Oxalic acid amide compound, pharmaceutical composition containing same, and preparation method and application thereof

Abstract

The invention discloses an oxalic acid amide compound, a pharmaceutical composition containing the same, and a preparation method and application of the oxalic acid amide compound. Specifically, the invention relates to a compound with a structure shown as a formula I. The compound shows excellent PRMT5 regulating activity and is used for preventing and / or treating diseases related to PRMT5 activity. # imgabs0 #

Description

Oxalic acid amide compound, pharmaceutical composition containing the same, preparation method and use thereof Technical Field

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

[0002] PRMT5 (Protein Arginine Methyltransferase 5) is an epigenetic enzyme and a member of the PRMT family (humans have PRMT1-11). It catalyzes the methylation of arginine residues on histones and certain non-histone substrates. PRMT5 is widely present in the nucleus and cytoplasm of human cells, including tissues such as the heart, muscle, and testes. PRMT5 is classified into types I, II, and III based on the mode of arginine methylation catalyzed by it. PRMT5 belongs to the type II symmetric dimethylating (sDMA) PRMT, whose methyl donor is S-adenosylmethionine (SAM).

[0003] PRMT5 regulates the expression of multiple target proteins by catalyzing the arginine methylation of substrates, participating in various physiological functions and playing an important role in tumor cell proliferation, metastasis, and malignant transformation. PRMT5 methylation of histones leads to the silencing of tumor suppressor genes such as p53, ST7, NM23, and Rb, thereby promoting the occurrence and development of tumors. PRMT5 regulation of non-histone proteins is mainly reflected in affecting the localization and expression of transcription factors (NF-κB / P65, E2F1, HoxA\GATA4), programmed cell death protein 4 (PDCD4), cell cycle and survival-related regulatory proteins E2F1, hypoxia-inducible factor 1 (HIF-1), cyclin-dependent kinases (CDKs), PI3K / Akt, etc. (Koh CM, Bezzi M, Guccione E. Curr Mol Bio Rep, 2015, 1(1):19-28). In lung cancer cells, PRMT5 can inhibit the transcription of the miR-99 family, increase FGFR3 expression, activate Erk1 / 2 and Ak pathways, leading to tumor cell growth and metastasis (Pengyu Jing, Nan Zhao, et al. Cancer Letters, 2018, 427, 38-48). In colon cancer, PRMT5 can methylate Eif4e and FGFR3, promoting tumor cell growth (ZHANG B, DONG S, ZHU R, et al. Oncotarget, 2015, 6(26): 22799-22811.).

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

[0005] PRMT5 has two cofactors: an activating cofactor (SAM) and an inhibitory cofactor (MTA; 5'-methylthioadenosine). In normal cells, MTAP is responsible for converting MTA to Met (methionine), while 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, partially inhibiting PRMT5 activity and making tumor cells more dependent on PRMT5. In these cases, inhibiting PRMT5 can further block the methylation function of PRMT5, causing tumor cell death.

[0006] In summary, inhibition of PRMT5 exhibits synthetic lethality in the absence of MTAP. Currently, no PRMT5 inhibitors are available. Therefore, the development of novel, highly effective, and low-toxic PRMT5 inhibitors is needed to meet clinical needs.

[0007] SUMMARY OF THE INVENTION

[0008] The present invention provides a novel oxalamide compound that can modulate PRMT5 activity and can be used to prevent or treat diseases or conditions associated with PRMT5 activity. The oxalamide compound provided by the present invention has a good inhibitory effect on MTAP-deficient tumor cells and has good pharmacokinetic properties.

[0009] One aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled form, polymorph, solvate, N-oxide, metabolite or prodrug thereof:

[0010] in:

[0011] Ring A is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group;

[0012] Ring B is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroaryl and C 6-10 Aryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group;

[0013] R 1 is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO2, -NR 10 R 11 、-CONR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted;

[0014] R 2 For LR 2 ';

[0015] L is independently a direct key or -(CR 5 R 6 ) p -;

[0016] R 2 ' is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Alkoxy, 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, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl and 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkenyl, alkynyl, 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 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted;

[0017] R 3 Selected from H, OH, halogen, CN, NR 10 R 11 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 heterocyclic substitution;

[0018] R 4 Each occurrence is independently selected from H, OH, oxo, halogen, CN, -NO2, -SF5, -NR 7 R 8 、-NHCOC 1-6 Alkyl, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0019] Or, R 3 and R 4 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclic group;

[0020] R 9 Each occurrence is independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, the alkyl, heteroalkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 heterocyclic substitution;

[0021] R 5 and R 6 Each independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by one or more halogen, OH, CN, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or

[0022] R 5 and R 6 The carbon atom connected to it forms C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, the cycloalkyl, heterocyclic group is optionally substituted by one or more OH, halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0023] R 7 、R 8 、R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or

[0024] R 7 and R 8 、R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, which is optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

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

[0026] n is 0, 1, 2, or 3;

[0027] p is 1 or 2.

[0028] 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.

[0029] Another aspect of the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug 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.

[0030] Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention for use in preventing or treating a disease or condition associated with PRMT5 activity.

[0031] Another aspect of the present invention provides a method for preventing or treating a disease or condition associated with PRMT5 activity, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0032] Another aspect of the present invention provides methods of preparing the compounds of the present invention.

[0033] Detailed Description of the Invention

[0034] definition

[0035] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0036] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps, even though the additional unrecited elements or method steps are not necessarily present (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of.").

[0037] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon group. 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 to 6 carbon atoms and 1 to 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 by 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).

[0038] As used herein, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds. 2-6 The term "alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one, two or three carbon-carbon double bonds (e.g., ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.), which is optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

[0039] As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds. 2-6The term "alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms and one, two or three carbon-carbon triple bonds (e.g., ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), which is optionally substituted with one or more (e.g., 1 to 3) substituents described herein.

[0040] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more backbone atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, in the backbone carbon atoms of the alkyl group. Numerical ranges (e.g., C 1-6 Assorted alkyl) refers to the number of carbons in the chain, which in this example includes 1-6 carbon atoms. 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 through heteroatoms or carbon atoms in the assorted alkyl chain.

[0041] 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 Halogenated alkyl, "C 1-6 Haloalkyl" and "C 1-4 The term "haloalkyl" refers to a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0042] 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, C 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.

[0043] As used herein, the term "alkoxy" refers to a group having an oxygen atom inserted into an alkyl group (as defined above) at any reasonable position, preferably a C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH2-OCH3, and the like, wherein the alkoxy groups are optionally substituted with one or more (such as 1 to 3) identical or different substituents. For example, the term "haloalkoxy" refers to an alkoxy group wherein the hydrogen atoms are substituted with one or more (such as 1 to 3) identical or different halogen atoms.

[0044] As used herein, the term "paracyclic" or "fused ring" refers to a ring system formed by two or more cyclic structures that share two adjacent atoms.

[0045] 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.

[0046] 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.

[0047] 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, annular (condensed) or bridged ring systems (i.e., spirocyclic alkyl, annular (condensed) alkyl and bridged cycloalkyl, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.). In the present invention, 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 Spiroalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Condensed cycloalkyl, C 5-6 Spiroalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl.

[0048] As used herein, the term "cycloalkoxy" refers to -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.

[0049] 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 The alkyl group is substituted with a substituent.

[0050] As used herein, the term "3-8 membered heterocyclyl" means a heterocyclyl containing 3-8 ring atoms, including but not limited to 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 4-7 membered nitrogen-containing heterocyclyl, 4-7 membered oxygen-containing heterocyclyl, 4-7 membered sulfur-containing heterocyclyl, 5-6 membered nitrogen-containing heterocyclyl, 5-6 membered oxygen-containing heterocyclyl, 5-6 membered sulfur-containing heterocyclyl, etc., wherein each of the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" optionally further contains one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 3-8 membered heterocyclyls include but are not limited to oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (such as ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl.

[0051] In the present invention, the heterocyclic group can form a parallel ring structure with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other groups can be on any heterocyclic group or cycloalkyl group. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic and heterocyclic groups, heterocyclic and cycloalkyl groups, monoheterocyclic and monoheterocyclic groups, and monoheterocyclic 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 and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0052] In the present invention, the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.

[0053] 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 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.

[0054] 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 a ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc., for example The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle" and "sulfur-containing spiroheterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.

[0055] Examples of the group obtained by condensing a heterocyclic group with an aryl group include, but are not limited to: wait.

[0056] As used herein, the term "aryl", "phenyl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π electron system. 6-15 "Aryl (aromatic ring)" means an aromatic group (aromatic ring) containing 6 to 15 carbon atoms, preferably C 6-10 Aryl (aromatic ring), preferably phenyl (phenyl ring) or naphthyl (naphthalene ring). Aryl is optionally substituted with one or more (such as 1 to 3) identical or different substituents (such as halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0057] In the present invention, an aryl group (e.g., a monoaryl group) can share two adjacent atoms with a heteroaryl group (e.g., a monoheteroaryl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group) or another aryl group (e.g., another monoaryl group) to form a parallel ring structure, and the connection point can be on any aromatic ring or on other rings, including but not limited to (mono)aryl and (mono)heteroaryl, (mono)aryl and (monocyclic)aryl, (mono)aryl and (mono)heterocyclic group and (mono)aryl and (mono)cycloalkyl, such as phenyl and 5-6 membered (mono)heteroaryl, phenyl and 3-8 membered (mono)heterocyclic group or phenyl and C 3-8 (mono) cycloalkyl, phenyl and 5-6 membered (mono) heterocyclic group, phenyl and C 4-6 (Mono)cycloalkyl, examples of which are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, benzothiazole, quinolyl, isoquinolyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, wait.

[0058] 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 groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which can have 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ring atoms, for example 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom can be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl are optionally substituted with oxo groups (for example, to form C=O, S(=O) or S(=O)2).

[0059] As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" means a heteroaryl group (heteroaromatic ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including a 5-10 membered nitrogen-containing heteroaryl group, a 5-10 membered oxygen-containing heteroaryl group, a 5-10 membered sulfur-containing heteroaryl group, a 5-6 membered nitrogen-containing heteroaryl group, a 5-6 membered oxygen-containing heteroaryl group, a 5-6 membered sulfur-containing heteroaryl group, etc. The "nitrogen-containing heteroaryl group," "oxygen-containing heteroaryl group," and "sulfur-containing heteroaryl group" each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, thienyl, furyl, 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, such as benzothiazolyl.

[0060] 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 monocycloalkyl 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 other ring, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (monocyclic)aryl. , (mono)heteroaryl and (mono)heterocyclyl and (mono)heteroaryl and (mono)cycloalkyl, for example, 5-6 membered (mono)heteroaryl and 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroarylphenyl, 5-6 membered (mono)heteroaryl and 3-8 membered (mono)heterocyclyl, 5-6 membered (mono)heteroaryl and 5-6 membered (mono)heterocyclyl, 5-6 membered (mono)heteroaryl and 3-8 membered (mono)cycloalkyl or 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, benzothiazole, quinolinyl, isoquinolinyl, pyrrolopyridinyl, wait.

[0061] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0062] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0063] 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 collectively, 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.

[0064] 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.

[0065] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0066] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0067] 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.

[0068] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent 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)); carbon isotopes (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 (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0069] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound 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 separate diastereomer. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). 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:

[0070] It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0071] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. 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 indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including 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 present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0072] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0073] A cocrystal refers to a drug active molecule and other physiologically acceptable acid, base, salt, or non-ionic compound molecules bound in the same crystal lattice by hydrogen bonds, π-π stacking, van der Waals forces, and other non-covalent bonds.

[0074] It should also be understood that certain compounds of the present invention may be used therapeutically in free form 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 that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0075] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0076] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate salts and meglumine salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0077] As used herein, the term "ester" refers to esters 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 the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0078] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0079] Those skilled in the art will appreciate that, because 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 dimethyldioxirane. 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 ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0080] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the 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 invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0081] 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 themselves have little or no pharmacological activity 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 readily 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", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). 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-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0082] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0083] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0084] Compound

[0085] In some embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled form, polymorph, solvate, N-oxide, metabolite, or prodrug thereof:

[0086] in:

[0087] Ring A is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group;

[0088] Ring B is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroaryl and C 6-10 Aryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group;

[0089] R 1 Each occurrence is independently selected from H, OH, oxo, halogen, CN, -NO2, NR 10 R 11 、-CONR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted;

[0090] R 2 For LR 2 ';

[0091] L is independently a direct key or -(CR 5 R 6 ) p -;

[0092] R 2 ' is independently selected from C 1-6 Alkyl, -C 2-6 Alkenyl, -C2-6 Alkynyl, 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, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl and 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkenyl, alkynyl, 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 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted;

[0093] R 3 Selected from H, OH, halogen, CN, NR 10 R 11 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 heterocyclic substitution;

[0094] R 4 Each occurrence is independently selected from H, OH, oxo, halogen, CN, -NO2, -SF5, -NR 7 R 8 、-NHCOC 1-6 Alkyl, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0095] Or, R 3 and R 4 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclic group;

[0096] R 9 Each occurrence is independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, the alkyl, heteroalkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 heterocyclic substitution;

[0097] R 5 and R 6 Each independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by one or more halogen, OH, CN, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8substituted by cycloalkoxy or 3-6 membered heterocyclic group; or

[0098] R 5 and R 6 The carbon atom connected to it forms C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, the cycloalkyl, heterocyclic group is optionally substituted by one or more OH, halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0099] R 7 、R 8 、R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or

[0100] R 7 and R 8 、R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, which is optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

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

[0102] n is 0, 1, 2, or 3;

[0103] p is 1 or 2.

[0104] In some embodiments, R 4 is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO2, -NR 7 R 8 、-NHCOC 1-6 Alkyl, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group.

[0105] In certain embodiments, the present invention provides compounds of Formula I wherein:

[0106] Ring A is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group;

[0107] Ring B is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group;

[0108] R 1 Each occurrence is independently selected from H, OH, oxo, halogen, CN, -NO2, NR 10R 11 、-CONR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted;

[0109] R 2 For LR 2 ';

[0110] L is independently a direct key or -(CR 5 R 6 ) p -;

[0111] R 2 ' is independently selected from C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 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 6-10Aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted;

[0112] R 3 Selected from H, OH, halogen, CN, NR 10 R 11 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 heterocyclic substitution;

[0113] R 4 is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO2, -NR 7 R 8 、-NHCOC 1-6 Alkyl, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10Aryl, 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0114] R 9 Each occurrence is independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, the alkyl, heteroalkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 heterocyclic substitution;

[0115] R 5 and R 6 Each independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by one or more halogen, OH, CN, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or

[0116] R 5 and R 6 The carbon atom connected to it forms C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, the cycloalkyl, heterocyclic group is optionally substituted by one or more OH, halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0117] R 7 、R 8 、R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or

[0118] R 7 and R 8 、R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, which is optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0119] m is 0, 1, 2, or 3;

[0120] n is 0, 1, 2, or 3;

[0121] p is 1 or 2.

[0122] In certain embodiments, the present invention provides compounds of formula I wherein:

[0123] Ring A is selected from C 6-15Aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, and 3-8 membered heterocyclyl;

[0124] Ring B is selected from a 5-10 membered nitrogen-containing heteroaromatic ring, a 6-membered heteroarylheterocyclyl, a 5-membered heteroarylphenyl, a 5-membered heterocyclylphenyl and a 6-membered heterocyclylphenyl;

[0125] R 1 Each occurrence is independently selected from H, OH, halogen, -NR 10 R 11 、-CONR 10 R 11 、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl; the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C3-6 heterocyclic group substituted; R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group;

[0126] R 2 For LR 2 ';

[0127] L is selected from a direct bond, -CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH(cyclopropyl)-, cyclopropylene, cyclobutylene, and cyclopentylene;

[0128] R 2 ' is independently selected from C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C3-6 heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted;

[0129] R 3 Selected from H, OH, halogen, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl and C 3-6 Cycloalkyl;

[0130] R 4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8cycloalkoxy and 3-6 membered heterocyclic substitution;

[0131] Or, R 3 and R 4 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclic group;

[0132] R 9 Each occurrence is independently selected from H, C 1-4 Alkyl and C 3-8 Cycloalkyl;

[0133] m is 0, 1, 2, or 3;

[0134] n is 0, 1, 2, or 3;

[0135] p is 1 or 2.

[0136] In certain embodiments, the present invention provides compounds of formula I wherein:

[0137] R 9 is H;

[0138] Ring A is selected from C 6-10 aromatic rings and 5-10 membered heteroaromatic rings;

[0139] Ring B is selected from C 6-10 aromatic rings and 5-10 membered heteroaromatic rings;

[0140] R 1 Each occurrence is independently selected from H, halogen, CN, -NH2, -CONH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkoxy;

[0141] R 2 For LR 2 ';

[0142] L is independently a direct key or -(CR 5 R 6 ) p -;

[0143] R 2 ' is independently 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, C3-8 Cycloalkoxy, C 6-10 Aryl, 5-10 membered heteroaryl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C3-6 heterocyclic group, C 6-10 Aryl, C 5-10 heteroaryl substitution;

[0144] R 3 Selected from H and C 1-4 alkyl;

[0145] R 4 Each occurrence is independently selected from H, OH, halogen, CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution;

[0146] R 5 and R 6 Each independently selected from H, C 1-4 Alkyl and C 3-8 Cycloalkyl;

[0147] R 7 and R 8 Each independently selected from H and C 1-4 Alkyl and C 3-8 Cycloalkyl;

[0148] m is 0, 1, 2, or 3;

[0149] n is 0, 1, 2, or 3;

[0150] p is 1 or 2.

[0151] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 Each occurrence is independently selected from H, halogen, -NH2, -CONH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl.

[0152] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 Each occurrence is independently selected from H, -NH2, -CONH2, C 1-4 Alkyl, C 1-4 Alkoxy.

[0153] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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.

[0154] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered 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 The cycloalkyl group or the 3-6 membered heterocyclic group may be substituted.

[0155] In certain embodiments, the present invention provides compounds of formula I, wherein R3 Selected from H and C 1-4 alkyl.

[0156] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 is independently selected at each occurrence from H, halogen, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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 by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group.

[0157] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 is independently selected at each occurrence from H, halogen, -NR 7 R 8 、C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, 5-10 membered heteroaryl, the heteroaryl being optionally substituted with one or more halogen, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Haloalkyl substitution.

[0158] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 and R 6 Each independently selected from H, C 1-4 Cycloalkyl and C 1-4 alkyl.

[0159] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 and R 6 Each is independently selected from H, methyl, ethyl and cyclopropyl.

[0160] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 and R 6Each independently selected from H and C 1-4 alkyl.

[0161] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 and R 6 Each is independently selected from H, methyl and ethyl. In certain embodiments, the present invention provides compounds of formula I, R 7 and R 8 Each independently selected from H and C 1-4 alkyl.

[0162] In certain embodiments, the present invention provides compounds of formula I, wherein m is 0, 1 or 2.

[0163] In certain embodiments, the present invention provides compounds of formula I wherein n is 0, 1 or 2.

[0164] In certain embodiments, the present invention provides compounds of formula I wherein p is 1.

[0165] In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from C 6-15 aromatic rings and 5-15 membered heteroaromatic rings.

[0166] In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from C 6-10 aromatic rings and 5-10 membered heteroaromatic rings.

[0167] In certain embodiments, in the compound of formula I provided by the present invention, Ring A is selected from a 5-10 membered nitrogen-containing heteroaromatic ring.

[0168] In certain embodiments, the present invention provides compounds of formula I, wherein ring A is selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, Preferably, ring A is selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,

[0169] In certain embodiments, the present invention provides compounds of formula I, wherein ring A is selected from pyridyl, Preferably, ring A is selected from pyridyl,

[0170] In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from Preferably, ring A is selected from

[0171] In certain embodiments, the present invention provides compounds of formula I, Selected from Preferably, Selected from

[0172] In certain embodiments, the present invention provides compounds of formula I, Selected from

[0173] In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from C 6-15 aromatic ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroarylphenyl and benzo 3-8 membered heterocyclic group.

[0174] In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from C 6-15 aromatic rings, 5-15 membered heteroaromatic rings and 3-8 membered heterocyclylphenyl groups.

[0175] In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, a 5-6 membered heteroarylphenyl ring and a 5-6 membered heterocyclylphenyl ring.

[0176] In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from C 6-10 aromatic rings, 5-10 membered heteroaromatic rings, and 5-6 membered heterocyclic phenyl groups.

[0177] In certain embodiments, the present invention provides compounds of formula I, wherein ring B is selected from a 5-10 membered nitrogen-containing heteroaromatic ring, a 6-membered heteroarylheterocyclyl, a 5-membered heteroarylphenyl, a 5-membered heterocyclylphenyl and a 6-membered heterocyclylphenyl.

[0178] In certain embodiments, the present invention provides compounds of formula I, wherein ring B is selected from a 5-10 membered nitrogen-containing heteroaromatic ring and a 6-membered heterocyclylphenyl group.

[0179] In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a benzene ring, a naphthalene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, an indole ring, an isoindole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring, a quinoline ring, an isoquinoline ring, Benzopiperidine ring, benzotetrahydrofuran ring and pyridopyran ring.

[0180] In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a benzene ring, a naphthalene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, an indole ring, an isoindole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring, a quinoline ring, an isoquinoline ring,

[0181] In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a benzene ring, a pyridine ring, a pyridazine ring, an indole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring, a benzopiperidine ring, benzotetrahydrofuran ring and pyridopyran ring.

[0182] In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a benzene ring, a pyridine ring, an indole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring,

[0183] In certain embodiments, the present invention provides compounds of formula I, wherein ring B is selected from benzene ring,

[0184] In certain embodiments, the present invention provides compounds of formula I, wherein ring B is selected from benzene ring,

[0185] In certain embodiments, the present invention provides compounds of formula I, Selected from

[0186] In certain embodiments, the present invention provides compounds of formula I, Selected from

[0187] In certain embodiments, the present invention provides compounds of formula I, Selected from

[0188] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 Each occurrence is independently selected from H, OH, halogen, NR 10 R 11 、-CONR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclyl; the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy are optionally substituted with one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C3-6 heterocyclic group substituted; R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0189] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 Each occurrence is independently selected from H, OH, halogen, NR 10 R 11 、-CONR 10 R 11 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl; the alkyl, alkoxy, heteroalkyl, cycloalkyl is optionally substituted by one or more halogen, OH, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy substituted; R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0190] In certain embodiments, the present invention provides compounds of formula I, wherein R 1Each occurrence is independently selected from H, OH, halogen, NR 10 R 11 、-CONR 10 R 11 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl; R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0191] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 Each occurrence is independently selected from H, halogen, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2, azetidinyl, pyrrolidinyl, piperidinyl, -NH2, -CONH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl.

[0192] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 Each occurrence is independently selected from H, -NH2, -CONH2, C 1-4 Alkyl, C 1-4 Alkoxy.

[0193] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 is independently selected at each occurrence from H, -CH3, -NH2, -OCH3 and -CONH2.

[0194] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 Each occurrence is independently selected from H, -CH3, -NH2, -OCH3.

[0195] In certain embodiments, the present invention provides compounds of formula I, wherein L is selected from a direct bond, -CH(C 1-6 Alkyl)-, C 3-6 Cycloalkyl.

[0196] In certain embodiments, the present invention provides compounds of formula I, wherein L is selected from a direct bond, -CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH(cyclopropyl)-, cyclopropylene, cyclobutylene, and cyclopentylene.

[0197] In certain embodiments, in the compound of formula I provided by the present invention, L is selected from a direct bond, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, cyclobutyl, and cyclopentyl.

[0198] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C3-6 heterocyclic group, C 6-10 aryl, or 5-10 membered heteroaryl.

[0199] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, OH, CN, -NR7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C3-6 heterocyclic group, C 6-10 aryl, or 5-10 membered heteroaryl.

[0200] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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.

[0201] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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.

[0202] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group or the 3-6 membered heterocyclic group may be substituted.

[0203] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group or the 3-6 membered heterocyclic group may be substituted.

[0204] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected at each occurrence from methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrimidinyl, -CH2OCH3, morpholinyl, pyranyl, pyrazolyl, pyridinyl, pyrrolopyridinyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyranyl, pyrazolyl, pyridyl, Optionally, one or more halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl substitution.

[0205] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected at each occurrence from methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, pyrimidinyl, -CH2OCH3, morpholinyl, pyrazolyl, pyridinyl, The methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, pyrimidinyl, morpholinyl, pyrazolyl, pyridyl, Optionally, one or more halogens, C 1-4 Alkyl, C1-4 Alkoxy substitution.

[0206] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected at each occurrence from methyl, trifluoromethyl, isopropyl, isobutyl, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclohexyl, cyclopentyl, dimethylcyclopentyl, -CH2OCH3,

[0207] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 ' is independently selected at each occurrence from methyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, -CH2OCH3,

[0208] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 is independently selected at each occurrence from methyl, isopropyl, trifluoroethyl, isobutyl,

[0209] In certain embodiments, the present invention provides compounds of formula I, wherein R 2 Each occurrence is independently selected from

[0210] In certain embodiments, the present invention provides compounds of formula I, wherein R 3 Selected from H, OH, halogen, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl and C 3-6 Cycloalkyl.

[0211] In certain embodiments, the present invention provides compounds of formula I, wherein R 3 Selected from H and C 1-4 alkyl.

[0212] In certain embodiments, the present invention provides compounds of formula I, wherein R 3 Selected from H and methyl.

[0213] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, -NR 7 R 8 、-NHCOCH3、C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 cycloalkoxy and 3-6 membered heterocyclic groups.

[0214] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 Each occurrence is independently selected from H, OH, halogen, CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group.

[0215] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, the alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 cycloalkoxy and 3-6 membered heterocyclic groups.

[0216] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 Each occurrence is independently selected from H, OH, halogen, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, 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, heteroaryl are optionally substituted with one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group.

[0217] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 is independently selected at each occurrence from H, oxo, CN, halogen, -NR 7 R 8 、C 1-4 Halogenated alkyl, 3-8 heterocyclic group, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, heteroaryl are optionally substituted with one or more halogen, -NR 5 R 6 、C 1-4 Alkyl and C 1-4 Haloalkyl substitution.

[0218] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 is independently selected at each occurrence from H, halogen, -NR 7 R 8 、C 1-4 Halogenated alkyl, C 1-4 Haloalkoxy, 5-10 membered heteroaryl, the heteroaryl being optionally substituted with one or more halogen, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Haloalkyl substitution.

[0219] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 Each occurrence is independently selected from H, oxo, CN, F, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2, azetidinyl, pyrrolidinyl, piperidinyl, CF3, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl and 5-6 membered heteroaryl, said alkoxy, heteroalkyl, heteroaryl are optionally substituted with one or more halogen, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Haloalkyl substitution.

[0220] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 Each occurrence is independently selected from H, F, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl) 2, azetidinyl, pyrrolidinyl, piperidinyl, CF3, 5-6 membered heteroaryl, the heteroaryl being optionally substituted with one or more halogen, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Haloalkyl substitution.

[0221] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 Each occurrence is independently selected from H, oxo, F, -N(CH3)2, CF3, CN, cyclopropyl, -SF5 and -OCF3.

[0222] In certain embodiments, the present invention provides compounds of formula I, wherein R 4Each occurrence is independently selected from H, F, -N(CH3)2, CF3,

[0223] In certain embodiments, the present invention provides compounds of formula I, wherein R 3 and R 4 Together with the atoms to which it is attached, it forms a 3-8 membered heterocyclic group, such as a 3-6 membered oxygen-containing heterocyclic group, such as a 5 membered oxygen-containing heterocyclic group and a 6 membered oxygen-containing heterocyclic group.

[0224] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 and R 6 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by one or more halogen, OH, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group substituted; or R 5 and R 6 The carbon atom connected to it forms C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, the cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 The cycloalkyl group or the 3-6 membered heterocyclic group may be substituted.

[0225] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 and R 6 Each independently selected from H, C 1-4 Alkyl; or R 5 and R 6 The carbon atom to which it is connected forms cyclopropyl, cyclobutyl, and cyclopentyl.

[0226] In certain embodiments, the present invention provides compounds of formula I, wherein R 7 and R 8 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, CN, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl, C1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or

[0227] R 7 and R 8 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group, which is optionally substituted by one or more halogen, CN, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group.

[0228] In certain embodiments, the present invention provides compounds of formula I, wherein R 7 and R 8 Each independently selected from H, C 1-6 Alkyl, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group.

[0229] In certain embodiments, the present invention provides compounds of formula I, wherein R 7 and R 8 Each independently selected from H and C 1-4 alkyl.

[0230] In certain embodiments, the present invention provides compounds of formula I, wherein R 9 Each occurrence is independently selected from H, C 1-6 Alkyl C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, CN, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Substituted with cycloalkyl or C3-6 heterocyclic group.

[0231] In certain embodiments, the present invention provides compounds of formula I, wherein R 9Each occurrence is independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl.

[0232] In certain embodiments, the present invention provides compounds of formula I, wherein R 9 For H.

[0233] In certain embodiments, the present invention provides compounds of formula I, wherein R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, CN, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or, R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, which is optionally substituted by one or more halogen, CN, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group.

[0234] In certain embodiments, the present invention provides compounds of formula I, wherein R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl.

[0235] In certain embodiments, the present invention provides compounds of formula I, wherein R 10 and R 11 Each independently selected from H, C 1-4 alkyl.

[0236] In certain embodiments, the present invention provides compounds of formula I, wherein m is 0, 1 or 2.

[0237] In certain embodiments, the present invention provides compounds of formula I, wherein m is 1 or 2, for example, m is 2.

[0238] In certain embodiments, the present invention provides compounds of formula I wherein n is 0, 1 or 2.

[0239] In certain embodiments, the present invention provides compounds of formula I, wherein n is 1 or 2, for example, n is 1.

[0240] In certain embodiments, the present invention provides compounds of formula I wherein p is 1.

[0241] In certain embodiments, the compound of formula I provided by the present invention is a compound of formula I-1:

[0242] in:

[0243] Ring A, Ring B, R 1 、R 2 、R 4 、R 9 , m, n are as defined above for the compound of formula I; and

[0244] q is 0 or 1.

[0245] In all of the above embodiments, the wavy line represents the point of attachment of the group to the rest of the molecule.

[0246] Those skilled in the art will appreciate that the present invention encompasses compounds obtained by any combination of the various embodiments. Embodiments obtained by combining the technical features or preferred technical features in one embodiment with the technical features or preferred technical features in another embodiment are also included within the scope of the present invention.

[0247] In some embodiments, compounds of the present invention include, but are not limited to:

[0248] Preparation method

[0249] The compounds of the present invention can be prepared by any method known in the art. Reagents and starting materials are readily available to those of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers can be separated or split at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Elel and SH. Wilen).

[0250] In certain embodiments, the present invention provides a method for preparing a compound of Formula I comprising the steps of:

[0251] Step 1: Compound IA-1 and R 2 NH2 undergoes reductive amination to generate compound IA-2;

[0252] Step 2: Compound IA-3 and acyl chloride Compound IA-4 is generated through condensation reaction;

[0253] Step 3: Compound IA-4 is hydrolyzed to generate compound IA-5;

[0254] Step 4: Compound IA-2 and compound IA-5 undergo condensation reaction to generate compound I;

[0255] If necessary, the fifth step is to remove the protecting group of the condensation product of the fourth step to generate compound I.

[0256] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4 、R 9 , m, n are as defined above.

[0257] In some embodiments of the present invention, the reductive amination reaction in the first step is preferably carried out in the presence of Ti(OiPr)4 and NaBH4, Ti(OiPr)4 and NaBH(OAc)3, or AcOH and NaBH(OAc)3, etc., and the solvent that can be used is, for example, THF, dichloromethane (DCM) or dichloroethane (DCE).

[0258] In some embodiments of the present invention, the condensation reaction in the second step is carried out in the presence of a base, preferably in the presence of a base such as triethylamine or diisopropylethylamine, and the solvent that can be used is, for example, THF.

[0259] In some embodiments of the present invention, the hydrolysis reaction in the third step is carried out in an aqueous base solution, preferably in an aqueous base solution such as LiOH or NaOH, and the solvent that can be used is, for example, THF, methanol or ethanol.

[0260] In some embodiments of the present invention, the condensation reaction in the fourth step is carried out in the presence of a condensing agent, preferably in the presence of one or more condensing agents such as HATU, PyBOP, T3P, EDCI, PyBrOP, etc., and the usable base is, for example, triethylamine or diisopropylethylamine, and the usable solvent is, for example, DMF or NMP.

[0261] In some embodiments of the present invention, the deprotection reaction in the fifth step is preferably carried out under the action of an acid.

[0262] In some embodiments of the present invention, the deprotection reaction in the fifth step is preferably carried out under the action of an acid such as aqueous hydrochloric acid solution, hydrochloric acid-ethyl acetate solution, hydrochloric acid-1,4-dioxane solution or trifluoroacetic acid.

[0263] In some embodiments of the present invention, the protecting group removed in the fifth step is preferably an amino protecting group.

[0264] In some embodiments of the present invention, the protecting group removed in the fifth step is preferably a protecting group such as tert-butyloxycarbonyl or 3,4-dimethoxybenzyl.

[0265] Those skilled in the art will appreciate that, depending on the desired product structure, one or more steps in the above-described preparation method may be omitted, and the order of the reaction steps may be appropriately adjusted, and protection / deprotection reaction steps may be added or omitted as needed.

[0266] Pharmaceutical compositions, preparations and methods of treatment

[0267] In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled, polymorph, solvate, N-oxide, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers.

[0268] In some embodiments, the present invention provides a pharmaceutical formulation, which is preferably a solid formulation, a semisolid formulation, a liquid formulation, or a gaseous formulation.

[0269] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise one or more additional therapeutic agents.

[0270] In some embodiments, the pharmaceutical composition or pharmaceutical formulation is preferably administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0271] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention for the preparation of a medicament for preventing or treating a disease or condition associated with PRMT5 activity.

[0272] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope label, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention for the preparation of a medicament for modulating (e.g., reducing or inhibiting) PRMT5 activity.

[0273] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled, polymorph, solvate, N-oxide, metabolite or prodrug 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.

[0274] In some embodiments, the present invention provides a method for preventing or treating a disease or condition associated with PRMT5 activity, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention.

[0275] In some embodiments, the disease or condition associated with PRMT5 activity is cancer or a tumor.

[0276] In some embodiments, the disease or condition associated with PRMT5 activity is preferably a cancer or tumor with MTAP deficiency.

[0277] In some embodiments, the cancer or tumor is preferably 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), lymphoma, etc.

[0278] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0279] 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).

[0280] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by any suitable route.

[0281] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0282] 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.

[0283] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be 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 or supervising the administration of the composition.

[0284] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, 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 can be enough, and in other cases, still can adopt larger doses when not causing any harmful side effects, condition is first divided into several smaller doses to be administered throughout the day.

[0285] The compound of the present invention may be contained in a pharmaceutical composition or formulation in an amount ranging from about 0.01 mg to about 1000 mg.

[0286] Unless otherwise indicated, as used herein, the term "prevention" refers to the preemptive 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 arts recognizes that the term "prevention" is not an absolute term. In the medical arts, it is understood that a drug is administered prophylactically to substantially reduce the likelihood or severity of a condition or the symptoms of a condition, which is the 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 the disease or condition before the disease or condition fully manifests itself.

[0287] The term "treating" means to reverse, alleviate, inhibit the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0288] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein 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.).

[0289] In some embodiments, the pharmaceutical compositions or pharmaceutical formulations of the present invention may further comprise one or more additional therapeutic or prophylactic agents (e.g., other drugs used to treat cancer or tumor diseases). In some embodiments, the therapeutic methods of the present invention may further comprise administering one or more additional therapeutic or prophylactic agents (e.g., other drugs used to treat cancer or tumor diseases). DETAILED DESCRIPTION

[0290] Example

[0291] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0292] The abbreviations used in this document have the following meanings:

[0293] The compounds of the present invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography (Flash column chromatography). 1 The reaction was confirmed by H NMR and / or MS. Reaction monitoring was performed by TLC or LC-MS.

[0294] 1 H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).

[0295] LC / MS uses Aglient 1260 Infinity / Aglient 6120 Quadrupole.

[0296] TLC used silica gel GF 254 as the stationary phase.

[0297] Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0298] Flash column chromatography was performed using a Biotage flash column chromatograph.

[0299] Prep-HPLC used Agilent 1260 and Waters 2489.

[0300] Microwave reactions were performed using a BiotageInitiator microwave reactor.

[0301] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0302] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Teber Chemical Company.

[0303] Synthesis Example:

[0304] Intermediate Int-A: 2-((6-((tert-Butoxycarbonyl)amino)-5-methylpyridin-3-yl)amino)-2-oxoacetic acid

[0305] Step 1: Synthesis of tert-butyl (3-methyl-5-nitropyridin-2-yl)carbamate (Compound Int A-2)

[0306] Int A-1 (5 g, 32.65 mmol) and (Boc)2O (7.84 g, 35.92 mmol) were added to DMF (50 mL), followed by the slow addition of NaH (1.44 g, 35.92 mmol). The mixture was stirred at 25°C for 16 hours. After the reaction was complete, water was added to the reaction solution to quench it. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 5:95) to obtain compound Int A-2 (2.5 g). MS (ESI, m / z): 254.1 [M+H] + .

[0307] Step 2: Synthesis of tert-butyl (5-amino-3-methylpyridin-2-yl)carbamate (Compound Int A-3)

[0308] Int A-2 (2.8 g, 11.06 mmol) was dissolved in MeOH (100 mL), the hydrogen atmosphere was replaced, and the mixture was stirred at 25°C under hydrogen balloon pressure for 2 hours. After the reaction was completed, the reaction mixture was filtered through a pad of celite, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain compound Int A-3 (2.45 g). MS (ESI, m / z): 224.2 [M+H] + .

[0309] Step 3: Synthesis of ethyl 2-((6-((tert-butoxycarbonyl)amino)-5-methylpyridin-3-yl)amino)-2-oxoacetate (Compound Int A-4)

[0310] Int A-3 (2.47 g, 11.06 mmol) and DIPEA (2.14 g, 16.59 mmol) were dissolved in THF (50 mL). Ethyl oxalyl chloride (1.66 g, 12.17 mmol) was slowly added and stirred at 25°C for 0.5 hr. After the reaction was complete, water was added to quench the reaction mixture and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 35:65) to obtain compound Int A-4 (2.7 g). MS (ESI, m / z): 324.1 [M+H] + .

[0311] Step 4: Synthesis of 2-((6-((tert-Butoxycarbonyl)amino)-5-methylpyridin-3-yl)amino)-2-oxoacetic acid (Compound Int A)

[0312] Int A-4 (100 mg, 309.27 μmol) and LiOH·H2O (26 mg, 618.54 μmol) were added to THF (5 mL) and H2O (1 mL). The mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, yielding compound Int A (90 mg). MS (ESI, m / z): 296.1 [M+H] + .

[0313] Intermediates Int B and Int C: (R)-1-(pyrimidin-2-yl)ethan-1-amine (Int B) and (R)1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethan-1-amine (Int C)

[0314] Step 1: Synthesis of (R)-2-methyl-N-(1-(pyrimidin-2-yl)ethylidene)propane-2-sulfenamide (Compound Int B-3)

[0315] Int B-1 (1 g, 8.19 mmol) and Int B-2 (1.78 g, 9.83 mmol) were dissolved in anhydrous THF (20 mL). Ti(iPrO)4 (4.65 g, 16.38 mmol, 4.85 mL) was slowly added. After addition, the temperature was raised to 75°C and the reaction was allowed to proceed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature to obtain compound Int B-3 (1.8 g), which was used directly in the next step. MS (ESI, m / z): 226.1 [M+H] + .

[0316] Step 2: Synthesis of (R)-2-methyl-N-((R)-1-(pyrimidin-2-yl)ethyl)propane-2-sulfenamide (Compound Int B-4)

[0317] NaBH4 (604.49 mg, 15.98 mmol) was added to the reaction flask containing Int B-3 (1.8 g, 7.99 mmol) from the previous step at 25°C. The reaction system was allowed to react for 2 hours at 25°C. After completion, an appropriate amount of water was added to quench the reaction, and the mixture 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 B-4 (1.5 g). MS (ESI, m / z): 228.1 [M+H] + .

[0318] Step 3: Synthesis of (R)-1-(pyrimidin-2-yl)ethane-1-amine (Compound Int B)

[0319] Int B-4 (1.5 g, 6.60 mmol) was dissolved in MeOH (15 mL), and then 4N HCl-1,4-dioxane (5 mL) was slowly added. The reaction system was allowed to react at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure and then dissolved in methanol. A few drops of triethylamine were added to adjust the pH to 7-8. The mixture was then concentrated under reduced pressure to obtain compound Int B (800 mg). MS (ESI, m / z): 124.1 [M+H] + .

[0320] Step 4: Synthesis of (R)-1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethane-1-amine (Int C)

[0321] Int B (600 mg, 1.46 mmol) and Int C-1 (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. NaBH(OAc)3 (464.65 mg, 2.19 mmol) was then added. After the addition was complete, the reaction system was allowed to react at 25°C for 1.5 hr. After completion, the reaction was quenched with methanol and 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] + .

[0322] Intermediate Int D: (5-(trifluoromethyl)pyridin-2-yl)methanamine

[0323] Int D-1 (2.00 g, 11.62 mmol), palladium on carbon (0.2 g), AcOH (697.82 mg, 11.62 mmol), and methanol (5 mL) were added to a high-pressure hydrogenation reactor. After hydrogen replacement, the reaction was carried out at 1 MPa and 25°C for 16 hours. After completion of the reaction, the mixture was filtered through a pad of Celite and the filtrate was concentrated. The crude product was dissolved in ethyl acetate and an equal volume of water was added. After separation, the organic layer was discarded and the aqueous layer was lyophilized to obtain compound Int D (724 mg). MS (ESI, m / z): 177.1 [M+H] + .

[0324] Intermediate Int E: 2-((7-((2,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)amino)-2-oxoacetic acid

[0325] Step 1: Synthesis of 4-bromo-7-chloro-1-methyl-1H-pyrazolo[3,4-c]pyridine (Compound Int E-2)

[0326] Int E-1 (5 g, 21.51 mmol) was dissolved in DMF (30 mL). NaH (1.72 g, 43.02 mmol) was slowly added under ice-cooling. The mixture was allowed to react for 30 minutes, followed by the addition of MeI (3.66 g, 25.81 mmol). Stirring was continued at 25°C for 2 hours. After the reaction was complete, water was added to quench the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 70:30) to obtain compound Int E-2 (3.0 g). MS (ESI, m / z): 245.9 [M+H] + .

[0327] Step 2: Synthesis of 4-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7-amine (Compound Int E-4)

[0328] Int E-2 (3.0 g, 12.17 mmol), Int E-3 (3.05 g, 18.26 mmol), and DIPEA (2.36 g, 18.26 mmol, 3.2 mL) were dissolved in NMP (10 mL), replaced with nitrogen, and stirred at 140°C for 5 hours. After the reaction was completed, water was added to the reaction solution to quench it, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA = 70:30) gave compound Int A-4 (4.0 g). MS (ESI, m / z): 377.0 [M+H] + .

[0329] Step 3: Synthesis of N-(2,4-dimethoxybenzyl)-4-((diphenylmethylene)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7-amine (Compound Int E-6)

[0330] Int E-4 (4.0 g, 10.60 mmol), Int E-5 (3.84 g, 21.21 mmol), tBuONa (3.06 g, 31.81 mmol), BINAP (660 mg, 1.06 mmol), and Pd2(dba)3 (485 mg, 0.53 mmol) were dissolved in toluene (10 mL). After replacing the atmosphere with nitrogen, the reaction temperature was raised to 80°C and stirred for 16 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (EA:PE = 90:10) to obtain compound Int A-6 (4.68 g). MS (ESI, m / z): 478.2 [M+H] + .

[0331] Step 4: N 7 Synthesis of -(2,4-dimethoxybenzyl)-1-methyl-1H-pyrazolo[3,4-c]pyridine-4,7-diamine (Compound Int E-7)

[0332] Int E-6 (4.68 g, 9.80 mmol) was dissolved in MeOH (30 mL), followed by the addition of 4N hydrochloric acid-1,4-dioxane (3 mL). After nitrogen displacement, the reaction was stirred at 30°C for 1 hour. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 90:10) to obtain compound Int E-7 (3 g). MS (ESI, m / z): 314.1 [M+H] + .

[0333] Step 5: Synthesis of ethyl 2-((7-((2,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)amino)-2-oxoacetate (Compound Int E-8)

[0334] Int E-7 (3 g, 9.57 mmol) and DIPEA (3.71 g, 28.72 mmol) were dissolved in THF (25 mL), and ethyl oxalyl chloride (1.57 g, 11.49 mmol) was slowly added. The mixture was stirred at 25°C for 0.5 hr. After the reaction was complete, water was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 50:50) to obtain compound Int E-8 (1.38 g). MS (ESI, m / z): 414.1 [M+H] + .

[0335] Step 6: Synthesis of 2-((7-((2,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)amino)-2-oxoacetic acid (Compound Int E)

[0336] Int E-8 (1.38 g, 3.34 mmol) and LiOH·H2O (280 mg, 6.68 mmol) were added to THF (15 mL) and H2O (3 mL). The mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, yielding compound Int E (1 g). MS (ESI, m / z): 386.1 [M+H] + .

[0337] Intermediate Int F: 2-((4-((4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)amino)-2-oxoacetic acid

[0338] Step 1: Synthesis of 2-amino-5-bromo-4-chloronicotinaldehyde (Compound Int F-2)

[0339] Int F-1 (1 g, 6.39 mmol) was dissolved in anhydrous DCE (20 mL), and NBS (1.25 g, 7.03 mmol) was added. After N protection, the temperature was raised to 60°C and the reaction was allowed to proceed for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the mixture was dissolved in water and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain the intermediate Int F-2 (1.4 g).

[0340] Step 2: Synthesis of 7-bromo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (Compound Int F-4)

[0341] Int F-2 (1.5 g, 6.37 mmol) and methylhydrazine sulfate (1.38 g, 9.56 mmol) were dissolved in EtOH (30 mL), and DIPEA (4.12 g, 31.85 mmol) was added. The mixture was heated to 80°C under N2 protection and allowed to react for 24 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 80:20) to obtain the intermediate Int F-4 (320 mg). MS (ESI, m / z): 226.9 [M+H] + .

[0342] Step 3: Synthesis of 7-bromo-N-(4-methoxybenzyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (Compound Int F-5)

[0343] Int F-4 (280 mg, 1.23 mmol) and DIPEA (318.74 mg, 2.47 mmol) were dissolved in anhydrous NMP (10 mL). PMBCl (289.68 mg, 1.85 mmol) was added. After N2 protection, the temperature was raised to 140°C and the reaction was allowed to proceed for 5 hours. After completion of the reaction, the mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product was separated and purified by normal phase flash chromatography (PE:EA = 92:8) to obtain the intermediate Int F-5 (150 mg). MS (ESI, m / z): 347.0 [M+H] + .

[0344] Step 4: Synthesis of 7-((diphenylmethylene)amino)-N-(4-methoxybenzyl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine (Compound Int F-6)

[0345] Int F-5 (200 mg, 576.02 μmol), Int E-5 (208.79 mg, 1.15 mmol), t-BuONa (166.07 mg, 1.73 mmol), BINAP (35.87 mg, 57.60 μmol), and Pd2(dba)3 (26.37 mg, 28.80 μmol) were dissolved in toluene (10 mL). The mixture was heated to 80°C under N2 protection and reacted for 16 hours. After completion of the reaction, the toluene was removed by concentration under reduced pressure. The crude product was then purified by normal phase flash chromatography (PE:EA = 79:21) to obtain the intermediate Int F-6 (80 mg). MS (ESI, m / z): 448.2 [M+H] + .

[0346] Step 5: N 4 -(4-methoxybenzyl)-1-methyl-1H-pyrazolo[4,3-c]pyridine-4,7-diamine (Compound Int F-7)

[0347] Int F-6 (80 mg, 178.76 μmol) was dissolved in methanol (3 mL), and 4N HCl-dioxane (0.3 mL) was added dropwise. The reaction system was allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was removed by concentration under reduced pressure. An appropriate amount of methanol was added to dissolve the product, and a few drops of TEA were added to adjust the pH to 7-8. The product was then concentrated under reduced pressure. The crude product was separated and purified by normal phase flash chromatography (DCM:MeOH = 93:7) to obtain the intermediate Int F-7 (50 mg). MS (ESI, m / z): 284.1 [M+H] + .

[0348] Step 6: Synthesis of ethyl 2-((4-((4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)amino)-2-oxoacetate (Compound Int F-8)

[0349] Int F-7 (90 mg, 317.65 μmol) and DIPEA (41.05 mg, 317.65 μmol) were dissolved in THF (10 mL). Ethyl oxalyl chloride (52.04 mg, 381.18 μmol) was slowly added. The reaction system was incubated at 25°C for 1 hour. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The crude product was purified by normal phase flash chromatography (DCM:MeOH = 90:10) to obtain the intermediate Int F-8 (110 mg). MS (ESI, m / z): 384.2 [M+H] + .

[0350] Step 7: Synthesis of 2-((4-((4-methoxybenzyl)amino)-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)amino)-2-oxoacetic acid (Compound Int F)

[0351] Int F-8 (120 mg, 312.99 μmol) was dissolved in THF (5 mL) and H₂O (1 mL). NaOH (25.04 mg, 625.98 μmol) was added. After addition, the reaction system was heated to 90°C and reacted for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain the intermediate Int F (115 mg). MS (ESI, m / z): 356.1 [M+H] + .

[0352] Intermediate Int G: (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine hydrochloride

[0353] Step 1: Synthesis of tert-butyl (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (Compound Int G-2)

[0354] The hydrochloride salt of Int G-1 (2.0 g, 8.35 mmol) was added to DCM (20 mL). TEA (2.11 g, 20.87 mmol) was added under ice-cooling. After stirring for 10 minutes, (Boc)2O (2.19 g, 10.02 mmol) was added and the temperature was naturally raised to 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated and the crude product was purified by silica gel column chromatography (mobile phase: DCM) to obtain compound Int G-2 (2.4 g).

[0355] Step 2: Synthesis of tert-butyl (S)-N-methyl-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (Compound Int G-3)

[0356] Compound Int G-2 (2.4 g, 7.9 mmol) was dissolved in anhydrous THF (20 mL). NaH (526.25 mg, 13.16 mmol) was added portionwise at 0°C and stirred for 0.5 hr. Finally, iodomethane (1.37 g, 9.65 mmol) was added dropwise and allowed to react overnight. After completion, a small amount of methanol was added to quench the reaction. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 98:2) to obtain compound Int G-3 (2.7 g).

[0357] Step 3: Synthesis of (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine hydrochloride (Compound Int G)

[0358] Compound Int G-3 (2.7 g, 8.51 mmol) was dissolved in DCM (15 mL). 4 M 1,4-dioxane hydrochloride solution (5 mL) was added dropwise at 0°C. The mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was dried to obtain compound Int G (2.07 g).

[0359] MS (ESI, m / z): 218.0 [M+H] + .

[0360] Example 1: N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(5,6,7,8-tetrahydroquinoxalin-5-yl)-N 2 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)oxalamide

[0361] Step 1: Synthesis of 5,6,7,8-tetrahydroquinoxaline-1-oxide (Compound 1-2)

[0362] 1-1 (10 g, 74.53 mmol) was added to a 250 mL flask and dissolved in DCM. m-CPBA (24.11 g, 111.79 mmol) was added portionwise in an ice bath. After completion, the temperature was naturally raised to 25°C and the reaction was allowed to proceed for 16 hours. After the reaction, saturated sodium thiosulfate solution was added in an ice bath to quench the peroxyacid. Saturated sodium bicarbonate aqueous solution was then added and stirred until weakly alkaline and no bubbles were generated. Solid sodium chloride was then added, and the mixture was extracted with DCM. Concentration afforded the crude product 1-2 (8.40 g), which was used directly in the next step without purification. MS (ESI, m / z): 151.1 [M+H] + .

[0363] Step 2: Synthesis of 5,6,7,8-tetrahydroquinoxaline-5-acetate (Compound 1-3)

[0364] Dissolve 1-2 (4 g, 26.64 mmol) in glacial acetic acid (30 mL) and react at 140°C for 36 hours. After completion of the reaction, remove most of the acetic acid by rotary evaporation under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase PE:EA = 1:1) to obtain compound 1-3 (4.04 g). MS (ESI, m / z): 193.1 [M+H] + .

[0365] Step 3: Synthesis of 5,6,7,8-tetrahydroquinoxaline-5-ol (Compound 1-4)

[0366] Dissolve 1-3 (4.04 g, 21.00 mmol) in THF (30 mL), and add lithium hydroxide (2.20 g, 52.51 mmol) in water (8 mL) dropwise. Allow to react at room temperature for 6 hours. After completion, add water, extract with DCM, and concentrate to obtain compound 1-4 (2.97 g). The crude product was dried and used directly. MS (ESI, m / z): 151.1 [M+H] + .

[0367] Step 4: Synthesis of 7,8-dihydroquinoxaline-5(6H)-one (Compound 1-5)

[0368] 1-4 (2.97 g, 19.76 mmol) was dissolved in DCM (60 mL). Dess-Martin oxidant was slowly added in portions under an ice bath and allowed to warm to room temperature for 5 hours. After completion of the reaction, most of the oxidant was removed by filtration. The filtrate was the crude product, which was purified by silica gel column chromatography (mobile phase EA) to obtain compound 1-5 (1.23 g). MS (ESI, m / z): 149.1 [M+H] + .

[0369] Step 5: Synthesis of N-((5-(trifluoromethyl)pyridin-2-yl)methyl)-5,6,7,8-tetrahydroquinoxaline-5-amine (Compound 1-6)

[0370] Int D (356.65 mg, 2.02 mmol) and 1-5 (300 mg, 2.02 mmol) were added to DCE (10 mL), and glacial acetic acid (243.18 mg, 4.05 mmol) was added dropwise. After stirring for 10 minutes, sodium triacetoxyborohydride (643.71 mg, 3.04 mmol) was added and allowed to react at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 95:5) to obtain compound 1-6 (147 mg). MS (ESI, m / z): 309.1 [M+H] + .

[0371] Step 6: Synthesis of tert-butyl (3-methyl-5-(2-oxo-2-(((5,6,7,8-tetrahydroquinoxalin-5-yl)((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)acetamido)pyridin-2-yl)carbamate (Compound 1-7)

[0372] 1-6 (40.13 mg, 130.16 μmol), Int A (42.28 mg, 143.18 μmol), and PyBrop (72.81 mg, 156.19 μmol) were added to anhydrous DMF (3 mL). DIPEA (25.23 mg, 195.24 μmol) was added dropwise and the mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, dried, and concentrated to obtain a crude product. The crude product was purified by reverse-phase HPLC to obtain compound 1-7 (15 mg). MS (ESI, m / z): 586.3 [M+H] + .

[0373] Step 7: N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(5,6,7,8-tetrahydroquinoxalin-5-yl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 1)

[0374] 1-7 (15 mg, 25.62 μmol) was added to a 4N hydrochloric acid-dioxane solution (1 mL) under an ice bath and allowed to react at room temperature (25°C) for 4 hours. After completion of the reaction, the temperature was lowered to 0°C, diluted with methanol, and adjusted to a weak alkalinity by dropwise addition of triethylamine. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase HPLC to yield compound 1 (4.69 mg). MS (ESI, m / z): 486.1 [M+H] + .

[0375] 1H NMR (400MHz, DMSO-d6) δ10.59–10.30(m,1H),8.89–8.82(m,1H),8.48–8.38(m,2H),8.23–8.16(m,1H),8.09– 7.59(m,2H),7.55–7.33(m,1H),5.75–5.26(m,3H),5.15–4.07(m,2H),3.05–2.78(m,2H),2.14–1.77(m,7H).

[0376] Example 2: (R)-N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)oxalamide

[0377] Step 1: Synthesis of tert-butyl (R)-(3-methyl-5-(2-oxo-2-((1-pyrimidin-2-yl)ethyl))((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)acetamido)pyridin-2-yl)carbamate (Compound 2-1)

[0378] Int C (43 mg, 152.39 μmol) and Int A (45 mg, 152.39 μmol) were dissolved in anhydrous DMF (2 mL). DIPEA (29.54 mg, 228.59 μmol) and HATU (69.53 mg, 182.87 μmol) were added, and the reaction system was incubated at 25°C for 1 hour. After completion, the reaction 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 2-1 (10 mg). MS (ESI, m / z): 560.1 [M+H] + .

[0379] Step 2: (R)-N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 2)

[0380] 2-1 (10 mg, 17.87 μmol) was dissolved in 4N hydrochloric acid-dioxane solution (1 mL). The reaction system was allowed to react at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure and then dissolved in an appropriate amount of methanol. A few drops of TEA were added to adjust the pH to 7-8. The mixture was concentrated under reduced pressure. The crude product was separated and purified by Prep-HPLC to obtain compound 2 (3 mg). MS (ESI, m / z): 460.1 [M+H] + .

[0381] 1 H NMR (400MHz, DMSO-d6) δ10.57–10.32(m,1H),8.92–8.66(m,3H),8.18–8.07(m,1H),8.07–7.87(m,1 H),7.71–7.30(m,3H),5.76–5.56(m,2H),5.21–4.54(m,3H),2.09–1.88(m,3H),1.68–1.49(m,3H).

[0382] Example 3: (R)-N 1 -(5-carbamoyl-6-methoxypyridin-3-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 -(5-(Trifluoromethyl)pyridin-2-yl)methyl)-oxalamide

[0383] Step 1: Synthesis of 2-methoxy-5-nitronicotinamide (Compound 3-2)

[0384] 3-1 (250 mg, 1.26 mmol), NH4Cl (675 mg, 12.62 mmol), EDCI (363 mg, 1.89 mmol), and HOBT (256 mg, 1.89 mmol) were placed in a reaction flask, and DMF (5 mL) and N-methylmorpholine (191 mg, 1.89 mmol) were added. The mixture was then reacted at room temperature for 2 hours. After completion of the reaction, 10 mL of water was added to quench the reaction mixture. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 90:10) to obtain compound 3-2 (200 mg). MS (ESI, m / z): 198.1 [M+H] + .

[0385] Step 2: Synthesis of 5-amino-2-methoxynicotinamide (Compound 3-3)

[0386] 3-2 (250 mg, 1.27 mmol) was dissolved in MeOH (8 mL), and Pd / C (154 mg, 0.13 mmol) was added. After replacing the hydrogen atmosphere, the reaction was maintained under a hydrogen atmosphere at room temperature for 16 hours. After completion of the reaction, the filtrate was filtered and concentrated to dryness under reduced pressure to obtain compound 3-3 (190 mg). MS (ESI, m / z): 168.1 [M+H] + .

[0387] Step 3: Synthesis of 2-((5-carbamoyl-6-methoxypyridin-3-yl)-2-(ethyl oxoacetate) (Compound 3-4)

[0388] Compound 3-3 (150 mg, 0.90 mmol) and DIPEA (174 mg, 1.35 mmol) were dissolved in THF (5 mL). Ethyl oxalyl chloride (123 mg, 0.90 mmol) was slowly added and stirred at 25°C for 0.5 hr. After the reaction was complete, water was added to quench the reaction mixture and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 3-4 (130 mg). MS (ESI, m / z): 268.1 [M+H] + .

[0389] Step 4: Synthesis of 2-((5-carbamoyl-6-methoxypyridin-3-yl)amino)-2-oxyethyl ester (Compound 3-5)

[0390] Compound 3-4 (250 mg, 0.94 mmol) and LiOH·H₂O (59 mg, 1.40 mmol) were added to THF (1 mL) and H₂O (1 mL) and stirred at 25°C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent. The solution was purified by HPLC (H₂O [0.05% TFA]:CAN = 70:30) and lyophilized to obtain compound 3-5 (40 mg). MS (ESI, m / z): 240.1 [M+H] + .

[0391] Step 5: (R)-N 1 -(5-carbamoyl-6-methoxypyridin-3-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 Synthesis of -(5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 3)

[0392] 3-5 (15 mg, 62.71 μmol), Int C (18 mg, 62.71 μmol), HATU (29 mg, 75.26 μmol), and DMF (2 mL) were added to the reaction flask and stirred to dissolve. DIPEA (12 mg, 94.07 μmol) was then added under nitrogen and allowed to react at 25°C for 1 hour. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate (10 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 the crude product. The crude product was separated and purified by pre-HPLC and lyophilized to obtain compound 3 (10 mg). MS (ESI, m / z): 504.1 [M+H] + .

[0393] 1 H NMR (400MHz, DMSO-d6) δ11.08–10.90(m,1H),8.85–8.72(m,3H),8.58–8.51(m,1H),8.45–8.39(m,1H),8.17–8.07(m,1H),7.81– 7.66(m,2H),7.52–7.35(m,2H),5.77–5.69(m,1H),5.23–4.98(m,1H),4.94–4.59(m,1H),3.99–3.90(m,3H),1.69–1.51(m,3H).

[0394] Example 4: N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(Bicyclo[1.1.1]pentan-1-yl)-N 2 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)oxalamide

[0395] Step 1: Synthesis of N-((5-(trifluoromethyl)pyridin-2-yl)methyl)bicyclo[1.1.1]pentan-1-amine (Compound 4-2)

[0396] 4-1 (177.57 mg, 1.48 mmol) and Int C-1 (200 mg, 1.14 mmol) were dissolved in anhydrous DCM (5 mL), and AcOH (137.17 mg, 2.28 mmol) was added. The resulting mixture was stirred at 25°C for 30 min. NaBH(OAc)3 (363.10 mg, 1.71 mmol) was then added, and the reaction system was allowed to react at 25°C for 1.5 hr. After completion, the reaction was quenched with methanol and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase PE:EA = 60:40) to obtain compound 4-2 (40 mg). MS (ESI, m / z): 243.1 [M+H] + .

[0397] Step 2: Synthesis of tert-butyl (5-(2-(bicyclo[1.1.1]pentan-1-yl((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-2-oxoacetamide)-3-methylpyridin-2-yl)carbamate (Compound 4-3)

[0398] 4-2 (35 mg, 144.48 μmol) and Int A (42.67 mg, 144.48 μmol) were added to a reaction flask and dissolved in DMF (2 mL). DIPEA (28.01 mg, 216.73 μmol) and HATU (65.92 mg, 173.38 μmol) were added. After the addition was complete, the reaction system was reacted at 25°C for 1 hour. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product was separated and purified by Prep-TLC (PE:EA = 1:1) to obtain compound 4-3 (30 mg). MS (ESI, m / z): 520.2 [M+H] + .

[0399] Step 3: N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(Bicyclo[1.1.1]pentan-1-yl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 4)

[0400] 4-4 (30 mg, 57.75 μmol) was dissolved in 4N hydrochloric acid-dioxane solution (1 mL). The reaction system was allowed to react at 25°C for 1 hour. After completion of the reaction, the reaction was concentrated under reduced pressure. An appropriate amount of methanol was added, and a few drops of TEA were added to adjust the pH to 7-8. The reaction was then concentrated under reduced pressure. The crude product was separated and purified by Prep-HPLC to obtain compound 4 (12 mg). MS (ESI, m / z): 420.1 [M+H] + .

[0401] 1 H NMR (400MHz, DMSO-d6) δ11.22–11.00(m,1H),8.99–8.87(m,1H),8.36–8.18(m,2H),7.88–7.79(m,2 H),7.65–7.50(m,1H),4.99–4.72(m,2H),2.48–2.36(m,1H),2.24–2.13(m,3H),2.08–1.95(m,6H).

[0402] The following compounds were prepared by the method and general steps described in Example 4. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0403] Example 5: (R)-N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(1-(6-fluoropyridin-2-yl)ethyl)-N 2 -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide

[0404] Step 1: Synthesis of 6-fluoro-N-methoxy-N-methylpicolinamide (Compound 5-3)

[0405] 5-1 (3 g, 21.26 mmol), 5-2 (2.28 g, 23.39 mmol), and HATU (9.70 g, 25.50 mmol) were placed in a reaction flask, DMF (50 mL) was added, and DIPEA (8.24 g, 63.78 mmol) was slowly added under water bath cooling. The mixture was then allowed to react at room temperature. After completion of the reaction, 100 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 90:10-80:20) to obtain compound 5-3 (3 g). MS (ESI, m / z): 185.1 [M+H] + .

[0406] Step 2: Synthesis of 1-(6-fluoropyridin-2-yl)ethan-1-one (Compound 5-4)

[0407] 5-3 (1.5 g, 8.14 mmol) was dissolved in dry THF (20 mL), cooled to 0°C, and then methylmagnesium bromide (0.5 M, 17.92 mL) was slowly added. The reaction was continued at 0°C. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution to quench the reaction. 60 mL of water was added to dilute the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 10:90) to obtain compound 5-4 (700 mg).

[0408] Step 3: Synthesis of (R)-N-(1-(6-fluoropyridin-2-yl)-ethylidene)-2-methylpropane-2-sulfenamide (Compound 5-5)

[0409] To the reaction flask, 5-4 (700 mg, 5.03 mmol), Int B-2 (1.09 g, 9.00 mmol), Ti(iPrO)4 (2.86 g, 10.06 mmol, 2.98 mL), and THF (30 mL) were added under nitrogen atmosphere at 70°C for 48 hours. After completion of the reaction, the mixture was cooled to room temperature and used directly in the next reaction. MS (ESI, m / z): 243.1 [M+H] + .

[0410] Step 4: Synthesis of (R)-N-((R)-(1-(6-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfenamide (Compound 5-6)

[0411] 5-5 (1.2 g, 4.95 mmol), THF (30 mL), and NaBH4 (374 mg, 9.90 mmol) were added to the reaction flask under nitrogen protection and reacted at 25°C for 1 hour. After the reaction was completed, water was added to the reaction solution to quench it, and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 35:65) to obtain compound 5-6 (710 mg). MS (ESI, m / z): 245.1 [M+H] + .

[0412] Step 5: Synthesis of (R)-1-(6-fluoropyridin-2-yl)ethane-1-amine (Compound 5-7)

[0413] Compound 5-6 (700 mg, 2.86 mmol), MeOH (10 mL), and 4N HCl-dioxane (2.86 mL) were added to a reaction flask under nitrogen atmosphere and allowed to react at 25°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove most of the solvent, then diluted with saturated NaHCO₃ solution and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound 5-7 (370 mg). MS (ESI, m / z): 141.1 [M+H] + .

[0414] Step 6: Synthesis of (R)-1-(6-fluoropyridin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethane-1-amine (Compound 5-8)

[0415] To a reaction flask, 5-8 (370 mg, 2.64 mmol), Int C-1 (370 mg, 2.11 mmol), DCE (20 mL), and acetic acid (238 mg, 3.96 mmol) were added under nitrogen atmosphere and reacted at 25°C for 5 hours. Sodium triacetoxyborohydride (840 mg, 3.96 mmol) was then added and the reaction continued at 25°C for 2 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with DCM (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA:PE = 35:65) to obtain compound 5-8 (85 mg). MS (ESI, m / z): 300.1 [M+H] + .

[0416] Step 7: Synthesis of tert-butyl (R)-(5-(2-((1-(6-fluoropyridin-2-yl)ethyl)((5-(trifluoromethyl)pyridin-2-yl)methyl)amino)-2-oxoacetamide)-3-methylpyridin-2-yl)carbamate (Compound 5-9)

[0417] To a reaction flask, 5-8 (15 mg, 50.12 μmol), Int A (22 mg, 75.18 μmol), HATU (23 mg, 60.15 μmol), and DMF (2 mL) were added. After stirring and dissolving, DIPEA (10 mg, 75.18 μmol) was added. The mixture was kept under nitrogen at 25°C for 1 hr. After completion of the reaction, the reaction solution was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a preparative plate using a developing solvent (DCM:MeOH = 10:1) to obtain compound 5-9 (10 mg). MS (ESI, m / z): 477.1 [M+H-Boc] + .

[0418] Step 8: (R)-N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -(1-(6-fluoropyridin-2-yl)ethyl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl))methyl)oxalamide (Compound 5)

[0419] 5-9 (10 mg, 17.34 μmol) and 4N hydrochloric acid-dioxane solution (1 mL) were added to the reaction flask under nitrogen atmosphere and reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then adjusted to alkaline pH by adding TEA to obtain the crude product. The crude product was purified by Pre-HPLC to obtain compound 5 (4 mg). MS (ESI, m / z): 477.1 [M+H] + .

[0420] 1 H NMR (400MHz, DMSO-d6) δ10.66–10.35(m,1H),8.82–8.75(m,1H),8.12–7.87(m,3H),7.57–7.52(m,1H),7.43–7.31(m,2 H),7.07–6.99(m,1H),5.75–5.53(m,3H),5.11–4.91(m,1H),4.79–4.57(m,1H),2.06–1.95(m,3H),1.61–1.46(m,3H).

[0421] Example 16: (R)-N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-N 2 -(1-(pyrimidin-2-yl)ethyl)oxalamide

[0422] Step 1: Synthesis of 6-vinyl-3,4-dihydroquinolin-2(1H)-one (Compound 16-2)

[0423] 16-1 (2.0 g, 8.85 mmol) was added to a 50 mL flask, followed by potassium ethylene trifluoroborate (1.42 g, 10.62 mmol), Pd(PPh3)2Cl2 (620 mg, 884.68 μmol), and Na2CO3 (1.88 g, 17.69 mmol). 1,4-Dioxane (10 mL) and H2O (1 mL) were added to dissolve the mixture. Under nitrogen, the temperature was raised to 100°C and the reaction was continued for 8 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The mixture was concentrated to obtain the crude product, which was then purified by silica gel column chromatography (mobile phase PE:EA = 1:1) to obtain compound 16-2 (1.22 g). MS (ESI, m / z): 174.1 [M+H] + .

[0424] Step 2: Synthesis of 2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (Compound 16-3)

[0425] 16-2 (500 mg, 2.89 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL). Potassium osmate dihydrate (159 mg, 433.00 μmol) and NaIO4 (2.49 g, 11.55 mmol) were added and reacted at 25°C for 4 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate. The mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 97:3) to obtain compound 16-3 (142 mg). MS (ESI, m / z): 175.1 [M+H] + .

[0426] Step 3: Synthesis of (R)-6-(((1-(pyrimidin-2-yl)ethyl)amino)methyl)-3,4-dihydroquinolin-2(1H)-one (Compound 16-4)

[0427] 16-3 (35 mg, 121.80 μmol) and Int B (50 mg, 121.80 μmol) were dissolved in DCM (5 mL). Acetic acid (14 mg, 243.59 μmol) was added dropwise. After stirring at room temperature for 10 min, sodium triacetoxyborohydride (39 mg, 182.70 μmol) was added and the mixture was allowed to react at room temperature for 5 hr. After completion of the reaction, methanol was added for dissolution and concentration was performed. The crude product was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 90:10) to obtain compound 16-4 (25 mg). MS (ESI, m / z): 283.2 [M+H] + .

[0428] Step 4: Synthesis of tert-butyl (R)-(3-methyl-5-(2-oxo-2-(((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl)(1-(pyrimidin-2-yl)ethyl)amino)acetamido)pyridin-2-yl)carbamate (Compound 16-5)

[0429] 16-4 (25 mg, 88.55 μmol), Int A (31 mg, 106.26 μmol), HATU (84 mg, 221.36 μmol), and DIPEA (45 mg, 354.17 μmol) were added to anhydrous DMF (3 mL) and reacted at 25°C for 1 hour. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate, dried, and concentrated to obtain a crude product. The crude product was purified by reverse-phase HPLC to obtain intermediate 16-5 (5 mg). MS (ESI, m / z): 560.2 [M+H] + .

[0430] Step 5: (R)-N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)methyl)-N 2 Synthesis of -(1-(pyrimidin-2-yl)ethyl)oxalamide (Compound 16)

[0431] 16-5 (5 mg, 8.93 μmol) was dissolved in DCM (5 mL) under ice-cooling, and a 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) was added dropwise. The reaction was allowed to proceed at 25°C for 1 hour. After completion of the reaction, the temperature was lowered to 0°C, diluted with methanol, and adjusted to a weak alkalinity by the addition of triethylamine. The reaction was concentrated under reduced pressure, and the crude product was purified by reverse-phase HPLC to yield 16 (2.51 mg). MS (ESI, m / z): 460.2 [M+H] + .

[0432] 1 H NMR (400MHz, DMSO-d6) δ10.53–10.28(m,1H),10.06–9.88(m,1H),8.80–8.70(m,2H),8.07–7.86(m,1H),7.54–7.31(m,2H),7.05–6.88(m, 2H),6.74–6.65(m,1H),5.68–5.43(m,3H),4.70–4.23(m,2H),2.81–2 .72(m,2H),2.44–2.36(m,2H),2.06–1.96(m,3H),1.63–1.51(m,3H).

[0433] Example 19: (R)-N 1-(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)oxalamide

[0434] Step 1: (R)-N 1 -(7-((2,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 19-1)

[0435] Int C (29.30 mg, 103.80 μmol), Int E (40.00 mg, 103.80 μmol), HATU (47.36 mg, 124.55 μmol), and DIPEA (20.12 mg, 155.69 μmol) were added to anhydrous DMF (3 mL) and reacted at 25°C for 5 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate, dried, and concentrated to obtain a crude product. The crude product was purified by reverse-phase HPLC to obtain intermediate 19-1 (8 mg). MS (ESI, m / z): 650.2 [M+H] + .

[0436] Step 2: (R)-N 1 -(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 19)

[0437] 19-1 (8 mg, 8.93 μmol) was dissolved in DCM (5 mL) under ice-cooling. Hydrochloric acid-dioxane solution (0.5 mL) was added dropwise and allowed to react at 25°C for 1 hour. After completion of the reaction, the temperature was lowered to 0°C and triethylamine was added dropwise to adjust the solution to a weak base. The reaction was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC to yield 19 (1.83 mg). MS (ESI, m / z): 500.2 [M+H] + .

[0438] 1H NMR (400MHz, DMSO-d6) δ10.76–10.54(m,1H),8.86–8.78(m,1H),8.78–8.74(m,1H),8.17–8.07(m,1H),7.89–7.46(m,4 H),7.42–7.35(m,1H),6.31–6.17(m,2H),5.83–5.64(m,1H),4.96–4.67(m,2H),4.32–4.18(m,3H),1.69–1.52(m,3H).

[0439] The following compounds were prepared by the method and general steps described in Example 19. Other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0440] Example 20: (R)-N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -((5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-N 2 -(1-(pyrimidin-2-yl)ethyl)oxalamide

[0441] Step 1: Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)pyridinecarboxaldehyde (Compound 20-3)

[0442] To a reaction flask were added 20-1 (500 mg, 2.69 mmol), 20-2 (587 mg, 2.82 mmol), Pd(dppf)Cl2 (195 mg, 269 μmol), K2CO3 (557 mg, 4.03 mmol), 1,4-dioxane (15 mL), and water (1 mL). The mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 96:4) to obtain compound 20-3 (320 mg). MS (ESI, m / z): 188.1 [M+H]+ .

[0443] Step 2: Synthesis of (R)-N-((5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-1-(pyrimidin-2-yl)ethane-1-amine (Compound 20-4)

[0444] To a reaction flask, 20-3 (50 mg, 267.10 μmol), Int B (33 mg, 267.10 μmol), DCM (3 mL), and acetic acid (32 mg, 534.19 μmol) were added under nitrogen atmosphere and reacted at 25°C for 5 hours. Sodium triacetoxyborohydride (85 mg, 400.65 μmol) was then added and the reaction continued at 25°C for 5 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with DCM (30 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 20-4 (70 mg). MS (ESI, m / z): 295.1 [M+H] + .

[0445] Step 3: Synthesis of tert-butyl (R)-(3-methyl-5-(2-(((5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)(1-(pyrimidin-2-yl)ethyl)amino)-2-oxoacetamido)pyridin-2-yl)carbamate (Compound 20-5)

[0446] 20-4 (25 mg, 84.66 μmol), Int A (25 mg, 84.66 μmol), HATU (39 mg, 101.59 μmol), and DMF (2 mL) were added to a reaction flask and stirred to dissolve. DIPEA (33 mg, 253.99 μmol) was then added under nitrogen atmosphere at 25°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a preparative plate (DCM:MeOH = 10:1) to obtain compound 20-5 (20 mg). MS (ESI, m / z): 572.2 [M+H] + .

[0447] Step 4: (R)-N 1 -(6-amino-5-methylpyridin-3-yl)-N 2 -((5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-N 2Synthesis of -(1-(pyrimidin-2-yl)ethyl)oxalamide (Compound 20)

[0448] 20-5 (20 mg, 34.99 μmol) and 4M HCl-1,4-dioxane (2 mL) were added to the reaction flask under nitrogen atmosphere and reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. TEA was added to adjust the pH to alkaline to obtain the crude product. The crude product was purified by Pre-HPLC to obtain compound 20 (5 mg). MS (ESI, m / z): 472.2 [M+H] + .

[0449] 1 H NMR (400MHz, DMSO-d6) δ10.55–10.37(m,1H),8.78–8.74(m,2H),8.68–8.64(m,1H),8.21(s,1H),8.07–7.90(m,2H),7.87–7.82(m,1H) ,7.54–7.17(m,3H),5.69–5.56(m,3H),5.08–4.83(m,1H),4.82–4.38(m,1H),3.88–3.86(m,3H),2.04–1.94(m,3H),1.64–1.48(m,3H).

[0450] Example 22: N 1 -(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -isobutyl-N 2 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)oxalamide

[0451] Step 1: Synthesis of 2-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)propan-1-amine (Compound 22-2)

[0452] Int C-1 (383.08 mg, 2.19 mmol) and 22-1 (200.00 mg, 2.73 mmol) were added to anhydrous DCM (10 mL). AcOH (328.43 mg, 5.47 mmol) was added dropwise and stirred for 10 min. Sodium triacetoxyborohydride (869.36 mg, 5.47 mmol) was added and reacted at 25°C for 1 hr. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 95:5) to obtain compound 22-2 (510 mg). MS (ESI, m / z): 233.2 [M+H] + .

[0453] Step 2: N 1 -(7-((2,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -isobutyl-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 22-3)

[0454] Int E (40.00 mg, 62.28 μmol) and DIPEA (16.10 mg, 124.55 μmol) were added to anhydrous DMF (5 mL). HATU (35.52 mg, 124.55 μmol) was added at 0°C. After stirring for 5 minutes, 22-2 (14.46 mg, 62.28 μmol) was added and allowed to react at 25°C for 1 hour. After completion of the reaction, water was added and stirred. The mixture was extracted with ethyl acetate and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 95:5) to obtain compound 22-3 (19.20 mg). MS (ESI, m / z): 600.2 [M+H] + .

[0455] Step 3: N 1 -(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -isobutyl-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 22)

[0456] 22-3 (19.20 mg, 32.02 μmol) was dissolved in DCM (5 mL) under ice-cooling, and TFA (2 mL) was added dropwise. The mixture was allowed to react at 25°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, washed with saturated sodium bicarbonate solution, and extracted with ethyl acetate to obtain a crude product. The crude product was purified by reverse-phase HPLC to obtain compound 22 (2.49 mg). MS (ESI, m / z): 450.2 [M+H] + .

[0457] 1 H NMR (400MHz, DMSO-d6) δ10.74–10.56(m,1H),8.96–8.91(m,1H),8.32–8.15(m,1H),7.89–7.79(m,1H),7.70–7.55(m,2 H),6.27–6.22(m,1H),4.95–4.79(m,2H),4.28–4.24(m,3H),3.26–3.25(m,2H),2.07–1.95(m,2H),0.91–0.84(m,6H).

[0458] Example 23: (R)-N 1 -(4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)oxalamide

[0459] Step 1: (R)-N 1 -(4-((4-methoxybenzyl)amino)-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 23-1)

[0460] Int C (30 mg, 106.28 μmol) and HATU (12.84 mg, 33.77 μmol) were dissolved in anhydrous DMF (2 mL). The resulting mixture was stirred at 25°C for 30 min before adding Int F (37.77 mg, 106.28 μmol). The reaction system was incubated at 25°C for 1 hour. After completion, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product was separated and purified by Prep-TLC (DCM:MeOH = 10:1) to obtain compound 23-1 (8 mg). MS (ESI, m / z): 620.2 [M+H] + .

[0461] Step 2: (R)-N 1 -(4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 23)

[0462] 23-1 (8 mg, 8.93 μmol) was dissolved in TFA (2 mL) on an ice bath and heated to 90°C for 1 hour. After completion of the reaction, the mixture was concentrated by distillation under reduced pressure, then dissolved in methanol. Triethylamine was added dropwise to adjust the solution to a weak base, and the mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase pre-HPLC to obtain compound 23 (1.83 mg). MS (ESI, m / z): 500.2 [M+H] + .

[0463] 1H NMR (400MHz, DMSO-d6) δ10.51–9.92(m,1H),8.88–8.65(m,3H),8.23–8.06(m,2H),7.67–7.47(m,1H),7.44–7.37(m,1H),7.15– 6.76(m,2H),5.82–5.76(m,1H),5.43–5.21(m,1H),5.05–4.90(m,1H),4.78–4.53(m,1H),4.08–3.89(m,3H),1.67–1.53(m,3H).

[0464] Example 28: (R)-N 1 -(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl)-N 2 -((5-(Trifluoromethyl)pyridin-2-yl)methyl)oxalamide

[0465] Step 1: Synthesis of methyl pyridine 3,4-dicarboxylate (Compound 28-2)

[0466] 28-1 (30 g, 179.51 mmol) and SOCl2 (100 mL) were added to a reaction flask, and the mixture was reacted at 80°C for 3 hours. The reaction solution was spin-dried, and SOCl2 (100 mL) was added again and the reaction was continued at 80°C for 3 hours. The reaction solution was spin-dried and added dropwise into MeOH (200 mL). After stirring at room temperature for 0.5 hours, the reaction solution was distilled under reduced pressure to remove the solvent, dissolved in ethyl acetate, washed twice with sodium bicarbonate aqueous solution, and the organic phase was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain compound 28-2 (30 g), MS (ESI, m / z): 196.1 [M+H] + .

[0467] Step 2: Synthesis of 3,4-bis(methoxycarbonyl)pyridine 1-oxide (Compound 28-3)

[0468] 28-2 (30 g, 153.71 mmol) was dissolved in DCM (300 mL) and added portionwise to m-CPBA (49.73 g, 230.57 mmol). The mixture was stirred at room temperature overnight. TLC monitoring confirmed that no starting material remained. Sodium thiosulfate aqueous solution (150 mL) was slowly added and stirred for 1 hour. The mixture was extracted three times with dichloromethane. The organic phases were combined and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure. Column chromatography (5% EA to 100% EA) gave compound 28-3 (26 g). MS (ESI, m / z): 212.1 [M+H] + .

[0469] Step 3: Synthesis of 2-chloropyridine 3,4-dicarboxylic acid methyl ester (Compound 28-4)

[0470] 28-3 (26.00 g, 123.12 mmol) was added to POCl3 (150 mL) and the reaction was carried out at 100°C overnight. The reaction was completed under LCMS monitoring. The reaction solution was cooled and the solvent was removed by distillation under reduced pressure. The mixture was poured into ice water. The pH value of the mixture was about 6 under sodium bicarbonate conditions. The mixture was extracted with ethyl acetate. The organic phases were combined and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure. Column chromatography (5% EA to 7% EA) gave compound 28-4 (12 g). MS (ESI, m / z): 230.1 [M+H] + .

[0471] Step 4: Synthesis of (2-chloropyridine-3,4-diyl)dimethanol (Compound 28-5)

[0472] 28-4 (12 g, 52.26 mmol) was dissolved in EtOH (120 mL), and NaBH4 (11.86 g, 313.57 mmol) was added in batches. After the addition was complete, the mixture was reacted at room temperature for 2 hours. The reaction was completed under LCMS monitoring. Formic acid was added dropwise to adjust the pH to about 5. The solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography (50% EA to 100% EA) to give compound 28-5 (7.87 g). MS (ESI, m / z): 174.1 [M+H] + .

[0473] Step 5: Synthesis of 4-chloro-1,3-dihydrofuro[3,4-c]pyridine (Compound 28-6)

[0474] 28-5 (7.87 g, 45.33 mmol) was dissolved in DCM (180 mL), and MnO2 (7.88 g, 90.67 mmol) was added portionwise. Et3SiH (32 mL) and TFA (64 mL) were added dropwise in sequence. The mixture was allowed to react overnight at room temperature. The reaction was completed under LCMS monitoring. The solvent was removed by distillation under reduced pressure, and compound 28-6 (2.69 g) was obtained by column chromatography (5% EA to 20% EA). MS (ESI, m / z): 156.1 [M+H] + .

[0475] Step 6: Synthesis of N-(2,4-dimethoxybenzyl)-1,3-dihydrofuro[3,4-c]pyridin-4-amine (Compound 28-7)

[0476] 28-6 (1 g, 6.43 mmol), Int E-3 (2.15 g, 12.86 mmol), t-BuNa (2.47 g, 25.71 mmol), BINAP (400.22 mg, 642.75 μmol), and Pd2(dba)3 (294.29 mg, 321.38 μmol) were dissolved in toluene (30 mL), replaced with nitrogen, and reacted at 100°C overnight. The solvent was evaporated under reduced pressure, and the mixture was purified by column chromatography (10% to 30% EA) to give compound 28-7 (1.6 g). MS (ESI, m / z): 287.1 [M+H] + .

[0477] Step 7: Synthesis of 1,3-dihydrofuro[3,4-c]pyridin-4-amine (Compound 28-8)

[0478] Compound 28-7 (1.6 g, 5.59 mmol) was dissolved in TFA (10 mL) and reacted at room temperature for 1 hour. The reaction was completed under LCMS monitoring. The solvent was removed by distillation under reduced pressure and flash purified to give compound 28-8 (470 mg). MS (ESI, m / z): 137.1 [M+H] + .

[0479] Step 8: Synthesis of 7-bromo-1,3-dihydrofuro[3,4-c]pyridin-4-amine (Compound 28-9)

[0480] 28-8 (460 mg, 3.38 mmol) was dissolved in MeCN (2 mL), and NBS (661.46 mg, 3.72 mmol) was added portionwise. The mixture was reacted at room temperature for 2 hours. LCMS monitoring showed that no starting material remained. The reaction solution was distilled under reduced pressure to remove the solvent. Column chromatography gave compound 28-9 (700 mg). MS (ESI, m / z): 215.0, 217.0 [M+H] + .

[0481] Step 9: Synthesis of 7-bromo-N, N-bis(4-methoxybenzyl)-1,3-dihydrofuro[3,4-c]pyridin-4-amine (Compound 28-10)

[0482] 28-9 (700 mg, 3.26 mmol) was dissolved in DMF (10 mL). NaH (520.82 mg, 13.02 mmol) was added portionwise at 0°C. The reaction was maintained at 0°C for 0.5 hours. PMBCl (1.53 g, 9.77 mmol) was then added dropwise and the reaction was continued at room temperature for 2 hours. The mixture was quenched with water, extracted with ethyl acetate, and washed with dilute brine. The organic phase was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure. Column chromatography (0% EA to 20% EA) gave compound 28-10 (0.93 g). MS (ESI, m / z): 455.1, 457.1 [M+H]. + .

[0483] Step 10: Synthesis of 7-((diphenylmethylene)amino)-N,N-bis(4-methoxybenzyl)-1,3-dihydrofuro[3,4-c]pyridin-4-amine (Compound 28-11)

[0484] Under nitrogen, 28-10 (0.93 g, 2.04 mmol), Int E-5 (740.30 mg, 4.08 mmol), t-BuONa (588.85 mg, 6.13 mmol), BINAP (127.18 mg, 204.24 μmol) and Pd2(dba)3 (93.51 mg, 102.12 μmol) were dissolved in 1,4-dioxane (12 mL) and reacted at 80°C overnight. The reaction solution was evaporated under reduced pressure to remove the solvent, and column chromatography (0% EA to 10% EA) gave compound 28-11 (800 mg). MS (ESI, m / z): 556.3 [M+H] + .

[0485] Step 11: N 4 , N 4 -Synthesis of bis(4-methoxybenzyl)-1,3-dihydrofuro[3,4-c]pyridine-4,7-diamine (Compound 28-12)

[0486] 28-11 (0.93 g, 1.67 mmol) was dissolved in DCM (12 mL), and then 4N HCl-1,4-dioxane (4 mL) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction was complete under LCMS monitoring. The solvent was removed by distillation under reduced pressure and the reaction solution was directly used in the next step to obtain compound 28-12 (500 mg). MS (ESI, m / z): 392.2 [M+H] + .

[0487] Step 12: Synthesis of ethyl 2-((4-(bis(4-methoxybenzyl)amino)-1,3-dihydrofuro[3,4-c]pyridin-7-yl)amino)-2-oxoacetate (Compound 28-13)

[0488] Compound 28-12 (500 mg, 1.28 mmol) was dissolved in THF (3 mL), DIEA (660.31 mg, 5.11 mmol) was added, and then ethyl oxalyl chloride (261.58 mg, 1.92 mmol) was added dropwise. The mixture was allowed to react at room temperature for 1 hour. LCMS monitored the reaction completion, and methanol was added to quench the reaction. The solvent was removed by distillation under reduced pressure, and compound 28-13 (370 mg) was obtained by column chromatography. MS (ESI, m / z): 492.2 [M+H] + .

[0489] Step 13: Synthesis of 2-((4-(bis(4-methoxybenzyl)amino)-1,3-dihydrofuro[3,4-c]pyridin-7-yl)amino)-2-oxoacetic acid (Compound 28-14)

[0490] 28-13 (370 mg, 752.74 μmol) was dissolved in THF (5 mL), and a solution of LiOH·H2O (63.18 mg, 1.51 mmol) in H2O (1 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 hours. LCMS monitored the reaction to be complete. The solvent was removed by distillation under reduced pressure and lyophilized to obtain compound 28-14 (330 mg). MS (ESI, m / z): 464.2 [M+H] + .

[0491] Step 14: (R)-N 1 -(4-(bis(4-methoxybenzyl)amino)-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-N 2 -(1-(pyrimidin-2-yl)ethyl))-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 28-15)

[0492] Int C (9.14 mg, 32.36 μmol) was dissolved in DMF (1 mL), followed by the addition of HATU (24.61 mg, 64.73 μmol) and the mixture was stirred for 20 minutes. A DMF solution of 28-14 (15 mg, 32.36 μmol) was then added dropwise, and the mixture was allowed to react at room temperature overnight. LCMS monitoring confirmed the absence of residual starting material. The mixture was diluted with ethyl acetate, and the organic phase was washed with dilute brine and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and compound 28-15 (6 mg) was obtained by scraping (DCM:MeOH = 20:1). MS (ESI, m / z): 728.3 [M+H]. + .

[0493] Step 15: (R)-N 1 -(4-amino-1,3-dihydrofuro[3,4-c]pyridin-7-yl)-N 2-(1-(pyrimidin-2-yl)ethyl)-N 2 Synthesis of -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 28)

[0494] 28-15 (6 mg, 8.24 μmol) was dissolved in TFA (2 mL) and reacted at 90°C for 4 hours. LCMS monitoring showed no residual starting material. The reaction solution was distilled under reduced pressure to remove the solvent, and the base was adjusted with ammonia to prepare compound 28 (1.8 mg). MS (ESI, m / z): 488.2 [M+H] + .

[0495] 1 H NMR (400MHz, DMSO-d6) δ10.48-10.36 (m, 1H), 8.83-8.82 (m, 1H), 8.78-8.74 (m, 2H), 8.15-8.11 (m, 1H), 7.80-7.61 (m, 1H), 7.45- 7.36 (m, 2H), 6.01-5.95 (m, 2H), 5.80-5.60 (m, 1H), 5.24-4.90 (m, 2H), 4.87-4.80 (m, 2H), 4.76-4.56 (m, 2H), 1.65-1.50 (m, 3H).

[0496] The following compounds were prepared by the method and general steps described in Example 28. The other required raw materials can be purchased commercially or synthesized by experienced synthesizers in the field of organic synthesis using conventional reactions from commercially purchased reagents.

[0497] Example 70: (S)-N 1 -(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -methyl-N 2 -(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxalamide

[0498] Step 1: (S)N 1 -(7-((2,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -methyl-N 2 Synthesis of -(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxamide (Compound 70-1)

[0499] To a reaction flask, Int E (189.92 mg, 394.25 μmol) and Int G (100 mg, 394.25 μmol) were added and dissolved in anhydrous DMF (10 mL). DIPEA (152.86 mg, 1.18 mmol) and HATU (224.86 mg, 591.37 μmol) were then added sequentially. The reaction system was incubated at 25°C for 1 hour. After completion, the reaction was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The crude product was isolated and purified by silica gel column chromatography (DCM:MeOH = 95:5) to obtain compound 70-1 (220 mg). MS (ESI, m / z): 585.2 [M+H] + .

[0500] Step 2: (S)N 1 -(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -methyl-N 2 Synthesis of -(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxamide (Compound 70)

[0501] 70-1 (220 mg, 376.36 g) was dissolved in DCM (10 mL) and TFA (2 mL) was added. The reaction system was allowed to react at 25°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, dissolved in EA, washed with saturated sodium bicarbonate aqueous solution, and then washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The crude product was separated and purified by Prep-HPLC to obtain compound 70 (130 mg). MS (ESI, m / z): 435.1 [M+H] + .

[0502] 1 H NMR (400MHz, DMSO) δ10.69 (s, 1H), 8.09-7.81 (m, 2H), 7.74-7.53 (m, 1H), 7.44-7. 23(m, 2H), 6.37-5.83(m, 3H), 4.89-4.62(m, 2H), 4.29(s, 3H), 2.82-2.56(m, 3H).

[0503] Example 73: (S)-N 1 -(8-aminoimidazo[1,5-a]pyrazin-5-yl)-N 2 -methyl-N 2 -(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxalamide

[0504] Step 1: Synthesis of 5-bromo-1-(4-methoxybenzyl)pyrazin-2(1H)-one (Compound 73-3)

[0505] DMF (35 mL) and NaH (1.31 g, 32.86 mmol) were added to the reaction flask, cooled in an ice-water bath, and then a solution of 73-1 (5 g, 28.57 mmol) in THF (15 mL) was slowly added. Under nitrogen protection, the reaction was allowed to proceed at 0°C for 30 min. Then, 73-2 (4.92 g, 31.43 mmol, 4.26 mL) was added and the temperature was naturally warmed to room temperature and allowed to react overnight. After the reaction was completed, the reaction solution was diluted with water and extracted with EA (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 the crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 98:2) to obtain compound 73-3 (6.74 g). MS (ESI, m / z): 295.3 [M+H] + .

[0506] Step 2: Synthesis of 5-bromo-7-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8(7H)-one (Compound 73-4)

[0507] NaH (945 mg, 23.63 mmol) and THF (15 mL) were added to the reaction flask, cooled in an ice-water bath, and then a solution of 73-3 (3.1 g, 10.50 mmol) and TosMIC (2.26 g, 11.55 mmol) in THF (15 mL) was added. The mixture was stirred at 0°C for 2 hours under nitrogen. After the reaction was completed, the mixture was diluted with water and extracted with EA (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 the crude product. The crude product was purified by silica gel column chromatography (mobile phase EA:PE = 60:40) to obtain compound 73-4 (2.75 g). MS (ESI, m / z): 334.0 [M+H] + .

[0508] Step 3: Synthesis of 5-bromoimidazo[1,5-a]pyrazin-8(7H)-one (Compound 73-5)

[0509] 73-4 (450 mg, 1.35 mmol), anisole (2.62 g, 24.24 mmol), trifluoromethanesulfonic acid (2.43 g, 16.16 mmol, 1.43 mL), and TFA (6 mL) were added to the reaction flask under nitrogen protection and reacted at 40°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, most of the solvent was removed by vortexing, and then isopropyl ether was added to slurry. The filter cake was washed with isopropyl ether and dried to obtain compound 73-5 (320 mg). MS (ESI, m / z): 213.9 [M+H] + .

[0510] Step 4: Synthesis of 5-bromo-8-chloroimidazo[1,5-a]pyrazine (Compound 73-6)

[0511] To the reaction flask were added 73-5 (3 g, 14.02 mmol), DIPEA (3.62 g, 28.03 mmol), and POCl3 (30 mL), and the mixture was reacted at 100°C under nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, diluted with saturated NaHCO3 solution, and extracted with EA (50 ml x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound 73-6 (3.2 g). MS (ESI, m / z): 231.8 [M+H] + .

[0512] Step 5: Synthesis of 5-bromo-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]pyrazin-8-amine (Compound 73-7)

[0513] 73-6 (3.2 g, 13.77 mmol), EtOH (100 mL), and Int E-3 (4.60 g, 27.53 mmol) were added to the reaction flask under nitrogen protection and reacted at 80°C for 16 hours. After the reaction was completed, the reaction solution was diluted with water and extracted with EA (50 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 the crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 98:2) to obtain compound 73-7 (4.4 g). MS (ESI, m / z): 363.1 [M+H] + .

[0514] Step 6: Synthesis of N-(2,4-dimethoxybenzyl)-5-((diphenylmethylene)amino)imidazo[1,5-a]pyrazin-8-amine (Compound 73-8)

[0515] 73-7 (200 mg, 550.65 μmol), Int E-5 (200 mg, 1.10 mmol), Pd2(dba)3 (51 mg, 55.06 μmol), BINAP (69 mg, 110.13 μmol), t-BuONa (159 mg, 1.65 mmol), and Toluene (8 mL) were added to the reaction flask under nitrogen protection and reacted at 100°C overnight. After the reaction was completed, the reaction solution was diluted with water and 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 the crude product. The crude product was purified by silica gel column chromatography (mobile phase EA:PE = 40:60) and the mixture was dried to obtain compound 73-8 (140 mg). MS (ESI, m / z): 464.2 [M+H]+ .

[0516] Step 7: Synthesis of tert-butyl (2,4-dimethoxybenzyl)(5-((diphenylmethylene)amino)imidazo[1,5-a]pyrazin-8-yl)carbamate (Compound 73-9)

[0517] 73-8 (140 mg, 302.03 μmol) and THF (5 mL) were added to the reaction flask. After dissolution, (Boc)2O (132 mg, 604.06 μmol), DIPEA (117 mg, 906.09 μmol), and DMAP (7 mg, 60.41 μmol) were added. The mixture was protected by nitrogen and reacted at 70°C overnight. After the reaction was completed, the reaction solution was diluted with water and extracted with EA (30 ml x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 73-9 (170 mg). MS (ESI, m / z): 564.2 [M+H] + .

[0518] Step 8: Synthesis of tert-butyl (5-aminoimidazo[1,5-a]pyrazin-8-yl)(2,4-dimethoxybenzyl)carbamate (Compound 73-10)

[0519] To the reaction flask were added 73-9 (170 mg, 301.61 μmol), hydroxylamine hydrochloride (210 mg, 3.02 mmol), and MeOH (10 mL). The mixture was stirred at 25°C for 3 hours under nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: DCM:MeOH = 95:5) and dried to obtain compound 73-10 (45 mg). MS (ESI, m / z): 400.2 [M+H] + .

[0520] Step 9: Synthesis of ethyl 2-((8-((tert-butoxycarbonyl)(2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-5-yl)amino)-2-oxoacetate (Compound 73-11)

[0521] To the reaction flask were added 73-10 (45 mg, 112.66 μmol), DIPEA (29 mg, 225.31 μmol), and THF (3 mL), followed by the dropwise addition of ethyl oxalyl chloride (17 mg, 123.92 μmol). The reaction was carried out at 25°C under nitrogen atmosphere for 2 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with EA (30 ml x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 73-11 (50 mg). MS (ESI, m / z): 500.3 [M+H]+ .

[0522] Step 10: Synthesis of 2-((8-((tert-Butoxycarbonyl)(2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-5-yl)amino)-2-oxoacetic acid (Compound 73-12)

[0523] To the reaction flask were added 73-11 (50 mg, 100.10 μmol), LiOH·H2O (8.40 mg, 200.19 μmol), THF (2 mL), and H2O (0.5 mL), protected by nitrogen, and reacted at 25°C for 1 hour. After completion of the reaction, the reaction solution was adjusted to pH 4-5 with 2M hydrochloric acid and directly concentrated under reduced pressure to obtain compound 73-12 (45 mg). MS (ESI, m / z): 472.2 [M+H] + .

[0524] Step 11: Synthesis of tert-butyl (S)-(2,4-dimethoxybenzyl)(5-(2-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)amino)-2-oxoacetamido)imidazo[1,5-a]pyrazin-8-yl)carbamate (Compound 73-13)

[0525] 73-12 (47 mg, 99.69 μmol), Int G (25 mg, 99.69 μmol), HATU (45 mg, 119.63 μmol), and NMP (2 mL) were added to the reaction flask and stirred to dissolve. DIPEA (19 mg, 149.53 μmol) was then added under nitrogen and allowed to react at 25°C for 3 hr. After the reaction was completed, the reaction solution was diluted with water and 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 the crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 97:3) and the mixture was dried to give compound 73-13 (20 mg). MS (ESI, m / z): 671.3 [M+H] + .

[0526] Step 12: (S)-N 1 -(8-aminoimidazo[1,5-a]pyrazin-5-yl)-N 2 -methyl-N 2 Synthesis of -(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)oxamide (Compound 73)

[0527] 73-13 (20 mg, 29.82 μmol), DCM (1 mL), and TFA (2 mL) were added to the reaction flask under nitrogen protection and reacted at 25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure at room temperature, diluted with saturated sodium bicarbonate solution, and 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 the crude product. The crude product was purified by Pre-HPLC and lyophilized to obtain compound 73 (3 mg). MS (ESI, m / z): 421.2 [M+H] + .

[0528] 1 H NMR (400MHz, DMSO) δ8.28-8.04 (m, 1H), 7.83-7.80 (m, 1H), 7.71-7.53 (m, 1H) , 7.40-6.97(m, 6H), 6.33-6.01(m, 1H), 4.86-4.66(m, 2H), 2.83-2.59(m, 3H).

[0529] Example 74: (S)-N 1 -(8-aminoimidazo[1,5-a]pyrazin-5-yl)-N 2 -methyl-N 2 -(7-(Trifluoromethyl)isochroman-4-yl)oxalamide

[0530] Step 1: Synthesis of 5-bromo-N-(2,4-dimethoxybenzyl)-N-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8-amine (Compound 74-1)

[0531] 73-7 (150 mg, 412.99 μmol) and DMF (3 mL) were added to the reaction flask and cooled in an ice-water bath. NaH (25 mg, 619.48 μmol) was slowly added and the reaction was kept in an ice-water bath for 20 min. 73-2 (78 mg, 495.58 μmol) was then added. The mixture was protected by nitrogen and reacted at 0°C for 2 hr. After the reaction was completed, the reaction solution was diluted with water and 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 the crude product. The crude product was purified by silica gel column chromatography (mobile phase EA:PE = 35:65) and the mixture was dried to obtain compound 74-1 (110 mg). MS (ESI, m / z): 483.1 [M+H] + .

[0532] Step 2: Synthesis of N-(2,4-dimethoxybenzyl)-5-((diphenylmethylene)amino)-N-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8-amine (Compound 74-2)

[0533] To a reaction flask were added 74-1 (300 mg, 825.97 μmol), Int E-5 (300 mg, 1.65 mmol), Pd2(dba)3 (76 mg, 82.60 μmol), BINAP (103 mg, 165.19 μmol), t-BuONa (238 mg, 2.48 mmol), and Toluene (10 mL). The mixture was stirred at 100°C for 16 hours under nitrogen atmosphere. After completion of the reaction, the reaction solution was diluted with water and 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 the crude product. The crude product was purified by silica gel column chromatography (mobile phase EA:PE = 50:50) to obtain compound 74-2 (160 mg). MS (ESI, m / z): 584.3 [M+H] + .

[0534] Step 3: N 8 -(2,4-dimethoxybenzyl)-N 8 Synthesis of -(4-methoxybenzyl)imidazo[1,5-a]pyrazine-5,8-diamine (Compound 74-3)

[0535] 74-2 (200 mg, 342.65 μmol), hydroxylamine hydrochloride (238 mg, 3.43 mmol), and MeOH (5 mL) were added to the reaction flask under nitrogen protection and reacted at 25°C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 95:5) and the mixture was dried to obtain compound 74-3 (60 mg). MS (ESI, m / z): 420.2 [M+H] + .

[0536] Step 4: Synthesis of ethyl 2-((8-((2,4-dimethoxybenzyl)(4-methoxybenzyl)amino)imidazo[1,5-a]pyrazin-5-yl)amino)-2-oxoacetate (Compound 74-4)

[0537] 74-3 (60 mg, 143.04 μmol), DIPEA (37 mg, 286.07 μmol), and THF (3 mL) were added to the reaction flask, followed by the dropwise addition of ethyl oxalyl chloride (22 mg, 157.34 μmol). The reaction was carried out at 25°C under nitrogen atmosphere for 2 hours. After the reaction was completed, the reaction solution was diluted with water and extracted with EA (30 ml x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 97:3) and the product was collected and dried to obtain compound 74-4 (30 mg). MS (ESI, m / z): 520.2 [M+H] + .

[0538] Step 5: Synthesis of 2-((8-((2,4-dimethoxybenzyl)(4-methoxybenzyl)amino)imidazo[1,5-a]pyrazin-5-yl)amino)-2-oxoacetic acid (Compound 74-5)

[0539] To the reaction flask were added 74-4 (30 mg, 57.74 μmol), LiOH·H2O (5 mg, 115.49 μmol), THF (1.5 mL), and H2O (0.5 mL), protected by nitrogen, and reacted at 25°C for 1 hr. After completion of the reaction, the pH of the reaction solution was adjusted to 4-5 with 2M hydrochloric acid and concentrated under reduced pressure to obtain compound 74-5 (25 mg). MS (ESI, m / z): 492.1 [M+H] + .

[0540] Step 6: (S)-N 1 -(8-((2,4-dimethoxybenzyl)(4-methoxybenzyl)amino)imidazo[1,5-a]pyrazin-5-yl)-N 2 -methyl-N 2 Synthesis of -(7-(trifluoromethyl))isochroman-4-yl)oxalamide (Compound 74-6)

[0541] To the reaction flask, 75-9 (14 mg, 61.04 μmol), 74-5 (30 mg, 61.04 μmol), NMP (2 mL), and DIPEA (11.83 mg, 91.56 μmol) were added and stirred to dissolve. HATU (28 mg, 73.25 μmol) was then added under nitrogen and allowed to react at 25°C for 3 hr. After completion of the reaction, the reaction solution was diluted with water and extracted with EA (30 ml x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 97:3) to obtain compound 74-6 (30 mg). MS (ESI, m / z): 705.2 [M+H]+ .

[0542] Step 7: (S)-N 1 -(8-aminoimidazo[1,5-a]pyrazin-5-yl)-N 2 -methyl-N 2 Synthesis of -(7-(trifluoromethyl)isochroman-4-yl)oxalamide (Compound 74)

[0543] 74-6 (30 mg, 42.57 μmol) and TFA (3 mL) were added to the reaction flask under nitrogen protection and reacted at 100°C for 12 hours. After the reaction was completed, the reaction solution was spin-dried, diluted with saturated NaHCO3 solution, and 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 the crude product. The crude product was purified by Pre-HPLC to obtain compound 74 (5 mg). MS (ESI, m / z): 435.2 [M+H] + .

[0544] 1 H NMR (400MHz, DMSO) δ11.21-11.02 (m, 1H), 8.13-8.10 (m, IH), 7.94-7.88 (m, 1H), 7.75-7.66 (m, 2H), 7.65-7.62 (m, 1H), 7.54-7.43 (m, 2H) ), 7.10-7.02(m, 1H), 5.66-5.18(m, 1H), 4.96-4.89(m, 1H), 4.77-4.69(m, 1H), 4.16-4.14(m, 1H), 4.11-4.07(m, 1H), 2.89-2.70(m, 3H).

[0545] Example 75: (S)-N 1 -(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -methyl-N 2 -(7-(Trifluoromethyl)isochroman-4-yl)oxalamide

[0546] Step 1: Synthesis of 2-((allyloxy)methyl)-1-bromo-4-(trifluoromethyl)benzene (Compound 75-3)

[0547] Compounds 75-1 (900 g, 3.53 mol) and 75-2 (1.28 kg, 10.5 mol) and tetrabutylammonium hydrogen sulfate (179 g, 529 mmol) were added to a reaction flask, followed by the slow addition of solid KOH (376 g, 6.71 mol) in an ice bath. After addition, the mixture was naturally warmed to 25°C and stirred for 16 hours. TLC (PE / EA = 20 / 1, Rf = 0.84) confirmed the reaction was complete. The reaction solution was diluted with water (1000 mL) and extracted three times with ethyl acetate (1000 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 100 / 1 to 20 / 1) to afford compound 75-3 (1.10 kg).

[0548] 1 H NMR (400MHz, CD3OD) δ7.72-7.83 (m, 2H), 7.49 (dd, J=8.4, 1.7Hz, 1H), 5.88-6.09 (m, 1H), 5.19-5.41 (m, 2H), 4.60 (s, 2H), 4.14-4.16 (m, 2H).

[0549] Step 2: Synthesis of 4-methylene-7-(trifluoromethyl)isochroman (Compound 75-4)

[0550] Compound 75-3 (250 g, 847 mmol) was dissolved in DMF (1.50 L), followed by the addition of PPh (33.3 g, 127 mmol) and CsCO (331 g, 1.02 mol). After thorough stirring, Pd(OAc) (9.51 g, 42.3 mmol) was added under a nitrogen atmosphere. The reaction mixture was heated to 90°C and stirred for 16 hours. TLC (PE / EA = 20 / 1, Rf = 0.62) confirmed the reaction was complete. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phases were combined and washed with saturated aqueous NaCl (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification followed by separation and purification by silica gel column chromatography (PE / EA = 100 / 1 to 20 / 1) afforded compound 75-4 (60.0 g).

[0551] 1 H NMR (400MHz, CD3OD) δ7.91 (d, J=8.4Hz, 1H), 7.52 (d, J=8.4Hz, 1H), 7.42 (s, 1H), 5.81 (s, 1H), 5.18 (s, 1H), 4.83 (s, 2H), 4.46 (s, 2H).

[0552] Step 3: Synthesis of 7-(trifluoromethyl)isochroman-4-one (Compound 75-5)

[0553] Compound 75-4 (323 g, 1.51 mol) was dissolved in a mixed solvent of 1,4-dioxane (1.50 L) and H₂O (1.50 L). After thorough stirring at room temperature, the mixture was cooled to 0°C and NaIO₄ (967 g, 4.52 mol, 250 mL) was added. Stirring was continued at 0°C for 0.10 hr. K₂OsO₄·2H₂O (27.7 g, 75.4 mmol) was then added. The reaction was stirred at 0°C for 0.5 hr, then warmed to 25°C and continued for 12 hr. TLC (PE / EA = 5 / 1, Rf = 0.48) confirmed the reaction was complete. The reaction solution was filtered and extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with saturated NaCl (500 mL x 3). The organic phases were collected, dried over anhydrous Na₂SO₄, filtered, and concentrated. After separation and purification by silica gel column chromatography (PE / EA=100 / 1 to 5 / 1), the product was concentrated to give compound 75-5 (250 g). MS (ESI, m / z): 216.9 [M+H] + .

[0554] 1 H NMR (400MHz, CD3OD) δ 8.14 (d, J=8.0Hz, 1H), 7.67-7.79 (m, 2H), 4.98 (s, 2H), 4.41 (s, 2H).

[0555] Step 4: Synthesis of (R, Z)-2-methyl-N-(7-(trifluoromethyl)isochroman-4-ylidene)propane-2-sulfenamide (Compound 75-6)

[0556] Compound 75-5 (176 g, 814.23 mmol) and compound Int B-2 (296 g, 2.44 mol) were dissolved in DCE (1.20 L), and then Ti(O i The reaction mixture was heated to 50°C and stirred for 16 hours. LCMS confirmed the reaction was successful. The mixture was concentrated without further purification to afford compound 75-6 (260 g, 814 mmol). MS (ESI, m / z): 320.1 [M+H] + .

[0557] Step 5: Synthesis of (R)-2-methyl-N-((S)-7-(trifluoromethyl)isochroman-4-yl)propane-2-sulfenamide (Compound 75-7)

[0558] Compound 75-6 (260 g, 814 mmol) was dissolved in THF (1200 mL). After nitrogen was replaced, the temperature was lowered to 0°C, and NaBH4 (154 g, 2.44 mol) was added portionwise. After the addition was complete, the reaction was stirred at 25°C for 2 hr. TLC (EA / DCM = 1 / 10, Rf = 0.46) confirmed the reaction was complete. After cooling to 0°C, the reaction mixture was quenched by the addition of saturated aqueous NaHCO3. Ethyl acetate was added, and the mixture was stirred for 10 min. The mixture was then filtered, and the filtrate was diluted with water (1500 mL) and extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. Purification was achieved by silica gel column chromatography (PE / EA = 100 / 1 to 10 / 1), followed by concentration to afford compound 75-7 (219 g, 681 mmol). MS (ESI, m / z): 321.9 [M+H] + .

[0559] 1 H NMR (400MHz, CD3OD) δ7.80 (d, J=8.0Hz, 1H), 7.54 (d, J=8.0Hz, 1H), 7.40 (s, 1H), 4.88 (s, 1H), 4.75-4.80 (m, 1H), 4.51 (d, J=4.4Hz, 1H), 4.02 (dd, J=11.6, 4.6Hz, 1H), 3.87 (dd, J=11.6, 6.1Hz, 1H), 1.24 (s, 9H).

[0560] Step 6: Synthesis of (R)-N,2-dimethyl-N-((S)-7-(trifluoromethyl)isochroman-4-yl)propane-2-sulfenamide (Compound 75-8)

[0561] Compound 75-7 (219 g, 681 mmol) was dissolved in THF (1700 mL) and NaH (40.9 g, 1.02 mol) was slowly added under ice bath. After the addition was complete, the mixture was kept at 0°C and stirred for 0.5 hr. Then, MeI (111 g, 784 mmol, 48.8 mL) was added, and the reaction solution was warmed to 25°C and stirred for 16 hrs. After the reaction was completed by LCMS, water (1000 mL) was added to quench the reaction, and the mixture was then extracted with ethyl acetate (500 mL x 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 75-8 (228 g). MS (ESI, m / z): 335.9 [M+H] + .

[0562] 1H NMR (400MHz, CD3OD) δ7.62-7.68(m, 1H), 7.55-7.59(m, 1H), 7.45(s, 1H), 4.88(br s, 1H), 4.69-4.76 (m, 1H), 4.59-4.66 (m, 1H), 4.09-4.15 (m, 1H), 4.01-4.08 (m, 1H), 2.50 (s, 3H), 1.23 (s, 9H).

[0563] Step 7: Synthesis of (S)-N-methyl-7-(trifluoromethyl)isochroman-4-amine (Compound 75-9)

[0564] Compound 75-8 (228 g, 680 mmol) was dissolved in CH2Cl2 (500 mL) and a 2M solution of 1,4-dioxane hydrochloride (500 mL) was added under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 1 hour. LCMS indicated the reaction was complete, as determined by TLC (CH2Cl2 / MeOH = 10 / 1, Rf = 0.45). The reaction mixture was directly concentrated, diluted with water (500 mL), and then extracted with ethyl acetate (500 mL x 3). NaHCO3 solution was added to the aqueous phase to adjust the pH to 9-10, followed by extraction with ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The product was separated by SFC (chiral column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 μm); mobile phase: [n-hexane-ethanol (0.1% IPAm)]; B%: 7%) and concentrated to give compound 75-9 (38.0 g, 164 mmol). MS (ESI, m / z): 231.8 [M+H] + .

[0565] 1 H NMR (400MHz, CD3OD) δ7.48-7.59 (m, 2H), 7.41 (s, 1H), 4.91 (s, 1H), 4.70-4.79 (m, 1H), 4.18 (dd, J=11.6, 2.6Hz, 1H), 3.83 (dd, J=11.6, 3.0Hz, 1H), 3.61 (s, 1H), 2.44 (s, 3H).

[0566] Step 8: (S)-N 1 -(7-((2,4-dimethoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -methyl-N 2 Synthesis of -(7-(trifluoromethyl)isochroman-4-yl)oxamide (Compound 75-10)

[0567] Int E (1.23 g, 3.18 mmol) and NMP (35 mL) were added to the reaction flask, stirred to dissolve, and nitrogen was bubbled for 5 min. Then, 75-9 (700 mg, 3.03 mmol), DIPEA (587 mg, 4.54 mmol), and HATU (1.38 g, 3.63 mmol) were added sequentially under nitrogen protection and reacted at 25°C for 2 hr. After the reaction was completed, the reaction solution was diluted with water and 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 the crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM:MeOH = 98:2) to obtain compound 75-10 (1.8 g). MS (ESI, m / z): 599.3 [M+H] + .

[0568] Step 9: (S)-N 1 -(7-amino-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-N 2 -methyl-N 2 Synthesis of -(7-(trifluoromethyl)isochroman-4-yl)oxamide (Compound 75)

[0569] To the reaction flask were added 75-10 (2.05 g, 3.42 mmol), TFA (10 mL), and DCM (25 mL), under nitrogen protection, and the reaction was carried out at 25°C for 3 hours. After the reaction was completed, the reaction solution was spin-dried, diluted with saturated NaHCO3 solution, and 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 the crude product. The crude product was purified by Pre-HPLC to obtain compound 75. MS (ESI, m / z): 449.1 [M+H] + .

[0570] 1H NMR (400MHz, DMSO-d6) δ10.91-10.70 (m, 1H), 8.14-7.49 (m, 5H), 6.34 (s, 2H), 5.66-4. 97 (m, 1H), 4.95-4.66 (m, 2H), 4.30-4.26 (m, 3H), 4.17-4.04 (m, 2H), 2.83-2.65 (m, 3H).

[0571] Separation method

[0572] The Prep-HPLC purification of the compounds in the examples was performed using an Aglient 1260 or Waters 2489 HPLC, and the separation column model was a Waters SunFire Prep C 18OBD(19mm×150mm×5.0μm), Waters Xbridge Prep C 18 OBD (19mm×150mm×5.0μm) or YMC Actus Triart C 18 (20 mm × 150 mm × 5.0 μm), the column temperature was 25°C, the detection wavelength was 214 nm, 254 nm, or 280 nm, mobile phase A was acetonitrile, 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 28 mL / min.

[0573] Biological evaluation

[0574] Experimental Example 1: Inhibitory effect of compounds on PRMT5-MTA methyltransferase activity

[0575] Experimental method 1: The prepared protein solution (PRMT5 / MEP50 (Reaction) and MTA (MCE) mixture) was pre-incubated with different concentrations of the test compound (1000 nM starting, 5-fold dilution, 7 points) at 25°C for 30 minutes, and then the prepared substrate solution (Biotinylated histone H4 peptide (Sangon)) was added, and the reaction was incubated at 25°C for 90 minutes. After the reaction, the prepared detection reagent mixture (Protein A-Eu (Cisbio), Anti-Histone H4 antibody (Abcam), and Streptavidin-D2 (Cisbio)) was added, and the reaction was incubated at 25°C for 60 minutes. The fluorescence signal ratio (Ratio) was detected using a BMG microplate reader.

[0576] 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:

[0577] Percent inhibition rate = (negative control Ratio - compound Ratio) / (negative control Ratio - blank control Ratio) × 100%;

[0578] The four-parameter equation Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*Hillslope)) fits the detection signal value and calculates IC50 Where Y is the relative inhibitory activity percentage, Top and Bottom are the maximum and minimum values ​​of the fitted curve, respectively, X is the logarithmic concentration of the compound, and Hillslope is the slope of the curve. The inhibitory effects of the compounds on PRMT5-MTA methyltransferase were determined according to the above method, and the results are shown in Table 1.

[0579] Table 1. Inhibitory activity of the compounds of the present invention against PRMT5-MTA

[0580] Experimental Method 2: The inhibitory effect of the compounds of the present invention on PRMT5-MTA methyltransferase activity was determined according to the instructions of the PRMT5TR-FRET kit (BPS Bioscience). A mixture of PRMT5 / MEP50 enzyme (BPS Bioscience) and MTA (BPS Bioscience) was preincubated with different concentrations of the test compound (100 nM, 20 nM, and 4 nM) at 25°C for 30 minutes. Then, a mixed working solution of Biotinylated histone H4 peptide (BPS Bioscience) / S-adenosylmethionine (BPS Bioscience) was added, and the reaction was incubated at 25°C for 120 minutes. A working solution of Eu-labeled antibody (BPS Bioscience) was added, and the reaction was slowly shaken at 25°C for 30 minutes. Then, a working solution of Dye-labeled acceptor (BPS Bioscience) was added, and the reaction was slowly shaken at 25°C for 30 minutes. The fluorescence signal ratio (Ratio) was measured using a microplate reader.

[0581] The vehicle group (DMSO) was used as the negative control, and the 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:

[0582] Percent inhibition rate = (negative control Ratio - compound Ratio) / (negative control Ratio - blank control Ratio) × 100%;

[0583] When the percentage inhibition rate was between 30% and 80%, the half-maximal inhibitory concentration (IC 50 ) or range:

[0584] IC 50 =X×(1-percent inhibition rate (%)) / percent inhibition rate (%), where: X is the test concentration of the compound when the inhibition rate is between 30-80%. The inhibitory effect of the compound on PRMT5-MTA was determined according to the above method, and the results are shown in Table 2.

[0585] Table 2. Inhibitory activity of the compounds of the present invention on PRMT5-MTA

[0586] The experimental results show that the compounds of the present invention have a strong inhibitory effect on PRMT5-MTA enzyme.

[0587] Experimental Example 2: Compound Inhibition Test on MTAP Deleted / Parental HCT116 Cell Proliferation

[0588] The inhibitory effect of the compounds of the present invention on cancer cell proliferation was further evaluated by testing the effects of the compounds of the present invention on cancer cell growth.

[0589] Experimental Method 1: In this experiment, MTAP Deleted / Parental HCT116 cells were used, which were obtained from Pharmaron Inc.

[0590] MTAP-Deleted / Parental HCT116 cells were cultured as monolayers in MCCOYS 5A medium (Invitrogen) supplemented with 10% FBS and 1% P / S at 37°C and 5% CO2. Cells in logarithmically growing phase were digested and the concentration adjusted. 150 cells were seeded per well in a 384-well plate and cultured overnight. Prediluted compounds (10-dose 4-fold dilutions at 10,000 nM starting point or 8-dose 5-fold dilutions at 5,000 nM starting point) were added. DMSO was added to the negative control group, and medium was added to the blank control group. After 10 days of incubation at 37°C and 5% CO2, 40 μL of CellTiter-Glo (Promega) was added to each well, and relative chemiluminescence units (RLUs) were measured using a microplate reader in chemiluminescence detection mode.

[0591] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0592] Percent inhibition rate = (1-(chemiluminescent signal value of the test compound-chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control-chemiluminescent signal value of the blank control)) × 100%

[0593] 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:

[0594] 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 fitted curve, respectively; x is the logarithmic concentration of the compound; and Hillslope is the slope of the curve.

[0595] The proliferation inhibitory activity of the compounds on MTAP Deleted / Parental HCT116 cells was determined according to the above method. The results are shown in Table 3.

[0596] Table 3. Proliferation inhibitory activity of the compounds of the present invention on MTAP Deleted / Parental HCT116 cells

[0597] Experimental method 2: In this experimental example, MTAP Deleted / Parental HCT116 cells were selected and purchased from HORIZON.

[0598] MTAP-Deleted / Parental HCT116 cells were cultured as monolayers in vitro in RPMI6140 medium (source culture) supplemented with 10% FBS and 1% P / S at 37°C and 5% CO2. Cells in logarithmic growth phase were digested and the concentration was adjusted. 250 cells per well were seeded into 96-well plates and cultured overnight. Pre-diluted compounds were added (5000 nM starting concentration, 4-fold dilution, 9 points). DMSO was added to the negative control group, and culture medium was added to the blank control group. After 7 days of incubation at 37°C and 5% CO2, 50 μl of CellTiter-Glo (Promega) was added to each well for lysis at room temperature in the dark for 10 minutes. The test solution was transferred to a 96-well opaque white plate, and the relative chemiluminescence units were read on a microplate reader in chemiluminescence detection mode.

[0599] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0600] Percent inhibition rate = (1-(chemiluminescent signal value of the test compound-chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control-chemiluminescent signal value of the blank control)) × 100%

[0601] 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:

[0602] 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 fitted curve, respectively; x is the logarithmic concentration of the compound; and Hillslope is the slope of the curve.

[0603] The proliferation inhibitory activity of the compounds on MTAP Deleted / Parental HCT116 cells was determined according to the above method. The results are shown in Table 4.

[0604] Table 4. Proliferation inhibitory activity of the compounds of the present invention on MTAP Deleted / Parental HCT116 cells

[0605] The experimental results show that the compound of the present invention has a strong inhibitory effect on MTAP Deleted HCT116 cells and has a certain selectivity for MTAP Parental HCT116 cells.

[0606] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from 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 having the structure of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof: in: Ring A is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups; Ring B is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroaryl and C 6-10 Aryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups; R 1 is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO2, -NR 10 R 11 、-CONR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted; R 2 For LR 2 '; L is independently a direct key or -(CR 5 R 6 ) p -; R 2 ' is independently selected from C at each occurrence 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl and 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkenyl, alkynyl, 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 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted; R 3 Selected from H, OH, halogen, CN, NR 10 R 11 、C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic groups are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 heterocyclic substitution; R 4 Each occurrence is independently selected from H, OH, oxo, halogen, CN, -NO2, -SF5, -NR 7 R 8 、-NHCOC 1-6 Alkyl, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution; Or, R 3 and R 4 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclic group; R 9 Each occurrence is independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclic groups are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 heterocyclic substitution; R 5 and R 6 Each independently selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by one or more halogen, OH, CN, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or R 5 and R 6 The carbon atom it is connected to forms C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, the cycloalkyl, heterocyclic group is optionally substituted by one or more OH, halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution; R 7 、R 8 、R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally One or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 substituted by cycloalkoxy or 3-6 membered heterocyclic group; or R 7 and R 8 、R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, which is optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-6 membered heterocyclic substitution; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Ring A is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, and 3-8 membered heterocyclyl; Ring B is selected from C 6-15 Aromatic ring, 5-15 membered heteroaromatic ring, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclic group, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclic group, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups; R 1 Each occurrence is independently selected from H, OH, halogen, -NR 10 R 11 、-CONR 10 R 11 、C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl; the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclyl substitution; R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; L is selected from a direct bond, -CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH(cyclopropyl)-, cyclopropylene, cyclobutylene, and cyclopentylene; R 2 ' is independently selected from C at each occurrence 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted; R 3 Selected from H, OH, halogen, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl and C 3-6 Cycloalkyl; R 4 Each occurrence is independently selected from H, oxo, OH, halogen, CN, -SF5, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 cycloalkoxy and 3-6 membered heterocyclic substitution; Or, R 3 and R 4 Together with the atoms to which they are attached, they form a 3-10 membered heterocyclic group; R 9 Each occurrence is independently selected from H, C 1-4 Alkyl and C 3-8 Cycloalkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Ring A is selected from C 6-15 Aromatic rings and 5-15 membered heteroaromatic rings; Preferably, ring A is selected from C 6-10 aromatic rings and 5-10 membered heteroaromatic rings; Preferably, ring A is selected from a 5-10 membered nitrogen-containing heteroaromatic ring; Preferably, ring A is selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, Preferably, ring A is selected from pyridyl, Preferably, ring A is selected from Preferably, Selected from The wavy line represents the point of attachment of the group to the rest of the molecule.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Ring B is selected from C 6-15 aromatic rings, 5-15 membered heteroaromatic rings, 5-15 membered heteroarylphenyl rings, and 3-8 membered heterocyclylphenyl rings; Preferably, ring B is selected from C 6-10 Aromatic ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroarylphenyl and 5-6 membered heterocyclylphenyl; Preferably, ring B is selected from a 5-10 membered nitrogen-containing heteroaromatic ring and a 6-membered heterocyclylphenyl group; Preferably, ring B is selected from benzene ring, naphthalene ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, indole ring, isoindole ring, indazole ring, benzimidazole ring, benzothiazole ring, quinoline ring, isoquinoline ring, Benzopiperidine ring, benzotetrahydrofuran ring and pyridopyran ring; Preferably, ring B is selected from a benzene ring, a pyridine ring, a pyridazine ring, an indole ring, an indazole ring, a benzimidazole ring, a benzothiazole ring, a benzopiperidine ring, benzotetrahydrofuran ring and pyridopyran ring; Preferably, ring B is selected from benzene ring, Preferably, Selected from The wavy line represents the point of attachment of the group to the rest of the molecule.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: R 1 Each occurrence is independently selected from H, OH, halogen, -NR 10 R 11 、-CONR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy and 3-8 membered heterocyclyl; the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclyl substitution; R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Preferably, R 1 Each occurrence is independently selected from H, OH, halogen, -NR 10 R 11 、-CONR 10 R 11 、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and C 3-8 Cycloalkyl; the alkyl, alkoxy, heteroalkyl, cycloalkyl is optionally substituted by one or more halogen, OH, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy substituted; R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Preferably, R 1 Each occurrence is independently selected from H, OH, halogen, -NR 10 R 11 、-CONR 10 R 11 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 3-8 Cycloalkyl; R 10 and R 11 Each independently selected from H, C 1-6 Alkyl, or R 10 and R 11 Together with the nitrogen atom to which it is attached, it forms a 4-6 membered heterocyclic group; Preferably, R 1 Each occurrence is independently selected from H, halogen, -NHC 1-4 Alkyl, -N(C 1-4 alkyl)2, azetidinyl, pyrrolidinyl, piperidinyl, -NH2, -CONH2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 3-8 Cycloalkyl; Preferably, R 1 Each occurrence is independently selected from H, -NH2, -CONH2, C 1-4 Alkyl and C 1-4 alkoxy; Preferably, R 1 is independently selected at each occurrence from H, -CH3, -NH2, -CONH2 and -OCH3.

6. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: L is selected from a direct bond, -CH(C 1-6 alkyl)- and C 3-6 Cycloalkyl; Preferably, L is selected from a direct bond, -CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH(cyclopropyl)-, cyclopropylene, cyclobutylene and cyclopentylene.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: R 2 ' is independently selected from C at each occurrence 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, OH, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, C 3-6 Heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl substituted; Preferably, R 2 ' is independently selected from C at each occurrence 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Substituted by cycloalkyl, 3-6 membered heterocyclyl, or 5-10 membered heteroaryl; Preferably, R 2 ' is independently selected from C at each occurrence 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted by one or more halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic substitution; Preferably, R 2 ' is independently selected at each occurrence from methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrimidinyl, -CH2OCH3, morpholinyl, pyranyl, pyrazolyl, pyridinyl, pyrrolopyridinyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyranyl, pyrazolyl, pyridyl, Optionally, one or more halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl substitution; Preferably, R 2 ' is independently selected at each occurrence from methyl, trifluoromethyl, isopropyl, isobutyl, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclohexyl, cyclopentyl, dimethylcyclopentyl, <h2 style=";text-align:left;direction:ltr">-CH2OCH3、<h2 style=";text-align:left;direction:ltr"> Preferably, R 2 is independently selected at each occurrence from methyl, isopropyl, trifluoroethyl, isobutyl, The wavy line represents the point of attachment of the group to the rest of the molecule.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Preferably, R 3 Selected from H, OH, halogen, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl and C 3-6 Cycloalkyl; Preferably, R 3 Selected from H and C 1-4 alkyl; Preferably, R 3 Selected from H and methyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: R 4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, -NR 7 R 8 、-NHCOCH3、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, the alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, heteroaryl are optionally substituted by one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 cycloalkoxy and 3-6 membered heterocyclic substitution; Preferably, R 4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, -NR 7 R 8 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, the alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, CN, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 cycloalkoxy and 3-6 membered heterocyclic substitution; Preferably, R 4 is independently selected at each occurrence from H, oxo, CN, halogen, -NR 7 R 8 、C 1-4 Halogenated alkyl, 3-8 heterocyclic group, C 1-4 Halogenated alkoxy, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, heteroaryl are optionally substituted with one or more halogen, -NR 5 R 6 、C 1-4 Alkyl and C 1-4 haloalkyl substitution; Preferably, R 4 Each occurrence is independently selected from H, oxo, CN, F, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 alkyl)2, azetidinyl, pyrrolidinyl, piperidinyl, CF3, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl and 5-6 membered heteroaryl, said alkoxy, heteroalkyl, heteroaryl are optionally substituted with one or more halogen, -NR 5 R 6 、C 1-4 Alkyl, C 1-4 haloalkyl substitution; Preferably, R 4 Each occurrence is independently selected from H, oxo, F, -N(CH3)2, CF3, CN, cyclopropyl, -SF5 and -OCF3.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: R 5 and R 6 Each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are optionally substituted by one or more halogen, OH, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group substituted; or R 5 and R 6 Compared with it The connected carbon atoms form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, the cycloalkyl, heterocyclic group is optionally substituted by one or more halogen, OH, -NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic substitution; Preferably, R 5 and R 6 Each independently selected from H, C 1-4 Alkyl; or R 5 and R 6 The carbon atom to which it is attached forms cyclopropyl, cyclobutyl, and cyclopentyl groups; Or, R 3 and R 4 Together with the atoms to which it is attached, it forms a 3-8 membered heterocyclic group.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: m is 0, 1 or 2.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: n is 0, 1 or 2.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: p is 1.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled form, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein the compound is a compound of formula I-1: where q is 0 or 1.

15. A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled form, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein the compound is selected from:

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.

17. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 15, in the preparation of a medicament for preventing and / or treating a disease or condition associated with PRMT5 activity; Preferably, the disease or condition associated with PRMT5 activity is a disease that is sensitive or responsive to inhibition of PRMT5 activity; Preferably, the disease or condition associated with PRMT5 activity is cancer or tumor, more preferably a cancer or tumor with MTAP deficiency; The cancer or tumor is preferably 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) or lymphoma, etc.

18. A method for preparing the compound according to any one of claims 1 to 15, comprising the steps of: Step 1: Compound IA-1 and R 2 NH2 undergoes reductive amination to generate compound IA-2; Step 2: Compound IA-3 and acyl chloride Compound IA-4 is generated through condensation reaction; Step 3: Compound IA-4 is hydrolyzed to generate compound IA-5; Step 4: Compound IA-2 and compound IA-5 undergo condensation reaction to generate compound I; If necessary, a fifth step is required: the condensation product of the fourth step is deprotected to generate compound I; in, Ring A, Ring B, R 1 、R 2 、R 3 、R 4 、R 9 , m, n and p are as defined in any one of claims 1-15.

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