Aminoquinoline derivative, pharmaceutical composition containing aminoquinoline derivative, and preparation method and application of aminoquinoline derivative

Abstract

The invention relates to an aminoquinoline derivative, a pharmaceutical composition containing the aminoquinoline derivative, and a preparation method and application of the aminoquinoline derivative. Specifically, the invention relates to a compound shown as a formula I or a pharmaceutically acceptable salt, a stereoisomer, a tautomer or an isotope-labeled compound thereof, a pharmaceutical composition containing the compound, and a preparation method and application of the compound. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to aminoquinoline derivatives, pharmaceutical compositions containing the same, preparation methods thereof and use thereof in preventing or treating diseases or conditions associated with PRMT5 activity. Background Art

[0002] Arginine N-terminal methyltransferase 5 (PRMT5) belongs to the PRMT family and is an important component of post-translational histone modification (arginine methylation) in eukaryotic cells. It is an epigenetic target. PRMT5 is widely present in the nucleus and cytoplasm of human cells, including tissues such as the heart, muscle, and testis. PRMT5 can catalyze the transfer of methyl groups on SAM to arginine guanidine groups in histones or non-histone proteins to generate monomethylated arginine (MMA) and symmetric dimethylarginine (sDMA) products, affecting multiple target genes and multiple signaling pathways. PRMT5 can also bind to methylosome protein 50 (MEP50) to form a hetero-octamer PRMT50 / MEP50 complex, enhancing the methyltransferase activity of PRMT5 (Stephen Antonysamy et al., Crystal structure of the human PRMT5: MEP50 complex, PNAS, 2012, vol. 109, no. 44, 17960–17965.). PRMT5 is involved in regulating gene expression (activation / repression), RNA metabolism, cell cycle and protein function.

[0003] PRMT5 can methylate and modify a variety of substrates to change their biological activity, or affect the transcriptional regulation of genes in related pathways. In breast cancer, PRMT5 is involved in FOXP1 transcription, upregulates FOXP1 expression, and promotes breast cancer stem cell self-renewal and tumorigenesis. In pancreatic cancer, PRMT5 can bind to the promoter region of the E3 ubiquitin ligase FBW7, inhibit FBW7 expression, enhance MYC stability, and promote tumor malignant progression. In lung cancer cells, PRMT5 can inhibit the transcription of the miR-99 family, increase FGFR3 expression, activate the Erk1 / 2 and Ak pathways, and lead to cell growth and metastasis.

[0004] MTAP is the gene encoding methylthioadenosine phosphorylase, located on chromosome 9p21, close to the tumor suppressor gene CDKN2A (which often undergoes homozygous deletion). Therefore, MTAP is often co-deleted with CDKN2A in tumors (Marjon K, Kalev P, Marks K. Annual Review of Cancer Biology, 2021, 5(1)). Approximately 15% of solid tumors suffer from MTAP deletion.

[0005] PRMT5 has two cofactors, namely the activating cofactor (SAM) and the inhibitory cofactor (MTA; 5'-methylthioadenosine). In normal cells, MTAP is responsible for converting MTA to Met (methionine), and PRMT5 is responsible for converting SAM to SAH (S-adenosyl-L-homocysteine). MTA is an endogenous competitive inhibitor of PRMT5-SAM. In tumor cells, the loss of MTAP leads to the accumulation of MTA, which partially inhibits the activity of PRMT5 and makes tumor cells more dependent on PRMT5. In the above case, inhibiting PRMT5 can further block the methylation function of PRMT5 and cause tumor cell death.

[0006] In summary, in the absence of MTAP, inhibition of PRMT5 shows synthetic lethality. Currently, there are no inhibitors targeting PRMT5 on the market. Therefore, it is necessary to develop new, highly effective and low-toxic PRMT5 inhibitors to meet clinical needs. Summary of the invention

[0007] The invention provides novel aminoquinoline derivatives, which have good inhibitory effects on MTAP-deficient tumor cells and good pharmacokinetic properties.

[0008] One aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof:

[0009]

[0010] in:

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

[0012] Ring A is selected from a 5-8 membered heterocyclic ring or a 5-8 membered heteroaromatic ring;

[0013] R 1 are independently selected from H, halogen, CN, C 1-4 Alkyl or C 1-4 haloalkyl; or two R 1 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl group;

[0014] R 2 and R 3 Each independently selected from H and C 1-4 alkyl;

[0015] R 4 Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0016] R5 Selected from C 6-10 aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more R 6 replace;

[0017] R 6 are independently selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -XLC 3-8 Cycloalkyl, -XL-heterocyclyl, -XLC 6-10 Aryl or -XLC 6-10 Heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 7 replace;

[0018] R 7 are independently selected from halogen, cyano, -NR 11 R 12 、-COCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, C 6-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-8 Cycloalkyl substitution;

[0019] R 11 and R 12 Independently from H and C 1-4 alkyl;

[0020] X is independently a direct bond, O, S or NR at each occurrence 13 ;

[0021] X 1 and X 2 are each independently selected from C or N;

[0022] X 3 , X 4 and X5 Each independently selected from N or CR 14 ;

[0023] R 13 and R 14 Each independently selected from H, halogen, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or 3-6 membered heterocyclic group;

[0024] L is independently a direct bond or -(CH2) at each occurrence. n -;

[0025] m is 0, 1 or 2;

[0026] n is 1 or 2.

[0027] Another aspect of the present invention provides a pharmaceutical composition comprising a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof and one or more pharmaceutically acceptable carriers.

[0028] Another aspect of the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a disease or condition associated with PRMT5 activity.

[0029] Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention for use in preventing or treating a disease or condition associated with PRMT5 activity.

[0030] Another aspect of the present invention provides a method for preventing or treating a disease or condition associated with PRMT5 activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention.

[0031] Another aspect of the invention provides processes for preparing the compounds of the invention.

[0032] definition

[0033] Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

[0034] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps, even though the other unrecited elements or method steps are not necessarily present (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of.").

[0035] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 4 carbon atoms. For example, as used herein, the term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.).

[0036] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-8 Haloalkyl", "C 1-6 "Haloalkyl" and "C 1-4 "Haloalkyl" refers to haloalkyl having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, for example, -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0037] As used herein, the term "hydroxyalkyl" refers to a group in which a hydrogen atom in an alkyl group is replaced by one or more hydroxyl groups, for example, 1-4 Hydroxyalkyl or C 1-3 Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, and the like.

[0038] As used herein, the term "alkoxy" refers to a group having an oxygen atom inserted into an alkyl group (as defined above) at any reasonable position, preferably a C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH2-OCH3, etc., and the alkoxy is optionally substituted with one or more (such as 1 to 3) identical or different substituents. For example, the term "haloalkoxy" refers to that the hydrogen atom of the alkoxy is substituted with one or more (such as 1 to 3) identical or different halogen atoms.

[0039] As used herein, the term "paracyclic ring" or "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.

[0040] As used herein, the term "spiro" or "spirocyclyl" refers to a ring system formed by two or more cyclic structures sharing one ring atom. In the present invention, "spiro" can be "aliphatic spiro" or "spiroheterocycle". As used herein, the term "aliphatic spiro" refers to an all-carbon ring system formed by two or more rings sharing one carbon atom, which may contain one or more double bonds, including but not limited to 5-10 membered aliphatic spiro, for example As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example The "nitrogen-containing spiro heterocycle", "oxygen-containing spiro heterocycle" and "sulfur-containing spiro heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiro heterocyclic group" refers to a spiro heterocyclic group containing a total of 6-10 ring atoms and at least one of the ring atoms being a nitrogen atom.

[0041] As used herein, the term "bridged ring" or "bridged ring group" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other. In the present invention, the "bridged ring" can be a "fat bridged ring" or a "bridged heterocycle". As used herein, the term "fat bridged ring" refers to an all-carbon ring system formed by two or more cyclic structures sharing two carbon atoms that are not directly connected to each other, which may contain one or more double bonds and can be divided into bicyclic, tricyclic, tetracyclic or polycyclic aliphatic bridged rings according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. "Fat bridged ring" includes but is not limited to 6-14 membered aliphatic bridged rings, 7-10 membered aliphatic bridged rings, for example As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3 or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example

[0042] The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle" and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0043] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or condensed polycyclic hydrocarbon ring group, including but not limited to monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and condensed cycloalkyl. In the present invention, the cycloalkyl is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl are optionally substituted with oxo groups (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms, such as C 3-6 The cycloalkyl group may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a condensed cycloalkyl group, such as C 5-8 Fused cycloalkyl or C 5-6 Fused cycloalkyl.

[0044] As used herein, the term "cycloalkoxy" means -O-cycloalkyl, wherein cycloalkyl is as defined above. Representative examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0045] As used herein, the term "heterocyclyl" or "heterocycle" refers to an aliphatic monocyclic or fused polycyclic group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms, including but not limited to oxygen atoms, nitrogen atoms and sulfur atoms, the carbon atoms and heteroatoms on the heterocyclyl group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0046] As used herein, the term "4-11 membered heterocyclyl" means a heterocyclyl group containing 4 to 11 ring atoms, including but not limited to a 4-10 membered heterocyclyl group, a 4-9 membered heterocyclyl group, a 4-8 membered heterocyclyl group, a 4-7 membered heterocyclyl group, a 5-6 membered heterocyclyl group, a 3-8 membered heterocyclyl group, a 3-7 membered heterocyclyl group, a 3-6 membered heterocyclyl group, a 4-7 membered nitrogen-containing heterocyclyl group, a 4-7 membered oxygen-containing heterocyclyl group, a 4-7 membered sulfur-containing heterocyclyl group, a 5-6 membered nitrogen-containing heterocyclyl group, a 5-6 membered oxygen-containing heterocyclyl group, a 5-6 membered sulfur-containing heterocyclyl group, and the like, wherein the "nitrogen-containing heterocyclyl group", "oxygen-containing heterocyclyl group" and "sulfur-containing heterocyclyl group" each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 4-11 membered heterocyclic groups include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (e.g. ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl.

[0047] In the present invention, the heterocyclic group can form a parallel ring structure with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other group can be on any heterocyclic group or cycloalkyl group. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic groups and heterocyclic groups, heterocyclic groups and cycloalkyl groups, monoheterocyclic groups and monoheterocyclic groups, and monoheterocyclic groups and monocycloalkyl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and (mono) cycloalkyl groups, 3-7 membered (mono) heterocyclic groups and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl-cyclopropyl, cyclopentyl-aziridine, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl,

[0048] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. 6-10 Aryl" or "C 6-10The term "aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring). The aryl group is optionally substituted by 1 or more (such as 1, 2 or 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2 or C 1-6 alkyl, etc.) substituted.

[0049] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, for example having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular containing 1, 2, 3, 4, 5, 6, 9 or 10 carbon atoms, and in each case may additionally be benzo-fused. For example, the heteroaryl or heteroaromatic ring can be selected from thienyl (ring), furanyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), etc., and benzo derivatives thereof; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), etc., and benzo derivatives thereof.

[0050] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0051] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds.

[0052] If a substituent is described as being "optionally substituted with one or more," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0053] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0054] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0055] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0056] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0057] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to the compounds of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g. 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); isotopes of oxygen (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotope-labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotope-labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0058] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a single diastereomer. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oxime can exist in the following tautomeric form equilibrium in solution:

[0059]

[0060] As used herein, the "*" marked in the compound formula indicates that the marked carbon atom is a chiral carbon atom, and the present invention includes a pair of enantiomers formed by the chiral carbon atom. If a compound contains two different chiral carbon atoms, the present invention includes four optical isomers formed by the chiral carbon atom.

[0061] It is to be understood that the scope of the present application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0062] In this article, solid lines (——), solid wedges Virtual wedge Depicting chemical bonds of the compounds of the invention. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0063] It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the above-mentioned various derivative forms of the compound.

[0064] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate, meglumine salt, etc. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002).

[0065] As used herein, the term "ester" means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form). The compounds of the present invention themselves may also be esters.

[0066] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0067] Those skilled in the art will appreciate that, since nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles can form N-oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. The synthetic method for preparing the N-oxide of heterocycles and tertiary amines is well known to those skilled in the art, including but not limited to oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ES G Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0068] The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P.GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Using methods known in the art, the protecting groups can be removed at an appropriate subsequent stage.

[0069] The term "about" means within ±10% of the stated numerical value, preferably within ±5%, more preferably within ±2%.

[0070] Compound

[0071] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof:

[0072]

[0073] in:

[0074] is a single bond or a double bond;

[0075] Ring A is selected from a 5-8 membered heterocyclic ring or a 5-8 membered heteroaromatic ring;

[0076] R 1 are each independently selected from H, halogen, CN, C 1-4 Alkyl or C 1-4 haloalkyl; or two R 1 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl group;

[0077] R 2 and R 3 Each independently selected from H and C 1-4 alkyl;

[0078] R 4 Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0079] R 5 Selected from C 6-10 aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more R 6 replace;

[0080] R 6 are independently selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -XLC 3-8 Cycloalkyl, -XL-heterocyclyl, -XLC 6-10 Aryl, -XLC 6-10 Heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 7 Substituted; preferably, R 6 are independently selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -XLC 3-8 Cycloalkyl, -XL-heterocyclyl, -XLC6-10 Aryl, -XLC 6-10 Heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 7 replace;

[0081] R 7 are independently selected from halogen, cyano, -NR 11 R 12 、-COCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, C 6-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl substitution;

[0082] R 11 and R 12 Independently from H and C 1-4 alkyl;

[0083] X is independently a direct bond, O, S or NR at each occurrence 13 ;

[0084] X 1 and X 2 are each independently selected from C or N;

[0085] X 3 , X 4 and X 5 Each independently selected from N or CR 14 ;

[0086] R 13 and R 14 Each independently selected from H, halogen, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy or 3-6 membered heterocyclic group; preferably, R 13 and R 14 Each independently selected from H, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 1-4 Haloalkoxy or 3-6 membered heterocyclic group;

[0087] L is independently a direct bond or -(CH2) at each occurrence. n -;

[0088] m is 0, 1 or 2;

[0089] n is 1 or 2.

[0090] In certain embodiments, in the compound of formula I provided by the present invention, ring A is selected from a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring.

[0091] In certain embodiments, the present invention provides compounds of formula I in which R 1 Select from H or C 1-4 alkyl.

[0092] In certain embodiments, the present invention provides compounds of formula I in which R 1 Selected from H or methyl.

[0093] In certain embodiments, the present invention provides compounds of formula I in which R 1 Selected from H.

[0094] In certain embodiments, the present invention provides compounds of formula I in which R 2 and R 3 Each is independently selected from H or methyl.

[0095] In certain embodiments, the present invention provides compounds of formula I in which R 2 and R 3 Selected from H.

[0096] In certain embodiments, the present invention provides compounds of formula I in which R 4 Selected from C 1-4 alkyl.

[0097] In certain embodiments, the present invention provides compounds of formula I in which R 4 Selected from methyl.

[0098] In certain embodiments, the present invention provides compounds of formula I in which R 5 Selected from C 6-10 aryl or 6-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more R 6 replace.

[0099] In certain embodiments, the present invention provides compounds of formula I in which R 5 is selected from phenyl, naphthyl or benzothienyl, wherein the phenyl, naphthyl or benzothienyl is optionally substituted by one or more R 6replace.

[0100] In certain embodiments, the present invention provides compounds of formula I in which R 6 are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -XLC 3-8 Cycloalkyl, -XL-heterocyclyl, -XLC 6-10 Aryl or -XLC 6-10 Heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 7 replace.

[0101] In certain embodiments, the present invention provides compounds of formula I in which R 6 are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkynyl, C 1-4 Haloalkyl, -XLC 3-8 Cycloalkyl or -XL-heterocyclyl, the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R 7 replace.

[0102] In certain embodiments, the present invention provides compounds of formula I in which R 6 are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, -XLC 3-8 Cycloalkyl or -XL-heterocyclyl, the alkyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R 7 replace.

[0103] In certain embodiments, the present invention provides compounds of formula I in which R 7 are independently selected from halogen, cyano, -NR 11 R 12 、-COCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group.

[0104] In certain embodiments, the present invention provides compounds of formula I in which X is independently a direct bond or O at each occurrence.

[0105] In certain embodiments, the present invention provides compounds of formula I in which R 6Each is independently selected from F, Cl, cyano, cyclopropyloxy, propynyl,

[0106] In certain embodiments, the present invention provides compounds of formula I in which R 5 Selected from

[0107] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 and X 2 Selected from C.

[0108] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 and X 2 All selected from C, For double bonds.

[0109] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 Select from N, X 2 Selected from C.

[0110] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 Select from N, X 2 Selected from C, For a single key.

[0111] In certain embodiments, the present invention provides compounds of formula I, wherein X 5 Selected from CH.

[0112] In certain embodiments, the present invention provides compounds of formula I, wherein X 3 Selected from CR 14 , R 14 Selected from H, cyano or C 3-6 Cycloalkyl.

[0113] In certain embodiments, the present invention provides compounds of formula I, wherein X 3 Selected from CR 14 , R 14 Selected from H, cyano or cyclopropyl.

[0114] In certain embodiments, the present invention provides compounds of formula I, wherein X 4 Selected from CR 14 , R 14 Selected from H, halogen or C 1-4 alkyl.

[0115] In certain embodiments, the present invention provides compounds of formula I, wherein X 4 Selected from CR 14 , R 14Selected from H, F or methyl.

[0116] In certain embodiments, the present invention provides compounds of formula I, wherein X 3 and X 5 Selected from CH, X 4 Selected from CR 14 .

[0117] In certain embodiments, the present invention provides compounds of formula I, wherein X 3 and X 5 Selected from CH, X 4 Selected from CR 14 , R 14 Selected from H, halogen or C 1-4 alkyl.

[0118] In certain embodiments, the present invention provides compounds of formula I, wherein X 3 and X 5 Selected from CH, X 4 Selected from CR 14 , R 14 Selected from H, F or methyl.

[0119] In certain embodiments, the present invention provides compounds of formula I, wherein X 4 and X 5 Selected from CH, X 3 Selected from CR 14 .

[0120] In certain embodiments, the present invention provides compounds of formula I, wherein X 4 and X 5 Selected from CH, X 3 Selected from CR 14 , R 14 Selected from H, cyano or C 3-6 Cycloalkyl.

[0121] In certain embodiments, the present invention provides compounds of formula I, wherein X 4 and X 5 Selected from CH, X 3 Selected from CR 14 , R 14 Selected from H, cyano or cyclopropyl.

[0122] In certain embodiments, the present invention provides compounds of formula I, wherein X 3 , X 4 and X 5 Selected from CH.

[0123] In certain embodiments, the present invention provides compounds of formula I in which R 13 and R 14are each independently selected from H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl.

[0124] In certain embodiments, the present invention provides compounds of formula I in which m is 0 or 1.

[0125] In some embodiments, the compounds of the present invention have the structure shown in Formula IA:

[0126]

[0127] in:

[0128] R 1 , R 4 , R 6 , X 1 , X 2 , m and Ring A are as defined above for Formula I, and p is 0, 1, 2, 3 or 4.

[0129] In certain embodiments, the present invention provides compounds of formula IA wherein p is 1, 2, 3 or 4.

[0130] In certain embodiments, the present invention provides compounds of formula IA wherein p is 1, 2 or 3.

[0131] In certain embodiments, the present invention provides compounds of formula IA wherein p is 3.

[0132] In some embodiments, the compounds of the present invention have the structure shown in Formula IB:

[0133]

[0134] in:

[0135] R 1 , R 4 , R 6 , X 1 , X 2 , m and Ring A are as defined above for Formula I, and p is 0, 1, 2, 3 or 4.

[0136] In certain embodiments, the present invention provides compounds of formula IB wherein p is 1, 2, 3 or 4.

[0137] In certain embodiments, the present invention provides compounds of formula IB wherein p is 1, 2 or 3.

[0138] In certain embodiments, the present invention provides compounds of formula IB wherein p is 1.

[0139] In some embodiments, the compounds of the present invention have the structure shown in Formula IC:

[0140]

[0141] in:

[0142] R 1 , R 4 , R 6 , X 1 , X 2 , m and Ring A are as defined above for Formula I, and p is 0, 1, 2, 3 or 4.

[0143] In certain embodiments, the present invention provides compounds of formula IC wherein p is 0.

[0144] The present invention covers any combination of the above embodiments.

[0145] In some embodiments, compounds of the invention include, but are not limited to:

[0146]

[0147] Preparation method

[0148] In certain embodiments, the present invention provides a method for preparing a compound of Formula IA comprising the steps of:

[0149] Route A

[0150]

[0151] in:

[0152] Pg is hydrogen, or tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, etc.;

[0153] The remaining groups are as defined above;

[0154] The reaction conditions of each step are as follows:

[0155] Step 1: Compound IA-1 and IA-2 undergo Suzuki coupling reaction to generate compound IA-3 or directly generate compound IA;

[0156] The catalyst that can be used in the Suzuki coupling reaction is, for example, Pd(OAc)2, Pd(PPh3)4, Pd(dppf)Cl2, Pd(dppf)Cl2·DCM or cataCXiumA Pd G3; the base that can be used is, for example, Cs2CO3, CsF, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3; the solvent that can be used is, for example, 1,4-dioxane / H2O or DMF / H2O; and the reaction temperature is 40°C to 120°C.

[0157] If Pg is tert-butyloxycarbonyl, 2,4-dimethoxybenzyl, etc., a second step reaction is required.

[0158] Step 2: Compound IA-3 is deprotected under acidic conditions to generate a compound of formula IA;

[0159] The acid that can be used in the reaction is, for example, HCl or TFA; the solvent that can be used is, for example, DCM, THF, EA, 1,4-dioxane or methanol; and the reaction temperature is 20°C to 80°C.

[0160] The preparation methods of Formula IB and Formula IC are similar to the preparation method of Formula IA described above.

[0161] Pharmaceutical compositions, preparations and methods of treatment

[0162] In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof and one or more pharmaceutically acceptable carriers.

[0163] In some embodiments, the present invention provides a pharmaceutical preparation comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, wherein the pharmaceutical preparation is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.

[0164] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise one or more additional therapeutic agents.

[0165] In some embodiments, the pharmaceutical composition or pharmaceutical formulation is preferably administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.

[0166] In some embodiments, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention in the preparation of a medicament for preventing or treating a disease or condition associated with PRMT5 activity.

[0167] In some embodiments, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention in the preparation of a medicament for modulating (e.g., reducing or inhibiting) PRMT5 activity.

[0168] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention, for use in preventing or treating a disease or condition associated with PRMT5 activity.

[0169] In some embodiments, the present invention provides a method for preventing or treating a disease or condition associated with PRMT5 activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention.

[0170] In some embodiments, the disease or condition associated with PRMT5 activity is preferably a cancer or tumor with MTAP deficiency.

[0171] In some embodiments, the cancer or tumor is preferably esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, bile duct cancer, bladder cancer, mesothelioma, colorectal cancer, head and neck squamous cell carcinoma, lymphoma, etc.

[0172] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic reaction or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0173] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0174] The pharmaceutical compositions of the invention can act systemically and / or locally. For this purpose, they can be administered by a suitable route.

[0175] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0176] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, relieves to some extent one or more of the symptoms of the condition being treated.

[0177] The dosage regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

[0178] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or condition treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50 mg per kg body weight per day. In some cases, the dosage level not higher than the lower limit of the aforementioned range may be sufficient, and in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0179] The content or dosage of the compound of the present invention in the pharmaceutical composition or pharmaceutical preparation may be about 0.01 mg to about 1000 mg.

[0180] Unless otherwise indicated, as used herein, the term "treating" means reversing, alleviating or eliminating the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "preventing" includes inhibiting and delaying the onset of a disease, and includes not only prevention prior to the development of a disease, but also prevention of the recurrence of a disease after treatment.

[0181] As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0182] In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present invention may also include one or more additional therapeutic or preventive agents (e.g., other drugs for treating cancer or tumor diseases). In some embodiments, the therapeutic methods of the present invention may also include administering one or more additional therapeutic or preventive agents (e.g., other drugs for treating cancer or tumor diseases). DETAILED DESCRIPTION

[0183] Example

[0184] The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0185] The abbreviations used herein have the following meanings:

[0186]

[0187]

[0188] The compounds of the present invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography. 1 The reaction was confirmed by H NMR and / or MS. The reaction was monitored by TLC or LC-MS.

[0189] 1 H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).

[0190] LC / MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0191] TLC used silica gel GF 254 as the stationary phase.

[0192] Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0193] Flash column chromatography was performed using a Biotage flash column chromatograph.

[0194] Agilent 1260 and Waters 2489 were used for Prep-HPLC.

[0195] Microwave reactions were performed using a BiotageInitiator microwave reactor.

[0196] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0197] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Teber Chemical Company.

[0198] Synthesis Example:

[0199] Intermediate Int A: 7-bromo-3-methyl-1,3-dihydrofuran[3,4-c]quinolin-4-amine

[0200]

[0201] Step 1: Synthesis of 2-methyl-4-oxotetrahydrofuran-3-carbonitrile (Int A-3)

[0202] NaH (4.44 g, 111 mmol) was dissolved in dry THF (60.0 mL), and Int A-1 (20.0 g, 222 mmol, 17.1 mL) was added under nitrogen atmosphere and maintained at 25 °C. Then, after the temperature was raised to 65 °C, Int A-2 (14.9 g, 222 mmol, 18.1 mL) was slowly added dropwise. After the addition was completed, the reaction continued to stir at 65 °C for 2 hours. TLC (petroleum ether: ethyl acetate = 1:1) detected that the reaction was complete. The reaction solution was adjusted to pH = 11 with NaOH (aq). Then, it was extracted with DCM (20.0 mL x 3), and the aqueous phase was acidified to pH about 1 with 2N HCl, and then extracted with DCM (20 mL x 3). The organic phases were combined and dried with anhydrous sulfuric acid, then filtered and concentrated. After separation and purification by silica gel column chromatography (mobile phase PE: EA = 100: 1 to 1: 1), compound Int A-3 (4.72 g) was obtained.

[0203] Step 2: Synthesis of 4-cyano-5-methyl-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Int A-4)

[0204] Int A-3 (4.99 g, 39.8 mmol) was dissolved in THF (100 mL), cooled to -78 °C, and Tf2O (15.7 g, 55.8 mmol, 9.21 mL) and DIEA (10.3 g, 79.7 mmol, 13.8 mL) were added in sequence. The mixture was kept at -78 °C and stirred for 0.25 hours. TLC (petroleum ether: ethyl acetate = 10:1) detected that the reaction was complete. The reaction solution was diluted with water (20.0 mL), then extracted with CH2Cl2 (20.0 mL x 3), the organic phases were combined and dried with anhydrous sulfuric acid, then filtered and concentrated. Compound Int A-4 (3.53 g) was obtained after separation and purification by silica gel column chromatography (mobile phase PE:EA = 100:1 to 10:1).

[0205] 1 H NMR (400MHz, CDCl3) δ5.03-5.19(m,1H),4.81-4.91(m,2H),1.50(d,J=6.4Hz,3H)

[0206] Step 3: Synthesis of (2-amino-4-bromophenyl)boronic acid (Int A-6)

[0207] Int A-5 (500 mg, 2.03 mmol) was dissolved in a mixed solvent of EtOH (4.0 mL) and H2O (1.0 mL), and then NH4Cl (326 mg, 6.10 mmol) and Fe (567 mg, 10.1 mmol) were added. The reaction was heated to 90 °C and stirred for 12 hours. LCMS detected that the reaction was complete. After filtration, the filtrate was diluted with water (20.0 mL) and extracted with DCM (20.0 mL x 3). The organic phases were combined and dried with anhydrous sulfuric acid, then filtered and concentrated to obtain compound Int A-6 (233 mg). MS m / z (ESI): 217.5 [M+H] + .

[0208] Step 4: Synthesis of 7-bromo-3-methyl-1,3-dihydrofuran[3,4-c]quinolin-4-amine (Int A)

[0209] Int A-6 (500 mg, 2.32 mmol) and Int A-4 (1.19 g, 4.63 mmol) were dissolved in 1,4-dioxane (4.0 mL) and H2O (1.0 mL), and then K2CO3 (960 mg, 6.95 mmol) and Pd(dppf)Cl2.CH2Cl2 (378 mg, 463 μmol) were added to replace the nitrogen. The reaction temperature was raised to 80 °C and stirred for 12 hours. LCMS detected that the reaction was complete. The reaction solution was diluted with water (10.0 mL) and extracted with DCM (15.0 mL x 3). The organic phases were combined and dried with anhydrous sulfuric acid, then filtered and concentrated, separated and purified by silica gel column chromatography (mobile phase, DCM: MeOH = 100: 1 to 10: 1), concentrated and purified by prep-SFC (neutral state; chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 5um); mobile phase: 40% [0.1% NH3*H2O in MeOH solution] + 60% supercritical fluid CO2, isocratic elution) to obtain compound Int A-P1 (101 mg, 99% ee, retention time = 1.991 min) and compound Int A-P2 (97.0 mg, 98% ee, retention time = 2.654 min). MS m / z (ESI): 279.1 [M+H] + .

[0210] Compound Int A-P1: 1 H NMR (400MHz, CD3OD) δ7.78(d,J=1.6Hz,1H),7.41-7.46(m,1H),7.34-7.40(m,1H),5.40-5.50(m,2H),5.29-5.34(m,1H),1.50(d,J=6.4Hz,3H).

[0211] Compound Int A-P2: 1 H NMR (400MHz, CD3OD) δ7.78(d,J=1.6Hz,1H),7.41-7.46(m,1H),7.34-7.39(m,1H),5.39-5.49(m,2H),5.28-5.33(m,1H),1.50(d,J=6.4Hz,3H).

[0212] Intermediate Int B: 8-bromo-N-(2,4-dimethoxybenzyl)-1,4-dihydro-2H-pyrano[3,4-c]quinolin-5-amine

[0213]

[0214] Step 1: Synthesis of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate (Int B-2)

[0215] Int B-1 (1.00 g, 6.32 mmol) and DTBMP (1.30 g, 6.32 mmol) were dissolved in THF (10 mL), Tf2O (1.78 g, 6.32 mmol, 1.04 mL) was added at 0°C, and the reaction was stirred at 0°C for 18 hours. LCMS detected that the reaction was complete. The reaction solution was filtered to remove the solid, and the filter cake was washed with DCM (50 mL). After the filtrate was concentrated, ether (80 ml) was added to slurry, and the solid was removed by suction again. After the filtrate was concentrated, it was separated and purified by silica gel column chromatography (mobile phase DCM: MeOH = 100: 1 to 10: 1) to obtain compound Int B-2 (1.00 g). MS m / z (ESI): 291.1 [M+H] + .

[0216] 1 H NMR (400MHz, CD3Cl3) δ4.44 (t, J = 2.8 Hz, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.82 (s, 3H), 2.54 (tt, J = 5.4, 2.8 Hz, 2H).

[0217] Step 2: Synthesis of 8-bromo-1,2,4,6-tetrahydro-5H-pyrano[3,4-c]quinolin-5-one (Int B-3)

[0218] Int A-6 (300 mg, 1.39 mmol), Na2CO3 (442 mg, 4.17 mmol), Pd(PPh3)4 (321 mg, 278 μmol) were dissolved in a mixed solvent of 1,4-dioxane (12 mL) and H2O (3 mL), and then Int B-2 (605 mg, 2.08 mmol) was added. After replacing nitrogen, the reaction was stirred at 80 ° C for 12 hours. LCMS detected that the reaction was complete, and the reaction solution was directly concentrated and separated and purified by silica gel column chromatography (mobile phase PE: EA = 100: 1 to 10: 1), and the concentrated compound Int B-3 (150 mg) was obtained. MS m / z (ESI): 279.9 [M+H] + .

[0219] Step 3: Synthesis of 8-bromo-5-chloro-1,4-dihydro-2H-pyrano[3,4-c]quinoline (Int B-4)

[0220] Int B-3 (150 mg, 535 μmol) was dissolved in MeCN (2 mL), and then POCl3 (411 mg, 2.68 mmol, 250 μL) and triethylamine hydrochloride (369 mg, 2.68 mmol) were added dropwise, and then the reaction temperature was raised to 120 ° C and stirred for 3 hours. LCMS detected that the reaction was complete. The reaction solution was directly concentrated and subjected to prep-TLC (developing solvent PE: EA = 5: 1) to obtain compound Int B-4 (135 mg). MS m / z (ESI): 297.9 [M+H] + .

[0221] Step 4: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-1,4-dihydro-2H-pyrano[3,4-c]quinolin-5-amine (Int B)

[0222] Int B-4 (125 mg, 419 μmol), DMBNH2 (105 mg, 628 μmol), DIEA (81.2 mg, 628 μmol) were dissolved in NMP (2 mL), and the reaction temperature was raised to 140 ° C and stirred for 12 hours. LCMS detected that the reaction was complete, the reaction solution was diluted with water (10 mL), and then extracted with ethyl acetate (10 mL x 3), the organic phases were combined and dried with anhydrous sulfuric acid, then filtered and concentrated, and separated and purified by silica gel column chromatography (mobile phase DCM: MeOH = 10: 1 to 3: 1), and compound Int B (76.5 mg) was obtained after concentration. MSm / z (ESI): 429.1 [M+H]+ . 1 H NMR (400MHz, CDCl3) δ7.88-8.05(m,1H),7.51(d,J=8.8Hz,1H),7.27-7.43(m,2H),6.42-6.51(m,2H),4 .60-4.80(m,3H),4.54(s,2H),4.03(t,J=5.6Hz,2H),3.87(s,3H),3.80(s,3H),3.00(t,J=5.6Hz,2H).

[0223] Intermediate Int C: 4-chloro-6-cyclopropyloxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile

[0224]

[0225] Step 1: Synthesis of 4-chloro-3,6-difluoro-2-iodobenzonitrile (Int C-2)

[0226] Compound Int C-1 (5.00 g, 28.81 mmol), Pd(OAc)2 (646.83 mg, 2.88 mmol), NIS (12.96 g, 57.62 mmol), p-TsOH (2.48 g, 14.41 mmol) and DCE (100 mL) were added to the reaction flask, and the mixture was reacted at 75°C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, diluted with DCM, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 95:5) to obtain compound IntC-2 (4.94 g).

[0227] Step 2: Synthesis of 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzonitrile (Int C-3)

[0228] Compound Int C-2 (3.00 g, 10.02 mmol), Pd(dtbpf)Cl2 (652.96 mg, 1.00 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (5.21 g, 25.05 mmol), Na2CO3 (2.12 g, 20.04 mmol), 1,4-dioxane (20 mL) and H2O (4 mL) were added to the reaction flask, and the mixture was reacted at 75°C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase PE:EA=78:22) to obtain compound Int C-3 (733 mg). MS m / z (ESI): 254.2 [M+H] + .

[0229] Step 3: Synthesis of 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile (Int C-4)

[0230] Compound Int C-3 (733 mg, 2.89 mmol), NIS (1.30 g, 5.78 mmol) and AcOH (20 mL) were added to the reaction flask and reacted at 80 ° C for 3 hours under nitrogen protection. After the reaction was completed, the acetic acid was removed by vacuum concentration, and the crude product was purified by silica gel column chromatography (mobile phase PE: EA = 85:15) to obtain compound Int C-4 (810 mg). MS m / z (ESI): 380.1 [M+H] + .

[0231] Step 4: Synthesis of 4-chloro-6-cyclopropyloxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile (Int C)

[0232] Under ice bath, NaH (25.3 mg, 632.4 μmol) was added to a solution of cyclopropanol (30.6 mg, 527.0 μmol) in THF (10.0 mL), stirred for 10 min, then Int C-4 (200.0 mg, 527.0 μmol) was added, and then reacted at 50°C for 1.5 hours. After the reaction was completed, water was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 90:10) to obtain compound Int C (200 mg). MS m / z (ESI): 417.9 [M+H] + .

[0233] Intermediate Int D: 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-pyrazolo[3,4-c]quinolin-4-amine

[0234]

[0235] Step 1: Synthesis of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole-5-carbonitrile (IntD-3)

[0236] Compound Int D-1 (400 mg, 2.15 mmol), Int D-2 (819.11 mg, 3.23 mmol), Pd(dppf)Cl2·DCM (132.90 mg, 163.95 μmol), potassium acetate (633.13 mg, 6.45 mmol) were dissolved in anhydrous 1,4-dioxane (15 mL), and the temperature was raised to 100°C for 12 hours under N2 protection. After the reaction was completed, the temperature was cooled to room temperature, and the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase PE:EA=65:35) to obtain compound Int D-3 (375 mg).

[0237] Step 2: Synthesis of 4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-7-ol (Int D-5)

[0238] Compound Int D-3 (175 mg, 750.83 μmol), Int D-4 (141.17 mg, 750.83 μmol), X-Phos (25.06 mg, 52.56 μmol), X-Phos Pd G3 (44.49 mg, 52.56 μmol), K3PO4 (318.75 mg, 1.50 mmol), 1,4-dioxane (8 mL) and H2O (1 mL) were added to the reaction flask, and the mixture was reacted at 100 °C for 5 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 94:6) to obtain compound Int D-5 (110 mg). MS (ESI, m / z): 215.1 [M+H] + .

[0239] Step 3: Synthesis of 4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl trifluoromethanesulfonate (Int D-7)

[0240] Compound Int D-5 (90 mg, 420.12 μmol) and DIPEA (271.48 mg, 2.10 mmol) were dissolved in dry DMF (5 mL), cooled to 0°C, and Int D-6 (300.18 mg, 840.25 μmol) was added. The reaction was continued at 0°C for 1 hour. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, and the organic layer was dried and concentrated. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 80:20) to obtain compound Int D-7 (120 mg). MS (ESI, m / z): 347.0 [M+H] + .

[0241] Step 4: Synthesis of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-pyrazolo[3,4-c]quinolin-4-amine (Int D)

[0242] Compound Int D-7 (100 mg, 288.78 μmol), Int D-2 (110.00 mg, 433.17 μmol), Pd(dppf)Cl2·DCM (23.41 mg, 28.88 μmol), potassium acetate (85.02 mg, 866.34 μmol) were dissolved in anhydrous 1,4-dioxane (10 mL), and the temperature was raised to 100 ° C for 12 hours after N2 protection. After the reaction was completed, the temperature was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 73:27) to obtain compound Int D (60 mg). MS (ESI, m / z): 325.1 [M+H] + .

[0243] Intermediate Int E: N-(2,4-dimethoxybenzyl)-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]quinoxalin-4-amine

[0244]

[0245] Step 1: Synthesis of N-(5-bromo-2-fluorophenyl)-4-methyl-1H-imidazole-5-carboxamide (Int E-3)

[0246] Int E-1 (1 g, 7.93 mmol) was dissolved in anhydrous DMF (20 mL) under an ice-water bath, and DIPEA (2.05 g, 15.86 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (4.52 g, 11.89 mmol) was added dropwise, and stirring was continued for 1 hour. Finally, an anhydrous DMF solution of Int E-2 (1.51 g, 7.93 mmol) was added dropwise, and the temperature was naturally raised to 25°C for 48 hours. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 53:37) to obtain compound Int E-3 (0.81 g). MS (ESI, m / z): 299.0 [M+H] + .

[0247] Step 2: Synthesis of 7-bromo-3-methylimidazo[1,5-a]quinoxaline-4(5H)-one (Int E-4)

[0248] Int E-3 (760 mg, 2.55 mmol) was dissolved in anhydrous DMF (10 mL), and NaH (152.96 mg, 3.82 mmol) was added in batches under ice bath, and stirred for 10 min and reacted at 120 ° C for 72 hours. After the reaction was completed, it was cooled to room temperature, stirred with water, and extracted with ethyl acetate and concentrated to obtain a crude product of compound Int E-4 (700 mg). MS (ESI, m / z): 278.0 [M+H] + .

[0249] Step 3: Synthesis of 7-bromo-N-(2,4-dimethoxybenzyl)-3-methylimidazo[1,5-a]quinoxaline-4-amine (IntE-6)

[0250] In anhydrous DMF (20 mL) was added with Int E-4 (650 mg, 701.18 μmol) and PyBOP (547.33 mg, 1.05 mmol) under ice bath, and DIPEA (271.86 mg, 2.10 mmol) was added dropwise and stirred for 10 min. Finally, Int E-5 (175.86 mg, 1.05 mmol) was added and reacted at 60°C for 5 hours. After the reaction was completed, water was added and stirred, and the crude product was extracted and concentrated with ethyl acetate to obtain a crude product, which was separated and purified by reverse phase column chromatography (MeCN: H2O [0.05% ammonium bicarbonate] = 64:36) to obtain compound Int E-6 (795 mg). MS (ESI, m / z): 427.1 [M+H] + .

[0251] Step 4: Synthesis of N-(2,4-dimethoxybenzyl)-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]quinoxaline-4-amine (Int E)

[0252] Int E-6 (100 mg, 234.03 μmol), KOAc (68.90 mg, 702.09 μmol), IntD-2 (89.14 mg, 351.05 μmol), Pd(dppf)2Cl2·DCM (18.97 mg, 23.40 μmol) were added to the reaction bottle, and dissolved with 5 mL of anhydrous 1,4-dioxane. After nitrogen replacement, the reaction was carried out at 100 ° C for 12 hours. After the reaction was completed, the temperature was cooled to room temperature, water was added and stirred, and the crude product was extracted and concentrated with ethyl acetate. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 65:35) to obtain compound Int E (50 mg). MS (ESI, m / z): 475.3 [M+H] + .

[0253] Intermediate Int F: N-(2,4-dimethoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)imidazo[1,5-a]quinoxalin-4-amine

[0254]

[0255] Step 1: Synthesis of N-(5-bromo-2-fluorophenyl)-1H-imidazole-5-carboxamide (Int F-2)

[0256] Int F-1 (1 g, 8.92 mmol) was dissolved in anhydrous DMF (15 mL) under an ice-water bath, and DIPEA (2.31 g, 17.84 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (5.09 g, 13.38 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of Int E-2 (1.86 g, 9.81 mmol) was added dropwise. The temperature was naturally raised to 25 °C and reacted for 16 hours. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 40:60) to obtain compound Int F-2 (2.10 g). MS (ESI, m / z): 284.0 [M+H] + .

[0257] Step 2: Synthesis of 7-bromoimidazo[1,5-a]quinoxalin-4(5H)-one (Int F-3)

[0258] Int F-2 (2.10 g, 7.39 mmol) was dissolved in anhydrous DMAc (20 mL), and NaH (443.53 mg, 11.09 mmol) was added in batches under ice bath, and stirred for 10 min and reacted at 140 ° C for 48 hours. After the reaction was completed, it was cooled to room temperature, stirred with water, extracted with ethyl acetate, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (mobile phase DCM: MeOH = 93:7) to obtain compound Int F-3 (854 mg). MS (ESI, m / z): 264.0 [M+H] + .

[0259] Step 3: Synthesis of 7-bromo-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]quinoxaline-4-amine (Int F-4)

[0260] In anhydrous DMF (20 mL) was added with Int F-3 (854 mg, 3.23 mmol) and PyBOP (3.37 g, 6.47 mmol) under ice bath, and DIPEA (1.25 g, 9.70 mmol) was added dropwise and stirred for 10 min. Finally, Int E-5 (1.08 g, 6.47 mmol) was added and reacted at 60 °C for 16 hours. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95:5) to obtain compound Int F-4 (795 mg). MS (ESI, m / z): 413.0 [M+H] + .

[0261] Step 4: Synthesis of N-(2,4-dimethoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)imidazo[1,5-a]quinoxaline-4-amine (Int F)

[0262] Int F-4 (800 mg, 1.94 mmol), KOAc (569.94 mg, 5.81 mmol), Int D-2 (737.36 mg, 2.90 mmol), Pd(dppf)2Cl2 (156.91 mg, 193.58 μmol) were added to the reaction bottle, and dissolved with 1,4-dioxane (20 mL). After nitrogen substitution, the reaction was carried out at 100 ° C for 12 hours. After the reaction was completed, the temperature was cooled to room temperature, water was added and stirred, and the crude product was extracted and concentrated with ethyl acetate. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95:5) to obtain compound Int F (467 mg). MS (ESI, m / z): 461.2 [M+H] + .

[0263] Intermediate Int G: 8-bromo-N-(2,4-dimethoxybenzyl)-3,4-dihydro-1H-pyrano[4,3-c]quinolin-5-amine

[0264]

[0265] Step 1: Synthesis of ethyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydro-2H-pyran-4-carboxylate (Int G-2)

[0266] Int G-1 (900 mg, 5.23 mmol) and DTBMP (1.07 g, 5.23 mmol) were dissolved in THF (15 mL), and then Tf2O (1.47 g, 5.23 mmol) was slowly added dropwise under an ice bath. After the addition was completed, the reaction was kept at 0°C and stirred for 12 hours. LCMS detected that the reaction was complete, and the filter cake was directly filtered, and the filter cake was washed with CH2Cl2 (50 mL). The filtrate was concentrated and slurried with ethyl acetate (80 mL), and the solid was removed by suction filtration. The filtrate was then concentrated and separated and purified by silica gel column chromatography (PE / EA=100 / 0 to 10 / 1), and the compound Int G-2 (1.16 g) was obtained by concentration. MS (ESI, m / z): 304.9 [M+H] + .

[0267] 1 H NMR (400MHz, CDCl3) δ4.31 (q, J = 7.2Hz, 2H), 4.18 (t, J = 2.4Hz, 2H), 3.81 (t, J = 5.2Hz, 2H), 2.63 (tt, J = 5.2, 2.4Hz, 2H), 1.31-1.36 (m, 3H).

[0268] Step 2: Synthesis of 8-bromo-4,6-dihydro-1H-pyrano[4,3-c]quinolin-5(3H)-one (Int G-3)

[0269] Int A-6 (497 mg, 2.30 mmol), Na2CO3 (732 mg, 6.90 mmol), Pd(PPh3)4 (266 mg, 230 μmol) were dissolved in 1,4-dioxane (9 mL) and H2O (3 mL), and then Int G-2 (700 mg, 2.30 mmol) was added. After replacing nitrogen, the reaction temperature was raised to 90 ° C and stirred for 4 hours. LCMS detected that the reaction was complete, and the solvent was removed by distillation under reduced pressure, and then separated and purified by silica gel column chromatography (PE / EA=100 / 0 to 10 / 1), and concentrated to obtain compound Int G-3 (220 mg), MS (ESI, m / z): 279.9 [M+H] + .

[0270] 1 H NMR (400MHz, DMSO-d6) δ7.49(s,1H),7.41-7.47(m,1H),7.28-7.36(m,1H),4.84(s,2H),3.87(s,2H),3.29-3.30(m,2H).

[0271] Step 3: Synthesis of 8-bromo-5-chloro-3,4-dihydro-1H-pyrano[4,3-c]quinoline (Int G-4)

[0272] Int G-3 (200 mg, 714 μmol) was dissolved in MeCN (5 mL), and then POCl3 (547 mg, 3.57 mmol) and TEA·HCl (491 mg, 3.57 mmol) were added, and then the reaction temperature was raised to 120°C and stirred for 3 hours. LCMS detected that the reaction was complete, and the solvent was removed by distillation under reduced pressure, and then separated and purified by silica gel column chromatography (PE / EA=5 / 1), and concentrated to obtain compound Int G-4 (135 mg), MS (ESI, m / z): 297.9 [M+H] + .

[0273] 1 H NMR (400MHz, CDCl3) δ8.20 (s, 1H), 7.61-7.66 (m, 1H), 7.52 (d, J = 8.8Hz, 1H), 5.14 (s, 2H), 4.08 (t, J = 5.6Hz, 2H), 2.96 (t, J = 5.6Hz, 2H).

[0274] Step 4: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-3,4-dihydro-1H-pyrano[4,3-c]quinolin-5-amine (Int G)

[0275] Int G-4 (100 mg, 335 μmol) and DMBNH2 (112 mg, 670 μmol), DIPEA (108 mg, 837 μmol) were dissolved in NMP (5 mL). After replacing nitrogen, the reaction temperature was raised to 140 ° C and stirred for 12 hours. LCMS monitored the completion of the reaction, and after cooling to room temperature, H2O (10 mL) was added and extracted with EA (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE / EA=3 / 1). Int G (71.5 mg) was obtained by concentration. MS (ESI, m / z): 429.0 [M+H] + .

[0276] 1 H NMR (400MHz, CDCl3) δ7.94(s,1H),7.36(d,J=8.0Hz,1H),7.27(d,J=1.2Hz,2H),6.49(d,J=2.4Hz,1H),6.45(dd,J=8.4, 2.4Hz, 1H), 5.01 (s, 3H), 4.73 (d, J = 5.2Hz, 2H), 4.03 (t, J = 5.6Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 2.48 (t, J = 5.6Hz, 2H).

[0277] Example 1: 2-(4-(4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthalenecarbonitrile

[0278]

[0279] Step 1: Synthesis of 5-bromo-7-fluoro-9-methyl-1,4-dihydro-1,4-p-iminonaphthalene (Compound 1-3)

[0280] Compound 1-1 (10 g, 34.68 mmol), toluene (100 mL), and compound 1-2 (5.63 g, 69.36 mmol, 6.16 mL) were added to a reaction flask, and n-BuLi (1.6 M, 22.76 mL) was added dropwise at -30 °C. After the addition was completed, the mixture was kept at -30 °C for 0.5 hours, and then the temperature was slowly raised to 25 °C for overnight reaction. The reaction was monitored by TLC, and some raw materials remained. Post-treatment steps: water was added to quench the reaction, and ethyl acetate (100 ml x 3) was used for extraction. The organic phases were combined, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography (PE: EA = 2: 1) was performed to obtain compound 1-3 (4.94 g).

[0281] Step 2: Synthesis of 1-bromo-3-fluoronaphthalene (Compound 1-4)

[0282] Compound 1-3 (24 mg, 104.24 μmol) and CHCl3 (50 mL) were added to the reaction flask, and m-CPBA (6.71 g, 38.88 mmol) was added in batches. After addition, the reaction was allowed to react at room temperature overnight. A small amount of raw materials remained under TLC monitoring, and sodium sulfite solution was added dropwise to quench the reaction. The mixture was stirred at room temperature for half an hour, extracted with ethyl acetate, the organic phases were combined, dried with sodium sulfate, and the solvent was removed by distillation under reduced pressure. The solvent was removed by column chromatography (10% EA) under reduced pressure to obtain compound 1-4 (2.2 g).

[0283] Step 3: Synthesis of 3-fluoro-1-naphthonitrile (Compound 1-5)

[0284] Under nitrogen protection, compound 1-4 (2.2 g, 9.78 mmol), DPPF (166.14 mg, 1.96 mmol), Zn (63.92 mg, 977.53 μmol), Zn (CN) 2 (2.87 g, 24.44 mmol), Pd 2 (dba) 3 (895.14 mg, 977.53 μmol), DMF (40 mL) were added to the reaction bottle and reacted at 115 ° C for 4 hours. TLC monitoring showed that there was no residual raw material, the reaction was cooled, diluted with ethyl acetate (120 ml), washed with dilute brine (100 mL x 3), the organic phase was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and column chromatography was performed to obtain (PE: EA = 0-5% EA) and the compound 1-5 (1.5 g, 8.76 mmol) was obtained by spin drying.

[0285] Step 4: Synthesis of 3-fluoro-2-iodo-1-naphthalenecarbonitrile (Compound 1-6)

[0286] Under nitrogen protection, n-BuLi (2.5M, 3.86mL) was added dropwise into diisopropylamine (1.15g, 11.39mmol) in THF (20mL) at -70℃. After keeping warm at -70℃ for 15 minutes, a solution of compound 1-5 (1.5g, 8.76mmol) in THF (20ml) was added dropwise. After keeping warm at -70℃ for 30 minutes, a solution of I2 (2.89g, 11.39mmol) in THF (15ml) was added dropwise. After the addition was completed, the mixture was kept warm at -70℃ for 30 minutes and then slowly returned to room temperature for reaction overnight. Monitored by TLC, 80 ml of water was added to quench the reaction, extracted with ethyl acetate (100 mL x 2), washed with sodium thiosulfate aqueous solution (100 mL), washed with brine (100 ml), dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. Column chromatography (PE: EA = 0-15% EA) was performed, and after concentration, Flash (0-0, 2 min, 60-85% ACN, 15 min, 100-100 ACN, 2 min) was performed and dried to obtain compound 1-6 (0.8 g).

[0287] Step 5: Synthesis of 3-fluoro-2-(1-methyl-1H-pyrazol-5-yl)-1-naphthalenecarbonitrile (Compound 1-7)

[0288] Under nitrogen protection, compound 1-6 (400 mg, 1.35 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (420.24 mg, 2.02 mmol), 1,4-dioxane (12 mL) and water (2.5 mL), NaHCO3 (339.36 mg, 4.04 mmol), Pd(dtbpf)Cl2 (43.47 mg, 67.33 μmol) were added to the reaction bottle and reacted at 80°C overnight under nitrogen protection. Post-treatment steps: cool the reaction, dilute with water (20 ml), extract with ethyl acetate (40 mL x 3), combine the organic phases, dry with sodium sulfate, and column chromatography (PE:EA = 0-20% EA) to obtain compound 1-7 (160 mg). MS (ESI, m / z): 252.0 [M+H] + .

[0289] Step 6: Synthesis of 3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-1-naphthalenecarbonitrile (Compound 1-8)

[0290] Compound 1-7 (160 mg, 636.80 μmol) was dissolved in acetonitrile (10 mL), and then NIS (716.33 mg, 3.18 mmol) was added. The reaction was continued at 80°C overnight. LCMS monitored that 20% of the raw material remained, and NIS (716.33 mg, 3.18 mmol) was added. The reaction was continued for 4 hours. The reaction solution was dried and column chromatography (PE: EA = 0-25% EA) was performed to obtain compound 1-8 (200 mg). MS (ESI, m / z): 378.0 [M+H] + .

[0291] Step 7: Synthesis of 2-(4-(4-amino-3-methyl-3H-pyrazolo[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthalenecarbonitrile (Compound 1)

[0292] Under nitrogen protection, compound 1-8 (25 mg, 66.29 μmol), Int D (19.34 mg, 59.66 μmol), NaHCO3 (16.71 mg, 198.86 μmol), Pd(dppf)Cl2 (4.81 mg, 6.63 μmol), 1,4-dioxane (1 mL) and H2O (0.2 mL) were added to the reaction bottle and reacted at 80 °C for 5 hours under nitrogen protection. The solvent was removed by distillation under reduced pressure, and after purification by TLC (PE: EA = 1: 1), compound 1 (3 mg) was obtained by prep-HPLC. MS (ESI, m / z): 448.1 [M+H] + .

[0293] 1H NMR (400MHz, DMSO-d6) δ8.51(d,J=10.1Hz,1H),8.33(s,1H),8.27–8.23(m,1H),8.17–8.13(m,1H),8.10(s,1H),7.94(d,J =8.2Hz,1H),7.89–7.85(m,2H),7.19(d,J=1.6Hz,1H),7.14(dd,J=8.2,1.8Hz,1H),6.61(s,2H),4.28(s,3H),3.77(s,3H).

[0294] Example 2: 2-(4-(4-amino-1,3-dihydrofuran[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthalenecarbonitrile

[0295]

[0296] Under nitrogen protection, compound 1-8 (21.75 mg, 57.66 μmol), compound 4-5 (20 mg, 64.07 μmol), NaHCO3 (16.15 mg, 192.20 μmol), Pd (dppf) Cl2 (4.65 mg, 6.41 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), replaced with nitrogen for 30 seconds, and the reaction temperature was raised to 80 ° C and stirred for 5 hours. The reaction solution was concentrated and separated by pre-TLC (developing solvent DCM: MeOH = 20: 1) to obtain a crude product, which was then purified and freeze-dried by pre-HPLC to obtain compound 2 (2.2 mg). MS (ESI, m / z): 436.1 [M+H] + .

[0297] 1 H NMR (400MHz, DMSO-d6) δ8.51(d,J=10.1Hz,1H),8.28–8.22(m,1H),8.17–8.12(m,2H),7.90–7.84(m,2H),7.38(d,J=8.3Hz ,1H),7.14(d,J=1.5Hz,1H),7.08(dd,J=8.3,1.7Hz,1H),6.42(s,2H),5.27–5.20(m,2H),4.93–4.91(m,2H),3.77(s,3H).

[0298] Example 3: 2-(4-(4-amino-1,3-dihydrofuran[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0299]

[0300] The intermediate Int C (42.14 mg, 100.91 μmol), compound 4-5 (35 mg, 112.12 μmol), NaHCO3 (28.26 mg, 336.35 μmol), Pd(dppf)Cl2 (8.14 mg, 11.21 μmol) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), replaced with nitrogen for 30 seconds, and reacted at 80°C for 5 hours. Pre-TLC (DCM: MeOH = 20: 1) to prepare compound 3 (6.6 mg). MS (ESI, m / z): 476.2 [M+H] + .

[0301] 1 H NMR (400MHz, DMSO-d6) δ8.06(s,1H),8.00(d,J=6.0Hz,1H),7.42(d,J=8.3Hz,1H),7.22(d,J=1.5Hz,1H),7.02(dd,J=8.3,1.7Hz,1H ), 6.52(s,2H),5.28(d,J=2.9Hz,2H),4.98(d,J=3.1Hz,2H),4.21–4.18(m,1H),3.74(s,3H),0.93–0.87(m,2H),0.83–0.76(m,2H).

[0302] Example 4: 2-(4-(4-amino-1,3-dihydrofuran[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropyloxy)benzonitrile

[0303]

[0304] Step 1: Synthesis of 4-cyano-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (Compound 4-2)

[0305] Compound 4-1 (1 g, 9.00 mmol) was dissolved in DCM (30 mL), and then DIPEA (1.40 g, 10.80 mmol) was added, and the temperature was lowered to -78 °C. Tf2O (2.54 g, 9.00 mmol, 1.51 mL) was slowly added dropwise at low temperature for 1 minute. After the addition was completed, the mixture was kept warm for 15 minutes. After the reaction was completed, water was added to the reaction solution to quench the mixture, and the mixture was extracted with dichloromethane, washed with brine, and the organic phase was dried with sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain compound 4-2.

[0306] Step 2: Synthesis of 7-chloro-1,3-dihydrofuro[3,4-c]quinolin-4-amine (Compound 4-4)

[0307] Under nitrogen protection, compound 4-2 (2.24 g, 9.23 mmol), compound 4-3 (1.8 g, 7.10 mmol), Pd(PPh3)4 (410 mg, 354.98 μmol), K2CO3 (3.92 g, 28.40 mmol) were dissolved in 1,4-dioxane (50 mL) and H2O (10 mL), and reacted at 80°C overnight. After the reaction, water was added to dilute the reaction solution, and a white solid precipitated. The impurities were extracted with ethyl acetate (50 ml), the aqueous phase was filtered under reduced pressure, the filter cake was washed with clean water and a small amount of ethyl acetate, and compound 4-4 was obtained after drying. MS (ESI, m / z): 221.1 [M+H] + .

[0308] Step 3: Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydrofuran[3,4-c]quinolin-4-amine (Compound 4-5)

[0309] Compound 4-4 (250 mg, 1.13 mmol), Int D-2 (345 mg, 1.36 mmol), KOAc (334 mg, 3.40 mmol), Xphos (54 mg, 113.30 μmol), Pd2(dba)3 (52 mg, 56.65 μmol), 1,4-dioxane (10 mL) were added to the reaction flask, replaced with nitrogen three times, and heated to 100 ° C for overnight reaction. After the reaction, the solvent was directly distilled off under reduced pressure, and purified by silica gel column chromatography (PE: EA = 50% EA ~ 100% EA) to obtain compound 4-5. MS (ESI, m / z): 313.2 [M+H] + .

[0310] Step 4: Synthesis of 2-(4-(4-amino-1,3-dihydrofuran[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropyloxy)benzonitrile (Compound 4)

[0311] Compound 4-5 (20 mg, 46.34 μmol), compound 4-6 (17 mg, 55.60 μmol), NaHCO3 (12 mg, 139.01 μmol), Pd(dppf)Cl2 (4 mg, 4.63 μmol) were dissolved in 1,4-dioxane (1 mL) and H2O (0.2 mL), replaced with nitrogen three times, and reacted at 80 ° C for 5 hours. After the reaction was completed, the reaction solution was dried, diluted with saturated NaHCO3 solution, extracted with ethyl acetate (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 4. MS (ESI, m / z): 490.2 [M+H] + .

[0312] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),7.81(d,J=6.4Hz,1H),7.42(d,J=8.4Hz,1H),7.24(d,J=2.0Hz,1H),7.00(dd,J=8.4,2.0Hz ,1H),6.52(s,2H),5.27(t,J=3.2Hz,2H),4.97(t,J=3.2Hz,2H),3.74(s,3H),1.57(s,3H),1.04–0.97(m,2H),0.93–0.87(m,2H).

[0313] Example 5: 2-(4-(4-amino-3-methylimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0314]

[0315] Step 1: Synthesis of 4-chloro-6-cyclopropyloxy-2-(4-(4-((2,4-dimethoxybenzyl)amino)-3-methylimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (Compound 5-1)

[0316] Int E (50 mg, 105.41 μmol), NaHCO3 (26.56 mg, 316.22 μmol), Int C (44.02 mg, 105.41 μmol), Pd(dppf)2Cl2 (8.54 mg, 10.54 μmol) were added to the reaction flask, and dissolved with 1,4-dioxane (5 mL) and water (0.5 mL). After nitrogen substitution, the reaction was carried out at 80 ° C for 5 hours. After the reaction was completed, the temperature was lowered to room temperature, water was added and stirred, and the crude product was extracted and concentrated with ethyl acetate. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95:5) to obtain compound 5-1 (20 mg). MS (ESI, m / z): 638.2 [M+H] + .

[0317] Step 2: Synthesis of 2-(4-(4-amino-3-methylimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 5)

[0318] Compound 5-1 (20 mg, 31.34 μmol) was added to TFA (2 mL) and reacted at 90°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and washed with saturated sodium bicarbonate solution until alkaline. The crude product was extracted and concentrated with ethyl acetate, and the crude product was purified by reverse phase HPLC to obtain compound 5 (8 mg). MS (ESI, m / z): 488.1 [M+H] + .

[0319] 1 H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.03(s,1H),8.02(d,J=4.0Hz,1H),8.00(d,J=1.2Hz,1H),7.07(d,J=2.0Hz,1H),6.9 8(dd,J=8.4,2.0Hz,1H),6.73(s,2H),4.23–4.17(m,1H),3.74(s,3H),2.60(s,3H),0.95–0.88(m,2H),0.83–0.76(m,2H).

[0320] Example 6: 2-(4-(4-amino-3-methyl-1,3-dihydrofuran[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compounds 6-P1 and 6-P2)

[0321]

[0322] The position of "*" indicates that the chiral center is in the R or S configuration obtained by resolution.

[0323] Step 1: Synthesis of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydrofuran[3,4-c]quinolin-4-amine (Compound 6-P1-1)

[0324] Int A-P1 (25 mg, 89.56 μmol), Int D-2 (25 mg, 98.52 μmol), KOAc (26 mg, 268.69 μmol), Pd(dppf)Cl2·DCM (7 mg, 8.96 μmol) were dissolved in 1,4-dioxane (2 mL) and added to the reaction bottle. The nitrogen was replaced three times and heated to 85 °C for overnight reaction. After the reaction, the reaction solution was dried, diluted with water, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-P1-1. MS (ESI, m / z): 327.2 [M+H] +.

[0325] Step 2: Synthesis of 2-(4-(4-amino-3-methyl-1,3-dihydrofuran[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 6-P1)

[0326] Compound 6-P1-1 (23 mg, 71.84 μmol), Int C (30 mg, 71.84 μmol), NaHCO3 (18 mg, 215.52 μmol), Pd(dppf)Cl2 (5 mg, 7.18 μmol) were dissolved in 1,4-dioxane (2 mL) and H2O (0.5 mL), replaced with nitrogen three times, and reacted at 80 ° C for 5 hours. After the reaction was completed, the reaction solution was spin-dried, diluted with water, extracted with ethyl acetate (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 6-P1. MS (ESI, m / z): 490.0 [M+H] + .

[0327] 1H NMR(400MHz, DMSO-d6)δ8.07(s,1H),8.02(d,J=6.0Hz,1H),7.44(dd,J=8.0,2.0Hz,1H),7.22(dd,J=8.0,2.0Hz,1H),7.06–7.01(m,1H),6.45(s,2H), 5.44–5.37(m,1H),5.34–5.27(m,1H),5.24–5.18(m,1H),4.24–4.18(m,1H) ,3.76(s,3H),1.39(d,J=6.0Hz,3H),0.96–0.89(m,2H),0.84–0.77(m,2H).

[0328]

[0329] ″*" The position indicates that the chiral center is in the R or S configuration obtained by resolution.

[0330] Step 1: Synthesis of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydrofuran[3,4-c]quinolin-4-amine (Compound 6-P2-1)

[0331] Int A-P2 (10 mg, 35.83 μmol), Int D-2 (12 mg, 46.57 μmol), KOAc (11 mg, 107.48 μmol), Pd(dppf)Cl2·DCM (3 mg, 3.58 μmol) were dissolved in 1,4-dioxane (1 mL), replaced with nitrogen three times, and heated to 85 °C for overnight reaction. After the reaction, the reaction solution was dried, diluted with water, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-P2-1. MS (ESI, m / z): 327.2 [M+H] + .

[0332] Step 2: Synthesis of 2-(4-(4-amino-3-methyl-1,3-dihydrofuran[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 6-P2)

[0333] Compound 6-P2-1 (10 mg, 31.13 μmol), Int C (13 mg, 31.13 μmol), NaHCO3 (8 mg, 93.39 μmol), Pd(dppf)Cl2 (2 mg, 3.11 μmol) were dissolved in 1,4-dioxane (2 mL) and H2O (0.5 mL), replaced with nitrogen three times, and reacted at 80 ° C for 5 hours. After the reaction was completed, the reaction solution was dried, diluted with water, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 6-P2. MS (ESI, m / z): 490.0 [M+H] + .

[0334] 1 H NMR (400MHz, DMSO-d6) δ8.06 (s, 1H), 8.02 (d, J = 6.0Hz, 1H), 7.44 (dd, J = 8.0, 1.6Hz,1H),7.23(dd,J=8.0,1.6Hz,1H),7.03(td,J=8.8,1.6Hz,1H),6.44(s, 2H),5.42–5.37(m,1H),5.33–5.27(m,1H),5.24–5.19(m,1H),4.24–4.18(m,1 H), 3.76 (s, 3H), 1.39 (d, J = 6.0Hz, 3H), 0.95–0.89 (m, 2H), 0.85–0.78 (m, 2H).

[0335] Example 7: 2-(4-(4-aminoimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0336]

[0337] Step 1: Synthesis of 4-chloro-6-cyclopropyloxy-2-(4-(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (Compound 7-1)

[0338] Int F (30 mg, 65.17 μmol), NaHCO3 (16.42 mg, 195.51 μmol), Int C (27.22 mg, 65.17 μmol), Pd(dppf)2Cl2 (5.28 mg, 6.52 μmol) were added to the reaction flask, and dissolved with 1,4-dioxane (5 mL) and water (0.5 mL). After nitrogen substitution, the mixture was reacted at 80 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, stirred with water, extracted with ethyl acetate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95:5) to obtain compound 7-1 (20 mg). MS (ESI, m / z): 624.2 [M+H] + .

[0339] Step 2: Synthesis of 2-(4-(4-aminoimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 7)

[0340] Compound 7-1 (20 mg, 31.34 μmol) was added to TFA (10 mL) and reacted at 100°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and washed with saturated sodium bicarbonate solution until alkaline. The crude product was extracted and concentrated with EA, and the crude product was purified by reverse phase HPLC to obtain compound 7 (2.35 mg). MS (ESI, m / z): 474.2 [M+H] + .

[0341] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.14–7.96(m,3H),7.86(s,1H),7.30(s,2H),7.12(d,J =2.0Hz,1H),7.02(dd,J=8.4,2.0Hz,1H),4.26–4.13(m,1H),3.74(s,3H),1.01–0.69(m,4H).

[0342] Example 8: 2-(4-(5-amino-1,4-dihydro-2H-pyrano[3,4-c]quinolin-8-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0343]

[0344] Step 1: Synthesis of N-(2,4-dimethoxybenzyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-pyrano[3,4-c]quinolin-5-amine (Compound 8-1)

[0345] Int B (20 mg, 46.59 μmol), Int D-2 (13 mg, 51.25 μmol), KOAc (9 mg, 93.17 μmol), Pd (dppf) Cl2·DCM (4 mg, 4.66 μmol) were dissolved in 1,4-dioxane (2 mL), replaced with nitrogen three times, and heated to 85 ° C for overnight reaction. After the reaction, the reaction solution was dried, diluted with water, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 8-1. MS (ESI, m / z): 477.2 [M+H] + .

[0346] Step 2: Synthesis of 4-chloro-6-cyclopropyloxy-2-(4-(5-((2,4-dimethoxybenzyl)amino)-1,4-dihydro-2H-pyrano[3,4-c]quinolin-8-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (Compound 8-2)

[0347] Compound 8-1 (22 mg, 46.18 μmol), Int C (20 mg, 46.18 μmol), NaHCO3 (12 mg, 138.55 μmol), Pd(dppf)Cl2 (3 mg, 4.62 μmol) were dissolved in 1,4-dioxane (1.5 mL) and H2O (0.2 mL), replaced with nitrogen three times, and reacted at 80 ° C for 5 hours. After the reaction was completed, the reaction solution was spin-dried, diluted with water, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 8-2. MS (ESI, m / z): 640.2 [M+H] + .

[0348] Step 3: Synthesis of 2-(4-(5-amino-1,4-dihydro-2H-pyrano[3,4-c]quinolin-8-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 8)

[0349] Compound 8-2 (10 mg, 15.62 μmol) and TFA (2 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 80 °C for 2 hours. After the reaction was completed, the reaction solution was dried, diluted with saturated NaHCO3 solution, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 8, MS (ESI, m / z): 490.1 [M+H] +.

[0350] 1H NMR (400MHz, DMSO-d6) δ8.05(s,1H),8.00(d,J=6.0Hz,1H),7.64(d,J=8.4Hz,1H),7.14(d,J=2.0Hz,1H),7.04(dd,J=8.4,2.0H z,1H),6.20(s,2H),4.50(s,2H),4.23–4.17(m,1H),3.94(t,J=5.6Hz,2H),3.74(s,3H),2.97–2.91(m,2H),0.92–0.77(m,4H).

[0351] The following compounds were prepared by the method and general steps described in Example 8. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0352]

[0353]

[0354] Example 9: 2-(4-(4-aminoimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthalenecarbonitrile

[0355]

[0356] Step 1: Synthesis of 2-(4-(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthalenecarbonitrile (Compound 9-1)

[0357] Compound 1-8 (20 mg, 54.31 μmol), Int F (25 mg, 54.31 μmol), NaHCO3 (14 mg, 162.93 μmol), Pd(dppf)Cl2 (4 mg, 5.43 μmol), 1,4-dioxane (1 mL) and H2O (0.2 mL) were added to the reaction bottle, replaced with nitrogen 3 times, reacted at 80°C for 5 hours, and after the reaction was completed, the reaction solution was directly spin-dried and purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3) to obtain compound 9-1 (10 mg). MS (ESI, m / z): 584.3 [M+H] + .

[0358] Step 2: Synthesis of 2-(4-(4-aminoimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthalenecarbonitrile (Compound 9)

[0359] Compound 9-1 (10 mg, 17.13 μmol) and TFA (1.5 mL) were added to the reaction flask, and the reaction was carried out at 80°C for 2 hours under nitrogen protection. After the conversion was complete, the reaction solution was spin-dried, diluted with saturated NaHCO3 solution, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 9. MS (ESI, m / z): 434.0 [M+H] + .

[0360] 1 H NMR(400MHz, DMSO-d6)δ8.96(s,1H),8.52(d,J=10.4Hz,1H),8.27–8.23(m,1H),8.18–8.14(m,1H),8.13(s,1H),8.04(d,J=8.4 Hz,1H),7.91–7.84(m,2H),7.81(d,J=0.8Hz,1H),7.21(s,2H),7.08(dd,J=8.4,2.0Hz,1H),7.03(d,J=2.0Hz,1H),3.77(s,3H).

[0361] Example 10: 2-(4-(4-aminoimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)benzo[b]thiophene-3-carbonitrile

[0362]

[0363] Step 1: Synthesis of 2-iodobenzo[b]thiophene-3-carbonitrile (Compound 10-2)

[0364] Under nitrogen protection, compound 10-1 (3 g, 18.84 mmol) was dissolved in anhydrous THF (35 mL), and after replacing nitrogen, the temperature was lowered to -65 ° C, and then a n-hexane solution of LDA (3.03 g, 28.27 mmol) was slowly added dropwise, and after stirring for 0.5 h, an anhydrous THF solution of I2 (7.17 g, 28.27 mmol) was added dropwise, and the mixture was naturally warmed to room temperature and continued to stir for 16 h. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the crude product was extracted and concentrated with EA to obtain a crude product, which was separated and purified by silica gel column chromatography (mobile phase: 100% DCM) and concentrated to obtain compound 10-2 (5.30 g).

[0365] Step 2: Synthesis of 2-(1-methyl-1H-pyrazol-5-yl)benzo[b]thiophene-3-carbonitrile (Compound 10-3)

[0366] Compound 10-2 (831 mg, 2.91 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.82 g, 8.74 mmol), PdCl2(dtbpf) (189.97 mg, 291.47 μmol) and Na2CO3 (926.78 mg, 8.74 mmol) were dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (3 mL), and reacted at 80°C for 3 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, stirred with water, extracted with EA, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (mobile phase: 100% DCM) to obtain compound 10-3 (473 mg). MS (ESI, m / z): 240.1 [M+H] + .

[0367] Step 3: Synthesis of 2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzo[b]thiophene-3-carbonitrile (Compound 10-4)

[0368] Compound 10-3 (150 mg, 626.84 μmol) and NIS (1.41 g, 6.27 mmol) were added to 10 mL of acetonitrile under ice bath, and reacted at 80°C for 16 hours under nitrogen protection. After the reaction, water was added and stirred, and EA was extracted and concentrated to obtain a crude product, which was purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3) to obtain compound 10-4 (134 mg). MS (ESI, m / z): 365.9 [M+H] + .

[0369] Step 4: Synthesis of 2-(4-(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)benzo[b]thiophene-3-carbonitrile (Compound 10-5)

[0370] Int F (60 mg, 130.34 μmol), NaHCO3 (32.85 mg, 391.02 μmol), compound 10-4 (71.40 mg, 195.51 μmol), Pd(dppf)Cl2 (10.57 mg, 13.03 μmol) were added to the reaction bottle, and dissolved with 1,4-dioxane (5 mL) and water (1 mL). After nitrogen replacement, the reaction was carried out at 80 ° C for 5 hours. After the reaction was completed, the temperature was cooled to room temperature, water was added and stirred, and EA was extracted and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3) to obtain compound 10-5 (26 mg). MS (ESI, m / z): 572.2 [M+H] + .

[0371] Step 5: Synthesis of 2-(4-(4-aminoimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)benzo[b]thiophene-3-carbonitrile (Compound 10)

[0372] Compound 10-5 (26 mg, 45.48 μmol) was added to TFA (3 mL) and reacted at 80°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and washed with saturated sodium bicarbonate solution until alkaline. The crude product was extracted and concentrated with EA, and the crude product was purified by reverse phase HPLC to obtain compound 10 (6.65 mg). MS (ESI, m / z): 422.1 [M+H] + .

[0373] 1 H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.35–8.24(m,1H),8.15–8.05(m,2H),8.04–7.96 (m,1H),7.83(s,1H),7.76–7.61(m,2H),7.25(s,2H),7.21–7.13(m,2H),3.90(s,3H).

[0374] Example 11: 2-(4-(4-amino-3-methyl-1,3-dihydrofuran[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-1-naphthalenecarbonitrile

[0375]

[0376] "＊” The position indicates that the chiral center is in the R or S configuration obtained by resolution.

[0377] Compound 1-8 (30 mg, 79.54 μmol), 6-P1-1 (26 mg, 79.54 μmol), NaHCO3 (20 mg, 238 μmol), Pd(dppf)Cl2 (6 mg, 7.95 μmol), 1,4-dioxane (1.5 mL), and H2O (0.2 mL) were added to the reaction flask, replaced with nitrogen 3 times, and reacted at 80°C for 5 hours. After the reaction was completed, the reaction solution was spin-dried, diluted with water, extracted with EA (30 ml x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 11-P1. MS (ESI, m / z): 450.1 [M+H] + .

[0378] 1 H NMR (400MHz, DMSO-d6) δ8.52(dd,J=10.0,5.6Hz,1H),8.27–8.23(m,1H),8.18–8.11(m,2H),7.91–7.84(m,2H),7.38(dd,J=8.4,3.2Hz, 1H),7.14–7.06(m,2H),6.34(s,2H),5.36–5.31(m,1H),5.27–5.22(m,1H),5.18–5.13(m,1H),3.77(s,3H),1.33(dd,J=6.0,2.4Hz,3H).

[0379] Example 12: 2-(4-(5-aminobenzo[c][2,6]naphthyridin-8-yl)-1-methyl-1H-pyrazol-5-yl)-3-chloro-6-cyclopropyloxy-4-fluorobenzonitrile

[0380]

[0381] Step 1: Synthesis of 8-bromobenzo[c][2,6]naphthyridine-5-amine (Compound 13-2)

[0382] Int A-6 (500 mg, 2.32 mmol) and compound 13-1 (422 mg, 2.32 mmol), Na2CO3 (737 mg, 6.95 mmol) were dissolved in 1,4-dioxane (3 mL) and H2O (1 mL), and Pd(PPh3)4 (268 mg, 0.46 mmol) was added after replacing nitrogen, and then the temperature was raised to 90°C for 12 hours. The reaction was completed by LCMS monitoring, and H2O (20 mL) was added after cooling to room temperature, and extracted with EA (20 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE / EA=100 / 0 to 3 / 1), and compound 13-2 (154 mg) was obtained after concentration, MS (ESI, m / z): 274.0 [M+H] + .

[0383] 1 H NMR(400MHz,MeOD)δ9.91(s,1H),8.78(d,J=5.6Hz,1H),8.48(d,J=8.4Hz,1H), 8.15 (dd, J = 5.6, 0.8 Hz, 1H), 7.78 ( d, J = 2.0 Hz, 1H), 7.52 ( dd, J = 8.8, 2.0 Hz, 1H).

[0384] Step 2: Synthesis of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][2,6]naphthyridin-5-amine (Compound 13-3)

[0385] Compound 13-2 (50 mg, 182.40 μmol), KOAc (53.70 mg, 547.21 μmol), Int D-2 (92.64 mg, 364.81 μmol), Pd(dppf)Cl2 (26.69 mg, 36.48 μmol) were added to the reaction bottle, and dissolved with 1,4-dioxane (5 mL). After nitrogen substitution, the reaction was carried out at 100 ° C for 12 hours. After the reaction was completed, the temperature was cooled to room temperature, water was added and stirred, and EA was extracted and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95: 5) to obtain compound 13-3 (20 mg). MS (ESI, m / z): 322.1 [M+H] + .

[0386] Step 3: Synthesis of 2-(4-(5-aminobenzo[c][2,6]naphthyridin-8-yl)-1-methyl-1H-pyrazol-5-yl)-3-chloro-6-cyclopropyloxy-4-fluorobenzonitrile (Compound 13)

[0387] Compound 13-3 (20 mg, 62.27 μmol), NaHCO3 (15.69 mg, 186.81 μmol), Int C (52.01 mg, 124.54 μmol), Pd(dppf)Cl2 (4.52 mg, 6.23 μmol) were added to the reaction bottle, and dissolved with 1,4-dioxane (5 mL) and water (1 mL). After nitrogen substitution, the reaction was carried out at 100 ° C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature, water was added and stirred, and EA was extracted and concentrated to obtain a crude product. The crude product was prepared and purified by reverse phase HPLC to obtain compound 13 (1.7 mg). MS (ESI, m / z): 485.1 [M+H] + .

[0388] 1 H NMR (400MHz, DMSO-d6) δ9.97(s,1H),8.78(d,J=5.2Hz,1H),8.57(d,J=8.4Hz,1H),8.17(d,J=5.6Hz,1H),8.12(s,1H),8.03(d,J=6.0Hz,1 H),7.35(s,2H),7.26(d,J=2.0Hz,1H),7.15(dd,J=8.4,2.0Hz,1H),4.23–4.18(m,1H),3.76(s,3H),0.96–0.88(m,2H),0.83–0.76(m,2H).

[0389] Example 13: 2-(4-(4-aminoimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropyloxy))benzonitrile

[0390]

[0391] Step 1: Synthesis of 4-chloro-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)-6-(1-methylcyclopropyloxy)benzonitrile (Compound 16-2)

[0392] Compound 16-1 (28.50 mg, 395.22 μmol) was dissolved in anhydrous THF (5 mL), and NaH (21.08 mg, 526.97 μmol) was slowly added and stirred for 30 min. Int C (100 mg, 263.48 μmol) was added, and the temperature was raised to 60 ° C for 7 hours after N2 protection. After the reaction was completed, the temperature was cooled to room temperature, and an appropriate amount of methanol was added to quench the reaction. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (mobile phase PE: EA = 75:25) to obtain compound 16-2 (60 mg). MS (ESI, m / z): 431.9 [M+H] + .

[0393] Step 2: Synthesis of 4-chloro-2-(4-(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-6-(1-methylcyclopropyloxy)benzonitrile (Compound 16-3)

[0394] Compound 16-2 (45 mg, 104.26 μmol), Int F (57.59 mg, 125.11 μmol), Pd(dppf)Cl2 (7.63 mg, 10.43 μmol), NaHCO3 (26.27 mg, 312.77 μmol), 1,4-dioxane (5 mL) and H2O (1 mL) were added to the reaction flask, and the mixture was reacted at 80°C for 5 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 96:4) to obtain compound 16-3 (10 mg). MS (ESI, m / z): 638.2 [M+H] + .

[0395] Step 3: Synthesis of 2-(4-(4-aminoimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-3-fluoro-6-(1-methylcyclopropyloxy))benzonitrile (Compound 16)

[0396] Compound 16-3 (10 mg, 15.67 μmol) was dissolved in TFA (3 mL), and the temperature was raised to 90°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, the sodium bicarbonate aqueous solution was adjusted to alkalinity, extracted with EA, and the organic layer was dried and concentrated and purified by Pre-HPLC to obtain compound 16 (3 mg). MS (ESI, m / z): 488.0 [M+H] + .

[0397] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.08(d,J=8.4Hz,1H),8.04(s,1H),7.86(s,1H),7.81(d,J=6.0Hz,1H),7.28(s,2 H),7.14(d,J=2.0Hz,1H),7.00(dd,J=8.4,2.0Hz,1H),3.74(s,3H),1.58(s,3H),1.06–1.00(m,2H),0.92–0.86(m,2H).

[0398] Example 14: 4-amino-7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]quinoxaline-9-carbonitrile

[0399]

[0400] Step 1: Synthesis of 4-bromo-2-iodo-6-nitroaniline (Compound 17-2)

[0401] I2 (3.51 g, 13.82 mmol) and MeOH (100 mL) were added to the reaction flask, stirred and dissolved, and then compound 17-1 (2 g, 9.22 mmol) and Ag2SO4 (2.44 g, 11.98 mmol) were added in sequence, nitrogen was protected, and the reaction was carried out at 25°C for 16 hours. The reaction solution was directly filtered, the filter cake was washed with EA, the filtrate was collected, washed with sodium thiosulfate solution and brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 17-2 (3 g).

[0402] Step 2: Synthesis of 2-amino-5-bromo-3-nitrobenzonitrile (Compound 17-3)

[0403] Compound 17-2 (850 mg, 2.48 mmol), Zn (32 mg, 495.75 mmol), dppf (275 mg, 495.75o mol), Pd2(dba)3 (227 mg, 247.87o mol), Zn(CN)2 (146 mg, 1.24 mmol), DMF (15 mL) were added to the reaction flask, and the mixture was reacted at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase EA: PE = 8: 92) to obtain compound 17-3 (350 mg). MS (ESI, m / z): 240.0 [MH] - .

[0404] Step 3: Synthesis of 5-bromo-2-chloro-3-nitrobenzonitrile (Compound 17-4)

[0405] Compound 17-3 (390 mg, 1.61 mmol), CuCl2·2H2O (330 mg, 1.93 mmol), MeCN (10 mL) and tert-butyl nitrite (249 mg, 2.42 mmol) were added to the reaction flask, and nitrogen was protected and reacted at 60°C for 16 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase EA: PE = 10: 90) to obtain compound 17-4 (330 mg).

[0406] Step 4: Synthesis of 3-amino-5-bromo-2-chlorobenzonitrile (Compound 17-5)

[0407] Compound 17-4 (330 mg, 1.26 mmol), Fe (352 mg, 6.31 mmol), NH4Cl (203 mg, 3.79 mmol), EtOH (15 mL), H2O (3 mL) were added to the reaction flask, and the mixture was reacted at 60°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated and diluted with water, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 17-5 (280 mg).

[0408] Step 5: Synthesis of N-(5-bromo-2-chloro-3-cyanophenyl)-1H-imidazole-5-carboxamide (Compound 17-7)

[0409] Compound 17-5 (280 mg, 1.21 mmol), DMF (10 mL), and NaH (242 mg, 6.05 mmol) were added to the reaction flask, and the reaction was continued at room temperature for 20 min before compound 17-6 (303 mg, 1.21 mmol) was added. The reaction was carried out under nitrogen protection at 25 °C for 16 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3). Compound 17-7 (290 mg) was collected and dried. MS (ESI, m / z): 324.9 [M+H] + .

[0410] Step 6: Synthesis of 7-bromo-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-9-carbonitrile (Compound 17-8)

[0411] Compound 17-7 (240 mg, 737.22 μmol), Cs2CO3 (480 mg, 1.47 mmol), and DMF (6 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 150°C for 2 hours. After the reaction was completed, the reaction solution was diluted with water, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with clean water and dried to obtain compound 17-8 (140 mg). MS (ESI, m / z): 289.0 [M+H] + .

[0412] Step 7: Synthesis of 7-bromo-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-9-carbonitrile (Compound 17-9)

[0413] Compound 17-8 (120 mg, 415.10 μmol), DMBNH2 (139 mg, 830.20 μmol), PyBOP (324 mg, 622.65 μmol), DIPEA (161 mg, 1.25 mmol), and DMF (5 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 60 °C for 5 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 98: 2), and the mixture was collected and dried to obtain compound 17-9 (120 mg). MS (ESI, m / z): 438.0 [M+H] + .

[0414] Step 8: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]quinoxaline-9-carbonitrile (Compound 17-10)

[0415] Compound 17-9 (35 mg, 79.86 μmol), Int D-2 (22 mg, 87.84 μmol), Pd(dppf)Cl2 (6 mg, 7.99 μmol), AcOK (24 mg, 239.57 μmol), 1,4-dioxane (2 mL) were added to the reaction flask, and the mixture was reacted at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 17-10. MS (ESI, m / z): 486.2 [M+H] + .

[0416] Step 9: Synthesis of 7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-((2,4-dimethoxybenzyl)amino)imidazole[1,5-a]quinoxaline-9-carbonitrile (Compound 17-11)

[0417] Int C (38 mg, 90.66 μmol), compound 17-10 (40 mg, 82.42 μmol), NaHCO3 (21 mg, 247.25 μmol), Pd(dppf)Cl2 (6 mg, 8.24 μmol), 1,4-dioxane (2 mL), H2O (0.5 mL) were added to the reaction flask, and nitrogen was protected and reacted at 80°C for 5 hours. The reaction solution was directly dried and purified by silica gel column chromatography (mobile phase DCM: MeOH = 98: 2), and compound 17-11 (33 mg) was collected and dried. MS (ESI, m / z): 649.2 [M+H] + .

[0418] Step 10: Synthesis of 4-amino-7-(5-(3-chloro-6-cyano-5-cyclopropyloxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]quinoxaline-9-carbonitrile (Compound 17)

[0419] Compound 17-11 (33 mg, 50.84 649.2) and TFA (3 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 80°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, diluted with saturated NaHCO3 solution, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by PreHPLC to obtain compound 17 (7.32 mg). MS (ESI, m / z): 499.0 [M+H] + .

[0420] 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.20(s,1H),8.07(d,J=6.0Hz,1H),8.00(s,1H),7.65(d,J=2.4Hz,1H) ,7.63(s,2H),7.25(d,J=2.0Hz,1H),4.25–4.19(m,1H),3.76(s,3H),0.95–0.89(m,2H),0.81–0.77(m,2H).

[0421] Example 15: 2-(4-(4-aminoimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluoro-4-(prop-1-yn-1-yl)benzonitrile

[0422]

[0423] Step 1: Synthesis of 6-cyclopropyloxy-2-(4-(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluoro-4-(prop-1-yn-1-yl)benzonitrile (Compound 18-2)

[0424] Compound 7-1 (50 mg, 80.12 μmol), compound 18-1 (132 mg, 400.60 μmol), CsF (26 mg, 400.60 μmol), 1,4-dioxane (2 mL) were added to the reaction flask, and Pd(PPh3)4 (19 mg, 16.02 μmol) was added after nitrogen replacement. The reaction was carried out at 100 °C for 20 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3), and the mixture was collected and dried to obtain compound 18-2 (5 mg). MS (ESI, m / z): 628.2 [M+H] + .

[0425] Step 2: Synthesis of 2-(4-(4-aminoimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-6-cyclopropyloxy-3-fluoro-4-(prop-1-yn-1-yl)benzonitrile (Compound 18)

[0426] Compound 18-2 (5 mg, 7.97 μmol) and TFA (2 mL) were added to the reaction flask, and the mixture was reacted at 80°C for 2 hours under nitrogen protection. The reaction solution was directly concentrated to dryness under reduced pressure, dissolved in THF and then spin-dried, and the process was repeated three times to remove the residual TFA to obtain a crude product. The crude product was purified by PreHPLC to obtain compound 18 (1.00 mg). MS (ESI, m / z): 478.2 [M+H] + .

[0427] 1H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.08(d,J=8.4Hz,1H),8.03(s,1H),7.85(s,1H),7.77(d,J=5.6Hz,1H),7.29(s,2H),7.09( d,J=2.0Hz,1H),7.02(dd,J=8.4,2.0Hz,1H),4.19–4.13(m,1H),3.72(s,3H),2.18(s,3H),0.92–0.86(m,2H),0.81–0.74(m,2H).

[0428] Example 16: 3-(4-(4-aminoimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-5-cyclopropyloxy-2-fluoroterephthalonitrile

[0429]

[0430] Step 1: Synthesis of 5-cyclopropyloxy-3-(4-(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-2-fluoroterephthalonitrile (Compound 19-1)

[0431] Compound 7-1 (50 mg, 80.12 μmol), Zn(CN)2 (19 mg, 160.24 μmol), t-BuXPhos Pd G3 (6. mg, 8.01 μmol), and DMAc (1.5 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 130 °C for 8 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 98: 2) to obtain compound 19-1 (6 mg). MS (ESI, m / z): 615.3 [M+H] + .

[0432] Step 2: Synthesis of 3-(4-(4-aminoimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-5-cyclopropyloxy-2-fluoroterephthalonitrile (Compound 19)

[0433] 19-1 (6 mg, 9.76 μmol) and TFA (2 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 80°C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness under reduced pressure, dissolved in THF and then spin-dried, and the residual TFA was removed by three times to obtain a crude product. The crude product was purified by Pre-HPLC to obtain the product compound 19 (1.79 mg). MS (ESI, m / z): 465.2 [M+H] + .

[0434] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),8.38(d,J=5.2Hz,1H),8.08–8.03(m,2H),7.86(s,1H),7.29(s,2H) ,7.16(d,J=2.0Hz,1H),6.99(dd,J=8.4,2.0Hz,1H),4.22–4.15(m,1H),3.76(s,3H),0.96–0.75(m,4H).

[0435] Example 17: 2-(4-(4-amino-9-cyclopropylimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0436]

[0437] Step 1: Synthesis of 4-chloro-2-iodo-6-nitroaniline (Compound 20-2)

[0438] I2 (3.34 g, 26.08 mmol) and MeOH (130 mL) were added to the reaction flask, stirred and dissolved, and then compound 20-1 (3 g, 17.38 mmol) and Ag2SO4 (4.61 g, 22.60 mmol) were added in sequence, nitrogen was protected, and the reaction was carried out at 50°C for 16 hours. The reaction solution was directly filtered, the filter cake was washed with EA, the filtrate was collected, washed with sodium thiosulfate solution and brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase EA: PE = 5: 95) to obtain compound 20-2 (2.33 g).

[0439] Step 2: Synthesis of 4-chloro-2-cyclopropyl-6-nitroaniline (Compound 20-4)

[0440] Compound 20-2 (1.5 g, 5.03 mmol), compound 20-3 (475 mg, 5.53 mmol), Pd(dppf)Cl2 (367.73 mg, 502.57 μmol), Cs2CO3 (4.09 g, 12.56 mmol), 1,4-dioxane (20 mL), H2O (2 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 100 °C for 16 hours. The reaction solution was diluted with water, extracted with EA (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase EA:PE = 5:95) to obtain compound 20-4 (700 mg). MS (ESI, m / z): 211.0 [MH] - .

[0441] Step 3: Synthesis of 5-chloro-1-cyclopropyl-2-iodo-3-nitrobenzene (Compound 20-5)

[0442] Compound 20-4 (600 mg, 2.82 mmol), I2 (2.15 g, 8.47 mmol), CuI (1.07 g, 5.64 mmol), MeCN (20 mL) were added to the reaction flask, and tert-butyl nitrite (436 mg, 4.23 mmol) was added, and the mixture was protected by nitrogen and reacted at 60 ° C for 5 hours. The reaction solution was diluted with water, extracted with EA (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase EA: PE = 1: 99), and the mixture was collected and dried to obtain compound 20-5 (840 mg). MS (ESI, m / z): 324.1 [M+H] + .

[0443] Step 4: Synthesis of 5-chloro-3-cyclopropyl-2-iodoaniline (Compound 20-6)

[0444] Compound 20-5 (940 mg, 2.91 mmol), Fe (811 mg, 14.53 mmol), NH4Cl (466 mg, 8.72 mmol), EtOH (15 mL), H2O (3 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 60°C for 3 hours. The reaction solution was spin-dried and diluted with water, extracted with EA (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20-6. MS (ESI, m / z): 294.0 [M+H] + .

[0445] Step 5: Synthesis of N-(5-chloro-3-cyclopropyl-2-iodophenyl)-1H-imidazole-5-carboxamide (Compound 20-7)

[0446] Compound 20-6 (750 mg, 2.56 mmol), DMF (15 mL), and NaH (511 mg, 12.78 mmol) were added to the reaction flask. After reacting at room temperature for 20 min, compound 17-6 (641 mg, 2.56 mmol) was added. The mixture was protected by nitrogen and reacted at 25 °C for 16 hours. The reaction solution was diluted with water, extracted with EA (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3). Compound 20-7 (740 mg) was collected and dried. MS (ESI, m / z): 388.0 [M+H] + .

[0447] Step 6: Synthesis of 7-chloro-9-cyclopropylimidazole [1,5-a] quinoxaline-4 (5H) -one (Compound 20-9)

[0448] Compound 20-7 (300 mg, 773.99 μmol), CuI (74 mg, 386.99 μmol), compound 20-8 (110 mg, 773.99 μmol), Cs2CO3 (504 mg, 1.55 mmol), and DMF (8 mL) were added to the microwave tube, and the mixture was protected by nitrogen and reacted at 100 °C for 3 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95: 5), and the mixture was collected and dried to obtain compound 20-9 (70 mg). MS (ESI, m / z): 260.1 [M+H] + .

[0449] Step 7: Synthesis of 7-chloro-9-cyclopropyl-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]quinoxaline-4-amine (Compound 20-10)

[0450] Compound 20-9 (140 mg, 539.10 μmol), DMBNH2 (180 mg, 1.08 mmol), PyBOP (420.82 mg, 808.65 μmol), DIPEA (209 mg, 1.62 mmol), and DMF (5 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 25 °C for 16 hours. The reaction solution was diluted with water, extracted with EA (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3) to obtain compound 20-10 (120 mg). MS (ESI, m / z): 409.0 [M+H] + .

[0451] Step 8: Synthesis of 9-cyclopropyl-N-(2,4-dimethoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]quinoxaline-4-amine (Compound 20-11)

[0452] Compound 20-10 (50 mg, 122.29 μmol), Int D-2 (37 mg, 146.74 μmol), KOAc (36 mg, 366.86 μmol), Xphos (11.66 mg, 24.46 μmol), Pd2(dba)3 (11.20 mg, 12.23 24.46, 1,4-dioxane (2 mL) were placed in a bottle, replaced with nitrogen three times, heated to 110 ° C and reacted overnight. The reaction solution was diluted with water and extracted with EA (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20-11. MS (ESI, m / z): 501.4 [M+H] + .

[0453] Step 9: Synthesis of 4-chloro-6-cyclopropyloxy-2-(4-(9-cyclopropyl-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (Compound 20-12)

[0454] Int C (55.08 mg, 131.90 μmol), compound 20-11 (60 mg, 119.91 μmol), NaHCO3 (30 mg, 359.72 μmol), Pd(dppf)Cl2 (8.77 mg, 11.99 μmol), 1,4-dioxane (2 mL), H2O (0.5 mL) were added to the reaction flask, and the reaction was carried out at 80°C for 5 hours under nitrogen protection. The reaction solution was diluted with water, extracted with EA (30 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 98: 2) to obtain compound 20-12 (22 mg). MS (ESI, m / z): 664.3 [M+H] + .

[0455] Step 10: Synthesis of 2-(4-(4-amino-9-cyclopropylimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 20)

[0456] Compound 20-12 (22 mg, 33.13 μmol) and TFA (3 mL) were added to the reaction flask, and the mixture was reacted at 80 °C for 2 hours under nitrogen protection. The reaction solution was diluted with water, extracted with EA (30 mL x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 20 (1.82 mg). MS (ESI, m / z): 514.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.09(s,1H),8.06(d,J=6.0Hz,1H),7.93(s,1H),7.22(s,2H),7.12(d,J=2.0Hz,1H),6.77(d,J=2.0 Hz,1H),4.25–4.19(m,1H),3.75(s,3H),2.40–2.36(m,1H),1.15–1.10(m,2H),0.96–0.88(m,2H),0.84–0.75(m,2H),0.60–0.51(m,2H).

[0457] Example 18: 2-(4-(4-aminoimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-difluoroazetidin-1-yl)-3-fluorobenzonitrile

[0458]

[0459] Step 1: Synthesis of 4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzonitrile (Compound 21-2)

[0460] Compound Int C (50 mg, 131.74 μmol), compound 21-1 (51 mg, 395.22 μmol) and DIPEA (85 mg, 658.71 μmol) were added to NMP (1.5 mL) and heated in a microwave at 100°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase EA: PE = 15:85) to obtain compound 21-2 (35 mg).

[0461] Step 2: Synthesis of 4-chloro-6-(3,3-difluoroazetidine-1-yl)-2-(4-(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (Compound 21-3)

[0462] Compound 21-2 (39 mg, 86.89 μmol), Int F (40 mg, 86.89 μmol), NaHCO3 (22 mg, 260.68 μmol), Pd(dppf)Cl2 (6 mg, 8.69 μmol), 1,4-dioxane (2 mL), H2O (0.5 mL) were added to the reaction flask, and the reaction was carried out at 80 °C for 20 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 98: 2) to obtain compound 21-3 (20 mg). MS (ESI, m / z): 659.2 [M+H] + .

[0463] Step 3: Synthesis of 2-(4-(4-aminoimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-(3,3-difluoroazetidine-1-yl)-3-fluorobenzonitrile (Compound 21)

[0464] Compound 21-3 (20 mg, 21.24 μmol) and TFA (3 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 80°C for 5 hours. After the reaction was completed, the reaction solution was directly concentrated to dryness under reduced pressure, dissolved in THF and then spin-dried, and the reaction was repeated three times to remove the residual TFA to obtain a crude product. The crude product was purified by PreHPLC to obtain compound 21 (0.95 mg). MS (ESI, m / z): 509.1 [M+H] + .

[0465] 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 8.09 (d, J = 8.4Hz, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.31–7. 27(m,3H),7.16(d,J=2.0Hz,1H),7.07(dd,J=8.4,2.0Hz,1H),4.70–4.56(m,4H),3.74(s,3H).

[0466] Example 19: 2-(4-(4-amino-8-methylimidazo[1,5-a]quinoxalin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0467]

[0468] Step 1: Synthesis of N-(5-bromo-2-fluoro-4-methylphenyl)-1H-imidazole-5-carboxamide (Compound 22-3)

[0469] Compound 22-1 (1.65 g, 14.70 mmol) was dissolved in anhydrous DMF (30 mL) under an ice-water bath, and DIPEA (5.70 g, 44.11 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (8.39 g, 22.05 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of compound 22-2 (3 g, 14.70 mmol) was added dropwise. The temperature was raised to 80 °C and reacted for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and stirred with water. EA was extracted and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 20:80) to obtain compound 22-3 (4 g). MS (ESI, m / z): 298.0 [M+H] + .

[0470] Step 2: Synthesis of 7-bromo-8-methylimidazo[1,5-a]quinoxaline-4(5H)-one (Compound 22-4)

[0471] Compound 22-3 (4.0 g, 13.42 mmol) was dissolved in anhydrous DMF (30 mL), K2CO3 (5.56 g, 40.25 mmol) was added, and the temperature was raised to 160°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, stirred with water, and filtered to obtain compound 22-4 (2.4 g). MS (ESI, m / z): 278.0 [M+H] + .

[0472] Step 3: Synthesis of 7-bromo-N-(2,4-dimethoxybenzyl)-8-methylimidazo[1,5-a]quinoxaline-4-amine (Compound 22-5)

[0473] In an ice bath, add compound 22-4 (2.3 g, 8.27 mmol) and PyBOP (6.46 g, 12.41 mmol) to anhydrous DMF (20 mL), continue to drop DIPEA (3.21 g, 24.81 mmol) and stir for 10 min, finally add DMBNH2 (2.77 g, 16.54 mmol), and react at 60 ° C for 16 hours. After the reaction is completed, add water and stir, extract and concentrate with EA to obtain a crude product, which is purified by silica gel column chromatography (mobile phase DCM: MeOH = 96: 4) to obtain compound 22-5 (1.3 g). MS (ESI, m / z): 428.0 [M+H] + .

[0474] Step 4: Synthesis of N-(2,4-dimethoxybenzyl)-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]quinoxaline-4-amine (Compound 22-6)

[0475] Compound 22-5 (600 mg, 1.40 mmol), KOAc (413.43 mg, 4.21 mmol), IntD-2 (534.87 mg, 2.11 mmol), Pd(PPh3)4 (162.26 mg, 140.42 μmol) were added to the reaction flask, and dissolved with 1,4-dioxane (20 mL). After nitrogen substitution, the mixture was reacted at 100 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, stirred with water, extracted with EA, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95:5) to obtain compound 22-6 (347 mg). MS (ESI, m / z): 475.2 [M+H] + .

[0476] Step 5: Synthesis of 4-chloro-6-cyclopropyloxy-2-(4-(4-((2,4-dimethoxybenzyl)amino)-8-methylimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzonitrile (Compound 22-7)

[0477] Compound 22-6 (100 mg, 210.81 μmol), NaHCO3 (53.13 mg, 632.43 μmol), Int C (88.04 mg, 210.81 μmol), Pd(dppf)Cl2 (17.09 mg, 21.08 μmol) were added to the reaction bottle, and dissolved with 1,4-dioxane (5 mL) and water (0.5 mL). After nitrogen replacement, the reaction was carried out at 80 ° C for 16 hours. After the reaction was completed, the temperature was cooled to room temperature, water was added and stirred, and EA was extracted and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 96: 4) to obtain compound 22-7 (47 mg). MS (ESI, m / z): 639.2 [M+H] + .

[0478] Step 6: Synthesis of 2-(4-(4-amino-8-methylimidazo[1,5-a]quinoxaline-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 22)

[0479] Compound 22-7 (47 mg, 73.66 μmol) was added to TFA (5 mL) and reacted at 80°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and washed with saturated sodium bicarbonate solution until alkaline. The crude product was extracted and concentrated with EA, and the crude product was purified by reverse phase HPLC to obtain compound 22 (2.27 mg). MS (ESI, m / z): 488.2 [M+H] + .

[0480] 1 H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.05(s,1H),7.87(d,J=6.0Hz,1H),7.83(s,1H),7.81(s,1H),7.20 (s,2H),6.89(s,1H),4.18–4.03(m,1H),3.77(s,3H),2.30(s,3H),0.91–0.79(m,2H),0.78–0.68(m,2H).

[0481] The following compounds were prepared by the method and general steps described in Reference Example 19. Other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0482]

[0483]

[0484] Example 20: 2-(4-(4-amino-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile

[0485]

[0486] Step 1: Synthesis of 7-bromo-3-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid (Compound 24-3)

[0487] Compound 24-1 (20.0 g, 88.5 mmol) was dissolved in compound 24-2 (57.0 mL), and the temperature was raised to 145°C for 5 hours. TLC (CH2Cl2 / MeOH=10 / 1, R f =0.50) to detect the completion of the reaction, after cooling to room temperature, pour the reaction solution into water, slowly add NaOH aqueous solution dropwise to alkaline under ice bath, and then heat under reflux for 30 min. After cooling, add 1N HCl aqueous solution to acidify, then filter, wash the filter cake with petroleum ether (500 mL), and dry to obtain compound 24-3 (17.0 g).

[0488] Step 2: Synthesis of methyl 7-bromo-2-chloro-3-methylquinoline-4-carboxylate (Compound 24-4)

[0489] Compound 24-3 (8.00 g, 28.4 mmol) was dissolved in POCl3 (19.1 g, 123 mmol, 11.6 mL), then heated to 115 °C and refluxed for 2 hours, then cooled to room temperature and concentrated by vacuum distillation. After concentration, MeOH (100 mL) was added and the reaction was continued at 25 °C for 1 hour. TLC (PE / EA=3 / 1, R f =0.60) and LCMS detected that the reaction was complete, and the mixture was directly concentrated and separated and purified by silica gel column chromatography (PE / EtOAc=1 / 0 to 5 / 1), and concentrated to obtain compound 24-4 (3.80 g), MS (ESI, m / z): 315.9 [M+H] + .

[0490] 1H NMR (400MHz, DMSO-d6) δ8.23(dd,J=6.0,2.0Hz,1H),7.80–7.85(m,1H),7.71–7.76(m,1H),4.00–4.07(m,3H),2.43(d,J=14.4Hz,3H).

[0491] Step 3: Synthesis of methyl 7-bromo-3-(bromomethyl)-2-chloroquinoline-4-carboxylate (Compound 24-5)

[0492] Compound 24-4 (3.00 g, 9.54 mmol) was dissolved in CCl4 (100 mL), and then NBS (1.87 g, 10.5 mmol) and BPO (2.31 g, 9.54 mmol) were added. The reaction temperature was raised to 80 °C and stirred for 2 hours. After LCMS detection, the reaction was completed. After vacuum distillation and concentration, a small amount of solvent was added in batches and the solid was removed by suction filtration. The filtrate was concentrated to obtain compound 24-5 (2.10 g), MS (ESI, m / z): 393.6 [M+H] + .

[0493] Step 4: Synthesis of 7-bromo-4-chloro-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (Compound 24-6)

[0494] Compound 24-5 (2.00 g, 5.08 mmol) was dissolved in MeOH (50 mL), and then DMBNH2 (1.02 g, 6.10 mmol) was added. After reacting at 25 °C for 1 hour, the reaction was completed by LCMS detection. The filter cake was washed with water and ethanol, and then vacuum dried to obtain compound 24-6 (2.10 g). MS (ESI, m / z): 446.9 [M+H] + .

[0495] Step 5: Synthesis of 4-(bis(2,4-dimethoxybenzyl)amino)-7-bromo-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (Compound 24-7)

[0496] Compound 24-6 (2.00 g, 4.47 mmol) and DMB2NH (1.42 g, 4.47 mmol) were dissolved in NMP (20 mL), and then DIPEA (1.73 g, 13.40 mmol) was added, and the temperature was raised to 140°C for 12 hours. TLC (PE / EA=1 / 1, R f=0.55) and LCMS detection reaction completion, cooling to room temperature, adding water (200mL) to dilute, and then extracted with EA (150mL x 3), after the organic phases were combined, anhydrous Na2SO4 was added to dry, filtered, concentrated, separated and purified by silica gel column chromatography (PE / EA=100 / 0 to 1 / 1), concentrated to give compound 24-7 (600mg), MS (ESI, m / z): 729.8[M+H] + .

[0497] Step 6: Synthesis of 4-(bis(2,4-dimethoxybenzyl)amino)-2-(2,4-dimethoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-1-one (Compound 24-8)

[0498] Compound 24-7 (500 mg, 686 μmol), Int D-2 (209 mg, 823 μmol), Pd(dppf)Cl2 (100 mg, 137 μmol), KOAc (202 mg, 2.06 mmol) were dissolved in 1,4-dioxane (5 mL). After replacing nitrogen, the temperature was raised to 90 °C and stirred for 2 hours. TLC (PE / EA=1 / 1, R f =0.45) and LCMS detection reaction completion, after cooling to room temperature, water (120mL) was added and then extracted with CH2Cl2 (80mL x 3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and separated and purified by silica gel column chromatography (PE / EA=100 / 0 to 1 / 1), and concentrated to give compound 24-8 (225mg), MS (ESI, m / z): 775.9[M+H] + .

[0499] Step 7: Synthesis of 2-(4-(4-(bis(2,4-dimethoxybenzyl)amino)-2-(2,4-dimethoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 24-9)

[0500] Int C (26.9 mg, 64.5 μmol), compound 24-8 (50.0 mg, 64.5 μmol), NaHCO3 (16.2 mg, 193 μmol), Pd(dtbpf)Cl2 (8.40 mg, 12.9 μmol) were dissolved in 1,4-dioxane (1.5 mL) and H2O (0.5 mL). After replacing nitrogen, the temperature was raised to 60 °C and stirred for 2 hours. TLC (PE / EA=1 / 1, R f=0.35) and LCMS detection reaction completion, after cooling to room temperature, water (50mL) was added and then extracted with CH2Cl2 (45mL x 3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and separated and purified by silica gel column chromatography (PE / EA=100 / 0 to 1 / 1), and concentrated to give compound 24-9 (60.0mg), MS (ESI, m / z): 939.3[M+H] + .

[0501] Step 8: Synthesis of 2-(4-(4-amino-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]quinolin-7-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropyloxy-3-fluorobenzonitrile (Compound 24)

[0502] Compound 24-9 (50.0 mg, 53.2 μmol) was dissolved in TFA (2 mL), and then heated to 80 ° C and stirred for 1 hour. LCMS detected that the reaction was complete. After cooling to room temperature, water (10 mL) was added to quench the reaction. Then, NaHCO3 aqueous solution was added under ice bath to alkalize. After adjusting the pH to 8-10, it was extracted with CH2Cl2 (8 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and then separated and purified by prep-HPLC. The compound 24 (6.69 mg) was lyophilized to obtain MS (ESI, m / z): 489.0 [M+H] + .

[0503] 1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.54(d,J=8.4Hz,1H),8.07(s,1H),8.00(d,J=6.0Hz,1H),7.27(d,J=1.6Hz,1H),7.10(dd,J=8. 4,1.6Hz,1H),6.78(s,2H),4.25(s,2H),4.16–4.21(m,1H),3.74(s,3H),0.90(d,J=6.0Hz,1H),0.86–0.95(m,1H),0.73–0.84(m,2H).

[0504] Separation methods

[0505] Prep-HPLC purification of some compounds in the examples was performed using Aglient 1260 or Waters 2489 HPLC, with a separation column model of Waters SunFire Prep C 18 OBD(19mm×150mm×5.0μm), WatersXbridge Prep C 18OBD (19mm×150mm×5.0μm) or YMC Actus Triart C 18 (20mm×150mm×5.0μm), the column temperature was 25°C, the detection wavelength was 214nm, 254nm or 280nm, the mobile phase A was acetonitrile, the mobile phase B was 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, the volume ratio of the mobile phase was adjusted according to the polarity of the compound; the mobile phase flow rate was 28mL / min.

[0506] Biological evaluation

[0507] Experimental Example 1: Test of the inhibitory effect of compounds on PRMT5-MTA methyltransferase activity

[0508] The prepared protein solutions (PRMT5 / MEP50 (Reaction) and MTA (MCE) mixed solutions) were pre-incubated with different concentrations of test compounds (1000 nM starting, 5-fold dilution, 7 points) at 25°C for 30 min, and then the prepared substrate solution (Biotinylated histone H4 peptide (Sangon)) was added and incubated at 25°C for 90 min. After the reaction, the prepared detection reagent mixture (Protein A-Eu (Cisbio), Anti-Histone H4 antibody (Abcam) and Streptavidin-D2 (Cisbio)) was added and incubated at 25°C for 60 min. The fluorescence signal ratio (Ratio) was detected using a BMG microplate reader.

[0509] The solvent group (DMSO) was used as the negative control and the reaction buffer group (without PRMT5·MTA enzyme) was used as the blank control. The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0510] Percent inhibition rate = (negative control Ratio - compound Ratio) / (negative control Ratio - blank control Ratio) × 100%;

[0511] Using the four-parameter equation "log(inhibitor)vs.response--Variable slope" in GraphPad Prism 8, Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hillslope)) fits the detection signal value and calculates IC 50Value. Wherein Y is the relative inhibitory activity percentage, Top and Bottom are the maximum and minimum values ​​of the fitting curve, respectively, X is the logarithmic concentration of the compound, and Hillslope is the slope of the curve. The inhibitory effect of the compound on PRMT5-MTA methyltransferase was determined according to the above method, and the results are shown in Table 1.

[0512] Table 1. Inhibitory activity of the compounds of the present invention on PRMT5-MTA

[0513] Compound No. <![CDATA[PRMT5-MTA(IC 50 ,nM)]]> 1 0.73 2 0.36 3 0.79

[0514] The experimental results show that the compounds of the present invention have a strong inhibitory effect on PRMT5-MTA enzyme.

[0515] Experimental Example 2: Compounds inhibit proliferation of MTAP Deleted / Parental HCT116 cells

[0516] In this example, MTAP Deleted / Parental HCT116 cells were selected and purchased from HORIZON.

[0517] MTAP Deleted / Parental HCT116 cells were cultured in vitro in a monolayer in RPMI6140 medium (source culture) containing 10% FBS + 1% P / S, at 37°C and 5% CO2. The cells in the logarithmic growth phase were digested and the concentration was adjusted. 250 cells were inoculated in each well of a 96-well plate and cultured overnight. Pre-diluted compounds (5000nM starting, 4-fold dilution, 9 points) were added. DMSO was added to the negative control group, and culture medium was added to the blank control group. After 8 days of culture in an incubator at 37°C and 5% CO2, 50μl CellTiter-Glo was added to each well and lysed at room temperature in the dark for 10 minutes. The test solution was transferred to a 96-well opaque white plate, and then the relative chemiluminescence unit value was read in the chemiluminescence detection mode of the microplate reader.

[0518] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0519] Percent inhibition rate = (1-(chemiluminescent signal value of the test compound-chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control-chemiluminescent signal value of the blank control)) × 100%

[0520] The percentage inhibition rate of different concentrations of compounds was plotted against the compound concentration, and the curve was fitted according to the four-parameter model to calculate the IC 50 value:

[0521] y=Min+(Max-Min) / (1+(x / IC 50)^(-Hillslope)), where: y is the percentage inhibition rate; Max and Min are the maximum and minimum values ​​of the fitting curve, respectively; x is the logarithmic concentration of the compound; and Hillslope is the slope of the curve.

[0522] The proliferation inhibitory activity of the compounds on MTAP Deleted / Parental HCT116 cells was determined according to the above method. The results are shown in Table 2.

[0523] Table 2. Proliferation inhibitory activity of the compounds of the present invention on MTAP Deleted / Parental HCT116 cells

[0524]

[0525]

[0526] The experimental results show that the compound of the present invention has a strong inhibitory effect on MTAP Deleted HCT116 cells and has a certain selectivity for MTAP Parental HCT116 cells.

[0527] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof: in: is a single bond or a double bond; Ring A is selected from a 5-8 membered heterocyclic ring or a 5-8 membered heteroaromatic ring; R 1 are independently selected from H, halogen, CN, C 1-4 Alkyl or C 1-4 haloalkyl; or two R 1 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl group; R 2 and R 3 Each independently selected from H and C 1-4 alkyl; R 4 Selected from H, C 1-4 Alkyl or C 1-4 Haloalkyl; R 5 Selected from C 6-10 aryl or 5-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more R 6 replace; R 6 are independently selected from H, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, -XLC 3-8 Cycloalkyl, -XL-heterocyclyl, -XLC 6-10 Aryl or -XLC 6-10 Heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 7 replace; R 7 are independently selected from halogen, cyano, -NR 11 R 12 、-COCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl, C 6-10 Heteroaryl, the cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl substitution; R 11 and R 12 Independently from H and C 1-4 alkyl; X is independently a direct bond, O, S or NR at each occurrence 13 ; X 1 and X 2 are each independently selected from C or N; X 3 , X 4 and X 5 Each independently selected from N or CR 14 ; R 13 and R 14 Each independently selected from H, halogen, hydroxyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or 3-6 membered heterocyclic group; L is independently a direct bond or -(CH2) at each occurrence. n -; m is 0, 1 or 2; n is 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein: Ring A is selected from a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein: R 1 Select from H or C 1-4 alkyl; Preferably, R 1 Selected from H or methyl; Preferably, R 1 Selected from H.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein: R 4 Selected from C 1-4 alkyl; Preferably, R 4 Selected from methyl.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein: R 5 Selected from C 6-10 aryl or 6-10 membered heteroaryl, the aryl or heteroaryl is optionally substituted by one or more R 6 replace; R 6 are independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkynyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -XLC 3-8 Cycloalkyl, -XL-heterocyclyl, -XLC 6-10 Aryl, -XLC 6-10 Heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 7 replace; R 7 are independently selected from halogen, cyano, -NR 11 R 12 、-COCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; Preferably, R 5 is selected from phenyl, naphthyl or benzothienyl, wherein the phenyl, naphthyl or benzothienyl is optionally substituted by one or more R 6 replace; R 6 Each is independently selected from F, Cl, cyano, cyclopropyloxy, propynyl, Preferably, R 5 Selected from 6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein: The compound has a structure shown in Formula IA, IB or IC: in: R 1 , R 4 , R 6 , X 1 , X 2 , m and ring A are as defined in any one of claims 1 to 5, and p is 0, 1, 2, 3 or 4.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein: The compound is selected from:

8. A pharmaceutical composition comprising a preventively or therapeutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof and one or more pharmaceutically acceptable carriers.

9. A pharmaceutical preparation comprising a preventive or therapeutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition according to claim 8, wherein the pharmaceutical preparation is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.

10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition according to claim 8, or a pharmaceutical preparation according to claim 9 in the preparation of a medicament for preventing or treating a disease or condition associated with PRMT5 activity.

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