Pyrrolo[2,3-d]pyrimidine or pyrazolo[3,4-d]pyrimidine derivatives and their uses

Abstract

The invention provides a compound, which is a stereoisomer, tautomer, deuterated compound, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I) or the compound having the structure represented by formula (I).

Description

Technical Field

[0001] The present invention relates to the field of medicine. Specifically, the present invention relates to pyrrolo[2,3-d]pyrimidine or pyrazolo[3,4-d]pyrimidine derivatives as LSD1 inhibitors and their uses. Background Art

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

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

[0004] LSD1 has been found to be dysregulated and overexpressed in various cancers, including acute myeloid leukemia, small cell lung cancer, breast cancer, colorectal cancer, etc. Especially those cancer types showing differentiation arrest, and the knockout of LSD1 shows effects such as inducing differentiation and inhibiting proliferation in various cancer subtypes. Therefore, LSD1 inhibitors have great potential for the treatment of various cancers clinically.

[0005] The early studied LSD1 inhibitors generally have the structure of phenylcyclopropylamine, which can covalently bind to flavin adenine dinucleotide (FAD) in the amine oxidase domain (AO) of LSD1, thereby irreversibly inhibiting the enzyme function. However, due to the key role of LSD1 in hematopoietic and embryonic stem cells, irreversible LSD1 inhibitors may show certain target-related toxicities. Currently, at least 5 irreversible LSD1 inhibitors (including INCB-59872, Bomedemstat, GSK-2879552, ladademstat, and Vafidemstat) have entered clinical studies to treat cancers such as small cell lung cancer and acute myeloid leukemia alone or in combination with other drugs. As mentioned above, irreversible LSD1 inhibitors covalently bind to FAD and easily affect embryonic stem cells and hematopoietic function, thus producing target-related side effects.

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

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

[0008] The present invention provides a reversible LSD1 inhibitor with a novel structure, which has high LSD1 inhibitory activity and can be used for the treatment of various hematological tumors and solid tumors.

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

[0010]

[0011] wherein, X1, X2, X3 and X4 are each independently selected from C or N;

[0012] Y is -(CH2) n -, O or N;

[0013] R1 is C 6-10 aryl or heteroaryl composed of 5-10 atoms, wherein the C 6-10 aryl and heteroaryl composed of 5-10 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R';

[0014] R2 is H, deuterium, C 1-6 alkyl, C 3-12 carbocyclic group, C 3-12 carbocyclic group-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, wherein the C 1-6 alkyl, C 3-12 carbocyclic group, C 3-12 carbocyclic group-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 1-4Each alkylene group is independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R″ groups;

[0015] R3 is H, deuterium, F, Cl, Br, CN, NO2, -OR a , -NR b R c , C 1-6 alkyl;

[0016] Each R′ and 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, a heterocyclic group composed of 3 - 12 atoms, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, a heterocyclic group composed of 3 - 12 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, CN, ═O, -OR a , -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, a heterocyclic group composed of 3 - 6 atoms or -CO-NR b R c ;

[0017] R a , R b , R c are each independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, a heterocyclic group composed of 3 - 6 atoms or R b , R c together with the nitrogen atom to which they are attached form a heterocyclic ring composed of 3 - 6 atoms, wherein the C 1-6 alkyl and the heterocyclic group composed of 3 - 6 atoms are independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, CN, OH, NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;

[0018] n is an integer between 0 and 6.

[0019] The compound represented by formula (I) according to an embodiment of the present invention is a reversible LSD1 inhibitor with a novel structure and has high LSD1 inhibitory activity.

[0020] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compound having the structure represented by formula (II):

[0021]

[0022] wherein Y, X1, X2, X3, X4, R1, R2, and R3 have the definitions as described in the present invention.

[0023] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compound having the structure represented by formula (III):

[0024]

[0025] wherein X1, X2, X3, X4, R1, R2, and R3 have the definitions as described in the present invention.

[0026] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compound having the structure represented by formula (IV):

[0027]

[0028] wherein n1 is 1, 2, or 3; Rn1 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ;

[0029] m1 is 0, 1, 2, 3, or 4;

[0030] X1, X2, X3, X4, R1, R3, R a , R b , R c have the definitions as described in the present invention.

[0031] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compound having the structure represented by formula (V):

[0032]

[0033] wherein, n2 is 1, 2 or 3; Rn2 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ; m2 is 0, 1, 2, 3 or 4;

[0034] X1, X2, X3, X4, R1, R3, R a , R b , R c have the definitions as described in the present invention.

[0035] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds having the structure shown in formula (VI):

[0036]

[0037] wherein, n3 is 1, 2 or 3; Rn3 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ; m3 is 0, 1, 2, 3 or 4;

[0038] X1, X2, X3, X4, R1, R3, R a , R b , R c have the definitions as described in the present invention.

[0039] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds having the structure shown in formula (VII):

[0040]

[0041] wherein, n4 is 1, 2 or 3; Rn4 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ; m4 is 0, 1, 2, 3 or 4;

[0042] X1, X2, X3, X4, R1, R3, R a , R b , R c have the definitions as described in the present invention.

[0043]

[0044] Wherein, n5 is 0 or 1; n6 is 0, 1, 2 or 3; Rn5 is deuterium, F, Cl, Br, CN, NO2, =O, -OR a , -NR b R c ; m5 is 0, 1, 2, 3 or 4;

[0045] X5 and X6 are each independently C or N, and at least one of X5 and X6 is N;

[0046] X1, X2, X3, X4, R1, R3, R a 、R b 、R c have the definitions as described in the present invention.

[0047] In some other embodiments, X3 is C.

[0048] In some other embodiments, Y is empty, -(CH2)n-, O or N, wherein n is an integer between 1 and 6, and the -(CH2)n- is unsubstituted or substituted by deuterium, F, Cl, Br, CN, NO2, =O, -OR a , -NR b R c substituted.

[0049] In some other embodiments, R1 is C 6-9 aryl or heteroaryl composed of 5 to 9 atoms, wherein the C 6-9 aryl and heteroaryl composed of 5 to 9 atoms are each independently unsubstituted or substituted by 1 or 2 R'.

[0050] In some other embodiments, R2 is H, deuterium, C 1-6 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group composed of 3 to 6 atoms, (heterocyclic group composed of 3 to 6 atoms)-C 1-4 alkylene, C 6-8 aryl, C 6-8 aryl-C 1-4 alkylene, heteroaryl composed of 5 to 8 atoms, (heteroaryl composed of 5 to 8 atoms)-C 1-4 alkylene, wherein the C 1-6 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group composed of 3 to 6 atoms, (heterocyclic group composed of 3 to 6 atoms)-C 1-4 alkylene, C 6-8Aryl, C 6-8 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-8 atoms, (heteroaryl composed of 5-8 atoms)-C 1-4 The alkylene groups are each independently unsubstituted or substituted by 1, 2, or 3 R″ groups.

[0051] In some other embodiments, R3 is H, deuterium, F, Cl, Br, CN, NO2, -OH, -NH2, or C 1-3 Alkyl.

[0052] In some 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 composed of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, CN, ═O, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, or -CO-NR b R c 。

[0053] In some 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 composed of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, CN, ═O, -OR a 、-NR b R c 、C 1-6 Alkyl, C 1-6Halogenoalkyl or -CO-NR b R c 。

[0054] In some other embodiments, X1 is C or N, X2 is N, X3 is C, and X4 is N.

[0055] In some other embodiments, Y is O.

[0056] In some other embodiments, R1 is phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiinyl, wherein the phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiinyl are each independently unsubstituted or are each independently unsubstituted or substituted by 1 or 2 R′s.

[0057] In some other embodiments, R2 is C 1-6 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms)-C 1-4 alkylene, wherein the C 1-6 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms)-C 1-4 alkylene are each independently unsubstituted or substituted by 1, 2 or 3 R″s.

[0058] In some other embodiments, R3 is F, Cl or Br.

[0059] In some other embodiments, each R′ is independently H, deuterium, F, Cl, Br, -NR b R c 、C 1-3 alkyl, wherein the C 1-3 alkyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, CN, =O, -OR a 、-NR b R c 、C 1-6 alkyl, C 1-6Halogenated alkyl, C 3-6 Cycloalkyl, a heterocyclic group composed of 3 to 6 atoms, or -CO-NR b R c .

[0060] In some other embodiments, each R″ is independently F, Cl, Br, -NR b R c .

[0061] In some other embodiments, R a , R b , R c are each independently H, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C 1-3 halogenated alkyl, a heterocyclic group composed of 3 to 6 atoms, or R b , R c together with the nitrogen atom to which they are attached form a heterocyclic ring composed of 3 to 6 atoms, wherein the methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl and the heterocyclic ring composed of 3 to 6 atoms are each independently unsubstituted or substituted with 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.

[0062] In some other embodiments, the present invention relates to a conjugate comprising the aforementioned compound, a linker chain and a ubiquitin ligase E3 ligand, the linker chain being disposed between the compound and the ubiquitin ligase E3 ligand, the linker chain being connected to the compound by a chemical bond, and the linker chain being connected to the ubiquitin ligase E3 ligand by a chemical bond.

[0063] In some other embodiments, the present invention relates to a pharmaceutical composition comprising an effective amount of the aforementioned compound or the aforementioned conjugate.

[0064] In some other embodiments, the pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

[0065] In some other embodiments, the pharmaceutical composition further comprises one or more therapeutic agents, wherein the therapeutic agent is selected from other anti-tumor drugs.

[0066] In some other embodiments, the therapeutic agent is an anti-mitotic drug, an alkylating agent, an anti-metabolic drug, a topoisomerase inhibitor, an estrogen receptor modulator, an androgen receptor modulator, a small molecule inhibitor targeting a protein kinase, an antibody drug targeting a protein kinase.

[0067] In some other embodiments, the antimitotic drug is paclitaxel or vincristine.

[0068] In some other embodiments, the alkylating agent is cisplatin, oxaliplatin, carboplatin or cyclophosphamide.

[0069] In some other embodiments, the antimetabolic drug is gemcitabine, 5-fluorouracil or methotrexate.

[0070] In some other embodiments, the topoisomerase inhibitor is epipodophyllotoxin, etoposide, topotecan or camptothecin.

[0071] In some other embodiments, the estrogen receptor modulator is tamoxifen or fulvestrant.

[0072] In some other embodiments, the androgen receptor modulator is bicalutamide.

[0073] In some other embodiments, the small molecule inhibitor targeting protein kinases is dasatinib, bosutinib, gefitinib, erlotinib, lapatinib, imatinib, nilotinib, sorafenib, tipifarnib, sunitinib, axitinib.

[0074] In some other embodiments, the antibody drug targeting protein kinases is trastuzumab, panitumumab, cetuximab.

[0075] In some other embodiments, the present invention relates to the use of the compounds, conjugates or pharmaceutical compositions described above in the preparation of a drug for preventing, treating, treating or alleviating diseases associated with overexpression or hyperactivity of LSD1 in a patient.

[0076] In some other embodiments, the disease associated with overexpression of LSD1 is a tumor.

[0077] In some 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 lymphoma.

[0078] In some other embodiments, the present invention relates to the use of the compounds, conjugates or pharmaceutical compositions described above in the preparation of a drug for inhibiting LSD1.

[0079] Unless otherwise stated, the present invention encompasses all stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention.

[0080] In some embodiments, the salt refers to a pharmaceutically acceptable salt. 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 being treated therewith.

[0081] The compounds of the present invention also include their salt forms, which are not necessarily pharmaceutically acceptable salts, but 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.

[0082] The compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention also includes their solvated and unsolvated forms.

[0083] On the other hand, the compounds of the present invention may contain several asymmetric centers or be in the form of the racemic mixtures commonly described. The present invention further includes racemic mixtures, partial racemic mixtures, and isolated enantiomers and diastereomers.

[0084] The compounds of the present invention can exist in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof. The present invention can further include mixtures of isomers, rotamers, atropisomers, tautomers of the compounds of the present invention, or partial mixtures of isomers, rotamers, atropisomers, tautomers, or isolated isomers, rotamers, atropisomers, tautomers.

[0085] On the other hand, the present invention relates to methods for preparing, separating and purifying the compounds encompassed by formula (I).

[0086] The foregoing only outlines certain aspects of the present invention and is not limited thereto. The content of these aspects and other aspects will be described in more specific and complete detail below.

[0087] Definitions and General Terms

[0088] Certain embodiments of the present invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The present invention is intended to cover all alternatives, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is in no way limited to the methods and materials described in the present invention. In the case where one or more of the incorporated documents, patents, and similar materials are different from or contradictory to the present application (including but not limited to the defined terms, term applications, the described technologies, etc.), the present application shall prevail.

[0089] It should be further recognized that certain features of the present invention, for the sake of clarity, are described in multiple independent embodiments, but can also be provided in combination in a single embodiment. Conversely, various features of the present invention, for the sake of brevity, are described in a single embodiment, but can also be provided individually or in any suitable sub-combination.

[0090] Unless otherwise indicated, the technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the technical field to which the present invention pertains. Unless otherwise indicated, all patent publications incorporated by reference in the entire disclosure of the present invention are hereby incorporated by reference in their entirety into the present invention.

[0091] The present invention will apply the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75, th Ed, 1994. Additionally, 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. Thus, all content of the present invention incorporates the references.

[0092] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. The subject also refers to a primate (e.g., a human), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other additional embodiments, the subject is a human.

[0093] The terms "subject" and "patient" as used in the present invention are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), particularly a "mammal" 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), and more particularly humans. In one embodiment, the subject is a non - human animal, such as a farm animal (e.g., a horse, cow, pig or sheep) or a pet (e.g., a dog, cat, guinea pig or rabbit). In other embodiments, the "patient" refers to a human.

[0094] The stereochemical definitions and conventions used in the present invention generally follow S.P. 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 or chiral centers and thus 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 also included within the scope of 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 an optically active compound, 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 (or chiral centers) in the molecule. The prefixes d and l or (+) and (–) are symbols used to specify the rotation of plane - polarized light caused by the compound, where (–) or l indicates that the compound is levorotatory. A compound with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of said isomers are commonly called mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and such racemic mixtures or racemates can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method.

[0095] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in the form of one or a mixture of the possible isomers, for example as pure enantiomers, or as a mixture of isomers such as a racemic and diastereoisomeric mixture, depending on the number of asymmetric carbon atoms. The optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral auxiliaries, 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 substituents on the cycloalkyl group may be in the cis- or trans-configuration.

[0096] The compounds of the present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereoisomers, enantiomers, and atropisomers and geometric (or conformational) isomers and mixtures thereof such as racemic mixtures, are within the scope of the present invention.

[0097] Unless otherwise indicated, the structures described in the present invention also represent all isomeric (e.g., enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational)) forms including such structures; for example, the R and S configurations at each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Accordingly, the individual stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, mixtures of diastereomers, and geometric (or conformational) isomer mixtures are within the scope of the present invention.

[0098] The terms "tautomer" or "tautomeric form" refer to structural isomers of different energy that can interconvert via a low energy barrier. If tautomerization is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0099] The "deuterated compound" used in the present invention refers to a compound formed by replacing one or more hydrogens of a compound with 2 H.

[0100] The "nitrogen oxide" used in the present invention means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) 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 L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperbenzoic acid (MCPBA).

[0101] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. The 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 in which the solvent molecule is water.

[0102] A "metabolite" refers to a product obtained by the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by experimental methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compound, including metabolites produced by bringing the compound of the present invention into sufficient contact with a mammal for a period of time.

[0103] The "pharmaceutically acceptable salts" used in the present invention refer to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well-known in the art, as described in the literature: S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. The salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reacting with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods described in books and literature such as ion exchange method to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and so on. The salts obtained by appropriate bases include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1-4 (alkyl)4. The present invention also contemplates quaternary ammonium salts formed from any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and so on. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.

[0104] The term "prodrug" used in the present invention represents a compound that is converted in vivo into the compound shown in formula (I). Such conversion is affected by the hydrolysis of the prodrug in the blood or enzymatic conversion in the blood or tissues into the parent structure. The prodrug compounds of the present invention can be esters, and in the existing inventions, 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 contains a hydroxyl group, and it can be acylated to obtain a compound in the prodrug form. Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylating the hydroxyl group on the parent compound. A complete discussion of prodrugs can be found in the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium 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 S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328 - 2345.

[0105] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention can exist in racemic or enantiomerically enriched form, for example, in the (R)-, (S)-, or (R,S)-configuration form. 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 the (R)- or (S)-configuration. If possible, the substituents on the atoms with unsaturated double bonds can exist in the cis-(Z)- or trans-(E)-form.

[0106] Thus, as described in the present invention, the compounds of the present invention can exist in one form or a mixture of possible isomers, rotamers, atropisomers, tautomers, etc., for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0107] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereoisomers, racemates, according to the physicochemical differences between the components, for example by chromatography and / or fractional crystallization.

[0108] The racemates of any resulting end product or intermediate can be resolved into the optical enantiomers by methods known to those skilled in the art, such as, by separation of the diastereomeric salts obtained therefrom. The racemic products can also be separated by chiral chromatography, such as, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, the 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 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0109] As described in the present invention, the compounds of the present invention may optionally be substituted by one or more substituents, such as the compounds of the general formula above, or as specific examples, subclasses, and a class of compounds included in the present invention in the examples. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". The terms "optionally", "optional", or "optionally" mean that the subsequent described event or condition may or may not occur, and the description includes the case where the event or condition occurs and the case where the event or condition does not occur. Generally, the term "optionally", whether before the term "substituted" or not, means that one or more hydrogen atoms in the given structure are replaced by specific substituents. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When there are more than one position in the given structural formula that can be substituted by one or more substituents selected from a specific group, the substituents can be the same or different at each position. The substituents described therein can be, 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 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 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.

[0110] In addition, it should be noted that, unless otherwise explicitly indicated, in the present invention, the description methods "each... independently is", "... independently is respectively", and "... independently is" can be interchanged, and should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can also mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0111] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group types or ranges. It should be specifically noted that the present invention includes each independent secondary combination of each member 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 independently disclosed.

[0112] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", then it should be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

[0113] The terms "alkyl" or "alkyl group" used in the present invention represent a monovalent hydrocarbon group of a saturated straight-chain or branched-chain containing 1 to 20 carbon atoms. Unless otherwise specified in detail, the alkyl group contains 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl group contains 1 to 9 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms; in other embodiments, the alkyl group contains 1 to 3 carbon atoms.

[0114] 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)CH2CH3), 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(CH3)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, etc., wherein the alkyl groups may be independently unsubstituted or substituted by one or more substituents described in the present invention.

[0115] The terms "alkyl" and its prefix "alk-" used in the present invention both include straight-chain and branched-chain saturated carbon chains.

[0116] The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a straight-chain or branched-chain saturated hydrocarbon radical. Unless otherwise specified in detail, the alkylene radical contains 1-10 carbon atoms. In some other embodiments, the alkylene radical contains 1-6 carbon atoms. In some other embodiments, the alkylene radical contains 1-4 carbon atoms. In some other embodiments, the alkylene radical contains 1-2 carbon atoms. Such examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylidene (-CH(CH3)CH2-), etc., where the alkylene radical can be independently unsubstituted or substituted by one or more substituents described in the present invention.

[0117] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, where at least one C-C position is in a sp 2 double-bond unsaturated state, and the alkenyl radical can be independently unsubstituted or substituted by one or more substituents described in the present invention, including the "cis", "trans" or "Z", "E" configurations, and specific examples include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.

[0118] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon radical having 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, where at least one C-C position is in a sp triple-bond unsaturated state, and the alkynyl radical can be independently unsubstituted or substituted by one or more substituents described in the present invention. Specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0119] The term "alkoxy" means that an alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified in detail, the alkoxy group contains 1-20 carbon atoms. In some embodiments, the alkoxy group contains 1-10 carbon atoms. In some other embodiments, the alkoxy group contains 1-8 carbon atoms. In some other embodiments, the alkoxy group contains 1-6 carbon atoms. In some other embodiments, the alkoxy group contains 1-4 carbon atoms. In some other embodiments, the alkoxy group contains 1-3 carbon atoms.

[0120] 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, where the alkoxy group may independently be unsubstituted or substituted with one or more substituents described in the present invention.

[0121] The terms "haloalkyl", "haloalkenyl", or "haloalkoxy" denote an alkyl, alkenyl, or alkoxy group substituted with one or more halogen atoms, and examples of such include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

[0122] The terms "carbocyclic", "carbocyclic group" or "carbocyclic" are used interchangeably herein and refer to a non-aromatic carbocyclic system that is saturated or contains one or more unsaturated units and contains 3-14 ring carbon atoms. 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 "carbocyclic group" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, where the attached moieties or points are on the carbocyclic ring. Bicyclic carbocyclic groups include bridged bicyclic carbocyclic groups, fused bicyclic carbocyclic groups and spirobicyclic carbocyclic groups, and a "fused" bicyclic ring system contains two rings sharing 2 adjacent ring atoms. Bridged bicyclic groups include two rings sharing 3 or 4 adjacent ring atoms. Spiro 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-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, 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.

[0123] The term "cycloalkyl" refers to a monocyclic, bicyclic or tricyclic system that is saturated, contains 3-12 ring carbon atoms and has one or more attachment points connecting to the rest of the molecule. In some of these embodiments, the cycloalkyl is a ring system containing 3-10 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system containing 3-8 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system containing 3-6 ring carbon atoms; in other embodiments, the cycloalkyl is a ring system containing 5-6 ring carbon atoms; and the cycloalkyl groups can be independently unsubstituted or substituted by one or more of the substituents described in the present invention.

[0124] The terms "heterocyclic group" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring system has one or more attachment points to the remainder of the molecule. The term "heterocyclic group" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems, and also includes polycyclic ring systems in which the heterocycle may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the attached group or point is on the heterocycle. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups and spirobicyclic heterocyclic groups. Unless otherwise specified, the heterocyclic group may be carbon-based or nitrogen-based, and the -CH2- group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to the N-oxide. In some embodiments, the heterocyclic group is a monocyclic or bicyclic heterocyclic group composed of 3 to 8 atoms; in other embodiments, the heterocyclic group is a monocyclic or bicyclic heterocyclic group composed of 3 to 6 atoms; in other embodiments, the heterocyclic group is a monocyclic or bicyclic heterocyclic group composed of 6 to 8 atoms; in other embodiments, the heterocyclic group is a heterocyclic group composed of 5 to 6 atoms; in other embodiments, the heterocyclic group is a heterocyclic group composed of 4 atoms; in other embodiments, the heterocyclic group is a heterocyclic group composed of 5 atoms; in other embodiments, the heterocyclic group is a heterocyclic group composed of 6 atoms; in other embodiments, the heterocyclic group is a heterocyclic group composed of 7 atoms; in other embodiments, the heterocyclic group is a heterocyclic group composed of 8 atoms.

[0125] 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, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothianyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, dithiolanyl, thioxolanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl yl, diaza yl, thiazinyl group, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Examples of the -CH2- group in the heterocyclic group being replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl, pyrimidinedionyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolanyl 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 said heterocyclic groups may optionally be substituted by one or more substituents described in the present invention.

[0126] The term "bridge" refers to a bond, atom or 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 the bridge are referred to as "bridgeheads".

[0127] The term "spiro" refers to a ring system having an atom (usually a quaternary carbon atom) as the only common atom between two rings.

[0128] The term "consisting of n atoms", where n is an integer, typically describes the number of ring-forming atoms in a molecule, and the number of ring-forming atoms in the said molecule is n. For example, piperidinyl is a heterocyclic group consisting of 6 atoms, and 1,2,3,4-tetrahydronaphthalenyl is a carbocyclic group consisting of 10 atoms.

[0129] The term "heteroatom" refers to O, S, N, P and Si, including any oxidized forms of N, S and P; the forms of primary, secondary, tertiary amines and quaternary ammonium salts; or the form in which the hydrogen on the nitrogen atom in the heterocycle is substituted, 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).

[0130] The term "halogen" refers to F, Cl, Br or I.

[0131] The term "N3" represents an azide structure. Such a group can be connected to other groups. For example, it can be connected to a methyl group to form azidomethane (MeN3), or to a phenyl group to form azidobenzene (PhN3).

[0132] The term "cyano" or "CN" represents a cyano structure. Such a group can be connected to other groups.

[0133] The term "nitro" or "NO2" represents a nitro structure. Such a group can be connected to other groups.

[0134] The term "aryl" can be used alone or as a major part of "aralkyl", "aralkoxy" or "aryloxyalkyl", and refers to a monocyclic, bicyclic, and tricyclic carbocyclic system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, each ring system contains a ring composed of 3-7 atoms, and has one or more attachment points connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic nucleus", and the aromatic ring can include phenyl, naphthyl, and anthracenyl. The aryl group can be independently unsubstituted or substituted by one or more substituents described in the present invention.

[0135] The term "heteroaryl" can be used alone or as a major part of "heteroarylalkyl" or "heteroarylalkoxy", and refers to a monocyclic, bicyclic, and tricyclic system 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, each ring system contains a ring composed of 5-7 atoms, and has one or more attachment points connected to the rest of the molecule. Unless otherwise specified, heteroaryl can be carbon-based or nitrogen-based, and the -CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide. The nitrogen atom of the ring can be optionally oxidized to N-oxide. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl composed of 5-12 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some other embodiments, heteroaryl is a heteroaryl composed of 5-10 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some other embodiments, heteroaryl is a heteroaryl composed of 5-6 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some other embodiments, heteroaryl is a heteroaryl composed of 5 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In some other embodiments, heteroaryl is a heteroaryl composed of 6 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N

[0136] In other embodiments, the heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furanyl, 3-furanyl, 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 (such as 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-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic groups, but is by no means limited to these bicyclic groups: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), oxathienyl, The heteroaryl group is optionally substituted with one or more substituents described in the present invention.

[0137] The term "carboxyl", whether used alone or in combination with other terms such as "carboxyalkyl", means -CO2H; the term "carbonyl", whether used alone or in combination with other terms such as "aminocarbonyl" or "acyloxy", means -(C=O)-.

[0138] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino group is independently substituted with one or two alkyl groups. In some embodiments, the alkylamino is a lower alkylamino group with one or two C 1-6 alkyl groups attached to the nitrogen atom. In other embodiments, the alkylamino is a lower alkylamino group of C 1-3 Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, and the like.

[0139] The term "aromatic amino group" means that the amino group is substituted by one or two aryl groups. Examples of such include, but are not limited to, N-phenylamino group. In some embodiments, the aromatic ring on the aromatic amino group can be further substituted.

[0140] The term "aminoalkyl" includes a C 1-10 straight-chain or branched-chain alkyl group substituted by one or more amino groups. In some embodiments, the aminoalkyl is a C 1-6 "lower aminoalkyl". Examples of such include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.

[0141] As described in the present invention, the ring system formed by a substituent drawing a bond to the central ring represents that the substituent can be substituted at any substitutable position on the ring. This ring system includes monocyclic, bicyclic, or polycyclic systems.

[0142] For a bicyclic system or a polycyclic system, if a bond of a substituent is drawn on each ring and connected to the corresponding ring, it represents that the substituent can be substituted at any substitutable position on the corresponding ring.

[0143] The term "conjugate" as used in the present application refers to a compound formed by covalently linking a compound described in the present application with biomolecules such as proteins, polypeptides, lipids, nucleic acids, and antibodies, as well as other small molecules, such as PROTAC compounds. According to specific embodiments of the present invention, the "conjugate" as used in the present application includes the compound described above in the present application, a linker, and an E3 ligase ligand. The linker is disposed between the compound and the E3 ligase ligand. The linker is connected to the compound through a chemical bond, and the linker is connected to the E3 ligase ligand through a chemical bond, thereby forming a "trimer" conjugate - the compound of the present application targeting LSD1 - Linker - E3 ligand. This conjugate adds a ubiquitination tag to the target protein LSD1 through the E3 ligase, initiating a powerful ubiquitination hydrolysis process in the cell, and specifically degrading the target protein LSD1 through the ubiquitin-proteasome pathway.

[0144] The term "unsaturated" as used in the present invention means that the group contains one or more degrees of unsaturation.

[0145] The term "comprising" or "including" is an open-ended expression, that is, it includes the content specified in the present invention, but does not exclude other aspects of the content.

[0146] As used in the present invention, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetening agent, flavoring agent, coloring agent, or a combination thereof, which carriers are known to those skilled in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Its use in therapeutic or pharmaceutical compositions is covered, except in cases where any conventional carrier is incompatible with the active ingredient.

[0147] The term "inhibiting LSD1" as used in the present invention includes reducing the expression level 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%.

[0148] The "effective amount" of the compounds of the present invention refers to the amount that elicits the desired biological response. In the present invention, the desired biological response is to inhibit LSD1, prevent the recurrence, progression, onset or development of symptoms associated with overexpression of LSD1, or enhance or improve the prophylactic or therapeutic effect of another anti-tumor therapy used. The exact amount of the compound administered to the subject to be treated will depend on the mode of administration, the severity and the characteristics of the subject to be treated, such as health status, age, gender, body weight and tolerance to the drug. Those skilled in the art will be able to determine the appropriate dose based on these and other factors. When administered in combination with other anti-tumor agents, for example, in combination with anti-mitotic drugs, the "effective amount" of the second agent will depend on the type of drug used. The appropriate doses of approved drugs are known and those skilled in the art can adjust them based on the condition of the subject to be treated, the type of condition being treated and the amount of the compound of the present invention used. In cases where the amount is not specifically indicated, an effective amount should be taken. For example, the compounds of the present invention can be administered to the subject to be treated for therapeutic or prophylactic treatment in a dose range of about 0.01 - 100 mg / kg body weight / day.

[0149] As used herein, the term "treatment" refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes alleviating or improving the progression, severity, and / or duration of a condition mediated or exacerbated by LSD1 overexpression, or improving one or more symptoms (particularly, one or more distinguishable symptoms) of a condition mediated or exacerbated by LSD1 overexpression, by administration of one or more therapies (e.g., one or more therapeutic agents such as the compounds and compositions of the present invention). In certain embodiments, therapeutic treatment includes improving at least one measurable physical parameter of a condition mediated by LSD1 overexpression or hyperactivity. In other embodiments, therapeutic treatment includes inhibiting the progression of a condition mediated or exacerbated by LSD1 overexpression, physically (e.g., by stabilizing distinguishable symptoms) or physiologically (e.g., by stabilizing physical parameters) or both. In other embodiments, therapeutic treatment includes alleviating or stabilizing a disease mediated by LSD1 overexpression or hyperactivity, 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 lymphoma.

[0150] The term "protecting group" or "PG" refers to a substituent that is typically used to block or protect a particular functionality when another functional group reacts. For example, an "amino protecting group" is a substituent attached to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" is a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. A "carboxy protecting group" is a substituent of a carboxy group used to block or protect the functionality of the carboxy group. Common carboxy 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. General descriptions of protecting groups can be found in the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P.J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0151] Description of the Compounds of the Invention

[0152] The present invention provides a reversible LSD1 inhibitor with a novel structure, which has higher LSD1 inhibitory activity and can be used for the treatment of various hematological tumors and solid tumors.

[0153] The present invention provides a compound which is a stereoisomer, tautomer, deuterated compound, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I) or the structure represented by formula (I),

[0154]

[0155] wherein X1, X2, X3 and X4 are each independently selected from C or N;

[0156] Y is -(CH2) n -, O or N;

[0157] R1 is C 6-10 aryl or heteroaryl composed of 5 - 10 atoms, wherein the C 6-10 aryl and heteroaryl composed of 5 - 10 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R';

[0158] R2 is H, deuterium, C 1-6 alkyl, C 3-12 carbocyclic group, C 3-12 carbocyclic group - 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, wherein the C 1-6 alkyl, C 3-12 carbocyclic group, C 3-12 carbocyclic group - 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 are each independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R'';

[0159] R3 is H, deuterium, F, Cl, Br, CN, NO2, -OR a 、-NRb R c 、C 1-6 alkyl

[0160] Each R′ and 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, a heterocyclic group composed of 3 - 12 atoms, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, a heterocyclic group composed of 3 - 12 atoms is each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, CN, ═O, -OR a 、-NR b R c 、C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, a heterocyclic group composed of 3 - 6 atoms or -CO-NR b R c ;

[0161] R a 、R b 、R c are each independently H, deuterium, C 1-6 alkyl, C 1-6 haloalkyl, a heterocyclic group composed of 3 - 6 atoms or R b 、R c and the nitrogen atom to which they are attached together form a heterocyclic ring composed of 3 - 6 atoms, wherein the C 1-6 alkyl and the heterocyclic group composed of 3 - 6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, CN, OH, NH2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;

[0162] n is an integer between 0 and 6.

[0163] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N - oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds having the structure shown in formula (II):

[0164]

[0165] Among them, Y, X1, X2, X3, X4, R1, R2, and R3 have the definitions as described in the present invention.

[0166] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of the compounds having the structure shown in formula (III):

[0167]

[0168] Among them, X1, X2, X3, X4, R1, R2, and R3 have the definitions as described in the present invention.

[0169] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of the compounds having the structure shown in formula (IV):

[0170]

[0171] Among them, n1 is 1, 2, or 3; Rn1 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ;

[0172] m1 is 0, 1, 2, 3, or 4;

[0173] X1, X2, X3, X4, R1, R3, R a , R b , R c have the definitions as described in the present invention.

[0174] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs of the compounds having the structure shown in formula (V):

[0175]

[0176] Among them, n2 is 1, 2, or 3; Rn2 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ; m2 is 0, 1, 2, 3, or 4;

[0177] X1, X2, X3, X4, R1, R3, Ra , R b , R c has the definition as described in the present invention.

[0178] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds having the structure shown in formula (VI):

[0179]

[0180] wherein, n3 is 1, 2 or 3; Rn3 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ; m3 is 0, 1, 2, 3 or 4;

[0181] X1, X2, X3, X4, R1, R3, R a , R b , R c has the definition as described in the present invention.

[0182] In some other embodiments, the present invention relates to stereoisomers, tautomers, deuterated compounds, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the compounds having the structure shown in formula (VII):

[0183]

[0184] wherein, n4 is 1, 2 or 3; Rn4 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ; m4 is 0, 1, 2, 3 or 4;

[0185] X1, X2, X3, X4, R1, R3, R a , R b , R c has the definition as described in the present invention.

[0186]

[0187] wherein, n5 is 0 or 1; n6 is 0, 1, 2 or 3; Rn5 is deuterium, F, Cl, Br, CN, NO2, ═O, -OR a , -NR b R c ; m5 is 0, 1, 2, 3 or 4;

[0188] X5 and X6 are each independently C or N, and at least one of X5 and X6 is N;

[0189] X1, X2, X3, X4, R1, R3, R a , R b , R c have the definitions as described in the present invention.

[0190] In some other embodiments, X3 is C.

[0191] In some other embodiments, Y is empty, -(CH2)n-, O or N, where n is an integer between 1 and 6, and the -(CH2)n- is unsubstituted or substituted by deuterium, F, Cl, Br, CN, NO2, =O, -OR a , -NR b R c substituted.

[0192] In some other embodiments, R1 is C 6-9 aryl or heteroaryl composed of 5 to 9 atoms, where the C 6-9 aryl and heteroaryl composed of 5 to 9 atoms are each independently unsubstituted or substituted by 1 or 2 R'.

[0193] In some other embodiments, R2 is H, deuterium, C 1-6 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group composed of 3 to 6 atoms, (heterocyclic group composed of 3 to 6 atoms)-C 1-4 alkylene, C 6-8 aryl, C 6-8 aryl-C 1-4 alkylene, heteroaryl composed of 5 to 8 atoms, (heteroaryl composed of 5 to 8 atoms)-C 1-4 alkylene, where the C 1-6 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group composed of 3 to 6 atoms, (heterocyclic group composed of 3 to 6 atoms)-C 1-4 alkylene, C 6-8 aryl, C 6-8 aryl-C 1-4 alkylene, heteroaryl composed of 5 to 8 atoms, (heteroaryl composed of 5 to 8 atoms)-C 1-4 alkylene are each independently unsubstituted or substituted by 1, 2 or 3 R".

[0194] In some other embodiments, R3 is H, deuterium, F, Cl, Br, CN, NO2, -OH, -NH2 or C 1-3 alkyl group.

[0195] In some 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 group, C 3-6 cycloalkyl group, a heterocyclic group composed of 3 to 6 atoms, wherein the C 1-3 alkyl group, C 3-6 cycloalkyl group, a heterocyclic group composed of 3 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, CN, ═O, -OR a , -NR b R c , C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, a heterocyclic group composed of 3 to 6 atoms or -CO-NR b R c .

[0196] In some 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 group, C 3-6 cycloalkyl group, a heterocyclic group composed of 3 to 6 atoms, wherein the C 1-3 alkyl group, C 3-6 cycloalkyl group, a heterocyclic group composed of 3 to 6 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, CN, ═O, -OR a , -NR b R c , C 1-6 alkyl group, C 1-6 haloalkyl group or -CO-NR b R c .

[0197] In some other embodiments, X1 is C or N, X2 is N, X3 is C, and X4 is N.

[0198] In some other embodiments, Y is O.

[0199] In some other embodiments, R1 is phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiinyl, wherein the phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiinyl are each independently unsubstituted or are each independently unsubstituted or substituted by 1 or 2 R′s.

[0200] In some other embodiments, R2 is C 1-6 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms)-C 1-4 alkylene, wherein the C 1-6 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms)-C 1-4 alkylene are each independently unsubstituted or substituted by 1, 2 or 3 R″s.

[0201] In some other embodiments, R3 is F, Cl or Br.

[0202] In some other embodiments, R3 is F.

[0203] In some other embodiments, each R′ is independently H, deuterium, F, Cl, Br, -NR b R c , C 1-3 alkyl, wherein the C 1-3 alkyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, CN, ═O, -OR a , -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, heterocyclic group composed of 3-6 atoms or -CO-NR b R c .

[0204] In some other embodiments, each R″ is independently F, Cl, Br, -NR b R c .

[0205] In some other embodiments, R a , R b , R c are each independently H, deuterium, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C 1-3 haloalkyl, a heterocyclic group composed of 3 to 6 atoms or R b , R c together with the nitrogen atom to which they are attached form a heterocycle composed of 3 to 6 atoms, wherein the methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl and the heterocycle composed 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 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.

[0206] In some other embodiments, the present invention relates to a compound having one of the following structures, or their stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof.

[0207]

[0208]

[0209] In some other embodiments, the present invention relates to a conjugate comprising the aforementioned compound, a linker chain and a ubiquitin ligase E3 ligand, the linker chain being disposed between the compound and the ubiquitin ligase E3 ligand, the linker chain being chemically bonded to the compound, and the linker chain being chemically bonded to the ubiquitin ligase E3 ligand.

[0210] In some other embodiments, the present invention relates to a pharmaceutical composition comprising an effective amount of the aforementioned compound or the aforementioned conjugate.

[0211] In some other embodiments, the pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

[0212] In some other embodiments, the pharmaceutical composition further comprises one or more therapeutic agents, wherein the therapeutic agents are selected from other anti-tumor drugs.

[0213] In other embodiments, the therapeutic agent is an anti-mitotic drug, an alkylating agent, an anti-metabolic drug, a topoisomerase inhibitor, an estrogen receptor modulator, an androgen receptor modulator, a small molecule inhibitor targeting a protein kinase, or an antibody drug targeting a protein kinase.

[0214] In other embodiments, the anti-mitotic drug is paclitaxel or vincristine.

[0215] In other embodiments, the alkylating agent is cisplatin, oxaliplatin, carboplatin, or cyclophosphamide.

[0216] In other embodiments, the anti-metabolic drug is gemcitabine, 5-fluorouracil, or methotrexate.

[0217] In other embodiments, the topoisomerase inhibitor is etoposide, teniposide, topotecan, or camptothecin.

[0218] In other embodiments, the estrogen receptor modulator is tamoxifen or fulvestrant.

[0219] In other embodiments, the androgen receptor modulator is bicalutamide.

[0220] In other embodiments, the small molecule inhibitor targeting a protein kinase is dasatinib, bosutinib, gefitinib, erlotinib, lapatinib, imatinib, nilotinib, sorafenib, tipifarnib, sunitinib, or axitinib.

[0221] In other embodiments, the antibody drug targeting a protein kinase is trastuzumab, panitumumab, or cetuximab.

[0222] In other embodiments, the present invention relates to the use of the foregoing compound, the foregoing conjugate, or the foregoing pharmaceutical composition in the preparation of a drug, wherein the drug is used for preventing, treating, or alleviating a disease associated with overexpression or hyperactivity of LSD1 in a patient.

[0223] In other embodiments, the disease associated with overexpression of LSD1 is a tumor.

[0224] In other embodiments, the tumor is papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial carcinoma, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer, or non-Hodgkin lymphoma.

[0225] In other embodiments, the present invention relates to the use of the foregoing compound, the foregoing conjugate, or the foregoing pharmaceutical composition in the preparation of a drug, wherein the drug is used for inhibiting LSD1.

[0226] In other embodiments, the present invention relates to a method for preventing, treating, or alleviating a disease associated with overexpression or hyperactivity of LSD1 in a patient. According to an embodiment of the present invention, the method includes administering to the patient a pharmaceutically acceptable dose of the foregoing compound, the foregoing conjugate, or the foregoing pharmaceutical composition.

[0227] In some embodiments, the salt refers to a pharmaceutically acceptable salt. 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 being treated therewith.

[0228] 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.

[0229] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromides, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, chlorides / hydrochlorides, choline salts, citrates, edisylates, fumarates, glucoheptonates, gluconates, glucuronates, hippurates, hydroiodides / iodides, hydroxyethylsulfonates, lactates, lactobionates, lauryl sulfates, malates, maleates, malonates, mandelates, mesylates, methyl sulfates, naphthoates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphates / monohydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, stearates, succinates, sulfosalicyclates, tartrates, toluenesulfonates, and trifluoroacetates.

[0230] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0231] 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.

[0232] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0233] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the periodic table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0234] 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, etc. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0235] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic moiety by conventional chemical methods. Generally, 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 hydroxides, carbonates, bicarbonates, etc.), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, in appropriate cases, 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).

[0236] Furthermore, the compounds of the present invention, including their salts, can also be obtained in their hydrate form, or include other solvents used for their crystallization. The compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include solvated and unsolvated forms.

[0237] Any structural formula given in the present invention is also intended to represent both the unlabeled form and the isotopically labeled form of these compounds. Isotopically labeled compounds have the structure depicted by the general formula given in the present invention, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F,31 P, 32 P, 36 S, 37 Cl or 125 I.

[0238] On the other hand, the compounds of the present invention include compounds defined by the present invention labeled with various isotopes. For example, those in which there are radioactive isotopes such as 3 H, 14 C and 18 F, or those in which there are non-radioactive isotopes such as 2 H and 13 C. Such isotopically labeled compounds can be used for metabolic studies (using 14 C), reaction kinetics studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including determination of the tissue distribution of a drug or a substrate, or can be used in radiotherapy of patients. 18 F-labeled compounds are particularly desirable for PET or SPECT studies. The isotopically labeled compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by replacing the originally used unlabeled reagents with appropriate isotopically labeled reagents as described in the examples and preparation procedures of the present invention.

[0239] In addition, heavier isotopes, especially deuterium (i.e., 2Substitution with H or D can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increased in vivo half-life or a reduced dose requirement or an improved therapeutic index. It should be understood that deuterium in this context is regarded as a substituent of the compound of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of the designated isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound has an isotopic enrichment factor 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) for each designated deuterium atom. Pharmaceutically acceptable solvates of the present invention include those solvates in which the crystallization solvent can be isotopically substituted, such as D2O, acetone-d6, or DMSO-d6.

[0240] Conjugates, Compositions, Formulations and Administrations of the Compounds of the Invention

[0241] The present invention provides a conjugate comprising the aforementioned compound, a linking chain, and a ubiquitin ligase E3 ligand, the linking chain being disposed between the compound and the ubiquitin ligase E3 ligand, the linking chain being chemically bonded to the compound, and the linking chain being chemically bonded to the ubiquitin ligase E3 ligand.

[0242] The present invention provides a pharmaceutical composition comprising an effective amount of the compound or a stereoisomer or a conjugate thereof of the present invention. According to specific embodiments 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 prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.

[0243] A pharmaceutically acceptable carrier may contain inert ingredients that do not overly inhibit the biological activity of the compound. A pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or without other adverse reactions or side effects once administered to a patient. Standard pharmaceutical techniques can be employed.

[0244] As described in the present invention, the pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or excipient, as used in the present invention, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. 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 formulating pharmaceutically acceptable compositions and their known preparation methods. In addition to conventional carrier vehicles that are incompatible with the compounds of the present invention, such as those that would produce adverse biological effects or have detrimental interactions with any other components in the pharmaceutically acceptable composition, any other conventional carrier vehicles and their uses are also contemplated within the scope of 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 (such as human serum albumin), buffering substances (such as Tween 80, phosphate, glycine, sorbic acid or potassium sorbate), mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salts), silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene-block copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (such as lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as 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 laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffer solutions and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and, according to the judgment of the formulator, coloring agents, anti-adhesive agents, coating agents, sweetening agents and flavoring agents, preservatives and antioxidants may also be present in the composition.

[0246] The compounds, conjugates or compositions of the present invention can be administered by any suitable means and can be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powder, ointment or drops), orally as a mouthwash or nasal spray, etc., depending on the severity of the disease being treated, with the above-described compounds and pharmaceutically acceptable compositions.

[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 forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially 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 the inert diluent, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and flavoring agents.

[0248] Injectable preparations can be formulated with suitable dispersing or wetting agents and suspending agents in accordance with known techniques, for example, as sterile injectable aqueous or oleaginous suspensions. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0249] For example, injectable preparations can be sterilized by filtration through a bacteria-retaining filter or by the addition of bactericides in the form of sterile solid compositions which are soluble or dispersible in sterile water or other sterile injectable medium prior to use.

[0250] To prolong the action of the compounds or compositions of the present invention, it is often desirable to slow the absorption of the compounds following subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, depends upon crystal size and form. Alternatively, delayed absorption of a parenterally-administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microcapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The rate of release of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot preparations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissue.

[0251] Compositions for rectal or vaginal administration are, in particular, 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 suppository waxes which are solid at ambient temperature but liquid at body temperature and will therefore melt in the rectal or vaginal cavity and release the active compound.

[0252] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate dibasic and / or a) fillers or swelling agents 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 retarders such as paraffin wax, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol 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 contain buffering agents.

[0253] Excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, can also be used to use similar types of solid compositions as fillers in soft and hard gel capsules. Solid dosage forms of tablets, troches, capsules, pills, and granules can be prepared with coating shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain emulsifying agents and may also have the property of the composition such that the active ingredient is released only in a delayed manner, optionally, or preferably, in a certain part of the intestine. Examples of embedding compositions that can be used include polymers and waxes. Excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, can also be used to use similar types of solid compositions as fillers in soft and hard gel capsules.

[0254] The active compound can also be in the form of microencapsulation with one or more of the above excipients. Solid dosage forms of tablets, troches, capsules, pills, and granules can be prepared with coating shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Generally, such dosage forms may also contain additional substances in addition to 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 contain buffering agents. They may optionally contain emulsifying agents and may also have the property of the composition such that the active ingredient is released only in a delayed manner, optionally, or preferably, in a certain part of the intestine. Examples of embedding compositions that can be used include polymers and waxes.

[0255] The topical or transdermal dosage forms of the compounds of the present invention include ointments, creams, gels, lotions, gels, powders, solutions, sprays, inhalants or patches. Under aseptic conditions, the active compounds are combined with pharmaceutically acceptable carriers and any necessary preservatives or buffering agents that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of skin patches which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Penetration 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 by inhalation spray, rectally, nasally, buccally, vaginally or by implantation of a cartridge. As used herein, the term "parenteral" includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intralesional and intracranial injection or infusion techniques. In particular, the compositions are administered orally, intraperitoneally or intravenously.

[0257] The sterile injectable form of the compositions of the present invention can be a water or oil suspension. These suspensions can be prepared using suitable dispersing or wetting agents and suspending agents in accordance with the techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland, fixed oil can be employed, including synthetic mono- or diglycerides. Additionally, natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids such as oleic acid and its glyceride derivatives are used in the preparation of injectables. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersing agent, such as carboxymethyl cellulose or similar dispersing agents 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 commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulating purposes.

[0258] The pharmaceutical composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, common carriers include but are not limited to lactose and starch. Lubricants, such as magnesium stearate, are usually also 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 emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

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

[0260] In particular, when the treatment target includes topical administration to easily accessible areas or organs, including eye, skin or lower intestinal diseases, the pharmaceutical composition of the present invention can also be topically administered. Suitable topical preparations are easily prepared for each of these areas or organs.

[0261] Topical administration to the lower intestine can be achieved with a rectal suppository preparation (see above) or a suitable enema preparation. Topical skin patches can also be used.

[0262] For topical administration, 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 administration 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 ester 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 especially 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 can 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 for use in the methods of the present invention can be formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unit doses for a subject, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be one of a single daily dose or multiple daily doses (e.g., about 1 - 4 times or more per day). When multiple daily doses are used, the unit dosage forms for each dose can be the same or different.

[0266] Use of the compounds, conjugates and compositions of the present invention

[0267] The above - mentioned compounds, conjugates and pharmaceutical compositions provided by the present invention can be used for preparing medicaments for preventing, treating or alleviating diseases associated with over - expression or hyper - activity of LSD1 in a patient. Preferably, the diseases associated with over - expression or hyper - activity of LSD1 are tumors. For example, the tumors are papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial carcinoma, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer or non - Hodgkin lymphoma.

[0268] The present invention also provides the use of the above - mentioned compounds, conjugates or their pharmaceutical compositions in preparing a medicament for inhibiting LSD1.

[0269] The present invention provides a method for treating, preventing or delaying diseases caused by over - expression or hyper - activity of LSD1, the method comprising administering to a subject in need of treatment a therapeutically effective amount of the above - mentioned compounds, conjugates or their pharmaceutical compositions. Wherein the diseases caused by over - expression or hyper - activity of LSD1 are tumors, such as papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial carcinoma, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer or non - Hodgkin lymphoma. Moreover, the above - mentioned compounds, conjugates or their pharmaceutical compositions provided by the present invention can be co - administered with other therapies or therapeutic agents. The mode of administration can be simultaneous, sequential or at certain time intervals.

[0270] The dose of the compound or pharmaceutical composition required to effect treatment, prevention or delay, etc. generally depends on the specific compound administered, the subject, the specific disease or disorder and its severity, the route of administration and frequency, etc., and needs to be determined by the attending physician according to the specific circumstances. For example, when the compound or pharmaceutical composition provided by the present invention is administered by the intravenous route, it can be administered once a week or even at longer intervals.

[0271] In summary, the present invention provides a novel compound, which can be used as an LSD1 inhibitor. The compound of the present invention is suitable for preparing drugs in various dosage forms and can be widely used in the treatment of tumors, such as papillary thyroid cancer, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, small cell lung cancer, prostate cancer or non-Hodgkin's lymphoma.

[0272] The compounds and pharmaceutical compositions of the present invention are useful for human treatment and can also be used in veterinary treatment of pets, introduced species of animals and mammals in farm animals. Other examples of animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0273] General synthesis process

[0274] To describe 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 suitably prepare many other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of the non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art by modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the 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 and Alfa Chemical Company, J&K Scientific Ltd. and were used without further purification unless otherwise indicated.

[0278] In the following examples, the LCMS models used for detection are Agilent 1200 Series, Agilent 1260 Infinity 2 or Agilent 1260 - 6125B, and the NMR model: Bruker AVANCE 3 400MHZ Ultra shieldTM Digital NMR.

[0279] Compounds are named according to the conventional naming rules in the art or using ChemDraw software.

[0280] The following synthetic schemes list the experimental steps for preparing the compounds disclosed in the present invention. Among them, each X1, X2, X3, X4, X5, X6, R1, R2, R3, R′, R″, R a 、R b 、R c 、n1, n2, n3, n4, n5, n6, Rn1, Rn2, Rn3, Rn4, Rn5, m1, m2, m3, m4, m5 have the definitions as described in the present invention.

[0281] Synthetic Scheme 1

[0282]

[0283] The haloheterocyclic compound I - a undergoes a Mitsunobu reaction with R2 - OH to obtain the intermediate I - b, and the latter undergoes a Suzuki coupling reaction with I - c to obtain the intermediate I - d. I - d and R1 - OH undergo an S N Ar reaction under the condition of using NaH as the base to obtain the compound I′.

[0284] Synthetic Scheme 2

[0285]

[0286] The synthesis method of the compound II’ is similar to that of the compound I’, and in the last step, the intermediate II - d and II - e undergo a Suzuki coupling to obtain the product II′.

[0287] Synthetic Scheme 3

[0288]

[0289] The synthesis method of the compound III’ is similar to that of the compound I’, and in the last step, the intermediate III - d and III - e undergo an S N Ar reaction to obtain the product III′. Specific Embodiments

[0290] The following examples are used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0291] Preparation Example

[0292] In the following preparation examples, the inventors took some compounds of the present invention as examples and described in detail the preparation process of the compounds of the present invention.

[0293] Example 1

[0294] (Synthesis of 4-(7-(4-aminocyclohexyl)-4-(3-fluoro-4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 1))

[0295]

[0296] Step 1

[0297] Dissolve Compound 1-1 (5 g, 17.9 mmol), Compound 1-1A (5.8 g, 26.9 mmol), and triphenylphosphine (9.36 g, 35.7 mmol) in tetrahydrofuran (100 mL). Add DIAD (7.23 g, 35.8 mmol) dropwise to the reaction system under ice bath, and react at room temperature for 2 h under nitrogen protection. Quench the reaction system with water, extract with ethyl acetate (3×100 mL), dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and prepare the crude product by column chromatography (PE:EA = 2:1) to obtain white solid Compound 1-2 (1.3 g, yield: 15%). LCMS (M+H) + = 477.1.

[0298] Step 2

[0299] Dissolve Compound 1-2 (550 mg, 1.15 mmol), Compound 1-2A (190 mg, 1.15 mmol), Pd(dppf)Cl2 (73.1 mg, 0.1 mmol), and K2CO3 (317.4 mg, 2.3 mmol) in 1,4-dioxane / H2O (12 / 2 mL), heat the reaction system to 100 °C, and react for 8 h under nitrogen protection. Quench the reaction system with water, extract with ethyl acetate (3×50 mL), dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and prepare the crude product by column chromatography (PE:EA = 2:1) to obtain white solid Compound 1-3 (100 mg, yield: 18%). LCMS (M+H) + = 470.0.

[0300] Step 3

[0301] Compound 1-3 (100 mg, 0.21 mmol), compound 1-3A (41 mg, 0.24 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol) and K2CO3 (55.2 mg, 0.42 mmol) were dissolved in 1,4-dioxane / H2O (3 / 0.5 mL). The reaction system was heated to 100 °C and reacted for 8 h under nitrogen protection. 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 prepared by column chromatography (PE:EA = 3:1) to obtain white solid compound 1-4 (50 mg, yield: 42%). LCMS (M+H) + = 560.1

[0302] Step 4

[0303] Compound 1-4 (50 mg, 0.09 mmol) was dissolved in DCM (2 mL), and then TFA (1 mL) was added dropwise to the reaction system. The reaction was carried out at room temperature for 2 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was separated by high performance liquid column to obtain white solid compound 1 (18 mg, yield: 43%). LCMS: (M+H) + = 460.2 1 H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.18 (s, 1H), 8.02 (s, 3H), 7.77 (m, 1H), 7.22 (dd, J = 12.2, 2.0 Hz, 1H), 7.09 (m, 4H), 5.00 (m, 1H), 3.85 (s, 3H), 3.54 (m, 1H), 2.21 (m, 2H), 1.95 (d, J = 12.5 Hz, 6H). 19 F NMR (376 MHz, DMSO) δ -75.45 (s, 4.77F), -110.35 (s, 1F), -135.62 (s, 1F).

[0304] Example 2

[0305] Synthesis of 2-fluoro-4-(4-(3-fluoro-4-methoxyphenyl)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 2)

[0306]

[0307]

[0308] Step 1

[0309] Dissolve compound 2-1 (5.5 g, 19.7 mmol) in tetrahydrofuran (60 mL). Under a nitrogen atmosphere, add compound 2-1A (5.9 g, 29.5 mmol), DEAD (7.9 g, 39.4 mmol) and triphenylphosphine (10.3 g, 39.4 mmol) to the reaction system. Replace the system with nitrogen three times and stir the reaction for 2 hours at 28 °C. Concentrate to remove most of the solvent, add water and ethyl acetate for extraction. Dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the resulting crude residue by column chromatography (PE:EA = 1:1) to obtain white solid compound 2-3 (2.3 g, yield: 25.3%). LCMS (M+H) + = 463.0

[0310] Step 2

[0311] Dissolve compound 2-2 (900 mg, 1.95 mmol), compound 2-2A (322 mg, 1.95 mmol) and potassium carbonate (538 mg, 3.9 mmol) in 1,4-dioxane / H2O (15 / 2 mL). At room temperature, add the catalyst Pd(dppf)Cl2 (146 mg, 0.1 mmol) to the reaction system and react at 70 °C for 2 h under nitrogen protection. Concentrate to remove most of the solvent, add water and ethyl acetate for extraction. Dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the resulting crude residue by column chromatography (PE:EA = 2:1) to obtain white solid compound 2-3 (245 mg, yield: 27.6%). LCMS (M+H) + = 456.0

[0312] Step 3

[0313] Dissolve compound 2-3 (100 mg, 0.22 mmol), compound 2-3A (74 mg, 0.44 mmol) and potassium carbonate (60 mg, 0.44 mmol) in 1,4-dioxane / H2O (4 / 0.5 mL). At room temperature, add the catalyst Pd(dppf)Cl2 (60 mg, 0.44 mmol) to the reaction system and react at 120 °C for 12 h under nitrogen protection. Concentrate to remove most of the solvent, add water and ethyl acetate for extraction. Dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the resulting crude residue by column chromatography (PE:EA = 2:1) to obtain white solid compound 2-4 (42 mg, yield: 35.0%). LCMS (M+H) + = 546.1

[0314] Step 4

[0315] Compound 2-4 (42 mg, 0.08 mmol) was dissolved in DCM (2 mL), and then TFA (1 mL) was added dropwise to the reaction system. The reaction mixture was stirred at room temperature for 2 h. After concentration, the crude product was separated by high performance liquid chromatography column to obtain white solid compound 2 (11 mg, yield: 32%). LCMS: (M+H) + = 446.1 1 H NMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.83 (s, 1H), 8.18 (s, 1H), 7.81–7.70 (m, 1H), 7.21 (dd, J = 12.2, 2.0 Hz, 1H), 7.14 (dd, J = 8.6, 1.6 Hz, 1H), 7.09 (d, J = 1.2 Hz, 1H), 7.07 (s, 1H), 7.04 (s, 1H), 4.47 (d, J = 7.2 Hz, 2H), 3.85 (d, J = 5.0 Hz, 3H), 3.31 (dd, J = 11.2, 4.4 Hz, 2H), 3.19–3.13 (m, 1H), 3.05 (dd, J = 12.0, 6.4 Hz, 1H), 2.98–2.92 (m, 1H), 2.00 (dt, J = 12.6, 6.4 Hz, 1H), 1.76 (dd, J = 13.0, 8.0 Hz, 1H). 19 FNMR (376 MHz, DMSO) δ -74.82 (s, 4.78F), -110.45 (s, 1F), -135.44 (s, 0.9F).

[0316] Example 3

[0317] Synthesis of 2-fluoro-4-(4-(3-fluoro-4-methoxyphenyl)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 3)

[0318]

[0319] Step 1

[0320] Compound 3-1A (127 mg, 1.30 mmol) was dissolved in DMF (20 mL). Under a nitrogen atmosphere, compound NaH (86 mg, 2.16 mmol) was added to the reaction system in portions. The reaction was stirred at 30 °C for 0.5 h. Compound 3-1 (500 mg, 1.08 mmol) was added to the reaction solution in portions, and the reaction was stirred at 60 °C for 1 h. The reaction solution was quenched with saturated ammonium chloride solution, extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated. The obtained crude residue was purified by column chromatography (PE:EA = 1:1) to obtain the white solid compound 3-2 (160 mg, yield: 28%). LCMS (M+H) + = 525.1

[0321] Step 2

[0322] Compound 3-2 (100 mg, 0.19 mmol), compound 3-2A (165 mg, 0.38 mmol), and potassium carbonate (52 mg, 0.38 mmol) were dissolved in 1,4-dioxane / water (3 / 0.5 mL). At room temperature, the catalyst Pd(dppf)Cl2 (27.1 mg, 0.019 mmol) was added to the reaction system, and the reaction was carried out at 100 °C for 12 h under nitrogen protection. The solvent was removed by concentration, and the obtained crude product was prepared by prep-HPLC to obtain the white solid compound 3-3 (35 mg, yield: 35.6%). LCMS (M+H) + = 518.2

[0323] Step 3

[0324] Compound 3-3 (35 mg, 0.068 mmol) was dissolved in DCM (2 mL), and then TFA (1 mL) was added dropwise to the reaction system. The reaction solution was reacted at room temperature for 2 h. After concentration of the reaction solution, the crude product was separated by a high-performance liquid chromatography column to obtain the white solid compound 3 (20 mg, yield: 71%). LCMS: (M+H) + = 418.1 11H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 8.04–7.98 (m, 1H), 7.97 (s, 1H), 7.91 (dd, J = 11.4, 1.4 Hz, 1H), 7.82 (dd, J = 8.2, 1.6 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 4.41 (d, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.36–3.24 (m, 2H), 3.16 (dd, J = 14.6, 9.2 Hz, 1H), 3.04 (dt, J = 12.0, 6.2 Hz, 1H), 2.91 (dt, J = 14.8, 7.4 Hz, 1H), 1.98 (td, J = 12.6, 7.4 Hz, 1H), 1.79–1.64 (m, 1H). 19 19F NMR (376 MHz, DMSO) δ -73.95 (s, 3.22F), -109.04 (s, 1F).

[0325] Example 4

[0326] Synthesis of 4-(7-(4-aminocyclohexyl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 4)

[0327]

[0328]

[0329] Step 1

[0330] Dissolve compound 4-1 (500 mg, 1.8 mmol) in DMF (7 mL). Under an ice-water bath, add NaH (129 mg, 5.4 mmol) portionwise. Stir at room temperature for 30 minutes. Dropwise add SEMCl (449 mg, 2.7 mmol) under an ice-water bath. Continue the reaction for 1 hour. Dropwise add ice-water to quench the reaction. Extract with ethyl acetate. Dry the organic phase over anhydrous sodium sulfate and concentrate. The crude residue obtained is purified by column chromatography (PE:EA = 10:1) to obtain white solid compound 4-2 (600 mg, yield: 82%). LCMS (M+H) + = 410.0

[0331] Step 2

[0332] Compound 4-3 (101 mg, 1 mmol) was dissolved in DMF (7 mL). NaH (41 mg, 1.7 mmol) was added portionwise under an ice-water bath condition, and the mixture was stirred at room temperature for 30 minutes. Then compound 4-2 (350 mg, 0.86 mmol) was added, and the temperature was raised to 60 °C and stirred for 1 hour. After cooling in an ice-water bath, ice water was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated. The obtained crude residue was purified by column chromatography (PE:EA = 1:1) to give white solid compound 4-4 (350 mg, yield: 87%). LCMS (M+H) + = 471.0

[0333] Step 3

[0334] Compound 4-4 (350 mg, 0.7 mmol), compound 4-5 (147 mg; 0.9 mmol), and potassium carbonate (205 mg, 1.05 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (1 mL). After adding Pd(dppf)Cl2 (54 mg, 0.07 mmol), the system was purged with nitrogen three times. The reaction system was heated to 100 °C and stirred for 2 hours. Most of the solvent was removed by rotary evaporation. The obtained crude residue was purified by column chromatography (PE:EA = 1:1) to give white solid compound 4-6 (150 mg, yield: 44%). LCMS (M+H) + = 465.0

[0335] Step 4

[0336] Compound 4-6 (1.1 g, 2.4 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (3 mL) was added. The reaction was carried out at room temperature for 5 hours. The solvent was removed by concentration. To the obtained crude residue, 12M ammonia in methanol solution (20 mL) was added, and the mixture was stirred at room temperature for another 30 minutes. The solvent was removed by rotary evaporation. The obtained white solid was slurried with an appropriate amount of dichloromethane and filtered. The obtained filter cake was redissolved in a large amount of ethyl acetate and washed with water several times to remove suspended solids. The organic phase was dried over anhydrous sodium sulfate, concentrated, to give white solid compound 4-7 (700 mg, yield: 88%). LCMS (M+H) + = 335.0

[0337] Step 5

[0338] Compound 4-7 (50 mg, 0.15 mmol), compound 4-8 (81 mg, 0.37 mmol), and triphenylphosphine (94 mg, 0.36 mmol) were dissolved in dioxane (4 mL). The system was purged with nitrogen three times. Under an ice-salt bath condition, DEAD (65 mg, 0.37 mmol) was added dropwise. After the addition, the temperature was raised to 70 °C and the mixture was stirred for 2 hours. The solvent was removed by concentration. The crude residue obtained was purified by prep-HPLC to give white solid compound 4-9 (6 mg, yield: 8%). LCMS (M+H) + = 532.0

[0339] Step 6

[0340] Compound 4-9 (6 mg, 0.01 mmol) was dissolved in dichloromethane (2 mL). Under an ice-water bath condition, TFA (0.5 mL) was added. The mixture was stirred at room temperature for 30 minutes. The solvent was removed by concentration. The crude residue obtained was purified by prep-HPLC to give white solid compound 4 (3 mg, yield: 62%). LCMS (M+H) + = 432.0 1 1H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 8.19 (s, 1H), 7.99 (dd, J = 16.8, 9.6 Hz, 5H), 7.90 (dd, J = 11.4, 1.4 Hz, 1H), 7.81 (dd, J = 8.2, 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 4.86 (d, J = 10.2 Hz, 1H), 3.85 (s, 3H), 3.51 (s, 1H), 2.28–2.15 (m, 2H), 1.92 (d, J = 9.8 Hz, 6H). 19 19F NMR (376 MHz, DMSO) δ -73.51 (s, 3F), -109.05 (s, 1F).

[0341] Example 5

[0342] Synthesis of 2-fluoro-4-(4-((1-methyl-1H-pyrazol-4-yl)oxy)-7-(piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 5)

[0343]

[0344]

[0345] Step 1

[0346] Dissolve compound 5-1 (3 g, 10.7 mmol) in dioxane (30 mL), add compound 5-2 (2.4 g; 11.8 mmol) and triphenylphosphine (6.7 g, 25.8 mmol). After displacing nitrogen three times, add DEAD (5.4 g, 26.9 mmol) dropwise under an ice-water bath. Concentrate to remove most of the solvent, add water and ethyl acetate for extraction. The organic phase is dried over anhydrous sodium sulfate, concentrated, and the obtained crude residue is purified by column chromatography (PE:EA = 1:1) to obtain white solid compound 5-3 (1000 mg, yield: 20%). LCMS (M+H) + = 463.0

[0347] Step 2

[0348] Dissolve compound 5-4 (70 mg, 0.7 mmol) in DMF (4 mL). Add NaH (328 mg, 1.6 mmol) portionwise under an ice-water bath and stir at room temperature for 0.5 h. At room temperature, add compound 5-3 (300 mg, 0.65 mmol) to the reaction system and heat to 60 °C for 1 h. Quench with ice water, extract with ethyl acetate, wash with saturated brine, and concentrate. The obtained crude residue is purified by column chromatography (PE:EA = 1:1) to obtain white solid compound 5-5 (200 mg, yield: 59%). LCMS (M+H) + = 525.0

[0349] Step 3

[0350] Dissolve compound 5-5 (200 mg, 0.38 mmol) in a mixed solution of dioxane (4 mL) and water (1 mL), add compound 5-6 (70 mg, 0.4 mmol), potassium carbonate (132 mg, 0.95 mmol) and catalyst Pd(dppf)Cl2 (28 mg, 0.04 mmol). Displace nitrogen three times, heat to 100 °C for 1 h, dilute with ethyl acetate and wash with saturated brine. The organic phase is dried over anhydrous sodium sulfate, concentrated, and the obtained crude residue is purified by column chromatography (PE:EA = 1:1) to obtain white solid compound 5-7 (80 mg, yield: 41%). LCMS (M+H) + = 518.0

[0351] Step 4

[0352] Compound 5-7 (80 mg, 0.16 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added dropwise under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed by concentration. The crude residue obtained was purified by prep-HPLC to give white solid compound 5 (13 mg, yield: 20%). LCMS (M+H) + = 418.0 1 H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 8.05–7.98 (m, 1H), 7.96 (s, 1H), 7.91 (dd, J = 11.4, 1.4 Hz, 1H), 7.83 (dd, J = 8.2, 1.6 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 3.85 (s, 3H), 3.39 (s, 2H), 2.89 (d, J = 9.4 Hz, 1H), 2.36–1.98 (m, 4H), 1.87 (d, J = 13.8 Hz, 1H). 19 F NMR (376 MHz, DMSO) δ -73.75 (s, 3F), -109.01 (s, 1F).

[0353] Example 6

[0354] Synthesis of 2-fluoro-4-(4-((1-methyl-1H-pyrazol-4-yl)oxy)-7-(pyrrolidin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 6)

[0355]

[0356] Step 1

[0357] Compound 6-1 (140 mg, 0.4 mmol), compound 6-2 (211 mg, 1 mmol), and triphenylphosphine (264 mg, 1 mmol) were dissolved in anhydrous dioxane (4 mL). DEAD (182 mg, 1 mmol) was added dropwise to the reaction system under a nitrogen atmosphere. The system was purged with nitrogen three times and stirred at 30 °C for 2 hours. Most of the solvent was removed by concentration, and the mixture was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude residue obtained was purified by column chromatography (PE:EA = 1:1) to give white solid compound 6-3 (160 mg, yield: 74%). LCMS (M+H) + = 518.0

[0358] Step 2

[0359] Compound 6-3 (160 mg, 0.3 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added dropwise under an ice-water bath. The reaction was stirred at room temperature for 1 hour. Most of the solvent was removed by concentration. The crude product obtained was prepared by prep-HPLC to give white solid compound 6 (30 mg, yield: 23%). LCMS (M+H) + = 418.0 1 H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 8.06–8.00 (m, 1H), 7.97 (s, 1H), 7.89 (dd, J = 11.2, 1.6 Hz, 1H), 7.81 (dd, J = 8.2, 1.6 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 4.64 (d, J = 6.8 Hz, 2H), 4.03 (s, 1H), 3.86 (s, 3H), 3.17 (s, 1H), 2.15–2.04 (m, 1H), 2.04–1.96 (m, 1H), 1.90 (dd, J = 12.2, 7.6 Hz, 1H), 1.77 (dt, J = 12.6, 8.8 Hz, 1H). 19 F NMR (376 MHz, DMSO) δ -73.53 (s, 3F), -108.86 (s, 1F).

[0360] Example 7

[0361] Synthesis of 4-(7-((1R,3R)-3-aminocyclopentyl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 7)

[0362]

[0363] Step 1

[0364] Compound 7-1 (60 mg, 0.11 mmol), compound 7-2 (21 mg, 0.13 mmol), and triphenylphosphine (72 mg, 0.28 mmol) were dissolved in dioxane (4 mL). DEAD (58 mg; 0.3 mmol) was added to the reaction system under a nitrogen atmosphere. The system was purged with nitrogen three times and stirred at 120 °C for 2 hours. Most of the solvent was removed by concentration. Water and ethyl acetate were added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product residue obtained was purified by column chromatography (PE:EA = 1:1) to give white solid compound 7-3 (30 mg, yield: 51%). LCMS (M+H) += 518.0。

[0365] Step 2

[0366] Dissolve compound 7-3 (30 mg, 0.06 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (1 mL) dropwise under an ice-water bath, stir the reaction at room temperature for 1 hour, concentrate to remove the solvent, and obtain white solid compound 7 (12 mg, yield: 50%) after purification by Prep-HPLC. LCMS (M+H) + = 418.0。 1 H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.28 (s, 1H), 7.96 (ddd, J = 13.4, 12.8, 4.8 Hz, 6H), 7.85 (dd, J = 8.2, 1.6 Hz, 1H), 7.54 (s, 1H), 5.52–5.42 (m, 1H), 3.94 (s, 1H), 3.85 (s, 3H), 2.41–2.27 (m, 4H), 2.13–2.05 (m, 1H), 1.79–1.69 (m, 1H). 19 F NMR (376 MHz, DMSO) δ -73.50 (s, 3F), -109.17 (s, 1F).

[0367] Example 8

[0368] Synthesis of 2-fluoro-4-(4-(pyrazolo[1,5-a]pyridin-3-yloxy)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 8)

[0369]

[0370] Step 1

[0371] Dissolve compound 8-1 (220 mg, 0.9 mmol) in THF (10 mL), add dropwise NaOH (1 M) aqueous solution (2 mL, 1.8 mmol) and H2O2 (30%) (0.2 mL, 1.8 mmol) under an ice-water bath, and react the reaction solution at room temperature for 2 h. Adjust the pH of the reaction system to 2 with dilute hydrochloric acid (1 M) under an ice-water bath, extract with DCM (3 * 20 mL), dry over anhydrous sodium sulfate, evaporate to dryness, and prepare a colorless oil 8-2 (100 mg, yield: 83%) by column chromatography (PE:EA = 1:2). LCMS (M+H) + = 135.1。

[0372] Step 2

[0373] Dissolve compound 8-2 (100 mg, 0.75 mmol) in DMF (5 mL). Add NaH (50 mg, 1.5 mmol) portionwise under an ice-water bath, and react for 0.5 h under nitrogen protection. Add compound 8-2A (344 mg, 0.75 mmol) to the reaction system, heat the reaction system to 60 °C, and react for 2 h under nitrogen protection. Quench the reaction system with water, extract with ethyl acetate (3 × 20 mL), dry over anhydrous sodium sulfate, evaporate to dryness, and prepare white solid 8-3 (60 mg, yield: 14%) by column chromatography (PE:EA = 1:1). LCMS (M+H) + = 561.1

[0374] Step 3

[0375] Dissolve compound 8-3 (60 mg, 0.11 mmol), compound 8-3A (21 mg, 0.13 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), and K2CO3 (30 mg, 0.22 mmol) in 1,4-dioxane / H2O (2 / 0.4 mL). Heat the reaction system to 110 °C, and react the reaction solution for 12 h under nitrogen protection. Concentrate the reaction solution, and separate the crude product by high-performance liquid column chromatography to obtain white solid 8-4 (19 mg, yield: 31%). LCMS (M+H) + = 554.0

[0376] Step 4

[0377] Dissolve compound 8-4 (19 mg, 0.03 mmol) in DCM (2 mL). Add TFA (0.5 mL) dropwise under an ice-water bath. React the reaction solution at room temperature for 2 h. Concentrate the reaction solution, and separate the crude product by high-performance liquid column chromatography to obtain white solid compound 8 (6.1 mg, yield: 39%). LCMS (M+H) + = 454.3 11H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.48 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 8.04 (d, J = 6.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.95–7.88 (m, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 8.6, 6.8 Hz, 1H), 6.93 (t, J = 6.8 Hz, 1H), 4.44 (d, J = 7.2 Hz, 2H), 3.31 (s, 2H), 3.18 (s, 1H), 3.07 (s, 1H), 2.99–2.86 (m, 1H), 2.00 (dd, J = 12.8, 5.4 Hz, 1H), 1.74 (dd, J = 13.2, 8.0 Hz, 1H). 19 19F NMR (376 MHz, DMSO) δ -73.55 (s, 3F), -109.05 (s, 1F).

[0378] Example 9

[0379] Synthesis of 2-Fluoro-4-(7-(pyrrolidin-3-ylmethyl)-4-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 9)

[0380]

[0381]

[0382] Step 1

[0383] Dissolve Compound 9-1 (330 mg, 1.2 mmol) in THF (10 mL), and dropwise add an aqueous solution of NaOH (1 M) (2.4 mL, 2.4 mmol) and H2O2 (30%) (0.27 mL, 2.4 mmol) under an ice-water bath. The reaction solution is reacted at room temperature for 2 h. The reaction system is adjusted to pH = 2 with dilute hydrochloric acid (1 M) under an ice-water bath, extracted with DCM (3 × 20 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation, and purified by column chromatography (PE:EA = 1:2) to obtain a colorless oil, Compound 9-2 (100 mg, yield: 50%). LCMS (M+H) + = 167.1

[0384] Step 2

[0385] Dissolve compound 9-2 (100 mg, 0.60 mmol) in DMF (5 mL). Add NaH (40 mg, 1 mmol) portionwise under an ice-water bath, and react for 0.5 h under nitrogen protection. Add 9-2A (231 mg, 0.5 mmol) to the reaction system, heat the reaction system to 60 °C, and react for 2 h under nitrogen protection. Quench the reaction system with water, extract with ethyl acetate (3 × 20 mL), dry over anhydrous sodium sulfate, evaporate to dryness, and prepare the white solid 9-3 (60 mg, yield: 20%) by column chromatography (PE:EA = 1:1). LCMS (M+H) + = 593.1

[0386] Step 3

[0387] Dissolve compound 9-3 (60 mg, 0.10 mmol), compound 9-3A (24 mg, 0.15 mmol), Pd(dppf)Cl2 (8 mg, 0.01 mmol), and K2CO3 (28 mg, 0.2 mmol) in 1,4-dioxane / H2O (3 / 0.5 mL). Heat the reaction system to 110 °C, and react the reaction solution for 12 h under nitrogen protection. Concentrate the reaction solution, and separate the crude product by high-performance liquid column chromatography to obtain the white solid 9-4 (22 mg, yield: 38%). LCMS (M+H) + = 586.0

[0388] Step 4

[0389] Dissolve compound 9-4 (22 mg, 0.04 mmol) in DCM (2 mL). Add TFA (0.5 mL) dropwise under an ice-water bath. React the reaction solution at room temperature for 2 h. Concentrate the reaction solution, and separate the crude product by high-performance liquid column chromatography to obtain the white solid compound 9 (6.5 mg, yield: 36%). LCMS (M+H) + = 486.1 1 1H-NMR (400 MHz, DMSO) δ 8.95 (d, J = 14.7 Hz, 1H), 8.56 (d, J = 5.6 Hz, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 8.06–7.97 (m, 1H), 7.92 (dd, J = 11.4, 1.2 Hz, 1H), 7.83 (dd, J = 8.2, 1.4 Hz, 1H), 7.75 (s, 1H), 5.16 (q, J = 9.2 Hz, 2H), 4.49–4.35 (m, 2H), 3.30 (s, 2H), 3.17 (d, J = 5.6 Hz, 1H), 3.01 (d, J = 31.2 Hz, 1H), 2.92 (dt, J = 15.2, 7.6 Hz, 1H), 1.99 (td, J = 12.8, 7.4 Hz, 1H), 1.81–1.60 (m, 1H).19 F-NMR (376 MHz, DMSO) δ -70.24 (s, 3F), -73.60 (s, 3F), -109.02 (s, 1F).

[0390] Example 10

[0391] Synthesis of 4-(4-((1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 10)

[0392]

[0393] Step 1

[0394] Dissolve Compound 10-1 (250 mg, 1 mmol) in THF (4 mL). Under an ice-water bath, add 0.67 mL of an aqueous solution of 3 M sodium hydroxide (81 mg, 2 mmol), and then add hydrogen peroxide (69 mg, 2 mmol). React at room temperature for 3 hours. Adjust the pH to weakly acidic with 3 M dilute hydrochloric acid. After diluting with water, add dichloromethane and methanol (10:1) for extraction, and wash the organic phase with saturated brine. Dry the organic phase over anhydrous sodium sulfate and concentrate to obtain Compound 10-2 as a colorless oil (120 mg, yield: 86%). LCMS (M+H) + = 139.0.

[0395] Step 2

[0396] Dissolve Compound 10-2 (120 mg, 0.8 mmol) in DMF (2 mL). Under an ice-water bath, add sodium hydride (42 mg, 1.7 mmol) portionwise. After stirring at room temperature for 0.5 hour, add Compound 10-3 (402 mg, 0.8 mmol), and heat to 100 °C for reaction for 3 h. Cool to room temperature, and under an ice-water bath, add the reaction solution dropwise to ice water for quenching. Extract with ethyl acetate, wash the organic phase with saturated brine. Dry the organic phase over anhydrous sodium sulfate and concentrate. The obtained crude product is purified by SGC (PE:EA = 1:1) to obtain Compound 10-4 as a white solid (240 mg, yield: 49%). LCMS (M+H) + = 565.0.

[0397] Step 3

[0398] Compound 10-4 (80 mg, 0.14 mmol), compound 10-5 (35 mg, 0.2 mmol), and potassium carbonate (39 mg, 0.3 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (1 mL). Pd(dppf)Cl2 (11 mg, 0.01 mmol) was added. The reaction system was purged with nitrogen three times and heated to 100 °C for 2 hours. The solvent was concentrated under reduced pressure. The crude product obtained was purified by SGC (PE:EA = 1:1) to give white solid compound 10-6 (68 mg, yield: 86%). LCMS (M+H)+ = 558.0.

[0399] Step 4

[0400] Compound 10-6 (68 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give white solid compound 10 (2 mg, yield: 4%). LCMS (M+H) + = 458.0. 1 1H NMR (400 MHz, DMSO) δ 8.73 (s, 2H), 8.54 (s, 1H), 8.20 (s, 1H), 8.02 (dd, J = 10.2, 5.2 Hz, 2H), 7.91 (dd, J = 11.4, 1.6 Hz, 1H), 7.82 (dd, J = 8.2, 1.6 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 4.41 (d, J = 7.2 Hz, 2H), 3.97 (d, J = 7.2 Hz, 2H), 3.15 (d, J = 5.6 Hz, 2H), 3.02 (dd, J = 12.2, 6.0 Hz, 2H), 2.91 (dd, J = 15.4, 7.8 Hz, 1H), 1.98 (dd, J = 12.8, 5.2 Hz, 1H), 1.71 (dd, J = 13.0, 8.2 Hz, 1H), 1.28–1.22 (m, 1H), 0.59–0.48 (m, 2H), 0.41–0.34 (m, 2H). 19 19F NMR (376 MHz, DMSO) δ -73.54 (s, 3F), -108.98 (s, 1F).

[0401] Example 11

[0402] Synthesis of 4-(4-((1-(Cyclopentylmethyl)-1H-pyrazol-4-yl)oxy)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 11)

[0403]

[0404] Step 1

[0405] Dissolve compound 11-1 (2 g, 10.3 mmol) in DMF (20 mL), and add NaH (619 mg, 25.7 mmol) portionwise under an ice-water bath. Stir the reaction at room temperature for 0.5 h, add compound 11-2 (2.5 g, 15.5 mmol), heat the reaction to 80 °C for 18 h, cool to room temperature, and quench the reaction solution by dropping it into ice water under an ice-water bath. Extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate, and obtain a colorless oily substance 11-3 (2 g, yield: 70%). LCMS (M+H) + = 277.0

[0406] Step 2

[0407] Dissolve compound 11-3 (200 mg, 0.73 mmol) in THF (4 mL), add an aqueous solution of 3 M sodium hydroxide (56 mg, 1.45 mmol), 0.48 mL under an ice-water bath, then add hydrogen peroxide (49 mg, 1.45 mmol), react at room temperature for 3 h, adjust the pH to weakly acidic with 3 M dilute hydrochloric acid, dilute with water, add dichloromethane and methanol (10:1) for extraction, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate, and obtain a colorless oily compound 11-4 (100 mg, yield: 83%). LCMS (M+H) + = 167.0

[0408] Step 3

[0409] Dissolve compound 11-4 (100 mg, 0.6 mmol) in DMF (4 mL), and add NaH (29 mg, 1.2 mmol) portionwise under an ice-water bath. Stir the reaction at room temperature for 0.5 h, add compound 11-5 (278 mg, 0.6 mmol), heat the reaction to 60 °C for 3 h, cool to room temperature, and quench the reaction solution by dropping it into ice water under an ice-water bath. Extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate, and obtain a colorless oily substance 11-6 (100 mg, yield: 28%). LCMS (M+H) + = 593.0

[0410] Step 4

[0411] Compound 11-6 (100 mg, 0.17 mmol), compound 11-7 (42 mg, 0.25 mmol), and potassium carbonate (47 mg, 0.34 mmol) were dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Pd(dppf)Cl2 (19 mg, 0.03 mmol) was added, and the reaction was carried out at 100 °C for 2 h under nitrogen protection. The solvent was removed by concentration, and the crude product obtained was purified by SGC (PE:EA = 1:3) to give white solid compound 11-8 (85 mg, yield: 86%). LCMS (M+H) + = 586.0

[0412] Step 5

[0413] Compound 11-8 (85 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 1 h. The solvent was removed by concentration, and the crude product obtained was purified by Prep-HPLC to give white solid compound 11 (25 mg, yield: 28%). LCMS (M+H) + = 486.0 1 1H NMR (400 MHz, DMSO) δ 8.85 (s, 2H), 8.52 (d, J = 12.2 Hz, 1H), 8.21 (s, 1H), 8.05–7.97 (m, 2H), 7.91 (dd, J = 11.4, 1.4 Hz, 1H), 7.82 (dd, J = 8.2, 1.6 Hz, 1H), 7.57 (s, 1H), 4.41 (d, J = 7.2 Hz, 2H), 4.01 (d, J = 7.6 Hz, 2H), 3.31–3.25 (m, 2H), 3.15 (s, 1H), 3.04 (s, 1H), 2.91 (dt, J = 15.2, 7.6 Hz, 1H), 2.38 (dt, J = 14.8, 7.6 Hz, 1H), 1.98 (td, J = 12.6, 7.2 Hz, 1H), 1.77–1.69 (m, 1H), 1.66–1.56 (m, 4H), 1.55–1.41 (m, 2H), 1.27 (dd, J = 12.0, 6.0 Hz, 2H). 19 19F NMR (376 MHz, DMSO) δ -73.53 (s, 3F), -109.01 (s, 1F).

[0414] Example 12

[0415] Synthesis of 2-fluoro-4-(4-((1-methyl-1H-pyrazol-3-yl)oxy)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 12)

[0416]

[0417]

[0418] Step 1

[0419] Dissolve compound 12-1 (440 mg, 2.1 mmol) in tetrahydrofuran (4 mL). Under an ice-water bath, add 1.4 mL of an aqueous solution of 3 M sodium hydroxide (169 mg, 4.2 mmol) portionwise, and then add hydrogen peroxide (144 mg, 4.2 mmol). Stir the reaction at room temperature for 3 hours. Adjust the pH to weakly acidic with dilute hydrochloric acid, dilute with water, extract with a mixed solvent of dichloromethane and methanol (10:1), wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain a colorless oil, 12-2 (200 mg, yield: 96%). LCMS (M+H) + = 99.0

[0420] Step 2

[0421] Dissolve compound 12-2 (100 mg, 1 mmol) in DMF (4 mL). Under an ice-water bath, add sodium hydride (49 mg, 2 mmol) portionwise, stir the reaction for 0.5 hour, add compound 12-3 (566 mg, 1.2 mmol), heat the reaction system to 60 °C and react for 2 hours. Cool to room temperature, and under an ice-water bath, add the reaction solution dropwise to ice water to quench the reaction. Extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate. The crude product obtained is purified by SGC (PE:EA = 1:3) to obtain a white solid, compound 12-4 (240 mg, yield: 45%). LCMS (M+H) + = 525.0

[0422] Step 3

[0423] Dissolve compound 12-4 (80 mg, 0.15 mmol), compound 12-5 (33 mg, 0.2 mmol), and potassium carbonate (32 mg, 0.23 mmol) in a mixed solution of dioxane (4 mL) and water (1 mL). Add Pd(dppf)Cl2 (11 mg, 0.01 mmol), and react at 90 °C for 3 h under nitrogen protection. Concentrate to remove the solvent. The crude product obtained is purified by SGC (PE:EA = 1:3) to obtain a white solid, compound 12-6 (45 mg, yield: 57%). LCMS (M+H) + = 518.0

[0424] Step 4

[0425] Compound 12-6 (45 mg, 0.09 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration, and the crude product obtained was purified by Prep-HPLC to give white solid Compound 12 (10 mg, yield: 28%). LCMS (M+H) + = 418.0 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 2H), 8.49 (s, 1H), 8.24 (s, 1H), 8.00 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 11.4 Hz, 1H), 7.82 (dd, J = 8.2, 1.4 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 6.15 (d, J = 2.4 Hz, 1H), 4.41 (d, J = 7.2 Hz, 2H), 3.79 (s, 3H), 3.30–3.27 (m, 1H), 3.15 (s, 1H), 3.04 (s, 1H), 2.90 (dd, J = 15.2, 7.6 Hz, 1H), 1.98 (dt, J = 12.8, 6.6 Hz, 1H), 1.78–1.66 (m, 1H). 19 F NMR (376 MHz, DMSO) δ -73.52 (s, 3F), -108.88 (s, 1F).

[0426] Example 13

[0427] Synthesis of 2-Fluoro-4-(4-((1-methyl-1H-pyrazol-5-yl)oxy)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 13)

[0428]

[0429] Step 1

[0430] Compound 13-1 (120 mg, 1.2 mmol) was dissolved in DMF (4 mL), and NaH (60 mg, 2.4 mmol) was added portionwise under an ice-water bath. The mixture was stirred at room temperature for 0.5 hour, Compound 13-2 (622 mg, 1.4 mmol) was added, and the mixture was heated to 100 °C and reacted for 1 hour. After cooling to room temperature, the reaction solution was quenched by dropping it into ice water under an ice-water bath, extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product residue obtained was purified by column chromatography (PE:EA = 1:1) to give white solid Compound 13-3 (40 mg, yield: 6%). LCMS (M+H) + = 525.0

[0431] Step 2

[0432] Dissolve compound 13-3 (40 mg, 0.08 mmol), compound 13-4 (19 mg, 0.1 mmol), and potassium carbonate (21 mg, 0.15 mmol) in a mixed solution of dioxane (4 mL) and water (1 mL). Add Pd(dppf)Cl2 (6 mg, 0.01 mmol), and react at 110 °C for 1 h under nitrogen protection. Concentrate to remove the solvent, and purify the obtained crude product by SGC (PE:EA = 1:3) to obtain white solid compound 13-5 (30 mg, yield: 76%). LCMS (M+H) + = 518.0

[0433] Step 3

[0434] Dissolve compound 13-5 (30 mg; 0.06 mmol) in dichloromethane (1 mL), dropwise add trifluoroacetic acid (0.5 mL), stir and react at room temperature for 1 h, concentrate to remove the solvent, and purify the obtained crude product by prep-HPLC to obtain white solid compound 13 (14 mg, yield: 58%). LCMS (M+H) + = 418.0 1 H NMR (400 MHz, DMSO) δ 8.82 (s, 2H), 8.57 (s, 1H), 8.26 (s, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.93 (dd, J = 11.2, 1.4 Hz, 1H), 7.83 (dd, J = 8.2, 1.6 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 4.43 (d, J = 7.2 Hz, 2H), 3.63 (s, 3H), 3.30–3.26 (m, 2H), 3.16 (s, 1H), 3.05 (s, 1H), 2.92 (dt, J = 15.4, 7.6 Hz, 1H), 1.99 (dd, J = 12.8, 5.6 Hz, 1H), 1.78–1.66 (m, 1H). 19 F NMR (376 MHz, DMSO) δ -73.51 (s.3F), -108.90 (s, 1F).

[0435] Example 14

[0436] Synthesis of 2-fluoro-4-(4-(pyrazolo[1,5-a]pyridin-3-yloxy)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 14)

[0437]

[0438]

[0439] Step 1

[0440] Dissolve compound 14-1 (250 mg, 2.3 mmol), 14-1A (531 mg, 1.15 mmol), and DIPEA (297 mg, 2.3 mmol) in NMP (5 mL). Heat the reaction system to 120 °C and react for 2 h under nitrogen protection. Quench the reaction system with water, extract with ethyl acetate (3 × 20 mL), dry over anhydrous sodium sulfate, evaporate to dryness, and prepare white solid 14-2 (100 mg, yield: 16.6%) by column chromatography (PE:EA = 1:1). LCMS (M+H) + = 524.1

[0441] Step 2

[0442] Dissolve compound 14-2 (100 mg, 0.19 mmol), compound 14-2A (40 mg, 0.23 mmol), Pd(dppf)Cl2 (10 mg, 0.02 mmol), and K2CO3 (52 mg, 0.38 mmol) in 1,4-dioxane / H2O (3 / 0.5 mL). Heat the reaction system to 110 °C and react the reaction solution for 12 h under nitrogen protection. Concentrate the reaction solution, and separate the crude product by high-performance liquid chromatography column to obtain white solid 14-3 (25 mg, yield: 26%). LCMS (M+H) + = 517.0

[0443] Step 3

[0444] Dissolve compound 14-3 (25 mg, 0.05 mmol) in DCM (2 mL), and add TFA (0.5 mL) dropwise under an ice-water bath. React the reaction solution at room temperature for 2 h. Concentrate the reaction solution, and separate the crude product by high-performance liquid chromatography column to obtain white solid compound 14 (6 mg, yield: 29%). LCMS (M+H) + = 417.3 11H NMR (400 MHz, DMSO) δ 8.87–8.63 (m, 2H), 8.39 (s, 1H), 8.17 (s, 1H), 8.04–7.99 (m, 1H), 7.99–7.95 (m, 1H), 7.79 (s, 1H), 7.65–7.56 (m, 1H), 7.53 (s, 1H), 7.50 (dd, J = 8.2, 1.6 Hz, 1H), 4.32 (d, J = 6.6 Hz, 2H), 3.82 (s, 3H), 3.33–3.21 (m, 2H), 3.15 (d, J = 5.0 Hz, 1H), 3.02 (dd, J = 12.2, 5.8 Hz, 1H), 2.91–2.81 (m, 1H), 1.97 (dd, J = 12.8, 5.6 Hz, 1H), 1.71 (dd, J = 13.2, 8.0 Hz, 1H). 19 19F NMR (376 MHz, DMSO) δ -74.15 (s, 3F), -108.79 (s, 1F).

[0445] Example 15

[0446] Synthesis of 4-(7-((1S,3S)-3-aminocyclopentyl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 15)

[0447]

[0448] Step 1

[0449] A mixture of Compound 15-1 (1000 mg, 3.6 mmol), Compound 15-2 (789 mg, 3.9 mmol) and triphenylphosphine (2.3 g, 9 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL). After purging with nitrogen three times, the reaction mixture was cooled in an ice-water bath under a nitrogen atmosphere. A solution of DIAD (1.8 g, 9 mmol) in tetrahydrofuran (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, and most of the solvent was removed by concentration. The resulting crude residue was purified by column chromatography (PE:EA = 2:1) to obtain white solid Compound 15-3 (900 mg, yield: 54%). LCMS (M+H) + = 463.0

[0450] Step 2

[0451] Compound 15-4 (60 mg, 0.6 mmol) was dissolved in anhydrous DMF (5 mL). After cooling in an ice-water bath, NaH (27 mg, 1.1 mmol) was added portionwise. The mixture was stirred at room temperature for half an hour, and then compound 15-3 (255 mg, 0.55 mmol) was added portionwise. The reaction solution was heated to 80 °C and stirred for 3 hours. After cooling to room temperature, the reaction solution was quenched by adding it to ice water. The mixture was extracted twice with ethyl acetate, and the organic phase was washed three times with saturated brine. The organic phase was dried and concentrated. The crude residue obtained was purified by column chromatography (PE:EA = 1:1) to obtain white solid compound 15-5 (130 mg, yield: 45%). LCMS (M+H) + = 525.0

[0452] Step 3

[0453] Compound 15-5 (130 mg, 0.25 mmol) was dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Compound 15-6 (62 mg, 0.37 mmol) and potassium carbonate (69 mg, 0.5 mmol) were added. Under nitrogen protection, catalyst Pd(dppf)Cl2 (18 mg, 0.025 mmol) was added. The reaction system was purged with nitrogen three times. The reaction solution was heated to 100 °C and reacted for 2 hours. After cooling to room temperature, most of the solvent was removed by concentration. The crude residue obtained was purified by column chromatography (PE:EA = 1:1) to obtain white solid compound 15-7 (80 mg, yield: 62%). LCMS (M+H) + = 518.0

[0454] Step 4

[0455] Compound 15-7 (80 mg, 0.16 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 mL) was added dropwise under an ice-water bath. The mixture was stirred at room temperature for 1 hour, and most of the solvent was removed by concentration. The crude product obtained was prepared by prep-HPLC to obtain white solid compound 15 (30 mg, yield: 46%). LCMS (M+H) + = 418.0 1 1H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.28 (s, 1H), 7.96 (ddd, J = 13.4, 12.8, 4.4 Hz, 6H), 7.85 (dd, J = 8.2, 1.6 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 5.48 (p, J = 8.0 Hz, 1H), 3.85 (s, 3H), 2.45–2.25 (m, 5H), 2.10 (dq, J = 12.4, 7.8 Hz, 1H), 1.75 (dt, J = 14.0, 7.0 Hz, 1H).19 F NMR (376 MHz, DMSO) δ -74.01 (s, 3F), -109.18 (s, 1F).

[0456] Example 16

[0457] Synthesis of cis-4-(7-((1S,3R)-3-aminocyclopentyl)-4-((1-methyl-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 16)

[0458]

[0459] Step 1

[0460] A mixture of Compound 16-1 (100 mg, 0.36 mmol), Compound 16-2 (72 mg, 0.36 mmol) and triphenylphosphine (235 mg, 0.9 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL). The mixture was purged with nitrogen three times. Under a nitrogen atmosphere, the temperature was lowered in an ice-water bath. A solution of DEAD (156 mg, 0.9 mmol) in tetrahydrofuran (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, concentrated to remove most of the solvent, and the resulting crude residue was purified by column chromatography (PE:EA = 2:1) to obtain white solid Compound 16-3 (160 mg, yield: 97%). LCMS (M+H) + = 463.0.

[0461] Step 2

[0462] Compound 16-4 (68 mg, 0.7 mmol) was dissolved in anhydrous DMF (3 mL). After cooling in an ice-water bath, NaH (17 mg, 0.7 mmol) was added portionwise. The mixture was stirred at room temperature for half an hour. Compound 16-3 (160 mg, 0.35 mmol) was added portionwise. The reaction solution was heated to 100 °C and stirred for 1 hour, then cooled to room temperature. The reaction solution was quenched by adding it to ice water, and extracted twice with ethyl acetate. The organic phase was washed three times with saturated brine, dried, concentrated, and the resulting crude residue was purified by column chromatography (PE:EA = 1:1) to obtain white solid Compound 16-5 (120 mg, yield: 66%). LCMS (M+H) + = 525.0.

[0463] Step 3

[0464] Compound 16-5 (60 mg, 0.1 mmol) was dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Compound 16-6 (38 mg, 0.23 mmol) and potassium carbonate (40 mg, 0.3 mmol) were added. Under nitrogen protection, catalyst Pd(dppf)Cl2 (10 mg, 0.01 mmol) was added. The reaction system was purged with nitrogen three times. The reaction solution was heated to 100 °C and reacted for 2 hours. After cooling to room temperature, most of the solvent was removed by concentration. The crude residue obtained was purified by column chromatography (PE:EA = 1:1) to obtain white solid compound 16-7 (40 mg, yield: 68%). LCMS (M+H) + = 518.0

[0465] Step 4

[0466] Compound 16-7 (40 mg, 0.08 mmol) was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 mL) was added dropwise under an ice-water bath, and the mixture was stirred at room temperature for 1 hour. Most of the solvent was removed by concentration. The crude product obtained was prepared by Prep-HPLC to obtain white solid compound 16 (28 mg, yield: 87%). LCMS (M+H) + = 418.0 1 H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.25–8.20 (m, 1H), 8.14–8.06 (m, 2H), 8.02–7.98 (m, 1H), 7.96 (s, 1H), 7.95–7.90 (m, 1H), 7.86–7.81 (m, 1H), 7.54 (s, 1H), 5.32–5.22 (m, 1H), 3.85 (s, 3H), 2.71–2.64 (m, 1H), 2.28–2.22 (m, 2H), 2.20–1.90 (m, 4H). 19 F NMR (376 MHz, DMSO) δ -73.66 (s, 3F), -109.09 (s, 1F).

[0467] Example 17

[0468] Synthesis of 2-fluoro-4-(4-((1-methyl-1H-pyrazol-4-yl)oxy)-7-(piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 17)

[0469]

[0470] Step 1

[0471] Dissolve compound 17-1 (1 g, 3.58 mmol), 17-1A (720 mg, 3.58 mmol), and PPh3 (1.8 g, 8.95 mmol) in THF (15 mL). Dropwise add DEAD (1.56 g, 8.95 mmol) at 0 °C. Warm the reaction system to room temperature and react for 2 h under nitrogen protection. Concentrate the reaction solution, and purify the crude product by SGC (PE:EA = 3:1) to obtain white solid compound 17-2 (550 mg, yield: 33%). LCMS (M+H) + = 463.1

[0472] Step 2

[0473] Dissolve compound 17-2 (550 mg, 1.2 mmol) in DMF (10 mL). Add NaH (72 mg, 1.8 mmol) portionwise in an ice-water bath. Stir the reaction at room temperature for 0.5 h, add compound 17-2A (665 mg, 1.44 mmol), heat to 70 °C and react for 3 h. Cool to room temperature, and quench the reaction solution by dropping it into ice water in an ice-water bath. Extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate, and obtain colorless oily substance 17-3 (280 mg, yield: 44%). LCMS (M+H) + = 525.1

[0474] Step 3

[0475] Dissolve compound 17-3 (150 mg, 0.3 mmol), compound 17-3A (74 mg, 0.45 mmol), and potassium carbonate (83 mg, 0.6 mmol) in a mixed solution of dioxane (4 mL) and water (1 mL). Add Pd(dppf)Cl2 (19 mg, 0.03 mmol), and react at 110 °C for 2 h under nitrogen protection. Concentrate to remove the solvent, and purify the obtained crude product by SGC (PE:EA = 1:1) to obtain white solid compound 17-4 (50 mg, yield: 32%). LCMS (M+H) + = 518.1

[0476] Step 4

[0477] Dissolve compound 17-4 (50 mg, 0.1 mmol) in dichloromethane (2.5 mL). Add trifluoroacetic acid (1 mL), stir the reaction at room temperature for 1 h, concentrate to remove the solvent, and purify the obtained crude product by prep-HPLC to obtain white solid compound 17 (25 mg, yield: 62%). LCMS (M+H) += 418.2. 1H NMR (400 MHz, DMSO) δ 8.91 (d, J = 9.4 Hz, 1H), 8.61 (d, J = 10.3 Hz, 1H), 8.53 (s, 1H), 8.18 (s, 1H), 8.00 (t, J = 7.7 Hz, 1H), 7.94 (d, J = 13.1 Hz, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 5.03 (t, J = 11.6 Hz, 1H), 3.85 (s, 3H), 3.50 (d, J = 12.2 Hz, 2H), 3.27–3.17 (m, 2H), 2.33 (dd, J = 22.3, 12.2 Hz, 2H), 2.23 (d, J = 11.7 Hz, 2H). 19F NMR (376 MHz, DMSO) δ -73.83 (s, 3F), -109.07 (s, 1F).

[0478] Example 18

[0479] Synthesis of 2-Fluoro-4-(4-((1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)oxy)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (Compound 18)

[0480]

[0481] Step 1

[0482] Dissolve Compound 18-1 (45 mg, 0.09 mmol), 18-1A (24 mg, 0.27 mmol), and K2CO3 (25 mg, 0.18 mmol) in ACN (3 mL). Heat the reaction system to 90 °C and react for 24 h under nitrogen protection. Quench the reaction system with water, extract with ethyl acetate (3 * 20 mL), dry over anhydrous sodium sulfate, evaporate to dryness, and prepare a white solid 18-2 (15 mg, yield: 29%) by column chromatography (PE:EA = 1:1). LCMS (M+H) + = 574.1.

[0483] Step 2

[0484] Dissolve Compound 18-2 (15 mg, 0.03 mmol) in DCM (2 mL) and add TFA (0.5 mL) dropwise under an ice-water bath. React the reaction solution at room temperature for 2 h. Concentrate the reaction solution and separate the crude product by high-performance liquid chromatography column to obtain a white solid Compound 18 (1.9 mg, yield: 15%) LCMS (M+H) + = 474.4. 11H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.77 (s, 2H), 8.57 (s, 1H), 8.28 (s, 1H), 7.98 (dd, J = 18.0, 9.8 Hz, 2H), 7.82 (d, J = 8.2 Hz, 1H), 5.22 (s, 1H), 4.73 (dd, J = 11.8, 8.2 Hz, 2H), 4.52–4.34 (m, 4H), 3.64 (d, J = 5.2 Hz, 2H), 3.11 (d, J = 48.8 Hz, 4H), 2.91 (s, 1H), 2.03–1.92 (m, 1H), 1.76–1.63 (m, 1H). 19 19F NMR (376 MHz, DMSO) δ -73.55 (s, 7.29F), -108.69 (s, 1F).

[0485] Example 19

[0486] Synthesis of 2-(4-((5-(4-cyano-3-fluorophenyl)-7-(pyrrolidin-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (Compound 19)

[0487]

[0488] Step 1

[0489] Compound 19-1 (40 mg, 0.08 mmol), 19-1A (24 mg, 0.16 mmol), and Cs2CO3 (60 mg, 0.24 mmol) were dissolved in ACN (3 mL). The reaction system was heated to 90 °C and reacted under nitrogen protection for 24 h. After concentration of the reaction solution, the crude product was separated by high-performance liquid chromatography column to obtain white solid 19-2 (13 mg, yield: 27%). LCMS (M+H) + = 589.1.

[0490] Step 2

[0491] Compound 19-2 (15 mg, 0.03 mmol) was dissolved in DCM (2 mL), and TFA (0.5 mL) was added dropwise under an ice-water bath. The reaction solution was reacted at room temperature for 2 h. After concentration of the reaction solution, the crude product was separated by high-performance liquid chromatography column to obtain white solid Compound 19 (3.5 mg, yield: 29%) LCMS (M+H) + = 489.1. 11H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.83–7.71 (m, 3H), 7.66 (s, 1H), 5.14 (s, 2H), 4.48 (d, J = 7.2 Hz, 2H), 3.46 (d, J = 4.4 Hz, 1H), 3.32–3.29 (m, 6H), 3.15 (s, 2H), 2.99 (s, 2H), 2.16 (d, J = 7.4 Hz, 1H), 1.95–1.82 (m, 1H). 19 19F NMR (376 MHz, DMSO) δ -77.02 (s, 4.79 F), -110.31 (s, 1F).

[0492] Example 20

[0493] Synthesis of 4-(7-((1R,3R)-3-aminocyclopentyl)-4-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 20)

[0494]

[0495] Step 1

[0496] Dissolve Compound 20-1 (2 g, 10.3 mmol), 20-1A (3.7 mg, 50 mmol), and K2CO3 (2.8 g, 20.6 mmol) in DMF (15 mL). Heat the reaction system to 100 °C and react for 2 h under nitrogen protection. After concentrating the reaction solution, the crude product is separated by high-performance liquid chromatography column to obtain white solid 20-2 (800 mg, yield: 29%). LCMS (M+H) + = 267.1.

[0497] Step 2

[0498] Dissolve Compound 20-2 (800 mg, 3.0 mmol) in THF (10 mL). Add an aqueous solution of 1 M sodium hydroxide (6 mL, 6.0 mmol) under an ice-water bath, and then add 30% hydrogen peroxide (680 mg, 6.0 mmol). React at room temperature for 3 h. Adjust the pH to 2 with 1 M dilute hydrochloric acid, dilute with water, add dichloromethane and methanol (10:1) for extraction, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain colorless oily Compound 20-3 (300 mg, yield: 64%). LCMS (M+H) + = 157.0.

[0499] Step 3

[0500] Dissolve compound 20-3 (200 mg, 1.3 mmol) in DMF (10 mL), and add NaH (100 mg, 2.6 mmol) portionwise under an ice-water bath. Stir the reaction at room temperature for 0.5 h, add compound 20-3A (460 mg, 1.0 mmol), heat the reaction to 70 °C for 3 h, cool to room temperature, and quench the reaction solution by dropping it into ice water under an ice-water bath. Extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain colorless oil 20-4 (100 mg, yield: 17%). LCMS (M+H) + = 583.0

[0501] Step 4

[0502] Dissolve compound 20-4 (100 mg, 0.17 mmol), compound 20-4A (42 mg, 0.25 mmol), and potassium carbonate (47 mg, 0.34 mmol) in a mixed solution of dioxane (4 mL) and water (1 mL), add Pd(dppf)Cl2 (19 mg, 0.03 mmol), and react at 110 °C for 2 h under nitrogen protection. Concentrate to remove the solvent, and purify the obtained crude product by SGC (PE:EA = 1:3) to obtain white solid compound 20-5 (25 mg, yield: 25%). LCMS (M+H) + = 576.2

[0503] Step 5

[0504] Dissolve compound 20-5 (25 mg, 0.04 mmol) in dichloromethane (2.5 mL), add trifluoroacetic acid (1 mL), stir the reaction at room temperature for 1 h, concentrate to remove the solvent, and purify the obtained crude product by prep-HPLC to obtain white solid compound 20 (4.5 mg, yield: 24%). LCMS (M+H) + = 476.3

[0505] 11H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.28 (s, 1H), 8.04–7.99 (m, 2H), 7.96 (s, 1H), 7.95–7.89 (m, 2H), 7.85 (dd, J = 8.2, 1.5 Hz, 1H), 7.57 (d, J = 0.6 Hz, 1H), 5.54–5.43 (m, 1H), 4.74 (s, 1H), 4.01 (s, 2H), 3.95 (s, 1H), 2.45–2.35 (m, 2H), 2.34–2.21 (m, 2H), 2.16–2.04 (m, 1H), 1.74 (dd, J = 21.0, 8.1 Hz, 1H), 1.09 (s, 6H). 19 19F NMR (376 MHz, DMSO) δ -73.50 (s, 3F), -109.20 (s, 1F).

[0506] Example 21

[0507] Synthesis of 4-(7-((1R,3R)-3-aminocyclopentyl)-4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 21)

[0508]

[0509] Step 1

[0510] Dissolve Compound 21-1 (300 mg, 1.2 mmol) in anhydrous tetrahydrofuran (4 mL), dropwise add an aqueous solution of NaOH (97 mg, 2.4 mmol) in water (0.8 mL) under an ice-water bath, then dropwise add hydrogen peroxide (83 mg, 2.4 mmol), and stir at room temperature for 3 hours. Adjust the pH to 3 - 4 with 3 M dilute hydrochloric acid, extract with a mixed solution of dichloromethane and methanol (10:1), backwash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product, a white solid Compound 21-2 (150 mg, yield: 90%). LCMS (M+H) + = 139.0

[0511] Step 2

[0512] Compound 21-2 (60 mg, 0.4 mmol) was dissolved in DMF (4 mL). Sodium hydride (11 mg, 0.4 mmol) was added portionwise under an ice-water bath. After addition, the mixture was stirred at room temperature for 30 minutes. Compound 21-3 (100 mg, 0.2 mmol) was added portionwise under an ice-water bath, and the temperature was raised to 100 °C and stirred for 3 hours. After cooling to room temperature, the mixture was added dropwise to an ice-water mixture to quench the reaction, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained by column chromatography (PE:EA = 1:1) to give white solid compound 21-4 (60 mg, yield: 49%). LCMS (M+H) + = 564.0.

[0513] Step 3

[0514] A mixture of compound 21-4 (45 mg, 0.08 mmol), compound 21-5 (27 mg; 0.16 mmol), and potassium carbonate (22 mg, 0.16 mmol) was dissolved in a mixed solvent of dioxane (5 mL) and water (1 mL). Catalyst Pd(dppf)Cl2 (6 mg, 0.01 mmol) was added. The reaction system was purged with nitrogen three times, the temperature was raised to 100 °C and stirred for 2 hours, concentrated to remove the solvent, and the crude product was obtained by column chromatography (PE:EA = 1:1) to give white solid compound 21-6 (10 mg, yield: 23%). LCMS (M+H) + = 558.0.

[0515] Step 4

[0516] Compound 21-6 (10 mg, 0.02 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 mixture was stirred at room temperature for 1 hour. The concentrated crude product was prepared by prep-HPLC to give white solid compound 21 (4.4 mg, yield: 54%). LCMS (M+H) + = 458.0. 1 1H NMR (400 MHz, DMSO) δ 8.57–8.49 (m, 1H), 8.32–8.24 (m, 1H), 8.03–7.92 (m, 6H), 7.89–7.83 (m, 1H), 7.60–7.52 (m, 1H), 5.56–5.42 (m, 1H), 4.00–3.93 (m, 3H), 2.41–2.27 (m, 4H), 2.18–2.04 (m, 1H), 1.83–1.67 (m, 1H), 1.33–1.16 (m, 1H), 0.59–0.51 (m, 2H), 0.43–0.34 (m, 2H). 19FNMR (376 MHz, DMSO) δ -73.54 (s, 3F), -109.17 (s, 1F).

[0517] Example 22

[0518] Synthesis of N-(2-Ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-(piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-2-amine (Compound 22)

[0519]

[0520] Step 1

[0521] Dissolve Compound 22-1 (450 mg, 2.3 mmol) in DMF (6 mL), add Compound 22-2 (441 mg, 2.3 mmol) and potassium carbonate (628 mg, 4.6 mmol), heat to 100 °C and stir for 2 hours. After cooling to room temperature, add water and ethyl acetate for extraction, backwash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and the crude product is purified by column chromatography (PE:EA = 2:1) to obtain white solid Compound 22-3 (200 mg, yield: 33%). LCMS (M+H) + = 265.0.

[0522] Step 2

[0523] Dissolve Compound 22-3 (60 mg, 0.23 mmol) in tetrahydrofuran (3 mL), dropwise add a solution of sodium hydroxide (18 mg, 0.46 mmol) in water (0.12 mL) under an ice-water bath, then dropwise add hydrogen peroxide (18 mg, 0.46 mmol). After dropping, restore to room temperature and stir for 2 hours. Adjust the pH of the reaction solution to 3 - 4 with 3M dilute hydrochloric acid, and the reaction solution is purified by prep-HPLC to obtain white solid Compound 22-4 (10 mg, yield: 29%). LCMS (M+H) + = 155.0.

[0524] Step 3

[0525] Compound 22-4 (10 mg, 0.07 mmol) was dissolved in DMF (3 mL). NaH (6 mg, 0.13 mmol) was added portionwise under an ice-water bath. The mixture was stirred at room temperature for 30 minutes. Compound 22-5 (45 mg, 0.1 mmol) was added portionwise under an ice-water bath. After addition, the temperature was raised to 30 °C and the reaction was stirred for 1 hour. The reaction mixture was poured into an ice-water mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC to obtain white solid compound 22-6 (16 mg, yield: 42%). LCMS (M+H) + = 581.0

[0526] Step 4

[0527] A mixture of compound 22-6 (16 mg, 0.03 mmol), compound 22-7 (10 mg; 0.06 mmol), and potassium carbonate (8 mg, 0.06 mmol) was dissolved in a mixed solvent of dioxane (2 mL) and water (0.5 mL). Catalyst Pd(dppf)Cl2 (2 mg, 0.01 mmol) was added. The reaction system was purged with nitrogen three times. The temperature was raised to 90 °C and the reaction was stirred for 1.5 hours. The solvent was removed by concentration. The crude product obtained was purified by prep-HPLC to obtain white solid compound 22-8 (12 mg, yield: 76%). LCMS (M+H) + = 574.0

[0528] Step 5

[0529] Compound 22-8 (12 mg, 0.02 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 obtained by concentration was prepared by prep-HPLC to obtain white solid compound 22 (5 mg, yield: 50%). LCMS (M+H) + = 474.0 1 H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.29 (s, 1H), 8.06 (s, 3H), 8.00 (s, 1H), 7.96–7.90 (m, 1H), 7.86 (d, J = 1.3 Hz, 1H), 7.61 (s, 1H), 5.54–5.43 (m, 1H), 5.05–4.98 (m, 1H), 3.96 (dd, J = 18.5, 5.1 Hz, 4H), 3.86–3.79 (m, 1H), 2.42–2.28 (m, 6H), 2.16–2.03 (m, 1H), 1.84–1.70 (m, 1H). 1919F NMR (376 MHz, DMSO) δ -73.54 (s, 3F), -109.17 (s, 1F).

[0530] Example 23

[0531] Synthesis of 4-(1-((1R,3R)-3-aminocyclopentyl)-4-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorobenzonitrile (Compound 23)

[0532]

[0533] Step 1

[0534] Dissolve Compound 23-1 (250 mg, 1.3 mmol), Compound 23-2 (367 mg, 1.9 mmol) and triphenylphosphine (794 mg, 3 mmol) in anhydrous tetrahydrofuran (3 mL), displace with nitrogen three times, and under an ice-water bath, add dropwise DEAD (527 mg, 3 mmol). After addition, restore to room temperature and stir for 2 hours. The crude reaction mixture was purified by column chromatography (PE:EA = 1:1) to obtain white solid Compound 23-3 (180 mg, yield: 31%). LCMS (M+H) + = 464.0.

[0535] Step 2

[0536] Dissolve Compound 23-4 (59 mg, 0.43 mmol) in DMF (3 mL), add sodium hydride (14 mg, 0.6 mmol) portionwise under an ice-water bath. After addition, stir at room temperature for 30 minutes. Then add Compound 23-3 (180 mg, 0.14 mmol) to the reaction mixture, and heat to 100 °C and react overnight. Quench the reaction mixture by adding it dropwise to ice water under an ice-water bath, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (PE:EA = 1:1) to obtain white solid Compound 23-5 (80 mg, yield: 36%). LCMS (M+H) + = 566.0.

[0537] Step 3

[0538] A mixture of compound 23-5 (80 mg, 0.14 mmol), compound 23-6 (47 mg, 0.28 mmol) and potassium carbonate (39 mg, 0.28 mmol) was dissolved in a mixed solvent of dioxane (3 mL) and water (0.6 mL). Catalyst Pd(dppf)Cl2 (10 mg, 0.014 mmol) was added. After purging with nitrogen three times, the reaction solution was heated to 100 °C and reacted for 2 hours. After diluting the reaction system with ethyl acetate, the crude product was purified by column chromatography (PE:EA = 1:1) to obtain white solid compound 23-7 (50 mg, yield: 63%). LCMS (M+H) + = 559.0.

[0539] Step 4

[0540] Compound 23-7 (50 mg, 0.1 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. After addition, the mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration, and the crude product was prepared by prep-HPLC to obtain white solid compound 23 (18 mg, yield: 44%). LCMS (M+H) + = 459.0. 1 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.14 (s, 3H), 8.09 (s, 1H), 8.00–7.95 (m, 2H), 7.62 (s, 1H), 5.75–5.60 (m, 1H), 3.99 (d, J = 7.2 Hz, 3H), 2.58–2.52 (m, 1H), 2.42–2.32 (m, 2H), 2.30–2.21 (m, 1H), 2.18–2.09 (m, 1H), 1.84–1.73 (m, 1H), 1.31–1.20 (m, 1H), 0.59–0.51 (m, 2H), 0.43–0.35 (m, 2H). 19 19F NMR (376 MHz, DMSO) δ -73.51 (s, 3F), -108.02 (s, 1F).

[0541] Example 24

[0542] Synthesis of 4-(7-((1R,3R)-3-aminocyclopentyl)-4-((1-cyclobutyl-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 24)

[0543]

[0544]

[0545] Step 1

[0546] Dissolve compound 24-1 (550 mg, 2.83 mmol), 24-1A (570 mg, 4.25 mmol), and K2CO3 (781 g, 5.66 mmol) in DMF (10 mL). Heat the reaction system to 100 °C and react for 12 h under nitrogen protection. After concentrating the reaction solution, the crude product is separated by high-performance liquid chromatography column to obtain white solid 24-2 (200 mg, yield: 28%). LCMS (M+H) + = 249.1

[0547] Step 2

[0548] Dissolve compound 24-2 (200 mg, 0.8 mmol) in THF (10 mL). Add an aqueous solution of 1 M sodium hydroxide (1.6 mL, 1.6 mmol) under an ice-water bath, and then add 30% hydrogen peroxide (181 mg, 1.6 mmol). React at room temperature for 3 h. Adjust the pH to 2 with 1 M dilute hydrochloric acid. After diluting with water, extract with dichloromethane and methanol (10:1). Wash the organic phase with saturated brine. Dry the organic phase over anhydrous sodium sulfate, concentrate, and obtain colorless oily compound 24-3 (80 mg, yield: 72%). LCMS (M+H) + = 139.0

[0549] Step 3

[0550] Dissolve compound 24-3 (80 mg, 0.58 mmol) in DMF (5 mL). Add NaH (35 mg, 0.87 mmol) portionwise under an ice-water bath. Stir and react at room temperature for 0.5 h. Add compound 24-3A (360 mg, 0.7 mmol), heat to 70 °C and react for 3 h. Cool to room temperature. Quench the reaction solution by dropping it into ice water under an ice-water bath. Extract with ethyl acetate. Wash the organic phase with saturated brine. Dry the organic phase over anhydrous sodium sulfate, concentrate, and obtain colorless oily substance 24-4 (45 mg, yield: 14%). LCMS (M+H) + = 565.1

[0551] Step 4

[0552] Compound 24-4 (45 mg, 0.08 mmol), compound 24-4A (20 mg, 0.12 mmol), and potassium carbonate (22 mg, 0.16 mmol) were dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Pd(dppf)Cl2 (7 mg, 0.01 mmol) was added, and the reaction was carried out at 110 °C for 2 h under nitrogen protection. The solvent was removed by concentration, and the crude product obtained was purified by SGC (PE:EA = 1:3) to give white solid compound 24-5 (30 mg, yield: 67%). LCMS (M+H) + = 558.2.

[0553] Step 5

[0554] Compound 24-5 (30 mg, 0.05 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 1 h. The solvent was removed by concentration, and the crude product obtained was purified by prep-HPLC to give white solid compound 24 (9.8 mg, yield: 43%). LCMS (M+H) + = 458.3. 1 H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 8.03–7.96 (m, 3H), 7.94–7.90 (m, 1H), 7.85 (dd, J = 8.2, 1.5 Hz, 1H), 7.60 (s, 1H), 5.52–5.44 (m, 1H), 4.86–4.78 (m, 1H), 3.94 (s, 1H), 2.46 (dd, J = 9.4, 7.1 Hz, 2H), 2.42–2.26 (m, 6H), 2.13–2.05 (m, 1H), 1.77 (ddd, J = 14.9, 9.7, 4.1 Hz, 3H). 19 F NMR (376 MHz, DMSO) δ -73.49 (s, 3F), -109.14 (s, 1F).

[0555] Example 25

[0556] Synthesis of 4-(7-((1R,3R)-3-aminocyclopentyl)-4-((1-((1-hydroxycyclobutyl)methyl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 25)

[0557]

[0558]

[0559] Step 1

[0560] Dissolve compound 25-1 (200 mg, 1 mmol) in DMF (10 mL), add potassium carbonate (285 mg, 2 mmol) and compound 25-2 (173 mg, 2 mmol). Heat the mixture to 100 °C and stir for 2 hours. After dilution with ethyl acetate, wash the organic phase with water. Dry the organic phase over anhydrous sodium sulfate, concentrate it, and purify the obtained crude product by SGC (PE:EA = 4:1) to obtain white solid compound 25-3 (160 mg, yield: 56%). LCMS (M+H) + = 279.0

[0561] Step 2

[0562] Dissolve compound 25-3 (160 mg, 0.576 mmol) in THF (3 mL). Add 0.3 mL of an aqueous solution of 3 M sodium hydroxide (46 mg, 1.15 mmol) under an ice-water bath, and then add hydrogen peroxide (44 mg, 1.15 mmol). React at room temperature for 3 hours. Adjust the pH to weakly acidic with 3 M dilute hydrochloric acid. After removing the solvent from the reaction mixture by a freeze dryer, obtain crude product 25-4 (90 mg, yield: 93%) as a white solid mixture. LCMS (M+H) + = 169.0

[0563] Step 3

[0564] Dissolve compound 25-4 (90 mg, 0.536 mmol) in DMF (2 mL). Add sodium hydride (21 mg, 0.857 mmol) portionwise under an ice-water bath. After stirring at room temperature for 0.5 hour, add compound 25-5 (371 mg, 0.8 mmol) and react at room temperature for 1 hour. Quench the reaction solution by dropping it into ice water under an ice-water bath. Extract with ethyl acetate, wash the organic phase with saturated brine. Dry the organic phase over anhydrous sodium sulfate, concentrate it, and purify the obtained crude product by SGC (PE:EA = 1:1) to obtain white solid compound 25-6 (80 mg, yield: 25%). LCMS (M+H) + = 595.0

[0565] Step 4

[0566] Compound 25-6 (80 mg, 0.14 mmol), compound 25-7 (45 mg, 0.27 mmol), and potassium carbonate (47 mg, 0.34 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (1 mL). Pd(dppf)Cl2 (10 mg, 0.01 mmol) was added. The reaction system was purged with nitrogen three times and heated to 90 °C for 1.5 h. The solvent was concentrated under reduced pressure. The crude product obtained was purified by SGC (PE:EA = 1:1) to give white solid compound 25-8 (60 mg, yield: 76%). LCMS (M+H)+ = 588.0.

[0567] Step 5

[0568] Compound 25-8 (60 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 h. The solvent was concentrated under reduced pressure. The crude residue obtained was purified by prep-HPLC to give white solid compound 25 (31 mg, yield: 62%). LCMS (M+H) + = 488.0. 1H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.28 (s, 1H), 7.94 (s, 6H), 7.87–7.83 (m, 1H), 7.56 (s, 1H), 5.53–5.38 (m, 2H), 4.16 (s, 2H), 3.99–3.88 (m, 1H), 2.39–2.30 (m, 3H), 2.15–2.05 (m, 3H), 1.99–1.90 (m, 2H), 1.79–1.70 (m, 1H), 1.68–1.59 (m, 1H), 1.54–1.44 (m, 1H). 19F NMR (376 MHz, DMSO) δ -73.54 (s, 2.46F), -109.196 (s, 1F).

[0569] Example 26

[0570] Synthesis of 4-(7-((1R,3R)-3-aminocyclohexyl)-4-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 26)

[0571]

[0572]

[0573] Step 1

[0574] Compound 26-1 (250 mg, 0.9 mmol) was dissolved in THF (5 mL), triphenylphosphine (587 mg, 2.2 mmol) and compound 26-2 (289 mg, 1.3 mmol) were added. The system was purged with nitrogen three times. DEDA (390 mg, 2.2 mmol) was added dropwise under an ice-water bath. After the addition, the reaction was stirred at room temperature overnight. The reaction solution was purified by prep-HPLC to obtain white solid compound 26-3 (35 mg, yield: 7%). LCMS (M+H) + = 477.0

[0575] Step 2

[0576] Compound 26-3 (35 mg, 0.07 mmol) was dissolved in DMF (2 mL). Sodium hydride (32 mg, 0.18 mmol) was added portionwise under an ice-water bath. After stirring at room temperature for 0.5 h, compound 26-4 (23 mg, 0.15 mmol) was added. The reaction was carried out at room temperature for 1 h. The reaction solution was quenched by dropping it into ice water under an ice-water bath, extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product obtained was purified by SGC (PE:EA = 1:1) to obtain white solid compound 26-5 (40 mg, yield: 0.07%). LCMS (M+H) + = 597.0

[0577] Step 3

[0578] Compound 26-5 (30 mg, 0.05 mmol), compound 26-6 (17 mg, 0.1 mmol), and potassium carbonate (21 mg, 0.15 mmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (1 mL). Pd(dppf)Cl2 (4 mg, 0.005 mmol) was added. The reaction system was purged with nitrogen 3 times and heated to 100 °C for 2 h. The solvent was removed by concentration, and the crude product obtained was purified by SGC (PE:EA = 1:1) to obtain white solid compound 26-7 (25 mg, yield: 84%). LCMS (M+H)+ = 590.0

[0579] Step 4

[0580] Compound 26-7 (25 mg, 0.1 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed by concentration, and the crude residue obtained was purified by prep-HPLC to obtain white solid compound 26 (20 mg, yield: 96%), LCMS (M+H) += 490.0. 1H NMR (400 MHz, DMSO) δ 8.57–8.53 (m, 1H), 8.35–8.29 (m, 1H), 8.21–8.05 (m, 3H), 8.05–7.98 (m, 1H), 7.98–7.91 (m, 2H), 7.89–7.83 (m, 1H), 7.60–7.55 (m, 1H), 5.29–5.15 (m, 1H), 4.83–4.58 (m, 1H), 4.01 (s, 2H), 3.81–3.66 (m, 1H), 2.40–2.32 (m, 1H), 2.19–2.07 (m, 1H), 2.04–1.95 (m, 2H), 1.85–1.73 (m, 3H), 1.09 (s, 6H). 19F NMR (376 MHz, DMSO) δ -73.504 (s, 2.58F), -109.194 (s, 1F).

[0581] Example 27

[0582] Synthesis of 4-(7-((1R,3R)-3-(dimethylamino)cyclopentyl)-4-((1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 27)

[0583]

[0584] Step 1

[0585] Dissolve Compound 27-1 (550 mg, 1.2 mmol) in 4M HCl in EA (10 mL), and react at room temperature for 2 h. After concentration of the reaction solution, a white solid 27-2 (350 mg, yield: 28%) was obtained. LCMS (M+H) + = 363.1.

[0586] Step 2

[0587] Dissolve Compound 27-2 (350 mg, 0.97 mmol) in ethanol (10 mL), add an aqueous solution of 37-39% formaldehyde aqueous solution (1 mL) under an ice-water bath, and react at room temperature for 1 h. Then add STAB (530 mg, 2.5 mmol), react at room temperature for 2 hours, dilute with water, add EA for extraction, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate, and the obtained crude product was purified by SGC (PE:EA = 1:1) to obtain a white solid Compound 27-3 (100 mg, yield: 26%). LCMS (M+H) + = 391.0.

[0588] Step 3

[0589] Dissolve compound 27-3 (100 mg, 0.25 mmol) in DMF (5 mL), and add NaH (31 mg, 0.75 mmol) portionwise under an ice-water bath. Stir the reaction at room temperature for 0.5 h, add compound 27-3A (78 mg, 0.5 mmol), heat the reaction to 70 °C for 3 h, cool to room temperature, and quench the reaction solution by dropping it into ice water under an ice-water bath. Extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate to obtain a colorless oil 27-4 (30 mg, yield: 25%). LCMS (M+H) + = 511.1

[0590] Step 4

[0591] Dissolve compound 27-4 (30 mg, 0.06 mmol), compound 27-4A (14 mg, 0.09 mmol), and potassium carbonate (17 mg, 0.12 mmol) in a mixed solution of dioxane (3 mL) and water (0.5 mL), add Pd(dppf)Cl2 (7 mg, 0.01 mmol), and react at 110 °C for 2 h under nitrogen protection. Concentrate to remove the solvent, and purify the obtained crude product by Prep-HPLC to obtain a white solid compound 27 (7.7 mg, yield: 26%). LCMS (M+H) + = 504.3 1 1H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 8.54 (s, 1H), 8.25 (s, 1H), 8.06–7.98 (m, 1H), 7.97–7.89 (m, 2H), 7.85 (dd, J = 8.2, 1.5 Hz, 1H), 7.57 (s, 1H), 5.44–5.36 (m, 1H), 4.73 (s, 1H), 4.01 (s, 2H), 3.97 (s, 1H), 2.83 (s, 6H), 2.46–2.40 (m, 2H), 2.36 (dd, J = 16.2, 6.6 Hz, 2H), 2.18 (dd, J = 15.0, 7.4 Hz, 1H), 1.95–1.85 (m, 1H), 1.09 (s, 6H). 19 19F NMR (376 MHz, DMSO) δ -73.46 (s, 3F), -109.16 (s, 1F).

[0592] Example 28

[0593] Synthesis of 4-(7-((1R,3R)-3-aminocyclohexyl)-4-((1-(3-hydroxy-3-methylcyclopentyl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 28)

[0594]

[0595] Step 1

[0596] Dissolve Compound 28-1 (1.1 g, 5.7 mmol) in acetonitrile (20 mL), add Compound 28-2 (465 mg, 5.7 mmol) and T3P (1.98 g, 26.24 mmol), stir the mixture at room temperature for 6 hours, concentrate, and purify the obtained crude product by SGC (PE:EA = 4:1) to obtain white solid Compound 28-3 (800 mg, yield: 51%).

[0597] Step 2

[0598] Dissolve Compound 28-3 (800 mg, 2.9 mmol) in THF (10 mL), after purging with nitrogen three times, cool the mixture to -30 °C in a dry ice bath, add a solution of 1 M methylmagnesium bromide (4.5 mL, 4.5 mmol) in THF dropwise, slowly warm the mixture to room temperature and react overnight, quench the reaction by adding saturated ammonium chloride aqueous solution in an ice bath, dilute with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the obtained crude product by SGC (PE:EA = 1:1) to obtain white solid Compound 28-4 (70 mg, yield: 8%). LCMS (M+H) + = 293.0

[0599] Step 3

[0600] Dissolve Compound 28-4 (70 mg, 0.246 mmol) in THF (2 mL), slowly add 0.48 mL of an aqueous solution of 1 M sodium hydroxide (20 mg, 0.48 mmol) in an ice bath, then add hydrogen peroxide (20 mg, 0.48 mmol), stir slowly for 1 hour in an ice bath, adjust the pH to weakly acidic with 1 M dilute hydrochloric acid, and lyophilize to obtain the crude product of Compound 28-5 (40 mg, yield: 92%). LCMS (M+H) + = 183.0

[0601] Step 4

[0602] Compound 28-5 (15 mg, 0.08 mmol) was dissolved in DMF (2 mL). Sodium hydride (4 mg, 0.16 mmol) was added portionwise under an ice-water bath. After stirring at room temperature for 30 minutes, compound 28-6 (40 mg, 0.08 mmol) was added under an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour, then added dropwise to ice water to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product obtained was purified by SGC (PE:EA = 1:1) to give white solid compound 28-7 (30 mg, yield: 59%). LCMS (M+H) + = 623.0

[0603] Step 5

[0604] Compound 28-7 (30 mg, 0.048 mmol) was dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Potassium carbonate (20 mg, 0.15 mmol), compound 28-8 (16 mg, 0.1 mmol) and catalyst Pd(dppf)Cl2 (4 mg, 0.005 mmol) were added. The mixture was purged with nitrogen three times and heated to 90 °C for reaction for 2 hours. Most of the solvent was removed by concentration. The residue obtained was purified by SGC (PE:EA = 1:2) to give white solid compound 28-9 (10 mg, yield: 34%). LCMS (M+H) + = 616.0

[0605] Step 6

[0606] Compound 28-9 (10 mg, 0.016 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 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 give white solid compound 28 (5.5 mg, yield: 67%), LCMS (M+H) += 516.3. 1H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.31 (s, 1H), 8.07 (d, J = 9.4 Hz, 3H), 7.99 (d, J = 7.4 Hz, 1H), 7.93 (d, J = 11.5 Hz, 1H), 7.85 (dd, J = 8.2, 1.5 Hz, 1H), 7.56 (s, 1H), 5.19 (s, 1H), 4.82–4.69 (m, 2H), 3.73 (s, 1H), 2.42–2.31 (m, 2H), 2.22–2.09 (m, 4H), 2.02–1.97 (m, 2H), 1.83 (d, J = 12.4 Hz, 4H), 1.72–1.57 (m, 2H), 1.28 (s, 3H). 19F NMR (376 MHz, DMSO) δ -73.54 (s, 3.32F), -109.13 (s, 1F).

[0607] Example 29

[0608] Synthesis of 4-(7-((1R,3R)-3-aminocyclohexyl)-4-((1-(3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 29)

[0609]

[0610] Step 1

[0611] Dissolve Compound 29-1 (1.1 g, 5.7 mmol) in acetonitrile (20 mL), add Compound 29-2 (1.7 g, 11.34 mmol) and potassium carbonate (1.56 g, 11.34 mmol). Stir the mixture at room temperature for 6 hours, concentrate, and purify the obtained crude product by SGC (PE:EA = 4:1) to obtain white solid Compound 29-3 (400 mg, yield: 27%). LCMS (M+H) + = 263.0.

[0612] Step 2

[0613] Compound 29-3 (300 mg, 1.15 mmol) was dissolved in THF (3 mL). After purging with nitrogen three times, the temperature was lowered to -30 °C in a dry ice bath. A solution of 1.6 M methyllithium (0.54 mL, 1.07 mmol) in THF was added dropwise. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched by adding saturated aqueous ammonium chloride solution in an ice bath. After dilution with water, the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product obtained was purified by SGC (PE:EA = 1:1) to give white solid compound 29-4 (60 mg, yield: 19%). LCMS (M+H) + = 279.0

[0614] Step 3

[0615] Compound 29-4 (60 mg, 0.217 mmol) was dissolved in THF (2 mL). Aqueous solution of 1 M sodium hydroxide (18 mg, 0.43 mmol), 0.43 mL, was slowly added in an ice bath, then hydrogen peroxide (17 mg, 0.43 mmol) was added. The mixture was slowly stirred for 1 hour in an ice bath. The pH was adjusted to weakly acidic with 1 M dilute hydrochloric acid, and the product was freeze-dried to obtain the crude product of compound 29-5 (30 mg, yield: 83%). LCMS (M+H) + = 169.0

[0616] Step 4

[0617] Compound 29-5 (30 mg, 0.18 mmol) was dissolved in DMF (2 mL). Sodium hydride (11 mg, 0.45 mmol) was added portionwise in an ice bath. After stirring at room temperature for 30 minutes, compound 29-6 (85 mg, 0.18 mmol) was added in an ice bath. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to ice water to quench the reaction. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product obtained was purified by SGC (PE:EA = 1:1) to give white solid compound 29-7 (30 mg, yield: 28%). LCMS (M+H) + = 609.0

[0618] Step 5

[0619] Compound 29-7 (30 mg, 0.049 mmol) was dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Potassium carbonate (34 mg, 0.25 mmol), compound 29-8 (16 mg, 0.1 mmol) and catalyst Pd(dppf)Cl2 (4 mg, 0.005 mmol) were added. After displacing with nitrogen three times, the mixture was heated to 90 °C and reacted for 2 hours. Most of the solvent was removed by concentration. The obtained residue was purified by SGC (PE:EA = 1:2) to give white solid compound 29-9 (20 mg, yield: 67%). LCMS (M+H) + = 602.0

[0620] Step 6

[0621] Compound 29-9 (20 mg, 0.033 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by concentration. The obtained crude residue was purified by prep-HPLC to give white solid compound 29 (11 mg, yield: 66%). LCMS (M+H) + = 502.2. 1H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.32 (s, 1H), 8.09 (s, 3H), 8.04 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H), 7.94 (dd, J = 11.5, 1.4 Hz, 1H), 7.86 (dd, J = 8.2, 1.5 Hz, 1H), 7.60 (d, J = 0.4 Hz, 1H), 5.30–5.14 (m, 2H), 4.49 (s, 1H), 3.76–3.69 (m, 1H), 2.54 (d, J = 7.6 Hz, 1H), 2.49 (d, J = 6.7 Hz, 2H), 2.47 (d, J = 1.8 Hz, 1H), 2.40–2.32 (m, 1H), 2.16–2.09 (m, 1H), 1.99 (s, 2H), 1.81 (s, 4H), 1.32 (s, 3H). 19F NMR (376 MHz, DMSO) δ -73.552 (s, 2.43F), -109.157 (s, 1F).

[0622] Example 30

[0623] Synthesis of 4-(7-((1R,3R)-3-aminocyclopentyl)-4-((1-(oxetan-3-yl)-1H-pyrazol-4-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluorobenzonitrile (Compound 30)

[0624]

[0625] Step 1

[0626] Dissolve compound 30-1 (300 mg, 1.55 mmol) in DMF (5 mL), add compound 30-2 (210 mg, 1.55 mmol), potassium carbonate (427 mg, 3.1 mmol) and sodium iodide (214 mg, 1.55 mmol). Heat the mixture to 130 °C and stir for 20 hours. Concentrate the mixture. The crude product obtained is purified by SGC (PE:EA = 4:1) to obtain white solid compound 30-3 (100 mg, yield: 26%). LCMS (M+H) + = 251.0

[0627] Step 2

[0628] Dissolve compound 30-3 (100 mg, 0.4 mmol) in THF (2 mL). Slowly add 0.8 mL of 1 M aqueous sodium hydroxide (32 mg, 0.8 mmol) solution under an ice-water bath. Then add hydrogen peroxide (32 mg, 0.8 mmol). Stir slowly for 1 hour under an ice-water bath. Adjust the pH to weakly acidic with 1 M dilute hydrochloric acid and lyophilize to obtain the crude product of compound 30-4 (100 mg). LCMS (M+H) + = 141.0

[0629] Step 3

[0630] Dissolve the crude product of compound 30-4 (100 mg, 0.4 mmol) in DMF (2 mL). Add sodium hydride (20 mg, 0.8 mmol) portionwise under an ice-water bath. Stir at room temperature for 30 minutes, then add compound 30-5 (185 mg, 0.4 mmol) under an ice-water bath. Stir the reaction mixture at room temperature for 1 hour. Drop the reaction mixture into ice water to quench the reaction. Extract with ethyl acetate and wash the organic phase with saturated brine. Dry the organic phase over anhydrous sodium sulfate and concentrate. The crude product obtained is purified by SGC (PE:EA = 1:1) to obtain white solid compound 30-6 (70 mg, yield: 31%). LCMS (M+H) + = 567.0

[0631] Step 4

[0632] Compound 30-6 (70 mg, 0.124 mmol) was dissolved in a mixed solution of dioxane (4 mL) and water (1 mL). Potassium carbonate (34 mg, 0.25 mmol), compound 30-7 (41 mg, 0.25 mmol) and catalyst Pd(dppf)Cl2 (9 mg, 0.01 mmol) were added. After displacing with nitrogen three times, the reaction was heated to 90 °C for 2 hours. Most of the solvent was removed by concentration. The obtained residue was purified by SGC (PE:EA = 1:2) to give white solid compound 30-8 (45 mg, yield: 65%). LCMS (M+H) + = 560.0

[0633] Step 5

[0634] Compound 30-8 (45 mg, 0.08 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at room temperature for 1 hour. The solvent was concentrated to obtain a crude residue, which was purified by prep-HPLC to give white solid compound 30 (17 mg, yield: 46%). LCMS (M+H) + = 460.3. 1H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 8.04–7.97 (m, 3H), 7.93 (dd, J = 11.4, 1.3 Hz, 1H), 7.85 (dd, J = 8.2, 1.5 Hz, 1H), 7.74 (s, 1H), 5.57 (d, J = 6.8 Hz, 1H), 5.53–5.42 (m, 1H), 4.93 (d, J = 2.7 Hz, 2H), 4.92 (d, J = 1.9 Hz, 2H), 4.01–3.88 (m, 1H), 2.43–2.27 (m, 4H), 2.13–2.04 (m, 1H), 1.81–1.70 (m, 1H). 19F NMR (376 MHz, DMSO) δ -73.505 (s, 2.11F), -109.144 (s, 1F).

[0635] Examples of Activity Tests

[0636] In the following examples, the inventors took some compounds of the present invention as examples to detect the LSD1 inhibitory activity and pharmacokinetic properties of the compounds of the present invention.

[0637] Example A: LSD1 inhibitory activity

[0638] The purpose of this experiment was to detect the in vitro inhibitory activity of the compounds of the present invention against LSD1.

[0639] Experimental Procedures and Methods

[0640] The purpose of this experiment is to detect the in vitro inhibitory activity of the compounds of the present invention against LSD1.

[0641] Experimental procedures and methods: The AlphaScreen method was used in this experiment to test the in vitro enzyme-level inhibitory activity of the compounds of the present invention against LSD1. The experimental procedures are described as follows:

[0642] a) Prepare 1x buffer

[0643] Prepare 1x buffer (modified Tris buffer)

[0644] b) Serial dilution of the compound

[0645] Transfer the compounds of the present invention to a multi-well plate using Echo, with a final DMSO concentration of 1%.

[0646] c) Prepare the enzyme solution

[0647] Prepare the enzyme solution in 1x buffer.

[0648] d) Prepare the substrate solution

[0649] Add the polypeptide in 1x buffer to prepare the substrate solution.

[0650] e) Transfer 5 μL of the enzyme solution or 1x buffer to the multi-well plate.

[0651] f) Incubate at room temperature for 15 minutes

[0652] g) Add 5 μL of the substrate solution to each well to initiate the reaction

[0653] h) Incubate at room temperature for 40 minutes

[0654] i) Prepare 1x Alphalisa buffer

[0655] j) Prepare 1x Alphalisa buffer solutions of the receptor and donor

[0656] Add 15 μL of the receptor and donor solutions in a dark environment and incubate at room temperature for 60 min.

[0657] k) Read the endpoint using the EnSpire Alpha mode

[0658] l) Data processing

[0659] Calculate the inhibition value using Equation 1:

[0660] Equation 1: Inh% = (Max - Signal) / (Max - Min)*100

[0661] Use XL-Fit to obtain the IC50 using Equation 2:

[0662] Equation 2: Y = Bottom + (Top - Bottom) / (1 + (IC50 / X)*HillSlope)

[0663] Y is the inhibition rate and X is the compound concentration.

[0664] Table 1 shows the experimental data of the inhibitory activities of some compounds of the present invention against LSD1.

[0665] Table 1:

[0666] Compound <![CDATA[LSD1 IC 50 (nM)]]> 3 87 5 86 7 11 8 54 9 37 10 18 11 21 12 87 15 24 16 91 17 31 20 9.9 21 5.1 22 7.2 23 8.2 24 2.7 25 2.9 26 3.6 27 7.1 28 0.56 29 2.7

[0667] The experimental results show that the compounds of the present invention have good inhibitory activities against LSD1.

[0668] Example B: Pharmacokinetic evaluation after intravenous injection or oral administration of the compound of the present invention to mice

[0669] The purpose of this experiment is to detect the pharmacokinetic properties of the compounds of the present invention in mice

[0670] Experimental procedures and methods:

[0671] The test compound is dissolved in 10% DMSO / 10% Solutol HS15 / 80% physiological saline, vortexed and sonicated to prepare a clear solution of the corresponding concentration, which is filtered through a microporous membrane and reserved. CD-1 mice weighing 21 to 27 g are selected and the test compound solution is administered intravenously at a dose of 5 mg / kg. The test compound is dissolved in 10% DMSO / 10% Solutol HS15 / 80% physiological saline, vortexed and sonicated to prepare a clear solution of the corresponding concentration, which is filtered through a microporous membrane and reserved. CD-1 mice weighing 21 to 27 g are selected and the test compound solution is administered orally at a dose of 5 mg / kg. Whole blood is collected at certain time points to prepare plasma, the drug concentration is analyzed by LC-MS / MS method, and the pharmacokinetic parameters are calculated using Phoenix WinNonlin software.

[0672] The experimental results show that the compounds of the present invention have a large exposure in the animals to be tested, are well absorbed, and have significant advantages in their pharmacokinetic properties.

[0673] In addition, the terms "first" and "second" are used for descriptive purposes only and cannot be construed as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present invention, "a plurality of" means at least two, such as two, three, etc., unless otherwise specifically defined.

[0674] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples", etc. means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions 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 a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0675] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound which is a compound represented by formula (I) or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt of the compound represented by formula (I), Formula (I), Among them, X1 and X3 are selected from C, and X2 and X4 are selected from N; Y is O or N; R1 is C 6-10 aryl or heteroaryl consisting of 5 - 10 atoms, wherein the C 6-10 aryl and heteroaryl consisting of 5 - 10 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 R's; R2 is C 3-12 a carbocyclic group, a heterocyclic group composed of 6 to 12 atoms, (a heterocyclic group composed of 3 to 12 atoms)-C 1-4 an alkylene group, wherein the C 3-12 a carbocyclic group, a heterocyclic group composed of 6 to 12 atoms, (a heterocyclic group composed of 3 to 12 atoms)-C 1-4 alkylene group is independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R''; R3 is H, deuterium, F, Cl, Br; Each R′ is independently H, deuterium, F, Cl, Br, -OR a , C 1-6 alkyl, C 3-8 cycloalkyl, a heterocyclic group composed of 3 to 12 atoms, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, a heterocyclic group composed of 3 to 12 atoms is each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, =O, -OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, a heterocyclic group composed of 3 to 6 atoms or -CO-NR b R c ; Each R″ is independently H, deuterium, F, Cl, Br, -NR b R c ; R a is H, C 1-6 alkyl; R b 、R c each independently is H, deuterium, C 1-6 alkyl group; The compound does not include: 、 、 。 2. The compound according to claim 1, which has the structure represented by formula (III): Formula (III).

3. The compound according to claim 1, which has the structures represented by formula (IV), formula (V), formula (VI), formula (VII) or formula (VIII): Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Among them, n1, n2, n3, n4 are each independently 1, 2 or 3; n5 is 0 or 1, n6 is 1, 2 or 3; or, n5 is 1 and n6 is 0; Rn1, Rn2, Rn3, Rn4, Rn5 are each independently deuterium, F, Cl, Br, -NR b R c ; m1, m2, m3, m4, m5 are each independently 0, 1, 2 or 3; X5 and X6 are each independently C or N, and one of X5 and X6 is N.

4. The compound according to any one of claims 1 to 3, wherein R1 is a heteroaryl composed of 5 to 9 atoms, and the heteroaryl composed of 5 to 9 atoms is each independently unsubstituted or substituted by 1 or 2 R'.

5. The compound according to any one of claims 1 to 2, wherein R2 is C 3-6 a carbocyclic group, a heterocyclic group composed of 6 atoms, (a heterocyclic group composed of 3-6 atoms)-C 1-4 an alkylene group, wherein, The said C 3-6 a carbocyclic group, a heterocyclic group composed of 6 atoms, (a heterocyclic group composed of 3-6 atoms)-C 1-4 The alkylene groups are each independently unsubstituted or substituted by 1, 2 or 3 R''.

6. The compound according to any one of claims 1 to 3, wherein R3 is F.

7. The compound according to any one of claims 1 to 3, wherein each R′ is independently H, deuterium, C 1-3 alkyl, C 3-6 cycloalkyl, or a heterocyclic group composed of 3 to 6 atoms, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, or the heterocyclic group composed of 3 to 6 atoms is independently unsubstituted or substituted with 1 or 2 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, -OH, C 1-6 alkyl, C 3-6 cycloalkyl, a heterocyclic group composed of 3 to 6 atoms, or -CO-NR b R c .

8. The compound according to any one of claims 1 to 3, wherein each R′ is independently H, deuterium, C 1-3 alkyl, C 3-6 cycloalkyl, or a heterocyclic group composed of 3 to 6 atoms, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, or the heterocyclic group composed of 3 to 6 atoms is independently unsubstituted or substituted by 1 or 2 substituents, and the substituents are independently selected from deuterium, F, Cl, Br, -OH, C 1-6 alkyl, C 3-6 cycloalkyl or a heterocyclic group composed of 3 to 6 atoms.

9. The compound according to any one of claims 1 to 2, wherein each R″ is independently H, -NR b R c .

10. The compound according to claim 1, wherein Y is O.

11. The compound according to any one of claims 1 to 3, wherein R1 is phenyl or pyrazolyl, and The phenyl group and pyrazolyl group are each independently unsubstituted or substituted by 1 or 2 R' which are each independently unsubstituted.

12. The compound according to any one of claims 1 to 2, wherein R2 is C 3-6 a carbocyclic group, wherein, Said C 3-6 The carbocyclic groups are each independently unsubstituted or substituted with 1, 2 or 3 R''.

13. The compound according to any one of claims 1 to 3, wherein each R′ is independently H, C 1-3 alkyl, C 3-6 cycloalkyl, or a heterocyclic group composed of 3 to 6 atoms, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, or the heterocyclic group composed of 3 to 6 atoms is independently unsubstituted or substituted with 1 or 2 substituents, and the substituents are independently selected from F, -OH, C 1-6 alkyl, or C 3-6 cycloalkyl.

14. The compound according to any one of claims 1 to 2, wherein each R″ is independently -NR b R c .

15. The compound according to any one of claims 1 to 3, R b and R c are each independently H or methyl.

16. A compound which has one of the following structures: ， or their stereoisomers, tautomers, or pharmaceutically acceptable salts.

17. A pharmaceutical composition which comprises an effective amount of the compound according to any one of claims 1 to 16 or its stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt.

18. The pharmaceutical composition according to claim 17, characterized in that, The pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, adjuvant or a combination thereof.

19. Use of the compound according to any one of claims 1 to 16 or its stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt, and the pharmaceutical composition according to any one of claims 17 to 18 in the preparation of a drug, wherein the drug is used for preventing, treating, treating or alleviating diseases associated with overexpression or hyperactivity of LSD1 in a patient.

20. The use according to claim 19, characterized in that, The diseases associated with overexpression of LSD1 are tumors.

21. The use according to claim 20, characterized in that, The tumors are papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, lung cancer, acute myeloid leukemia, prostate cancer or non-Hodgkin lymphoma.

22. The use according to claim 20, characterized in that, The tumor is small cell lung cancer.

23. Use of the compound according to any one of claims 1 to 16 or its stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt, and the pharmaceutical composition according to any one of claims 17 to 18 in the preparation of a drug, wherein the drug is used for inhibiting LSD1.

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