Pyrrolopyridine compound, composition thereof and application of pyrrolopyridine compound in medicine

Abstract

The invention relates to the technical field of medicines, in particular to a pyrrolopyridine compound, a composition of the pyrrolopyridine compound and application of the pyrrolopyridine compound to medicines. The pyrrolopyridine compound disclosed by the invention has a structure as shown in a formula (I). The compound can be used as an LSD1 inhibitor and has good activity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to pyrrolopyridine compounds, compositions thereof and uses thereof in medicine. Background Art

[0002] Histone methylation is an important type of histone covalent modification in epigenetic regulation. It was previously considered to be a relatively stable epigenetic modification. It was not until 2004 that Shi Yang et al. discovered the first specific lysine demethylase 1 (LSD1, KDM1A). People gradually realized that histone methylation and demethylation are a dynamic equilibrium process. Structurally, LSD1 can be divided into three parts: the Tower domain, the C-terminal amino oxidase (AOL) domain, and the N-terminal SWIRM domain. The Tower domain is composed of a group of reverse parallel α helices, which plays a very important role in the catalytic function of LSD1. The N-terminal domain contains an α helix, which can form a protein-protein complex with certain proteins, such as CoREST, NuRD and other proteins. This form is conducive to maintaining protein stability, so that the protein is not easy to deconstruct and inactivate while performing higher-level functions. The C-terminal AOL domain is the structural center of the entire LSD1 catalytic function. It is the hub for recognizing FAD and is also the site for specific binding to FAD. The reduction in LSD1 enzyme activity is likely to be caused by the allosteric inactivation of this domain to a large extent. LSD1 belongs to the amine oxidase family, which relies on FAD to catalyze the oxidation reaction of H3K4 and H3K9 to produce formaldehyde and a demethylated lysine residue to remove the methyl group.

[0003] LSD1 regulates many cell signaling pathways, and its dysfunction is closely related to the occurrence and development of many diseases, such as cancer, neurodegenerative diseases, cardiovascular diseases, inflammation, and viral infections. Abnormal high expression of LSD1 occurs in human blood tumors and solid tumor cells, such as acute myeloid leukemia, small cell lung cancer, breast cancer, neuroblastoma, colorectal cancer, prostate cancer, liver cancer, gastric cancer, and oral cancer. Inhibiting the activity of LSD1 can inhibit the differentiation, proliferation, migration, invasion, and tumor growth of cancer cells. In addition, the inhibition of LSD1 can enhance the tumor immunotherapy efficacy of PD-1 antibodies, which provides theoretical support for the combination of small molecule LSD1 inhibitors and tumor immunotherapy. Therefore, LSD1 is a very potential therapeutic target. Summary of the invention

[0004] The purpose of the present invention is to provide a pyrrolopyridine compound, a composition thereof and a medical use thereof.

[0005] The first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

[0006]

[0007] in,

[0008] R 1 is selected from halogen, substituted 5-14 membered heteroaryl or substituted C 6-14 Aryl;

[0009] R 2 is selected from hydrogen, halogen, substituted or unsubstituted -R 0 -NH3, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 3-12 Cycloalkyl C 6-14 Aryl or substituted or unsubstituted 3-10 membered heterocycloalkyl and C 6-14 Aryl;

[0010] R 0 Selected from C 1-4 Alkylene;

[0011] Indicates a double bond or a single bond;

[0012] when When it represents a double bond,

[0013] X is selected from -N(R 3 )-, Y is selected from N or -C(R 4 )=, Z is selected from -C(R 5 )=;

[0014] when When a single key is indicated,

[0015] X is selected from -C(=O)- or -CH(R 3 )-, Y is selected from -C(=O)- or -CH(R 4 )-, Z is selected from -N(R 5 )-;

[0016] W 1 Selected from C(R 6a ) or N;

[0017] W 2 Selected from C(R 6b ) or N;

[0018] R 3is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, 3-10 membered heterocycloalkyl, or substituted or unsubstituted 5-14 membered heteroaryl;

[0019] R 4 is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-12 Cycloalkyl;

[0020] R 5 is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, 3-10 membered heterocycloalkyl, acyl, or substituted or unsubstituted 5-14 membered heteroaryl;

[0021] R 6a and R 6b are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

[0022] In some embodiments, W 1 Selected from N.

[0023] In some embodiments, W 2 Selected from C(R 6b ).

[0024] In some embodiments, R 6b Selected from hydrogen.

[0025] In some embodiments, Represents a double bond.

[0026] In some embodiments, R 1 Selected from one or more R 1a substituted 5-14 membered heteroaryl or one or more R 1a Substituted C 6-14 Aryl;

[0027] R 1a Each occurrence is independently selected from halogen, cyano or C 1-6 alkyl.

[0028] In some embodiments, R 1 Selected from one or more R 1a Substituted phenyl.

[0029] In some embodiments, R 1aEach occurrence is independently selected from F or cyano.

[0030] In some embodiments, R 2 Selected from one or more R 2a Substituted or unsubstituted 5-14 membered heteroaryl, 2a Substituted or unsubstituted C 6-14 Aryl, one or more R 2a Substituted or unsubstituted C 3-12 Cycloalkyl C 6-14 Aryl or one or more R 2a Substituted or unsubstituted 3-10 membered heterocycloalkyl 6-14 Aryl;

[0031] R 2a Selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -R 2b -C(=O)OR 2c or C 3-6 Cycloalkyl;

[0032] R 2b Selected from C 1-6 Alkylene;

[0033] R 2c Selected from C 1-6 alkyl.

[0034] In some embodiments, R 2a Selected from -F, -Cl, C 1-3 Alkyl, F-substituted C 1-3 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-3 Alkoxy, F-substituted C 1-3 Alkoxy, -R 2b -C(=O)OR 2c or C 3-6 Cycloalkyl.

[0035] In some embodiments, R 2a Selected from -F, methyl, ethyl, methoxy, -CF3, -OCF3, -CH2-C(CH3)(CH3)OH or -CH2-C(=O)OCH2CH3.

[0036] In some embodiments, the compound has a structure shown in formula (II):

[0037]

[0038] wherein Ar is selected from 5-14 membered heteroaryl, C 6-14 Aryl, C 3-12 Cycloalkyl C 6-14 Aryl or 3-10 membered heterocycloalkyl 6-14 Aryl;

[0039] m is selected from 0, 1, 2 or 3;

[0040] n is selected from 1, 2, 3 or 4.

[0041] In some embodiments, Ar is selected from 5-6 membered heteroaryl, phenyl, C 3-6 Cycloalkylphenyl or 3-6 membered heterocycloalkylphenyl.

[0042] In some embodiments, the compound has a structure shown in any one of formula (II-1) to formula (II-3):

[0043]

[0044] Among them, Ar a Selected from C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0045] In some embodiments, the compound has a structure shown in any one of Formula (II-2a) to Formula (II-2f):

[0046]

[0047]

[0048] In some embodiments, R 3 Selected from hydrogen, C 1-3 Alkyl, with one or more R 3a Substituted C 1-3 alkyl;

[0049] R 3a Each occurrence is independently selected from halogen, C 3-12 cycloalkyl, 3-10 membered heterocycloalkyl or 5-14 membered heteroaryl.

[0050] In some embodiments, R 3 Selected from hydrogen, C 1-3 Alkyl, -CH2-CHF2, -CH2-CF3 or one of the following substituents:

[0051]

[0052] In some embodiments, R 5 Selected from -(C(R7 )2) P -N(R 5a )(R 5b ) or -C(=O)-N(R 5a )(R 5b );

[0053] R 7 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or halogenated C 3-6 Cycloalkyl;

[0054] P is selected from 1, 2, 3 or 4;

[0055] R 5a , R 5b Each independently selected from H or -(CH2) q -R 5c , or R 5a , R 5b and the N connected to it forms a 5c a substituted or unsubstituted 5-14-membered heterocycloalkyl group;

[0056] q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14;

[0057] R 5c Each occurrence is independently selected from C 1-6 Alkyl or NH(R 5d );

[0058] R 5d Selected from hydrogen or C 1-6 alkyl.

[0059] In some embodiments, R 5 Selected from -CH2-N(R 5a )(R 5b ).

[0060] In some embodiments, R 5 Selected from -CH2-NH(R 5b ) or one of the following substituents:

[0061]

[0062] t is selected from 1, 2, 3 or 4.

[0063] In some embodiments, the compound has a structure represented by any one of formula (III-1) to formula (III-5):

[0064]

[0065] In some embodiments, the compound has a structure shown in formula (III-1a):

[0066]

[0067] In some embodiments, the compound has a structure shown in formula (III-2a):

[0068]

[0069] In some embodiments, the compound has a structure shown in formula (III-3a):

[0070]

[0071] In some embodiments, the compound has a structure shown in formula (III-4a):

[0072]

[0073] In some embodiments, the compound has a structure shown in formula (III-5a):

[0074]

[0075] In some embodiments, the compound is selected from one of the structures shown in Table 1:

[0076] Table 1

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] The second invention of the present invention provides a pharmaceutical composition, which includes the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0085] The third aspect of the present invention provides the use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition described in the second aspect of the present invention in the preparation of a drug for treating and / or preventing diseases related to or mediated by LSD1 activity.

[0086] In some embodiments, the disease comprises cancer, neurodegenerative disease, cardiovascular disease, inflammation or viral infection

[0087] Beneficial effects:

[0088] The present invention provides a series of pyrrolopyridine compounds with novel structures, which can be used as LSD1 inhibitors with good activity and can be used to prepare drugs for treating and / or preventing diseases related to or mediated by LSD1 activity. DETAILED DESCRIPTION

[0089] Definition of terms

[0090] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0091] The term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon group. 1-10 "Alkyl" refers to an alkyl group having 1 to 10 carbon atoms, preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl is similarly defined. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, etc.

[0092] The term "alkenyl" refers to an unsaturated branched or straight chain group having at least one double bond. 2-8 "Alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms, preferably C 2-6 Alkenyl, more preferably C 2-4 Alkenyl is similarly defined. Alkenyl includes, but is not limited to, propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, heptenyl, octenyl, and the like.

[0093] The term "alkynyl" refers to an unsaturated branched or straight chain group having at least one triple bond. 2-8 "Alkynyl" refers to an alkynyl group having 2 to 8 carbon atoms, preferably C 2-6 Alkynyl, more preferably C 2-4 Alkynyl is similarly defined. Alkynyl includes, but is not limited to, propynyl, 1-butynyl, hexynyl, pentynyl, hexynyl, heptynyl, octynyl, and the like.

[0094] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon group which may be fused with an aryl or heteroaryl group. 3-12 "Cycloalkyl" refers to a fully saturated monocyclic, bicyclic or polycyclic hydrocarbon group with 3 to 12 ring carbon atoms, preferably C 3-9 Cycloalkyl, more preferably C 3-6 Cycloalkyl, similar definition. Monocyclic cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl. Bicyclic cycloalkyl includes but is not limited to bornyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, 6,6-dimethyl bicyclo [3.1.1] heptyl, 2,6,6-trimethyl bicyclo [3.1.1] heptyl, bicyclo [1.1.1] pentane or bicyclo [2.2.2] octyl. Polycyclic cycloalkyl includes but is not limited to adamantyl.

[0095] The term "cycloalkenyl" refers to a partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group having one or more double bonds. 3-12 "Cycloalkenyl" refers to a partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group having 3 to 12 ring carbon atoms and having one or more double bonds. Preferably, "C 3-9 Cycloalkenyl", more preferably "C 3-6 "Cycloalkenyl" is similarly defined. Monocyclic cycloalkenyls include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and the like. Bicyclic cycloalkenyls include, but are not limited to, bicyclo[2.2.1]hept-5-enyl and bicyclo[2.2.2]oct-2-enyl.

[0096] The term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more halogen groups. Preferably, haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl can have an iodine, bromine, chlorine or fluorine substituent. Dihaloalkyl and polyhaloalkyl can be substituted with two or more identical halogen groups or a combination of different halogen groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Perhaloalkyl refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Preferred haloalkyls are trifluoromethyl and difluoromethyl.

[0097] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0098] The term "heterocycloalkyl" refers to a fully saturated monocyclic, bicyclic or tricyclic heterocycloalkyl, and "3-10 membered heterocycloalkyl" refers to a ring containing 3-10 ring members, wherein at least one ring member is a heteroatom and wherein up to 8 ring members may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S may be optionally oxidized to various oxidation states. In one embodiment, the heterocycloalkyl is a 4 to 7 membered heterocycloalkyl. Examples of heterocycloalkyl groups include dihydrofuranyl, [1,3]dioxolane, 1,4-dioxane, 1,4-dithiane, piperazinyl, 1,3-dioxolane, imidazolidinyl, imidazolinyl, pyrrolidine, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathianyl, thiomorpholinyl, oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepine, Azepinyl, oxa Oxapinyl, oxazepine Oxazepinyl and diazepine Base (diazepinyl).

[0099] The term "heterocycloalkenyl" refers to partially unsaturated monocyclic, bicyclic or tricyclic heterocycloalkenyl, "3-10 membered heterocycloalkenyl" refers to 3-10 ring members, having at least one double bond, at least one ring member is a heteroatom and up to 8 ring members can be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S can be optionally oxidized to various oxidation states. In one embodiment, heterocycloalkenyl is a 4 to 7 membered heterocycloalkenyl. Examples of heterocycloalkenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 3,4-dihydro-2H-pyran, dihydrofuranyl, fluoro-dihydro-furanyl, dihydro-thienyl and dihydro-thiopyranyl.

[0100] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, which may be fused to a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring, or a heteroaryl ring. 6-14 The term "aryl" refers to a monocyclic or bicyclic aromatic group having 6 to 14 carbon atoms. Non-limiting examples of aryl include phenyl, naphthyl, and the like.

[0101] "Heteroaryl" refers to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. "5-14 membered heteroaryl" refers to a 5-14 membered monocyclic, bicyclic or polycyclic ring system having 1 to 10 heteroatoms independently selected from N, O or S, wherein N and S may be optionally oxidized to various oxidation states, and wherein at least one ring in the ring system is aromatic. In the present invention, heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. Examples of monocyclic heteroaryl groups include pyridyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl. Examples of bicyclic heteroaryl groups include quinolyl, quinazolinyl, 2,3-naphthyridinyl, quinoxalinyl, cinnolinyl, 1,5-naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, pteridinyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzothiadiazolyl, 1,5- 3-benzodioxol, azaindolyl, purine, imidazopyridinyl, pyrrolopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolotriazinyl, oxazolopyridinyl, isoxazolopyridinyl, thiazolopyridinyl, isothiazolopyridinyl, indolyl, benzofuranyl, quinoline, isoquinolyl, indazolyl, dihydroindole, isoindolyl, indolizinyl, benzimidazolyl and quinolyl.

[0102] Cycloalkylaromatic refers to a group in which a cycloalkyl ring is fused to an aryl ring to form a bicyclic, tricyclic or polycyclic ring system, wherein the cycloalkyl is as defined above and the aryl is as defined above.

[0103] Heterocycloalkylaromatic refers to a group in which a heterocycloalkyl ring is fused to an aryl ring to form a bicyclic, tricyclic or polycyclic ring system, wherein heterocycloalkyl is as defined above and aryl is as defined above.

[0104] The term "alkoxy" refers to alkyl-O-, wherein alkyl is as defined above. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy, and the like. Preferably, the alkoxy has 1-6 carbon atoms, more preferably 1-4 carbon atoms.

[0105] In the chemical structure of the compound described in the present invention, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be "or" ”, or both configurations.

[0106] The compounds of the present invention may contain one or more asymmetric centers and may produce diastereomers and optical isomers, including all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0107] When the compound represented by the general formula (I) exists in tautomerism, unless otherwise stated, the present invention includes any possible tautomerism and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0108] The term "substituted" or "substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0109] In the present invention, the single bond to which the substituent is connected runs through the corresponding ring, indicating that the substituent can be connected to any position of the ring, for example R is connected to any substitutable position of the benzene ring.

[0110] In the present invention, " ” indicates connections to other atoms.

[0111] The term "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "C optionally (optionally) substituted with halogen or cyano" 1-6 "Alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0112] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers, diluents or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0113] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which may be selected from an inorganic salt or an organic salt. Such salts are safe and effective when used in mammals and have the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

[0114] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0115] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0116] The term "prevention and / or treatment" includes not only preventing and / or treating a disease, but also generally includes preventing the onset of a disease, slowing or reversing the progression of a disease, preventing or slowing the onset of one or more symptoms associated with a disease, reducing and / or alleviating one or more symptoms associated with a disease, reducing the severity and / or duration of the disease and / or any symptoms associated therewith and / or preventing a further increase in the severity of the disease and / or any symptoms associated therewith, preventing, reducing or reversing any physiological damage caused by the disease, and generally any pharmacological effect that is beneficial to the patient being treated.

[0117] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0118] The structures of the compounds in the following examples are determined by nuclear magnetic resonance spectroscopy ( 1 H NMR) or / and mass spectrometry (MS). The unit of NMR shift (δ) is 10 -6(ppm). NMR was measured using a Buker AVANCE III-400 nuclear magnetic resonance instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), etc. as the solvent, and tetramethylsilane (TMS) as the internal standard. MS was measured using a Finnigan LCQ / Deca (ESI) mass spectrometer. High performance liquid chromatography (HPLC) analysis was performed using a Gilson-215 high pressure liquid chromatograph.

[0119] The thin layer chromatography silica gel plates in the following examples use Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plates. The silica gel plates used in thin layer chromatography (TLC) have a specification of 0.15 mm-0.2 mm, and the specifications used for the thin layer chromatography separation and purification products are 0.4 mm-0.5 mm. Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0120] The known starting materials in the following examples can be synthesized by methods known in the art, or can be purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd., Bid Pharmaceuticals, etc. Unless otherwise specified in the examples, the reactions can be carried out under argon atmosphere or nitrogen atmosphere.

[0121] The reaction progress in the following examples was monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography included a dichloromethane / methanol system and a petroleum ether / ethyl acetate system, and the volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0122] In the following examples, unless otherwise specified, room temperature refers to ambient temperature, which is 10°C-35°C. Overnight refers to 8-15 hours. Reflux refers to the reflux temperature of the solvent under normal pressure.

[0123] Example 1

[0124] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-1-methyl-2-(piperidin-1-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 1

[0125]

[0126] first step

[0127] 3-Bromo-2-hydroxy-4-methyl-5-nitropyridine 1b

[0128] 2-Hydroxy-4-methyl-5-nitropyridine 1a (20.0 g, 129.7 mmol) was added to 100 mL of water, heated to 40 °C, and bromine (7.3 mL, 142.7 mmol) was slowly added dropwise under stirring. After 8 h of reaction, TLC monitored the complete reaction of the raw material (DCM / MeOH = 15:1). The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 100 mL of water. 50 mL of saturated aqueous solution of Na2S2O3 was added to the filtrate to remove bromine. After the filter cake was dried, the title compound 1b was obtained as a light yellow solid of 28.1 g, with a yield of 93.4%. 1 HNMR(400MHz,DMSO-d6)δ8.58(s,1H),2.57(s,3H).

[0129] Step 2

[0130] 3-Bromo-2-chloro-4-methyl-5-nitropyridine 1c

[0131] 3-Bromo-2-hydroxy-4-methyl-5-nitropyridine (28.1 g, 121.2 mol) was added to 100 mL of phosphorus oxychloride, heated to 110°C, stirred for 10 hours, and the reaction of the raw material was complete after TLC monitoring (PE / EA=20:1). The reaction solution was concentrated under reduced pressure, and the obtained residue was added with 100 mL of ice water, extracted with ethyl acetate three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and separated and purified by silica gel column chromatography to obtain the title compound 1c as a white solid of 27.8 g, with a yield of 91.5%. 1 H NMR(400MHz,Chloroform-d)δ8.79(s,1H),2.73(s,3H).

[0132] Step 3

[0133] 2-(3-Bromo-2-chloro-5-nitropyridin-4-yl)-N,N-1-amine 1d

[0134] 3-Bromo-2-chloro-4-methyl-5-nitropyridine (27.8 g, 111.0 mol) was dissolved in 200 mL of toluene, and DMF-DMA (44.2 mL, 333.0 mol) was added at room temperature. After stirring for 12 hours, TLC monitored that the reaction of the raw material was complete (PE / EA=5:1). The reaction solution was concentrated under reduced pressure to remove toluene, and the resulting oil was separated and purified by silica gel column chromatography to obtain the title compound 1d, a red solid of 25.6 g, with a yield of 75.5%. 1 H NMR (400MHz, Chloroform-d) δ8.32 (s, 1H), 7.02 (d, J = 13.5Hz, 1H), 5.26 (d, J = 13.3Hz, 1H), 3.00 (s, 6H).

[0135] Step 4

[0136] 4-Bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine 1e

[0137] 2-(3-bromo-2-chloro-5-nitropyridin-4-yl)-N,N-1-amine (25.6 g, 83.8 mmol) was dissolved in 200 mL of acetic acid, and iron powder (23.5 g, 419.1 mmol) was added at room temperature. After stirring at 70°C for 3 h, TLC monitored the complete reaction of the raw material (DCM / MeOH=15:1). Celite was used as a filter aid, the reaction solution was filtered, and washed with 50 mL of methanol 3 times. The filtrate layer was concentrated under reduced pressure and separated and purified by silica gel column chromatography to obtain the title compound 1e, a dark green solid of 11.9 g, with a yield of 61.5%. MS (ESI) m / z: 231.17. 1 H NMR (400MHz, Chloroform-d) δ8.52 (s, 1H), 7.51 (t, J = 2.8Hz, 1H), 6.64 (t, J = 2.3Hz, 1H).

[0138] Step 5

[0139] 4-Bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine 1f

[0140] Dissolve 4-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (11.9 g, 51.5 mmol) in dry 100 mL DMF, cool the reaction solution to 0°C, add NaH (1.9 g, 77.3 mmol) under stirring, continue stirring and reacting for 5 min, slowly add iodomethane (4.8 mL, 77.3 mmol) dropwise, move to room temperature and stir and react for 2 h, TLC monitoring shows that the raw material reaction is complete (PE / EA=2:1). Add 100 mL of water to the reaction solution to quench the reaction, extract with 100 mL of ethyl acetate 3 times, combine the organic layers, wash with saturated brine 3 times, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, separate and purify by silica gel column chromatography to obtain the title compound 1f, 11.5 g of yellow-brown solid, yield: 91.1%. MS (ESI) m / z: 245.18. 1 H NMR (400MHz, Chloroform-d) δ8.46 (s, 1H), 7.29 (d, J = 3.2Hz, 1H), 6.54 (d, J = 3.0Hz, 1H), 3.92 (s, 3H).

[0141] Step 6

[0142] 4-Bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carbonyl 1g

[0143] Dissolve 4-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (11.5 g, 46.9 mmol) in 150 mL dry THF, cool the reaction solution to -78 °C, add 2M lithium diisopropylamide (34.3 mL, 70.5 mmol) THF solution under stirring, continue stirring and reacting for 30 min, slowly dropwise add N-formylmorpholine (9.5 mL, 93.9 mmol) in 10 mL tetrahydrofuran solution, continue stirring and reacting at this temperature for 30 min, warm to room temperature and stir and react for 2 h, TLC monitoring raw material reaction complete (PE / EA=1:1). Add 50 mL NH4Cl saturated aqueous solution to the reaction solution to quench the reaction, extract with 50 mL ethyl acetate 3 times, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, separate and purify by silica gel column chromatography to obtain 1 g of the title compound, 11.6 g of yellow-brown solid, yield: 90.5%. MS (ESI) m / z: 273.19. 1 H NMR (400MHz, Chloroform-d) δ10.06(s,1H),8.65(s,1H),7.26(s,1H),4.18(s,3H).

[0144] Step 7

[0145] 4-(5-Chloro-2-formyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 1h

[0146] 4-Bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine-2-formyl (3.0 g, 10.9 mmol), 3-fluoro-4-cyano-phenylboronic acid (1.9 g, 11.2 mmol), Na2CO3 (3.49 g, 32.9 mmol) and Pd(PPh3)4 (633.7 mg, 0.5 mmol) were added to 20 mL of toluene, 10 mL of ethanol and 5 mL of water. The reaction was carried out at 80 °C for 12 h under nitrogen protection. TLC monitored the complete reaction of the raw materials (PE / EA = 1:1). The reaction solution was concentrated under reduced pressure, extracted with 25 mL of ethyl acetate three times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The title compound 1h was obtained as a yellow-brown solid of 2.3 g, with a yield of 65.6%. MS (ESI) m / z: 314.28. 1H NMR (400MHz, Chloroform-d) δ10.00(s,1H),8.79(d,J=0.9Hz,1H),7.87–7.71(m,1H),7.49–7.36(m,2H),6.98(d,J=0.9Hz,1H),4.23(s,3H).

[0147] Step 8

[0148] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-formyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 1i

[0149] 4-(5-chloro-2-formyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile (2.2 g, 7.2 mmol), 3-fluoro-4-methoxyphenylboronic acid (1.8 g, 10.8 mmol), K3PO4 (3.1 g, 14.4 mmol), X-phos (343.8 mg, 0.7 mmol) and Pd(OAc)2 (81.0 mg, 0.4 mmol) were added to 30 mL of n-butanol and 7.5 mL of water. The mixture was reacted at 110 °C for 16 h under nitrogen protection. TLC monitored the complete reaction of the raw materials (PE / EA = 1:1). The reaction solution was concentrated under reduced pressure, extracted with 25 mL of ethyl acetate for 3 times, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The title compound 1i was separated and purified by silica gel column chromatography to obtain 1.0 g of yellow-brown solid with a yield of 35.1%. MS (ESI) m / z: 404.37. 1 H NMR(400MHz,Chloroform-d)δ10.01(s,1H),9.06(s,1H),7.64(dd,J=8.1,6.6Hz,1H),7.24–71 4(m,3H),7.08(s,1H),6.94(d,J=8.2Hz,1H),6.83(t,J=8.5Hz,1H),4.27(s,3H),3.89(s,3H).

[0150] Step 9

[0151] Tert-butyl 4-((4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperazine-1-carbamate 1j

[0152] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-formyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (50.0 mg, 0.12 mmol) and tert-butyl piperazine-1-carboxylate (34.6 mg, 0.2 mmol) were dissolved in 5.00 mL DCE at room temperature, and NaBH(OAc)3 (78.8 mg, 0.4 mmol) was added. The reaction was stirred for 3 h, and the reaction was complete after TLC monitoring (DCM / MeOH=15:1). 10 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution to quench the reaction, and 15 mL of ethyl acetate was used for extraction 3 times. The organic layers were combined, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The title compound 1j was separated and purified by silica gel column chromatography to obtain 52.5 mg of white solid in a yield of 81.6%. MS (ESI) m / z: 573.45 [M+H] + .

[0153] Step 10

[0154] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-1-methyl-2-(piperidin-1-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 1

[0155] Tert-butyl 4-((4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperazine-1-carbamate (52.5 mg, 0.1 mmol) was dissolved in 1 mL DCM, 2 mL (4 mol / L) HCl / Dioxane was added, and the reaction was continued to stir for 1 h. TLC monitored the complete reaction of the raw material (DCM / MeOH(NH3)=15:1). The reaction solution was concentrated under reduced pressure and neutralized with ammonia methanol solution to obtain the title compound 1 as a white solid of 38.7 mg, yield: 91.2%. MS (ESI) m / z: 474.37 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.80(s,1H),7.71(t,J=7.4Hz,1H),7.28(dd,J=10.1,1.5Hz,1H),7.23(dd,J=7.9,1.5Hz,1H),7.09(d d,J=12.3,1.9Hz,1H),6.98–6.92(m,2H),6.34(s,1H),4.01(s,3H),3.85(s,3H),3.75(s,2H),2.91(t,J=5.0Hz,4H),2.53(s,4H).

[0156] Example 2

[0157] 4-(2-((4-aminopiperidin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 2 was prepared by using the synthetic route of Example 1, replacing the raw material of the ninth step, piperazine-1-carboxylic acid tert-butyl ester, with piperidin-4-ylcarbamic acid tert-butyl ester to obtain the title compound 2 (35.5 mg). MS (ESI) m / z: 488.39 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.79 (s, 1H), 7.71 (t, J = 7.4Hz, 1H), 7.28 (dd, J = 10.1, 1.5Hz ,1H),7.24(dd,J=8.0,1.5Hz,1H),7.09(dd,J=12.3,1.9Hz,1H),7.00–6.91(m,2H),6.31( s,1H),4.00(s,3H),3.85(s,3H),3.72(s,2H),2.96–2.82(m,2H),2.67(dt,J=10.7,5.2Hz ,1H),2.12(dt,J=11.6,2.4Hz,2H),1.81(d,J=12.6Hz,2H),1.42(dt,J=11.9,6.0Hz,2H).

[0158] Example 3

[0159] Synthesis of 2-fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-1-methyl-2-((4-(methylamino)piperidin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-benzonitrile

[0160] The synthetic route of Example 1 was used to replace the raw material of step 9, tert-butyl piperazine-1-carboxylate, with 4-N-tert-butyloxycarbonyl-4-N-methylaminopiperidine to obtain the title compound 3 (34.9 mg). MS (ESI) m / z: 502.39 [M+H] + . 1H NMR (600MHz, Meth piperidine anol-d4) δ8.78 (s, 1H), 7.70 (t, J = 7.3Hz, 1H), 7.27 (d, J = 10.0Hz, 1H), 7 .23(dd,J=8.0,1.5Hz,1H),7.09(dd,J=12.3,2.0Hz,1H),6.98–6.92(m,2H),6.31(s,1H),3.9 9(s,3H),3.85(s,3H),3.71(s,2H),2.93(d,J=11.2Hz,2H),2.45–2.40(m,1H),2.38(s,3H),2 .11(dt,J=11.9,2.4Hz,2H),1.92–1.88(m,2H),1.39(d,J=5.1Hz,1H),1.37(d,J=3.4Hz,1H).

[0161] Example 4

[0162] 4-(2-((4-amino-4-methylpiperidin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile

[0163] The synthetic route of Example 1 was used to replace the raw material of step 9, tert-butyl piperazine-1-carboxylate, with tert-butyl (4-methylpiperidin-4-yl)carbamate to obtain the title compound 4 (35.2 mg). MS (ESI) m / z: 502.35 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.79(s,1H),7.72(t,J=7.4Hz,1H),7.29(dd,J=10.2,1.4Hz,1H),7.23(dd,J=8.1,1.5Hz,1H),7.09(dd,J=12.3,1.9Hz,1H), 7.00–6.92(m,2H),6.34(s,1H),4.00(s,3H),3.85(s,3H),3.79(s,2H),2.75 –2.64(m,2H),2.47(d,J=9.9Hz,2H),1.73(q,J=5.6,5.1Hz,4H),1.30(s,3H).

[0164] Example 5

[0165] 4-(2-((4-amino-3,3-dimethylpiperidin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 5

[0166] The synthetic route of Example 1 was used to replace the raw material of step 9, tert-butyl piperazine-1-carboxylate, with tert-butyl (3,3-dimethylpiperidin-4-yl)carbamate to obtain the title compound 5 (33.9 mg). MS (ESI) m / z: 516.36 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.77(s,1H),7.69(dd,J=8.0,6.8Hz,1H),7.25(dd,J=10.1,1.4Hz,1H),7.2 2(dd,J=7.9,1.5Hz,1H),7.08(dd,J=12.4,1.8Hz,1H),6.98–6.91(m,2H),6.28(s,1H),4.01(s,3H),3.8 4(s,3H),3.63(s,2H),2.89–2.78(m,1H),2.46(dd,J=11.1,1.8Hz,1H),2.38(dd,J=11.1,4.4Hz,1H),2. 09–2.01(m,1H),1.83(d,J=11.3Hz,1H),1.66–1.61(m,1H),1.59–1.49(m,1H),0.93(s,3H),0.89(s,3H).

[0167] Example 6

[0168] (S)-4-(2-((3-aminopiperidin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 6

[0169] The synthetic route of Example 1 was used to replace the raw material of step 9, piperazine-1-carboxylic acid tert-butyl ester, with (S)-3-tert-butyloxycarbonylaminopiperidine to obtain the title compound 6 (35.7 mg). MS (ESI) m / z: 488.40 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.78(s,1H),7.69(t,J=7.4Hz,1H),7.29–7.24(m,1H),7.21(dd,J=8.0, 1.5Hz,1H),7.08(dd,J=12.3,1.9Hz,1H),6.98–6.90(m,2H),6.32(s,1H),3.99(s,3H),3.84(s,3H),3 .76–3.65(m,2H),2.83–2.76(m,2H),2.68(s,1H),2.17(d,J=13.2Hz,1H),2.01–1.91(m,1H),1.83(d d,J=12.2,4.6Hz,1H),1.72(dt,J=13.2,4.2Hz,1H),1.61–1.49(m,1H),1.21–1.11(m,J=10.9Hz,1H).

[0170] Example 7

[0171] (R)-4-(2-((3-aminopiperidin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 7

[0172] The synthetic route of Example 1 was used to replace the raw material of step 9, tert-butyl piperazine-1-carboxylate, with (R)-3-tert-butyloxycarbonylaminopiperidine to obtain the title compound 7 (33.8 mg). MS (ESI) m / z: 488.36 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.78(s,1H),7.69(t,J=7.4Hz,1H),7.28–7.24(m,1H),7.21(dd,J= 8.0,1.5Hz,1H),7.08(dd,J=12.3,1.9Hz,1H),6.98–6.90(m,2H),6.32(s,1H),3.99(s,3H),3.84 (s,3H),3.76–3.65(m,2H),2.80(dt,J=9.6,9.0,4.2Hz,2H),2.68(s,1H),2.17(d,J=13.2Hz,1H ),1.95(s,1H),1.87–1.78(m,1H),1.76–1.68(m,1H),1.60–1.50(m,1H),1.17(d,J=10.9Hz,1H).

[0173] Example 8

[0174] (S)-4-(2-((4-1H-azepin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 8

[0175] The synthetic route of Example 1 was used to replace the raw material of step 9, piperazine-1-carboxylic acid tert-butyl ester, with (S)-4-tert-butyloxycarbonyl-1H-azepine to obtain the title compound 8 (35.1 mg). MS (ESI) m / z: 502.35 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.78(s,1H),7.69(t,J=7.4Hz,1H),7.29–7.24(m,1H),7.21(dd,J=8.0, 1.5Hz,1H),7.08(dd,J=12.3,1.9Hz,1H),6.98–6.90(m,2H),6.32(s,1H),3.99(s,3H),3.84(s,3H),3 .76–3.65(m,2H),2.83–2.76(m,2H),2.68(s,1H),2.17(d,J=13.2Hz,1H),2.03–1.90(m,1H),1.83(d d,J=12.2,4.6Hz,1H),1.72(dt,J=13.2,4.2Hz,1H),1.61–1.49(m,1H),1.21–1.12(m,J=10.9Hz,1H).

[0176] Example 9

[0177] (R)-4-(2-((4-1H-azepin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 9

[0178] The synthetic route of Example 1 was used to replace the raw material of step 9, piperazine-1-carboxylic acid tert-butyl ester, with (R)-4-tert-butyloxycarbonyl-1H-azepine to obtain the title compound 9 (34.7 mg). MS (ESI) m / z: 502.41 [M+H] + . 1H NMR(600MHz, Methanol-d4)δ8.78(d,J=0.8Hz,1H),7.70(dd,J=8.0,6.8Hz,1H),7.27(dd ,J=10.2,1.5Hz,1H),7.23(dd,J=7.9,1.5Hz,1H),7.09(dd,J=12.2,2.0Hz,1H),6.98–6. 92(m,2H),6.30(s,1H),4.02(s,3H),3.85(s,3H),3.80(s,2H),3.17–3.07(m,1H),2.77– 2.64(m,3H),2.62–2.58(m,1H),1.86–1.82(m,2H),1.78–1.72(m,1H),1.62–1.52(m,3H).

[0179] Example 10

[0180] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 10

[0181] The synthetic route of Example 1 was used to replace the raw material of step 9, piperazine-1-carboxylic acid tert-butyl ester, with (S)-3-tert-butyloxycarbonylaminopyrrolidine to obtain the title compound 10 (38.0 mg). MS (ESI) m / z: 474.37 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.78 (s, 1H), 7.71 (t, J = 7.4Hz, 1H), 7.27 (dd, J = 10.2, 1.5Hz, 1H) ,7.23(dd,J=8.0,1.5Hz,1H),7.09(dd,J=12.3,1.9Hz,1H),6.99–6.92(m,2H),6.33(s,1H),4 .00(s,3H),3.86(s,2H),3.85(s,3H),3.47–3.42(m,1H),2.78(dt,J=9.2,8.8,5.8Hz,2H),2. 54(dt,J=8.7,6.3Hz,1H),2.40(dd,J=9.5,4.5Hz,1H),2.23–2.16(m,1H),1.59–1.51(m,1H).

[0182] Embodiment 11

[0183] (R)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 11

[0184] The synthetic route of Example 1 was used to replace the raw material of step 9, piperazine-1-carboxylic acid tert-butyl ester, with (R)-3-tert-butyloxycarbonylaminopyrrolidine to obtain the title compound 11 (35.9 mg). MS (ESI) m / z: 474.37 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.78(s,1H),7.70(dd,J=8.0,6.8Hz,1H),7.27(dd,J=10.1,1.5H z,1H),7.23(dd,J=7.9,1.5Hz,1H),7.09(dd,J=12.3,1.9Hz,1H),6.99–6.92(m,2H),6.33(s, 1H),4.00(s,3H),3.86(s,2H),3.85(s,3H),3.48–3.42(m,1H),2.78(dt,J=9.5,6.6Hz,2H),2 .54(dt,J=8.6,6.2Hz,1H),2.39(dd,J=9.5,4.5Hz,1H),2.23–2.16(m,1H),1.59–1.51(m,1H).

[0185] Example 12

[0186] 4-(1-methyl-2-(piperidin-1-ylmethyl)-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 12

[0187]

[0188] first step

[0189] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-(hydroxymethyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 12j

[0190] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-formyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 1i (100.0 mg, 0.2 mmol) was dissolved in 5 mL of methanol, the reaction solution was cooled to 0°C, NaBH4 (13.7 mg, 0.4 mmol) was slowly added, and the reaction was continued to stir for 1 h. TLC monitored the complete reaction of the raw material (DCM / MeOH=15:1). 5 mL of ammonium chloride aqueous solution was added to the reaction solution to quench the reaction, and the mixture was extracted 3 times with 10 mL of ethyl acetate. The organic layers were combined, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The title compound 12j was separated and purified by silica gel column chromatography to obtain 84.1 mg of a light yellow solid with a yield of 86.5%. 1 H NMR(400MHz,Chloroform-d)δ8.72(s,1H),7.53(t,J=7.3Hz,1H),7.15–7.04(m,3H),6.86(dt, J=8.8,1.4Hz,1H),6.75(t,J=8.5Hz,1H),6.25(s,1H),4.77(s,2H),3.89(s,3H),3.84(s,3H).

[0191] Step 2

[0192] 4-(2-(Chloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 12k

[0193] 2-Fluoro-4-(5-(3-fluoro-4-methoxyphenyl)-2-(hydroxymethyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 12j (13.7 mg, 0.2 mmol) was dissolved in anhydrous 5 mL DCM, and then SOCl2 (30.0 mg, 0.3 mmol) was slowly added to the reaction solution at room temperature, and the reaction was continued to stir for 6 h. TLC monitored the complete reaction of the raw material (DCM / MeOH=15:1). 5 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution to quench the reaction, and the mixture was extracted 3 times with 10 mL of ethyl acetate. The organic layers were combined, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The title compound 12k was separated and purified by silica gel column chromatography to obtain 77.0 mg of a light yellow solid in a yield of 86.5%. 1H NMR(400MHz,Chloroform-d)δ8.86(s,1H),7.58(t,J=7.3Hz,1H),7.21–7.10(m,3H),6.95 –6.88(m,1H),6.81(t,J=8.5Hz,1H),6.42(s,1H),4.76(s,2H),3.98(s,3H),3.87(s,3H).

[0194] Step 3

[0195] 4-(2-(Aminomethyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 12

[0196] 4-(2-(Chloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile (77.0 mg, 0.2 mmol) was dissolved in Dioxane (2 mL) at room temperature, and 2 mL of aqueous ammonia was added. The reaction solution was heated to 100°C and stirred for 6 h. TLC monitored the complete reaction of the raw materials (DCM / MeOH(NH3)=20:1). The reaction solution was cooled to room temperature, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain the title compound 12 as a yellow solid (43.7 mg). Yield: 60.2%. MS (ESI) m / z: 405.35 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.79(d,J=2.1Hz,1H),7.76–7.67(m,1H),7.31(d,J=10.4Hz,1H),7.23(d,J =8.0Hz,1H),7.13–7.06(m,1H),7.00–6.92(m,2H),6.42(s,1H),4.07(s,2H),3.92(s,3H),3.85(s,3H).

[0197] Embodiment 13

[0198] 4-(1-methyl-2-(piperidin-1-ylmethyl)-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile

[0199]

[0200] first step

[0201] 4-(5-Chloro-2-formyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 13h

[0202] Using 4-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl (3.0 g, 10.9 mmol), 4-cyano-phenylboronic acid (1.6 g, 11.2 mmol), Na2CO3 (3.5 g, 32.9 mmol) and Pd(PPh3)4 (633.8 mg, 0.5 mmol) as raw materials, the synthesis method was the same as that of intermediate 1h to obtain the title compound 13h, 2.2 g of yellow-brown solid, with a yield of 66.1%. 1 H NMR (400MHz, Chloroform-d) δ9.98(s,1H),8.77(s,1H),7.84(d,J=8.1Hz,2H),7.66(d,J=8.1Hz,2H),6.96(s,1H),4.23(s,3H).

[0203] Step 2

[0204] 4-(2-Formyl-1-methyl-5-(p-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 13i

[0205] The synthesis method was the same as that of intermediate 1i, using 4-(5-chloro-2-formyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (2.2 g, 7.3 mmol), 4-methyl-phenylboronic acid (1.6 g, 11.2 mmol), K3PO4 (3.1 g, 14.5 mmol), X-phos (348.0 mg, 0.7 mmol) and Pd(OAc)2 (81.0 mg, 0.4 mmol) as raw materials. The title compound 13i was obtained as a yellow-brown solid (949.1 mg) with a yield of 36.9%. MS (ESI) m / z: 352.40. 1 H NMR(400MHz,Chloroform-d)δ9.99(s,1H),9.06(s,1H),7.65(d,J=7.9Hz,2H),7.42(d,J=8.0 Hz,2H),7.19(d,J=7.8Hz,2H),7.07(d,J=4.6Hz,2H),7.05(s,1H),4.26(s,3H),2.32(s,3H).

[0206] Step 3

[0207] Tert-butyl 4-((4-(4-cyanophenyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperidin-1-carbamate 13j

[0208] Using formyl-1-methyl-5-(p-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile (50.0 mg, 0.2 mmol) and piperazine-1-carboxylic acid tert-butyl ester (39.7 g, 0.2 mmol) as raw materials, the synthesis method was the same as that of the target compound 1j to obtain the title compound 13j, a light yellow solid of 61.4 mg, with a yield of 84.2%. MS (ESI) m / z: 522.27. 1 HNMR(400MHz,Chloroform-d)δ8.82(s,1H),7.59(d,J=8.0Hz,2H),7.39(d,J=7.9Hz,2H),7.17(d,J=7.8Hz,2H),7.02(d,J= 7.8Hz,2H),6.22(s,1H),3.96(s,3H),3.64(s,2H),3.40(t,J=4.9Hz,4H),2.40(t,J=5.0Hz,4H),2.30(s,3H),1.44(s,9H).

[0209] Step 4

[0210] 4-(1-methyl-2-(piperidin-1-ylmethyl)-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 13

[0211] The title compound 13 was obtained by the same synthesis method as the target compound 1, using tert-butyl 4-((4-(4-cyanophenyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperidine-1-carbamate (61.4 g, 0.1 mmol) as the starting material. The white solid was 46.4 mg, with a yield of 91.9%. MS (ESI) m / z: 422.37 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.77(s,1H),7.64–7.60(m,2H),7.37(d,J=8.2Hz,2H),7.11(d,J=8.1Hz,2H),7. 03(d,J=7.9Hz,2H),6.29(s,1H),3.99(s,3H),3.72(s,2H),2.92(t,J=4.9Hz,4H),2.54(s,4H),2.28(s,3H).

[0212] Embodiment 14

[0213] 4-(2-((4-aminopiperidin-1-yl)methyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 14

[0214] The synthetic route of Example 13 was adopted, and the raw material of the third step, piperazine-1-carboxylic acid tert-butyl ester, was replaced with piperidin-4-ylcarbamic acid tert-butyl ester to prepare the title compound 14 (41.0 mg). MS (ESI) m / z: 436.38 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.76(s,1H),7.65(dd,J=8.3,1.8Hz,2H),7.42–7.39(m,2H),7.15–7.12(m,2H),7.06(d,J=7.9Hz,2H),6.28(s,1H),3.99(s ,3H),3.70(s,2H),2.91(d,J=11.4Hz,2H),2.72–2.65(m,1H),2.15–2.07(m, 2H),1.86–1.78(m,2H),1.45(dd,J=11.6,3.9Hz,1H),1.41(d,J=4.5Hz,1H).

[0215] Embodiment 15

[0216] (S)-4-(2-((3-aminopiperidin-1-yl)methyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 15

[0217] The synthetic route of Example 13 was used to replace the raw material of the third step, tert-butyl piperazine-1-carboxylate, with (S)-3-tert-butyloxycarbonylaminopiperidine to obtain the title compound 15 (38.8 mg). MS (ESI) m / z: 436.37 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ8.76(s,1H),7.66–7.60(m,2H),7.40–7.35(m,2H),7.12( d,J=8.1Hz,2H),7.04(d,J=8.0Hz,2H),6.28(s,1H),3.98(s,3H),3.74–3.63(m,2H),2 .81–2.71(m,2H),2.67(s,1H),2.29(s,3H),2.15(d,J=13.2Hz,1H),1.94(s,1H),1.82 (dd,J=12.6,4.5Hz,1H),1.74–1.67(m,1H),1.60–1.49(m,1H),1.16(d,J=11.3Hz,1H).

[0218] Example 16

[0219] (R)-4-(2-((3-aminopiperidin-1-yl)methyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 16

[0220] The synthetic route of Example 13 was adopted, and the raw material of the third step, piperazine-1-carboxylic acid tert-butyl ester, was replaced with (R)-3-tert-butyloxycarbonylaminopiperidine to prepare the title compound 16 (39.8 mg). MS (ESI) m / z: 436.38 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.76(s,1H),7.63(dt,J=8.1,2.1Hz,2H),7.38(dt,J=8.2,1.9Hz,2H),7. 11(d,J=7.7Hz,2H),7.04(d,J=7.8Hz,2H),6.28(s,1H),3.98(d,J=1.4Hz,3H),3.76–3.64(m,2H),2.93 –2.81(m,1H),2.80(d,J=10.8Hz,1H),2.66(s,1H),2.29(s,3H),2.19(d,J=13.6Hz,1H),2.02(s,1H), 1.84(dd,J=13.0,4.9Hz,1H), 1.73(dd,J=11.3,6.1Hz,1H), 1.63–1.49(m,1H), 1.24(d,J=17.5Hz,1H).

[0221] Embodiment 17

[0222] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 17

[0223] The synthetic route of Example 13 was used to replace the raw material of the third step, tert-butyl piperazine-1-carboxylate, with (S)-3-tert-butyloxycarbonylaminopyrrolidine to obtain the title compound 17 (39.5 mg). MS (ESI) m / z: 422.36 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.78–8.74(m,1H),7.66–7.60(m,2H),7.40–7. 35(m,2H),7.14–7.09(m,2H),7.04(d,J=8.0Hz,2H),6.30(s,1H),3.98(s,3 H),3.55–3.49(m,1H),2.81(td,J=8.7,5.2Hz,1H),2.74(dd,J=9.8,6.5Hz, 1H),2.54–2.46(m,2H),2.29(s,3H),2.26–2.17(m,1H),1.65–1.56(m,1H).

[0224] Embodiment 18

[0225] (R)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile A18

[0226] The synthetic route of Example 13 was used to replace the raw material of the third step, piperazine-1-carboxylic acid tert-butyl ester, with (R)-3-tert-butyloxycarbonylaminopyrrolidine to obtain the title compound 18 (40.6 mg). MS (ESI) m / z: 422.37 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ8.76(s,1H),7.66–7.60(m,2H),7.40–7.35(m,2H),7.12(d d,J=8.2,2.8Hz,2H),7.04(d,J=7.9Hz,2H),6.29(s,1H),3.98(d,J=2.8Hz,3H),3.83(t, J=4.6Hz,2H),3.52–3.45(m,1H),2.76(dt,J=9.0,8.5,6.0Hz,2H),2.52(dt,J=8.7,6.2 Hz,1H),2.43–2.37(m,1H),2.29(d,J=2.5Hz,3H),2.24–2.16(m,1H),1.59–1.50(m,1H).

[0227] Embodiment 19

[0228] 4-(2-(((2-ethylamino)amino)methyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 19

[0229] The synthetic route of Example 13 was used to replace the raw material of the third step, tert-butyl piperazine-1-carboxylate, with tert-butyl (2-aminoethyl)carbamate to obtain the title compound 19 (40.7 mg). MS (ESI) m / z: 396.37 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.76(s,1H),7.67–7.63(m,2H),7.43–7.39(m,2H),7.13(d,J=8.1Hz, 2H),7.06(d,J=7.9Hz,2H),6.37(s,1H),4.01(s,2H),3.96(s,3H),2.89–2.74(m,4H),2.30(s,3H).

[0230] Embodiment 20

[0231] 4-(2-(((2-propylamino)amino)methyl)-1-methyl-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 20

[0232] The synthetic route of Example 13 was used to replace the raw material of the third step, tert-butyl piperazine-1-carboxylate, with tert-butyl (3-aminopropyl)carbamate to prepare the title compound 20 (40.4 mg). MS (ESI) m / z: 410.37 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.76(s,1H),7.67–7.62(m,2H),7.43–7.38(m,2H),7.13(d,J=8.1Hz,2H),7.05(d,J=8 .0Hz,2H),6.36(s,1H),3.99(s,2H),3.95(s,3H),2.75(dt,J=8.9,7.1Hz,4H),2.30(s,3H),1.72(p,J=7.1Hz,2H).

[0233] Embodiment 21

[0234] 4-(1-methyl-2-(((2-(methylamino)ethyl)amino)methyl)-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 21

[0235] The synthetic route of Example 13 was used to replace the raw material of the third step, tert-butyl piperazine-1-carboxylate, with N-Boc-(2-aminoethyl)-N-methylamine to obtain the title compound 21 (38.0 mg). MS (ESI) m / z: 410.34 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.77(s,1H),7.64(dd,J=8.3,1.7Hz,2H),7.39(dd,J=8.2,1.7Hz,2H),7.12(d,J=7.9Hz,2H),7.05( d,J=7.9Hz,2H),6.30(s,1H),4.00(s,3H),3.74(s,2H),2.76(t,J=6.2Hz,2H),2.54(t,J=6.2Hz,2H),2.30(s,3H),2.25(s,3H).

[0236] Embodiment 22

[0237] 4-(1-methyl-2-(((2-(methylamino)propyl)amino)methyl)-5-(4-methylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 22

[0238] The synthetic route of Example 13 was used to replace the raw material of the third step, tert-butyl piperazine-1-carboxylate, with 3-(N-Boc-N-methylamino)propylamine to obtain the title compound 22 (41.4 mg). MS (ESI) m / z: 424.30 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.77(s,1H),7.66(d,J=7.9Hz,2H),7.41(d,J=7.9Hz,2H),7.14(d,J=7.8Hz,2H),7.06(d,J=7.9Hz,2H), 6.30(s,1H),3.99(s,3H),3.72(s,2H),2.70(t,J=7.1Hz,2H),2.50(t,J=7.0Hz,2H),2.30(s,3H),2.24(s,3H),1.71(p,J=6.9Hz,2H).

[0239] Embodiment 23

[0240] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 23

[0241]

[0242] first step

[0243] (S)-(1((4-((4-bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 23a

[0244] Using 4-bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carbonyl 1g (3.00g, 10.97mmol) and (S)-3-tert-butyloxycarbonylaminopyrrolidine (3.05g, 16.45mmol) as raw materials, the operation steps were the same as 1j to obtain the title compound 23a, a yellow-brown solid of 4.20g, with a yield of 86.6%. MS (ESI) m / z: 443.07 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.38(s,1H),6.39(s,1H),4.72(d,J=8.2Hz,1H),4.19(s,1H),3.86(s,3H),3.75(s,2H),2.77(dt,J=8.7,4.6Hz, 1H),2.70(dd,J=9.7,6.6Hz,1H),2.52(dd,J=9.6,3.6Hz,1H),2.39(dt,J=8.7,6.6Hz,1H),2.34–2.21(m,1H),1.65–1.53(m,1H),1.42(s,9H).

[0245] Step 2

[0246] Tert-butyl (S)-(1((4-((5-chloro-4-(cyanophenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperidin-3-yl)carbamate 23b

[0247] Using tert-butyl (S)-(1((4-((4-bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperidin-3-yl)carbamate (500 mg, 1.13 mmol), 4-cyano-phenylboronic acid (169.13 mg, 1.15 mmol), Na2CO3 (358.85 mg, 3.38 mmol) and Pd(PPh3)4 (65.30 mg, 0.06 mmol) as raw materials, the operation steps were the same as 1h to obtain the title compound 23b as a yellow-brown solid (367.4 mg). Yield: 71.2%. MS (ESI) m / z: 466.14 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.50(s,1H),7.79(d,J=8.1Hz,2H),7.64(d,J=8.0Hz,2H),6.09(s,1H),4.69(d,J=8.2Hz,1H),4.17(s,1H),3.91(s,3H),3 .71(s,2H),2.80–2.69(m,1H),2.66(t,J=8.1Hz,1H),2.48(dd,J=9.6,3.6Hz ,1H),2.41–2.33(m,1H),2.28–2.19(m,1H),1.63–1.51(m,1H),1.42(s,9H).

[0248] Step 3

[0249] Tert-butyl (S)-(1((4-((4-(cyanophenyl)-5-(4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperidin-3-yl)carbamate 23c

[0250] Using tert-butyl (S)-(1((4-((5-chloro-4-(cyanophenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperidin-3-yl)carbamate (100.00 mg, 0.22 mmol), 4-methoxy-phenylboronic acid (54.60 mg, 0.32 mmol), K3PO4 (91.30 mg, 0.43 mmol), X-phos (10 mg, 0.02 mmol) and Pd(OAc)2 (2.40 mg, 0.01 mmol) as raw materials, the operation steps were the same as 1i to obtain the title compound 23c as a yellow-brown solid (62.50 mg). Yield: 51.2%. MS (ESI) m / z: 538.30 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.80(s,1H),7.60(d,J=8.2Hz,2H),7.39(d,J=8.3Hz,2H),7.23 –7.17(m,2H),6.80–6.71(m,2H),6.20(s,1H),4.74(d,J=8.1Hz,1H),4.17(s,1H),3.94(s,3H) ,3.78(s,3H),3.74(d,J=1.7Hz,2H),2.76(d,J=11.9Hz,1H),2.65(dd,J=9.6,6.4Hz,1H),2.50 (dd,J=9.7,3.6Hz,1H),2.41–2.32(m,1H),2.28–2.20(m,1H),1.62–1.54(m,1H),1.42(s,9H).

[0251] Step 4

[0252] Synthesis of (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile

[0253] Tert-butyl 4-((4-(4-cyano-3-fluorophenyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)piperidin-1-carbamate (62.50 mg, 0.11 mmol) was used as the starting material and the operation steps were the same as 1 to obtain the title compound 23 (43.80 mg) with a yield of 91.2%. MS (ESI) m / z: 438.87 [M+H] + . 1 H-NMR(400MHz,Methanol-d4)δ8.75(d,J=0.8Hz,1H),7.68–7.64(m,2H),7.42–7.38 (m,2H),7.18–7.14(m,2H),6.81–6.77(m,2H),6.29(s,1H),3.98(s,3H),3.88–3.79( m,2H),3.76(s,3H),3.51–3.43(m,1H),2.77(dt,J=9.3,8.8,5.9Hz,2H),2.53(dt,J =8.6,6.2Hz,1H),2.39(dd,J=9.5,4.5Hz,1H),2.24–2.16(m,1H),1.57–1.49(m,1H).

[0254] Embodiment 24

[0255] A24 of (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile

[0256] The synthetic route of Example 23 was adopted, and the raw material 4-methoxyphenylboronic acid in the third step was replaced by 3-fluoro-4-methoxyphenylboronic acid to prepare the title compound 24 (35.5 mg). MS (ESI) m / z: 456.36 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.76(d,J=0.8Hz,1H),7.71–7.66(m,2H),7.44–7.3 9(m,2H),7.06–7.01(m,1H),6.95–6.89(m,2H),6.30(s,1H),3.99(s,3H),3.84(s ,2H),3.83(s,3H),3.51–3.42(m,1H),2.77(dt,J=9.3,6.7Hz,2H),2.53(dt,J=8. 6,6.1Hz,1H),2.39(dd,J=9.5,4.5Hz,1H),2.23–2.16(m,1H),1.57–1.48(m,1H).

[0257] Embodiment 25

[0258] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzonitrile 25 The synthetic route of Example 23 was adopted, and the raw material 4-methoxyphenylboronic acid in the third step was replaced with 4-trifluoromethylphenylboronic acid to obtain the title compound 25 (36.5 mg). MS (ESI) m / z: 476.34 [M+H] + . 1 HNMR(500MHz, Methanol-d4)δ8.84(d,J=0.8Hz,1H),7.74–7.67(m,2H),7.55(d,J=8.2Hz,2H),7.49–7.42(m,4H),6.34(s,1H),4.02(s,3 H),3.91–3.82(m,2H),2.78(dt,J=9.4,7.0Hz,2H),2.55(dt,J=8.7,6.2Hz,1H),2.43–2.37(m,1H),2.23–2.15(m,1H),1.58–1.49(m,1H).

[0259] Embodiment 26

[0260] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 26

[0261] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 4-methylphenylboronic acid to prepare the title compound 26 (36.5 mg). MS (ESI) m / z: 440.35 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.78 (s, 1H), 7.66 (t, J = 7.4Hz, 1H), 7.21 (d, J = 9.2Hz, 2 H),7.15(d,J=7.9Hz,2H),7.09(d,J=8.0Hz,2H),6.34(s,1H),4.00(s,3H),3.90–3. 80(m,2H),3.49–3.41(m,1H),2.78(dt,J=9.7,6.0Hz,2H),2.54(dt,J=8.6,6.2Hz,1 H),2.39(dd,J=9.5,4.6Hz,1H),2.32(s,3H),2.23–2.15(m,1H),1.60–1.50(m,1H).

[0262] Embodiment 27

[0263] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 27

[0264] The synthetic route of Example 23 was adopted, and the second step raw material 4-cyanophenylboronic acid was replaced with 3-fluoro-4-cyanophenylboronic acid to prepare the title compound 27 (33.6 mg). MS (ESI) m / z: 456.33 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.77(s,1H),7.68(t,J=7.5Hz,1H),7.26–7.17(m ,4H),6.83(dd,J=9.0,2.7Hz,2H),6.34(s,1H),4.00(s,3H),3.90–3.81(m,2H) ,3.78(s,3H),3.49–3.42(m,1H),2.77(dd,J=9.3,6.4Hz,2H),2.55(dt,J=8.7, 6.3Hz,1H),2.40(dd,J=9.5,4.5Hz,1H),2.22–2.14(m,1H),1.60–1.51(m,1H).

[0265] Embodiment 28

[0266] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-ethylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 28

[0267] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 4-ethylphenylboronic acid to prepare the title compound 28 (35.8 mg). MS (ESI) m / z: 454.35 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.78(s,1H),7.67(dd,J=8.2,6.8Hz,1H),7.24–7.16(m,4 H),7.12(d,J=8.0Hz,2H),6.34(s,1H),4.00(s,3H),3.91–3.80(m,2H),3.49–3.41(m,1 H),2.78(dt,J=9.7,6.0Hz,2H),2.63(q,J=7.6Hz,2H),2.55(dt,J=8.6,6.2Hz,1H),2. 39(dd,J=9.5,4.6Hz,1H),2.22–2.14(m,1H),1.60–1.50(m,1H),1.21(t,J=7.6Hz,3H).

[0268] Embodiment 29

[0269] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-cyclopropylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 29

[0270] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 4-cyclopropylphenylboronic acid to obtain the title compound 29 (32.8 mg). MS (ESI) m / z: 466.38 [M+H] + . 1 H NMR (600MHz, Methanol-d4) δ8.77(d,J=1.6Hz,1H),7.67(t,J=7.4Hz,1H),7.21(dd,J=8.0,4.0,2H),7.1 4(dd,J=8.3,2.3Hz,2H),6.98(dd,J=8.3,2.7Hz,2H),6.34(s,1H),3.99(d,J=1.9Hz,3H),3.90–3.82(m,2 H),3.48–3.41(m,1H),2.81–2.71(m,2H),2.54(dt,J=8.7,6.3Hz,1H),2.44(dd,J=9.9,4.3Hz,1H),2.20 (dt,J=7.7,6.4,3.5Hz,1H),1.91–1.83(m,1H),1.61–1.55(m,1H),0.98–0.93(m,2H),0.70–0.61(m,2H).

[0271] Embodiment 30

[0272] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(6-methylpyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 30

[0273] The synthetic route of Example 23 was used to prepare the title compound 30 (32.2 mg), by replacing the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 6-methylpyridine-3-boronic acid. MS (ESI) m / z: 441.31 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.87(s,1H),8.28(d,J=2.3Hz,1H),7.74(dd,J=7.9,6.8Hz,1H), 7.69(dd,J=8.0,2.3Hz,1H),7.33(dd,J=10.0,1.5Hz,1H),7.28–7.24(m,2H),6.37(s,1H),4. 02(s,3H),3.92–3.83(m,2H),3.49–3.41(m,1H),2.79(dt,J=9.3,6.5Hz,2H),2.56(dd,J=8.7 ,6.4Hz,1H),2.52(s,3H),2.40(dd,J=9.5,4.5Hz,1H),2.24–2.15(m,1H),1.60–1.51(m,1H).

[0274] Embodiment 31

[0275] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-trifluoromethoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 31

[0276] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 4-trifluoromethoxyphenylboronic acid to prepare the title compound 31 (33.5 mg). MS (ESI) m / z: 510.25 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.82(s,1H),7.70(t,J=7.4Hz,1H),7.41–7.35(m,2H ),7.27(dt,J=9.6,2.2Hz,1H),7.21(t,J=8.5Hz,3H),6.36(s,1H),4.01(s,3H),3. 86(d,J=4.5Hz,2H),3.49–3.41(m,1H),2.77(dt,J=8.7,5.3Hz,2H),2.55(dt,J=8 .7,6.1Hz,1H),2.39(dd,J=9.5,4.6Hz,1H),2.21–2.13(m,1H),1.60–1.49(m,1H).

[0277] Embodiment 32

[0278] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3-fluorophenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 32

[0279] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 3-fluorophenylboronic acid to obtain the title compound 32 (36.4 mg). MS (ESI) m / z: 444.30 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ8.82(s,1H),7.75–7.66(m,1H),7.30–7.22(m,3H) ,7.08(dt,J=9.9,2.1Hz,1H),7.02(dt,J=8.5,2.3Hz,2H),6.36(s,1H),4.01(s ,3H),3.91–3.82(m,2H),3.49–3.41(m,1H),2.82–2.75(m,2H),2.55(dt,J=8.6 ,6.3Hz,1H),2.41(dd,J=9.5,4.5Hz,1H),2.25–2.16(m,1H),1.61–1.51(m,1H).

[0280] Embodiment 33

[0281] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 33

[0282] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 3-methylphenylboronic acid to obtain the title compound 33 (34.2 mg). MS (ESI) m / z: 440.29 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.80 (s, 1H), 7.68 (t, J = 7.3Hz, 1H), 7.23 (d, J = 9.1Hz ,2H),7.19–7.07(m,3H),6.99(dt,J=7.4,1.9Hz,1H),6.37(s,1H),4.01(s,3H),3. 95–3.84(m,2H),3.63–3.54(m,1H),2.88(dt,J=8.7,4.9Hz,1H),2.75(dd,J=10.0, 6.4Hz,1H),2.63–2.47(m,2H),2.29(s,3H),2.27–2.17(m,1H),1.73–1.63(m,1H).

[0283] Embodiment 34

[0284] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3-fluoro-4-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 34

[0285] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 3-fluoro-4-methylphenylboronic acid to obtain the title compound 34 (35.2 mg). MS (ESI) m / z: 458.29 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.79 (s, 1H), 7.70 (t, J = 7.4Hz, 1H), 7.26 (dd, J = 10.1, 1.5Hz, 1H), 7.23 (dd,J=7.9,1.5Hz,1H),7.11(t,J=7.9Hz,1H),7.01(dd,J=10.7,1.7Hz,1H),6.91(dd,J=7.8,1.7Hz ,1H),6.34(s,1H),4.00(s,3H),3.90–3.81(m,2H),3.51–3.43(m,1H),2.81–2.73(m,2H),2.54(dt, J=8.6,6.2Hz,1H),2.39(dd,J=9.5,4.5Hz,1H),2.24(s,3H),2.22–2.14(m,1H),1.60–1.49(m,1H).

[0286] Embodiment 35

[0287] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3-chloro-4-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 35

[0288] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 3-chloro-4-methylphenylboronic acid to obtain the title compound 35 (34.8 mg). MS (ESI) m / z: 474.34 [M+H] + . 1 H NMR(500MHz,Methanol-d4)δ8.80(d,J=0.7Hz,1H),7.71(dd,J=8.0,6.8Hz,1H),7.36(d,J=1.8Hz,1H ),7.28(dd,J=10.1,1.6Hz,1H),7.23(dd,J=8.0,1.5Hz,1H),7.17(d,J=8.0Hz,1H),7.03(dd,J=7.8,1 .8Hz,1H),6.35(s,1H),4.01(s,3H),3.89–3.83(m,2H),3.51–3.43(m,1H),2.82–2.74(m,2H),2.54(d t,J=8.6,6.2Hz,1H),2.41(dd,J=9.6,4.4Hz,1H),2.35(s,3H),2.21–2.17(m,1H),1.59–1.54(m,1H).

[0289] Embodiment 36

[0290] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2-fluoro-4-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 36

[0291] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 2-fluoro-4-methylphenylboronic acid to prepare the title compound 36 (33.9 mg). MS (ESI) m / z: 458.29 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.81(s,1H),7.65(t,J=7.4Hz,1H),7.27(t,J=7.7Hz,1H ),7.24–7.19(m,2H),7.01(d,J=7.8Hz,1H),6.81(d,J=10.8Hz,1H),6.37(s,1H),4.0 1(s,3H),3.91–3.81(m,2H),3.49–3.41(m,1H),2.84–2.72(m,2H),2.54(dt,J=8.6,6 .2Hz,1H),2.42(d,J=4.5Hz,1H),2.34(s,3H),2.25–2.15(m,1H),1.60–1.51(m,1H).

[0292] Embodiment 37

[0293] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4-dimethylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 37

[0294] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 3,4-dimethylphenylboronic acid to obtain the title compound 37 (36.6 mg). MS (ESI) m / z: 454.31 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.81(s,1H),7.65(t,J=7.4Hz,1H),7.27(t,J=7.7Hz,1H ),7.24–7.19(m,2H),7.01(d,J=7.8Hz,1H),6.81(d,J=10.8Hz,1H),6.37(s,1H),4.0 1(s,3H),3.91–3.81(m,2H),3.51–3.44(m,1H),2.84–2.72(m,2H),2.54(dt,J=8.6,6 .2Hz,1H),2.42(d,J=4.5Hz,1H),2.34(s,3H),2.25–2.15(m,1H),1.60–1.51(m,1H).

[0295] Embodiment 38

[0296] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,4-dimethylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 38

[0297] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 2,4-dimethylphenylboronic acid to obtain the title compound 38 (33.6 mg). MS (ESI) m / z: 454.31 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.78(s,1H),7.62(t,J=7.5Hz,1H),7.21(dd,J=8.0,1.5Hz,1H ),7.17(dd,J=10.3,1.5Hz,1H),7.00(s,1H),6.95(q,J=7.8Hz,2H),6.37(s,1H),4.01(s,3 H),3.93–3.83(m,2H),3.49–3.42(m,1H),2.82–2.74(m,2H),2.56(dt,J=8.6,6.2Hz,1H),2 .40(dd,J=9.5,4.5Hz,1H),2.29(s,3H),2.25–2.14(m,1H),1.98(s,3H),1.60–1.51(m,1H).

[0298] Embodiment 39

[0299] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,5-dimethylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 39

[0300] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 3,5-dimethylphenylboronic acid to obtain the title compound 39 (35.2 mg). MS (ESI) m / z: 454.30 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.77(s,1H),7.68(dd,J=8.1,6.7Hz,1H),7.26–7.19( m,2H),6.93(s,1H),6.88(s,2H),6.34(s,1H),4.00(s,3H),3.91–3.81(m,2H),3.49 –3.41(m,1H),2.78(dt,J=9.3,8.6,5.9Hz,2H),2.55(dt,J=8.6,6.2Hz,1H),2.40(d d,J=9.5,4.6Hz,1H),2.21(s,6H),2.18(dd,J=13.0,7.4Hz,1H),1.60–1.51(m,1H).

[0301] Embodiment 40

[0302] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2-fluoro-4-methoxy-phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 40

[0303] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 2-fluoro-4-methoxyphenylboronic acid to prepare the title compound 40 (33.9 mg). MS (ESI) m / z: 474.28 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.81(s,1H),7.68(dd,J=8.1,6.8Hz,1H),7.30(t,J=8.5Hz,1H ),7.23(t,J=8.2Hz,2H),6.78(dd,J=8.6,2.4Hz,1H),6.57(dd,J=11.8,2.4Hz,1H),6.37(s, 1H),4.01(s,3H),3.92–3.82(m,2H),3.79(s,3H),3.49–3.41(m,1H),2.83–2.72(m,2H),2.5 5(dt,J=8.6,6.3Hz,1H),2.41(dd,J=9.6,4.5Hz,1H),2.25–2.15(m,1H),1.59–1.51(m,1H).

[0304] Embodiment 41

[0305] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2-methyl-4-methoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 41

[0306] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 2-methyl-4-methoxyphenylboronic acid to prepare the title compound 41 (32.5 mg). MS (ESI) m / z: 470.31 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.77(s,1H),7.63(t,J=7.4Hz,1H),7.23–7.16(m,2H),6.99(d,J=8.4Hz,1H),6.74(d, J=2.6Hz,1H),6.68(dd,J=8.4,2.6Hz,1H),6.37(s,1H),4.01(s,3H),3.93–3.82(m,2H),3.76(s,3H),3.50–3.41(m ,1H),2.82–2.73(m,2H),2.56(dt,J=8.6,6.2Hz,1H),2.41(dd,J=9.5,4.5Hz,1H),2.25–2.16(m,1H),2.00(s,3H), 1.60–1.51(m,1H).111.91,101.24,100.36(d,J=15.6Hz),63.57,55.61,54.11,52.37,51.63,34.97,30.90,20.33.

[0307] Embodiment 42

[0308] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,4-dimethoxyphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 42

[0309] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 2,4-methoxyphenylboronic acid to prepare the title compound 42 (32.0 mg). MS (ESI) m / z: 486.30 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.74(s,1H),7.63(t,J=7.4Hz,1H),7.24–7.16(m,3H),6.55 (dd,J=8.4,2.3Hz,1H),6.40(d,J=2.3Hz,1H),6.34(s,1H),3.99(s,3H),3.91–3.81(m,2 H),3.79(s,3H),3.49–3.43(m,1H),3.42(s,3H),2.78(dt,J=9.3,8.8,5.8Hz,2H),2.55( dt,J=8.6,6.2Hz,1H),2.39(dd,J=9.5,4.6Hz,1H),2.25–2.15(m,1H),1.60–1.51(m,1H).

[0310] Embodiment 43

[0311] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,5-difluoro-4-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 43

[0312] The synthetic route of Example 23 was used to prepare the title compound 43 (32.8 mg), by replacing the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 3,5-difluoro-4-methylphenylboronic acid. MS (ESI) m / z: 476.31 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.81 (s, 1H), 7.74 (dd, J = 8.0, 6.8 Hz, 1H), 7.31 (dd, J = 10. 0,1.5Hz,1H),7.25(dd,J=8.0,1.5Hz,1H),6.83(d,J=7.4Hz,2H),6.35(s,1H),4.01(s, 3H),3.86(d,J=4.3Hz,2H),3.49–3.41(m,1H),2.80–2.74(m,2H),2.54(dt,J=8.6,6.2H z,1H),2.39(dd,J=9.5,4.6Hz,1H),2.24–2.18(m,1H),2.16(s,3H),1.59–1.51(m,1H).

[0313] Embodiment 44

[0314] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,3-difluoro-4-methylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 44

[0315] The synthetic route of Example 23 was used to prepare the title compound 44 (32.5 mg), by replacing the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 2,3-difluoro-4-methylphenylboronic acid. MS (ESI) m / z: 476.31 [M+H] + . 1 H NMR (600MHz, Methanol-d4) δ8.83(d,J=0.8Hz,1H),7.68(dd,J=8.0,6.8Hz,1H),7.26(dd,J=10.1 ,1.5Hz,1H),7.22(dd,J=8.0,1.5Hz,1H),7.06–7.00(m,2H),6.39(s,1H),4.02(s,3H),3.91–3.8 4(m,2H),3.55–3.48(m,1H),2.83(dt,J=8.7,5.3Hz,1H),2.76(dd,J=9.7,6.5Hz,1H),2.53(dt,J =8.7,6.4Hz,1H),2.48(dd,J=9.7,4.2Hz,1H),2.29(s,3H),2.25–2.18(m,1H),1.63–1.58(m,1H).

[0316] Embodiment 45

[0317] Synthesis of (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-fluoro-3,5-dimethylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile (A45)

[0318] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 4-fluoro-3,5-dimethylphenylboronic acid to obtain the title compound 45 (33.6 mg). MS (ESI) m / z: 472.32 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.77(s,1H),7.70(t,J=7.4Hz,1H),7.28–7.20(m,2H ),6.95(d,J=6.9Hz,2H),6.34(s,1H),4.00(s,3H),3.85(d,J=4.9Hz,2H),3.49–3 .41(m,1H),2.78(dt,J=9.6,6.1Hz,2H),2.55(dt,J=8.6,6.2Hz,1H),2.39(dd,J= 9.5,4.6Hz,1H),2.24–2.18(m,1H),2.16(s,3H),2.15(s,3H),1.59–1.50(m,1H).

[0319] Embodiment 46

[0320] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,4,5-trimethylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 46

[0321] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 2,3,5-trimethylphenylboronic acid to obtain the title compound 46 (33.2 mg). MS (ESI) m / z: 468.43 [M+H] + . 1 H NMR (600MHz, Methanol-d4) δ8.77(s,1H),7.61(dd,J=8.0,6.8Hz,1H),7.22(dd,J=8.0,1.5H z,1H),7.18(dd,J=10.3,1.5Hz,1H),6.91(d,J=19.4Hz,2H),6.37(s,1H),4.01(s,3H),3.95– 3.84(m,2H),3.49–3.41(m,1H),2.82–2.74(m,2H),2.56(dt,J=8.7,6.3Hz,1H),2.40(dd,J=9 .5,4.5Hz,1H),2.21(s,3H),2.21–2.17(m,1H),2.15(s,3H),1.91(s,3H),1.63–1.54(m,1H).

[0322] Embodiment 47

[0323] Synthesis of (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4,5-trimethylphenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile (A47)

[0324] The synthetic route of Example 23 was used to prepare the title compound 47 (34.7 mg), by replacing the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 3,4,5-trimethylphenylboronic acid. MS (ESI) m / z: 468.45 [M+H] + . 1 H NMR(500MHz,Methanol-d4)δ8.75(d,J=0.9Hz,1H),7.68–7.64(m,1H),7.24–7 .21(m,2H),6.89(s,2H),6.32(s,1H),3.99(s,3H),3.85(d,J=7.5Hz,2H),3.4 9–3.41(m,1H),2.81–2.75(m,2H),2.54(dt,J=8.7,6.3Hz,1H),2.40(dd,J=9. 5,4.5Hz,1H),2.23–2.19(m,1H),2.18(s,6H),2.16(s,3H),1.58–1.52(m,1H).

[0325] Embodiment 48

[0326] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 48

[0327] The synthetic route of Example 23 was used to prepare the title compound 48 (35.7 mg) by replacing the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 4-benzocyclobutene-boronic acid. MS (ESI) m / z: 452.32 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.77(s,1H),7.65(dd,J=8.2,6.8Hz,1H),7.23–7.19(m,2H) ,7.05(dd,J=7.6,1.4Hz,1H),6.98(s,1H),6.92(d,J=7.6Hz,1H),6.33(s,1H),3.99(s,3H ),3.85(d,J=5.1Hz,2H),3.50–3.41(m,1H),3.16–3.10(m,4H),2.82–2.75(m,2H),2.54( dt,J=8.6,6.2Hz,1H),2.41(dd,J=9.5,4.5Hz,1H),2.22–2.16(m,1H),1.59–1.53(m,1H).

[0328] Embodiment 49

[0329] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 49

[0330] The synthetic route of Example 23 was used to prepare the title compound 49 (36.7 mg), by replacing the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with (2,3-dihydro-1H-inden-5-yl)boronic acid. MS (ESI) m / z: 466.38 [M+H] + . 1 H NMR (500MHz, Methanol-d4) δ8.76 (s, 1H), 7.66–7.61 (m, 1H), 7.21 (dd, J = 3.5, 1.4Hz, 1H), 7.20–7.1 6(m,2H),7.06(d,J=7.7Hz,1H),6.93(dd,J=7.7,1.7Hz,1H),6.32(s,1H),3.98(s,3H),3.87–3.80( m,2H),3.49–3.40(m,1H),2.85(dt,J=20.6,7.4Hz,4H),2.77(dt,J=9.5,5.8Hz,2H),2.54(dt,J=8. 7,6.3Hz,1H),2.39(dd,J=9.5,4.6Hz,1H),2.22–2.13(m,1H),2.08–1.97(m,2H),1.59–1.53(m,1H).

[0331] Embodiment 50

[0332] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(phenyl[d][1.3]dioxy-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 50

[0333] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with benzo[d][1,3]dioxol-5-ylboronic acid to obtain the title compound 50 (36.1 mg). MS (ESI) m / z: 470.31 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.76(s,1H),7.69(t,J=7.4Hz,1H),7.27–7.21(m,2 H),6.78(d,J=1.5Hz,1H),6.72–6.66(m,2H),6.33(s,1H),5.94(s,2H),3.99(s, 3H),3.85(d,J=4.4Hz,2H),3.49–3.40(m,1H),2.82–2.74(m,2H),2.54(dt,J=8. 6,6.1Hz,1H),2.38(dd,J=9.5,4.6Hz,1H),2.22–2.15(m,1H),1.58–1.50(m,1H).

[0334] Embodiment 51

[0335] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(4-(2-hydroxy-2-methylpropyl)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 51

[0336] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinane-2-yl)phenyl)propan-2-ol to obtain the title compound 51 (32.1 mg). MS (ESI) m / z: 498.42 [M+H] + . 1H NMR (500MHz, Methanol-d4) δ8.79 (s, 1H), 7.66 (dd, J = 8.0, 6.8 Hz, 1H), 7.23 (dd, J =8.0,1.5Hz,1H),7.21–7.13(m,6H),6.36(s,1H),4.00(s,3H),3.87(d,J=8.3Hz,2 H),3.54–3.45(m,1H),2.85–2.75(m,2H),2.74(s,2H),2.54(dt,J=8.7,6.3Hz,1H ), 2.44(dd,J=9.7,4.3Hz,1H),2.23–2.17(m,1H),1.62–1.55(m,1H),1.15(s,6H).

[0337] Embodiment 52

[0338] (S)-ethyl 2-(4-(2-((3-aminopyrrolidin-1-yl)methyl)-4-(4-cyano-3-fluorophenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)phenyl)acetate 52

[0339] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate to obtain the title compound 51 (35.5 mg). MS (ESI) m / z: 512.41 [M+H] + . 1 H NMR(600MHz,Methanol-d4)δ8.79(s,1H),7.67(dd,J=8.2,6.7Hz,1H),7.25–7.19 (m,6H),6.35(s,1H),4.12(q,J=7.1Hz,2H),4.00(s,3H),3.91–3.82(m,2H),3.62( s,2H),3.52–3.43(m,1H),2.82–2.75(m,2H),2.54(dt,J=8.7,6.3Hz,1H),2.42(d d,J=9.6,4.4Hz,1H),2.25–2.15(m,1H),1.61–1.54(m,1H),1.21(t,J=7.1Hz,3H).

[0340] Embodiment 53

[0341] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(1-methyl-1H-benzo[d]imidazol-6-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 53

[0342] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with (1-methyl-1H-benzo[d]imidazol-5-yl)boronic acid to prepare the title compound 53 (33.0 mg). MS (ESI) m / z: 480.31 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.83(s,1H),8.12(s,1H),7.63(t,J=7.4Hz,1H),7.57(d,J=1.5Hz, 1H),7.49(d,J=8.4Hz,1H),7.32(d,J=8.4Hz,1H),7.24(dd,J=14.7,9.1Hz,2H),6.37(s,1H),4. 02(s,3H),3.90(s,3H),3.88(s,2H),3.48(d,J=7.2Hz,1H),2.79(dt,J=10.0,9.2,5.5Hz,2H),2 .59–2.51(m,1H),2.44(dd,J=10.0,4.2Hz,1H),2.21(dt,J=14.9,6.7Hz,1H),1.61–1.53(m,1H).

[0343] Embodiment 54

[0344] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(1-methyl-1H-indazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 54

[0345] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with 1-methyl-1H-indazol-5-yl-5-boronic acid to prepare the title compound 54 (34.2 mg). MS (ESI) m / z: 480.30 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.82(s,1H),7.95(s,1H),7.69(d,J=1.5Hz,1H),7.62(t,J=7.4Hz,1H), 7.44(d,J=8.7Hz,1H),7.32(dd,J=8.8,1.6Hz,1H),7.27(dd,J=10.2,1.5Hz,1H),7.20(dd,J=8.0,1. 5Hz,1H),6.37(s,1H),4.05(s,3H),4.01(s,3H),3.92–3.82(m,2H),3.49–3.41(m,1H),2.83–2.74(m ,2H),2.55(dt,J=8.6,6.2Hz,1H),2.40(dd,J=9.5,4.6Hz,1H),2.25–2.15(m,1H),1.61–1.50(m,1H).

[0346] Embodiment 55

[0347] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2-methyl-2H-indazol-5-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 55

[0348] The synthetic route of Example 23 was used to replace the second step raw material 4-cyanophenylboronic acid with 3-fluoro-4-cyanophenylboronic acid and the third step raw material 4-methoxyphenylboronic acid with (2-methyl-2H-indazol-5-yl)boronic acid to prepare the title compound 55 (32.4 mg). MS (ESI) m / z: 480.30 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.81 (s, 1H), 8.14 (s, 1H), 7.63 (dd, J = 8.0, 6.8Hz, 1H), 7.5 8(t,J=1.2Hz,1H),7.50(d,J=8.9Hz,1H),7.32–7.20(m,3H),6.37(s,1H),4.19(s,3H), 4.01(s,3H),3.92–3.82(m,2H),3.50–3.41(m,1H),2.78(dd,J=9.3,6.4Hz,2H),2.55(d t,J=8.6,6.2Hz,1H),2.41(dd,J=9.5,4.5Hz,1H),2.25–2.16(m,1H),1.60–1.51(m,1H).

[0349] Embodiment 56

[0350] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl-5-(3,4-dimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 56

[0351]

[0352] first step

[0353] 4-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine 56a

[0354] The synthesis method was the same as 1f using 4-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine 1e (5.00 g, 21.65 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (5.75 mL, 32.48 mmol) as raw materials. The title compound 56a was obtained as a yellow-brown solid (4.95 g) with a yield of 63.2%. MS (ESI) m / z: 361.16. 1 H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.39(d,J=3.2Hz,1H),6.57(d,J=3.0H z,1H),5.51(s,2H),3.46(dd,J=8.8,7.5Hz,2H),0.91–0.86(m,2H),-0.06(s,9H).

[0355] Step 2

[0356] 4-Bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate 56b

[0357] Using 4-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine 56a (4.95 g, 13.68 mmol) and N-formylmorpholine (10.30 mL, 20.50 mmol) as raw materials, the synthesis method was the same as 1g to obtain the title compound 56b, a yellow-brown solid of 3.1 g, with a yield of 59.6%. MS (ESI) m / z: 389.08 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ10.06(s,1H),8.80(d,J=0.7Hz,1H),7.30(d,J=0.8H z,1H),6.02(s,2H),3.59–3.48(m,2H),0.88(dd,J=8.8,7.6Hz,2H),-0.07(s,9H).

[0358] Step 3

[0359] Tert-butyl (S)-(1-((4-((4-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56c

[0360] Using 4-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl-1H-pyrrolo[2,3-c]pyridine-2-carbonyl 56b (3.10 g, 8.16 mmol) and (S)-N-Boc-3-aminopyrrolidine (2.23 g, 12.23 mmol) as raw materials, the synthesis method was the same as 1h to obtain the title compound 56c as a yellow-brown solid (3.89 g). Yield: 85.6%. MS (ESI) m / z: 559.19 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H),6.38(s,1H),5.59(d,J=2.5Hz,2H),4 .97–4.79(m,1H),4.11(s,1H),3.76(s,2H),3.51–3.38(m,2H),2.72(dt,J=8.5,4 .6Hz,1H),2.65(dd,J=9.6,6.5Hz,1H),2.51–2.42(m,1H),2.38–2.30(m,1H),2.2 5–2.15(m,1H),1.60–1.51(m,2H),1.36(s,9H),0.85–0.81(m,2H),-0.11(s,9H).

[0361] Step 4

[0362] Tert-butyl (S)-(1-((5-chloro-4-(4-cyano-3-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56d

[0363] Using tert-butyl (S)-(1-((4-((4-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56c (3.89 g, 6.98 mmol) and 3-fluoro-4-cyanophenylboronic acid (1.21 g, 7.33 mmol) as raw materials, the synthesis method was the same as 1i. The title compound 56d was obtained as a yellow-brown solid (2.85 g). Yield: 68.2%. MS (ESI) m / z: 600.27 [M+H]+ . 1 H-NMR(400MHz,Chloroform-d)δ8.67–8.60(m,1H),7.74(dd,J=7.9,6.6Hz,1H),7.41(dd,J=8.8,1.5Hz ,2H),6.14(s,1H),5.69(d,J=1.4Hz,2H),4.76(s,1H),4.12(d,J=7.2Hz,1H),3.77(s,2H),3.58–3.50( m,2H),2.79–2.71(m,1H),2.66(dd,J=9.7,6.4Hz,1H),2.47(dd,J=9.6,3.7Hz,1H),2.37(dt,J=8.7,6. 6Hz,1H),2.32–2.17(m,1H),1.60–1.51(m,1H),1.40(s,9H),0.91(dd,J=8.8,7.4Hz,2H),-0.04(s,9H).

[0364] Step 5

[0365] Tert-butyl (S)-(1-((4-(4-(4-cyano-3-fluorophenyl)-5-(3,4-dimethylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56e

[0366] Using the intermediate tert-butyl (S)-(1-((5-chloro-4-(4-cyano-3-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56d (2.00 g, 3.34 mmol) and 3,4-dimethyl-phenylboronic acid (750.50 mg, 5.00 mmol) as raw materials, the synthesis method was the same as 1j to obtain the title compound 56e as a yellow-brown solid 1002.4 mg, yield: 49.4%. 1H NMR(400MHz,Chloroform-d)δ8.94(d,J=0.8Hz,1H),7.54(dd,J=7.9,6.6Hz,1H),7.22(d,J=1.6Hz,1H),7.21–7.15(m,2H ),6.94(d,J=7.8Hz,1H),6.86(dd,J=7.7,1.9Hz,1H),6.26(s,1H),5.74(d,J=1.5Hz,2H),4.85–4.73(m,1H),4.17(s,1H), 3.82(d,J=3.6Hz,2H),3.65–3.53(m,2H),2.79(s,1H),2.67(dd,J=9.7,6.4Hz,1H),2.52(d,J=9.6Hz,1H),2.38(q,J=8.2H z,1H),2.27(s,1H),2.23(s,3H),2.21(s,3H),1.63–1.56(m,1H),1.42(s,9H),0.94(dd,J=8.8,7.4Hz,2H),-0.03(s,9H).

[0367] Step 6

[0368] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl-5-(3,4-dimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 56

[0369] Tert-butyl (S)-(1((4-((4-(3-fluoro-cyanophenyl)-5-(3,4-dimethylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56e (50 mg, 0.07 mmol) was dissolved in DCM (2 mL), TFA (2 mL) was added dropwise, and the reaction was continued to stir for 1 h. TLC monitored that the reaction of the raw material was complete (DCM / MeOH(NH3)=10:1). The reaction solution was concentrated under reduced pressure, neutralized with ammonia methanol, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain the title compound 56 as a white solid (27.2 mg). Yield: 82.6%. MS (ESI) m / z: 440.33 [M+H] + . 1HNMR(400MHz, Methanol-d4)δ8.68(s,1H),7.66(t,J=7.4Hz,1H),7.25–7.23(m,1H),7.21(s,1H) ),7.11(d,J=1.8Hz,1H),7.00(d,J=7.7Hz,1H),6.91(dd,J=7.7,1.9Hz,1H),6.31(s,1H),3.90– 3.81(m,2H),3.54–3.46(m,1H),2.83(dt,J=8.7,5.4Hz,1H),2.76(dd,J=9.6,6.4Hz,1H),2.55( dt,J=8.7,6.4Hz,1H),2.45(dd,J=9.6,4.3Hz,1H),2.24(s,3H),2.20(s,4H),1.61–1.54(m,1H).

[0370] Embodiment 57

[0371] Synthesis of (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4-dimethylphenyl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile

[0372]

[0373] first step

[0374] Tert-butyl (S)-(1-((4-(4-(4-cyano-3-fluorophenyl)-5-(3,4-dimethylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56e

[0375] Using the intermediate tert-butyl (S)-(1-((5-chloro-4-(4-cyano-3-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56d (2.00 g, 3.34 mmol) and 3,4-dimethyl-phenylboronic acid (750.50 mg, 5.00 mmol) as raw materials, the synthesis method was the same as 1j to obtain the title compound 56e as a yellow-brown solid 1002.4 mg, yield: 49.4%. 1H NMR(400MHz,Chloroform-d)δ8.94(d,J=0.8Hz,1H),7.54(dd,J=7.9,6.6Hz,1H),7.22(d,J=1.6Hz,1H),7.21–7.15(m,2H),6.94(d,J=7.8Hz,1H), 6.86(dd,J=7.7,1.9Hz,1H),6.26(s,1H),5.74(d,J=1.5Hz,2H),4.85–4. 73(m,1H),4.17(s,1H),3.82(d,J=3.6Hz,2H),3.65–3.53(m,2H),2.79(s,

[0376] 1H),2.67(dd,J=9.7,6.4Hz,1H),2.52(d,J=9.6Hz,1H),2.38(q,J=8.2Hz,1H),2.27(s,1H),2.23 (s,3H),2.21(s,3H),1.63–1.56(m,1H),1.42(s,9H),0.94(dd,J=8.8,7.4Hz,2H),-0.03(s,9H).

[0377] Step 2

[0378] Tert-butyl (S)-(1-((4-(4-cyano-3-fluorophenyl)-5-(3,4-dimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 57a

[0379] The intermediate tert-butyl (S)-(1-((4-(4-(4-cyano-3-fluorophenyl)-5-(3,4-dimethylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56e (1.05 g, 1.64 mmol) was dissolved in DMF, TBAF (1.04 g, 3.28 mmol) and ethylenediamine (19 7.60mg, 3.28mmol), heated to 60℃ for 6h, TLC monitored the complete reaction of the raw material (PE / EA=1:1). The reaction solution was cooled to room temperature, 25mL of water was added to the reaction solution, extracted 3 times with 25mL of ethyl acetate, the organic layers were combined, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain the title compound 57a as a yellow-brown solid 252mg, yield: 28.5%. 1H NMR(400MHz,Chloroform-d)δ8.82(s,1H),7.53(dd,J=8.0,6.7Hz,1H),7.23–7.18(m,2H),7.17(dd,J =8.0,1.5Hz,1H),6.93(d,J=7.8Hz,1H),6.86(dd,J=7.7,1.9Hz,1H),6.21(s,1H),4.90(d,J=7.9Hz,1 H),4.20(s,1H),3.79(d,J=2.1Hz,2H),2.82(dt,J=8.8,4.7Hz,1H),2.72(s,1H),2.59(d,J=9.8Hz,1H ),2.42(d,J=8.3Hz,1H),2.36–2.26(m,1H),2.22(s,3H),2.18(s,3H),1.67–1.58(m,1H),1.44(s,9H).

[0380] Step 3

[0381] Tert-butyl (S)-(1-((4-(4-cyano-3-fluorophenyl)-5-(3,4-dimethylphenyl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56b

[0382] Tert-butyl (S)-(1((4-(4-(3-fluoro-cyanophenyl)-5-(3,4-dimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 56b (30.00 mg, 0.05 mmol) was dissolved in DMF (5 mL) at room temperature, cesium carbonate (36.30 mg, 0.11 mmol) and iodoethane (18.50 mg, 0.11 mmol) were added, and the temperature was raised to 80°C for 12 h. TLC monitored the complete reaction of the raw material (PE / EA=1:1). The reaction solution was cooled to room temperature, 10 mL of water was added to the reaction solution, and the mixture was extracted three times with 15 mL of ethyl acetate. The organic layers were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The title compound 57b was separated and purified by silica gel column chromatography to obtain 24.5 mg of a yellow-brown solid in a yield of 78.6%. 1HNMR(400MHz,Chloroform-d)δ8.82(s,1H),7.53(dd,J=7.9,6.7Hz,1H),7.22(d,J=1.9Hz,1H),7.19(dd,J=9.8,1.4H z,1H),7.16(dd,J=7.9,1.5Hz,1H),6.94(d,J=7.8Hz,1H),6.85(dd,J=7.7,1.9Hz,1H),6.20(s,1H),4.71(d,J=8.2Hz ,1H),4.40(q,J=7.2Hz,2H),4.15(d,J=19.2Hz,1H),3.74(s,2H),2.74(dd,J=8.8,4.7Hz,1H),2.68(dd,J=9.6,6.4Hz ,1H),2.50(dd,J=9.6,3.7Hz,1H),2.43–2.34(m,1H),2.27(d,J=9.3Hz,1H),2.22(s,3H),2.21(s,3H),1.62–1.52(m,

[0383] 1H), 1.48 (t, J = 7.2Hz, 3H), 1.42 (s, 9H).

[0384] Step 4

[0385] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4-dimethylphenyl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 57

[0386] Tert-butyl (S)-(1((4-((4-(3-fluoro-cyanophenyl)-5-(3,4-dimethylphenyl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)pyrrolidin-3-yl)carbamate 57c (24.50 mg, 0.04 mmol) was used as the starting material and the operation steps were the same as 1 to obtain the title compound 57 as a white solid (17.1 mg). Yield: 91.5%. MS (ESI) m / z: 468.42 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.78(s,1H),7.67(dd,J=8.2,6.8Hz,1H),7.24(d,J=1.4Hz,1H),7.21(s,1H ),7.12(d,J=1.9Hz,1H),7.01(d,J=7.8Hz,1H),6.91(dd,J=7.7,1.9Hz,1H),6.33(s,1H),4.50(q,J=7.2 Hz,2H),3.85(s,2H),3.51–3.42(m,1H),2.82–2.71(m,2H),2.55(dt,J=8.6,6.1Hz,1H),2.40(dd,J=9.5 ,4.6Hz,1H),2.24(s,3H),2.21(s,3H),2.18(d,J=7.8Hz,1H),1.61–1.53(m,1H),1.46(t,J=7.2Hz,3H).

[0387] Embodiment 58

[0388] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4-dimethylphenyl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 58

[0389] Using the synthetic route of Example 57, the raw material iodoethane in the third step was replaced with 2-iodopropane to prepare the title compound 58 (17.5 mg). MS (ESI) m / z: 482.43 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.95 (s, 1H), 7.68 (t, J = 7.3Hz, 1H), 7.23 (d, J = 2.1Hz, 1H), 7.21 (s, 1H), 7.12 (d,J=1.8Hz,1H),7.01(d,J=7.8Hz,1H),6.91(dd,J=7.8,1.9Hz,1H),6.27(s,1H),5.14(p,J=7.0Hz,1H),3 .83(s,2H),3.44(d,J=7.6Hz,1H),2.73(dt,J=9.3,5.8Hz,2H),2.51(q,J=8.0Hz,1H),2.37(dd,J=9.5,4. 6Hz, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 2.18 (d, J = 4.3Hz, 1H), 1.72 (dd, J = 6.9, 3.7Hz, 6H), 1.61–1.54 (m, 1H).

[0390] Embodiment 59

[0391] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-(2,2-difluoroethyl)-5-(3,4-dimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 59

[0392] Using the synthetic route of Example 57, the raw material iodoethane in the third step was replaced with 2,2-difluoroethyl trifluoromethanesulfonate to prepare the title compound 59 (15.8 mg). MS (ESI) m / z: 504.40 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.84(d,J=1.1Hz,1H),7.70(dd,J=8.1,6.8Hz,1H),7.27(dd,J=5.1,1.4Hz,1H), 7.25–7.23(m,1H),7.15(d,J=1.9Hz,1H),7.03(d,J=7.8Hz,1H),6.94(dd,J=7.7,1.9Hz,1H),6.42(s,1H),6.3 9–6.28(m,1H),5.00(td,J=15.3,3.4Hz,2H),3.89(s,2H),3.50–3.41(m,1H),2.82–2.71(m,2H),2.54(dt,J= 8.6, 6.2Hz, 1H), 2.37 (dd, J = 9.5, 4.7Hz, 1H), 2.26 (s, 3H), 2.22 (s, 3H), 2.22–2.17 (m, 1H), 1.61–1.51 (m, 1H).

[0393] Embodiment 60

[0394] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4-dimethylphenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 60

[0395] Using the synthetic route of Example 57, the raw material iodoethane in the third step was replaced with 2,2,2-trifluoroethyl trifluoromethanesulfonate to prepare the title compound 60 (17.0 mg). MS (ESI) m / z: 522.36 [M+H] + . 1H NMR(500MHz, Methanol-d4)δ8.87(s,1H),7.67(dd,J=8.1,6.8Hz,1H),7.27–7.20(m,2H),7.13 (d,J=1.8Hz,1H),6.99(d,J=7.8Hz,1H),6.92(dd,J=7.8,1.9Hz,1H),6.43(s,1H),5.52–5.40( m,2H),3.97–3.81(m,2H),3.51–3.40(m,1H),2.80–2.69(m,2H),2.49(dt,J=8.6,6.4Hz,1H),2 .38(dd,J=9.5,4.4Hz,1H),2.23(s,3H),2.19(s,3H),2.16(d,J=8.6Hz,1H),1.62–1.53(m,1H).

[0396] Embodiment 61

[0397] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-(cyclopropylmethyl)-5-(3,4-dimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 61

[0398] Using the synthetic route of Example 57, the raw material iodoethane in the third step was replaced with (iodomethyl)cyclopropane to obtain the title compound 61 (18.1 mg). MS (ESI) m / z: 494.45 [M+H] + . 1 H NMR(500MHz,Methanol-d4)δ8.81(s,1H),7.65(t,J=7.4Hz,1H),7.23–7.19(m,2H),7.12(d,J=1.9Hz,1H) ,6.99(d,J=7.7Hz,1H),6.90(dd,J=7.7,1.9Hz,1H),6.34(s,1H),4.37(d,J=6.8Hz,2H),3.86(s,2H),3.49 –3.41(m,1H),2.80–2.71(m,2H),2.54(td,J=8.6,6.1Hz,1H),2.39(dd,J=9.5,4.7Hz,1H),2.23(s,3H),2. 19(s,3H),2.18–2.14(m,1H),1.58–1.50(m,1H),1.35–1.31(m,1H),0.62–0.57(m,2H),0.51–0.47(m,2H).

[0399] Embodiment 62

[0400] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-(cyclobutylmethyl)-5-(3,4-dimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 62

[0401] Using the synthetic route of Example 57, the raw material iodoethane in the third step was replaced with (iodomethyl)cyclobutane to obtain the title compound 62 (17.8 mg). MS (ESI) m / z: 508.47 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.95(s,1H),7.87(t,J=7.5Hz,1H),7.41(dd,J=10.3,1.5Hz,1H),7.23–7.19(m,2H),6.94(d ,J=7.9Hz,1H),6.84(dd,J=7.7,1.9Hz,1H),6.22(s,1H),4.43(d,J=7.2Hz,2H),3.75(d,J=3.0Hz,2H),3.35–3.31(m, 1H),2.89–2.82(m,1H),2.68(dd,J=9.1,6.5Hz,1H),2.59(dt,J=8.6,6.0Hz,1H),2.49–2.44(m,1H),2.20(d,J=8.3Hz ,1H),2.17(s,3H),2.15(s,3H),2.03–1.98(m,1H),1.95(q,J=7.3,6.3Hz,2H),1.89–1.77(m,4H),1.40–1.31(m,1H).

[0402] Embodiment 63

[0403] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4-dimethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 63

[0404] Using the synthetic route of Example 57, the raw material iodoethane in the third step was replaced with 4-(iodomethyl)tetrahydro-2H-pyran to obtain the title compound 63 (17.9 mg). MS (ESI) m / z: 538.49 [M+H] + . 1H NMR (500MHz, Methanol-d4) δ8.82(s,1H),7.65(dd,J=8.2,6.8Hz,1H),7.22(dd,J=4.0,1.4Hz,1H),7.21(d,J=2.0Hz,1H),7.12(d,J=1. 9Hz,1H),6.99(d,J=7.8Hz,1H),6.90(dd,J=7.7,1.9Hz,1H),6.37(s,1H),4.37(d,J=7.5Hz,2H),3.95–3.91(m,2H),3.89–3.84(m,2H), 3.49–3.41(m,1H),3.35(dt,J=11.9,6.1Hz,2H),2.81(dd,J=9.5,6.6Hz,1H),2.75(dt,J=8.7,5.8Hz,1H),2.56(dt,J=8.6,6.1Hz,1H), 2.38(dd,J=9.5,4.8Hz,1H),2.32–2.26(m,1H),2.23(s,3H),2.19(s,3H),2.18–2.14(m,1H),1.60–1.51(m,1H),1.50(q,J=4.0Hz,4H).

[0405] Embodiment 64

[0406] (S)-4-(1-((1λ 2 -piperidin-4-yl)methyl)-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4-dimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 64

[0407] Using the synthetic route of Example 57, the raw material iodoethane in the third step was replaced with 4-(iodomethyl)piperidine to obtain the title compound 63 (15.7 mg). MS (ESI) m / z: 537.46 [M+H] + . 1H NMR (600MHz, Methanol-d4) δ8.81(s,1H),7.64(t,J=7.4Hz,1H),7.22(d,J=8.0Hz,1H),7.19(d,J=10.2Hz,1H),7.10(s ,1H),6.98(d,J=7.7Hz,1H),6.92(d,J=7.8Hz,1H),6.36(s,1H),4.37(d,J=7.5Hz,2H),3.88(s,2H),3.54–3.49(m,1H), 3.16(d,J=12.6Hz,2H),2.83–2.77(m,2H),2.70–2.63(m,2H),2.58–2.54(m,1H),2.46(dd,J=9.9,4.5Hz,1H),2.30–2.2 3(m,1H),2.22(s,3H),2.20(d,J=6.5Hz,1H),2.18(s,3H),1.68–1.63(m,2H),1.60(q,J=7.6Hz,1H),1.51–1.44(m,2H).

[0408] Embodiment 65

[0409] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl-5-(2,4,5-trimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 65

[0410] Using the synthetic route of Example 56, the raw material of step 5, 3,4-dimethylphenylboronic acid, was replaced with 2,4,5-trimethylphenylboronic acid to obtain the title compound 65 (26.5 mg). MS (ESI) m / z: 454.38 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.67(s,1H),7.62(t,J=7.4Hz,1H),7.24(dd,J=8.0,1.5Hz,1H),7.19( dd,J=10.4,1.5Hz,1H),6.91(d,J=11.3Hz,2H),6.35(s,1H),3.91–3.82(m,2H),3.57–3.49(m,1H),2 .86(dt,J=8.7,5.3Hz,1H),2.77(dd,J=9.6,6.4Hz,1H),2.56(dt,J=8.7,6.4Hz,1H),2.49(dd,J=9.7 ,4.2Hz,1H),2.26(dd,J=8.5,5.0Hz,1H),2.22(s,3H),2.16(s,3H),1.91(s,3H),1.61–1.52(m,1H).

[0411] Embodiment 66

[0412] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,4,5-trimethylphenyl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 66

[0413] Using the synthetic route of Example 57, the first step raw material 3,4-dimethylphenylboronic acid was replaced with 2,4,5-trimethylphenylboronic acid to obtain the title compound 65 (18.2 mg). MS (ESI) m / z: 482.44 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.78(s,1H),7.63(dd,J=8.0,6.9Hz,1H),7.23(dd,J=8.0,1.5Hz,1H),7.19 (dd,J=10.4,1.5Hz,1H),6.93(s,1H),6.90(s,1H),6.37(s,1H),4.52(q,J=7.2Hz,2H),3.87(s,2H),3.47 (d,J=7.6Hz,1H),2.79(dt,J=14.0,11.8,7.1Hz,2H),2.56(q,J=8.2Hz,1H),2.41(dd,J=9.5,4.6Hz,1H) ,2.22(s,3H),2.18(d,J=8.0Hz,1H),2.16(s,3H),1.92(s,3H),1.60–1.51(m,1H),1.48(t,J=7.1Hz,3H).

[0414] Embodiment 67

[0415] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,4,5-trimethylphenyl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 67

[0416] Using the synthetic route of Example 57, the first step raw material 3,4-dimethylphenylboronic acid was replaced by 2,4,5-trimethylphenylboronic acid and the third step raw material iodoethane was replaced by 2-iodopropane to obtain the title compound 67 (17.3 mg). MS (ESI) m / z: 496.44 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.94(s,1H),7.62(dd,J=8.0,6.8Hz,1H),7.22(dd,J=8.0,1.5Hz,1H),7.18(dd ,J=10.3,1.5Hz,1H),6.92(s,1H),6.90(s,1H),6.31(s,1H),5.16(p,J=6.9Hz,1H),3.85(d,J=2.1Hz,2H),3 .49–3.40(m,1H),2.74(dt,J=8.7,8.3,5.9Hz,2H),2.52(dt,J=8.6,6.0Hz,1H),2.37(dd,J=9.4,4.6Hz,1H) ,2.22(s,3H),2.20–2.17(m,1H),2.16(s,3H),1.92(s,3H),1.72(dd,J=7.0,3.9Hz,6H),1.61–1.51(m,1H).

[0417] Embodiment 68

[0418] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-(2,2-difluoroethyl)-5-(2,4,5-trimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 68

[0419] The synthetic route of Example 57 was used to replace the first step raw material 3,4-dimethylphenylboronic acid with 2,4,5-trimethylphenylboronic acid and the third step raw material iodoethane with 2,2-difluoroethyl trifluoromethanesulfonate to obtain the title compound 68 (16.6 mg). MS (ESI) m / z: 518.41 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.82 (s, 1H), 7.64 (t, J = 7.4Hz, 1H), 7.24 (dd, J = 8.0, 1.5Hz, 1H), 7.20 (d, J=10.4Hz,1H),6.93(s,1H),6.90(s,1H),6.45(s,1H),6.33(d,3.4Hz,2H),4.99(dt,J=15.4,3.3Hz,2 H),3.90(s,2H),3.83–3.44(m,1H),2.77(dt,J=9.2,5.7Hz,2H),2.53(dt,J=8.6,6.2Hz,1H),2.42(dd ,J=9.5,4.4Hz,1H),2.22(s,3H),2.18(d,J=7.8Hz,1H),2.16(s,3H),1.92(s,3H),1.63–1.52(m,1H).

[0420] Embodiment 69

[0421] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,4,5-trimethylphenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 69

[0422] The synthetic route of Example 57 was used to replace the first step raw material 3,4-dimethylphenylboronic acid with 2,4,5-trimethylphenylboronic acid and the third step raw material iodoethane with 2,2,2-trifluoroethyl trifluoromethanesulfonate to obtain the title compound 68 (18.1 mg). MS (ESI) m / z: 536.41 [M+H] + . 1 H NMR (500MHz, Methanol-d4) δ8.86 (s, 1H), 7.63 (t, J = 7.4Hz, 1H), 7.24 (dd, J = 8.0, 1.6Hz, 1H), 7.21 (dd, J=10.1,1.6Hz,1H),6.91(d,J=13.0Hz,2H),6.48(s,1H),5.55–5.45(m,2H),3.96–3.85(m,2H),3.51–3. 44(m,1H),2.78(dt,J=8.6,5.3Hz,1H),2.72(dd,J=9.5,6.6Hz,1H),2.50(dt,J=8.7,6.5Hz,1H),2.40( dd,J=9.6,4.3Hz,1H),2.21(s,3H),2.19(d,J=5.8Hz,1H),2.15(s,3H),1.92(s,3H),1.60–1.51(m,1H).

[0423] Embodiment 70

[0424] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-(cyclopropylmethyl)-5-(2,4,5-trimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 70

[0425] The synthetic route of Example 57 was used to replace the first step raw material 3,4-dimethylphenylboronic acid with 2,4,5-trimethylphenylboronic acid and the third step raw material iodoethane with (iodomethyl)cyclopropane to obtain the title compound 70 (18.1 mg). MS (ESI) m / z: 508.46 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.80(d,J=0.8Hz,1H),7.63(dd,J=8.0,6.8Hz,1H),7.24(dd,J=8.0,1.5Hz,1H),7.20( dd,J=10.4,1.5Hz,1H),6.93(s,1H),6.90(s,1H),6.39(s,1H),4.40(d,J=6.7Hz,2H),3.90(d,J=1.8Hz,2H),3.52– 3.43(m,1H),2.78(dt,J=8.8,8.2,5.9Hz,2H),2.56(dt,J=8.6,6.1Hz,1H),2.42(dd,J=9.5,4.6Hz,1H),2.22(s,3H ),2.20–2.17(m,1H),2.16(s,3H),1.92(s,3H),1.67–1.50(m,2H),0.62(dt,J=10.6,3.0Hz,2H),0.53–0.49(m,2H).

[0426] Embodiment 71

[0427] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(2,4,5-trimethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 71

[0428] The synthetic route of Example 57 was used to replace the first step raw material 3,4-dimethylphenylboronic acid with 2,4,5-trimethylphenylboronic acid and the third step raw material iodoethane with 4-(iodomethyl)tetrahydro-2H-pyran to obtain the title compound 71 (18.1 mg). MS (ESI) m / z: 552.52 [M+H] + . 1H NMR (400MHz, Methanol-d4) δ8.82–8.80(m,1H),7.63(dd,J=8.0,6.8Hz,1H),7.23(dd,J=8.0,1.5Hz,1H),7.19(dd,J =10.3,1.5Hz,1H),6.92(s,1H),6.89(s,1H),6.41(s,1H),4.39(d,J=7.5Hz,2H),3.95(dt,J=11.0,3.1Hz,2H),3.89 (d,J=2.3Hz,2H),3.51–3.41(m,1H),3.42–3.31(m,2H),2.83–2.74(m,2H),2.58(dt,J=8.6,6.0Hz,1H),2.39(dd,J= 9.5, 4.7Hz, 1H), 2.34–2.26 (m, 1H), 2.22 (s, 3H), 2.18 (d, J = 7.6Hz, 1H), 2.16 (s, 3H), 1.91 (s, 3H), 1.58–1.44 (m, 4H).

[0429] Embodiment 72

[0430] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl-5-(3,4,5-trimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 72

[0431] Using the synthetic route of Example 56, the raw material of step 5, 3,4-dimethylphenylboronic acid, was replaced with 3,4,5-trimethylphenylboronic acid to obtain the title compound 72 (27.1 mg). MS (ESI) m / z: 454.35 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.67(s,1H),7.65(dd,J=7.5,2.9Hz,1H),7.25–7.19(m, 2H),6.89(s,2H),6.29(s,1H),3.89–3.79(m,2H),3.48(dt,J=8.4,7.9,4.3Hz,1H),2. 83(dt,J=8.7,5.3Hz,1H),2.76(dd,J=9.6,6.5Hz,1H),2.54(q,J=8.1Hz,1H),2.45(d d,J=9.6,4.3Hz,1H),2.26–2.20(m,1H),2.18(s,6H),2.15(s,3H),1.61–1.51(m,1H).

[0432] Embodiment 73

[0433] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4,5-trimethylphenyl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 73

[0434] Using the synthetic route of Example 57, the first step raw material 3,4-dimethylphenylboronic acid was replaced with 3,4,5-trimethylphenylboronic acid to obtain the title compound 73 (17.9 mg). MS (ESI) m / z: 482.44 [M+H] + . 1 H NMR(400MHz, Methanol-d4)δ8.77(s,1H),7.66(dd,J=8.2,6.8Hz,1H),7.25–7.22(m, 1H),7.21(s,1H),6.90(s,2H),6.32(s,1H),4.50(q,J=7.2Hz,2H),3.84(s,2H),3.45( m,1H),2.81–2.71(m,2H),2.55(dt,J=8.6,6.1Hz,1H),2.38(dd,J=9.5,4.7Hz,1H),2 .24–2.19(m,1H),2.18(s,6H),2.16(s,3H),1.58–1.51(m,1H),1.46(t,J=7.2Hz,3H).

[0435] Embodiment 74

[0436] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4,5-trimethylphenyl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 74

[0437] The synthetic route of Example 57 was used to replace the first step raw material 3,4-dimethylphenylboronic acid with 3,4,5-trimethylphenylboronic acid and the third step raw material iodoethane with 2-iodopropane to obtain the title compound 74 (17.5 mg). MS (ESI) m / z: 496.44 [M+H] + . 1H NMR(400MHz, Methanol-d4)δ8.94(s,1H),7.66(dd,J=8.2,6.8Hz,1H),7.23(q,J=1.4Hz, 1H),7.20(s,1H),6.90(s,2H),6.26(s,1H),5.14(p,J=7.0Hz,1H),3.82(s,2H),3.47–3.3 8m,1H),2.77–2.68(m,2H),2.50(dt,J=8.7,6.0Hz,1H),2.35(dd,J=9.4,4.5Hz,1H),2.2 3–2.19(m,1H),2.18(s,6H),2.15(s,3H),1.71(dd,J=7.0,3.8Hz,6H),1.57–1.49(m,1H).

[0438] Embodiment 75

[0439] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-(cyclopropylmethyl)-5-(3,4,5-trimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 75

[0440] The synthetic route of Example 57 was used to replace the first step raw material 3,4-dimethylphenylboronic acid with 3,4,5-trimethylphenylboronic acid and the third step raw material iodoethane with (iodomethyl)cyclopropane to obtain the title compound 75 (17.5 mg). MS (ESI) m / z: 508.47 [M+H] + . 1 H NMR(500MHz,Methanol-d4)δ8.80(s,1H),7.67(dd,J=8.2,6.8Hz,1H),7.24(dd,J=3.5,1.4Hz,1H),7.2 3(d,J=1.8Hz,1H),6.91(s,2H),6.35(s,1H),4.38(d,J=6.7Hz,2H),3.88(s,2H),3.52–3.41(m,,1H),2 .80–2.74(m,2H),2.55(dt,J=8.7,6.2Hz,1H),2.41(dd,J=9.6,4.6Hz,1H),2.24–2.19(m,1H),2.19(s, 6H), 2.16 (s, 3H), 1.59–1.53 (m, 1H), 1.35–1.32 (m, 1H), 0.60 (dt, J = 8.3, 3.0Hz, 2H), 0.52–0.48 (m, 2H).

[0441] Embodiment 76

[0442] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-1-(cyclobutylmethyl)-5-(3,4,5-trimethylphenyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 76

[0443] The synthetic route of Example 57 was used to replace the first step raw material 3,4-dimethylphenylboronic acid with 3,4,5-trimethylphenylboronic acid and the third step raw material iodoethane with (iodomethyl)cyclobutane to obtain the title compound 76 (17.5 mg). MS (ESI) m / z: 522.48 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.80(d,J=0.8Hz,1H),7.66(dd,J=8.2,6.8Hz,1H),7.24(dd,J=4.5,1.4Hz,1H ),7.21(q,J=1.5Hz,1H),6.90(s,2H),6.34(s,1H),4.48(d,J=7.1Hz,2H),3.85(s,2H),3.50–3.41(m,1H),2 .91(p,J=7.8,7.1Hz,1H),2.82–2.72(m,2H),2.56(dt,J=8.6,6.1Hz,1H),2.37(dd,J=9.5,4.8Hz,1H),2.21 (dd,J=8.6,5.9Hz,1H),2.18(s,6H),2.15(s,3H),2.06–2.01(m,2H),1.95–1.88(m,4H),1.58–1.50(m,1H).

[0444] Embodiment 77

[0445] (S)-4-(2-((3-aminopyrrolidin-1-yl)methyl)-5-(3,4,5-trimethylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-fluorobenzonitrile 77

[0446] The synthetic route of Example 57 was used to replace the first step raw material 3,4-dimethylphenylboronic acid with 3,4,5-trimethylphenylboronic acid and the third step raw material iodoethane with 4-(iodomethyl)tetrahydro-2H-pyran to obtain the title compound 77 (16.6 mg). MS (ESI) m / z: 552.52 [M+H] + . 1H-NMR(400MHz,Methanol-d4)δ8.81(s,1H),7.66(dd,J=8.1,6.8Hz,1H),7.26–7.21(m,2H),6.90(s,2H),6.37(s,1H) ,4.37(d,J=7.5Hz,2H),3.95(d,J=3.2Hz,1H),3.93(t,J=3.0Hz,1H),3.87(s,2H),3.50–3.40(m,1H),3.36(dt,J=11. 0,6.1Hz,2H),2.80(dd,J=9.5,6.6Hz,1H),2.75(dt,J=8.6,5.7Hz,1H),2.57(dt,J=8.5,6.0Hz,1H),2.37(dd,J=9.5, 4.8Hz,1H),2.29(t,J=6.7Hz,1H),2.24–2.19(m,1H),2.18(s,6H),2.15(s,3H),1.59–1.54(m,1H),1.53–1.46(m,4H).

[0447] Biological evaluation

[0448] Test Example 1: In vitro enzyme inhibition activity assay - LSD1

[0449] The purpose of this experiment is to detect the in vitro inhibitory activity of compounds on LSD1. The human recombinant LSD1 protein used in the experiment was purchased from Active Motif, and the enzyme level activity test of LSD1 was performed using the Lance Ultra LSD1 histone H3 lysine 4 demethylase assay kit (PerkinElmer). First, Tris buffer (50mM Tris-HCl, 50mMNaCl, 0.01% Tween-20, 1mM DTT, 10μM FAD, 10% glycerol, pH 9.0) needs to be prepared. After the preparation is completed, the LSD1 components required for the test need to be placed in the buffer and cultured at room temperature for one hour. The components include 4μL substrate solution (2.5μM Bio-H3K4me2, 1-24aa), 4μL enzyme solution (4nM LSD1) and 2μL inhibitor in a 384-well microplate. After these operations were completed, 5 μL of the detection mixture containing Eu-labeled H3K4me0 antibody and ULight-streptavidin was added to the system. After that, Envision (PerkinElmer) was used to detect the fluorescence intensity of the components to be tested. The test mode was set in TR-FRET mode (excitation wavelength of 320 nm, emission wavelength of 665 nm). To reduce the error, the test was repeated three times in total. The final IC 50The data were calculated by GraphPad Prism 5 software, and the sigmoidal dose-response (variable slope) method was used to obtain the fitting curve.

[0450] Table 2 provides the LSD1 inhibitory activities of the compounds synthesized in some examples and the positive control compound CC90011, wherein all compounds were tested in the form of HCl salt.

[0451] Table 2

[0452]

[0453]

[0454]

[0455] Note: 1. Biochemical determination of IC 50 The data is specified in the following ranges:

[0456] A: ≤30nM

[0457] B: >30nM to ≤300nM

[0458] 2.CC90011 chemical structure:

[0459]

[0460] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0461] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof: in, R 1 is selected from halogen, substituted 5-14 membered heteroaryl or substituted C 6-14 Aryl; R 2 is selected from hydrogen, halogen, substituted or unsubstituted -R 0 -NH3, substituted or unsubstituted C 3-12 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 3-12 Cycloalkyl C 6-14 Aryl or substituted or unsubstituted 3-10 membered heterocycloalkyl and C 6-14 Aryl; R 0 Selected from C 1-4 Alkylene; Indicates a double bond or a single bond; when When it represents a double bond, X is selected from -N(R 3 )-, Y is selected from N or -C(R 4 )=, Z is selected from -C(R 5 )=; when When a single key is indicated, X is selected from -C(=O)- or -CH(R 3 )-, Y is selected from -C(=O)- or -CH(R 4 )-, Z is selected from -N(R 5 )-; W 1 Selected from C(R 6a ) or N; W 2 Selected from C(R 6b ) or N; R 3 is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, 3-10 membered heterocycloalkyl, or substituted or unsubstituted 5-14 membered heteroaryl; R 4 is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-12 Cycloalkyl; R 5 is selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-12 Cycloalkyl, 3-10 membered heterocycloalkyl, acyl, or substituted or unsubstituted 5-14 membered heteroaryl; R 6a and R 6b are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 1 Selected from one or more R 1a substituted 5-14 membered heteroaryl or one or more R 1a Substituted C 6-14 Aryl; R 1a Each occurrence is independently selected from halogen, cyano or C 1-6 alkyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 2 Selected from one or more R 2a Substituted or unsubstituted 5-14 membered heteroaryl, 2a Substituted or unsubstituted C 6-14 Aryl, one or more R 2a Substituted or unsubstituted C 3-12 Cycloalkyl C 6-14 Aryl or one or more R 2a Substituted or unsubstituted 3-10 membered heterocycloalkyl 6-14 Aryl; R 2a Selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -R 2b -C(=O)OR 2c or C 3-6 Cycloalkyl; R 2b Selected from C 1-6 Alkylene; R 2c Selected from C 1-6 alkyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a structure shown in formula (II): wherein Ar is selected from 5-14 membered heteroaryl, C 6-14 Aryl, C 3-12 Cycloalkyl C 6-14 Aryl or 3-10 membered heterocycloalkyl 6-14 Aryl; m is selected from 0, 1, 2 or 3; n is selected from 1, 2, 3 or 4.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a structure shown in any one of formula (II-1) to formula (II-3): Among them, Ar a Selected from C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a structure shown in any one of formula (II-2a) to formula (II-2f):

7. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 3 Selected from hydrogen, C 1-3 Alkyl, with one or more R 3a Substituted C 1-3 alkyl; R 3a Each occurrence is independently selected from halogen, C 3-12 cycloalkyl, 3-10 membered heterocycloalkyl or 5-14 membered heteroaryl.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 3 Selected from hydrogen, C 1-3 Alkyl, -CH2-CHF2, -CH2-CF3 or one of the following substituents:

9. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 5 Selected from -(C(R 7 )2) P -N(R 5a )(R 5b ) or -C(=O)-N(R 5a )(R 5b ); R 7 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl or halogenated C 3-6 Cycloalkyl; P is selected from 1, 2, 3 or 4; R 5a , R 5b Each independently selected from H or -(CH2) q -R 5c , or R 5a , R 5b and the N connected to it forms a 5c a substituted or unsubstituted 5-14-membered heterocycloalkyl group; q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14; R 5c Each occurrence is independently selected from C 1-6 Alkyl or NH(R 5d ); R 5d Selected from hydrogen or C 1-6 alkyl.

10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: R 5 Selected from -CH2-NH(R 5b ) or one of the following substituents: t is selected from 1, 2, 3 or 4.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound has a structure represented by any one of formula (III-1) to formula (III-5):

12. The compound according to any one of claims 1-3, 5-6, 8, 10-11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: The compound is selected from one of the following structures:

13. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and a pharmaceutically acceptable carrier, diluent or excipient.

14. Use of the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating and / or preventing a disease associated with or mediated by LSD1 activity.

15. The use according to claim 14, characterized in that The diseases include cancer, neurodegenerative diseases, cardiovascular diseases, inflammation or viral infections.

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