Amide compound, pharmaceutical composition containing the same, preparation method and use thereof

Abstract

The present invention relates to an amide compound, a pharmaceutical composition containing the same, and a preparation method and use thereof. Specifically, the present invention relates to an amide compound of formula I, which has a good inhibitory effect on MTAP-deficient tumor cells and has good pharmacokinetic properties.

Description

Technical Field

[0001] The present invention relates to an amide compound, a pharmaceutical composition comprising the same, a method for preparing the same, 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., Cancer Dependencies: PRMT5 and MAT2A in MTAP / p16-DeletedCancers, Annual Review of Cancer Biology, 2021, 5(1): 371-390.). 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 present invention provides an amide compound, which has a good inhibitory effect on MTAP-deficient tumor cells and has 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] Ring A is selected from C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings;

[0012] R is selected from:

[0013]

[0014] R 1 are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl;

[0015] X 1 , X 2 , X 3 Each independently selected from CR 9 and N;

[0016] R 2 For LR 2 ';

[0017] L is selected from a direct bond and -(CR 5 R 6 ) p -;

[0018] R 2 'Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted with one or more halogen, -OH, -CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl substituted;

[0019] R 3 Selected from H and C 1-4 alkyl;

[0020] R 4 is independently selected at each occurrence from H, -OH, halogen, -CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted with one or more halogen, -CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclic group; or, R 3 , R 4 The atoms connected to it form a 3-8 membered heterocyclic group, a 5-8 membered cycloalkyl group, a C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings;

[0021] R 5 and R 6 Each independently selected from H, C 1-4 Alkyl and C 3-8 Cycloalkyl;

[0022] R 7 and R 8 Each independently selected from H and C 1-4 alkyl;

[0023] R 9 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0024] m is 0, 1 or 2;

[0025] n is 0, 1, 2 or 3;

[0026] p 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 present invention provides a process for preparing the compounds of formula I of the present 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 6 carbon atoms. For example, as used herein, the term "C 1-6 Alkyl" and "C 1-4 "Alkyl" refers to a linear or branched group having 1-6 carbon atoms and 1-4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), 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.). The term "C 1-4"Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0036] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more backbone chain atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, in the main chain carbon atoms of the alkyl group. Numerical ranges (e.g., C 1-6 Assorted alkyl) refers to the number of carbons in the chain, including 1-6 carbon atoms in this example. For example, a -CH2OCH2CH3 group is referred to as a C3 assorted alkyl, and a -CH2OCH2CH2NHCH3 group is referred to as a C4 assorted alkyl. Connection to the rest of the molecule can be made through heteroatoms or carbon atoms in the assorted alkyl chain.

[0037] 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.

[0038] 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.

[0039] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group is as described above. The alkoxy group herein may contain 1 to 12 carbon atoms, preferably 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, 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 atoms of the alkoxy are substituted with one or more (such as 1 to 3) identical or different halogen atoms.

[0040] 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.

[0041] As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.

[0042] As used herein, the term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other.

[0043] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including but not limited to monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl, including spirocyclic, paracyclic (condensed) or bridged ring systems (i.e., spirocyclic alkyl, paracyclic (condensed) alkyl and bridged cycloalkyl, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.). 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 (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 Cycloalkyl, which may be a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic alkyl, such as C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Fused cycloalkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged 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 polycyclic (e.g., cyclic, spirocyclic or bridged) 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, wherein the carbon atoms and heteroatoms on the heterocyclyl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or are optionally substituted with one or more (e.g., 1 to 3) independently selected from halogen and C 1-3 Alkyl groups are substituted by substituents. For example, C 3-8 A heterocyclic group refers to a heterocyclic group having 3 to 8 carbon atoms, such as C 3-6 Heterocyclic group.

[0046] The term "3-11 membered heterocyclyl" means a heterocyclyl containing 3-11 ring atoms, including but not limited to a 4-10 membered heterocyclyl, a 4-9 membered heterocyclyl, a 4-8 membered heterocyclyl, a 4-7 membered heterocyclyl, a 5-6 membered heterocyclyl, a 3-10 membered heterocyclyl, a 3-8 membered heterocyclyl, a 3-7 membered heterocyclyl, a 4-7 membered nitrogen-containing heterocyclyl, a 4-7 membered oxygen-containing heterocyclyl, a 4-7 membered sulfur-containing heterocyclyl, a 5-6 membered nitrogen-containing heterocyclyl, a 5-6 membered oxygen-containing heterocyclyl, a 5-6 membered sulfur-containing heterocyclyl, and the like, wherein the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" 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 may also include a parallel ring structure formed with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other group may be on any heterocyclic group or on the 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] In the present invention, the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.

[0049] 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

[0050] 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.

[0051] 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

[0052] 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.

[0053] Examples of the group obtained by condensing a heterocyclic group with an aryl group include, but are not limited to:

[0054] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π electron system. 6-12 "Aryl (aromatic ring)" means an aromatic group (aromatic ring) containing 6 to 12 carbon atoms, preferably C 6-10 Aryl (aromatic ring), preferably phenyl (benzene ring) or naphthyl (naphthalene ring). Aryl is optionally substituted by one or more (such as 1 to 3) identical or different substituents (such as halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0055] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl and a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, such as 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0056] As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" means a heteroaromatic group (heteroaromatic ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, etc. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl" and "sulfur-containing heteroaryl" each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples include, but are not limited to, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and 5-10 membered cyclic groups containing these groups.

[0057] As used herein, the term “C 3-10 "Heteroaryl" refers to a heteroaryl group containing 3 to 10 carbon atoms, such as C 5-10 Heteroaryl, C 5-6 Heteroaryl or C 3-5 Heteroaryl.

[0058] In the present invention, a heteroaryl group (e.g., a monoheteroaryl group) can share two adjacent atoms with an aryl group (e.g., a monocyclic aryl group, such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocyclic alkyl group) or another heteroaryl group (e.g., another monoheteroaryl group) to form a parallel ring structure, and the connection point can be on any heteroaryl ring or on other rings, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (monocyclic) aryl, (mono)heteroaryl and (mono)heterocyclic group and (mono)heteroaryl and (mono)cycloalkyl, such as a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heteroaryl, a 5-6-membered (mono)heteroaryl and phenyl group, a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heterocyclic group or a 5-6-membered (mono)heteroaryl and C 4-6(Mono)cycloalkyl (e.g., 5-6 membered heteroarylcyclobutyl, 5-6 membered heteroarylcyclopentyl or 5-6 membered heteroarylcyclohexyl), examples of which are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, quinolyl, isoquinolyl, wait.

[0059] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0060] The term "replacement" refers to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the replacement forms a stable compound. The combination of substituents and / or variables is permitted only when such a combination forms a stable compound. The compounds of the present invention can also be substituted by suitable substituents in suitable positions, and suitable substituents adopt the substituents described above in the application and the substituents adopted by those skilled in the art.

[0061] 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.

[0062] 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.

[0063] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0064] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0065] 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.

[0066] 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 13 N) 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.

[0067] 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:

[0068]

[0069] 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%).

[0070] In this article, solid lines can be used Solid wedge 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).

[0071] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.

[0072] Cocrystal refers to a drug active molecule and other physiologically acceptable acid, base, salt, non-ionic compound molecules combined in the same crystal lattice by hydrogen bonds, π-π stacking, van der Waals forces and other non-covalent bonds.

[0073] 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.

[0074] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0075] 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).

[0076] 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.

[0077] 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.

[0078] 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.

[0079] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0080] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have less pharmacological activity or no pharmacological activity themselves, and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0081] 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.

[0082] The term "about" means within ±10%, preferably within ±5%, more preferably within ±2% of the stated value. It should be noted that if there is a difference between the described structure and the name of the structure, the described structure will be given greater weight.

[0083] Compound

[0084] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof:

[0085]

[0086] in:

[0087] Ring A is selected from C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings;

[0088] R is selected from:

[0089]

[0090] R 1 are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl;

[0091] X 1 , X 2 , X 3 Each independently selected from CR 9 and N;

[0092] R 2 For LR 2 ';

[0093] L is selected from a direct bond and -(CR 5 R 6 ) p -;

[0094] R 2 'Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted with one or more halogen, -OH, -CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl substituted;

[0095] R 3 Selected from H and C 1-4 alkyl;

[0096] R 4 is independently selected at each occurrence from H, -OH, halogen, -CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted with one or more halogen, CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclic group; or, R 3 , R 4 The atoms connected to it form a 3-8 membered heterocyclic group, a 5-8 membered cycloalkyl group, a C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings;

[0097] R 5 and R 6 Each independently selected from H, C 1-4 Alkyl and C 3-8 Cycloalkyl;

[0098] R 7 and R 8 Each independently selected from H and C 1-4 alkyl;

[0099] R 9 are each independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0100] m is 0, 1 or 2;

[0101] n is 0, 1, 2 or 3;

[0102] p is 1 or 2.

[0103] In certain embodiments, the present invention provides compounds of formula I in which ring A is selected from phenyl and pyridinyl.

[0104] In certain embodiments, the present invention provides compounds of formula I in which R 1 Each independently selected from H and C 1-4 alkyl.

[0105] In certain embodiments, the present invention provides compounds of formula I in which R 1 are each independently selected from H and methyl.

[0106] In certain embodiments, the present invention provides compounds of formula I, wherein L is selected from a direct bond or -(CR 5 R 6 ) p -, p is 1.

[0107] In certain embodiments, the present invention provides compounds of formula I in which R 5 and R 6 Each independently selected from H and C 1-4 alkyl.

[0108] In certain embodiments, the present invention provides compounds of formula I in which R 5 and R 6 are each independently selected from H and methyl.

[0109] In certain embodiments, the present invention provides compounds of formula I in which L is selected from a direct bond, -CH2- and -CH(CH3)-.

[0110] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, 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 3-6 The alkyl radicals are substituted with cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl.

[0111] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The group may be substituted with a cycloalkyl or a 3-6 membered heterocyclic group.

[0112] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Independently selected from C 1-4 Alkyl, C1-4 Alkoxy, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The group may be substituted with a cycloalkyl or a 3-6 membered heterocyclic group.

[0113] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Independently selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The group may be substituted with a cycloalkyl or a 3-6 membered heterocyclic group.

[0114] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic and C 5-10 Heteroaryl, the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, 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 3-6 Cycloalkyl, C 3-6 Heterocyclic group, C 5-10 Heteroaryl substitution.

[0115] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Heterocyclic and C 5-10 Heteroaryl, the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6Heterocyclic substitution.

[0116] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, C 3-6 Heterocyclic and C 5-6 Heteroaryl, the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic substitution.

[0117] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Independently selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl and C 5-6 Heteroaryl, the alkyl, heteroalkyl, cycloalkyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclic substitution.

[0118] In certain embodiments, R 2 ' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Pyrazolyl and -C 1-4 Alkyl-OC 1-4 Alkyl, the methyl, pyrimidinyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl are optionally replaced by C 1-4 Alkyl, halogen substituted.

[0119] In certain embodiments, the present invention provides compounds of formula I in which R 2 ' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Pyrazolyl and -CH2-O-CH3, the methyl, pyrimidinyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl are optionally substituted with methyl, ethyl, propyl, F, Cl, Br and I.

[0120] In certain embodiments, R 2 ' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Pyrazolyl and -CH2-O-CH3, the methyl, pyrimidinyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl are optionally substituted by methyl, F.

[0121] In certain embodiments, the present invention provides compounds of formula I in which R 2 'Independently selected from methyl, pyrimidinyl, isopropyl, cyclopropyl, Pyrazolyl and -CH2-O-CH3, the methyl, cyclopropyl, pyrazolyl are optionally substituted by methyl.

[0122] In certain embodiments, the present invention provides compounds of formula I in which R 3 Selected from H and C 1-4 alkyl.

[0123] In certain embodiments, the present invention provides compounds of formula I in which R 3 Selected from H, methyl, ethyl, propyl and butyl.

[0124] In certain embodiments, the present invention provides compounds of formula I in which R 3 Selected from H and methyl.

[0125] In certain embodiments, the present invention provides compounds of formula I in which R 3 For H.

[0126] In certain embodiments, the present invention provides compounds of formula I in which R 4 is independently selected at each occurrence from H, halogen, CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, wherein the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, heteroaryl are optionally substituted with one or more halogen, CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy or 3-6 membered heterocyclic group.

[0127] In certain embodiments, the present invention provides compounds of formula I in which R 4 is independently selected at each occurrence from H, halogen, C1-4 Haloalkyl, C 1-4 haloalkoxy, 5-6 membered heteroaryl, wherein the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Haloalkyl substitution.

[0128] In certain embodiments, the present invention provides compounds of formula I in which R 4 is independently selected at each occurrence from H, halogen, C 1-4 Haloalkyl, C 1-4 haloalkoxy, 5-6 membered heteroaryl, the heteroaryl being optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Haloalkyl substitution.

[0129] In certain embodiments, the present invention provides compounds of formula I in which R 4 Each occurrence is independently selected from C 1-4 Haloalkyl, C 1-4 haloalkoxy and 5-6 membered heteroaryl (eg pyrazolyl), the heteroaryl being optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Haloalkyl substitution.

[0130] In certain embodiments, the present invention provides compounds of formula I in which R 4 Each occurrence is independently selected from C 1-4 Haloalkyl, C 1-4 Haloalkoxy and

[0131] In certain embodiments, the present invention provides compounds of formula I in which R 4 is independently selected at each occurrence from H, halogen, CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, C3-C8 heterocyclic group, C 5-10 Heteroaryl, the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic substitution.

[0132] In certain embodiments, the present invention provides compounds of formula I in which R 4 is independently selected at each occurrence from H, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 5-10 Heteroaryl, optionally substituted by one or more halogen, C 1-4 Alkyl, C 1-4 Haloalkyl substitution.

[0133] In certain embodiments, the present invention provides compounds of formula I in which R 4 Each occurrence is independently selected from C 1-4 Haloalkyl and C 1-4 Halogenated alkoxy.

[0134] In certain embodiments, the present invention provides compounds of formula I in which R 4 Each occurrence is independently selected from C 1-4 Halogenated alkyl.

[0135] In certain embodiments, the present invention provides compounds of formula I in which R 4 is independently trifluoromethyl, trifluoromethoxy and

[0136] In certain embodiments, the present invention provides compounds of formula I in which R 4 and independently at each occurrence trifluoromethyl and trifluoromethoxy.

[0137] In certain embodiments, the present invention provides compounds of formula I in which R 4 is independently trifluoromethyl at each occurrence.

[0138] In certain embodiments, the present invention provides compounds of formula I in which R 3 and R 4 The atoms to which it is connected together form a 5-6-membered heterocyclic group, such as a 5-membered oxygen-containing heterocyclic ring or a 6-membered oxygen-containing heterocyclic ring.

[0139] In certain embodiments, the present invention provides compounds of formula I in which R 3 and R 4 The atoms to which it is attached together form a 5-6-membered heterocyclic group, such as a 5-membered oxygen-containing heterocyclic ring.

[0140] In certain embodiments, the present invention provides compounds of formula I in which R3 and R 4 The atoms to which it is attached together form the following group:

[0141] In certain embodiments, the present invention provides compounds of formula I in which R 7 and R 8 Each independently selected from H and C 1-4 alkyl.

[0142] In certain embodiments, the present invention provides compounds of formula I in which R 7 and R 8 Each is independently selected from H, methyl, ethyl, propyl and butyl.

[0143] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 , X 2 Each independently selected from CR 9 and N.

[0144] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 and X 2 Each independently selected from CR 9 .

[0145] In certain embodiments, the present invention provides compounds of formula I in which R 9 Selected from H, halogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0146] In certain embodiments, the present invention provides compounds of formula I in which R 9 Selected from H, F, Cl, methyl and trifluoromethyl.

[0147] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 It is CH, CF, CCl, C(CH3), C(CF3) and N.

[0148] In certain embodiments, the present invention provides compounds of formula I, wherein X 1 For CH.

[0149] In certain embodiments, the present invention provides compounds of formula I, wherein X 2 is selected from CH and N.

[0150] In certain embodiments, the present invention provides compounds of formula I, wherein X 2 Selected from CH.

[0151] In certain embodiments, the present invention provides compounds of formula I, wherein X 3 Selected from N.

[0152] In certain embodiments, the present invention provides compounds of formula I in which m is 0 or 1.

[0153] In certain embodiments, the present invention provides compounds of formula I wherein m is 0.

[0154] In certain embodiments, the present invention provides compounds of formula I, wherein n is 0, 1 or 2, for example, n is 1 or 2.

[0155] In certain embodiments, the present invention provides compounds of formula I wherein p is 1.

[0156] In certain embodiments, the present invention provides Formula I further as Formula I-1 or I-2,

[0157]

[0158] Among them, ring A, R, R 2 , R 4 As defined above, q is 0, 1 or 2, for example 1 or 2.

[0159] In some embodiments, the present invention provides a compound of Formula IA or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof:

[0160]

[0161] Among them, ring A, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , m, and n are as defined above.

[0162] In some embodiments, Formula I is further Formula IA-1 or IA-2:

[0163]

[0164] Among them, ring A, R 1 , R 2 , R 4 , X 1 , X 2 , m is as defined above, and q is 0, 1 or 2, for example 1 or 2.

[0165] In some embodiments, Formula I is further Formula IA-1a, IA-1b, IA-2a or IA-2b:

[0166]

[0167] Among them, ring A, R 1 , R 2 , R 4 , X 1 , X 2 , m is as defined above, and q is 0, 1 or 2, for example 1 or 2.

[0168] In some embodiments, the present invention provides a compound of Formula IB or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof:

[0169]

[0170] Among them, ring A, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , m, and n are as defined above.

[0171] In certain embodiments, the present invention provides a compound of Formula IA or IB, wherein:

[0172] Ring A is selected from phenyl and pyridyl;

[0173] R 1 Each independently selected from H and C 1-4 alkyl;

[0174] R 2 For LR 2 ';

[0175] L is selected from a direct bond or -(CR 5 R 6 ) p -;

[0176] R 5 and R 6 Each independently selected from H and C 1-4 alkyl;

[0177] R 2 'Independently selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl (e.g. 5-6 membered heteroaryl), wherein the alkyl, heteroalkyl, cycloalkyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic substitution;

[0178] R 3Selected from H and C 1-4 alkyl;

[0179] R 4 is independently selected at each occurrence from H, halogen, C 1-4 Haloalkyl, C 1-4 haloalkoxy, 5-10 membered heteroaryl, the heteroaryl being optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 haloalkyl substituted; or, R 3 and R 4 The atoms to which it is attached together form a 3-8 membered heterocyclic ring;

[0180] X 1 and X 2 Each independently selected from CR 9 and N, preferably, X 1 and X 2 Each independently selected from CR 9 ;

[0181] R 9 Selected from H, halogen, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0182] m is 0 or 1;

[0183] n is 1 or 2;

[0184] p is 1.

[0185] In certain embodiments, the present invention provides a compound of Formula IA or IB, wherein:

[0186] Ring A is selected from phenyl and pyridyl;

[0187] R 1 are each independently selected from H and methyl;

[0188] L is selected from a direct bond, -CH2- and -CH(CH3)-;

[0189] R 2 ' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Pyrazolyl and -CH2-O-CH3, wherein the methyl, pyrimidinyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl and pyrazolyl are optionally substituted by methyl or F;

[0190] R 3 Selected from H and C 1-4 alkyl;

[0191] R 4 is independently selected at each occurrence from H, halogen, C1-4 Haloalkyl, C 1-4 haloalkoxy, 5-6 membered heteroaryl, the heteroaryl being optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 haloalkyl substituted; or, R 3 and R 4 The atoms to which it is attached together form a 3-8 membered heterocyclic ring;

[0192] X 1 and X 2 Each independently selected from CR 9 and N;

[0193] R 9 Selected from H, F, Cl, C 1-3 Alkyl (such as methyl) and C 1-3 Haloalkyl (e.g. trifluoromethyl);

[0194] m is 0 or 1; n is 1 or 2.

[0195] In certain embodiments, the present invention provides a compound of Formula IA or IB, wherein:

[0196] Ring A is selected from phenyl and pyridyl;

[0197] R 1 Each independently selected from H and C 1-4 alkyl;

[0198] L is selected from a direct bond or -(CR 5 R 6 ) p -;

[0199] R 5 and R 6 Each independently selected from H and C 1-4 alkyl;

[0200] R 2 'Independently selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl and C 5-6 Heteroaryl, the alkyl, heteroalkyl, cycloalkyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Heterocyclyl substitution;

[0201] R 3 Selected from H and C 1-4 alkyl;

[0202] R4 is independently selected at each occurrence from H, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 5-10 Heteroaryl, optionally substituted by one or more halogen, C 1-4 Alkyl, C 1-4 haloalkyl substituted; or, R 3 and R 4 Together they form a 3-8 membered heterocyclic ring;

[0203] X 1 and X 2 Each independently selected from CR 9 ;

[0204] R 9 Selected from H, halogen, C 1-3 Alkyl and C 1-3 Haloalkyl;

[0205] m is 0 or 1;

[0206] n is 1 or 2;

[0207] p is 1.

[0208] In certain embodiments, the present invention provides a compound of Formula IA or IB, wherein:

[0209] Ring A is selected from phenyl and pyridyl;

[0210] R 1 are each independently selected from H and methyl;

[0211] L is selected from a direct bond, -CH2- and -CH(CH3)-;

[0212] R 2 ' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Pyrazolyl and -CH2-O-CH3, wherein the methyl, pyrimidinyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, pyrazolyl are optionally substituted with methyl, ethyl, propyl, F, Cl, Br and I;

[0213] R 3 Selected from H and C 1-4 alkyl;

[0214] R 4 Each occurrence is independently selected from C 1-4 Haloalkyl, C 1-4 Haloalkoxy and Or, R 3 and R 4The atoms to which it is attached together form a 5-6 membered heterocyclic ring;

[0215] X 1 and X 2 Each independently selected from CR 9 ;

[0216] R 9 Selected from H, F, Cl, C 1-3 Alkyl (such as methyl) and C 1-3 Haloalkyl (e.g. trifluoromethyl);

[0217] m is 0 or 1;

[0218] n is 1 or 2.

[0219] In certain embodiments, the present invention provides a compound of Formula IA or IB, wherein:

[0220] Ring A is selected from phenyl and pyridyl;

[0221] R 1 are each independently selected from H and methyl;

[0222] L is selected from a direct bond, -CH2- and -CH(CH3)-;

[0223] R 2 ' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, Pyrazolyl and -CH2-O-CH3, wherein the methyl, pyrimidinyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl and pyrazolyl are optionally substituted by methyl or F;

[0224] R 3 Selected from H and C 1-4 alkyl;

[0225] R 4 Each occurrence is independently selected from C 1-4 Haloalkyl and C 1-4 Haloalkoxy; or, R 3 and R 4 The atoms to which it is attached together form a 5-6 membered heterocyclic ring;

[0226] X 1 and X 2 Each independently selected from CR 9 ;

[0227] R 9 Selected from H, F, Cl, C 1-3 Alkyl (such as methyl) and C 1-3 Haloalkyl (e.g. trifluoromethyl);

[0228] m is 0 or 1;

[0229] n is 1 or 2.

[0230] In certain embodiments, the present invention provides a compound of Formula IA or IB, wherein:

[0231] Ring A is selected from phenyl and pyridyl;

[0232] R 1 are each independently selected from H and methyl;

[0233] L is selected from a direct bond, -CH2- and -CH(CH3)-;

[0234] R 2 'Independently selected from methyl, pyrimidinyl, isopropyl, cyclopropyl, Pyrazolyl and -CH2-O-CH3, wherein the methyl, cyclopropyl and pyrazolyl are optionally substituted with methyl;

[0235] R 3 Selected from H and C 1-4 alkyl;

[0236] R 4 Each occurrence is independently selected from C 1-4 haloalkyl; or, R 3 and R 4 The atoms to which it is attached together form a 5-6 membered heterocyclic ring;

[0237] X 1 and X 2 Each independently selected from CR 9 ;

[0238] R 9 is H;

[0239] m is 0 or 1; n is 1 or 2.

[0240] In some embodiments, in the compounds of Formula I, I-1, I-2, IA, IB, IA-1, IA-2, IA-1a, IA-1b, IA-2a or IA-2b of the present invention, one or more of the following are satisfied:

[0241] (1) Ring A is selected from phenyl and pyridyl; preferably selected from phenyl;

[0242] (2)R 1 Each independently is H;

[0243] (3)X 1 and X 2 Each independently selected from CR 9 and N; preferably selected from CR 9;

[0244] (4)R 2 'Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, non-cyclopropyl C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and non-pyrazolyl 5-10 membered heteroaryl, preferably selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl, or preferably selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, non-cyclopropyl C 3-6 Cycloalkyl and non-pyrazolyl 5-10 membered heteroaryl, preferably selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, cyclobutyl, cyclopentyl, Pyrimidinyl, pyridinyl, preferably selected from C 1-4 Alkyl, C 2-6 heteroalkyl, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, -OH, -CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl substitution;

[0245] (5)R 4 is independently selected at each occurrence from H, -OH, halogen, -CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10Aryl and non-pyrazolyl 5-10 membered heteroaryl, preferably selected from H, -OH, halogen, -CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl, preferably selected from H, halogen, CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, preferably selected from H, halogen, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, non-pyrazolyl 5-10 membered heteroaryl, preferably selected from C 1-4 Haloalkyl and C 1-4 Halogenated alkoxy, preferably selected from C 1-4 haloalkyl, wherein the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, -CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0246] (6)R 5 and R 6 Each independently selected from H, C 1-4 alkyl;

[0247] (7)R 9 are each independently selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl, preferably selected from halogen, preferably selected from F;

[0248] (8) m is 0 or 1, preferably 0;

[0249] (9) n is 0, 1 or 2, preferably 1 or 2;

[0250] (10) p is 1;

[0251] (11) q is 0, 1 or 2, preferably 1 or 2.

[0252] In some embodiments, the present invention provides a compound of formula IA-1, wherein,

[0253] Ring A is selected from phenyl and pyridyl;

[0254] R 1 Each independently is H;

[0255] X 1 and X 2 Each independently selected from CR 9 and N, preferably selected from CR 9 ;

[0256] R 2 For LR 2 ';

[0257] L is selected from a direct bond or -(CR 5 R 6 ) p -;

[0258] R 2 'Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, non-cyclopropyl C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and non-pyrazolyl 5-10 membered heteroaryl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, -OH, -CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl substitution;

[0259] R 4 is independently selected at each occurrence from H, -OH, halogen, -CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 aryl and non-pyrazolyl 5-10 membered heteroaryl, wherein the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted with one or more halogen, -CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0260] R 5 and R 6 Each independently selected from H and C 1-4 alkyl;

[0261] R 7 and R 8 Each independently selected from H and C 1-4 alkyl;

[0262] R 9 are each independently selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0263] m is 0 or 1;

[0264] q is 1 or 2;

[0265] And p is 1.

[0266] In some embodiments, the present invention provides a compound of formula IA-1, wherein,

[0267] Ring A is selected from phenyl and pyridyl;

[0268] R 1 Each independently is H;

[0269] X 1 and X 2 Each independently selected from CR 9 and N, preferably selected from CR 9 ;

[0270] R 2 For LR 2 ';

[0271] L is selected from a direct bond or -(CR5 R 6 ) p -;

[0272] R 2 'Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, heterocyclyl, cycloalkyloxy, aryl are optionally substituted with one or more halogen, -OH, -CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl substitution;

[0273] R 4 is independently selected at each occurrence from H, -OH, halogen, -CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl, the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl are optionally substituted by one or more halogen, -CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0274] R 5 and R 6 Each independently selected from H and C 1-4 alkyl;

[0275] R 7 and R 8 Each independently selected from H and C1-4 alkyl;

[0276] R 9 are each independently selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0277] m is 0 or 1;

[0278] q is 1 or 2;

[0279] And p is 1.

[0280] In some embodiments, the present invention provides a compound of Formula I, I-1, I-2, IA, IB, IA-1, IA-2, IA-1a, IA-1b, IA-2a or IA-2b, which satisfies one or more of the following:

[0281] (1)X 1 and X 2 Each independently selected from CR 9 ;

[0282] (2)R 2 'Independently selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, the alkyl, heteroalkyl is optionally replaced by C 1-4 Alkyl or halogen substitution;

[0283] (3)R 4 Each occurrence is independently selected from C 1-4 Haloalkyl and C 1-4 Haloalkoxy;

[0284] (4)R 9 are each independently selected from halogen.

[0285] The present invention covers any combination of the above embodiments.

[0286] In some embodiments, compounds of the invention include, but are not limited to:

[0287]

[0288]

[0289]

[0290] In some embodiments, the compound of the invention is not the following:

[0291]

[0292]

[0293]

[0294] Preparation method

[0295] In certain embodiments, the present invention provides a method for preparing a compound of Formula IA comprising the steps of:

[0296] Route A

[0297] Step 1: Compound IA-1 and IA-2 undergo condensation reaction to generate compound IA-3;

[0298]

[0299] Step 2: Compound IA-3 is heated and deprotected under acidic conditions to generate compound IA;

[0300]

[0301] in:

[0302] Each group is as defined above;

[0303] The reaction conditions of each step are as follows:

[0304] Step 1: Compound IA-1 and IA-2 are subjected to a condensation reaction (e.g., HATU and DIPEA; POCl3 and pyridine, etc.) to generate compound IA-3;

[0305] Step 2: Compound IA-3 is heated and deprotected under acidic conditions (trifluoroacetic acid or the like is used as an acid) to generate compound IA;

[0306] The synthesis method of the compound of formula IB is similar to the above method.

[0307] Pharmaceutical compositions, preparations and methods of treatment

[0308] 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.

[0309] In some embodiments, the present invention provides a pharmaceutical formulation selected from the group consisting of a solid formulation, a semisolid formulation, a liquid formulation, and a gaseous formulation.

[0310] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise one or more additional therapeutic agents.

[0311] In some embodiments, the pharmaceutical composition or pharmaceutical formulation is administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] In some embodiments, the disease or condition associated with PRMT5 activity is a cancer or tumor in which MTAP is deficient.

[0317] In some embodiments, the cancer or tumor is selected from esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, melanoma, gastric cancer, colon cancer, leukemia (B-CLL) and lymphoma.

[0318] 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.

[0319] 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).

[0320] The pharmaceutical compositions of the invention can act systemically and / or locally. For this purpose, they can be administered by a suitable route.

[0321] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] Unless otherwise indicated, as used herein, the term "prevention" refers to the pre-administration of a drug to avoid or prevent the appearance of one or more symptoms of a disease or condition. One of ordinary skill in the medical field recognizes that the term "prevention" is not an absolute term. In the medical field, it is understood that the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or the symptoms of a condition is a meaning intended in this disclosure. The Physician's Desk Reference, a standard text in the field, uses the term "prevention" hundreds of times. As used therein, the term "prevention" with respect to a condition or disease refers to avoiding the cause, effect, symptom, or progression of a disease or condition before the disease or condition fully manifests itself.

[0327] The term "treating" means to reverse, alleviate, inhibit the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0328] 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.).

[0329] 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 treatment 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

[0330] Example

[0331] 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. The abbreviations used herein have the following meanings:

[0332]

[0333]

[0334] 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.

[0335] 1 H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).

[0336] LC / MS uses Aglient 1260 Infinity / Aglient 6120 Quadrupole.

[0337] TLC used silica gel GF 254 as the stationary phase.

[0338] Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0339] Flash column chromatography was performed using a Biotage flash column chromatograph.

[0340] Agilent 1260 and Waters 2489 were used for Prep-HPLC.

[0341] Microwave reactions were performed using a BiotageInitiator microwave reactor.

[0342] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0343] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Teber Chemical Company.

[0344] Synthesis Example:

[0345] Intermediate Int-A: 4-((2,4-dimethylbenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid

[0346]

[0347] Step 1: Synthesis of intermediate N-(4-bromo-2-fluorophenyl)-1H-imidazole-5-carboxamide (Compound Int A-3)

[0348] Int A-1 (15 g, 133.83 mmol) was dissolved in anhydrous DMF (50 mL) under an ice-water bath, and DIPEA (34.59 g, 267.65 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (76.33 g, 200.74 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of Int A-2 (27.97 g, 147.21 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 the intermediate Int A-3 (16.00 g). MS (ESI, m / z): 284.0 [M+H] + .

[0349] Step 2: Synthesis of intermediate 8-bromoimidazo[1,5-a]quinoxaline-4(5H)-one (Compound Int A-4)

[0350] Int A-3 (2.27 g, 7.98 mmol) was dissolved in anhydrous DMAc (20 mL), and NaH (479.01 mg, 11.98 mmol) was added in batches under ice bath, and stirred for 10 min, and then reacted at 140 ° C for 48 hours under nitrogen protection. After the reaction was completed, most of the DMAc was dried under reduced pressure, cooled to room temperature, stirred with water, and filtered. The filter cake was rinsed with water twice to obtain the intermediate Int A-4 (2.0 g), which was used after drying. MS (ESI, m / z): 264.0 [M+H] + .

[0351] Step 3: Synthesis of intermediate 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (compound IntA-5)

[0352] Int A-4 (2.0 g, 7.57 mmol), TEA (2.30 g, 22.72 mmol), Pd(dppf)2Cl2 (613.90 mg, 757.35 μmol) were added to the autoclave and dissolved with methanol (30 mL). After CO substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature and filtered. The filter cake was the intermediate Int A-5 (700 mg), which was used after drying. MS (ESI, m / z): 244.1 [M+H]+.

[0353] Step 4: Synthesis of intermediate 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (Compound Int A-7)

[0354] In anhydrous DMF (20 mL) was added with Int A-5 (700 mg, 2.88 mmol) and PyBOP (2.25 g, 4.32 mmol) under ice bath, and DIPEA (1.12 g, 8.63 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (962.46 mg, 5.76 mmol) was added and reacted at 60 °C for 16 hr. After the reaction was completed, 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 = 95:5) to obtain the intermediate Int A-7 (904 mg). MS (ESI, m / z): 393.2 [M+H] + .

[0355] Step 5: Synthesis of intermediate 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int A)

[0356] Int A-7 (904 mg, 2.30 mmol) was dissolved in 30 mL of methanol under ice bath, and an aqueous solution (15 mL) of NaOH (552.90 mg, 13.82 mmol) was added dropwise, and the temperature was naturally raised to 25°C for 16 hours. After the reaction, the methanol was dried by spin drying, and dilute hydrochloric acid was added dropwise to the remaining part under ice bath until the solution was acidic, and the filter cake was washed with water twice to obtain the intermediate Int A (840 mg). MS (ESI, m / z): 379.2 [M+H] + .

[0357] Intermediate Int-B: 5-(bis(4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylic acid

[0358]

[0359] Step 1: Synthesis of 6-bromo-4-methylquinazolin-2-amine (Compound Int B-2)

[0360] Int B-1 (1 g, 4.67 mmol) and 4M HCl 1,4-dioxane solution (10 mL) were added to the reaction flask, stirred at room temperature for 20 min, and the reaction solution was concentrated to dryness under reduced pressure. Then, cyanamide aqueous solution (5.00 mL) was added to the reaction flask, and nitrogen was protected and reacted at 50°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with water, saturated Na2CO3 solution was added to adjust the pH to 8-9, filtered, and the filter cake was washed with clean water and dried to obtain compound Int B-2. MS (ESI, m / z): 238.0 [M+H] + .

[0361] Step 2: Synthesis of 9-bromoimidazo[1,5-c]quinazoline-5-amine (Compound Int B-3)

[0362] Int B-2 (1.1 g, 4.62 mmol), glycine (694 mg, 9.24 mmol), TBAI (341 mg, 924.05 μmol), DMSO (10 mL), AcOH (832 mg, 13.86 mmol), TBHP (6 M, 3.08 mL) were added to the reaction flask, and the mixture was reacted at 95 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water, and saturated Na2CO3 solution was added to adjust the pH to 8-9, filtered, and the filter cake was washed with clean water and dried to obtain compound Int B-3 (1 g). MS (ESI, m / z): 263.0 [M+H] + .

[0363] Step 3: Synthesis of 9-bromo-N,N-bis(4-methoxybenzyl)imidazo[1,5-c]quinazoline-5-amine (Compound Int B-4)

[0364] Int B-3 (200 mg, 760.19 μmol) and DMF (10 mL) were added to the reaction flask and dissolved, and then placed in an ice-water bath to cool down. NaH (122 mg, 3.04 mmol) was added, and the reaction was kept in an ice-water bath for 30 min. PMBCl (357 mg, 2.28 mmol) was added, and the reaction was carried out at 0 ° C for 20 min, and then the temperature was slowly raised to room temperature for 16 hours. The reaction solution was then 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 silica gel column chromatography (mobile phase EA: PE = 35: 65), and the compound Int B-4 (130 mg) was collected and dried. MS (ESI, m / z): 503.1 [M+H] + .

[0365] Step 4: Synthesis of methyl 5-(bis(4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate (Compound Int B-5)

[0366] Int B-4 (130 mg, 258.25 μmol), Pd(dppf)Cl2·DCM (19 mg, 25.82 μmol), MeOH (10 mL), and TEA (78 mg, 774.75 μmol) were added to the autoclave. After replacing CO twice, the pressure was filled to 10-12 atmospheres, and the temperature was raised to 120°C for reaction for 5 hours. After the reaction was completed, it was diluted with water and 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 silica gel column chromatography (mobile phase EA:PE=35:65) to obtain compound Int B-5 (90 mg). MS (ESI, m / z): 483.2 [M+H] + .

[0367] Step 5: Synthesis of 5-(bis(4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylic acid (Compound IntB)

[0368] 212e (90 mg, 186.52 μmol) and THF (3 mL) were added to the reaction flask, and after dissolution, a solution of LiOH·H2O (20 mg, 466.29 μmol) in H2O (0.5 mL) was added. The mixture was protected by nitrogen and reacted at 50°C for 8 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with 2M hydrochloric acid, and the solvent was directly concentrated to dryness under reduced pressure to obtain compound Int B. MS (ESI, m / z): 469.2 [M+H] + .

[0369] Intermediate Int C: (R)-1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (Int C)

[0370]

[0371] Step 1: Synthesis of (R)-2-methyl-N-(1-(pyrimidin-2-yl)ethylidene)propane-2-sulfenamide (Compound Int C-3)

[0372] Dissolve Int C-1 (1 g, 8.19 mmol) and Int C-2 (1.78 g, 9.83 mmol) in anhydrous THF (20 mL), slowly add Ti(iPrO)4 (4.65 g, 16.38 mmol, 4.85 mL), raise the temperature to 75°C and react for 12 hours. After the reaction is completed, cool to room temperature to obtain compound Int C-3 (1.8 g), which is directly used for the next step. MS (ESI, m / z): 226.1 [M+H] + .

[0373] Step 2: Synthesis of (R)-2-methyl-N-((R)-1-(pyrimidin-2-yl)ethyl)propane-2-sulfenamide (Compound IntC-4)

[0374] At 25°C, NaBH4 (604.49 mg, 15.98 mmol) was added to the reaction bottle of Int C-3 (1.8 g, 7.99 mmol) in the previous step. After the addition, the reaction system continued to react at 25°C for 2 hours. After the reaction was completed, an appropriate amount of water was added to quench the reaction, and the reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 93:7) to obtain compound Int C-4 (1.5 g). MS (ESI, m / z): 228.1 [M+H] + .

[0375] Step 3: Synthesis of (R)-1-(pyrimidin-2-yl)ethane-1-amine (Compound Int C-5)

[0376] Dissolve Int C-4 (1.5 g, 6.60 mmol) in MeOH (15 mL), then slowly add 4N HCl in 1,4-dioxane solution (5 mL), react at 25°C for 1 hour, concentrate under reduced pressure after the reaction is complete, then add an appropriate amount of methanol to dissolve, add a few drops of triethylamine to adjust the pH to 7-8, and concentrate under reduced pressure to obtain compound Int C-5 (800 mg). MS (ESI, m / z): 124.1 [M+H] + .

[0377] Step 4: Synthesis of (R)-1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethane-1-amine (IntC)

[0378] Int C-5 (600 mg, 1.46 mmol) and Int C-6 (255.93 mg, 1.46 mmol) were dissolved in anhydrous DCM (20 mL), and AcOH (175.53 mg, 2.92 mmol) was added. The resulting mixture was stirred at 25 ° C for 30 min. Then NaBH (OAc) 3 (464.65 mg, 2.19 mmol) was added. After the addition was completed, the reaction system continued to react at 25 ° C for 1.5 hr. After the reaction was completed, methanol was used to quench the reaction, and the reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 92: 8) to obtain compound Int C (230 mg). MS (ESI, m / z): 283.1 [M+H] + .

[0379] Intermediate Int D: 4-((2,4-dimethylbenzyl)amino)-3-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Int D)

[0380]

[0381] Step 1: Synthesis of N-(4-bromo-2-fluorophenyl)-4-methyl-1H-imidazole-5-carboxamide (Compound Int D-2)

[0382] Int D-1 (5 g, 39.65 mmol) was dissolved in anhydrous DMF (60 mL) under an ice-water bath, and DIPEA (10.25 g, 79.29 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (22.61 g, 59.47 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of Int A-2 (8.29 g, 43.61 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 D-2 (5.40 g). MS (ESI, m / z): 298.0 [M+H] + .

[0383] Step 2: Synthesis of 8-bromo-3-methylimidazo[1,5-a]quinoxaline-4(5H)-one (Compound Int D-3)

[0384] Int D-2 (5.40 g, 18.11 mmol) was dissolved in anhydrous DMAc (50 mL), and 60% pure sodium hydride (1.09 g, 27.17 mmol) was added in batches under ice bath, and stirred for 10 min and reacted at 140°C for 48 hr. After the reaction was completed, it was cooled to room temperature, stirred with water, and extracted with ethyl acetate and concentrated to obtain compound Int D-3 (3.50 g). MS (ESI, m / z): 278.0 [M+H] + .

[0385] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-3-methylimidazo[1,5-a]quinoxaline-4-amine (Compound Int D-4)

[0386] In anhydrous DMF (20 mL) was added with Int D-3 (2.00 g, 7.19 mmol) and PyBOP (7.48 g, 14.38 mmol) under ice bath, and DIPEA (2.79 g, 21.57 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (2.40 g, 14.38 mmol) was added and reacted at 60°C for 16 hr. 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 reverse phase HPLC column chromatography (mobile phase H2O [0.05% NH4HCO3]: ACN = 20:80) to obtain compound Int D-4 (1.20 g). MS (ESI, m / z): 427.1 [M+H] + .

[0387] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)-3-methylimidazo[1,5-a]quinoxaline-8-carboxylate (Compound Int D-5)

[0388] Int D-4 (1.20 g, 2.81 mmol), TEA (852.54 mg, 8.43 mmol), Pd(dppf)2Cl2 (227.64 mg, 280.84 μmol) were added to the autoclave and dissolved with methanol (30 mL). After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature and filtered. The filter cake was compound Int D-5 (614 mg). MS (ESI, m / z): 407.2 [M+H] + .

[0389] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-3-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int D)

[0390] Int D-5 (614 mg, 1.51 mmol) was dissolved in methanol (10 mL) under ice bath, and an aqueous solution (2 mL) of sodium hydroxide (181.28 mg, 4.53 mmol) was added dropwise, and the mixture was reacted at 55°C for 3 hours. After the reaction, the methanol was dried by spin drying, and dilute hydrochloric acid was added dropwise to the remaining portion under ice bath until the solution was acidic, and the mixture was filtered by suction, and the filter cake was washed with water twice to obtain compound Int D (446 mg). MS (ESI, m / z): 393.1 [M+H] + .

[0391] Intermediate Int E: (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (Int E)

[0392]

[0393] Step 1: Synthesis of tert-butyl (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (Int E-2)

[0394] Int E-1 (200 mg, 984.44 μmol) and TEA (109.58 mg, 1.08 mmol) were dissolved in DCM (15 mL) under ice-water bath, (Boc)2O (214.85 mg, 984.44 μmol) was slowly added, and the temperature was naturally raised to 25°C for 16 hours. After the reaction, it was directly concentrated and mixed with silica gel, and then purified by silica gel column chromatography (mobile phase DCM: MeOH = 98:2) to obtain compound IntE-2 (295.45 mg).

[0395] Step 2: Synthesis of tert-butyl (S)-methyl (6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (IntE-3)

[0396] Int E-2 (100 mg, 329.73 μmol) was dissolved in anhydrous THF (10 mL), and 60% pure sodium hydride (19.78 mg, 494.60 μmol) was added in batches under ice bath, and iodomethane (51.48 mg, 362.71 μmol) was added dropwise after stirring for 15 min, and the mixture was reacted at 0°C for 16 hours. After the reaction, the mixture was directly concentrated and mixed with silica gel, and then purified by silica gel column chromatography (mobile phase DCM: MeOH = 100:0) to obtain compound Int E-3 (100.00 mg).

[0397] Step 3: Synthesis of (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (Int E) hydrochloride

[0398] Int E-3 (100 mg, 315.16 μmol) was dissolved in dichloromethane (9 mL), and 4M dioxane hydrochloride solution (1.5 mL) was added dropwise at 0°C, and the temperature was naturally raised to 25°C for 6 hours. After the reaction was completed, the mixture was directly concentrated to obtain compound Int E hydrochloride (68.8 mg). MS (ESI, m / z): 218.2 [M+H] + .

[0399] Intermediate Int F: 4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Int F)

[0400]

[0401] Step 1: Synthesis of N-(4-bromo-2-fluoro-5-methylphenyl)-1H-imidazole-5-carboxamide (Int F-2)

[0402] Int A-1 (3 g, 26.77 mmol) was dissolved in anhydrous DMF (50 mL) under an ice-water bath, and DIPEA (6.92 g, 53.53 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (15.27 g, 40.15 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of Int F-1 (6.01 g, 29.44 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 crude product was extracted and concentrated with ethyl acetate. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 15: 85) to obtain compound Int F-2 (5.65 g). MS (ESI, m / z): 298.0 [M+H] + .

[0403] Step 2: Synthesis of 8-bromo-7-methylimidazo[1,5-a]quinoxaline-4(5H)-one (Int F-3)

[0404] Int F-2 (5.65 g, 18.95 mmol) was dissolved in anhydrous DMAc (35 mL), and NaH (1.14 g, 28.43 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 and precipitated naturally. Compound Int F-3 (1.70 g) was obtained by suction filtration. The crude product was dried and used. MS (ESI, m / z): 278.0 [M+H] + .

[0405] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-7-methylimidazo[1,5-a]quinoxaline-4-amine (IntF-4)

[0406] In anhydrous DMF (20 mL) was added with Int F-3 (700 mg, 2.52 mmol) and PyBOP (1.96 g, 3.78 mmol) under ice bath, and DIPEA (975.91 mg, 7.55 mmol) was added dropwise and stirred for 10 min, and finally Int A-6 (841.72 mg, 5.03 mmol) was added and reacted at 60°C for 16 hr. 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 reverse phase HPLC column chromatography (mobile phase H2O:ACN=20:80) to obtain compound Int F-4 (900 mg). MS (ESI, m / z): 427.0 [M+H] + .

[0407] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylate (Int F-5)

[0408] Int F-4 (800 mg, 1.87 mmol), TEA (568.36 mg, 5.62 mmol), Pd(dppf)2Cl2 (151.76 mg, 187.22 μmol) were added to the autoclave and dissolved with 30 mL of methanol. After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature 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 Int F-5 (332 mg), which was used after drying. MS (ESI, m / z): 407.1 [M+H] + .

[0409] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Int F)

[0410] Int F-5 (332 mg, 816.86 μmol) was dissolved in methanol (10 mL) under ice bath, and an aqueous solution (2 mL) of NaOH (98.02 mg, 2.45 mmol) was added dropwise, and the mixture was reacted at 55°C for 3 hours. After the reaction, the methanol was dried by spin drying, and dilute hydrochloric acid was added dropwise to the remaining portion under ice bath until the solution was acidic, and the mixture was filtered and the filter cake was washed with water twice to obtain compound Int F (236.80 mg), which was used without purification after drying. MS (ESI, m / z): 393.1 [M+H] + .

[0411] Intermediate Int G: 4-((2,4-dimethoxybenzyl)amino)-7-trifluoromethylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Int G)

[0412]

[0413] Step 1: Synthesis of N-(4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)-1H-imidazole-5-carboxamide (Int G-2)

[0414] Int A-1 (2.17 g, 19.38 mmol) was dissolved in anhydrous DMF (50 mL) under ice-water bath, DIPEA (3.76 g, 29.07 mmol) was slowly added dropwise, HATU (8.84 g, 23.25 mmol) was added after stirring evenly, stirring was continued for 1 h, and finally IntG-1 (5 g, 19.38 mmol) was added, and the temperature was naturally raised to 25 °C for 16 hours. After the reaction was completed, 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 PE: EA = 47:53) to obtain compound Int G-2 (1.55 g). MS (ESI, m / z): 351.9 [M+H] + .

[0415] Step 2: Synthesis of 8-bromo-7-(trifluoromethyl)imidazo[1,5-a]quinoxalin-4(5H)-one (Int G-3)

[0416] Int G-2 (1.55 g, 4.40 mmol) was dissolved in anhydrous DMAc (50 mL), sodium hydride (264.14 mg, 6.60 mmol) was added in batches under ice bath, stirred for 10 min and reacted at 100 °C for 12 hr. After the reaction was completed, it was cooled to room temperature, stirred with water, extracted with ethyl acetate and concentrated to obtain compound Int G-3 (1.40 g). MS (ESI, m / z): 332.0 [M+H] + .

[0417] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-7-(trifluoromethyl)imidazo[1,5-a]quinoxaline-4-amine (Int G-4)

[0418] In anhydrous DMF (5 mL) was added with Int G-3 (0.40 g, 1.20 mmol) and PyBOP (940.25 mg, 1.81 mmol) under ice bath, and DIPEA (467.03 mg, 3.61 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (302.11 mg, 302.11 mg) was added and reacted at 60°C for 16 hr. 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 reverse phase HPLC column chromatography (mobile phase H2O:ACN=36:64) to obtain compound Int G-4 (0.25 g). MS (ESI, m / z): 481.1 [M+H] + .

[0419] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)-7-(trifluoromethyl)imidazo[1,5-a]quinoxaline-8-carboxylate (Int G-5)

[0420] Int G-4 (0.25 g, 519.46 μmol), TEA (157.69 mg, 1.56 mmol), Pd(dppf)2Cl2 (42.11 mg, 51.95 μmol) were added to the autoclave, and dissolved with methanol (10 mL). After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120 ° C for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, concentrated under reduced pressure, and separated and purified by Prep-TLC (PE: EA = 8: 2) to obtain compound Int G-5 (70 mg). MS (ESI, m / z): 461.1 [M+H] + .

[0421] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-7-(trifluoromethyl)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Int G)

[0422] Int G-5 (70 mg, 152.04 μmol) was dissolved in ethanol (10 mL) and H2O (2 mL), and NaOH (12.16 mg, 304.08 μmol) was added, and the mixture was reacted at 55°C for 3 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain compound Int G (65 mg). MS (ESI, m / z): 447.1 [M+H] + .

[0423] Intermediate Int H: N-methyl-6-(trifluoromethyl)isochroman-4-amine (Int H)

[0424]

[0425] Step 1: Synthesis of 1-((allyloxy)methyl)-2-bromo-4-(trifluoromethyl)benzene (Compound Int H-2)

[0426] Int H-1 (10.50 g, 41.17 mmol), allyl bromide (14.94 g, 123.51 mmol), tert-butylammonium hydrogen sulfate (2.10 g, 6.18 mmol), KOH (4.39 g, 78.23 mmol) were added to the reaction flask, and the reaction was maintained at 25 ° C for 16 hours without solvent under nitrogen protection. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate (150 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), and the compound Int H-2 (11.87 g) was obtained by spin drying.

[0427] Step 2: Synthesis of 4-methylene-6-(trifluoromethyl)isochroman (Compound Int H-3)

[0428] Int H-2 (11.87 g, 40.22 mmol), DMF (100 mL), PPh3 (3.17 g, 12.07 mmol), Cs2CO3 (15.73 g, 48.27 mmol) were added to the reaction flask, and Pd(OAc)2 (903 mg, 4.02 mmol) was added after stirring. The mixture was protected by nitrogen and reacted at 90 °C for 16 hours. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate (80 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), and the compound Int H-3 (6.5 g) was obtained by spin drying.

[0429] Step 3: Synthesis of 6-(trifluoromethyl)isochroman-4-one (Compound Int H-4)

[0430] Int H-3 (6 g, 28.01 mmol), 1,4-dioxane (75 mL), H2O (75 mL) were added to the reaction flask, stirred evenly, and then placed in an ice-water bath to cool, and then NaIO4 (17.98 g, 84.04 mmol) was added, and K2OsO4·2H2O (516 mg, 1.40 mmol) was added after stirring for 5 min, and the reaction was carried out at 0°C for 3 hours. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate (80 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 = 15: 85), and the compound Int H-4 (4.65 g) was obtained by spin drying.

[0431] Step 4: Synthesis of 6-(trifluoromethyl)isochroman-4-ol (Compound Int H-5)

[0432] Int H-4 (4.65 g, 21.51 mmol) and MeOH (80 mL) were added to the reaction flask, and after dissolving, the mixture was placed in an ice-water bath to cool down. NaBH4 (1.06 g, 27.97 mmol) was then added, and the mixture was protected by nitrogen and reacted at 0°C for 1 hour. After the reaction was completed, water was added to the reaction solution to quench the reaction, and the solvent was concentrated to dryness under reduced pressure. After dilution with water, the mixture was extracted with ethyl acetate (60 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 Int H-5 (4.5 g). MS (ESI, m / z): 201.1 [M+H-18] + .

[0433] Step 5: Synthesis of 6-(trifluoromethyl)isochroman-4-yl 4-methylbenzenesulfonate (Compound Int H-6)

[0434] Compound Int H-5 (4.7 g, 21.54 mmol), TsCl (4.52 g, 23.70 mmol), DCM (100 mL), DMAP (131 mg, 1.08 mmol), TEA (5.45 g, 53.86 mmol) were added to the reaction flask, and the mixture was reacted at 25°C for 30 min under nitrogen protection. After the reaction was completed, water was added to dilute the reaction solution, and the mixture was extracted with DCM (80 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 Int H-6 (8.3 g). MS (ESI, m / z): 390.2 [M+18] + .

[0435] Step 6: Synthesis of 1-(6-(trifluoromethyl)isochroman-4-yl)triazine (Compound Int H-7)

[0436] Int H-6 (8.3 g, 22.29 mmol), NaN3 (2.17 g, 33.44 mmol), acetone (150 mL) were added to the reaction flask, nitrogen was protected, and the reaction was carried out at 40 ° C for 16 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (60 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) and spin-dried to obtain compound Int H-7 (5.2 g).

[0437] Step 7: Synthesis of 6-(trifluoromethyl)isochroman-4-amine (Compound Int H-8)

[0438] Int H-7 (5.4 g, 22.21 mmol), Pd / C (2.70 g, 22.21 mmol), and MeOH (100 mL) were added to the reaction flask, replaced with a hydrogen balloon, and reacted at 25°C for 3 hours. After the reaction was completed, the reaction solution was directly filtered through diatomaceous earth, the filter cake was washed with MeOH, and the filtrate was collected and concentrated under reduced pressure to obtain compound Int H-8 (4.6 g). MS (ESI, m / z): 218.1 [M+H] + .

[0439] Step 8: Synthesis of tert-butyl (6-(trifluoromethyl)isochroman-4-yl)carbamate (Compound Int H-9)

[0440] Int H-8 (4.6 g, 21.18 mmol), TEA (2.57 g, 25.42 mmol), di-tert-butyl dicarbonate (4.62 g, 21.18 mmol) were added to DCM (200 mL) and stirred at room temperature overnight. After the reaction was completed, water was added to dilute the reaction solution, extracted with DCM (80 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 = 10: 90) and spin-dried to obtain compound Int H-9 (4.65 g). MS (ESI, m / z): 262.1 [M+H-56] + .

[0441] Step 9: Synthesis of tert-butyl (6-(trifluoromethyl)isochroman-4-yl)carbamate (Compound Int H-10)

[0442] Int H-9 (4.65 g, 14.65 mmol) and THF (120 mL) were added to the reaction flask, nitrogen was protected, and the temperature was cooled in an ice-water bath. NaH (879.29 mg, 21.98 mmol) was added, and CH3I (2.39 g, 16.85 mmol, 1.05 mL) was added after reacting at 0°C for 30 min. The temperature was naturally raised to room temperature and reacted for 16 hours. After the reaction was completed, water was added to dilute the reaction solution, and it was extracted with ethyl acetate (70 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 Int H-10 (4.5 g). MS (ESI, m / z): 276.1 [M-56] + .

[0443] Step 10: Synthesis of N-methyl-6-(trifluoromethyl)isochroman-4-amine (Compound Int H)

[0444] Int H-10 (4.5 g, 13.58 mmol), 4M HCl in 1,4-dioxane solution (25 mL), and DCM (50 mL) were added to the reaction flask, and the mixture was reacted at 25°C for 2 hours under nitrogen protection. After the reaction was completed, the crude product was obtained by direct concentration under reduced pressure. The mixture was diluted with saturated sodium bicarbonate solution, extracted with ethyl acetate (60 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 Int H (3 g, 12.98 mmol). MS (ESI, m / z): 232.1 [M+H] + .

[0445] Step 11: Synthesis of (R)-N-methyl-6-(trifluoromethyl)isochroman-4-amine (Compound Int H-Peak 1) and (S)-N-methyl-6-(trifluoromethyl)isochroman-4-amine (Compound Int H-Peak 2)

[0446] Int H was separated by SFC (chromatographic column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: phase A: n-hexane, phase B: ethanol (0.1% isopropylamine), elution gradient: A%:B%=100%:0%, isocratic elution mode) to give (R)-N-methyl-6-(trifluoromethyl)isochroman-4-amine (compound Int H-peak 1) (retention time 1.889 min, 93.8% ee) and (S)-N-methyl-6-(trifluoromethyl)isochroman-4-amine (compound Int H-peak 2) (retention time 2.226 min, 98.9% ee).

[0447] Compound Int H-Peak 1: 1 H NMR(400MHz,CD3OD)δ7.48-7.58(m,2H),7.40(s,1H),4.90(s,1H),4.70-4.78(m,1H), 4.17(dd,J=12.0,2.4Hz,1H), 3.82(dd,J=12.0,2.8Hz,1H), 3.61(s,1H), 2.43(s,3H).

[0448] Compound Int H-Peak 2: 1 H NMR(400MHz,CD3OD)δ7.48-7.58(m,2H),7.40(s,1H),4.90(s,1H),4.70-4.77(m,1H), 4.17(dd,J=12.0,2.4Hz,1H), 3.82(dd,J=12.0,2.8Hz,1H), 3.61(s,1H), 2.43(s,3H).

[0449] Intermediate Int I: 7-chloro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Int I)

[0450]

[0451] Step 1: Synthesis of N-(4-bromo-5-chloro-2-fluorophenyl)-1H-imidazole-5-carboxamide (Compound Int I-2)

[0452] Int A-1 (2.50 g, 22.28 mmol) was dissolved in anhydrous DMF (50 mL) under an ice-water bath, and DIPEA (8.64 g, 66.83 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (16.94 g, 44.55 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of Int I-1 (5.0 g, 22.28 mmol) was added dropwise. The temperature was naturally raised to 80 °C and reacted for 16 h. 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 = 24:76) to obtain compound Int I-2 (3.94 g). MS (ESI, m / z): 317.9 [M+H] + .

[0453] Step 2: Synthesis of 8-bromo-7-chloroimidazo[1,5-a]quinoxaline-4(5H)-one (Compound Int I-3)

[0454] Int I-2 (3.94 g, 12.37 mmol) was dissolved in anhydrous DMAc (40 mL), sodium hydride (742.16 mg, 18.55 mmol) was added in batches under ice bath, stirred for 10 min and reacted at 140°C for 48 hr. After the reaction was completed, it was cooled to room temperature, stirred with water, extracted with ethyl acetate and concentrated to obtain compound Int I-3 (2.59 g). MS (ESI, m / z): 298.0 [M+H] + .

[0455] Step 3: Synthesis of 8-bromo-7-chloro-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]quinoxaline-4-amine (Compound Int I-4)

[0456] In anhydrous DMF (20 mL) was added with Int I-3 (2.59 g, 8.68 mmol) and PyBOP (9.03 g, 17.35 mmol) under ice bath, and DIPEA (3.36 g, 26.03 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (4.35 g, 26.03 mmol) was added and reacted at 60 °C for 16 hr. 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 reverse phase HPLC column chromatography (mobile phase H2O:ACN=20:80) to obtain compound Int I-4 (1.00 g). MS (ESI, m / z): 447.1 [M+H] + .

[0457] Step 4: Synthesis of methyl 7-chloro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (Compound Int I-5)

[0458] Int I-4 (1.00 g, 2.23 mmol), TEA (678.05 mg, 6.70 mmol), Pd(dppf)2Cl2 (163.43 mg, 223.36 μmol) were added to the autoclave, and dissolved with methanol (30 mL). After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature and directly concentrated to obtain compound Int I-5 (950 mg). MS (ESI, m / z): 427.2 [M+H] + .

[0459] Step 5: Synthesis of 7-chloro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int I)

[0460] Int I-5 (950 mg, 2.23 mmol) was dissolved in methanol (30 mL) under ice bath, and an aqueous solution (4 mL) of sodium hydroxide (267.07 mg, 6.68 mmol) was added dropwise, and the mixture was reacted at 55°C for 3 hours. After the reaction was completed, dilute hydrochloric acid was added dropwise under ice bath until the solution was acidic, and the solution was concentrated to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H2O:ACN=44:56) to obtain compound IntI (200 mg). MS (ESI, m / z): 413.0 [M+H] + .

[0461] Intermediate Int J: 7-Fluoro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Int J)

[0462]

[0463] Step 1: Synthesis of N-(4-bromo-2,5-difluorophenyl)-1H-imidazole-5-carboxamide (Compound Int J-2)

[0464] Int A-1 (2.69 g, 24.04) was dissolved in anhydrous DMF (150 mL) under ice-water bath, DIPEA (4.66 g, 36.06 mmol) was slowly added dropwise, HATU (10.97 g, 28.85 mmol) was added after stirring evenly, stirring was continued for 1 h, and finally Int J-1 (5 g, 24.04) was added, and the temperature was raised to 60 ° C for 48 hours. After the reaction was completed, 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 = 63: 37) to obtain compound Int J-2 (6.0 g). MS (ESI, m / z): 302.0 [M+H] + .

[0465] Step 2: Synthesis of 8-bromo-7-fluoroimidazo[1,5-a]quinoxaline-4(5H)-one (Compound Int J-3)

[0466] Int J-2 (6.0 g, 19.86 mmol) was dissolved in anhydrous DMAc (100 mL), sodium hydride (1.19 g, 29.79 mmol) was added in batches under ice bath, stirred for 10 min, and then heated to 140 ° C for 72 hours. After the reaction was completed, it was cooled to room temperature, stirred with water, extracted with ethyl acetate, and concentrated, and then separated and purified by reverse phase column chromatography (H2O [0.05% ammonium bicarbonate]: MeCN = 72:28) to obtain compound Int J-3 (0.5 g). MS (ESI, m / z): 282.0 [M+H] + .

[0467] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-7-fluoroimidazo[1,5-a]quinoxaline-4-amine (Compound Int J-4)

[0468] In anhydrous DMF (30 mL) was added with Int J-3 (380 mg, 1.35 mmol) and PyBOP (1.05 g, 2.02 mmol) under ice bath, and DIPEA (522.33 mg, 4.04 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (337.88 mg, 2.02 mmol) was added and reacted at 60 °C for 16 hr. 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 reverse phase column chromatography (mobile phase H2O:ACN=36:64) to obtain compound Int J-4 (0.50 g). MS (ESI, m / z): 431.1 [M+H] + .

[0469] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylate (Compound Int J-5)

[0470] Int J-4 (0.50 g, 1.16 mmol), TEA (351.96 mg, 3.48 mmol), Pd(dppf)2Cl2 (93.98 mg, 115.94 μmol) were added to the autoclave, and dissolved with methanol (20 mL). After carbon monoxide substitution, the pressure was increased to 1.2 MPa and the reaction was carried out at 120°C for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, and concentrated under reduced pressure to obtain compound Int J-5 (70 mg). MS (ESI, m / z): 411.1 [M+H] + .

[0471] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int J)

[0472] Int J-5 (400 mg, 974.66 μmol) was dissolved in ethanol (10 mL) and H2O (2 mL), sodium hydroxide (77.97 mg, 1.95 mmol) was added, and the temperature was raised to 90°C for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the compound Int J (320 mg) was obtained by purification by reverse phase column chromatography (mobile phase H2O [0.05% formic acid]: ACN = 65:35). MS (ESI, m / z): 397.1 [M+H] + .

[0473] Intermediate Int K: 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (Int K)

[0474]

[0475] Step 1: Synthesis of N-(4,6-dichloropyridin-3-yl)-1H-imidazole-5-carboxamide (Compound Int K-3)

[0476] Compound Int K-1 (8 g, 49.08 mmol) was dissolved in anhydrous THF (100 mL), cooled to -10 °C, and NaHDMS (2M, 49.08 mL, 98.16 mmol) was added. After the addition, it was stirred at -10 °C for 1 hour, and then a THF solution (100 mL) of Int K-2 (5.77 g, 24.54 mmol) was added. After the addition, the temperature was raised to 25 °C and the reaction was continued for 2 hours. After the reaction was completed, an appropriate amount of acetic acid was added to quench, and the reaction was concentrated under reduced pressure. Then, a saturated sodium bicarbonate aqueous solution was added, and the solid product was collected by filtration, washed with water and hexane, and dried to obtain compound Int K-3 (10 g). MS (ESI, m / z): 257.0 [M+H] + .

[0477] Step 2: Synthesis of 8-chloroimidazo[1,5-a]pyrido[3,4-e]pyrazin-4(5H)-one (Compound Int K-4)

[0478] Compound Int K-3 (10 g, 38.90 mmol) was dissolved in anhydrous DMF (100 mL), and DBU (17.77 g, 116.70 mmol) was added. After the addition, the temperature was raised to 160°C and the mixture was reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, added with water, dissolved with saturated aqueous ammonium chloride solution, filtered, washed with water, the filter cake was collected, dried, and concentrated to obtain compound Int K-4 (8 g). MS (ESI, m / z): 221.0 [M+H] + .

[0479] Step 3: Synthesis of 8-chloro-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-4-amine (Compound Int K-5)

[0480] Compound Int K-4 (5 g, 22.66 mmol), DIPEA (4.39 g, 34.00 mmol), Int A-6 (5.68 g, 34.00 mmol) were dissolved in anhydrous DMF (300 mL), and PyBOP (12.97 g, 24.93 mmol) was added in batches under stirring. After the addition, the temperature was raised to 60°C and the reaction was continued for 5 hours. After the reaction was completed, the mixture was diluted with water, extracted and concentrated with EA to obtain a crude product, which was purified by reverse phase column chromatography (mobile phase H2O (0.05% ammonium bicarbonate): ACN = 36:64) to obtain compound Int K-5 (4.5 g). MS (ESI, m / z): 370.1 [M+H] + .

[0481] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylate (Compound Int K-6)

[0482] Compound Int K-5 (4.50 g, 12.17 mmol), TEA (3.69 g, 36.51 mmol), Pd(dppf)Cl2·DCM (986.37 mg, 1.22 mmol) were added to the autoclave, and dissolved with methanol (20 mL). After carbon monoxide substitution, the pressure was increased to 1.2 MPa, and then the temperature was raised to 120°C for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, and concentrated under reduced pressure to obtain compound Int K-6 (4.7 g). MS (ESI, m / z): 394.1 [M+H] + .

[0483] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (Compound Int K-7)

[0484] Compound Int K-6 (4.7 g, 11.95 mmol) was dissolved in methanol (150 mL) and H2O (30 mL), and sodium hydroxide (955.78 mg, 23.89 mmol) was added. After the addition, the temperature was raised to 60°C and the mixture was reacted for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove methanol, and a small amount of water was added to dilute the mixture. 1N hydrochloric acid was used to adjust the pH to about 6. Solids were precipitated, filtered, washed with water, and the filter cake was dried to obtain compound Int K-7 (4.3 g). MS (ESI, m / z): 380.2 [M+H] + .

[0485] Step 6: Synthesis of 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (Compound Int K)

[0486] Compound Int K-7 (4.3 g, 3.78 mmol) was dissolved in TFA (80 mL), and the temperature was raised to 90°C for reaction for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain compound Int K (3.8 g). MS (ESI, m / z): 230.0 [M+H] + .

[0487] Intermediate Int L: 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid (Int L)

[0488]

[0489] Step 1: Synthesis of N-(2,6-dichloropyridin-3-yl)-1H-imidazole-5-carboxamide (Compound Int L-2)

[0490] Int L-1 (5.1 g, 31.29 mmol) was dissolved in anhydrous THF (100 mL), cooled to -10 °C, and NaHDMS (2.0 M, 31.29 mL, 62.57 mmol) was added. After the addition, it was stirred at -10 °C for 1 hour, and then a THF solution (50 mL) of Int K-2 (2.94 g, 15.64 mmol) was added. After the addition, the temperature was raised to 25 °C and the reaction was continued for 2 hours. After the reaction was completed, an appropriate amount of acetic acid was added to quench, and the reaction was concentrated under reduced pressure. Then, a saturated sodium bicarbonate aqueous solution was added, filtered, and the solid product was collected, washed with water and hexane, and dried to obtain compound Int L-2 (4.7 g). MS (ESI, m / z): 257.0 [M+H] + .

[0491] Step 2: Synthesis of 2-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one (Compound Int L-3)

[0492] Compound Int L-2 (14.7 g, 18.28 mmol) was dissolved in anhydrous DMAc (100 mL), and K2CO3 (7.58 g, 54.85 mmol) was added. The temperature was raised to 130°C and the mixture was reacted for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, added with water, dissolved with saturated aqueous ammonium chloride solution, filtered, washed with water, the filter cake was collected, dried, and concentrated to obtain compound Int L-3 (3.4 g). MS (ESI, m / z): 221.0 [M+H] + .

[0493] Step 3: Synthesis of 2-chloro-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]pyrido[3,2-e]pyrazine-6-amine (Compound Int L-4)

[0494] Compound Int L-3 (3.4 g, 15.41 mmol), DIPEA (2.99 g, 23.12 mmol), Int A-6 (3.87 g, 23.12 mmol) were dissolved in anhydrous DMF (200 mL), and PyBOP (9.62 g, 18.49 mmol) was added in batches under stirring. After the addition, the temperature was raised to 60°C and the reaction was continued for 16 hours. After the reaction was completed, the mixture was diluted with water, extracted and concentrated with EA to obtain a crude product, which was purified by reverse phase column chromatography (mobile phase H2O (0.05% ammonium bicarbonate): ACN = 36:64) to obtain compound Int L-4 (2.4 g). MS (ESI, m / z): 370.1 [M+H] + .

[0495] Step 4: Synthesis of methyl 6-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (Compound Int L-5)

[0496] Int L-4 (2.4 g, 6.49 mmol), Pd(dppf)Cl2·DCM (526.07 mg, 648.99 μmol), TEA (1.97 g, 19.47 mmol) were added to the autoclave, and dissolved with methanol (15 mL). After carbon monoxide substitution, the pressure was increased to 1.2 MPa, and then the temperature was raised to 120°C for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, and concentrated under reduced pressure to obtain compound Int L-5 (2.5 g). MS (ESI, m / z): 394.1 [M+H] + .

[0497] Step 5: Synthesis of 6-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid (Compound Int L-6)

[0498] Compound Int L-5 (2.5 g, 6.35 mmol) was dissolved in methanol (100 mL) and H2O (20 mL), and sodium hydroxide (508.39 mg, 12.71 mmol) was added. After the addition, the temperature was raised to 60°C and the reaction was continued for 2 hours. After the reaction was completed, the methanol was removed by concentration under reduced pressure, and a small amount of water was added to dilute it. 1N hydrochloric acid was used to adjust the pH to about 6. Solids precipitated, filtered, washed with water, and the filter cake was dried to obtain compound Int L-6 (2.4 g). MS (ESI, m / z): 380.2 [M+H] + .

[0499] Step 6: Synthesis of 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid (Compound Int L)

[0500] Int L-6 (0.1 g, 263.60 μmol) was dissolved in TFA (2 mL), and the temperature was raised to 90°C for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain compound Int L (90 mg). MS (ESI, m / z): 230.1 [M+H] + .

[0501] Intermediate Int M: 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxylic acid (Int M)

[0502]

[0503] Step 1: Synthesis of N-(5-bromo-3-chloropyridin-2-yl)-1H-imidazole-5-carboxamide (Compound Int M-3)

[0504] Int M-1 (1.75 g, 8.43 mmol) was dissolved in anhydrous THF (10 mL) under an ice-water bath, and NaH (674.16 mg, 16.85 mmol) was slowly added in batches. After stirring at room temperature for 30 min, Int M-2 (1.10 g, 8.43 mmol) was added and the temperature was naturally raised to room temperature for 8 hours. After the reaction was completed, a small amount of water was added to quench the reaction. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 90: 10) to obtain compound Int M-3 (1.00 g). MS (ESI, m / z): 300.9 [M+H] + .

[0505] Step 2: Synthesis of 8-bromoimidazo[1,5-a]pyrido[2,3-e]pyrazin-4(5H)-one (Compound Int M-4)

[0506] Int M-3 (1.00 g, 3.32 mmol) was dissolved in anhydrous DMF (10 mL), K2CO3 (1.38 g, 9.95 mmol) was added, and the mixture was reacted at 160°C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, stirred with water, and then extracted and concentrated with EA to obtain compound IntM-4 (380 mg). MS (ESI, m / z): 265.0 [M+H] + .

[0507] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]pyrido[2,3-e]pyrazine-4-amine (Compound Int M-5)

[0508] In anhydrous DMF (10 mL) was added with Int M-4 (380 mg, 1.43 mmol) and PyBOP (392.88 mg, 2.15 mmol) under ice bath, and DIPEA (555.84 mg, 4.30 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (479.41 mg, 2.87 mmol) was added and reacted at 80°C for 16 hr. After the reaction was completed, 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 = 95:5) to obtain compound Int M-5 (340 mg). MS (ESI, m / z): 414.0 [M+H] + .

[0509] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxylate (Compound Int M-6)

[0510] Int M-5 (340 mg, 822.8 μmol), TEA (249.15 mg, 2.46 mmol), Pd(dppf)2Cl2 (60.06 mg, 82.08 μmol) were added to the autoclave, and dissolved with methanol (30 mL). After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature and concentrated to obtain a crude product. The crude product was purified by reverse phase HPLC (mobile phase H2O:ACN=30:70) to obtain compound Int M-6 (250 mg). MS (ESI, m / .z): 394.2 [M+H] + .

[0511] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxylic acid (Compound Int M)

[0512] Int M-6 (200 mg, 510.00 μmol) was dissolved in methanol (10 mL) under ice bath, and an aqueous solution (2 mL) of sodium hydroxide (81.34 mg, 2.04 mmol) was added dropwise, and the mixture was reacted at 60°C for 3 hours. After the reaction, the methanol was dried by spin drying, and dilute hydrochloric acid was added dropwise to the remaining portion under ice bath until the solution was acidic, and the mixture was filtered by suction, and the filter cake was washed with water twice to obtain compound Int M (190.00 mg). MS (ESI, m / z): 380.2 [M+H] + .

[0513] Intermediate Int N: 4-amino-9-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (Int N)

[0514]

[0515] Step 1: Synthesis of N-(4-bromo-2,3-difluorophenyl)-1H-imidazole-5-carboxamide (Compound Int N-2)

[0516] Int N-1 (2 g, 9.62 mmol) was dissolved in anhydrous THF (10 mL) under ice-water bath, and NaH (1.54 g, 38.46 mmol) was slowly added in batches. After stirring at room temperature for 15 min, Int K-2 (2.89 g, 11.54 mmol) was added, and the temperature was raised to 60°C for 16 hours. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with EA to obtain compound Int N-2 (1.50 g). MS (ESI, m / z): 302.0 [M+H] + .

[0517] Step 2: Synthesis of 8-bromo-9-fluoroimidazo[1,5-a]quinoxaline-4(5H)-one (Compound Int N-3)

[0518] Dissolve Int N-2 (1.50 g, 4.97 mmol) in anhydrous DMF (10 mL), add K2CO3 (2.06 g, 14.90 mmol), and react at 160°C for 4 hours. After the reaction is completed, cool to room temperature, add water and stir to precipitate solids, and filter to obtain compound Int N-3 (1.00 g). MS (ESI, m / z): 282.0 [M+H] + .

[0519] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-9-fluoroimidazo[1,5-a]quinoxaline-4-amine (Compound Int N-4)

[0520] In anhydrous DMF (10 mL) was added with Int N-3 (400 mg, 1.42 mmol) and PyBOP (1.11 g, 2.13 mmol) under ice bath, and DIPEA (549.82 mg, 4.25 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (474.21 mg, 2.84 mmol) was added and reacted at 60°C for 16 hr. After the reaction was completed, 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 Int N-4 (294 mg). MS (ESI, m / z): 431.0 [M+H] + .

[0521] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)-9-fluoroimidazo[1,5-a]quinoxaline-8-carboxylate (Compound Int N-5)

[0522] Int N-4 (294 mg, 681.73 μmol), TEA (206.95 mg, 2.05 mmol), Pd(dppf)2Cl2 (55.26 mg, 68.17 μmol) were added to the autoclave, and dissolved with methanol (25 mL). After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 5 hours. After the reaction was completed, the temperature was lowered to room temperature and concentrated to obtain a crude product. The crude product was purified by reverse phase HPLC (mobile phase: H2O:ACN=30:70) to obtain compound Int N-5 (212 mg). MS (ESI, m / .z): 411.2 [M+H] + .

[0523] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-9-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int N-6)

[0524] Compound Int N-5 (212 mg, 516.57 μmol) was dissolved in methanol (10 mL) under ice bath, and an aqueous solution (2 mL) of sodium hydroxide (82.65 mg, 2.07 mmol) was added dropwise, and the mixture was reacted at 55°C for 3 hours. After the reaction, the methanol was dried by spin drying, and dilute hydrochloric acid was added dropwise to the remaining portion under ice bath until the solution was acidic, and the mixture was filtered by suction, and the filter cake was washed with water twice to obtain compound Int N-6 (200.00 mg). MS (ESI, m / z): 397.1 [M+H] + .

[0525] Step 6: Synthesis of 4-amino-9-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int N)

[0526] Int N-6 (200 mg, 504.58 μmol) was added to TFA (10 mL) under ice bath and reacted at 80°C for 2 hours. After the reaction, TFA was dried to obtain compound Int N (120 mg). MS (ESI, m / z): 247.2 [M+H] + .

[0527] Example 1: (R)-5-amino-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-c]quinazoline-9-carboxamide

[0528]

[0529] Step 1: Synthesis of (R)-5-(bis(4-methoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-c]quinazoline-9-carboxamide (Compound 1-1)

[0530] Int B (30 mg, 51.23 μmol), Int C (15 mg, 51.23 μmol), HATU (24 mg, 61.47 μmol) and DMF (2 mL) were added to the reaction flask, and DIPEA (10 mg, 76.84 μmol) was added after stirring and dissolving. The mixture was protected by nitrogen and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was 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 silica gel plate scraping (developing solvent DCM: MeOH = 10: 1) to obtain compound 1-1 (13 mg).

[0531] Step 2: Synthesis of (R)-5-amino-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-c]quinazoline-9-carboxamide (Compound 1)

[0532] Compound 1-1 (13 mg, 17.74 μmol) and TFA (3 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 90°C for 5 hours. After the reaction was completed, the reaction solution was dried, diluted with a 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 1. MS (ESI, m / z): 493.2 [M+H] + .

[0533] 1H NMR (400MHz, DMSO-d6) δ8.86–8.78(m,3H),8.64(s,1H),8.22–8.08(m,2H),7.94–7.74(m,3H),7.58(d,J=8.0Hz, 2H), 7.46–7.37 (m, 2H), 5.52–5.35 (m, 1H), 4.92 (d, J = 17.2Hz, 1H), 4.57 (d, J = 16.8Hz, 1H), 1.62 (d, J = 7.2Hz, 3H).

[0534] Example 2: 5-amino-N-isobutyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-c]quinazoline-9-carboxamide

[0535]

[0536] Step 1: Synthesis of 5-(bis(4-methoxybenzyl)amino)-N-isobutyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-c]quinazoline-9-carboxamide (Compound 2-2)

[0537] Int B (30 mg, 51.23 μmol), 2-1 (12 mg, 51.23 μmol), HATU (24 mg, 61.47 μmol) and DMF (2 mL) were added to the reaction flask, and DIPEA (10 mg, 76.84 μmol) was added after stirring and dissolving. The mixture was protected by nitrogen and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was 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 silica gel column chromatography (mobile phase DCM: MeOH = 97: 3) to obtain compound 2-2 (20 mg). MS (ESI, m / z): 683.3 [M+H] + .

[0538] Step 2: Synthesis of 5-amino-N-isobutyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-c]quinazoline-9-carboxamide (Compound 2)

[0539] 2-2 (20 mg, 29.29 μmol) and TFA (3 mL) were added to the reaction flask, nitrogen was protected, and the reaction was carried out at 90°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 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 2. MS (ESI, m / z): 443.2 [M+H] + .

[0540] 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.62(d,J=8.4Hz,1H),8.19(d,J=25.2Hz,1H),8.03(d,J=25.2Hz,1H),7.85– 7.63(m,3H),7.49–7.24(m,3H),4.89–4.73(m,2H),3.27(d,J=7.2Hz,2H),2.08(br,1H),0.94(s,3H),0.70(s,3H).

[0541] Example 3: (R)-4-amino-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0542]

[0543] Step 1: Synthesis of (R)-4-((2,4-dimethoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazole[1,5-a]quinoxaline-8-carboxamide (Compound 3-1)

[0544] Int A (50 mg, 132.14 μmol) and Int C (31.08 mg, 110.12 μmol) were dissolved in anhydrous DMF (2 mL) under ice-water bath, HATU (62.81 mg, 165.18 μmol) was added after stirring, and DIPEA (42.70 mg, 330.36 μmol) was added dropwise, and the mixture was reacted at 25°C for 5 hours. After the reaction, 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 = 92: 8) to obtain compound 3-1 (43.00 mg). MS (ESI, m / z): 643.3 [M+H] + .

[0545] Step 2: Synthesis of (R)-4-amino-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 3)

[0546] Compound 3-1 (43 mg, 66.91 μmol) was dissolved in a mixed solvent of TFA (5 mL) and methanol (1 mL) and reacted at 100°C for 2 hours. After the reaction was completed, it was washed with saturated sodium bicarbonate solution until neutral, extracted and concentrated with ethyl acetate, and the crude product was purified by reverse phase HPLC to obtain compound 3 (4.0 mg). MS (ESI, m / z): 493.3 [M+H] + .

[0547] 1 H NMR(400MHz, DMSO-d6)δ9.16(s,1H),8.85(s,1H),8.79(d,J=4.9Hz,2H),8.39(s,1H),8.11(d,J=7.9Hz,1H),7.92(s,1H),7.63–7.5 3(m,2H),7.45(dt,J=9.7,6.6Hz,4H),5.45(t,J=12.3Hz,1H),4.93(d,J=17.0Hz,1H),4.57(d,J=16.8Hz,1H),1.64(d,J=6.5Hz,3H).

[0548] The following compounds were prepared by the method and general steps described in Reference Example 3. 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.

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558] Example 32: (S)-4-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0559]

[0560] Step 1: Synthesis of (S)-4-((2,4-dimethoxybenzyl)amino)-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 31-1)

[0561] Int A (45 mg, 118.93 μmol) and Int H-peak 2 compound (27.50 mg, 118.93 μmol) were dissolved in anhydrous DMF (2 mL) under ice-water bath, HATU (54.26 mg, 142.71 μmol) was added after stirring, and DIPEA (23.06 mg, 178.39 μmol) was added dropwise, and the mixture was reacted at 60°C for 5 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 = 97: 3) to obtain compound 31-1 (40.0 mg). MS (ESI, m / z): 592.2 [M+H] + .

[0562] Step 2: Synthesis of (S)-4-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 31)

[0563] Compound 31-1 (40 mg, 67.62 μmol) was dissolved in TFA (2 mL) and reacted at 80°C for 2 hours. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution until neutral, extracted with ethyl acetate and concentrated. The crude product was purified by reverse phase HPLC to obtain compound 31 (12.51 mg). MS (ESI, m / z): 442.0 [M+H] + .

[0564] 1 H NMR (400MHz, DMSO-d6) δ9.26–9.16(m,1H),8.41–8.34(m,1H),7.92(s,1H),7.72–7.42(m,7H),5.81–4.62(m,3H),4.22–4.07(m,2H),2.76(s,3H).

[0565] Example 33: (R)-4-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0566]

[0567] Step 1: Synthesis of (R)-4-((2,4-dimethoxybenzyl)amino)-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 32-1)

[0568] Int A (45 mg, 118.93 μmol) and Int H-peak 1 compound (27.50 mg, 118.93 μmol) were dissolved in anhydrous DMF (2 mL) under ice-water bath, HATU (54.26 mg, 142.71 μmol) was added after stirring, and DIPEA (23.06 mg, 178.39 μmol) was added dropwise, and the mixture was reacted at 60°C for 5 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 = 97: 3) to obtain compound 32-1 (30.0 mg). MS (ESI, m / z): 592.2 [M+H] + .

[0569] Step 2: Synthesis of (R)-4-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 32)

[0570] Compound 32-1 (25 mg, 41.77 μmol) was dissolved in TFA (2 mL) and reacted at 80°C for 2 hours. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate solution until neutral, extracted with ethyl acetate and concentrated. The crude product was purified by reverse phase HPLC to obtain compound 32 (7.71 mg). MS (ESI, m / z): 442.0 [M+H] + .

[0571] 1 H NMR (400MHz, DMSO) δ9.25–9.16(m,1H),8.41–8.34(m,1H),7.91(s,1H),7.71–7.39(m,7H),5.81–4.62(m,3H),4.22–4.07(m,2H),2.76(s,3H).

[0572] Example 34: (S)-4-amino-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0573]

[0574] Step 1: Synthesis of 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound 33-1)

[0575] Int J (1.5 g, 3.78 mmol) was dissolved in TFA (20 mL), and the temperature was raised to 90°C for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain compound 33-1 (1.35 g). MS (ESI, m / z): 247.0 [M+H] + .

[0576] Step 2: Synthesis of (S)-4-amino-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 33)

[0577] 33-1 (1.35 g, 3.75 mmol) and Int E (950.60 mg, 3.75 mmol) were dissolved in anhydrous NMP (20 mL), and DIPEA (2.42 g, 18.74 mmol) and HATU (1.71 g, 4.50 mmol) were added. The reaction system was reacted at 25°C for 2 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was separated and purified by silica gel column chromatography (DCM: MeOH = 93: 7), and then separated and purified by reverse phase column chromatography (mobile phase H2O (0.05% ammonium bicarbonate): ACN = 58: 42) to obtain compound 33 (1.2 g). MS (ESI, m / z): 446.0 [M+H] + .

[0578] 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.49–8.25(m,1H),8.00–7.88(m,1H), 7.74–7.17(m,6H),6.58–5.59(m,1H),4.93–4.62(m,2H),2.73–2.59(m,3H).

[0579] Example 35: (S)-4-amino-7-chloro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0580]

[0581] Step 1: Synthesis of (S)-7-chloro-4-((2,4-dimethoxybenzyl)amino)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 34-1)

[0582] Int E (25 mg, 96.89 μmol), Int I (40 mg, 96.89 μmol), HATU (44 mg, 116.27 μmol) and NMP (2 mL) were added to the reaction flask, and DIPEA (19 mg, 145.34 μmol) was added after stirring and dissolving. 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 = 97: 3) to obtain compound 34-1 (36 mg). MS (ESI, m / z): 612.2 [M+H] + .

[0583] Step 2: Synthesis of (S)-4-amino-7-chloro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 34)

[0584] DDQ (67 mg, 294.12 μmol) was added to a DCM (5 mL) solution of compound 34-1 (36 mg, 58.82 μmol), and the mixture was reacted at 25°C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then spin-dried, diluted with a saturated NaHCO3 solution, extracted with EA (30 ml x 3), and 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 34 (14 mg). MS (ESI, m / z): 462.0 [M+H] + .

[0585] 1 H NMR(400MHz,DMSO-d6)δ9.22–9.06(m,1H),8.60–8.29(m,1H),7.96–7.90(m,1H),7.70–7 .46(m,4H),7.38–7.23(m,2H),6.64–5.46(m,1H),4.93–4.58(m,2H),2.74–2.52(m,3H).

[0586] Example 36: (S)-4-amino-7-chloro-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0587]

[0588] Step 1: Synthesis of (S)-7-chloro-4-((2,4-dimethoxybenzyl)amino)-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 36-1)

[0589] Int H-peak 2 (22 mg, 96.89 μmol), Int I (40 mg, 96.89 μmol), HATU (44 mg, 116.27 μmol) and NMP (2 mL) were added to the reaction flask, and DIPEA (19 mg, 145.34 μmol) was added after stirring and dissolving. 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 = 97: 3) to obtain compound 36-1 (40 mg). MS (ESI, m / z): 626.2 [M+H] + .

[0590] Step 2: Synthesis of (S)-4-amino-7-chloro-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 36)

[0591] TFA (2 mL) and 36-1 (40 mg, 53.06 μmol) were added to the reaction flask, nitrogen protection was applied, and the reaction was carried out at 80°C for 2 hours. 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 36 (14 mg). MS (ESI, m / z): 476.1 [M+H] + .

[0592] 1 H NMR(400MHz,DMSO-d6)δ9.21–9.09(m,1H),8.62–8.27(m,1H),7.95–7.91(m,1H ),7.80–7.47(m,6H),5.89–4.59(m,3H),4.22–3.99(m,2H),2.82–2.58(m,3H).

[0593] Example 37: (S)-4-amino-N-methyl-7-(trifluoromethyl)-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0594]

[0595] Step 1: Synthesis of (S)-4-((2,4-dimethoxybenzyl)amino)-N-methyl-7-(trifluoromethyl)-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 38-1)

[0596] Int H-peak 2 (21 mg, 89.61 μmol), Int G (40 mg, 89.61 μmol), HATU (41 mg, 107.5 μmol) and NMP (2 mL) were added to the reaction flask, and DIPEA (17 mg, 132.34 μmol) was added after stirring and dissolving. The mixture was protected by nitrogen and reacted at 60 °C for 1 hour. 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) to obtain compound 38-1 (20 mg). MS (ESI, m / z): 660.2 [M+H] + .

[0597] Step 2: Synthesis of (S)-4-amino-N-methyl-7-(trifluoromethyl)-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 38)

[0598] TFA (2 mL) and 38-1 (35 mg, 53.06 μmol) were added to the reaction flask, nitrogen protection was applied, and the reaction was carried out at 80°C for 2 hours. 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 38 (16 mg). MS (ESI, m / z): 510.2 [M+H] + .

[0599] 1H NMR(400MHz,DMSO-d6)δ9.32–9.20(m,1H),8.63–8.36(m,1H),8.03–7.94(m,1H),7.8 1–7.30(m,6H),5.83(s,1H),4.99–4.59(m,2H),4.37–3.84(m,2H),2.80–2.52(m,3H).

[0600] Example 38: (S)-6-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxamide

[0601]

[0602] Int L (80 mg, 233.09 μmol) and Int E (50.62 mg, 199.58 μmol) were dissolved in anhydrous NMP (3 mL), and DIPEA (150.62 mg, 1.17 mmol) and HATU (106.29 mg, 279.71 μmol) were added. After the addition, the reaction system was reacted at 25 °C for 2 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was separated and purified by Prep-HPLC to obtain compound 48 (70 mg). MS (ESI, m / z): 429.2 [M+H] + .

[0603] 1 H NMR(400MHz,DMSO-d6)δ9.09–8.88(m,1H),8.06–7.59(m,6H),7.41–7.30(m,1H) ),7.29–7.19(m,1H),6.51–6.11(m,1H),4.95–4.66(m,2H),2.94–2.61(m,3H).

[0604] Example 39: (S)-4-amino-9-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 49)

[0605]

[0606] Int N (50 mg, 203.09 μmol), Int E (51.51 mg, 203.09 μmol), HATU (115.83 mg, 304.63 μmol) were added to NMP (8 mL), and finally DIPEA (78.74 mg, 609.27 μmol) was added dropwise, and the mixture was reacted at 60°C for 2 hours. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with EA to obtain a crude product, which was purified by reverse phase HPLC to obtain compound 49 (10 mg). MS (ESI, m / z): 446.2 [M+H] + .

[0607] 1 H NMR(400MHz,DMSO-d6)δ9.09–8.60(m,1H),8.14–7.87(m,1H),7.73–7.49(m,3H ),7.47–7.10(m,4H),6.57–5.57(m,1H),5.07–4.35(m,2H),2.76–2.54(m,3H).

[0608] Example 40: (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxamide (Compound 50)

[0609]

[0610] Step 1: Synthesis of (S)-4-((2,4-dimethoxybenzyl)amino)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxamide (Compound 50-1)

[0611] Int M (100 mg, 263.60 μmol), Int E (66.86 mg, 263.60 μmol), HATU (200.57 mg, 527.20 μmol), DIPEA (102.20 mg, 790.79 μmol) were added to NMP (10 mL) under ice bath and reacted at 60°C for 2 hours. After the reaction was completed, 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 = 95:5) to obtain compound 50-1 (60 mg). MS (ESI, m / z): 579.2 [M+H] + .

[0612] Step 2: Synthesis of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxamide (Compound 50)

[0613] 50-1 (60 mg, 103.71 μmol) and DDQ (47.08 mg, 207.42 μmol) were added to DCM (10 mL) and reacted at 25°C for 3 hours. After the reaction was completed, saturated sodium bicarbonate solution was added for washing, and EA was extracted and concentrated to obtain a crude product, which was purified by reverse phase HPLC to obtain compound 50 (10 mg). MS (ESI, m / z): 429.2 [M+H] + .

[0614] 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.82–8.65(m,1H),8.66–8.53(m,1H),8.11–7.79(m,3H ),7.75–7.60(m,1H),7.48–7.09(m,2H),6.59–6.15(m,1H),5.03–4.41(m,2H),2.72(s,3H).

[0615] Example 41: (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide

[0616]

[0617] Int K (3.5 g, 10.20 mmol) and Int E (2.59 g, 10.20 mmol) were dissolved in anhydrous NMP (100 mL), and DIEA (6.59 g, 50.99 mmol) and HATU (4.65 g, 12.24 mmol) were added. The reaction system was reacted at 25°C for 3 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was separated and purified by silica gel column chromatography (DCM: MeOH = 92: 8), and then separated and purified by reverse phase column chromatography (mobile phase H2O (0.05% ammonium bicarbonate): ACN = 58: 42) to obtain compound 47 (3.45 g). MS (ESI, m / z): 429.2 [M+H] + .

[0618] 1H NMR(400MHz,DMSO-d6)δ9.36–9.28(m,1H),8.72–8.63(m,1H),8.59–8.50(m,1H),8.02–7.96(m,1H ),7.81–7.56(m,3H),7.40–7.23(m,2H),6.49–6.00(m,1H),4.91–4.67(m,2H),2.80–2.66(m,3H).

[0619] Example 42: 4-amino-N-isobutyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0620]

[0621] Step 1: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-N-isobutyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 4-1)

[0622] Int A (50 mg, 132.14 μmol) was added to anhydrous THF (10 mL), and pyridine (41.81 mg, 528.57 μmol) and phosphorus oxychloride (30.39 mg, 198.21 μmol) were added dropwise in an ice bath. After stirring for 10 min, 2-1 (30.69 mg, 132.14 μmol) was added and the mixture was naturally heated to room temperature for 3 hours. After the reaction was completed, water was added to quench the reaction, and the crude product was extracted and concentrated with ethyl acetate to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95:5) to obtain compound 4-1 (10 mg). MS (ESI, m / z): 593.2 [M+H] + .

[0623] Step 2: Synthesis of 4-amino-N-isobutyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 4)

[0624] Compound 4-1 (10 mg, 16.87 μmol) was added to TFA (8 mL) and reacted at 60°C for 4 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. The crude product was purified by reverse phase HPLC to obtain compound 4 (3.99 mg). MS (ESI, m / z): 443.2 [M+H] + .

[0625] 1H NMR(400MHz,DMSO-d6)δ9.28–9.05(m,1H),8.98(s,1H),8.54–7.63(m,4H),7.53–7.27(m,4 H), 4.99–4.69 (m, 2H), 3.29 (d, J = 7.4Hz, 2H), 2.14–1.85 (m, 1H), 0.95 (s, 3H), 0.71 (s, 3H).

[0626] The following compounds were prepared by the method and general steps described in Reference Example 42. 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.

[0627]

[0628]

[0629] Example 44: (R)-4-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0630]

[0631] Step 1: Synthesis of (R)-4-((2,4-dimethylbenzyl)amino)-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 10-1)

[0632] Int D (60 mg, 137.61 μmol) was added to anhydrous THF (10 mL), and pyridine (65.31 mg, 825.67 μmol) and phosphorus oxychloride (63.30 mg, 412.84 μmol) were added dropwise in an ice bath. After stirring for 10 min, Int C (38.84 mg, 137.61 μmol) was added and reacted at 60 ° C for 3 hours. After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate and concentrated to obtain compound 10-1 (50 mg). MS (ESI, m / z): 657.2 [M+H] + .

[0633] Step 2: Synthesis of (R)-4-amino-3-methyl-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 10)

[0634] 10-1 (50 mg, 76.14 μmol) was added to TFA (12 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 ethyl acetate. The crude product was purified by reverse phase HPLC to obtain compound 10 (24.01 mg). MS (ESI, m / z): 507.2 [M+H] + .

[0635] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.86(s,1H),8.80(d,J=4.8Hz,2H),8.33(s,1H),8.12(d,J=7.6Hz,1H) ,7.71–7.15(m,4H),6.92(s,2H),5.61–5.26(m,1H),5.12–4.38(m,2H),2.65(s,3H),1.64(d,J=6.4Hz,3H).

[0636] Example 45: 4-amino-N-isobutyl-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0637]

[0638] Step 1: Synthesis of 4-((2,4-dimethylbenzyl)amino)-N-isobutyl-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 11-1)

[0639] Int D (7 mg, 17.84 μmol) and DIPEA (4.61 mg, 35.68 μmol) were added to anhydrous DMF (5 mL) under ice bath, HATU (10.17 mg, 26.76 μmol) was slowly added, and 2-1 (4.14 mg, 17.84 μmol) was added after stirring for 10 min, and the mixture was reacted at 25°C for 3 hr. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with ethyl acetate and concentrated to obtain compound 11-1 (6 mg). MS (ESI, m / z): 607.3 [M+H] + .

[0640] Step 2: Synthesis of 4-amino-N-isobutyl-3-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 11)

[0641] 11-1 (6 mg, 9.89 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 ethyl acetate. The crude product was purified by reverse phase HPLC to obtain compound 11 (1.62 mg). MS (ESI, m / z): 457.2 [M+H] + .

[0642] 1 H NMR (400MHz, DMSO-d6) δ9.24–8.86(m,2H),8.43–8.08(m,2H),7.93–7.22(m,3H),6.92(d,J=8.4Hz,2H ),5.39–4.18(m,2H),3.34(d,J=7.2Hz,3H),2.68(s,2H),2.22–1.84(m,1H),1.01(s,3H),0.76(s,3H).

[0643] Example 46: (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0644]

[0645] Step 1: Synthesis of (S)-4-((2,4-dimethylbenzyl)amino)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 13-1)

[0646] Int A (84 mg, 222.00 μmol) was added to anhydrous THF (10 mL), and pyridine (105.36 mg, 1.33 mmol) and phosphorus oxychloride (136.16 mg, 887.99 μmol) were added dropwise in an ice bath. After stirring for 10 min, the hydrochloride of Int E (56.31 mg, 222.00 μmol) was added and the temperature was naturally raised to room temperature for 16 hours. After the reaction was completed, water was added to quench the reaction, and the crude product was extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by silica gel column chromatography (mobile phase DCM: MeOH = 90: 10), compound 13-1 (36 mg). MS (ESI, m / z): 578.1 [M+H] + .

[0647] Step 2: Synthesis of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (Compound 13)

[0648] 13-1 (10 mg, 17.31 μmol) was dissolved in dichloromethane (10 mL), and DDQ (58.96 mg, 259.72 μmol) was added thereto under ice bath, and the temperature was naturally raised to 25°C for 24 hours. After the reaction was completed, the solution was spin-dried and purified by reverse phase HPLC to obtain compound 13 (1.20 mg). MS (ESI, m / z): 428.1 [M+H] + .

[0649] 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.34(s,1H),7.92(s,1H),7.64(d,J=7.6Hz,1H),7.57–7.4 0(m,4H),7.34(d,J=7.6Hz,1H),7.26(s,1H),6.50–6.28(m,1H),5.00–4.41(m,2H),2.68(s,3H).

[0650] The following compounds were prepared by the method and general steps described in Reference Example 46. 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.

[0651]

[0652]

[0653] Example 51: (S)-4-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide

[0654]

[0655] Step 1: Synthesis of (S)-4-((2,4-dimethoxybenzyl)amino)-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide (Compound 51-1)

[0656] Int H-peak 2 (30.50 mg, 131.92 μmol) and Int K-7 (50 mg, 101.43 μmol) were dissolved in anhydrous NMP (3 mL), and DIPEA (65.49 mg, 506.70 μmol) and HATU (66.43 mg, 121.61 μmol) were added. After the addition, the reaction system was reacted at 20°C for 2 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was separated and purified by silica gel column chromatography (DCM: MeOH = 93: 7) to obtain compound 51-1 (40 mg). MS (ESI, m / z): 593.3 [M+H] + .

[0657] Step 2: Synthesis of (S)-4-amino-N-methyl-N-(7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide (Compound 51)

[0658] 51-1 (40 mg, 67.50 μmol) was dissolved in TFA (3 mL), heated to 90°C for 2 hours, and concentrated under reduced pressure after the reaction was completed. The mixture was dissolved in EA, washed with saturated sodium bicarbonate aqueous solution, and the organic layer was dried and concentrated. The compound 51 (18 mg) was purified by reverse phase column chromatography (mobile phase H2O (0.05% formic acid): ACN = 60:40) to obtain compound 51. MS (ESI, m / z): 443.2 [M+H] + .

[0659] 1 HNMR(400MHz,DMSO-d6)δ9.34–9.28(m,1H),8.69–8.63(m,1H),8.61–8.52(m,1H),8.01–7.96(m,1 H),7.78–7.51(m,5H),5.85–5.34(m,1H),4.95–4.65(m,2H),4.17–4.07(m,2H),2.82–2.74(m,3H).

[0660] Separation methods

[0661] The Prep-HPLC purification of the compounds in the examples was performed using Aglient 1260 or Waters 2489 HPLC, and the separation column model was Waters SunFire Prep C 18 OBD(19mm×150mm×5.0μm), WatersXbridge Prep C 18 OBD (19mm×150mm×5.0μm) or YMC Actus Triart C18 (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.

[0662] Reference Example 1:

[0663]

[0664] The preparation process refers to WO2022169948A1.

[0665] Reference Example 2:

[0666]

[0667] The preparation process refers to WO2022169948A1.

[0668] Reference Example 3:

[0669]

[0670] The preparation process refers to WO2022169948A1.

[0671] Reference Example 4:

[0672]

[0673] The preparation process refers to WO2022169948A1.

[0674] Reference Example 5:

[0675]

[0676] The preparation process refers to WO2022169948A1.

[0677] Reference Example 6:

[0678]

[0679] The preparation process refers to WO2022169948A1.

[0680] Biological evaluation

[0681] Experimental Example 1: Test of the inhibitory effect of compounds on PRMT5-MTA methyltransferase activity

[0682] The prepared protein solution (PRMT5 / MEP50 (Reaction) and MTA (MCE) mixed solution) was pre-incubated with different concentrations of the test compound of the present invention (500nM starting, 5-fold dilution, 7 points; or 100nM starting, 5-fold dilution, 7 points) at 25°C for 30 minutes, and then the prepared substrate solution (biotinylated histoneH4 peptide (Biotinylated histoneH4 peptide, Sangon)) was added and incubated at 25°C for 90 minutes. After the reaction, the prepared detection reagent mixture (Protein A-Eu (Cisbio), anti-histone H4 antibody (Anti-Histone H4 antibody, Abcam) and Streptavidin-D2 (Cisbio)) was added, incubated at 25°C for 60 minutes, and the fluorescence signal ratio (Ratio) was detected using a BMG microplate reader.

[0683] 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:

[0684] Percent inhibition rate = (negative control Ratio - test compound Ratio) / (negative control Ratio - blank control Ratio) × 100%.

[0685] 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 50 Value. 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.

[0686] Table 1. Inhibitory activity of the compounds of the present invention on PRMT5-MTA

[0687] Compound No. <![CDATA[PRMT5-MTA(IC 50 ,nM)]]> 1 0.73 2 1.04 3 0.78 4 1.16

[0688] The experimental results show that the compounds of the present invention have a strong inhibitory effect on PRMT5-MTA enzyme.

[0689] Experimental Example 2: Compounds inhibit proliferation of MTAP-deleted / parental HCT116 cells

[0690] MTAP-deficient / parental HCT116 cells (purchased from HORIZON) were cultured in vitro in monolayers under the conditions of RPMI6140 medium (source culture) containing 10% FBS + 1% P / S, 37°C, 5% CO2. The cells in the logarithmic growth phase were digested and the concentration was adjusted. 250 cells per well were inoculated in a 96-well plate and cultured overnight. The pre-diluted test compound (5000nM starting, 4-fold dilution, 9 points) was added. The negative control group was added with DMSO, and the blank control group was added with culture medium. After culturing in an incubator at 37°C, 5% CO2 for 8 days, 50μl CellTiter-Glo (Promega) 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.

[0691] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0692] 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)) x 100%.

[0693] 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:

[0694] 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.

[0695] The proliferation inhibitory activity of the compounds on MTAP-deficient / parental HCT116 cells was determined according to the above method. The results are shown in Table 2.

[0696] Table 2. Proliferation inhibitory activity of the compounds of the present invention on MTAP-deficient / parental HCT116 cells

[0697]

[0698]

[0699]

[0700] The experimental results show that the compound of the present invention has a strong inhibitory effect on MTAP-deficient HCT116 cells and has a certain selectivity relative to MTAP parent HCT116 cells.

[0701] Experimental Example 3: Liver microsome stability test

[0702] Human liver microsomal solution was used to investigate the stability of the compounds of the present invention and the reference compounds in microsomes. The compounds of the present invention and the reference compounds were added to the liver microsomal solution and mixed by blowing, 50 μl was mixed with 25 μl PBS, and after pre-incubation (37°C) for 5 minutes, NADPH (25 μl) was added to make the final concentration of the test compound 1 μM, the final concentration of human liver microsomal protein 0.5 mg / ml, and the incubation time was 0 and 15 minutes. After the corresponding reaction time, 300 μl of ice acetonitrile containing the internal standard was added to terminate the reaction, vortexed, and temporarily stored at -80°C for testing. The LC-MS / MS method was used to detect the prototype of the test compound in the sample, and the prototype remaining rate after 15 minutes of incubation was calculated. The results of the liver microsomal stability test are shown in Table 3 below.

[0703] Table 3. The residual rate of the original form of the compounds of the present invention and the reference example compounds after incubation in human liver microsomes for 15 min

[0704] Compound No. 15-minute prototype remaining rate (%) 28 99.5 31 87.1 33 92.8 Reference Example 6 82.2 Reference Example 2 83.7 Reference Example 4 80.6

[0705] The experimental results show that the compound of the present invention is relatively stable in human liver microsomes.

[0706] Experimental Example 4: In vitro permeability test

[0707] In vitro permeability was tested using MDCK cells. Permeability experiments were performed in duplicate in a transwell system at a single concentration (2 μM) and incubated for 120 minutes. The apical to basolateral (A to B, A to B) transport and basolateral to apical (B to A, B to A) transport of the corresponding compounds were measured, and the permeation rate (apparent permeability) of the test compound was calculated (P app x 10 -6 The results of the in vitro permeability test are shown in Table 4 below.

[0708] Table 4. In vitro permeability data of the compounds of the present invention and reference examples

[0709]

[0710] Note: Permeability level: Low: Papp≤0.5(×10 -6 cm / s); Moderate: 0.5<Papp<2.5(×10 -6cm / s); High: Papp≥2.5(×10 -6 cm / s).

[0711] The test results show that the compounds of the present invention have good penetration into MDCK cells.

[0712] Experimental Example 5: Biochemical hERG inhibition assay

[0713] 1. Test system:

[0714] Kit: Predictor TM hERG Fluorescence Polarization Assay,(ThermoFisher),

[0715] The kit contains:

[0716] Positive control compound hERG potassium channel blocker E4031;

[0717] hERG cell membrane;

[0718] Affinity tracer Tracer;

[0719] hERG buffer.

[0720] 2. Test parameters:

[0721] hERG concentration: 1×

[0722] Tracer concentration: 1nM

[0723] Incubation time: 2h

[0724] BMG PHERAstar FS FP

[0725] 3. Test methods:

[0726] Carry out the test according to the instructions of the kit, the steps are as follows:

[0727] Test group: Different concentrations of the test compound were added to the microplate containing hERG cell membrane, and a tracer with high hERG affinity was added to each well. After the microplate was incubated at room temperature for 2 hours, the changes in fluorescence polarization (Excitation: 540nm; Emission: 590nm) values ​​were detected using a multifunctional microplate reader.

[0728] Positive control group: 30 μM positive control compound E4031 was used instead of the test compound, and the experimental method was the same as that of the test group.

[0729] Blank control group: hERG buffer was used instead of the test compound, and no hERG cell membrane was added. The experimental method was the same as that of the test group.

[0730] 4. Data processing:

[0731] According to the following formula, the percentage inhibition rate of hERG by the compounds of the present invention at different concentrations was calculated.

[0732] Percent inhibition rate = (1-(fluorescence polarization value of the test compound-fluorescence polarization value of the positive control group) / (fluorescence polarization value of the blank control group-fluorescence polarization value of the positive control group))*100%

[0733] When the percentage inhibition rate is between 30-80%, the half inhibitory concentration (IC) of the compound on hERG is estimated according to the following formula: 50 ) or range:

[0734] IC 50 =X×(1-percent inhibition rate (%)) / percent inhibition rate (%), wherein: X is the test concentration of the compound when the inhibition rate is between 30-80%.

[0735] 5. Experimental results:

[0736] The above method was used to determine the inhibition of hERG by the compounds. The results are shown in Table 5 below.

[0737] Table 5. hERG inhibition test results

[0738] Compound No. <![CDATA[IC 50 (μM)]]> 11 >10 22 >10 34 >10 13 3.77 31 >10 33 >10 47 >10 Reference Example 5 1.96 Reference Example 1 0.38 Reference Example 2 4.82 Reference Example 4 8.77

[0739] The test results show that the compounds of the present invention have no obvious hERG inhibitory activity.

[0740] Experimental Example 6: Pharmacokinetics of Compounds in Balb / c Mice

[0741] The compound of the present invention and the reference example compound were administered intravenously (1 mg / kg) and intragastrically (10 mg / kg). The IV solvent was 5% DMSO + 5% Solutol + 90% Saline, and the PO solvent was 10% Solutol + 90% H2O. Blood was collected from the eye sockets at 0 h before administration and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 h after administration (intravenous), and at 0 h before administration and 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 h after administration (oral administration), 40-50 μl, placed in a K2-EDTA anticoagulant tube, centrifuged at 4000 rpm for 10 min (4°C), and the plasma was separated and stored at -80°C for testing. 10 μl of plasma sample was added with 90 μl of acetonitrile containing internal standard, shaken and mixed, centrifuged at 4000 rpm, 4°C for 10 min, and the supernatant was taken for LC-MS / MS analysis. WinNonlin 6.3 software was used to calculate the pharmacokinetic parameters using the non-compartmental model. The results are shown in Table 6.

[0742] Table 6: Pharmacokinetic parameters of the compounds in mice

[0743]

[0744]

[0745] in conclusion:

[0746] The above experimental results show that the compound of the present invention has a low clearance rate in mice, a high blood drug concentration and a high in vivo exposure, and has a good oral absorption effect.

[0747] 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 IA or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof: in: Ring A is selected from C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings; R 1 are each independently selected from H; X 1 Selected from CR 9 and N, where R 9 Selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; X 2 Selected from CR 9 and N, where R 9 Selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; R 2 For LR 2 '; L is selected from a direct bond and -(CR 5 R 6 ) p -; R 2 'Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C 5-8 Bridged cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 aryl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C 5-8 bridged cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, optionally substituted with one or more halogen, -OH, -CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl substitution; R 3 , R 4 The atom to which it is attached forms a 3-8 membered heterocyclic group; Not with R 3 Ring R 4 Each occurrence is independently selected from -OH, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, C 2-6 Heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl, thienyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, the heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, cycloalkyloxy, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl are optionally substituted with one or more halogen, -CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution; R 5 and R 6 Each independently selected from H and C 1-4 alkyl; R 7 and R 8 Each independently selected from H and C 1-4 alkyl; m is 0, 1 or 2; n is 2 or 3; p is 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein ring A is selected from phenyl and pyridyl.

3. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 'Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, C 5-8 bridged cycloalkyl, 3-8 membered heterocyclic group, pyrimidinyl, pyridinyl, the alkyl, alkoxy, heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, C 5-8 The bridged cycloalkyl, heterocyclyl, pyrimidinyl, pyridinyl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 The group may be substituted with a haloalkoxy group or a 3-6 membered heterocyclic group.

4. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 'Independently selected from C 1-6 Alkyl, C 2-6 Heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, C 5-8 bridged cycloalkyl, pyrimidinyl, pyridinyl, the alkyl, heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, C 5-8 The bridged cycloalkyl, pyrimidinyl, pyridinyl groups are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy or 3-6 membered heterocyclic group.

5. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 2 ' is independently selected from methyl, pyrimidinyl, pyridinyl, isopropyl, cyclobutyl, cyclopentyl, and -CH2-O-CH3, wherein the methyl, pyrimidinyl, pyridyl, cyclobutyl and cyclopentyl are optionally substituted by methyl or F.

6. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which is not 3 Ring R 4 Each occurrence is independently selected from -NR 7 R 8 , C 1-4 Alkyl, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, C 2-6 heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, wherein the heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl is optionally substituted with one or more halogen, CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy or 3-6 membered heterocyclic group.

7. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which is not 3 Ring R 4 Each occurrence is independently selected from -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3.

8. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: Ring A is selected from phenyl and pyridyl; R 1 are each independently selected from H; R 2 For LR 2 '; L is selected from a direct bond or -(CR 5 R 6 ) p -; R 5 and R 6 Each independently selected from H and C 1-4 alkyl; R 2 'Independently selected from C 1-6 Alkyl, C 2-6 Heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C 5-8 bridged cycloalkyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, the alkyl, heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C 5-8 bridged cycloalkyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Heterocyclyl substitution; R 3 and R 4 The atoms connected to it together form a 3-8 membered heterocyclic group; 3 Ring R 4 is independently selected at each occurrence from -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, thienyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, said thienyl, furanyl, pyrrolyl, oxazolyl, imidazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 haloalkyl substitution; X 1 Selected from CR 9 and N, where R 9 Selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; X 2 Selected from CR 9 and N, where R 9 Selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; m is 0 or 1; n is 2; and p is 1.

9. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R 3 and R 4 The atoms to which it is attached together form a 5-6 membered heterocyclic group.

10. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 3 and R 4 The atoms to which it is connected together form a 5-membered oxygen-containing heterocyclic ring or a 6-membered oxygen-containing heterocyclic ring.

11. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R 3 and R 4 The atoms to which it is connected together form a 5-membered oxygen-containing heterocyclic ring.

12. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which satisfies one or more of the following: (1) Ring A is selected from phenyl; (2)X 1 Selected from CR 9 , where R 9 Selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; (3)X 2 Selected from CR 9 , where R 9 Selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; (4) Not with R 3 Ring R 4 is independently selected at each occurrence from -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3; (5) m is 0 or 1; (6)n is 2.

13. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 3 and R 4 The atoms to which it is attached together form the following group:

14. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: Formula IA is further Formula IA-1 or Formula IA-2: Here, q is 1 or 2.

15. A compound according to claim 1, 9, 10 or 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in, Ring A is selected from phenyl and pyridyl; R 1 Each independently is H; X 1 Selected from CR 9 and N, where R 9 Selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; X 2 Selected from CR 9 and N, where R 9 Selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; R 2 For LR 2 '; L is selected from a direct bond or -(CR 5 R 6 ) p -; R 2 'Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, heterocyclyl, cycloalkyloxy, aryl are optionally substituted with one or more halogen, -OH, -CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl substitution; Not with R 3 Ring R 4 Each occurrence is independently selected from -OH, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, C 2-6 Heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 The aryl group, the heteroalkyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, heterocyclyl group, cycloalkoxy group are optionally substituted with one or more halogen, -CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution; R 5 and R 6 Each independently selected from H and C 1-4 alkyl; R 7 and R 8 Each independently selected from H and C 1-4 alkyl; m is 0 or 1; n is 2 or 3; And p is 1.

16. The compound according to claim 15 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which satisfies one or more of the following: (1)X 1 Selected from CR 9 , where R 9 Selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; (2)X 2 Selected from CR 9 , where R 9 Selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; (3)R 2 'Independently selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, the alkyl, heteroalkyl is optionally replaced by C 1-4 Alkyl or halogen substitution; (4) Not with R 3 Ring R 4 Each occurrence is independently selected from -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3.

17. The compound according to claim 14 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound has a structure of Formula IA-1, in, Ring A is selected from phenyl and pyridyl; R 1 Each independently is H; X 1 Selected from CR 9 and N, where R 9 Selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; X 2 Selected from CR 9 and N, where R 9 Selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; R 2 For LR 2 '; L is selected from a direct bond or -(CR 5 R 6 ) p -; R 2 'Independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, heterocyclyl, cycloalkyloxy, aryl are optionally substituted with one or more halogen, -OH, -CN, -NR 7 R 8 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic group, C 6-10 Aryl substitution; R 4 Each occurrence is independently selected from -OH, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3, C 2-6 Heteroalkyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 The aryl group, the heteroalkyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, heterocyclyl group, cycloalkoxy group are optionally substituted with one or more halogen, -CN, -NR 5 R 6 , C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution; R 5 and R 6 Each independently selected from H and C 1-4 alkyl; R 7 and R 8 Each independently selected from H and C 1-4 alkyl; m is 0 or 1; q is 1 or 2; And p is 1.

18. The compound according to claim 17 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which satisfies one or more of the following: (1)X 1 Selected from CR 9 , where R 9 Selected from halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; (2)X 2 Selected from CR 9 , where R 9 Selected from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; (3)R 2 'Independently selected from C 1-4 Alkyl, C 2-6 Heteroalkyl, the alkyl, heteroalkyl is optionally replaced by C 1-4 Alkyl or halogen substitution; (4)R 4 Each occurrence is independently selected from -CHF2, -CH2F, -CH2CF3, -CH2Cl, -CH2CH2CF3.

19. The compound shown below or its pharmaceutically acceptable salt, stereoisomer, or tautomer:

20. A pharmaceutical composition comprising the compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers.

21. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, or a pharmaceutical composition according to claim 20 in the preparation of a medicament for preventing or treating a disease or condition associated with PRMT5 activity.

22. The use according to claim 21, wherein A disease or condition associated with PRMT5 activity is a cancer in which MTAP is deficient.

23. The use according to claim 21, wherein A disease or condition associated with PRMT5 activity is a tumor in which MTAP is deleted.

24. The use according to claim 22 or 23, wherein The cancer or tumor is selected from esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, melanoma, gastric cancer, colon cancer, leukemia and lymphoma.

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