or a partial mixture of isomers, rotamers, atropisomers and tautomers or separated isomers, rotamers, atropisomers and tautomers.

[0080] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I).

[0081] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0082] Definitions and General Terms

[0083] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0084] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0085] Unless otherwise specified, technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs, and unless otherwise specified, all patent publications cited in the entire disclosure of the present invention are incorporated herein by reference in their entirety.

[0086] The following definitions shall apply to the present invention unless otherwise indicated. For the purposes of this invention, the chemical elements are those according to the Periodic Table of the Elements, CAS version and Handbook of Chemicals, 75, th Ed, 1994. In addition, general principles of organic chemistry can be found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are incorporated herein by reference.

[0087] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. Subject also refers to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0088] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quail, or turkeys, or mammals), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), more particularly humans. In one embodiment, the subject is a non-human animal, such as livestock (e.g., horses, cows, pigs, or sheep) or a pet (e.g., dog, cat, guinea pig, or rabbit). In other embodiments, the "patient" refers to a human.

[0089] The stereochemical definitions and conventions used herein are generally in accordance with SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, are encompassed by the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center(s) in the molecule. The prefixes d and l, or (+) and (–), are symbols used to designate the rotation of plane-polarized light caused by a compound, where (–) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers may also be referred to as enantiomers, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0090] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0091] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0092] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomers, diastereomeric atropisomers, and geometric (or conformational)) forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention.

[0093] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0094] As used herein, "deuterated" refers to a compound in which one or more hydrogen atoms are replaced by 2 The compound generated after H substitution.

[0095] As used herein, "nitrogen oxide" refers to a compound containing several amine functional groups in which one or more nitrogen atoms are oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. Available oxidizing agents, such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids), can be used to treat the corresponding amines to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, an amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0096] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0097] "Metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0098] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., "Describe Pharmaceutically Acceptable Salts in Detail in J. Pharmaceutical Sciences, 1977, 66: 1-19." Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0099] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzyme conversion to the parent structure in the blood or tissue. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0100] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of (R)- or (S)-configuration. Substituents on atoms with unsaturated double bonds may exist in cis-(Z)- or trans-(E)-form, if possible.

[0101] Thus, as described herein, the compounds of the invention may exist in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0102] Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0103] Any resulting racemate of the final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separating the resulting diastereomeric salts. The racemic products can also be separated by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0104] As described herein, the compounds of the present invention may optionally be substituted with one or more substituents, such as the compounds of the general formula above, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." The terms "optionally," "optionally," or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs as well as instances where it does not. In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at every substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position. Examples of substituents include, but are not limited to, F, Cl, Br, CN, N3, OH, NH2, NO2, oxo (=O), OR a , -NR b R c , C 1-6 Alkyl, C 1-6 Aliphatic, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms or (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, wherein the R a , R b , R c Has the definition as described in the present invention.

[0105] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0106] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0107] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0108] The term "alkyl" or "alkyl group" as used herein refers to a saturated linear or branched monovalent hydrocarbon radical containing 1 to 20 carbon atoms. Unless otherwise specified, an alkyl group contains 1 to 20 carbon atoms, in some embodiments, 1 to 10 carbon atoms, in other embodiments, 1 to 9 carbon atoms; in other embodiments, 1 to 8 carbon atoms, in other embodiments, 1 to 6 carbon atoms, in other embodiments, 1 to 4 carbon atoms, and in other embodiments, 1 to 3 carbon atoms.

[0109] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3 ), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2C H3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH 3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like, wherein the alkyl groups can independently be unsubstituted or substituted with one or more substituents described herein.

[0110] As used herein, the term "alkyl" and its prefix "alkane" encompass both straight and branched saturated carbon chains.

[0111] The term "alkylene" refers to a saturated divalent hydrocarbon group derived by removing two hydrogen atoms from a straight-chain or branched saturated hydrocarbon group. Unless otherwise specified, an alkylene group contains 1-10 carbon atoms, in some embodiments, 1-6 carbon atoms, in some embodiments, 1-4 carbon atoms, and in some embodiments, 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like, wherein the alkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0112] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position CC is sp 2 Double bond unsaturation, wherein the alkenyl group can be independently unsubstituted or substituted with one or more substituents described herein, including groups with "cis", "trans" or "Z" or "E" orientations, specific examples of which include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0113] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position C—C is in an sp triple bond unsaturated state, wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described herein, specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), and the like.

[0114] The term "alkoxy" refers to an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as defined herein. Unless otherwise specified, the alkoxy group contains 1-20 carbon atoms, with some embodiments containing 1-10 carbon atoms, others containing 1-8 carbon atoms, others containing 1-6 carbon atoms, others containing 1-4 carbon atoms, and still others containing 1-3 carbon atoms.

[0115] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC( CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-1-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-1-butoxy (-OCH2CH(CH3)CH2CH3), and the like, wherein the alkoxy groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0116] The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.

[0117] The terms "carbocycle," "carbocyclyl," or "carbocyclic" are used interchangeably herein and refer to non-aromatic carbocyclic ring systems containing 3-14 ring carbon atoms, which are saturated or contain one or more unsaturated units. In some embodiments, the number of carbon atoms is 3-12; in other embodiments, the number of carbon atoms is 3-10; in other embodiments, the number of carbon atoms is 3-8; in other embodiments, the number of carbon atoms is 5-6; in other embodiments, the number of carbon atoms is 6-8. This "carbocyclyl" includes monocyclic, bicyclic, or polycyclic fused, spiro, or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings, or combinations thereof, wherein the radical or point of attachment is on the carbocyclic ring. Bicyclic carbocyclyls include bridged bicyclic carbocyclyls, fused bicyclic carbocyclyls, and spiro bicyclic carbocyclyls, and "fused" bicyclic ring systems comprise two rings that share two adjacent ring atoms. Bridged bicyclic groups include two rings that share 3 or 4 adjacent ring atoms. Spirocyclic ring systems share 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridged carbocyclic groups include, but are not limited to, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, and the like.

[0118] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic ring system containing 3-12 ring carbon atoms with one or more points of attachment to the rest of the molecule. In some embodiments, cycloalkyl groups have 3-10 ring carbon atoms; in other embodiments, cycloalkyl groups have 3-8 ring carbon atoms; in other embodiments, cycloalkyl groups have 3-6 ring carbon atoms; and in other embodiments, cycloalkyl groups have 5-6 ring carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0119] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen, and wherein the ring system has one or more points of attachment to the rest of the molecule. The term "heterocyclyl" includes monocyclic, bicyclic, or polycyclic fused, spiro, or bridged heterocyclic ring systems, as well as polycyclic ring systems in which the heterocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings, or a combination thereof, wherein the radical or point of attachment is on the heterocyclic ring. Bicyclic heterocyclyls include bridged bicyclic heterocyclyls, fused bicyclic heterocyclyls, and spiro bicyclic heterocyclyls. Unless otherwise specified, a heterocyclyl group may be carbon or nitrogen-based, and a -CH2- group may be optionally replaced by -C(=O)-. Ring sulfur atoms may be optionally oxidized to S-oxides. Ring nitrogen atoms may be optionally oxidized to N-oxides. In some embodiments, the heterocyclyl is a monocyclic or bicyclic heterocyclyl consisting of 3-8 atoms; in other embodiments, the heterocyclyl is a monocyclic or bicyclic heterocyclyl consisting of 3-6 atoms; in other embodiments, the heterocyclyl is a monocyclic or bicyclic heterocyclyl consisting of 6-8 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 5-6 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 4 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 5 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 6 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 7 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 8 atoms.

[0120] Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. Bridged heterocyclic groups include, but are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and the like. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0121] The term "bridge" refers to a bond, an atom, or an unbranched chain of atoms that connects two different parts of a molecule. The two atoms (usually, but not always, two tertiary carbon atoms) connected by a bridge are denoted as "bridgeheads."

[0122] The term "spiro" refers to a ring system having one atom (usually a quaternary carbon atom) as the only common atom between the two rings.

[0123] The term "n-atom group," where n is an integer, typically describes the number of ring atoms in a molecule, where the number of ring atoms is n. For example, piperidinyl is a 6-atom heterocyclyl group, while 1,2,3,4-tetrahydronaphthyl is a 10-atom carbocyclyl group. In bridged or spiro rings, the number of ring atoms includes the atoms in the bridge or spiro ring.

[0124] The term "heteroatom" refers to O, S, N, P and Si, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring substituted with a hydrogen, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl).

[0125] The term "halogen" refers to F, Cl, Br or I.

[0126] The term "N3" represents an azide structure. This group can be linked to other groups, for example, to a methyl group to form methyl azide (MeN3), or to a phenyl group to form phenyl azide (PhN3).

[0127] The term "aryl" can be used alone or as part of an "aralkyl," "aralkyloxy," or "aryloxyalkyl" group to refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6-14 ring atoms, 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises 3-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring," for example, aromatic rings can include phenyl, naphthyl, and anthracenyl. The aryl groups can independently be unsubstituted or substituted with one or more substituents described herein.

[0128] The term "heteroaryl" can be used alone or as part of "heteroarylalkyl" or "heteroarylalkoxy" to refer to monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. Unless otherwise specified, heteroaryl groups can be carbon or nitrogen groups, and -CH2- groups can be optionally replaced by -C(=O)-. Ring sulfur atoms can be optionally oxidized to S-oxides. Ring nitrogen atoms can be optionally oxidized to N-oxides. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." In some embodiments, heteroaryl is a 5-12-atom heteroaryl group comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 5-10-atom heteroaryl group comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 5-6-atom heteroaryl group comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 5-atom heteroaryl group comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a 6-atom heteroaryl group comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

[0129] In other embodiments, heteroaryl includes the following monocyclic groups, but is not limited to these monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl) , 1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl , pyrazinyl, 1,3,5-triazinyl; also include the following bicyclic groups, but are in no way limited to these bicyclic groups: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), oxathiol, and The heteroaryl group is optionally substituted with one or more substituents described herein.

[0130] The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", refers to -CO2H; the term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", refers to -(C=O)-.

[0131] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino groups are independently substituted with one or two alkyl groups. In some embodiments, the alkylamino group is one or two C 1-6 Alkyl is attached to the nitrogen atom of the lower alkylamino group. In other embodiments, alkylamino is C 1-3 Suitable alkylamino groups can be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.

[0132] The term "arylamino" refers to an amino group substituted with one or two aryl groups, such examples include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.

[0133] The term "aminoalkyl" includes C 1-10 In some embodiments, aminoalkyl is a C substituted with one or more amino groups. 1-6 Examples of "lower aminoalkyl" include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

[0134] As described in the present invention, a substituent is connected to the central ring by a bond to form a ring system, which means that the substituent can be substituted at any substitutable position on the ring. This ring system includes a monocyclic, bicyclic or polycyclic system.

[0135] As used herein, the term "unsaturated" means that the group contains one or more degrees of unsaturation.

[0136] The term "include" or "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0137] As used herein, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, which are known to those skilled in the art (e.g., as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except for the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is encompassed.

[0138] As used herein, the term "inhibit LSD1" includes reducing the expression or activity of LSD1 (e.g., reducing by at least 10%) and completely inhibiting the expression or activity of LSD1 (i.e., 100% inhibition of the expression or activity of LSD1). In some embodiments, the expression or activity of LSD1 is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

[0139] The term "effective amount" of a compound of the present invention refers to an amount that elicits the desired biological response. In the present invention, the desired biological response is inhibition of LSD1, prevention of the recurrence, development, onset, or progression of symptoms associated with LSD1 overexpression, or potentiating or improving the prophylactic or therapeutic effect of another anti-tumor therapy being administered. The exact amount of compound administered to a subject will depend on the mode of administration and the severity and characteristics of the subject, such as health, age, sex, weight, and tolerance to drugs. A skilled artisan will be able to determine an appropriate dosage based on these and other factors. When administered in combination with other anti-tumor agents, such as anti-mitotic drugs, the "effective amount" of the second agent will depend on the type of drug used. Appropriate dosages for approved agents are known and can be adjusted by the skilled artisan based on the subject's condition, the type of condition being treated, and the amount of the compound of the present invention being administered. Where an amount is not specifically indicated, an effective amount should be assumed. For example, a compound of the present invention may be administered to a subject for therapeutic or prophylactic treatment in a dosage range of approximately 0.01-100 mg / body weight / day.

[0140] As used herein, the term "treat" refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or ameliorating the progression, severity, and / or duration of a condition mediated by LSD1 overexpression or overactivity, or ameliorating one or more symptoms (particularly, one or more discernible symptoms) of a condition mediated by LSD1 overexpression or overactivity, due to the administration of one or more therapies (e.g., one or more therapeutic agents (e.g., compounds and compositions of the present invention)). In certain embodiments, therapeutic treatment includes ameliorating at least one measurable physical parameter of a condition mediated by LSD1 overexpression or overactivity. In other embodiments, therapeutic treatment includes inhibiting the progression of a condition mediated by LSD1 overexpression or overactivity, for example, physically by stabilizing a discernible symptom, or physiologically by stabilizing a physical parameter, or both. In other embodiments, therapeutic treatment includes alleviating or stabilizing a disease mediated by LSD1 overexpression or overactivity, such as papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer, or non-Hodgkin's lymphoma.

[0141] The term "protecting group" or "PG" refers to a substituent that is attached to an amino group and is typically used to block or protect a specific functionality when reacting with another functional group. For example, an "amino-protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent attached to a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxyl-protecting group" refers to a substituent attached to a carboxyl group that blocks or protects the carboxyl functionality. Typical carboxyl-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, please refer to the following references: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P J Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0142] Description of the compounds of the present invention

[0143] The present invention provides a reversible LSD1 inhibitor with a novel structure, which has higher LSD1 inhibitory activity and lower hERG inhibitory activity.

[0144] The present invention provides a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, deuterated product, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I).

[0145]

[0146] wherein X is C, N or O;

[0147] X1, X2, X3, and X4 are independently selected from C or N, provided that X1 and X2 are different, X1 and X4 are different, and X2 and X3 are different;

[0148] R1 and R2 are each independently H, deuterium, C 1-6 Alkyl, C 3-12 Carbocyclic group, C 3-12 Carbocyclyl-C 1-4Alkylene, heterocyclic group composed of 3-12 atoms, (heterocyclic group composed of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms, (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, or R1, R1 and the X to which they are attached, together form C 3-12 A carbon ring or a heterocycle consisting of 3-12 atoms, wherein the C 1-6 Alkyl, C 3-12 Carbocyclic group, C 3-12 Carbocyclyl-C 1-4 Alkylene, heterocyclic group composed of 3-12 atoms, (heterocyclic group composed of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms, (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, or R1, R2 and the X to which they are attached, together form C 3-12 The carbocyclic ring or heterocyclic ring composed of 3-12 atoms is independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R's;

[0149] R3 is C 6-10 Aryl or heteroaryl composed of 5-10 atoms, wherein the C 6-10 Aryl and heteroaryl consisting of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R";

[0150] R4 is H, deuterium, F, Cl, Br, CN, NO2, -OR a 、-NR b R c 、C 1-6 alkyl;

[0151] Each R', R" is independently H, deuterium, F, Cl, Br, CN, NO2, =O, -OR a 、-NR b R c 、-S(=O)2R a 、C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8Cycloalkenyl, heterocyclic group consisting of 3-12 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, Br, CN, =O, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c ;

[0152] R a 、R b 、R c are independently H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, heterocyclic group consisting of 3-6 atoms or R b 、R c Together with the nitrogen atoms to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms, wherein the C 1-6 The alkyl group and the heterocyclic ring of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino.

[0153] In other embodiments, the present invention relates to stereoisomers, tautomers, deuterated forms, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of compounds having the structure represented by formula (II) or (III),

[0154]

[0155] Among them, ring A is C 3-6 A carbocyclic ring or a heterocyclic ring composed of 3-6 atoms;

[0156] Ring B is a bridged ring composed of 6 to 8 atoms;

[0157] m is 0, 1, 2, 3, 4 or 5;

[0158] X, X1, X2, X3, X4, R3, R4, and R' have the same meanings as described in the present invention.

[0159] The structural compounds represented by formula (II) or (III) according to the embodiments of the present invention have better LSD1 inhibitory activity.

[0160] In other embodiments, the present invention relates to stereoisomers, tautomers, deuterated forms, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of compounds having structures represented by formula (IV), formula (V), formula (VI) or formula (VII).

[0161]

[0162]

[0163] wherein X5 is empty or C, X6 and X7 are independently selected from C or N, and X8 is O, S, C or N;

[0164] n is 0, 1, 2, 3 or 4;

[0165] X, X1, X2, X3, X4, R1, R2, R4, and R″ have the same definitions as those described in the present invention.

[0166] The structural compounds represented by formula (VI) or (VII) according to the embodiments of the present invention have lower hERG inhibitory activity.

[0167] In other embodiments, the present invention relates to stereoisomers, tautomers, deuterated forms, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof of compounds having the structure represented by formula (VIII) or formula (IX):

[0168]

[0169] Among them, ring A is C 3-6 A carbocyclic ring or a heterocyclic ring composed of 3-6 atoms;

[0170] Ring B is a bridged ring composed of 6 to 8 atoms;

[0171] m is 0, 1, 2, 3, 4 or 5;

[0172] n is 1, 2, 3 or 4;

[0173] R″ is C 1-6 Alkyl, C 3-8 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-8 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c;

[0174] X, X1, X2, X3, X4, R4, and R' have the same definitions as described in the present invention.

[0175] The structural compound represented by formula (VIII) or (IX) according to the embodiments of the present invention has better LSD1 inhibitory activity and lower hERG inhibitory activity.

[0176] In other embodiments, the present invention relates to stereoisomers, tautomers, deuterated forms, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof of compounds having the structure represented by formula (X) or formula (XI):

[0177]

[0178] Among them, ring A is C 3-6 A carbocyclic ring or a heterocyclic ring composed of 3-6 atoms;

[0179] Ring B is a bridged ring composed of 6 to 8 atoms;

[0180] m is 0, 1, 2, 3, 4 or 5;

[0181] n is 0, 1, 2, 3 or 4.

[0182] X, X1, X2, X3, X4, R4, R' and R" have the same definitions as described in the present invention.

[0183] The structural compound represented by formula (X) or (XI) according to the embodiments of the present invention has better LSD1 inhibitory activity and lower hERG inhibitory activity.

[0184] In some other embodiments, X in the compounds represented by the structures of the above formula (I) to formula (XI) is N.

[0185] In other embodiments, R1 and R2 are each independently H, deuterium, C 1-6 Alkyl, C 3-6 Carbocyclic group, C 3-6 Carbocyclyl-C 1-4 Alkylene, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms)-C 1-4 Alkylene, C 6-8 Aryl, C 6-8 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-8 atoms, (heteroaryl composed of 5-8 atoms)-C 1-4 Alkylene, or R1, R2 and the X to which they are attached, together form C 3-8 A carbon ring or a heterocycle consisting of 3-8 atoms, wherein the C 1-6Alkyl, C 3-6 Carbocyclic group, C 3-6 Carbocyclyl-C 1-4 Alkylene, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms)-C 1-4 Alkylene, C 6-8 Aryl, C 6-8 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-8 atoms, (heteroaryl composed of 5-8 atoms)-C 1-4 Alkylene, or R1, R2 and the X to which they are attached, together form C 3-8 The carbocyclic ring or heterocyclic ring composed of 3 to 8 atoms is independently unsubstituted or substituted with 1, 2 or 3 R's.

[0186] In other embodiments, R3 is C 6-9 Aryl or heteroaryl consisting of 5-9 atoms, wherein the C 6-9 Aryl and heteroaryl groups of 5 to 9 atoms are each independently unsubstituted or substituted with 1 or 2 R".

[0187] In other embodiments, R4 is H, deuterium, F, Cl, Br, CN, NO2, -OH, -NH2, or C 1-3 alkyl.

[0188] In other embodiments, each R' is independently H, deuterium, F, Cl, Br, CN, NO2, =O, -OR a 、-NR b R c 、-S(=O)OR a 、C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, Br, CN, =O, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

[0189] In other embodiments, each R" is independently H, deuterium, F, Cl, Br, CN, NO2, =O, -OR a 、-NR b R c、-S(=O)OR a 、C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, wherein the C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, Br, CN, =O, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c

[0190] In other embodiments, such as in the compounds of formula (VI), formula (VII), formula (VIII) or formula (IX), said R" is C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

[0191] In other embodiments, R1 and R2 are each independently H, deuterium, C 1-6 Alkyl, C 3-6 Carbocyclic group, heterocyclic group composed of 3-6 atoms or R1, R2 and X connected to them together form C 3-8 A carbon ring or a heterocycle consisting of 3-8 atoms, wherein the C 1-6 Alkyl, C 3-6 Carbocyclic group, heterocyclic group composed of 3-6 atoms, or R1, R2 and X connected to them together form C 3-8 The carbocyclic ring or heterocyclic ring composed of 3 to 8 atoms is independently unsubstituted or substituted with 1, 2 or 3 R's.

[0192] In other embodiments, R1 and R2 are each independently H, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, Wherein, the methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl groups are unsubstituted or replaced by cyclopropyl, cyclobutyl, cyclopentyl, substituted; wherein the cyclopropyl, cyclobutyl, cyclopentyl, is unsubstituted or substituted with -NH2; t is 0 or 1.

[0193] In other embodiments, the R1 and R2 together with the X to which they are attached form S is 0, 1 or 2, V is 1 or 2, wherein the Unsubstituted or substituted by deuterium, F, Cl, Br, -NR b R c replaced.

[0194] In other embodiments, Ring A is S is 0, 1 or 2, Unsubstituted or substituted by deuterium, F, Cl, Br, -NR b R c replaced.

[0195] In other embodiments, Ring B is V is 1 or 2, the Unsubstituted or substituted by deuterium, F, Cl, Br, -NR b R c replaced.

[0196] In other embodiments, R3 is phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiyl, wherein the phenyl, naphthyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiyl are each independently unsubstituted or substituted with 1 or 2 R".

[0197] In other embodiments, R3 is phenyl, which is unsubstituted or substituted with F, Cl, Br, or -OCH3.

[0198] In other embodiments, R3 is naphthyl, and the phenyl group is unsubstituted or substituted with R".

[0199] In other embodiments, R3 is described Unsubstituted or substituted by methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl.

[0200] In other embodiments, R3 described Unsubstituted or substituted with R″.

[0201] In other embodiments, R3 described is substituted by R″, wherein R″ is C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1 or 2 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

[0202] In other embodiments, R4 is F, Cl, or Br.

[0203] In other embodiments, each R' is independently H, deuterium, F, Cl, Br, -NR b R c .

[0204] In other embodiments, each R" is independently H, deuterium, F, Cl, Br, CN, NO2, =O, -OR a 、-NR b R c 、C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

[0205] In other embodiments, such as in the compounds of formula (VI), formula (VII), formula (VIII) or formula (IX), said R" is C1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1 or 2 substituents independently selected from deuterium, F, Cl, Br, CN, ═O, —OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

[0206] In other embodiments, R a 、R b 、R c are independently H, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C 1-3 Haloalkyl, heterocyclic group consisting of 3-6 atoms or R b 、R c Together with the nitrogen atom to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms, wherein the methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl and the heterocyclic ring consisting of 3 to 6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 substituents, and the substituents are independently selected from deuterium, F, Cl, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkylamino.

[0207] In another aspect of the present invention, the present invention provides a compound having one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof having the structure shown below.

[0208]

[0209]

[0210]

[0211]

[0212] In other embodiments, the present invention relates to a pharmaceutical composition comprising an effective amount of the aforementioned compound.

[0213] In other embodiments, the pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

[0214] In other embodiments, the pharmaceutical composition further comprises one or more therapeutic agents, wherein the therapeutic agents are selected from other anti-tumor drugs.

[0215] In other embodiments, the therapeutic agent is an antimitotic drug, an alkylating agent, an antimetabolite drug, a topoisomerase inhibitor, an estrogen receptor modulator, an androgen receptor modulator, a small molecule inhibitor targeting protein kinase, or an antibody drug targeting protein kinase.

[0216] In other embodiments, the anti-mitotic drug is paclitaxel or vincristine.

[0217] In other embodiments, the alkylating agent is cisplatin, oxaliplatin, carboplatin, or cyclophosphamide.

[0218] In other embodiments, the antimetabolite drug is gemcitabine, 5-fluorouracil, or methotrexate.

[0219] In other embodiments, the topoisomerase inhibitor is epipodophyllotoxin, etoposide, topotecan, or camptothecin.

[0220] In other embodiments, the estrogen receptor modulator is tamoxifen or fulvestrant.

[0221] In other embodiments, the androgen receptor modulator is bicalutamide.

[0222] In other embodiments, the small molecule inhibitor targeting protein kinase is dasatinib, bosutinib, gefitinib, erlotinib, lapatinib, imatinib, nilotinib, sorafenib, tipifarnib, sunitinib, or axitinib.

[0223] In other embodiments, the antibody drug targeting protein kinase is trastuzumab, panitumumab, or cetuximab.

[0224] In other embodiments, the present invention relates to the use of the aforementioned compound or pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to prevent, manage, treat or alleviate a disease associated with LSD1 overexpression or overactivity in a patient.

[0225] In other embodiments, the disease associated with LSD1 overexpression is a tumor.

[0226] In other embodiments, the tumor is papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer, or non-Hodgkin's lymphoma.

[0227] In other embodiments, the present invention relates to the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicament for inhibiting LSD1.

[0228] In some embodiments, the salts are pharmaceutically acceptable salts.The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith.

[0229] The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for preparing and / or purifying the compounds of the present invention and / or for separating the enantiomers of the compounds of the present invention.

[0230] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0231] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0232] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

[0233] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0234] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0235] Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0236] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic moiety using conventional chemical methods. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0237] Moreover, the compounds of the present invention, including their salts, may also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); Therefore, the present invention is intended to include solvated and unsolvated forms.

[0238] Any structural formula given herein is also intended to represent unlabeled forms of these compounds as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 36 S, 37 Cl or 125 I.

[0239] On the other hand, the compounds of the present invention include compounds defined herein that are labeled with various isotopes, for example, where a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-labeled compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or may be used in the context of radiotherapy of patients. 18 F-labeled compounds are particularly ideal for PET or SPECT studies. Isotope-labeled compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparations herein using an appropriate isotope-labeled reagent in place of the unlabeled reagent originally used.

[0240] In addition, heavier isotopes, particularly deuterium (i.e. 2Substitution with H or D) can provide certain therapeutic advantages resulting from greater metabolic stability. For example, this can result in an increased in vivo half-life, a reduced dosage requirement, or an improved therapeutic index. It should be understood that deuterium in this context is considered a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, or DMSO-d6.

[0241] Compositions, formulations and administration of compounds of the present invention

[0242] The present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention or a stereoisomer thereof. According to a specific embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, and optionally, other therapeutic and / or preventive ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.

[0243] Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the biological activity of the compound. Pharmaceutically acceptable carriers should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or have no other adverse reactions or side effects once administered to a patient. Standard pharmaceutical techniques can be used.

[0244] As described herein, the pharmaceutical compositions or pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable carriers, adjuvants, or excipients, including any solvents, diluents, liquid excipients, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, or lubricants suitable for the specific target dosage form, as used herein. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, disclose various carriers used in the formulation of pharmaceutically acceptable compositions and their known preparation methods. Except for conventional carrier media that are incompatible with the compounds of the present invention, such as those that may produce adverse biological effects or adversely interact with any other components of the pharmaceutically acceptable composition, any other conventional carrier media and their uses are also contemplated by the present invention.

[0245] Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropyl methylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose), , ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl lauryl ester), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffers, and other nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), and coloring agents, anti-adherent agents, coating agents, sweetening and flavoring agents, preservatives and antioxidants, according to the judgment of the formulator, may also be present in the composition.

[0246] The compounds or compositions of the present invention can be administered by any suitable route, and can be administered to humans or other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (such as by powders, ointments or drops), orally as an oral or nasal spray, etc., depending on the severity of the disease being treated.

[0247] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0248] Injectable preparations can be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable aqueous or oily suspensions. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any odorless fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used to prepare injections.

[0249] For example, the injectable formulation can be sterilized by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0250] To prolong the effects of the compounds or compositions of the present invention, it is often desirable to slow down the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of poorly water-soluble crystals or amorphous substances. The absorption rate of the compound then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable storage forms can be prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. Depending on the ratio of the compound to the polymer and the properties of the particular polymer employed, the compound release rate can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable storage formulations can also be prepared by entrapping the compound in liposomes or microemulsions compatible with body tissues.

[0251] Compositions for rectal or vaginal administration are particularly suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0252] Oral solid dosage forms include capsules, tablets, pills, powders, and granules in which the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or expanders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0253] Also can use as the filler in soft and hard gel capsules the solid composition of similar type using excipients such as lactose or milk sugar and macromolecular polyethylene glycol.Available coating and shell, for example enteric coating and other well-known coatings of pharmaceutical field prepare the solid dosage form of tablet, lozenge, capsule, pill and granule.They can optionally contain emulsifier and can also have the character of composition, so that optionally only release active ingredient in a delayed manner, or preferably, release in a certain part of intestinal tract.The example of spendable embedded composition comprises polymer and wax.Also can use as the filler in soft and hard gel capsules the solid composition of similar type using excipients such as lactose or milk sugar and macromolecular polyethylene glycol.

[0254] The active compound may also be in a micro-encapsulated form with one or more of the above-mentioned excipients. Available coatings and shells, such as enteric coatings, controlled release coatings, and other well-known coatings in the pharmaceutical field, can be used to prepare solid dosage forms of tablets, lozenges, capsules, pills, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Generally, such dosage forms may also include other substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. They may optionally contain an emulsifier and may also have the properties of a composition so as to optionally release only the active ingredient in a delayed manner, or preferably, release in a certain part of the intestinal tract. Examples of usable embedding compositions include polymers and waxes.

[0255] Topical or transdermal dosage forms for the compounds of the present invention include ointments, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. Under sterile conditions, the active compound is mixed with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be needed. Ophthalmic preparations, ear drops, and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of skin patches that provide the additional advantage of controlling the delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0256] The compositions of the present invention can also be administered orally, parenterally, topically, rectally, nasally, orally, vaginally, or via an inhalation spray, or via an implanted cartridge. As used herein, the term "parenteral" includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In particular, the compositions can be administered orally, intraperitoneally, or intravenously.

[0257] Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions can be prepared using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any odorless, fixed oil may be used, including synthetic mono- or diglycerides. Furthermore, natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms, and fatty acids such as octadecenoic acid and its glyceride derivatives are used to prepare injectables. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0258] The pharmaceutical compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of oral tablets, common carriers include but are not limited to lactose and starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0259] Alternatively, the pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing reagents with non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0260] The pharmaceutical compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0261] Topical application to the lower intestinal tract can be accomplished in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical skin patches may also be used.

[0262] For topical application, the pharmaceutical composition can be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers suitable for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0263] For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension in isotonic pH adjusted sterile saline, or particularly as a solution in isotonic pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment, such as petrolatum.

[0264] The pharmaceutical composition may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0265] The compounds used in the methods of the present invention can be formulated in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for a subject, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be a single daily dose or one of multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form for each dose can be the same or different.

[0266] Uses of the compounds and compositions of the present invention

[0267] The above-mentioned compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for preventing, treating or alleviating LSD1 overexpression or overactivity-related diseases in patients. Preferably, the LSD1 overexpression or overactivity-related diseases are tumors, for example, the tumors are papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer or non-Hodgkin's lymphoma.

[0268] The present invention also provides use of the above compound or its pharmaceutical composition in preparing a drug for inhibiting LSD1.

[0269] The present invention provides a method for treating, preventing, or delaying the onset of a disease caused by overexpression or hyperactivity of LSD1, comprising administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutical composition thereof to a patient in need of treatment. The disease caused by overexpression or hyperactivity of LSD1 is a tumor, such as papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer, or non-Hodgkin's lymphoma. Furthermore, the above-mentioned compound or pharmaceutical composition thereof provided by the present invention can be co-administered with other therapies or therapeutic agents. Administration can be simultaneous, sequential, or at intervals.

[0270] The dosage of the compound or pharmaceutical composition required to achieve the therapeutic, preventive or delaying effect generally depends on the specific compound administered, the patient, the specific disease or condition and its severity, the route of administration and frequency, etc., and needs to be determined by the attending physician based on the specific circumstances. For example, when the compound or pharmaceutical composition provided by the present invention is administered intravenously, it can be administered once a week or even at longer intervals.

[0271] In summary, the present invention provides a novel compound that can be used as an LSD1 inhibitor. The compound of the present invention is suitable for formulation into various pharmaceutical formulations and can be widely used to treat tumors, such as papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer, or non-Hodgkin's lymphoma.

[0272] In addition to being beneficial for human treatment, the compounds and pharmaceutical compositions of the present invention may also be used in veterinary treatment of pets, imported species, and mammals in farm animals. Other examples of animals include horses, dogs, and cats. The compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0273] General synthesis process

[0274] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0275] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following reaction schemes and examples are provided to further illustrate the present invention.

[0276] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0277] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Solvents used in the present invention are commercially available. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company, Alfa Chemical Company, and J&K Scientific Ltd. and used without further purification unless otherwise indicated.

[0278] The LCMS model used for detection in the following examples is Agilent 1200 Series, Agilent 1260 Infinity 2 or Agilent 1260-6125B, and the NMR model is Bruker AVANCE 3 400 MHZ Ultra shield™ Digital NMR.

[0279] The compounds were named according to conventional naming rules in the art or using ChemDraw software.

[0280] The following synthesis scheme lists the experimental steps for preparing the compounds disclosed in the present invention. a 、R b 、R c , Ring A, Ring B, m, n, s, t, and v have the definitions described in the present invention,

[0281] Synthesis Scheme 1

[0282]

[0283] 4-Bromoacetophenone compound Ia reacts with Zn(CN)2 under palladium catalysis to yield the corresponding 4-cyanoacetophenone compound Ib. This latter reacts with PTSA and NCS to yield intermediate Ic, which then undergoes ring closure with an aminoheterocyclic compound at high temperature to yield intermediate Ie. This latter is then brominated to yield If, which then undergoes nucleophilic substitution with Ig to yield Ih. Finally, Ih is coupled with the corresponding boronic acid compound under palladium catalysis to yield compound I'.

[0284] Synthesis Scheme 2

[0285]

[0286] 4-Cyanobenzoic acid compound II-a was methylated in dimethyl sulfate to give intermediate II-b, which then reacted with acetonitrile to give II-c. II-c then underwent a ring-closure reaction with hydrazine to give II-d, which was then further ring-closed with II-e to give intermediate II-f. II-f reacted with phosphorus oxychloride to give the corresponding chloro compound II-g, which was then brominated with NBS to give II-h. Nucleophilic substitution gave II-i, which then underwent a Suzuki coupling reaction with the corresponding boronic acid compound to give II'. DETAILED DESCRIPTION

[0287] The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention.

[0288] Preparation Example

[0289] In the following preparation examples, the inventors describe in detail the preparation process of the compounds of the present invention by taking some of the compounds of the present invention as examples.

[0290] Example 1

[0291] Synthesis of 4-(8-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 1)

[0292]

[0293] Step 1

[0294] Compound 1-1 (6 g, 27.65 mmol), Zn(CN)2 (2.03 g, 17.28 mmol), N,N,N',N'-tetramethylethylenediamine (0.7 g, 6.05 mmol), Pd2(dba)3 (0.79 g, 1.73 mmol), and Xant-Phos (2 g, 6.92 mmol) were dissolved in DMF (50 mL). The reaction system was heated to 120°C and reacted under nitrogen for 4 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 100 mL), dried over anhydrous sodium sulfate, and dried by spin drying. The product was purified by column chromatography (PE:EA = 6:1) to afford compound 1-2 (4.1 g, 90% yield) as a yellow solid. 1 HNMR (400MHz, DMSO) δ8.13 (d, J = 6.6 Hz, 1H), 7.97 (dd, J = 26.0, 9.0 Hz, 2H), 2.65 (s, 3H).

[0295] Step 2

[0296] Compound 1-2 (4.1 g, 25.15 mmol) was dissolved in acetonitrile (50 mL), and NCS (2.0 g, 15.1 mmol) and PTSA (2.4 g, 12.6 mmol) were added to the reaction system. The reaction mixture was heated to 80°C and reacted under nitrogen for 1 h. The reaction system was quenched with water, extracted with ethyl acetate (3*80 mL), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was purified by column chromatography (PE:EA = 5:1) to obtain compound 1-3 (3.5 g, yield: 70%) as a yellow oil. 1 HNMR (400MHz, CDCl3) δ7.85 (d, J = 9.4Hz, 1H), 7.81 (dd, J = 8.6, 4.9Hz, 2H), 4.66 (s, 2H).

[0297] Step 3

[0298] Compound 1-3 (3.5 g, 17.8 mmol) and compound 1-3A (3.43 g, 17.8 mmol) were dissolved in DMF (50 mL). The reaction mixture was heated to 120°C and reacted under nitrogen for 24 h. The reaction system was quenched with water, extracted with ethyl acetate (3*80 mL), dried over anhydrous sodium sulfate, and dried by spin chromatography. The mixture was purified by column chromatography (PE:EA=1:1) to obtain compound 1-4 (1.1 g, yield: 22%) as a white solid. LCMS (M+H) + =273.2.

[0299] Step 4

[0300] Compound 1-4 (800 mg, 2.94 mmol) was dissolved in acetonitrile (20 mL), and NBS (575.9 mg, 3.23 mmol) was added to the reaction system. The reaction mixture was heated to 40°C and reacted under nitrogen for 12 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 40 mL), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (PE:EA = 1:1) to afford compound 1-5 (450 mg, yield: 43%) as a white solid. LCMS (M+H) + =351.1.

[0301] Step 5

[0302] Compound 1-5 (300 mg, 0.86 mmol) was dissolved in NMP (8.0 mL), followed by the addition of DIPEA (221.9 mg, 1.72 mmol) and compound 1-5A (172 mg, 0.86 mmol). The reaction mixture was heated to 120°C and allowed to react for 4 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 30 mL), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was purified by column chromatography (PE:EA = 3:1) to afford compound 1-6 (150 mg, yield: 33%) as a white solid. LCMS: (M+H) + =515.2.

[0303] Step 6

[0304] Compound 1-6 (140 mg, 0.27 mmol), compound 1-6A (69.46 mg, 0.41 mmol), Pd(dppf)Cl2 (13.91 mg, 0.03 mmol), and K2CO3 (75.18 mg, 0.54 mmol) were dissolved in 1,4-dioxane / H2O (4 / 0.5 mL). The reaction system was heated to 100°C and the reaction solution was reacted under nitrogen for 5 h. The reaction system was quenched with water, extracted with ethyl acetate (3*20 mL), dried over anhydrous sodium sulfate, and dried by spin drying. The product was purified by column chromatography (PE:EA=1:1) to obtain compound 1-7 (50 mg, yield: 33%) as a white solid. LCMS: (M+H) + =561.3.

[0305] Step 7

[0306] Compound 1-7 (50 mg, 0.09 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 1 (10.5 mg, yield: 22%) as a white solid. LCMS: (M+H) +=461.0. 1 H NMR(400MHz,DMSO)δ7.94(m,3H),7.66(m,1H),7.49(m,2H),7.37(m,2H),7.29(m,1 H),5.47(m,2H),3.96(s,3H),3.42(m,1H),3.23(m,2H),2.05(m,2H),1.57(m,2H). 19 F NMR(376MHz, DMSO)δ-74.23(s,4.73F),-107.94(s,1F),-133.25(s,1F).

[0307] Example 2

[0308] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 2)

[0309]

[0310] Step 1

[0311] Compound 2-1 (220 mg, 0.63 mmol) was dissolved in NMP (8.0 mL), and DIPEA (162.6 mg, 1.26 mmol) and compound 2-2 (125.7 mg, 0.63 mmol) were added to the reaction system. The reaction solution was heated to 120°C and stirred for 4 hours. The reaction system was quenched with water, extracted with ethyl acetate (3*30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 3:1) to obtain compound 2-3 (100 mg, yield: 30.1%) as a white solid. LCMS: (M+H) + =515.2.

[0312] Step 2

[0313] Compound 2-3 (100 mg, 0.20 mmol), compound 2-4 (49.61 mg, 0.29 mmol), Pd(dppf)Cl2 (14.22 mg, 0.02 mmol), and K2CO3 (53.7 mg, 0.39 mmol) were dissolved in 1,4-dioxane / H2O (4 / 0.5 mL). The reaction system was heated to 100°C and the reaction solution was reacted under nitrogen for 5 h. The reaction system was quenched with water, extracted with ethyl acetate (3*20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain compound 2-5 (50 mg, yield: 41.0%) as a white solid. LCMS: (M+H)+ =561.3.

[0314] Step 3

[0315] Compound 2-5 (50 mg, 0.09 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction solution was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was separated by HPLC to obtain compound 2 (13.1 mg, yield: 33%) as a white solid. LCMS: (M+H) + =461.2. 1 H NMR(400MHz,DMSO)δ8.08(m,3H),7.89(m,1H),7.76(m,1H),7.46(m,2H),7.39(m,2H),7.28(m,1 H),5.08(m,2H),3.96(s,3H),3.56(m,2H),3.35(m,1H),2.09(m,1H),1.89(m,1H),1.68(m,2H). 19 F NMR(376MHz, DMSO)δ-74.34(s,4.2F),-107.92(s,1F),-133.21(s,1F).

[0316] Example 3

[0317] Synthesis of 4-(7-(4-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)imidazo[1,5-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 3)

[0318]

[0319] Step 1

[0320] Compound 3-1 (11 g, 85 mmol), dimethyl sulfate (16.12 g, 128 mmol), and potassium carbonate (21.18 g, 153 mmol) were dissolved in acetone (100 mL). The reaction system was heated to 60°C and reacted under nitrogen for 4 h. Water was added to the reaction system, and the mixture was extracted with ethyl acetate (3 x 100 mL). The mixture was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain compound 3-2 (9.3 g, yield: 61%) as a white solid. 1 H NMR (400MHz, DMSO) δ8.17–8.05 (m, 1H), 7.96 (dd, J = 16.1, 9.0Hz, 2H), 3.91 (s, 3H).

[0321] Step 2

[0322] Compound 3-2 (5.4 g, 30.2 mmol) was dissolved in tetrahydrofuran (60 mL). LiHMDS (45.3 mL, 45.3 mmol) was added dropwise to the reaction system at -78°C and allowed to react under nitrogen for 0.5 h. Acetonitrile (1.48 g, 36.2 mmol) was added dropwise to the reaction system at -78°C. The reaction system was warmed to 0°C and allowed to react under nitrogen for 1 h. The reaction solution was concentrated under reduced pressure until a large amount of solid precipitated. The filter cake was filtered, washed with dichloromethane (50 mL*3), and dried to obtain compound 3-3 (3.7 g, yield: 65%) as a yellow solid. LCMS (M+H) + =189.0.

[0323] Step 3

[0324] Compound 3-3 (3.5 g, 18.6 mmol) and hydrazine hydrate (2.8 g, 55.8 mmol) were dissolved in ethanol (50 mL). Acetic acid (3 mL) was added, and the reaction mixture was heated to 75°C and reacted under nitrogen for 8 h. The reaction system was quenched with water, extracted with ethyl acetate (3*80 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=1:1) to obtain compound 3-4 (1.5 g, yield: 31%) as a white solid. LCMS (M+H) + =260.1.

[0325] Step 4

[0326] Compound 3-4 (1.5 g, 5.79 mmol) was dissolved in ethanol (20 mL), and compound 3-4A (1.65 g, 8.68 mmol) was added to the reaction system. 4M HCl / 1,4-dioxane (3 mL) was added dropwise at room temperature. The reaction solution was heated to 110°C and reacted under nitrogen for 1 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 2:1) to obtain compound 3-5 (400 mg, yield: 27%) as a colorless oil. LCMS (M+H) + =255.2.

[0327] Step 5

[0328] Compound 3-5 (400 mg, 1.57 mmol) was dissolved in POCl3 (10 mL), and DIPEA (608 mg, 4.71 mmol) was added to the reaction system. The reaction solution was heated to 100°C and reacted under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA = 3:1) to obtain compound 3-6 (350 mg, yield: 82%) as a white solid. LCMS: (M+H)+ =272.0.

[0329] Step 6

[0330] Compound 3-6 (350 mg, 1.29 mmol) was dissolved in acetonitrile (10 mL), and NBS (344 mg, 1.94 mmol) was added to the reaction system. The reaction solution was heated to 50°C and reacted under nitrogen for 2 h. The reaction system was quenched with water, extracted with ethyl acetate (3*30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 3:1) to obtain compound 3-7 (200 mg, yield: 44.0%) as a white solid. LCMS: (M+H) + =351.2.

[0331] Step 7

[0332] Compound 3-7 (100 mg, 0.28 mmol) was dissolved in NMP (8.0 mL), followed by the addition of DIPEA (162.6 mg, 0.56 mmol) and compound 3-7A (84 mg, 0.42 mmol). The reaction mixture was heated to 120°C and reacted under nitrogen for 4 h. The reaction system was quenched with water, extracted with ethyl acetate (3*30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 3:1) to afford compound 3-8 (68 mg, yield: 47%) as a white solid. LCMS: (M+H) + =515.3.

[0333] Step 8

[0334] Compound 3-8 (68 mg, 0.13 mmol), compound 3-8A (33.74 mg, 0.20 mmol), Pd(dppf)Cl2 (7.3 mg, 0.01 mmol), and K2CO3 (35.9 mg, 0.26 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 100°C and the reaction solution was reacted under nitrogen for 8 hours. The reaction system was quenched with water, extracted with ethyl acetate (3*30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain compound 3-9 (52 mg, yield: 41.0%) as a white solid. LCMS: (M+H) + =561.3.

[0335] Step 9

[0336] Compound 3-9 (52 mg, 0.09 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction was allowed to proceed at room temperature for 2 h under nitrogen. The reaction solution was concentrated under reduced pressure, and the crude product was separated by HPLC to obtain compound 3 (21 mg, yield: 51%) as a white solid. LCMS: (M+H) + =461.0. 1 HNMR (400MHz, DMSO) δ8.37(d,J=5.1Hz,1H),8.00(d,J=7.2Hz,3H),7.73(d,J=1 0.5Hz,1H),7.55(d,J=9.5Hz,1H),7.34(d,J=12.7Hz,1H),7.21(t,J=8.9Hz,1H) ,7.13(d,J=9.8Hz,1H),6.61(m,1H),4.56(d,J=12.7Hz,2H),3.88(s,3H),3.40 (m,1H),3.22(t,J=12.1Hz,2H),2.08(d,J=12.7Hz,2H),1.74(d,J=15.3Hz,2H). 19 F NMR(376MHz,DMSO)δ-74.55(s,3.35F),-109.92(s,1F),

[0337] -135.21(s,1F).

[0338] Example 4

[0339] Synthesis of (R)4-(7-(3-aminopiperidin-1-yl)-3-(3-fluoro-4-methoxyphenyl)imidazo[1,5-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 4)

[0340]

[0341] Step 1

[0342] Compound 4-1 (100 mg, 0.28 mmol) was dissolved in NMP (8.0 mL), followed by the addition of DIPEA (162.6 mg, 0.56 mmol) and compound 4-1A (84 mg, 0.42 mmol). The reaction mixture was heated to 120°C and reacted under nitrogen for 4 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 3:1) to afford compound 4-2 (90 mg, yield: 63%) as a white solid. LCMS: (M+H) + =515.2.

[0343] Step 2

[0344] Compound 4-2 (90 mg, 0.17 mmol), compound 4-2A (43.35 mg, 0.25 mmol), Pd(dppf)Cl2 (14.6 mg, 0.02 mmol), and K2CO3 (46.9 mg, 0.34 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 100°C and the reaction solution was reacted under nitrogen for 8 hours. The reaction system was quenched with water, extracted with ethyl acetate (3*30 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=1:1) to obtain compound 4-3 (65 mg, yield: 68.3%) as a white solid. LCMS: (M+H) + =561.0.

[0345] Step 3

[0346] Compound 4-3 (65 mg, 0.12 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction was allowed to proceed at room temperature for 2 h under nitrogen. The reaction solution was concentrated under reduced pressure, and the crude product was separated by HPLC to obtain compound 4 (41 mg, yield: 74%) as a white solid. LCMS: (M+H) + =461.0. 1 HNMR(400MHz,DMSO)δ8.40(d,J=5.1Hz,1H),8.11(M,3H),8.02(m,1H),7.81(dd,J=10 .5,1.2Hz,1H),7.55(dd,J=8.1,1.4Hz,1H),7.30(dd,J=20.4,18.4Hz,1H),7.20(d,J =8.9Hz,1H),7.12(m,1H),6.64(d,J=5.2Hz,1H),4.47(d,J=9.2Hz,1H),4.02(d,J=13 .2Hz,1H),3.88(s,3H),3.46(m,2H),3.36(t,J=9.9Hz,1H),2.00(m,2H),1.73(m,2H). 19 F NMR(376MHz, DMSO)δ-74.45(s,3.29F),-106.42(s,1F),-135.21(s,1F).

[0347] Example 5

[0348] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(1-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 5)

[0349]

[0350]

[0351] Step 1

[0352] Compound 5-1 (70 mg, 0.2 mmol), compound 5-1A (42 mg, 0.2 mmol), and DIPEA (53 mg, 0.4 mmol) were dissolved in NMP (3 mL). The reaction system was heated to 120°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain compound 5-2 (60 mg, yield: 55%) as a white solid. LCMS: (M+H) + =529.1.

[0353] Step 2

[0354] Compound 5-2 (60 mg, 0.11 mmol), compound 5-2A (30 mg, 0.16 mmol), Pd(dppf)Cl2 (9 mg, 0.01 mmol), and K2CO3 (30 mg, 0.22 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain compound 5-3 (15 mg, yield: 24%) as a white solid. LCMS: (M+H) + =575.1.

[0355] Step 3

[0356] Compound 5-3 (15 mg, 0.03 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 5 (7.4 mg, yield: 60%) as a white solid. LCMS: (M+H) + =465.3. 1HNMR(400MHz,DMSO)δ8.03(s,2H),7.92–7.85(m,1H),7.70(d,J=10.6Hz,1H),7.49(dd,J=8 .8,1.8Hz,1H),7.47–7.45(m,1H),7.43(t,J=8.8Hz,1H),7.38(d,J=4.6Hz,1H),7.33(d,J= 4.6Hz,1H),7.30(d,J=8.4Hz,1H),4.41(s,2H),3.96(s,3H),3.89(dd,J=14.4,6.6Hz,2H), 3.69(s,1H),1.90(d,J=8.8Hz,2H),1.78(d,J=35.2Hz,2H),1.51(dd,J=50.4,11.6Hz,2H). 19 F NMR(376MHz, DMSO)δ-74.02(s,3.78F),-107.95(s,1F),-108.00(s,0.92F).

[0357] Example 6

[0358] Synthesis of 2-fluoro-4-(3-(3-fluoro-4-methoxyphenyl)-8-((pyrrolidin-2-ylmethyl)amino)imidazo[1,2-a]pyrazin-2-yl)benzonitrile (Compound 6)

[0359]

[0360] Step 1

[0361] Compound 6-1 (150 mg, 0.43 mmol), compound 6-1A (85 mg, 0.43 mmol), and DIPEA (111 mg, 0.86 mmol) were dissolved in NMP (3 mL). The reaction system was heated to 100°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain compound 6-2 (80 mg, yield: 36%) as a white solid. LCMS: (M+H) + =515.1.

[0362] Step 2

[0363] Compound 6-2 (80 mg, 0.16 mmol), compound 6-2A (92 mg, 0.24 mmol), Pd(dppf)Cl2 (12 mg, 0.02 mmol), and K2CO3 (44 mg, 0.32 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain compound 6-3 (30 mg, yield: 33%) as a white solid. LCMS: (M+H) + =561.1.

[0364] Step 3

[0365] Compound 6-3 (30 mg, 0.05 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 6 (7 mg, yield: 30%) as a white solid. LCMS: (M+H) + =461.3. 1 HNMR(400MHz,DMSO)δ9.03(s,1H),8.69(s,1H),8.09(t,J=5.8Hz,1H),7.95–7.87(m,1H),7.69(d,J= 11.0Hz,1H),7.51–7.48(m,1H),7.47(dd,J=5.8,1.8Hz,1H),7.42(t,J=8.8Hz,1H),7.37–7.31(m,2H) ,7.27(d,J=14.0Hz,1H),7.06(d,J=50.8Hz,1H),3.96(s,3H),3.86(d,J=6.2Hz,1H),3.81–3.76(m,2 H),3.28–3.14(m,2H),2.08(dd,J=12.2,4.8Hz,1H),2.00–1.84(m,2H),1.77(dd,J=12.4,8.0Hz,1H). 19 F NMR(376MHz, DMSO)δ-74.11(s,6F),-108.23(s,1F),-133.32(s,0.92F).

[0366] Example 7

[0367] Synthesis of 2-fluoro-4-(3-(9,3-fluoro-4-methoxyphenyl)-8-(piperidin-3-ylamino)imidazo[1,2-a]pyrazin-2-yl)benzonitrile (Compound 7)

[0368]

[0369] Step 1

[0370] Compound 7-1 (150 mg, 0.43 mmol), compound 7-1A (85 mg, 0.43 mmol), and DIPEA (111 mg, 0.86 mmol) were dissolved in DMF (3 mL). The reaction system was heated to 120°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain compound 7-2 (40 mg, yield: 36%) as a white solid. LCMS: (M+H) + =515.1.

[0371] Step 2

[0372] Compound 7-2 (40 mg, 0.08 mmol), compound 7-2A (20 mg, 0.12 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), and K2CO3 (22 mg, 0.32 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain compound 7-3 (20 mg, yield: 45%) as a white solid. LCMS: (M+H) + =561.1.

[0373] Step 3

[0374] Compound 7-3 (20 mg, 0.04 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 7 (10 mg, yield: 55%) as a white solid. LCMS: (M+H) + =461.3. 1HNMR(400MHz,DMSO)δ8.75(d,J=28.6Hz,2H),7.94–7.86(m,1H),7.82(d,J=8.2Hz,1H),7. 72(d,J=11.0Hz,1H),7.49(d,J=1.2Hz,1H),7.47(dd,J=4.2,1.8Hz,1H),7.41(t,J=8.8Hz ,1H),7.32(s,1H),7.30(d,J=10.4Hz,1H),4.50(s,1H),3.96(s,3H),3.34(dd,J=66.2,11 .2Hz,2H),2.93(dd,J=57.4,10.2Hz,2H),1.98(d,J=24.2Hz,2H),1.77(t,J=10.0Hz,2H). 19 F NMR(376MHz, DMSO)δ-74.25(s,4.88F),-108.30(s,1F),-133.35(s,0.94F).

[0375] Example 8

[0376] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(1-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 8)

[0377]

[0378] Step 1

[0379] Compound 8-1 (60 mg, 0.1 mmol), compound 8-1A (26.4 mg, 0.15 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol), and K2CO3 (27 mg, 0.2 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain compound 8-2 (20 mg, yield: 23%) as a white solid. LCMS: (M+H) + =567.1.

[0380] Step 3

[0381] Compound 8-2 (20 mg, 0.02 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 8 (8 mg, yield: 80%) as a white solid. LCMS: (M+H)+ =467.3. 1 H NMR (400MHz, DMSO) δ8.20(d,J=0.8Hz,1H),8.09(d,J=4.2Hz,2H),7.98(d,J=1.4Hz,1H) ,7.93(d,J=8.8Hz,1H),7.86–7.79(m,1H),7.74(dd,J=11.2,1.2Hz,1H),7.44(ddd,J=8 .2,5.4,1.6Hz,2H),7.36(dd,J=13.6,4.6Hz,2H),5.08(dd,J=38.8,11.6Hz,2H),4.16( s,3H),3.64–3.55(m,2H),3.37(s,1H),2.09(s,1H),1.91(s,1H),1.69(d,J=8.6Hz,2H). 19 F NMR(376MHz, DMSO)δ-74.13(s,3.85F),-108.00(s,1F).

[0382] Example 9

[0383] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 9)

[0384]

[0385] Step 1

[0386] Compound 9-1 (330 mg, 1.45 mmol), 9-1A (188 mg, 2.2 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), tricyclohexylphosphine (81 mg, 0.29 mmol), and potassium acetate (284 mg, 2.9 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction system was heated to 110°C and reacted under nitrogen for 12 h. The reaction system was quenched with water, extracted with ethyl acetate (3*50 mL), dried over anhydrous sodium sulfate, and dried by spin drying. The product was purified by column chromatography (PE:EA=1:1) to obtain compound 9-2 (120 mg, yield: 30%) as a colorless oil. LCMS (M+H) + =276.1.

[0387] Step 2

[0388] Compound 9-2 (120 mg, 0.43 mmol), compound 9-2A (147 mg, 0.29 mmol), Pd(dppf)Cl2 (20 mg, 0.03 mmol), and K2CO3 (80 mg, 0.58 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain compound 9-3 (20 mg, yield: 8%) as a white solid. LCMS: (M+H) + =584.1.

[0389] Step 3

[0390] Compound 9-3 (20 mg, 0.034 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 9 (6.7 mg, yield: 41%) as a white solid. LCMS: (M+H) + =484.1. 1 HNMR (400MHz, DMSO) δ8.06 (s, 2H), 7.93–7.85 (m, 1H), 7.75 (d, J = 11.2Hz, 1H), 7.58 (d d,J=8.2,1.4Hz,1H),7.36(q,J=4.6Hz,2H),6.91–6.85(m,2H),6.78(d,J=1.8Hz,1H), 5.03(dd,J=37.2,11.2Hz,2H),4.32–4.25(m,2H),3.58(d,J=12.0Hz,2H),3.41–3.36 (m,2H),3.36–3.28(m,1H),2.95(s,3H),2.07(s,1H),1.89(s,1H),1.74–1.60(m,2H).

[0391] 19 F NMR(376MHz,DMSO)δ-73.88(s,4F),-108.20(s,1F).

[0392] Example 10

[0393] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 10)

[0394]

[0395] Step 1

[0396] Compound 10-1 (330 mg, 0.94 mmol), 10-1A (188 mg, 0.94 mmol), and DIPEA (242.5 mg, 1.88 mmol) were dissolved in NMP (10 mL). The reaction system was heated to 120°C and reacted under nitrogen for 12 h. The reaction system was quenched with water, extracted with ethyl acetate (3*50 mL), dried over anhydrous sodium sulfate, and dried by spin drying. The mixture was purified by column chromatography (PE:EA=1:1) to obtain a brown solid compound 10-2 (180 mg, yield: 37%). LCMS (M+H) + =514.1.

[0397] Step 2

[0398] Compound 10-2 (60 mg, 0.1 mmol), compound 10-2A (26.4 mg, 0.15 mmol), Pd(dppf)Cl2 (7 mg, 0.01 mmol), and K2CO3 (27 mg, 0.2 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain compound 10-3 (13 mg, yield: 19%) as a white solid. LCMS: (M+H) + =585.1.

[0399] Step 3

[0400] Compound 10-3 (13 mg, 0.02 mmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added dropwise to the reaction system. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 10 (3.2 mg, yield: 30%) as a white solid. LCMS: (M+H) + =485.1. 1 H NMR (400MHz, DMSO) δ8.31(s,1H),8.04(s,2H),7.95(d,J=8.2Hz,1H),7.92(s,1H),7.76–7.72(m,1H),7.69(dd,J=8.2,1.6Hz,1H),7.44(d,J=4 .6Hz,1H),7.41(d,J=4.6Hz,1H),5.31(d,J=9.0Hz,2H),5.05(d,J=13.8Hz,2H),3.33(s,2H),2.06(s,2H),1.88(s,1H),1.66(d,J=8.2Hz,2H). 19F NMR(376MHz, DMSO)δ-70.22(s,2.85F),-73.88(s,4.25F),-108.20(s,1F).

[0401] Example 11

[0402] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 11)

[0403]

[0404] Step 1

[0405] Compound 11-1 (550 mg, 2.3 mmol), 11-1A (811 mg, 11.2 mmol), and K2CO3 (580 mg, 4.5 mmol) were dissolved in DMF (8 mL). The reaction system was heated to 100°C and microwave-treated for 2 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and spin-dried. The product was purified by column chromatography (PE:EA = 1:1) to afford 11-2 (100 mg, yield: 14%) as a white solid. LCMS (M+H) + =317.1.

[0406] Step 2

[0407] Compound 11-2 (100 mg, 0.32 mmol), compound 11-2A (110 mg, 0.21 mmol), Pd(dppf)Cl2 (10 mg, 0.02 mmol), and K2CO3 (58 mg, 0.42 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 11-3 (25 mg, yield: 19%). LCMS (M+H) + =625.0.

[0408] Step 3

[0409] Compound 11-3 (25 mg, 0.05 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise in an ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was separated by HPLC to obtain compound 11 (5.3 mg, yield: 20%) as a white solid. LCMS (M+H) + =525.2. 1H NMR (400MHz, DMSO) δ8.21(s,1H),8.07(d,J=4.2Hz,2H),7.96(d,J=8.8Hz,2H),7.8 7–7.79(m,1H),7.73(d,J=11.2Hz,1H),7.47(dd,J=8.2,1.2Hz,1H),7.40(d,J=10.2 Hz,1H),7.36(dd,J=9.2,4.6Hz,2H),5.17–4.97(m,2H),4.41(s,2H),3.62(d,J=8.4 Hz, 3H), 3.36 (s, 1H), 2.09 (s, 1H), 1.91 (s, 1H), 1.69 (d, J = 5.8Hz, 2H), 1.20 (s, 6H). 19 F NMR(376MHz, DMSO)δ-74.15(s,4.27F),-108.11(s,1F).

[0410] Example 12

[0411] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 12)

[0412]

[0413]

[0414] Step 1

[0415] Compound 12-1 (450 mg, 2.1 mmol), 12-1A (756 mg, 10.5 mmol), and K2CO3 (580 mg, 4.2 mmol) were dissolved in DMF (8 mL). The reaction system was heated to 100°C and microwave-treated for 2 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (PE:EA = 1:2) to afford 12-2 (205 mg, yield: 33%) as a white solid. LCMS (M+H) + =288.1.

[0416] Step 2

[0417] Compound 12-2 (120 mg, 0.42 mmol), compound 12-2A (150 mg, 0.63 mmol), Pd2(dba)3 (38 mg, 0.04 mmol), tricyclohexylphosphine (24 mg, 0.08 mmol), and potassium acetate (82 mg, 0.84 mmol) were dissolved in 1,4-dioxane (3 mL). The reaction system was heated to 110°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 12-3 (45 mg, yield: 42%). LCMS (M+H) + =254.0.

[0418] Step 3

[0419] Compound 12-3 (45 mg, 0.18 mmol), compound 12-3A (110 mg, 0.18 mmol), Pd(dppf)Cl2 (10 mg, 0.02 mmol), and K2CO3 (50 mg, 0.36 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain 12-4 (15 mg, yield: 13%) as a white solid. LCMS (M+H) + =644.2.

[0420] Step 4

[0421] Compound 12-4 (15 mg, 0.02 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under an ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 12 (1.7 mg, yield: 16%) as a white solid (LCMS (M+H)). + =544.2. 1 H NMR (400MHz, DMSO) δ8.44(d,J=5.2Hz,1H),8.08(d,J=9.2Hz,4H),7.86(d,J=8.0Hz,1H),7.79(d,J=11.8Hz,1H),7.50–7.35( m,3H),5.08(s,1H),4.94(s,1H),4.69(s,2H),3.37(s,3H),2.10(s,1H),1.88(s,1H),1.71(s,2H),1.26(s,3H),1.20(s,3H). 19F NMR (376 MHz, DMSO) δ -73.79 (s, 5.93F), -107.73 (s, 1F), -114.67 (s, 1F). (1.8 mg, yield: 16%). LCMS (M+H) + =544.2. 1 H NMR (400MHz, DMSO) δ8.44(d,J=5.2Hz,1H),8.08(d,J=9.2Hz,4H),7.86(d,J=8.0Hz,1H),7.79(d,J=11.8Hz,1H),7.50–7.35( m,3H),5.08(s,1H),4.94(s,1H),4.69(s,2H),3.37(s,3H),2.10(s,1H),1.88(s,1H),1.71(s,2H),1.26(s,3H),1.20(s,3H). 19 F NMR(376MHz, DMSO)δ-73.79(s,6.58F),-107.68(s,0.95F),-107.73(s,0.2F),-114.35(s,0.22F),-119.26(s,1F).

[0422] Example 13

[0423] Synthesis of 2-fluoro-4-(3-(3-fluoro-4-methoxyphenyl)-8-((pyrrolidin-3-ylmethyl)amino)imidazo[1,2-a]pyrazin-2-yl)benzonitrile (Compound 13)

[0424]

[0425] Step 1

[0426] Compound 13-1 (70 mg, 0.2 mmol) was dissolved in NMP (4 mL), and compound 13-2 (80 mg, 0.4 mmol) and DIPA (129 mg, 1 mmol) were added. The reaction mixture was heated to 100°C and stirred for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate and the organic phase was backwashed 3 to 4 times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography (PE:EA=2:1) ​​to obtain compound 13-3 (70 mg, yield: 68%) as a white solid. LCMS (M+H) + =515.0.

[0427] Step 2

[0428] Compound 13-3 (70 mg, 0.14 mmol), compound 13-4 (47 mg, 0.3 mmol), and potassium carbonate (47 mg, 0.34 mmol) were dissolved in a mixture of dioxane (2 mL) and water (0.5 mL). Catalyst Pd(dppf)Cl2 (10 mg, 0.14 mmol) was added under nitrogen. The mixture was heated to 100°C and stirred under nitrogen for 1.5 hours. The solvent was then concentrated to remove most of the solvent. The crude residue was purified by column chromatography (PE:EA = 1:1) to obtain compound 13-5 (35 mg, yield: 46%) as a white solid. LCMS (M+H) + =561.0.

[0429] Step 3

[0430] Compound 13-5 (35 mg, 0.06 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added dropwise under an ice-water bath. The mixture was stirred at room temperature for 1 hour. The solvent was concentrated to remove most of the solvent. The crude product was purified by Prep-HPLC to obtain compound 13 (10 mg, yield: 35%) as a white solid. LCMS (M+H) + =461.0. 1 H NMR(400MHz,DMSO)δ8.73–8.66(m,1H),8.42–8.10(m,1H),7.94–7.88(m,1H ),7.74–7.67(m,1H),7.51–7.45(m,2H),7.44–7.38(m,1H),7.34–7.26(m,3 H),3.95(s,3H),3.60–3.57(m,2H),3.33–3.25(m,2H),3.20–3.11(m,1H),3 .05–2.96(m,1H),2.81–2.71(m,1H),2.10–1.99(m,1H),1.80–1.69(m,1H). 19 F NMR(376MHz, DMSO)δ-74.11(s.3F),-108.28(s,1F),-133.35(s,1F).

[0431] Example 14

[0432] Synthesis of cis-4-(8-((1R,3S)-3-aminocyclopentyl)amino)-3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 14)

[0433]

[0434] Step 1

[0435] Compound 14-1 (110 mg, 0.29 mmol), 14-1A (57 mg, 0.29 mmol), and DIPEA (75 mg, 0.58 mmol) were dissolved in NMP (5 mL). The reaction system was heated to 120°C and reacted under nitrogen for 4 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and dried by spin chromatography. The mixture was purified by column chromatography (PE:EA = 1:1) to afford 14-2 (40 mg, yield: 35%) as a brown solid. LCMS (M+H) + =515.1.

[0436] Step 2

[0437] Compound 14-2 (40 mg, 0.08 mmol), compound 14-2A (20 mg, 0.12 mmol), Pd(dppf)Cl2 (10 mg, 0.02 mmol), and K2CO3 (22 mg, 0.16 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain a white solid 14-3 (23 mg, yield: 50%). LCMS (M+H) + =561.2.

[0438] Step 3

[0439] Compound 14-3 (23 mg, 0.04 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under an ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 14 (7 mg, yield: 38%) as a white solid. LCMS (M+H) + =461.3. 1 HNMR (400MHz, DMSO) δ7.93(d,J=9.0Hz,3H),7.89(d,J=7.2Hz,1H),7.72(dd,J=11.2,1.2Hz,1H),7.48(dt,J=2.8,2.0Hz,2H),7.41(t,J=8.8Hz,1H) ,7.32(d,J=4.8Hz,1H),7.29(d,J=4.8Hz,2H),4.54(s,1H),3.95(s,3H), 3.59(d,J=5.8Hz,2H),2.03(s,1H),2.01–1.86(m,2H),1.83–1.66(m,2H). 19F NMR(376MHz, DMSO)δ-74.12(s,3.9F),-108.26(s,1F),-133.36(s,0.92F).

[0440] Example 15

[0441] Synthesis of trans-4-(8-((1R,3R)-3-aminocyclopentyl)amino)-3-(3-fluoro-4-methoxyphenyl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 15)

[0442]

[0443]

[0444] Step 1

[0445] Compound 15-1 (80 mg, 0.23 mmol) was dissolved in NMP (4 mL), and compound 15-2 (92 mg, 0.46 mmol) and DIPA (148 mg, 1.1 mmol) were added. The reaction mixture was heated to 100°C and stirred for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate and the organic phase was backwashed 3 to 4 times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography (PE:EA=2:1) ​​to obtain compound 15-3 (95 mg, yield: 81%) as a white solid. LCMS (M+H) + =515.0.

[0446] Step 2

[0447] Compound 15-3 (95 mg, 0.2 mmol), compound 15-4 (47 mg, 0.3 mmol), and potassium carbonate (51 mg, 0.37 mmol) were dissolved in a mixture of dioxane (2 mL) and water (0.5 mL). Catalyst Pd(dppf)Cl2 (14 mg, 0.02 mmol) was added under nitrogen. The mixture was heated to 100°C and stirred under nitrogen for 2 hours. The solvent was then concentrated to remove most of the solvent. The crude residue was purified by column chromatography (PE:EA = 1:1) to obtain compound 15-5 (60 mg, yield: 58%) as a white solid. LCMS (M+H) + =561.0.

[0448] Step 3

[0449] Compound 15-5 (60 mg, 0.1 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added dropwise under an ice-water bath. The mixture was stirred at room temperature for 1 hour. The solvent was then concentrated to remove most of the solvent. The crude product was purified by prep-HPLC to obtain compound 15 (22 mg, yield: 45%) as a white solid. LCMS (M+H) + =461.0. 1 H NMR (500MHz, DMSO) δ7.92–7.85(m,4H),7.75–7.70(m,1H),7.48(d,J=9.8Hz,2H),7.44–7.39(m,1H),7.30(s,3H),4.75–4 .70(m,1H),3.96(s,3H),3.76–3.72(m,1H),2.24–2.13(m,3H),2.09–2.03(m,1H),1.82–1.74(m,1H),1.63–1.57(m,1H). 19 F NMR(376MHz, DMSO)δ-74.186(s.4F),-108.317(s,1F),-133.382(s,1F).

[0450] Example 16

[0451] Synthesis of 2-fluoro-4-(3-(3-fluoro-4-methoxyphenyl)-8-(pyrrolidin-3-ylamino)imidazo[1,2-a]pyrazin-2-yl)benzonitrile (Compound 16)

[0452]

[0453] Step 1

[0454] Compound 16-1 (200 mg, 0.57 mmol), 16-1A (106 mg, 0.57 mmol), and DIPEA (147 mg, 1.14 mmol) were dissolved in NMP (5 mL). The reaction system was heated to 120°C and reacted under nitrogen for 4 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (PE:EA = 1:1) to afford 16-2 (100 mg, yield: 35%) as a brown solid. LCMS (M+H) + =501.1.

[0455] Step 2

[0456] Compound 16-2 (100 mg, 0.2 mmol), compound 16-2A (51 mg, 0.3 mmol), Pd(dppf)Cl2 (10 mg, 0.02 mmol), and K2CO3 (55 mg, 0.4 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain 16-3 (38 mg, yield: 35%) as a white solid. LCMS (M+H) + =547.2.

[0457] Step 3

[0458] Compound 16-3 (38 mg, 0.07 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise in an ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was separated by HPLC to obtain compound 16 (7 mg, yield: 22%) as a white solid. LCMS (M+H) + =447.1. 1 HNMR(400MHz, DMSO)δ8.84(s,1H),8.00(d,J=6.8Hz,1H),7.96–7.86(m,1H),7.76–7.67(m,1H),7.48(dd,J=6.6,5.2Hz,2H),7.41(t,J=8.8Hz,1H), 7.35(s,2H),7.30(d,J=8.4Hz,1H),4.80(s,1H),3.95(s,3H),3.48(dd,J= 13.6, 6.8Hz, 2H), 3.35–3.25 (m, 2H), 2.29 (s, 1H), 2.16 (d, J = 20.2Hz, 1H). 19 F NMR(376MHz, DMSO)δ-74.11(s,4.03F),-108.28(s,1F),-133.36(s,0.97F).

[0459] Example 17

[0460] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 17)

[0461]

[0462] Step 1

[0463] Compound 17-1 (15 mg, 0.32 mmol), compound 17-1A (20 mg, 0.04 mmol), Pd(dppf)Cl2 (5 mg, 0.01 mmol), and K2CO3 (5.5 mg, 0.08 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain 17-2 (6 mg, yield: 19%) as a white solid. LCMS (M+H) + =567.0.

[0464] Step 2

[0465] Compound 17-2 (6 mg, 0.01 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise in an ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After concentration, the crude product was separated by HPLC to obtain compound 17 (3 mg, yield: 46%) as a white solid. LCMS (M+H) + =467.3. 1 HNMR (400MHz, DMSO) δ8.51(s,1H),8.09(s,2H),7.95(s,1H),7.84(dd,J=12.4,5.6Hz,2H),7.75(d,J=10.8Hz,1H),7.49(dd,J=8.2,1.2Hz,1H),7.3 8(s,2H),7.22(dd,J=8.8,1.6Hz,1H),5.06(d,J=34.0Hz,2H),4.25(s,3H) ,3.59(d,J=12.8Hz,2H),2.09(s,2H),1.91(s,1H),1.69(d,J=8.4Hz,2H). 19 F NMR(376MHz,DMSO)δ-73.77(s,4.77F),-108.07(s,1F).

[0466] Example 18

[0467] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 18)

[0468]

[0469] Step 1

[0470] Compound 18-1 (300 mg, 1.23 mmol), 18-1A (405 mg, 2.46 mmol), and Cs2CO3 (1.2 g, 3.69 mmol) were dissolved in DMF (10 mL). The reaction system was heated to 60°C and reacted under nitrogen for 2 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and dried by spin chromatography. The product was purified by column chromatography (PE:EA = 2:1) to afford 18-2 (120 mg, yield: 30%) as a white solid. LCMS (M+H) + =330.1.

[0471] Step 2

[0472] Compound 18-2 (60 mg, 0.18 mmol), compound 18-2A (60 mg, 0.12 mmol), Pd(dppf)Cl2 (10 mg, 0.02 mmol), and K2CO3 (50 mg, 0.36 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 110°C and the reaction mixture was reacted under nitrogen for 12 hours. The reaction mixture was concentrated and the crude product was separated by HPLC to obtain a white solid 18-3 (20 mg, yield: 20%). LCMS (M+H) + =638.1.

[0473] Step 3

[0474] Compound 18-3 (20 mg, 0.03 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 18 (3 mg, yield: 19%) as a white solid (LCMS (M+H)). + =538.3. 1 H NMR (400MHz, DMSO) δ8.21 (s, 1H), 8.06 (s, 2H), 7.99 (s, 1H), 7.84 (dd, J = 12. 8,8.0Hz,2H),7.75(d,J=10.8Hz,1H),7.47(d,J=8.2Hz,1H),7.42(d,J=8.6 Hz,1H),7.37(s,2H),5.53(s,2H),5.07(d,J=21.0Hz,2H),3.16(s,3H),2.8 8(s,3H),2.67(s,2H),2.33(s,1H),2.09(s,1H),1.92(s,1H),1.69(s,2H). 19 F NMR(376MHz, DMSO)δ-73.79(s,4.77F),-107.97(s,1F).

[0475] Example 19

[0476] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 19)

[0477]

[0478] Step 1

[0479] Compound 19-1 (1 g, 4.7 mmol) was dissolved in DMF (15 mL), and compound 19-2 (673 mg, 9.35 mmol) and potassium carbonate (1.3 g, 9.35 mmol) were added. The mixture was heated to 110°C and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was concentrated, and the crude product was purified by column chromatography (PE:EA = 1:2) to obtain compound 19-3 (600 mg, yield: 45%) as a white solid. LCMS (M+H) + =287.0.

[0480] Step 2

[0481] A mixture of compound 19-3 (300 mg, 1 mmol), tricyclohexylphosphine (59 mg, 0.2 mmol), compound 19-4 (400 mg, 1.57 mmol), and potassium acetate (290 mg, 2.1 mmol) was dissolved in dioxane (10 mL). Catalyst Pd2(dba)3 (96 mg, 0.1 mmol) was added. The system was purged with nitrogen three times, and the temperature was raised to 100°C for 2 hours. After cooling to room temperature, the solvent was removed by concentration, and the mixture was extracted with water and ethyl acetate. The organic phase was backwashed with saturated brine and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (PE:EA=1:1) to obtain compound 19-5 (200 mg, yield: 76%) as a white solid. LCMS (M+H) + =253.0.

[0482] Step 3

[0483] Compound 19-5 (70 mg, 0.28 mmol) was dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). Compound 19-6 (143 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol), and catalyst Pd(dppf)Cl2 (21 mg, 0.03 mmol) were added. The system was purged with nitrogen three times, and the temperature was raised to 100°C for 2 hours. After cooling to room temperature, the solvent was removed by concentration, and the mixture was extracted with water and ethyl acetate. The organic phase was backwashed with saturated brine and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain compound 7 (100 mg, yield: 56%) as a white solid. LCMS (M+H) + =643.0.

[0484] Step 4

[0485] Compound 19-7 (50 mg, 0.08 mmol) was dissolved in dichloromethane (2 mL). A solution of trifluoroacetic acid (1 mL) in dichloromethane (1 mL) was added dropwise under an ice-water bath. The reaction was stirred at room temperature for 1 hour. The crude product was concentrated and subjected to prep-HPLC to afford compound 19 (27 mg, yield: 64%) as a white solid. LCMS (M+H) + =543.0. 1 H NMR (400MHz, DMSO) δ8.23(s,1H),8.12–8.01(m,4H),7.91–7.83(m,2H),7.81–7.75(m,1H),7.49–7.34(m,3H),5.18–4.90(m,2H),4.46 –4.31(m,2H),3.42–3.30(m,2H),2.43–2.21(m,1H),2.17–2.02(m,1H),1.98–1.82(m,1H),1.77–1.62(m,2H),1.20(d,J=19.3Hz,6H). 19 FNMR(376MHz,DMSO)δ-73.94(s,3F),-107.80(s,1F),-116.61(s,1F).

[0486] Example 20

[0487] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 20)

[0488]

[0489] Step 1

[0490] Compound 20-1 (1 g, 5.1 mmol), 20-1A (1.8 g, 25.5 mmol), and K2CO3 (1.4 g, 10.2 mmol) were dissolved in DMF (15 mL). The reaction system was heated to 100°C and microwave-treated for 2 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 100 mL), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (PE:EA = 1:2) to afford 20-2 (250 mg, yield: 18%) as a white solid. LCMS (M+H) + =270.1.

[0491] Step 2

[0492] Compound 20-2 (250 mg, 0.93 mmol), compound 20-2A (354 mg, 1.4 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), tricyclohexylphosphine (56 mg, 0.2 mmol), and potassium acetate (176 mg, 1.8 mmol) were dissolved in 1,4-dioxane (15 mL). The reaction system was heated to 110°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 20-3 (100 mg, yield: 46%). LCMS (M+H) + =236.0.

[0493] Step 3

[0494] Compound 20-3 (100 mg, 0.45 mmol), compound 20-3A (154 mg, 0.3 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), and K2CO3 (83 mg, 0.6 mmol) were dissolved in 1,4-dioxane / H2O (4 / 0.5 mL). The reaction system was heated to 110°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 20-4 (50 mg, yield: 27%). LCMS (M+H) + =626.2.

[0495] Step 4

[0496] Compound 20-4 (50 mg, 0.08 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 20 (22 mg, yield: 52%) as a white solid (LCMS (M+H)). + =526.3.

[0497] 1 H NMR (400MHz, DMSO) δ8.30 (s, 1H), 8.15 (d, J = 8.7Hz, 4H), 7.86–7.79 (m, 1H), 7.77–7.7 0(m,1H),7.58(dd,J=8.6,1.4Hz,1H),7.44(dd,J=8.2,1.4Hz,1H),7.42–7.35(m,2H), 5.15(d,J=11.3Hz,1H),5.05(d,J=12.5Hz,1H),4.72(s,2H),3.65–3.52(m,2H),3.37( s,1H),2.09(s,1H),1.91(d,J=4.5Hz,1H),1.69(dd,J=17.6,9.4Hz,2H),1.23(s,6H). 19 F NMR(376MHz, DMSO)δ-74.17(s,3F),-107.97(s,1F).

[0498] Example 21

[0499] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(6-fluoro-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 21)

[0500]

[0501] Step 1

[0502] Compound 21-1 (1 g, 4.7 mmol) was dissolved in DMF (15 mL), and compound 21-2 (673 mg, 9.35 mmol) and potassium carbonate (1.3 g, 9.35 mmol) were added. The mixture was heated to 110°C and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was concentrated, and the crude product was purified by column chromatography (PE:EA = 1:2) to obtain compound 21-3 (450 mg, yield: 34%) as a white solid. LCMS (M+H) + =287.0.

[0503] Step 2

[0504] A mixture of compound 21-3 (390 mg, 1.4 mmol), tricyclohexylphosphine (77 mg, 0.3 mmol), compound 21-4 (520 mg, 2 mmol), and potassium acetate (377 mg, 2.7 mmol) was dissolved in dioxane (10 mL), and catalyst Pd2(dba)3 (125 mg, 0.14 mmol) was added. The system was purged with nitrogen three times, and the temperature was raised to 100°C for 2 hours. After cooling to room temperature, the solvent was removed by concentration, and the mixture was extracted with water and ethyl acetate. The organic phase was backwashed with saturated brine and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (PE:EA=1:1) to obtain compound 21-5 (180 mg, yield: 52%) as a white solid. LCMS (M+H) + =253.0.

[0505] Step 3

[0506] Compound 21-5 (100 mg, 0.4 mmol) was dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). Compound 21-6 (204 mg, 0.4 mmol), potassium carbonate (110 mg, 0.8 mmol), and catalyst Pd(dppf)Cl2 (29 mg, 0.04 mmol) were added. The system was purged with nitrogen three times, and the temperature was raised to 100°C for 2 hours. After cooling to room temperature, the solvent was removed by concentration, and the mixture was extracted with water and ethyl acetate. The organic phase was backwashed with saturated brine and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (PE:EA=1:1) to obtain compound 21-7 (200 mg, yield: 79%) as a white solid. LCMS (M+H) + =643.0.

[0507] Step 4

[0508] Compound 21-7 (30 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL). A solution of trifluoroacetic acid (0.5 mL) in dichloromethane (1 mL) was added dropwise under an ice-water bath. The reaction was stirred at room temperature for 1 hour. The crude product was concentrated and subjected to prep-HPLC to afford compound 21 (8 mg, yield: 32%) as a white solid. LCMS (M+H) + =543.0. 1H NMR (400MHz, DMSO) δ8.54–8.49(m,1H),8.18–8.05(m,4H),7.91–7.85(m,1 H),7.84–7.77(m,1H),7.77–7.69(m,1H),7.52–7.45(m,1H),7.41(s,2H),5 .22–4.81(m,3H),4.40(s,2H),3.44–3.31(m,2H),2.40–2.26(m,1H),2.14– 2.04(m,1H),1.98–1.86(m,1H),1.78–1.63(m,2H),1.17(d,J=18.3Hz,6H). 19 F NMR(376MHz, DMSO)δ-73.69(s,3F),-108.02(s,1F),-118.02(s,1F).

[0509] Example 22

[0510] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 22)

[0511]

[0512]

[0513] Step 1

[0514] Compound 22-1 (800 mg, 3 mmol) was dissolved in THF (6 mL). 6 mL of a 1 M solution of methylmagnesium bromide (22-2) (6 mmol) in tetrahydrofuran was added dropwise at -40°C. After the addition was complete, the mixture was allowed to stir at room temperature for 2 hours. Saturated ammonium chloride solution was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate and the organic phase was backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by SGC (PE:EA=3:1) to give compound 22-3 (600 mg, yield: 79%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.49–7.44 (m, 1H), 7.02 (dd, J=9.6, 1.9 Hz, 1H), 6.90 (dd, J=8.2, 1.9 Hz, 1H), 2.73 (s, 2H), 1.23 (s, 6H).

[0515] Step 2

[0516] Compound 22-3 (20 mg, 0.08 mmol) and compound 22-4 (25 mg, 0.1 mmol) were dissolved in dioxane (5 mL), potassium acetate (16 mg, 0.163 mmol) and Pd(dppf)Cl2 (6 mg, 0.008 mmol) were added, and the reaction system was purged with nitrogen three times. The mixture was heated under reflux and reacted overnight. After cooling to room temperature, the solvent was removed by concentration. The crude product was purified by SGC (PE:EA = 2:1) to obtain compound 22-5 (18 mg, yield: 75%) as a white solid. LCMS (M+H) + =295.0.

[0517] Step 3

[0518] Compound 22-5 (18 mg, 0.06 mmol), compound 22-6 (47 mg, 0.09 mmol), and potassium carbonate (25 mg, 0.18 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (1 mL). Pd(dppf)Cl2 (5 mg, 0.006 mmol) was added, and the reaction system was purged with nitrogen three times. The reaction was heated to 100°C for 3 hours, and the solvent was removed by concentration. The crude product was purified by prep-HPLC to obtain compound 22-7 (30 mg, yield: 81%) as a white solid. LCMS (M+H) + =603.0.

[0519] Step 4

[0520] Compound 22-7 (30 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated to obtain a crude residue, which was purified by prep-HPLC to obtain white solid compound 22 (5.5 mg, yield: 22%). LCMS (M+H) + =503.0.1H NMR (400MHz, DMSO) δ8.17–8.01(m,3H),7.95–7.89(m,1H),7.73–7.65(m,1H),7.56–7.50(m,1H),7.49–7.41(m,2H),7.40–7.28(m,3H),5.14–4 .83(m,2H),3.43–3.28(m,2H),2.87–2.77(m,2H),2.37–2.22(m,1H),2. 14–2.02(m,1H),1.97–1.84(m,1H),1.76–1.63(m,2H),1.15(s,6H).19F NMR(376MHz,DMSO)δ-73.836(s,3F),-107.991(s,1F),-114.191(s,1F).

[0521] Example 23

[0522] Synthesis of (S)-4-(8-(3-aminopiperidin-1-yl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 23)

[0523]

[0524] Step 1

[0525] A mixture of compound 23-1 (225 mg, 0.64 mmol), compound 23-2 (155 mg, 0.77 mmol), DIPA (166 mg, 1.3 mmol), and NMP (5 mL) was heated to 100°C and stirred for 1 hour. After cooling to room temperature, the reaction solution was added dropwise to ice water and extracted with ethyl acetate. The crude product was concentrated and purified by SGC (DCM:MeOH=20:1) to obtain compound 23-3 (50 mg, yield: 15%) as a white solid. LCMS (M+H) + =515.0.

[0526] Step 2

[0527] Compound 23-3 (25 mg, 0.05 mmol), compound 23-4 (13 mg, 0.05 mmol), and potassium carbonate (71 mg, 0.5 mmol) in an aqueous solution (0.5 mL) were dissolved in dioxane (1 mL). Tetrakistriphenylphosphine palladium (6 mg, 0.005 mmol) was added. The reaction system was purged with nitrogen three times, heated to 100°C and microwaved for 15 minutes. The solvent was then concentrated and removed. The crude product was purified by SGC (PE:EA = 1:1) to afford compound 23-5 (20 mg, yield: 64%) as a white solid. LCMS (M+H) = 644.0.

[0528] Step 3

[0529] Compound 23-5 (20 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated to obtain a crude residue, which was purified by prep-HPLC to obtain white solid compound 23 (5 mg, yield: 30%). LCMS (M+H) +=544.0.1H NMR (400MHz, DMSO) δ8.47–8.43(m,1H),8.07(s,4H),7.88–7.83(m,1H),7.82–7.77(m,1H),7.43(s,3H),5.12–4.95(m,2 H),4.69(s,2H),3.48–3.28(m,3H),2.12–2.07(m,1H),1.94–1.88(m,1H),1.75–1.66(m,2H),1.23(d,J=25.0Hz,6H).19F NMR(376MHz, DMSO)δ-74.185(s,4.26F),-107.739(s,1F),-114.368(s,1F).

[0530] Example 24

[0531] Synthesis of (R)-4-(8-(3-aminopyrrolidin-1-yl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 24)

[0532]

[0533] Step 1

[0534] Compound 24-1 (300 mg, 0.857 mmol) was dissolved in NMP (3 mL), and compound 24-2 (192 mg, 1.0 mmol) and DIPA (222 mg, 1.714 mmol) were added. The mixture was heated to 120°C and stirred for 2 hours. The mixture was then cooled to room temperature and quenched by adding ice water under an ice-water bath. The mixture was extracted with ethyl acetate, and the organic phase was backwashed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by SGC (PE:EA=1:1) to obtain compound 24-3 (110 mg, yield: 26%) as a white solid. LCMS (M+H) + =501.0.

[0535] Step 2

[0536] Compound 24-3 (70 mg, 0.14 mmol), compound 24-4 (54 mg, 0.21 mmol), and potassium carbonate (39 mg, 0.28 mmol) were dissolved in a mixed solvent of dioxane (2 mL) and water (0.5 mL). Tetrakistriphenylphosphine palladium (17 mg, 0.014 mmol) was added, and the reaction system was purged with nitrogen three times. The mixture was heated to 130°C for 2 hours in a microwave oven. After cooling, the solvent was removed by concentration. The crude product was purified by prep-HPLC to afford compound 24-5 (10 mg, yield: 11%) as a white solid. LCMS (M+H) = 630.0.

[0537] Step 3

[0538] Compound 24-5 (10 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated to obtain a crude residue, which was purified by prep-HPLC to obtain a white solid compound 24 (0.9 mg, yield: 9%). LCMS (M+H) + =530.0.1HNMR(400MHz,DMSO)δ8.51–8.41(m,1H),8.26–8.03(m,4H),7.93–7.83(m,1H),7.78–7.69(m,1H),7.45–7.41(m,1H),7.41–7.28(m, 2H),4.99–4.86(m,1H),4.73–4.66(m,2H),4.09–3.96(m,2H),2.62–2. 56(m,1H),2.43–2.31(m,2H),2.21–2.10(m,1H),1.29–1.17(m,6H).19F NMR(376MHz,DMSO)δ-73.659(s,6F),-107.878(s,1F),-114.446(s,1F).

[0539] Example 25

[0540] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(6-fluoro-1-((1-hydroxycyclobutyl)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 25)

[0541]

[0542] Step 1

[0543] Compound 25-1 (268 mg, 1.25 mmol), 25-2 (210 mg, 2.5 mmol), and K2CO3 (345 mg, 2.5 mmol) were dissolved in DMF (5 mL). The reaction system was heated to 100°C and allowed to react for 2 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (PE:EA = 1:1) to afford 25-3 (140 mg, yield: 38%) as a white solid. LCMS (M+H) + =300.1.

[0544] Step 2

[0545] Compound 25-3 (140 mg, 0.47 mmol), bisborane (238 mg, 0.94 mmol), Pd2(dba)3 (129 mg, 0.14 mmol), tricyclohexylphosphine (78 mg, 0.28 mmol), and potassium acetate (135 mg, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction system was heated to 125°C and the reaction solution was reacted under nitrogen for 1 h. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 25-4 (45 mg, yield: 36%). LCMS (M+H) + =266.0.

[0546] Step 3

[0547] Compound 25-4 (45 mg, 0.17 mmol), compound 25-5 (87 mg, 0.17 mmol), Pd(PPh3)4 (39 mg, 0.03 mmol), and 1M K2CO3 aqueous solution (1 mL) were dissolved in 1,4-dioxane (2 mL). The reaction system was heated to 110°C MW and the reaction solution was reacted under nitrogen for 30 min. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 25-6 (15 mg, yield: 13%). LCMS (M+H) + =656.2.

[0548] Step 4

[0549] Compound 25-6 (15 mg, 0.02 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 25 (12 mg, yield: 100%) as a white solid (LCMS (M+H)). +=556.3.1H NMR (400MHz, DMSO) δ8.45(d,J=5.9Hz,1H),8.08–8.00(m,3H),7.89–7.83(m,1H),7.80(d,J=8.6Hz,1H),7.47–7.36(m,3H),5.60(s,1H),5.08(s ,2H),4.90(dd,J=25.0,10.6Hz,3H),3.70(d,J=20.8Hz,2H),2.24(d,J=5.3Hz,2H),2.06(d,J=12.2Hz,2H),1.91(s,2H),1.78–1.66(m,4H).19F NMR(376MHz,DMSO)δ-73.87(s,3F),-107.68(s,1F),-114.31(s,1F).

[0550] Compound 26

[0551] Synthesis of (S)-4-(8-(3-aminopiperidin-1-yl)-3-(1-(2-ethyl-2-hydroxybutyl)-6-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 26)

[0552]

[0553]

[0554] Step 1

[0555] Compound 26-1 (71 mg, 0.33 mmol), 26-2 (110 mg, 1.10 mmol), and K2CO3 (91 mg, 0.66 mmol) were dissolved in DMF (2 mL). The reaction system was heated to 100°C and microwave-treated for 1 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, and spin-dried. The product was purified by column chromatography (PE:EA = 1:1) to afford 26-3 (60 mg, yield: 57%) as a white solid. LCMS (M+H) + =316.1.

[0556] Step 2

[0557] Compound 26-3 (50 mg, 0.16 mmol), bisborane (81 mg, 0.32 mmol), Pd2(dba)3 (27 mg, 0.03 mmol), tricyclohexylphosphine (17 mg, 0.06 mmol), and potassium acetate (47 mg, 0.48 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction system was heated to 110°C and the reaction solution was microwave-treated under nitrogen for 1 h. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 26-4 (20 mg, yield: 44%). LCMS (M+H) + =288.0.

[0558] Step 3

[0559] Compound 26-4 (20 mg, 0.07 mmol), compound 26-5 (36 mg, 0.07 mmol), Pd(PPh3)4 (2 mg, 0.02 mmol), and 1M K2CO3 aqueous solution (1 mL) were dissolved in 1,4-dioxane (2 mL). The reaction system was heated to 110°C MW and the reaction solution was reacted under nitrogen for 15 minutes. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 26-6 (5 mg, yield: 13%). LCMS (M+H) + =672.2.

[0560] Step 4

[0561] Compound 26-6 (5 mg, 0.01 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under an ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 26 (2.7 mg, yield: 63%) as a white solid (LCMS (M+H)). + =572.3.1H NMR(400MHz,DMSO)δ8.45(s,1H),8.09(s,4H),7.86(s,1H),7.81(s,1H),7.42(s,3H),5.10(s,1H),4.96(s,1H),4.69( s,2H),3.41–3.31(m,3H),2.09(s,2H),1.91(s,2H),1.70(s,2H),1.48(s,2H),1.39(s,2H),0.94(d,J=7.1Hz,6H).19F NMR(376MHz,DMSO)δ-73.83(s,7F),-107.69(s,1F),-114.52(s,1F).

[0562] Compound 27

[0563] Synthesis of 4-(8-(rel-(1S,2S,4R)-2-amino-7-azabicyclo[2.2.1]heptane-7-yl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 27)

[0564]

[0565] Step 1

[0566] Compound 27-1 (400 mg, 1.14 mmol), 27-2 (relative configuration) (240 mg, 0.76 mmol), DMAP (12 mg, 0.1 mmol), and DIPEA (196 mg, 1.52 mmol) were dissolved in NMP (8 mL). The reaction system was heated to 120°C and microwave-treated for 30 min. The reaction system was quenched with water, extracted with ethyl acetate (3 x 100 mL), dried over anhydrous sodium sulfate, and dried by spin drying. The product was purified by column chromatography (PE:EA = 1:2) to afford 27-3 (100 mg, yield: 25%) as a white solid. LCMS (M+H) + =527.1.

[0567] Step 2

[0568] Compound 27-3 (100 mg, 0.19 mmol), compound 27-4 (70 mg, 0.28 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and 1M K2CO3 aqueous solution (1 mL) were dissolved in 1,4-dioxane (2 mL). The reaction system was heated to 110°C (MW) and the reaction solution was reacted under nitrogen for 15 minutes. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 27-5 (30 mg, yield: 24%). LCMS (M+H) + =656.2.

[0569] Step 4

[0570] Compound 27-5 (30 mg, 0.04 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 27 (20.5 mg, yield: 82%) as a white solid (LCMS (M+H)). +=556.3.1H NMR (400MHz, DMSO) δ8.43(t,J=6.0Hz,1H),8.22(s,2H),8.14(d,J=9.7Hz,1H),7.91–7 .84(m,1H),7.79(d,J=10.8Hz,1H),7.60(d,J=4.6Hz,1H),7.45(d,J=4.8Hz,2H),5.78 (s,1H),4.73(s,2H),3.98(s,2H),3.71(s,1H),2.32(d,J=7.5Hz,1H),1.95(d,J=11.1 Hz,1H),1.85(s,2H),1.73(d,J=11.6Hz,1H),1.45(d,J=11.8Hz,1H),1.25(s,6H).19F NMR(376MHz, DMSO)δ-74.23(s,4F),-107.77(s,1F),-115.39(s,1F).

[0571] Example 28

[0572] Synthesis of ((1R,3r,5S)-8-(2-(4-cyano-3-fluorophenyl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-8-yl)-8-azabicyclo[3.2.1]octan-3-yl)carbamate (Compound 28)

[0573]

[0574] Step 1

[0575] Compound 28-1 (387 mg, 1.11 mmol), 28-2 (250 mg, 1.11 mmol), and K2CO3 (306 mg, 2.22 mmol) were dissolved in NMP (8 mL). The reaction system was heated to 120°C and allowed to react for 2 h. The reaction system was quenched with water, extracted with ethyl acetate (3 x 100 mL), dried over anhydrous sodium sulfate, and spin-dried. The mixture was purified by column chromatography (PE:EA = 1:2) to afford 28-3 (100 mg, yield: 17%) as a white solid. LCMS (M+H) + =541.1.

[0576] Step 2

[0577] Compound 28-3 (100 mg, 0.19 mmol), compound 28-4 (70 mg, 0.28 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and 1M K2CO3 aqueous solution (1 mL) were dissolved in 1,4-dioxane (2 mL). The reaction system was heated to 110°C (MW) and the reaction solution was reacted under nitrogen for 30 min. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 28-5 (12 mg, yield: 9%). LCMS (M+H) + =670.2.

[0578] Step 4

[0579] Compound 28-5 (12 mg, 0.02 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under an ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 28 (8.9 mg, yield: 87%) as a white solid (LCMS (M+H)). + =570.3.1H NMR (400MHz, DMSO) δ8.43(d,J=6.3Hz,1H),8.08(d,J=9.2Hz,1H),7.85(d,J=7.4Hz,3H),7.74(d ,J=11.4Hz,1H),7.45(d,J=8.6Hz,1H),7.39(dd,J=10.8,4.7Hz,2H),4.96(s,1H),4.69(s,2H),3 .28–3.24(m,1H),2.67(s,1H),2.33(s,1H),2.19(s,2H),2.02(s,2H),1.76(d,J=14.8Hz,2H),1 .26(s,3H),1.20(s,3H).19FNMR(376MHz,DMSO)δ-73.8(s,9F),-107.73(s,1F),-114.27(s,1F).

[0580] Example 29

[0581] Synthesis of (R)-4-(8-(3-aminopiperidin-1-yl)-3-(6-fluoro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)imidazo[1,2-a]pyrazin-2-yl)-2-fluorobenzonitrile (Compound 30)

[0582]

[0583] Step 1

[0584] Compound 30-1 (130 mg, 0.56 mmol), bisborane (286 mg, 1.12 mmol), Pd2(dba)3 (64 mg, 0.06 mmol), tricyclohexylphosphine (40 mg, 0.12 mmol), and potassium acetate (117 mg, 1.12 mmol) were dissolved in 1,4-dioxane (15 mL). The reaction system was heated to 110°C and the reaction solution was reacted under nitrogen for 12 hours. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 30-2 (85 mg, yield: 78%). LCMS (M+H) + =196.0.

[0585] Step 2

[0586] Compound 30-2 (85 mg, 0.45 mmol), compound 30-3 (154 mg, 0.3 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol), and K2CO3 (83 mg, 0.6 mmol) were dissolved in 1,4-dioxane / H2O (4 / 0.5 mL). The reaction system was heated to 110°C and the reaction solution was reacted under nitrogen for 30 min. The reaction solution was concentrated and the crude product was separated by HPLC to obtain a white solid 30-4 (25 mg, yield: 14%). LCMS (M+H) + =586.2.

[0587] Step 3

[0588] Compound 30-4 (25 mg, 0.04 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added dropwise under ice-water bath. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction mixture was concentrated, the crude product was separated by HPLC to obtain compound 30 (18 mg, yield: 93%) as a white solid (LCMS (M+H)). + =486.2.1H NMR (400MHz, DMSO) δ8.48–8.43(m,1H),8.17(d,J=9.1Hz,1H),8.07(s,2H),7.82(dd,J=16.7,9.2Hz,2H),7.42(d,J=4.9Hz,3H ),5.03(dd,J=43.4,15.6Hz,2H),4.39(s,3H),3.68(d,J=10.6Hz,2H),3.39(s,1H),2.09(s,1H),1.92(s,1H),1.71(s,2H).19F NMR(376MHz,DMSO)δ-73.87(s,3F),-107.68(s,1F),

[0589] -114.31(s,1F).

[0590] Activity Test Example

[0591] In the following examples, the inventors took some of the compounds of the present invention as examples to detect the LSD1 inhibitory activity and pharmacokinetic properties of the compounds of the present invention.

[0592] Example A: LSD1 inhibitory activity

[0593] The purpose of this experiment is to detect the in vitro inhibitory activity of the compounds of the present invention on LSD1.

[0594] Experimental Procedure and Methods: This experiment uses the AlphaScreen method to test the in vitro enzyme inhibitory activity of the compounds of the present invention against LSD1. The experimental procedures are as follows:

[0595] a) Prepare 1x buffer

[0596] Prepare 1x buffer (modified Tris buffer)

[0597] b) Compound serial dilution

[0598] Compounds of the invention were transferred to multiwell plates using an Echo, with a final DMSO concentration of 1%.

[0599] c) Prepare enzyme solution

[0600] Prepare enzyme solution in 1x buffer.

[0601] d) Prepare substrate solution

[0602] Prepare substrate solution by adding peptide in 1x buffer.

[0603] e) Transfer 5 μL of enzyme solution or 1x buffer to a multiwell plate.

[0604] f) Incubate at room temperature for 15 minutes

[0605] g) Add 5 μL of substrate solution to each well to start the reaction

[0606] h) Incubate at room temperature for 40 minutes

[0607] i) Prepare 1x Alphalisa buffer

[0608] j) Prepare 1x Alphalisa buffer solutions of acceptor and donor

[0609] Add 15 μL of acceptor and donor solutions and incubate at room temperature for 60 min in a dark environment.

[0610] k) Read endpoints using EnSpire Alpha mode

[0611] l) Data processing

[0612] Calculate the inhibition value using Equation 1:

[0613] Equation 1: Inh% = (Max-Signal) / (Max-Min)*100

[0614] Using XL-Fit, calculate the IC50 using Equation 2:

[0615] Equation 2: Y = Bottom + (Top - Bottom) / (1 + (IC50 / X) * Hill Slope)

[0616] Y is the inhibition rate, and X is the concentration of the compound.

[0617] Table 1 shows the experimental data of the LSD1 inhibitory activity of some compounds of the present invention.

[0618] Table 1:

[0619]

[0620]

[0621] The experimental results show that the compound of the present invention has good LSD1 inhibitory activity.

[0622] Example B: Pharmacokinetic evaluation of the compound of the present invention after intravenous or oral administration in mice

[0623] The purpose of this experiment is to test the pharmacokinetic properties of the compound of the present invention in mice

[0624] Experimental steps and methods:

[0625] The test compound was dissolved in 10% DMSO / 10% Solutol HS15 / 80% saline, vortexed and sonicated to obtain a clear solution of the appropriate concentration, which was then filtered through a microporous filter and used for later use. CD-1 mice weighing 21 to 27 grams were administered the test compound solution intravenously at a dose of 5 mg / kg. The test compound was dissolved in 10% DMSO / 10% Solutol HS15 / 80% saline, vortexed and sonicated to obtain a clear solution of the appropriate concentration, which was then filtered through a microporous filter and used for later use. CD-1 mice weighing 21 to 27 grams were administered the test compound solution orally at a dose of 5 mg / kg. Whole blood was collected at specific time points, and plasma was prepared. Drug concentrations were analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

[0626] The experimental results show that the compound of the present invention has a large exposure amount in the test animals, is well absorbed, and has significant advantages in its pharmacokinetic properties.

[0627] Example C: hERG inhibitory activity

[0628] The purpose of this experiment is to detect the inhibitory activity of the compounds of the present invention on hERG in vitro.

[0629] Experimental steps and methods:

[0630] This method uses a HEKA EPC 10 USB patch clamp amplifier (HEKA Elektronik, Germany) for whole-cell recording. The coverslip carrying a large number of single CHO hERG cells on the surface is removed and placed in a continuous perfusion (about 1 ml / min) and loaded into the recording tank of an inverted microscope. The hERG channel current of a single cell is recorded using a standard whole-cell recording method. The cell is voltage-clamped to a fixed voltage of -80mV. The hERG current is activated by depolarizing at +20mV for 5 seconds, and then the current is changed back to -50mV and held for 5 seconds to remove the passivation effect and observe the deactivated tail current. The potassium ion tail current observed in the hERG channel in this step is stabilized by continuous perfusion. The cells are then treated with the drug of the present invention until steady state is reached. Steady state is considered to be reached when three consecutive superimposable currents are recorded. At this time point, the cells are treated again with an extracellular solvent until the current amplitude returns to a level close to that before administration. Cisapride is used in control experiments to verify that the quality and response of hERG cells are in normal state.

[0631] Table 2 shows the experimental data of the hERG inhibitory activity of some compounds of the present invention.

[0632] Table 2:

[0633] Compound hERG inhibition rate (%@10μM) 12 27.01 18 43.72 20 26.74

[0634] The experimental results show that the compound of the present invention has low hERG inhibitory activity.

[0635] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of the technical features being referred to. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "plurality" means at least two, such as two, three, etc., unless otherwise specifically defined.

[0636] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0637] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound which is a stereoisomer of a compound represented by formula (IV), formula (V), formula (VI) or formula (VII), or a pharmaceutically acceptable salt thereof, in, X is N; X1 and X3 are selected from N, and X2 and X4 are selected from C; X5, X6, and X7 are all C, or X5 is empty, and X6 and X7 are selected from N; X8 is O, S, C or N; n is 0, 1, 2, 3 or 4; R1, R2 and the X to which they are attached together form a heterocyclic ring consisting of 3 to 12 atoms; wherein the heterocyclic ring consisting of 3 to 12 atoms formed by R1, R2 and the X to which they are attached together are independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R'; R4 is F, Cl, or Br; Each R' is independently H, deuterium, F, Cl, Br, -NR b R c , a heterocyclic group consisting of 3-12 atoms; Each R" is independently H, deuterium, F, Cl, Br, -OR a 、C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-12 atoms, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-12 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, the substituents being independently selected from deuterium, F, Cl, Br, -NR b R c 、-OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c ; R a H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, R b 、R c are independently H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, or R b 、R c Together with the nitrogen atom to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms.

2. The compound according to claim 1, which has a structure represented by formula (VIII) or formula (IX): in, Ring A is a heterocyclic ring composed of 3 to 6 atoms; Ring B is a bridged ring composed of 6 to 8 atoms; m is 0, 1, 2, or 3; n is 1, 2, 3 or 4; R″ is F, Cl, Br, C 1-6 Alkyl, C 3-8 Cycloalkyl, wherein the C 1-6 Alkyl, C 3-8 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, -OR a 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

3. The compound according to claim 1, which has a structure represented by formula (X) or formula (XI): in, Ring A is a heterocyclic ring composed of 3 to 6 atoms; Ring B is a bridged ring composed of 6 to 8 atoms; m is 0, 1, 2, or 3; n is 0, 1, 2, 3 or 4.

4. The compound according to claim 1, wherein R1, R2 and the X to which they are attached together form a heterocyclic ring consisting of 3-8 atoms; wherein, The R1, R2 and the X to which they are connected together form a heterocyclic ring consisting of 3 to 8 atoms, which are independently unsubstituted or substituted by 1, 2 or 3 R's. The compound according to any one of claims 1 to 3, wherein R4 is F.

6. The compound according to any one of claims 1 to 3, wherein each R' is independently -NR b R c , R b 、R c are independently H, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

7. The compound according to any one of claims 1 and 3, wherein each R" is independently F, Cl, Br, -OR a 、C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, -OR a or -CO-NR b R c .

8. The compound according to claim 2, wherein R" is F, C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from -OR a , or -CO-NR b R c .

9. The compound according to claim 1, wherein each of the compounds is independently unsubstituted or substituted with 1 or 2 R".

10. The compound according to any one of claims 1 and 3, wherein each R" is independently H, deuterium, F, Cl, Br, -OR a 、C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Haloalkyl or -CO-NR b R c .

11. The compound according to claim 2, wherein R" is C 1-3 Alkyl, C 3-6 Cycloalkyl, wherein the C 1-3 Alkyl, C 3-6 Each cycloalkyl group is independently unsubstituted or substituted with 1 or 2 substituents independently selected from -OR a , or -CO-NR b R c .

12. The compound according to any one of claims 1 to 3, wherein R a H, R b 、R c are independently H, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C 1-3 Haloalkyl, or R b 、R c Together with the nitrogen atom to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms.

13. A compound having one of the following structures: or their stereoisomers, or pharmaceutically acceptable salts.

14. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 13. The pharmaceutical composition according to claim 14 , further comprising: a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

16. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to any one of claims 14 to 15 in the preparation of a medicament, wherein the medicament is used to prevent, treat or alleviate a disease associated with overexpression or overactivity of LSD1 in a patient. The use according to claim 16 , wherein the disease associated with LSD1 overexpression is a tumor.

18. The use according to claim 17, wherein the tumor is papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer or non-Hodgkin's lymphoma.

19. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to any one of claims 14 to 15 in the preparation of a medicament, wherein the medicament is used to inhibit LSD1.

20. Use of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to any one of claims 14 to 15 in the preparation of an LSD1 inhibitor.

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