WO2024104244A1

WO2024104244A1 - Oxamide compound, pharmaceutical composition containing same, and preparation method therefor and use thereof

Info

Publication number: WO2024104244A1
Application number: PCT/CN2023/130657
Authority: WO
Inventors: 陈忠辉; 梅红江; 田强; 宋宏梅; 葛均友
Original assignee: 四川科伦博泰生物医药股份有限公司
Priority date: 2022-11-15
Filing date: 2023-11-09
Publication date: 2024-05-23

Abstract

An oxamide compound, a pharmaceutical composition containing same, and a preparation method therefor and the use thereof. Specifically, disclosed is a compound having the structure of formula I, which compound exhibits excellent PRMT5 regulatory activity and is used for preventing and/or treating diseases related to PRMT5 activity.

Description

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

Technical Field

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 technique

PRMT5 (Protein Arginine Methyltransferase 5) is an epigenetic enzyme and a member of the PRMT family (the human body has PRMT1-11). It can catalyze the methylation modification of arginine residues of 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 testis. According to the different ways of catalyzing arginine methylation, it is divided into types I, II and III. PRMT5 belongs to type II symmetric dimethylation (sDMA) PRMT, and its methyl donor is S-adenosylmethionine (SAM).

PRMT5 regulates the expression of multiple target proteins by catalyzing the arginine methylation of substrates, participates in multiple physiological functions, and plays an important role in tumor cell proliferation, metastasis, and malignant transformation. PRMT5 methylation modification 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 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.).

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.

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

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

SUMMARY OF THE INVENTION

The present invention provides a novel oxalamide compound, which can regulate PRMT5 activity and can be used to prevent or treat diseases or conditions related to 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.

One aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer or 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 heterocyclyl, 5-6 membered heteroaryl and 3-8 membered cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocyclyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl;

Ring B is selected from C _6-15 aromatic ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroaryl and C _6-10 aromatic 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, C _3-8 cycloalkyl, 3-8 membered heterocyclyl;

R ¹ is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO ₂ , -NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, _3-8 membered heterocyclyl, C _6-10 aromatic ring and 5-10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C substituted by C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl;

R ² is LR ² ';

L is independently a direct bond or -(CR ⁵ R ⁶ ) _p - at each occurrence;

R ² 'at each occurrence 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 heterocyclyl, C 3-8} _{cycloalkyloxy} , 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 and 3-8 membered cycloalkyl and 5-6 membered heteroaryl and 3-8 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C substituted with _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl;

R ³ is 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 heterocyclyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl is optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, C _3-6 heterocyclyl;

^R4 is independently selected at each occurrence from H, OH, oxo, halogen, CN, _-NO2 , ^-SF5 , ^-NR7R8 , _{-NHCOC1-6alkyl, C1-6alkyl} _, _-C2-6alkenyl _, _-C2-6alkynyl , C1-6haloalkyl, _C1-6alkoxy , _{C2-6heteroalkyl} , C1-6haloalkoxy, _{C3-8cycloalkyl} , _3-8 membered heterocyclyl, _{C3-8cycloalkyloxy} , _C6-10aryl , 5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl _, heterocyclyl, cycloalkyloxy, aryl, heteroaryl being optionally _substituted with one or _more halogen, CN, ^-NR5R6 , ^C1-4alkyl , C1-4haloalkyl, _C1-4alkoxy , _{C1-4haloalkoxy} , _{C3-6cycloalkyl} , C _3-8- membered cycloalkoxy, 3-6-membered heterocyclic group substitution;

Alternatively, R ³ and R ⁴ together with the atoms to which they are attached form a 3-10 membered heterocyclic group;

R ⁹ is independently selected at each occurrence _from H, C _1-6 alkyl, C _1-6 alkoxy, C 2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, said alkyl, heteroalkyl, cycloalkyl, heterocyclyl being optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl _, C 1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, C _3-6 heterocyclyl;

^R5 and ^R6 are each independently selected from H, OH, halogen, _C1-6 alkyl, _C1-6 alkoxy and _C3-8 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more halogen, OH, CN, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkyloxy, 3-6 membered heterocyclyl; or

^R5 and ^R6 , together with the carbon atom to which they are attached, form a _C3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, wherein the cycloalkyl group or the heterocyclyl group is optionally substituted by one or more OH, ^halogen , CN, ^-NR5R6 , _C1-4 alkyl group, _C1-4 haloalkyl group, _C1-4 alkoxy group, _C1-4 haloalkoxy group, _C3-6 cycloalkyl group, _C3-8 cycloalkoxy group or a 3-6 membered heterocyclyl group;

R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more halogen, CN, -NR ⁵ R ⁶ , C _1-4 alkyl, C 1-4 _haloalkyl , C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, 3-6 membered heterocyclyl; or

^R7 and ^R8 , ^R10 and ^R11 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, which is optionally substituted with one or more halogen, CN, ^-NR5R6 , ^C1-4 alkyl, _C1-4 haloalkyl _, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkoxy, or a 3-6 membered heterocyclic group;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 2.

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.

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, 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.

Another aspect of 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, for use in preventing or treating a disease or condition associated with PRMT5 activity.

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

Another aspect of the invention provides a process for preparing the compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

definition

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

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

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, for example 1 to 6 carbon atoms. For example, as used herein, the terms "C _1-6 alkyl" and "C _1-4 alkyl" refer to a linear or branched group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) having 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively, which is optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl") (e.g., CH ₂ F, CHF ₂ , CF ₃ , CCl ₃ , C ₂ F ₅ , C ₂ Cl ₅ , CH ₂ CF ₃ , CH ₂ Cl or -CH ₂ CH ₂ CF ₃ , 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).

As used herein, the term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon double bonds. For example, the term " _C2-6 alkenyl" used herein refers to an alkenyl group (such as vinyl, 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.) with 2-6 carbon atoms and one, two or three carbon-carbon double bonds, which is optionally substituted with one or more (such as 1-3) substituents described herein.

As used herein, the term "alkynyl" refers to a straight or branched aliphatic hydrocarbon group with one or more carbon-carbon triple bonds. For example, the term " _C2-6alkynyl " as used herein refers to an alkynyl group (such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.) with 2-6 carbon atoms and one, two or three carbon-carbon triple bonds, which is optionally substituted with one or more (such as 1-3) substituents described herein.

As used herein, the term "heteroalkyl" refers to an alkyl group with one or more backbone chain atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, in the main chain carbon atoms. Numerical ranges may be given (e.g., C _1-6 heteroalkyl) referring to the number of carbons in the chain, which in this example includes 1-6 carbon atoms. For example, a -CH ₂ OCH ₂ CH ₃ group is referred to as a C ₃ heteroalkyl group, and a -CH ₂ OCH ₂ CH ₂ NHCH ₃ group is referred to as a C ₄ heteroalkyl group. Connection to the rest of the molecule may be through a heteroatom or a carbon atom in the heteroalkyl chain.

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, and the terms “C _1-8 haloalkyl”, “C _1-6 haloalkyl” and “C _1-4 haloalkyl” refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, for example, -CF ₃ , -C ₂ F ₅ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CH ₂ Cl or -CH ₂ CH ₂ CF ₃ , etc.

As used herein, the term "hydroxyalkyl" refers to a group formed by replacing the hydrogen atoms in an alkyl group with one or more hydroxy groups, such as a _C1-4 hydroxyalkyl group or a _C1-3 hydroxyalkyl group, examples of which include but are not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH) _CH3 , and the like.

As used herein, the term "alkoxy" means a group in which an oxygen atom is inserted at any reasonable position of an alkyl group (as defined above), preferably a C _1-8 alkoxy, a C _1-6 alkoxy, a C _1-4 alkoxy or a C _1-3 alkoxy. Representative examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH ₂ -OCH ₃ , etc., wherein the alkoxy is optionally substituted with one or more (such as 1 to 3) identical or different substituents. For example, the term "haloalkoxy" means that the hydrogen atoms of the alkoxy are substituted with one or more (such as 1 to 3) identical or different halogen atoms.

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

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.

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.

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, cyclocyclic (condensed) or bridged ring systems (i.e., spirocyclic alkyl, cyclocyclic (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 " _C3-8 cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring-forming carbon atoms, for example, a _C3-6 cycloalkyl group, which may be a monocyclic alkyl group, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic alkyl group, for example, a _C5-8 spirocycloalkyl group, a _C5-8 bridged cycloalkyl group, _{a C5-8} fused cycloalkyl group, a _C5-6 spirocycloalkyl group, a _C5-6 bridged cycloalkyl group or a _C5-6 fused cycloalkyl group.

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

As used herein, the term "heterocyclyl" or "heterocycle" refers to an aliphatic monocyclic or polycyclic (e.g., fused, spiro 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, the carbon atoms and heteroatoms on the heterocyclyl group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O) ₂ ), or are optionally substituted with one or more (e.g., 1 to 3) substituents independently selected from halogen and _C1-3 alkyl.

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 the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 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.

In the present invention, the heterocyclic group can form a parallel ring structure with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other group can be on any heterocyclic group or on the cycloalkyl group. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic groups and heterocyclic groups, heterocyclic groups and cycloalkyl groups, monoheterocyclic groups and monoheterocyclic groups, and monoheterocyclic groups and monocycloalkyl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and (mono) cycloalkyl groups, and 3-7 membered (mono) heterocyclic groups and _C4-6 (mono) cycloalkyl groups. Examples thereof include but 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,

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

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.

As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example The "nitrogen-containing spiro heterocycle", "oxygen-containing spiro heterocycle" and "sulfur-containing spiro heterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiro heterocyclic group" refers to a spiro heterocyclic group containing a total of 6-10 ring atoms and at least one of the ring atoms being a nitrogen atom.

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

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. As used herein, the term "C _6-15 aryl (aromatic ring)" means an aryl (aromatic ring) containing 6 to 15 carbon atoms, preferably a C _6-10 aryl (aromatic ring), preferably a phenyl (benzene ring) or a naphthyl (naphthalene ring). The aryl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO ₂ , C ₁ -C ₆ alkyl, etc.).

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 (mono)heteroaryl, (mono)aryl (monocyclic)aryl, (mono)aryl (mono)heterocyclic group and (mono)aryl (mono)cycloalkyl, such as phenyl 5-6 membered (mono)heteroaryl, phenyl 3-8 membered (mono)heterocyclic group or phenyl C _3-8 (mono)cycloalkyl, phenyl 5-6 membered (mono)heterocyclic group, phenyl C _4-6 (mono)cycloalkyl, examples of which include but are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, benzothiazole, quinolyl, isoquinolyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, wait.

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 may have 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ring atoms, such as 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O) ₂ ).

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

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 cyclic structure. The point of attachment may be on any heteroaromatic ring or on other rings, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (mono)heterocyclyl, and (mono)heteroaryl and (mono)cycloalkyl, such as 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, quinolyl, isoquinolyl, pyrrolopyridinyl, wait.

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

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

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

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.

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

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

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.

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 atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( ^2H ), tritium ( ^3H )); isotopes of carbon (e.g., ^11C , ^13C , and ^14C ); isotopes of chlorine (e.g., ^36Cl ); isotopes of fluorine (e.g., ^18F ); isotopes of iodine (e.g., ^123I and ^125I ); isotopes of nitrogen (e.g., ^13N and ^15N ); isotopes of oxygen (e.g., ^15O , ^17O , and ^18O ); isotopes of phosphorus (e.g., ^32P ); and isotopes of sulfur (e.g., ^35S ). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioisotopes) are useful in drug and/or substrate tissue distribution studies (e.g., assays). The radioisotopes tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) are particularly useful for this purpose because they are easily incorporated and easily detected. Substitution with positron emitting isotopes (e.g., ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by methods similar to those described in the accompanying routes and/or in the examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D ₂ O, acetone-d ₆ or DMSO-d ₆ .

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

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

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

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

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

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

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

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

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

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

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

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

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 less pharmacological activity or no pharmacological activity, which when administered into or onto the body can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). 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)).

The present invention also encompasses compounds of the present invention containing protecting groups. In 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 by conventional protecting groups, for example, those described in T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.

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

Compound

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

in:

R ¹ is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO ₂ , NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, _3-8 membered heterocyclyl, C _6-10 aromatic ring and 5-10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C substituted by C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl;

R ² is LR ² ';

L is independently a direct bond or -(CR ⁵ R ⁶ ) _p - at each occurrence;

R ² 'is independently selected at each occurrence 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 heterocyclyl, C _3-8 cycloalkyloxy, 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 and 3-8 membered cycloalkyl, and 5-6 membered heteroaryl and 3-8 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C substituted with _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl;

R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, wherein 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 haloalkyl, C 1-4} _alkoxy , C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, 3-6 membered heterocyclyl; or

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 2.

In some embodiments, ^R4 is independently selected at each occurrence from H, OH, oxo, halogen, CN, _-NO2 , ^-NR7R8 ^, -NHCOC1-6 alkyl, _C1-6 alkyl, _-C2-6 alkenyl, _-C2-6 alkynyl, C1-6 haloalkyl, _C1-6 alkoxy, _C2-6 heteroalkyl, _C1-6 haloalkoxy, _C3-8 cycloalkyl, _3-8 membered heterocyclyl, _C3-8 cycloalkyloxy, _C6-10 aryl, _5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, _{aryl, heteroaryl being optionally substituted with one or more halogen, CN, -NR5R6, C1-4 alkyl, C1-4} ^haloalkyl ^, _C1-4 _alkoxy , _C1-4 haloalkoxy, _C3-6 cycloalkyl, C _3-8- membered cycloalkoxy or 3-6-membered heterocyclic group.

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, 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, C _3-8 cycloalkyl, 3-8 membered heterocyclyl;

R ² is LR ² ';

L is independently a direct bond or -(CR ⁵ R ⁶ ) _p - at each occurrence;

R ² 'is independently selected at each occurrence 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 heterocyclyl, C _3-8 cycloalkyloxy, 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, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C substituted by C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C _3-6 heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl;

^R4 is independently selected at each occurrence from H, OH, oxo, halogen, CN, _-NO2 , ^-NR7R8 ^, -NHCOC1-6alkyl, _C1-6alkyl , _-C2-6alkenyl _, -C2-6alkynyl, _{C1-6haloalkyl} , _C1-6alkoxy , _{C2-6heteroalkyl} , C1-6haloalkoxy, _{C3-8cycloalkyl} , 3-8 membered heterocyclyl, _{C3-8cycloalkyloxy} , _C6-10aryl , _5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, _heteroalkyl , cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl being optionally _substituted with one or more halogen, CN, ^-NR5R6 , ^C1-4alkyl , _{C1-4haloalkyl} , _C1-4alkoxy , _{C1-4haloalkoxy} , _{C3-6cycloalkyl} , C _3-8- membered cycloalkoxy, 3-6-membered heterocyclic group substitution;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 2.

Ring A is selected from the group consisting of a C _6-15 aromatic ring, a 5-15 membered heteroaromatic ring, a benzo 3-8 membered cycloalkyl group, a benzo 3-8 membered heterocyclyl group, a 5-6 membered heteroaryl 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl 3-8 membered heterocyclyl group, and a 3-8 membered heterocyclyl group;

Ring B is selected from a 5-10 membered nitrogen-containing heteroaromatic ring, a 6-membered heteroaryl-heterocyclyl, a 5-membered heteroaryl-phenylene, a 5-membered heterocyclyl-phenylene and a 6-membered heterocyclyl-phenylene;

R ¹ is independently selected at each occurrence 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 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _1-4 hydroxyalkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl; said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy ^, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, C _3-6 heterocyclyl; R ₁₀ and R ^{R 11} is each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

R ² is LR ² ';

L is selected from a direct bond, _-CH2- , -CH( _CH3 )-, -CH( _CH3 ) _CH2- , -CH(cyclopropyl)-, cyclopropylene, cyclobutylene, and cyclopentylene;

R ² 'is independently selected at each occurrence from Ci _-6 alkyl, Ci-6 alkoxy, C _2-6 heteroalkyl, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, 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, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , Ci _-4 alkyl, Ci _-4 haloalkyl, Ci-4 alkoxy, Ci _-4 _haloalkoxy , C substituted with C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C ₃ - ₆ heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl;

R ³ is selected from H, OH, halogen, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , C _1-4 alkyl and C _3-6 cycloalkyl;

^R4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, ^-NR7R8 , _-NHCOCH3 , ^C1-4 alkyl, _C1-4 haloalkyl, _C1-6 alkoxy, _C2-6 heteroalkyl, _C1-4 haloalkoxy, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, _C6-10 aryl and _5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl being optionally substituted with one or more halogen, CN, ^-NR5R6 , ^C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkyloxy and _3-6 membered heterocyclyl;

R ⁹ , at each occurrence, is independently selected from H, C _1-4 alkyl and C _3-8 cycloalkyl;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 2.

^R9 is H;

Ring A is selected from C _6-10 aromatic rings and 5-10 membered heteroaromatic rings;

Ring B is selected from C _6-10 aromatic rings and 5-10 membered heteroaromatic rings;

R ¹ is independently selected at each occurrence from H, halogen, CN, -NH ₂ , -CONH ₂ , C _1-4 alkyl, C 1-4 haloalkyl, C _1-4 alkoxy, C _1-4 _haloalkoxy , C _1-4 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkoxy;

R ² is LR ² ';

L is independently a direct bond or -(CR ⁵ R ⁶ ) _p - at each occurrence;

R ² 'is independently selected at each occurrence _from C _1-6 alkyl, C _1-6 alkoxy, C 1-6 hydroxyalkyl, C _2-6 heteroalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _3-8 cycloalkyloxy, C _6-10 aryl, 5-10 membered heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy, C ₃ - ₆ heterocyclyl, C _6-10 aryl, C _5-10 heteroaryl;

^R3 is selected from H and _C1-4 alkyl;

R ⁴ is independently selected at each occurrence from H, OH, halogen, CN, -NR ⁷ R ⁸ , -NHCOCH ₃ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _{1-4 haloalkoxy, C 3-8} _cycloalkyl , 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, said heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl optionally substituted with one or more halogen, CN, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl, C 1-4 alkoxy _, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, 3-6 membered heterocyclyl;

R ⁵ and R ⁶ are each independently selected from H, C _1-4 alkyl and C _3-8 cycloalkyl;

^R7 and ^R8 are each independently selected from H and _C1-4 alkyl and _C3-8 cycloalkyl;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 2.

In certain embodiments, in the compound of formula I provided by the present invention, R ¹ is independently selected from H, halogen, -NH ₂ , -CONH ₂ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-8 cycloalkyl at each occurrence.

In certain embodiments, in the compound of formula I provided by the present invention, R ¹ is independently selected from H, -NH ₂ , -CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy at each occurrence.

In certain embodiments, in the compounds of formula I provided by the present invention, 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 at each occurrence, and the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 haloalkyl, C 1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, 5-10 membered heteroaryl.

In certain embodiments, in the compounds of formula I provided by the present invention, 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 at each occurrence, and the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I, wherein R ³ is selected from H and C _1-4 alkyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁴ is independently selected from H, halogen, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _{1-4 haloalkyl, C 1-4} _{alkoxy, C 2-6} _heteroalkyl , C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, and the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, heteroaryl are optionally substituted with one or more halogen, CN, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl _, C 1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, 3-6 membered heterocyclyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁴ is independently selected from H, halogen, -NR ⁷ R ⁸ , C _1-4 haloalkyl, C _1-4 haloalkoxy, 5-10 membered heteroaryl at each occurrence, wherein the heteroaryl is optionally substituted with one or more halogen, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁵ and R ⁶ are each independently selected from H, C _1-4 cycloalkyl and C _1-4 alkyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁵ and R ⁶ are each independently selected from H, methyl, ethyl and cyclopropyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁵ and R ⁶ are each independently selected from H and C _1-4 alkyl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ⁵ and R ⁶ are each independently selected from H, methyl and ethyl. In certain embodiments, in the compounds of formula I provided by the present invention, R ⁷ and R ⁸ are each independently selected from H and C _1-4 alkyl.

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

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

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

In certain embodiments, in the compound of formula I provided by the present invention, Ring A is selected from a C _6-15 aromatic ring and a 5-15 membered heteroaromatic ring.

In certain embodiments, in the compound of formula I provided by the present invention, ring A is selected from a C _6-10 aromatic ring and a 5-10 membered heteroaromatic ring.

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.

In certain embodiments, in the compounds of formula I provided by the present invention, 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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,

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,

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

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

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

In certain embodiments, in the compound of formula I provided by the present invention, 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 ring.

In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from C _6-15 aromatic ring, 5-15 membered heteroaromatic ring and 3-8 membered heterocyclylphenyl.

In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from C _6-10 aromatic ring, 5-10 membered heteroaromatic ring, 5-6 membered heteroarylphenyl and 5-6 membered heterocyclylphenyl.

In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from C _6-10 aromatic ring, 5-10 membered heteroaromatic ring and 5-6 membered heterocyclylphenyl.

In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a 5-10 membered nitrogen-containing heteroaromatic ring, a 6-membered heteroaryl heterocyclyl, a 5-membered heteroarylphenyl, a 5-membered heterocyclylphenyl and a 6-membered heterocyclylphenyl.

In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a 5-10 membered nitrogen-containing heteroaromatic ring and a 6-membered heterocyclylphenyl group.

In certain embodiments, in the compounds 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.

In certain embodiments, in the compounds 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,

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.

In certain embodiments, in the compounds 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,

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

In certain embodiments, in the compound of formula I provided by the present invention, R ¹ 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 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, 3-8 membered heterocyclyl; the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl _, cycloalkyl, heterocyclyl, cycloalkyloxy are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, C _3-6 heterocyclyl; _R R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ¹ is independently selected from H, OH, halogen, NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-6 alkyl, C _{1-6 haloalkyl, C 1-6} _alkoxy , C _2-6 heteroalkyl, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl at each occurrence; the alkyl, alkoxy, heteroalkyl, cycloalkyl are optionally substituted with one or more halogen, OH, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy; R ¹⁰ and R ¹¹ are independently selected from H, C _1-6 alkyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ¹ is independently selected from H, OH, halogen, NR ¹⁰ R ¹¹ , -CONR ¹⁰ R ¹¹ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-8 cycloalkyl at each occurrence; R ¹⁰ and R ¹¹ are independently selected from H, C _1-6 alkyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ¹ is independently selected from H, halogen, -NHC _1-4 alkyl, -N(C _1-4 alkyl) ₂ , azetidinyl, pyrrolidinyl, piperidinyl, -NH ₂ , -CONH ₂ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, and C _3-8 cycloalkyl at each occurrence.

In certain embodiments, the present invention provides compounds of formula I in which R ¹ at each occurrence is independently selected from H, -CH ₃ , -NH ₂ , -OCH ₃ and -CONH ₂ .

In certain embodiments, the present invention provides compounds of formula I, wherein each occurrence of R ¹ is independently selected from H, -CH ₃ , -NH ₂ , and -OCH ₃ .

In certain embodiments, in the compound of formula I provided by the present invention, L is selected from a direct bond, -CH(C _1-6 alkyl)-, and C _3-6 cycloalkyl.

In certain embodiments, the present invention provides compounds of formula I in which L is selected from a direct bond, _-CH2- , -CH( _CH3 )-, -CH( _CH3 ) _CH2- , -CH(cyclopropyl)-, cyclopropylene, cyclobutylene, and cyclopentylene.

In certain embodiments, in the compound of formula I provided by the present invention, L is selected from a direct bond, -CH(CH ₃ )-, -CH(cyclopropyl)-, cyclopropyl, cyclobutyl, and cyclopentyl.

In certain embodiments, in the compounds of formula I provided by the present invention, 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, 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, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C The radical may be substituted with a C _1-4 haloalkoxy, a C _3-6 cycloalkyl, a C _3-8 cycloalkoxy, a C _3-6 heterocyclyl, a C _6-10 aryl, or a _5-10 membered heteroaryl.

In certain embodiments, in the compounds of formula I provided by the present invention, 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, 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, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, OH, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _The invention can be substituted with C _3-8 cycloalkyloxy, C _3-6 heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl.

In certain embodiments, in the compound of formula I provided by the present invention, R ² 'at each occurrence 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, and the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ² 'at each occurrence 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, and 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 haloalkyl, C _1-4 alkoxy, C 1-4 haloalkoxy, C _3-6 cycloalkyl, _3-6 membered heterocyclyl, 5-10 membered heteroaryl.

In certain embodiments, in the compound of formula I provided by the present invention, R ² 'at each occurrence 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, and the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ² 'at each occurrence 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, and 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 cycloalkyl, 3-6 membered heterocyclyl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ² 'at each occurrence is independently selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrimidinyl, -CH ₂ OCH ₃ , morpholinyl, pyranyl, pyrazolyl, pyridinyl, pyrrolopyridinyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyranyl, pyrazolyl, pyridyl, Optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ² 'at each occurrence is independently selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, pyrimidinyl, -CH ₂ OCH ₃ , morpholinyl, pyrazolyl, pyridinyl, The methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, pyrimidinyl, morpholinyl, pyrazolyl, pyridyl, Optionally substituted with one or more halogen, C _1-4 alkyl, C _1-4 alkoxy.

In certain embodiments, in the compounds of formula I provided by the present invention, R ² 'at each occurrence is independently selected from methyl, trifluoromethyl, isopropyl, isobutyl, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclohexyl, cyclopentyl, dimethylcyclopentyl, -CH ₂ OCH ₃ ,

In certain embodiments, in the compounds of formula I provided by the present invention, R ² 'at each occurrence is independently selected from methyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, -CH ₂ OCH ₃ ,

In certain embodiments, the present invention provides compounds of formula I, ^R2 at each occurrence is independently selected from methyl, isopropyl, trifluoroethyl, isobutyl,

In certain embodiments, the present invention provides compounds of formula I, ^R2 at each occurrence is independently selected from

In certain embodiments, in the compound of formula I provided by the present invention, R ³ is selected from H, OH, halogen, -NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , C _1-4 alkyl and C _3-6 cycloalkyl.

In certain embodiments, the present invention provides compounds of formula I wherein R ³ is selected from H and methyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁴ is independently selected from H, oxo, OH, halogen, CN, -NR ⁷ R ⁸ , -NHCOCH ₃ , C _1-4 alkyl, C _{1-4 haloalkyl, C 1-6} _alkoxy , C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, and the alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, CN, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy _{, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8} _{cycloalkyloxy} _and 3-6 membered heterocyclyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁴ is independently selected from H, OH, halogen, CN, -NR ⁷ R ⁸ , -NHCOCH ₃ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and the heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, CN, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, 3-6 membered heterocyclyl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ⁴ is independently selected from H, oxo, OH, halogen, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, and 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 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy and 3-6 membered heterocyclyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁴ is independently selected from H, OH, halogen, CN, -NR ⁷ R ⁸ , C _1-4 alkyl, C _1-4 haloalkyl, C 1-4 alkoxy, C _2-6 heteroalkyl, C _1-4 haloalkoxy, C _3-8 cycloalkyl, _3-8 membered heterocyclyl, 5-10 membered heteroaryl, and the heteroalkyl, cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted with one or more halogen, CN, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl _, C 1-4 alkoxy, C _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkyloxy, and 3-6 membered heterocyclyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁴ is independently selected from H, oxo, CN, halogen, -NR ⁷ R ⁸ , C _1-4 haloalkyl _{, 3-8 heterocyclyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 1-6 alkoxy, C 2-6} _heteroalkyl _and _5-10 membered heteroaryl at each occurrence, and the alkoxy, heteroalkyl, heteroaryl are optionally substituted with one or more halogen, -NR ⁵ R ⁶ , C _1-4 alkyl and C _1-4 haloalkyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁴ is independently selected from H, oxo, CN, F, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , azetidinyl, pyrrolidinyl, piperidinyl, CF ₃ , C _3-8 cycloalkyl, C _1-6 alkoxy, C _2-6 heteroalkyl and 5-6 membered heteroaryl, and the alkoxy, heteroalkyl and heteroaryl are optionally substituted with one or more halogen, -NR ⁵ R ⁶ , C _1-4 alkyl and C _1-4 haloalkyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁴ is independently selected from H, F, -NH ₂ , -NH(C _1-4 alkyl), -N(C _1-4 alkyl) ₂ , azetidinyl, pyrrolidinyl, piperidinyl, CF ₃ , 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more halogen, -NR ⁵ R ⁶ , C _1-4 alkyl, C _1-4 haloalkyl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ⁴ is independently selected at each occurrence from H, oxo, F, -N(CH ₃ ) ₂ , CF ₃ , CN, cyclopropyl, -SF ₅ and -OCF ₃ .

In certain embodiments, in the compounds of formula I provided by the present invention, R ⁴ is independently selected at each occurrence from H, F, -N(CH ₃ ) ₂ , CF ₃ ,

In certain embodiments, in the compound of formula I provided by the present invention, R ³ and R ⁴ together with the atoms to which they are attached form 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.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁵ and R ⁶ are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy and C _3-8 cycloalkyl, and the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more halogen, OH, C _1-4 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl; or R ⁵ and R ⁶ form a C _3-6 cycloalkyl, 3-6 membered heterocyclyl with the carbon atom to which they are connected, and the cycloalkyl, heterocyclyl is optionally substituted with one or more halogen, OH, -NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 haloalkyl, C _{1-4 alkoxy, C 1-4 haloalkoxy, C 3-6} _cycloalkyl _, 3-6 membered heterocyclyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁵ and R ⁶ are each independently selected from H, C _1-4 alkyl; or R ⁵ and R ⁶ form cyclopropyl, cyclobutyl, or cyclopentyl with the carbon atom to which they are attached.

In certain embodiments, in the compound of formula I provided by the present invention, ^R7 and ^R8 are each independently selected from H, _C1-6 alkyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl, heterocyclyl is optionally substituted with one or more halogen, CN, _-NH2 , NH( _C1-4 alkyl), N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkyloxy, 3-6 membered heterocyclyl; or

^R7 and ^R8 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group, which is optionally substituted by one or more halogen, CN, _-NH2 , NH( _C1-4 alkyl), N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkoxy, or a 3-6 membered heterocyclic group.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁷ and R ⁸ are each independently selected from H, C _1-6 alkyl, or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group.

In certain embodiments, in the compound of formula I provided by the present invention, R ⁷ and R ⁸ are each independently selected from H and C _1-4 alkyl.

In certain embodiments, in the compounds of formula I provided by the present invention, R ⁹ is independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl at each occurrence, and the alkyl, cycloalkyl, heterocyclyl is optionally substituted with one or more halogen, OH, CN, -NH ₂ , NH(C _1-4 alkyl), N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _{3-6 cycloalkyl, C 3-6} _heterocyclyl _.

In certain embodiments, in the compounds of formula I provided by the present invention, R ⁹ is independently selected from H, C _1-4 alkyl, C _3-8 cycloalkyl at each occurrence.

In certain embodiments, the present invention provides compounds of formula I wherein R ⁹ is H.

In certain embodiments, in the compound of formula I provided by the present invention, ^R10 and ^R11 are each independently selected from H, _C1-6 alkyl, _C3-8 cycloalkyl, 3-8 membered heterocyclyl, and the alkyl, cycloalkyl, heterocyclyl are optionally substituted by one or more halogen, CN, _-NH2 , NH( _C1-4 alkyl), N( _C1-4 alkyl) ₂ , _C1-4 alkyl, C1-4 haloalkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C3-6 cycloalkyl, _C3-8 cycloalkyloxy, _3-6 membered heterocyclyl; or, ^R10 and ^R11 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclyl, and the heterocyclyl is optionally substituted by one or more halogen, CN, _-NH2 , NH( _C1-4 alkyl), N( _C1-4 alkyl) ₂ , C1-4 alkyl, _C1-4 haloalkyl, C1-4 alkoxy, _C1-4 haloalkoxy, C3-6 cycloalkyl, C3-8 cycloalkyloxy, _3-6 membered heterocyclyl. The group may be substituted with _1-4 haloalkoxy, C _3-6 cycloalkyl, C _3-8 cycloalkoxy or 3-6 membered heterocyclic group.

In certain embodiments, in the compound of formula I provided by the present invention, R ¹⁰ and R ¹¹ are each independently selected from H, C _1-6 alkyl, C _3-8 cycloalkyl.

In certain embodiments, in the compound of formula I provided by the present invention, R ¹⁰ and R ¹¹ are each independently selected from H, C _1-4 alkyl.

In certain embodiments, in the compound of formula I provided by the present invention, m is 1 or 2, for example, m is 2.

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

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

in:

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

q is 0 or 1.

In all of the above embodiments, the wavy line It indicates the point of attachment of the group to the rest of the molecule.

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.

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

Preparation

The compounds of the present invention may be prepared by any method known in the art. Reagents and starting materials are readily available to one of ordinary skill in the art. Individual isomers, enantiomers and diastereomers may be separated or resolved 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. Eliel and S. H. Wilen).

In certain embodiments, the present invention provides a method for preparing a compound of formula I, comprising the steps of:

Step 1: Compound IA-1 and R ² NH ₂ undergo reductive amination reaction 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, the fifth step is to remove the protecting group from the condensation product of the fourth step to generate compound I.

wherein Ring A, Ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁹ , m and n are as defined above.

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 NaBH ₄ , 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).

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.

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

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 base used is, for example, triethylamine or diisopropylethylamine, and the solvent used is, for example, DMF or NMP.

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

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.

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

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.

It should be understood by those skilled in the art that one or more of the above preparation methods may be omitted depending on the desired product structure. The order of the reaction steps can be adjusted appropriately as needed, and protection/deprotection reaction steps can be added or omitted.

Pharmaceutical compositions, preparations and methods of treatment

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

In some embodiments, the present invention provides a pharmaceutical preparation, which is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.

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

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

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.

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.

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.

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

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

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

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.

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

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).

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

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

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.

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

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

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

Unless otherwise indicated, as used herein, the term "prevention" refers to the preemptive administration of a drug to avoid or prevent the occurrence 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 the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or the symptoms of a condition is a term that is not intended to be used in the present disclosure. Meaning intended in context. 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 means avoiding the causes, effects, symptoms, or progression of a disease or condition before the disease or condition fully manifests itself.

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

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

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

Detailed ways

Example

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

The abbreviations used herein have the following meanings:

The compounds of the present invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and/or flash column chromatography, and their structures are confirmed by ¹ H NMR and/or MS. Reaction monitoring is performed by TLC or LC-MS.

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

LC/MS used Aglient 1260 Infinity/Aglient 6120 Quadrupole.

TLC used silica gel GF 254 as the stationary phase.

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

Flash column chromatography was performed using a Biotage flash column chromatograph.

Prep-HPLC used Agilent 1260 and Waters 2489.

Microwave reactions were performed using a BiotageInitiator microwave reactor.

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

The reagents used in this application were purchased from companies such as Acros Organics, Aldrich Chemical Company or Teber Chemical.

Synthesis Example:

Intermediate Int-A: 2-((6-((tert-butoxycarbonyl)amino)-5-methylpyridin-3-yl)amino)-2-oxoacetic acid

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

Int A-1 (5 g, 32.65 mmol) and (Boc) ₂ O (7.84 g, 35.92 mmol) were added to DMF (50 mL), and then NaH (1.44 g, 35.92 mmol) was slowly added. The mixture was stirred at 25°C for 16 hours. After the reaction was completed, water was added to the reaction solution to quench the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

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

Int A-2 (2.8 g, 11.06 mmol) was dissolved in MeOH (100 mL), and after replacing hydrogen, the mixture was stirred at 25°C for 2 hours under hydrogen balloon pressure. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, 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] ⁺ .

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

Int A-3 (2.47 g, 11.06 mmol) and DIPEA (2.14 g, 16.59 mmol) were dissolved in THF (50 mL), and then ethyl oxalyl chloride (1.66 g, 12.17 mmol) was slowly added. After the addition, the mixture was stirred at 25 °C for 0.5 hr. After the reaction was completed, water was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

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

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

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

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

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), and Ti(iPrO)4 (4.65 g, 16.38 mmol, 4.85 mL) was slowly added. After the addition, the temperature was raised to 75°C and the mixture was reacted for 12 hours. After the reaction was completed, the temperature was lowered to room temperature to obtain compound Int B-3 (1.8 g), which was directly used for the next step. MS (ESI, m/z): 226.1 [M+H] ⁺ .

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

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

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

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 reacted at 25°C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and then an appropriate amount of methanol was added to dissolve it. A few drops of triethylamine were added to adjust the pH to 7-8, and the compound Int B (800 mg) was obtained by concentration under reduced pressure. MS (ESI, m/z): 124.1 [M+H] ⁺ .

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

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. Then NaBH(OAc) ₃ (464.65 mg, 2.19 mmol) was added. After the addition was completed, the reaction system continued to react at 25°C for 1.5 hr. After the reaction was completed, methanol was used to quench the reaction, and the reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 92: 8) to obtain compound Int C (230 mg). MS (ESI, m/z): 283.1 [M+H] ⁺ .

Intermediate Int D: (5-(trifluoromethyl)pyridin-2-yl)methylamine

Int D-1 (2.00 g, 11.62 mmol), palladium 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 25 ° C under a pressure of 1 MPa for 16 hours. After the reaction was completed, diatomaceous earth was pad and the filtrate was concentrated. The crude product was dissolved in ethyl acetate and an equal volume of water was added. After extraction and separation, the organic layer was discarded and the aqueous layer was freeze-dried to obtain compound Int D (724 mg). MS (ESI, m/z): 177.1 [M+H] ⁺ .

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

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

Int E-1 (5 g, 21.51 mmol) was dissolved in DMF (30 mL), and NaH (1.72 g, 43.02 mmol) was slowly added in an ice bath. After the addition, the mixture was reacted for 30 min, and then MeI (3.66 g, 25.81 mmol) was added. After the addition, the mixture was stirred at 25 °C for 2 hr. After the reaction was completed, water was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, 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] ⁺ .

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

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 hr. After the reaction was completed, water was added to the reaction solution to quench, and ethyl acetate (50 mL x3) was used for extraction. The organic phases were combined, washed with water and saturated brine in turn, 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] ⁺ .

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)

Int E-4 (4.0 g, 10.60 mmol), Int E-5 (3.84 g, 21.21 mmol), ^t BuONa (3.06 g, 31.81 mmol), BINAP (660 mg, 1.06 mmol) and Pd ₂ (dba) ₃ (485 mg, 0.53 mmol) were dissolved in toluene (10 mL). After replacing nitrogen, the reaction temperature was raised to 80°C and stirred for 16 hours. After the reaction was completed, 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] ⁺ .

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

Int E-6 (4.68 g, 9.80 mmol) was dissolved in MeOH (30 mL), and then 4N hydrochloric acid-1,4-dioxane (3 mL) was added. After replacing nitrogen, the reaction was stirred at 30 ° C for 1 hour. After the reaction was completed, it 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] ⁺ .

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)

Int E-7 (3 g, 9.57 mmol) and DIPEA (3.71 g, 28.72 mmol) were dissolved in THF (25 mL), and then ethyl oxalyl chloride (1.57 g, 11.49 mmol) was slowly added. After the addition, the mixture was stirred at 25 °C for 0.5 hr. After the reaction was completed, water was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

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)

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

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

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

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 ₂ protection, the temperature was raised to 60°C and reacted for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, water was added to dissolve, and ethyl acetate was used for extraction. The organic layer was dried and concentrated to obtain the intermediate Int F-2 (1.4 g).

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

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 reacted for 24 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was separated and 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] ⁺ .

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

Int F-4 (280 mg, 1.23 mmol) and DIPEA (318.74 mg, 2.47 mmol) were dissolved in anhydrous NMP (10 mL), and PMBCl (289.68 mg, 1.85 mmol) was added. After the addition of N ₂ protection, the temperature was raised to 140°C for reaction for 5 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was separated and purified by normal phase Flash separation (PE: EA = 92: 8) to obtain the intermediate Int F-5 (150 mg). MS (ESI, m/z): 347.0 [M+H] ⁺ .

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

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 Pd ₂ (dba) ₃ (26.37 mg, 28.80 μmol) were dissolved in toluene (10 mL), and the mixture was heated to 80°C for 16 hours under N2 protection. After the reaction was completed, the mixture was concentrated under reduced pressure to remove toluene, and the crude product was separated and purified by normal phase Flash separation (PE:EA=79:21) to obtain the intermediate Int F-6 (80 mg). MS (ESI, m/z): 448.2 [M+H] ⁺ .

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

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 reacted at 25°C for 1 hour. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and then an appropriate amount of methanol was added to dissolve it. A few drops of TEA were added to adjust the pH to 7-8, and the reaction was concentrated under reduced pressure. The crude product was separated and purified by normal phase Flash (DCM: MeOH = 93: 7) to obtain the intermediate Int F-7 (50 mg). MS (ESI, m/z): 284.1 [M+H] ⁺ .

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)

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

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)

Int F-8 (120 mg, 312.99 μmol) was dissolved in THF (5 mL) and H ₂ O (1 mL), and NaOH (25.04 mg, 625.98 μmol) was added. After the addition, the reaction system was heated to 90°C and reacted for 2 hours. After the reaction was completed, 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] ⁺ .

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

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

The hydrochloride of Int G-1 (2.0 g, 8.35 mmol) was added to DCM (20 mL), and TEA (2.11 g, 20.87 mmol) was added under ice bath, and (Boc) ₂ O (2.19 g, 10.02 mmol) was added after stirring for 10 min, and the temperature was naturally raised to 25° C. to react for 16 hours. After the reaction was completed, 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).

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

Compound Int G-2 (2.4 g, 7.9 mmol) was dissolved in anhydrous THF (20 mL), and NaH (526.25 mg, 13.16 mmol) was added in batches at 0°C and stirred for 0.5 hr. Finally, iodomethane (1.37 g, 9.65 mmol) was added dropwise and the reaction was allowed to proceed overnight. After the reaction was completed, a small amount of methanol was added to quench the reaction, and the reaction solution was concentrated. 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).

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

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

MS (ESI, m/z): 218.0 [M+H] ⁺ .

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

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

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

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

Dissolve 1-2 (4 g, 26.64 mmol) in glacial acetic acid (30 mL) and react at 140°C for 36 hours. After the reaction is completed, remove most of the acetic acid by rotary evaporation under reduced pressure to obtain a crude product, which is 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] ⁺ .

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

1-3 (4.04 g, 21.00 mmol) was dissolved in THF (30 mL), and an aqueous solution (8 mL) of lithium hydroxide (2.20 g, 52.51 mmol) was added dropwise thereto. The mixture was reacted at room temperature for 6 hours. After the reaction was completed, water was added, and the mixture was extracted and concentrated with DCM to obtain compound 1-4 (2.97 g). The crude product was dried and used directly. MS (ESI, m/z): 151.1 [M+H] ⁺ .

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

1-4 (2.97 g, 19.76 mmol) was dissolved in DCM (60 mL), and Dess-Martin oxidant was slowly added thereto in batches under an ice bath, and the temperature was naturally raised to room temperature for reaction for 5 hours. After the reaction was completed, most of the oxidant was removed by filtration, and the filtrate was a 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] ⁺ .

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

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 min, sodium triacetoxyborohydride (643.71 mg, 3.04 mmol) was added thereto, and the mixture was reacted at room temperature for 4 hours. After the reaction was completed, 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] ⁺ .

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

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

Step 7: Synthesis of 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 (Compound 1)

1-7 (15 mg, 25.62 μmol) was added to 4N hydrochloric acid-dioxane solution (1 mL) under ice bath, and then reacted at room temperature 25°C for 4 hours. After the reaction was completed, the temperature was lowered to 0°C, methanol was added to dilute, and triethylamine was added dropwise to adjust to weak alkalinity, and the mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to obtain compound 1 (4.69 mg). MS (ESI, m/z): 486.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59–10.30 (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).

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

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)

Int C (43 mg, 152.39 μmol) and Int A (45 mg, 152.39 μmol) were dissolved in anhydrous DMF (2 mL), and DIPEA (29.54 mg, 228.59 μmol) and HATU (69.53 mg, 182.87 μmol) were added. 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, 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] ⁺ .

Step 2: Synthesis of (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 (Compound 2)

2-1 (10 mg, 17.87 μmol) was dissolved in 4N hydrochloric acid-dioxane solution (1 mL), and the reaction system was reacted at 25°C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and then dissolved in an appropriate amount of methanol, and a few drops of TEA were added to adjust the pH to 7-8, and 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] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.57–10.32 (m, 1H), 8.92–8.66 (m, 3H), 8.18–8.07 (m, 1H), 8.07–7.87 (m, 1H), 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).

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

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

3-1 (250 mg, 1.26 mmol), NH ₄ Cl (675 mg, 12.62 mmol), EDCI (363 mg, 1.89 mmol) and HOBT (256 mg, 1.89 mmol) were placed in a reaction bottle, DMF (5 mL) was added, N-methylmorpholine (191 mg, 1.89 mmol) was added, and then reacted at room temperature for 2 hours. After the reaction was completed, 10 mL of water was added to the reaction solution to quench the reaction, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

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

3-2 (250 mg, 1.27 mmol) was dissolved in MeOH (8 mL), Pd/C (154 mg, 0.13 mmol) was added, and the hydrogen was replaced, and the reaction was kept under a hydrogen atmosphere at room temperature for 16 hours. After the reaction was completed, 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] ⁺ .

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

3-3 (150 mg, 0.90 mmol) and DIPEA (174 mg, 1.35 mmol) were dissolved in THF (5 mL), and then ethyl oxalyl chloride (123 mg, 0.90 mmol) was slowly added, and stirred at 25°C for 0.5 hr. After the reaction was completed, water was added to the reaction solution to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water and saturated brine in turn, 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] ⁺ .

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

3-4 (250 mg, 0.94 mmol) and LiOH·H ₂ O (59 mg, 1.40 mmol) were added to THF (1 mL) and H ₂ O (1 mL), and stirred at 25°C for 1 hr. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent, purified by HPLC (H ₂ O [0.05% TFA]:CAN=70:30), and freeze-dried to obtain compound 3-5 (40 mg). MS (ESI, m/z): 240.1 [M+H] ⁺ .

Step 5: Synthesis of (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 (Compound 3)

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 DIPEA (12 mg, 94.07 μmol) was added after stirring and dissolving. The mixture was protected by nitrogen and reacted at 25 °C for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (10 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by pre-HPLC and freeze-dried to obtain compound 3 (10 mg). MS (ESI, m/z): 504.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08–10.90 (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).

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

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

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. Then NaBH(OAc) ₃ (363.10 mg, 1.71 mmol) was added. After the addition, the reaction system continued to react at 25°C for 1.5 hr. After the reaction was completed, methanol was used to quench the reaction, and the reaction was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase PE:EA=60:40) to obtain compound 4-2 (40 mg). MS (ESI, m/z): 243.1 [M+H] ⁺ .

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)

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

Step 3: Synthesis of 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 (Compound 4)

4-4 (30 mg, 57.75 μmol) was dissolved in 4N hydrochloric acid-dioxane solution (1 mL), and the reaction system was reacted at 25°C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and then an appropriate amount of methanol was added. A few drops of TEA were added to adjust the pH to 7-8, and the reaction was 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] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.22–11.00 (m, 1H), 8.99–8.87 (m, 1H), 8.36–8.18 (m, 2H), 7.88–7.79 (m, 2H), 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).

The following compounds were prepared by the method and general steps described in Example 4. 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.

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

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

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, DIPEA (8.24 g, 63.78 mmol) was slowly added under water bath cooling, and then reacted at room temperature. After the reaction was completed, 100 mL of water was added to the reaction solution to quench the reaction, and ethyl acetate (60 mL x3) was used for extraction. The organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

Step 2: Synthesis of 1-(6-fluoropyridin-2-yl)ethane-1-one (Compound 5-4)

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, and the reaction was continued at 0 ° C. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and then 60 mL of water was added to dilute it, and ethyl acetate (50 mL x 3) was extracted, and the organic phases were combined, and the organic phases were washed with clean water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (EA: PE = 10: 90) to obtain compound 5-4 (700 mg).

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

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 to the reaction flask, and the mixture was reacted at 70°C for 48 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature and used directly in the next reaction. MS (ESI, m/z): 243.1 [M+H] ⁺ .

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

5-5 (1.2 g, 4.95 mmol), THF (30 mL) and NaBH ₄ (374 mg, 9.90 mmol) were added to the reaction flask, nitrogen was protected, and the reaction was carried out at 25°C for 1 hour. After the reaction was completed, water was added to the reaction solution to quench, and ethyl acetate (50 mL x3) was used for extraction. The organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

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

5-6 (700 mg, 2.86 mmol), MeOH (10 mL), 4N HCl-dioxane (2.86 mL) were added to the reaction flask, nitrogen was protected, and the reaction was carried out at 25°C for 2 hours. After the reaction was completed, most of the solvent was removed by concentration under reduced pressure, and then saturated NaHCO ₃ solution was added for dilution, 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 compound 5-7 (370 mg). MS (ESI, m/z): 141.1 [M+H] ⁺ .

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

5-8 (370 mg, 2.64 mmol), Int C-1 (370 mg, 2.11 mmol), DCE (20 mL), acetic acid (238 mg, 3.96 mmol) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 25°C for 5 hours. Sodium triacetoxyborohydride (840 mg, 3.96 mmol) was then added and reacted at 25°C for 2 hours. After the reaction was completed, water was added to the reaction solution to quench the mixture, and DCM (50 mL x 3) was used for extraction. The organic phases were combined and the organic phases were successively purified by The product was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

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)

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 to the reaction flask, and DIPEA (10 mg, 75.18 μmol) was added after stirring and dissolving. The mixture was protected by nitrogen and reacted at 25 °C for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (50 mL x3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative plate with a developing solvent (DCM: MeOH = 10: 1) to obtain compound 5-9 (10 mg). MS (ESI, m/z): 477.1 [M + H-Boc] ⁺ .

Step 8: Synthesis of (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 (Compound 5)

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66–10.35 (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, 2H), 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).

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

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

16-1 (2.0 g, 8.85 mmol) was added to a 50 mL flask, followed by potassium trifluoroborate (1.42 g, 10.62 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (620 mg, 884.68 μmol) and Na ₂ CO ₃ (1.88 g, 17.69 mmol), 1,4-dioxane (10 mL) and H ₂ O (1 mL) were added to dissolve, and the temperature was raised to 100° C. under nitrogen protection for 8 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate and concentrated to obtain a crude product, which was 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] ⁺ .

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

16-2 (500 mg, 2.89 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL), potassium osmate dihydrate (159 mg, 433.00 μmol) and NaIO ₄ (2.49 g, 11.55 mmol) were added, and the mixture was reacted at 25°C for 4 hours. After the reaction, water was added and the mixture was extracted with ethyl acetate and 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] ⁺ .

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

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, and the mixture was stirred at room temperature for 10 min. Then, sodium triacetoxyborohydride (39 mg, 182.70 μmol) was added and the mixture was stirred at room temperature. The reaction was continued for 5 hours. After the reaction was completed, methanol was added to dissolve the mixture and then concentrated. 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] ⁺ .

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)

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

Step 5: Synthesis of (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 (Compound 16)

16-5 (5 mg, 8.93 μmol) was dissolved in DCM (5 mL) under ice bath, 4N hydrochloric acid-1,4-dioxane solution (0.5 mL) was added dropwise, and the mixture was reacted at 25°C for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, methanol was added to dilute, and triethylamine was added dropwise to adjust to weak alkalinity, and the mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to obtain 16 (2.51 mg). MS (ESI, m/z): 460.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.53–10.28 (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).

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

Step 1: Synthesis of (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 -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 19-1)

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

Step 2: Synthesis of (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 (Compound 19)

19-1 (8 mg, 8.93 μmol) was dissolved in DCM (5 mL) under ice bath, hydrochloric acid-dioxane solution (0.5 mL) was added dropwise, and the reaction was carried out at room temperature of 25°C for 1 hour. After the reaction was completed, the temperature was lowered to 0°C, triethylamine was added dropwise to adjust to weak alkalinity, and the mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to obtain 19 (1.83 mg). MS (ESI, m/z): 500.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76–10.54 (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, 4H), 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).

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.

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

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

20-1 (500 mg, 2.69 mmol), 20-2 (587 mg, 2.82 mmol), Pd(dppf)Cl ₂ (195 mg, 269 μmol), K ₂ CO ₃ (557 mg, 4.03 mmol), 1,4-dioxane (15 mL) and water (1 mL) were added to the reaction flask, and the mixture was reacted at 80°C for 16 hours under nitrogen protection. After the reaction was completed, water was added to dilute the reaction solution, and ethyl acetate (50 mL x 3) was used for extraction. The organic phases were combined, washed with clean water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

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)

20-3 (50 mg, 267.10 μmol), Int B (33 mg, 267.10 μmol), DCM (3 mL), acetic acid (32 mg, 534.19 μmol) were added to the reaction flask, nitrogen was protected, and the reaction was carried out at 25°C for 5 hours. Sodium triacetoxyborohydride (85 mg, 400.65 μmol) was added, and the reaction was carried out at 25°C for 5 hours. After the reaction was completed, water was added to the reaction solution to quench, and DCM (30 mL x3) was used for extraction. The organic phases were combined, washed with clean water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a 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] ⁺ .

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)

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 the reaction flask, and DIPEA (33 mg, 253.99 μmol) was added after stirring and dissolving. The mixture was protected by nitrogen and reacted at 25 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate (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 a 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] ⁺ .

Step 4: Synthesis of (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 (Compound 20)

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55–10.37 (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).

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

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

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 the mixture was reacted at 25°C for 1 hr. After the reaction was completed, water was added, extracted with ethyl acetate, dried, and concentrated to obtain a crude product, which 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] ⁺ .

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

Int E (40.00 mg, 62.28 μmol) and DIPEA (16.10 mg, 124.55 μmol) were added to anhydrous DMF (5 mL), and HATU (35.52 mg, 124.55 μmol) was added at 0°C. After stirring for 5 min, 22-2 (14.46 mg, 62.28 μmol) was added and reacted at 25°C for 1 hr. After the reaction was completed, water was added and stirred, and 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] ⁺ .

Step 3: Synthesis of 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 (Compound 22)

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.74–10.56 (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, 2H), 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).

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

Step 1: Synthesis of (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 -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 23-1)

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, and then Int F (37.77 mg, 106.28 μmol) was added. After the addition, 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, filtered, and 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] ⁺ .

Step 2: Synthesis of (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 (Compound 23)

23-1 (8 mg, 8.93 μmol) was dissolved in TFA (2 mL) under ice bath, heated to 90°C and reacted for 1 hour. After the reaction was completed, it was concentrated by distillation under reduced pressure, then dissolved in methanol, triethylamine was added dropwise to adjust to weak alkalinity, and 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] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51–9.92 (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).

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

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

28-1 (30 g, 179.51 mmol) and SOCl ₂ (100 mL) were added to a reaction flask, reacted at 80°C for 3 hours, the reaction solution was spin-dried, SOCl ₂ (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 hour, the reaction solution was distilled under reduced pressure to remove the solvent, dissolved in ethyl acetate, washed twice with sodium bicarbonate aqueous solution, the organic phase was dried over sodium sulfate, and the solvent was distilled under reduced pressure to obtain compound 28-2 (30 g), MS (ESI, m/z): 196.1 [M+H] ⁺ .

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

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

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

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

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

28-4 (12 g, 52.26 mmol) was dissolved in EtOH (120 mL), and NaBH ₄ (11.86 g, 313.57 mmol) was added in batches. After the addition was completed, 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 column chromatography (50% EA to 100% EA) was performed to obtain compound 28-5 (7.87 g), MS (ESI, m/z): 174.1 [M+H] ⁺ .

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

28-5 (7.87 g, 45.33 mmol) was dissolved in DCM (180 mL), MnO ₂ (7.88 g, 90.67 mmol) was added in batches, Et ₃ SiH (32 mL) and TFA (64 mL) were added dropwise in sequence, and the mixture was reacted at room temperature overnight. The reaction was completed after monitoring by LCMS. 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] ⁺ .

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

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 Pd ₂ (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 removed by distillation under reduced pressure, and compound 28-7 (1.6 g) was obtained by column chromatography (10% to 30% EA), MS (ESI, m/z): 287.1 [M+H] ⁺ .

Step 7: Synthesis of 1,3-dihydrofurano[3,4-c]pyridine-4-amine (Compound 28-8)

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 reaction solution was distilled under reduced pressure to remove the solvent and flash purified to obtain compound 28-8 (470 mg). MS (ESI, m/z): 137.1 [M+H] ⁺ .

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

28-8 (460 mg, 3.38 mmol) was dissolved in MeCN (2 mL), and NBS (661.46 mg, 3.72 mmol) was added in batches. 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] ⁺ .

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

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

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

Under nitrogen protection, 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 Pd ₂ (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 distilled under reduced pressure to remove the solvent, and the compound 28-11 (800 mg) was obtained by column chromatography (0% EA to 10% EA), MS (ESI, m/z): 556.3 [M+H] ⁺ .

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

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 completed under LCMS monitoring. The reaction solution was distilled under reduced pressure to remove the solvent and directly subjected to the next step to obtain compound 28-12 (500 mg). MS (ESI, m/z): 392.2 [M+H] ⁺ .

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

28-12 (500 mg, 1.28 mmol) was dissolved in THF (3 mL), DIEA (660.31 mg, 5.11 mmol) was added, and ethyl oxalyl chloride (261.58 mg, 1.92 mmol) was added dropwise, and the mixture was reacted at room temperature for 1 hour. The reaction was completed after LCMS monitoring, 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] ⁺ .

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

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

Step 14: Synthesis of (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 -((5-(trifluoromethyl)pyridin-2-yl)methyl)oxalamide (Compound 28-15)

Int C (9.14 mg, 32.36 μmol) was dissolved in DMF (1 mL), and then HATU (24.61 mg, 64.73 μmol) was added to the reaction flask and stirred for 20 minutes. A DMF solution of 28-14 (15 mg, 32.36 μmol) was added dropwise, and the reaction was allowed to react overnight at room temperature. LCMS monitoring showed that there was no residual raw material, and the mixture was diluted with ethyl acetate, and the organic phase was washed with dilute brine and dried with 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] ⁺ .

Step 15: Synthesis of (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 (Compound 28)

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.48-10.36 (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).

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.

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

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

Int E (189.92 mg, 394.25 μmol) and Int G (100 mg, 394.25 μmol) were added to the reaction flask and dissolved in anhydrous DMF (10 mL). DIPEA (152.86 mg, 1.18 mmol) and HATU (224.86 mg, 591.37 μmol) were added in sequence. After the addition, 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, filtered, and the crude product was separated 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] ⁺ .

Step 2: Synthesis of (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 (Compound 70)

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

¹ H NMR (400 MHz, DMSO) δ 10.69 (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).

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

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

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, nitrogen was protected, and the reaction was carried out at 0°C for 30 min, and then 73-2 (4.92 g, 31.43 mmol, 4.26 mL) was added, and the temperature was naturally raised to room temperature and reacted overnight. After the reaction was completed, the reaction solution was diluted with water, 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 a 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] ⁺ .

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

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, and the mixture was protected by nitrogen and reacted at 0°C for 2 hours. After the reaction was completed, the mixture was diluted with water, 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 a 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] ⁺ .

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

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), TFA (6 mL) were added to the reaction flask, and the mixture was reacted at 40°C for 2 hours under nitrogen protection. 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, filtered, and 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] ⁺ .

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

73-5 (3 g, 14.02 mmol), DIPEA (3.62 g, 28.03 mmol), and POCl ₃ (30 mL) were added to the reaction flask, and the reaction was carried out at 100°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, diluted with saturated NaHCO ₃ solution, and washed with EA (50 ml x 3). After extraction, 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 73-6 (3.2 g). MS (ESI, m/z): 231.8 [M+H] ⁺ .

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

73-6 (3.2 g, 13.77 mmol), EtOH (100 mL), Int E-3 (4.60 g, 27.53 mmol) were added to the reaction flask, and the mixture was reacted at 80°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, 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 a 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] ⁺ .

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

73-7 (200 mg, 550.65 μmol), Int E-5 (200 mg, 1.10 mmol), Pd ₂ (dba) ₃ (51 mg, 55.06 μmol), BINAP (69 mg, 110.13 μmol), t-BuONa (159 mg, 1.65 mmol), Toluene (8 mL) were added to the reaction flask, and the mixture was reacted at 100°C overnight under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase EA: PE = 40: 60) and the compound 73-8 (140 mg) was collected and dried. MS (ESI, m/z): 464.2 [M+H] ⁺ .

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

73-8 (140 mg, 302.03 μmol) and THF (5 mL) were added to the reaction flask, and after dissolution, (Boc) ₂ O (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] ⁺ .

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

73-9 (170 mg, 301.61 μmol), hydroxylamine hydrochloride (210 mg, 3.02 mmol), and MeOH (10 mL) were added to the reaction flask, and the mixture was protected by nitrogen 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 compound 73-10 (45 mg) was collected and dried. MS (ESI, m/z): 400.2 [M+H] ⁺ .

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)

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

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)

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

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)

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 DIPEA (19 mg, 149.53 μmol) was added after stirring and dissolving. The mixture was protected by nitrogen and reacted at 25°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3) and the mixture was collected and dried to obtain compound 73-13 (20 mg). MS (ESI, m/z): 671.3 [M+H] ⁺ .

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

73-13 (20 mg, 29.82 μmol), DCM (1 mL), and TFA (2 mL) were added to the reaction flask, and the mixture was protected by nitrogen 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, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC and freeze-dried to obtain compound 73 (3 mg). MS (ESI, m/z): 421.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 8.28-8.04 (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).

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

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

Add 73-7 (150 mg, 412.99 μmol) and DMF (3 mL) to the reaction flask and cool it in an ice-water bath. Slowly add NaH (25 mg, 619.48 μmol). After the addition is complete, keep the reaction in an ice bath for 20 min. Then add 73-2 (78 mg, 495.58 μmol), protect with nitrogen, and react at 0°C for 2 hr. After the reaction is completed, dilute the reaction solution with water, extract with EA (30 ml x 3), combine the organic phases, wash with brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (mobile phase EA: PE = 35: 65) and collected and dried to obtain compound 74-1 (110 mg). MS (ESI, m/z): 483.1 [M+H] ⁺ .

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

74-1 (300 mg, 825.97 μmol), Int E-5 (300 mg, 1.65 mmol), Pd ₂ (dba) ₃ (76 mg, 82.60 μmol), BINAP (103 mg, 165.19 μmol), t-BuONa (238 mg, 2.48 mmol), Toluene (10 mL) were added to the reaction flask, and the mixture was reacted at 100°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase EA: PE = 50: 50) to obtain compound 74-2 (160 mg). MS (ESI, m/z): 584.3 [M+H] ⁺ .

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

74-2 (200 mg, 342.65 μmol), hydroxylamine hydrochloride (238 mg, 3.43 mmol), and MeOH (5 mL) were added to the reaction flask, and the mixture was reacted at 25°C for 3 hours under nitrogen protection. 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 compound 74-3 (60 mg) was collected and dried. MS (ESI, m/z): 420.2 [M+H] ⁺ .

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)

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

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)

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

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

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 to the reaction flask, stirred and dissolved, and then HATU (28 mg, 73.25 μmol) was added. The mixture was protected by nitrogen and reacted at 25°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 97: 3) to obtain compound 74-6 (30 mg). MS (ESI, m/z): 705.2 [M+H] ⁺ .

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

74-6 (30 mg, 42.57 μmol) and TFA (3 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 100 °C for 12 hours. After the reaction was completed, the reaction solution was dried, diluted with a saturated NaHCO ₃ solution, extracted with EA (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 74 (5 mg). MS (ESI, m/z): 435.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO) δ 11.21-11.02 (m, 1H), 8.13-8.10 (m, 1H), 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).

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

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

Compound 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 the reaction flask, and then solid KOH (376 g, 6.71 mol) was slowly added under an ice bath. After the addition was completed, the temperature was naturally raised to 25 ° C and stirred for 16 hours. TLC (PE/EA = 20/1, Rf = 0.84) detected that 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 and concentrated, separated and purified by silica gel column chromatography (PE/EA = 100/1 to 20/1), and concentrated to obtain compound 75-3 (1.10 kg).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.72-7.83 (m, 2H), 7.49 (dd, J=8.4, 1.7 Hz, 1H), 5.88-6.09 (m, 1H), 5.19-5.41 (m, 2H), 4.60 (s, 2H), 4.14-4.16 (m, 2H).

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

Compound 75-3 (250 g, 847 mmol) was dissolved in DMF (1.50 L), and then PPh ₃ (33.3 g, 127 mmol) and Cs ₂ CO ₃ (331 g, 1.02 mol) were added. After sufficient stirring, Pd(OAc) ₂ (9.51 g, 42.3 mmol) was added under nitrogen atmosphere. The reaction temperature was raised to 90°C and stirred for 16 hrs. TLC (PE/EA=20/1, Rf=0.62) detected that the reaction was complete. The reaction solution was diluted with water (500 mL), and then extracted with ethyl acetate (500 mL x 3). The organic phases were combined and washed with saturated NaCl aqueous solution (500 mL x 3). After the organic phases were combined, The residue was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by silica gel column chromatography (PE/EA=100/1 to 20/1) and concentrated to obtain compound 75-4 (60.0 g).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.91 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 5.81 (s, 1H), 5.18 (s, 1H), 4.83 (s, 2H), 4.46 (s, 2H).

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

Compound 75-4 (323 g, 1.51 mol) was dissolved in a mixed solvent of 1,4-dioxane (1.50 L) and H ₂ O (1.50 L). After being stirred at room temperature, the temperature was lowered to 0°C and NaIO ₄ (967 g, 4.52 mol, 250 mL) was added. The mixture was stirred at 0°C for 0.10 hr. K ₂ OsO ₄ ·2H ₂ O (27.7 g, 75.4 mmol) was then added. The reaction was stirred at 0°C for 0.5 hr, then the temperature was raised to 25°C and the reaction was continued for 12 hrs. TLC (PE/EA=5/1, Rf=0.48) detected that the reaction was complete. The reaction solution was filtered and extracted with ethyl acetate (500 mL x 3). The organic phases were combined and washed with saturated NaCl (500 mL x 3). The organic phases were collected, dried over anhydrous Na ₂ SO ₄ , 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] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (d, J=8.0 Hz, 1H), 7.67-7.79 (m, 2H), 4.98 (s, 2H), 4.41 (s, 2H).

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

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 Ti(O ⁱ Pr) ₄ (1.16 kg, 4.07 mol, 1.20 L) was then added. The reaction was heated to 50°C and stirred for 16 hrs. LCMS detected that the reaction was successful. Without further purification, the product was directly concentrated to obtain compound 75-6 (260 g, 814 mmol). MS (ESI, m/z): 320.1 [M+H] ⁺ .

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

Compound 75-6 (260 g, 814 mmol) was dissolved in THF (1200 mL), and the temperature was lowered to 0°C after nitrogen replacement, and then NaBH ₄ (154 g, 2.44 mol) was added in batches. After the addition was completed, the reaction was kept at 25°C and stirred for 2 hrs. TLC (EA/DCM=1/10, Rf=0.46) detected that the reaction was complete. After cooling to 0°C, saturated NaHCO ₃ aqueous solution was added to the reaction solution to quench the reaction. After adding ethyl acetate, the mixture was stirred for 10 min, filtered, and the filtrate was diluted with water (1500 mL), and then extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. After separation and purification by silica gel column chromatography (PE/EA=100/1 to 10/1), the mixture was concentrated to obtain compound 75-7 (219 g, 681 mmol). MS (ESI, m/z): 321.9 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.80 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 4.88 (s, 1H), 4.75-4.80 (m, 1H), 4.51 (d, J=4.4 Hz, 1H), 4.02 (dd, J=11.6, 4.6 Hz, 1H), 3.87 (dd, J=11.6, 6.1 Hz, 1H), 1.24 (s, 9H).

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

Compound 75-7 (219 g, 681 mmol) was dissolved in THF (1700 mL), and NaH (40.9 g, 1.02 mol) was slowly added in an ice bath. After the addition was completed, 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 heated 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 then the mixture was extracted with ethyl acetate (500 mL x 3). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to obtain compound 75-8 (228 g). MS (ESI, m/z): 335.9 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.62-7.68 (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).

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

Compound 75-8 (228 g, 680 mmol) was dissolved in CH ₂ Cl ₂ (500 mL), and a 2M hydrochloric acid 1,4-dioxane solution (500 mL) was added under a nitrogen atmosphere. The reaction solution was stirred at 25° C. for 1 hr. The reaction was completed by LCMS, TLC (CH ₂ Cl ₂ /MeOH=10/1, Rf=0.45). The reaction solution was directly concentrated, diluted with water (500 mL), and then extracted with ethyl acetate (500 mL x 3). NaHCO ₃ solution was added to the aqueous phase to adjust the pH to 9-10, and then ethyl acetate (500 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. After SFC (chiral column: DAICEL CHIRALPAK IG (250 mm*50 mm, 10 um); mobile phase: [n-hexane-ethanol (0.1% IPAm)]; B%: 7%) separation and concentration, compound 75-9 (38.0 g, 164 mmol) was obtained. MS (ESI, m/z): 231.8 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 7.48-7.59 (m, 2H), 7.41 (s, 1H), 4.91 (s, 1H), 4.70-4.79 (m, 1H), 4.18 (dd, J=11.6, 2.6 Hz, 1H), 3.83 (dd, J=11.6, 3.0 Hz, 1H), 3.61 (s, 1H), 2.44 (s, 3H).

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

Int E (1.23 g, 3.18 mmol) and NMP (35 mL) were added to the reaction flask, stirred and dissolved, 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 in sequence, and nitrogen was protected and reacted at 25°C for 2 hr. After the reaction was completed, water was added to dilute the reaction solution, extracted with ethyl acetate (60 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a 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] ⁺ .

Step 9: Synthesis of (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 (Compound 75)

75-10 (2.05 g, 3.42 mmol), TFA (10 mL), and DCM (25 mL) were added to the reaction flask, and the mixture was reacted at 25°C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was spin-dried, diluted with a saturated NaHCO ₃ solution, extracted with ethyl acetate (30 ml x 3), and the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC to obtain compound 75. MS (ESI, m/z): 449.1 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.91-10.70 (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).

Separation method

Prep-HPLC purification of the compounds in the examples was carried out using Aglient 1260 or Waters 2489 HPLC, the separation column model was Waters SunFire Prep C ₁₈ OBD (19 mm×150 mm×5.0 μm), Waters Xbridge Prep C ₁₈ OBD (19 mm×150 mm×5.0 μm) 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, the mobile phase A was acetonitrile, the mobile phase B was 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, the volume ratio of the mobile phase was adjusted according to the polarity of the compound; the mobile phase flow rate was 28 mL/min.

Biological evaluation

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

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

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:

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

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

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

Experimental method 2: The inhibitory effect of the compounds of the present invention on the activity of PRMT5-MTA methyltransferase was determined according to the instructions of the PRMT5TR-FRET kit (BPS Bioscience). The mixture of PRMT5/MEP50 enzyme (BPS Bioscience) and MTA (BiDe Pharmaceutical) was pre-incubated with different concentrations of the test compound (100nM, 20nM, 4nM) at 25°C for 30min, and then the 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 120min; the working solution of Eu-labeled antibody (BPS Bioscience) was added, and the reaction was slowly shaken at 25°C for 30min, and then the working solution of Dye-labeled acceptor (BPS Bioscience) was added, and the reaction was slowly shaken at 25°C for 30min, and then the fluorescence signal ratio (Ratio) was detected by an enzyme reader.

The solvent 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:

When the percentage inhibition rate is between 30-80%, the half maximal inhibitory concentration (IC ₅₀ ) or range of the compound is calculated according to the following formula:

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

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

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

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

The inhibitory effect of the compounds of the present invention on cancer cell proliferation is further evaluated by testing the effects of the compounds of the present invention on cancer cell growth.

Experimental method 1: In this experimental example, MTAP Deleted/Parental HCT116 cells from Pharmaron Inc. were used.

MTAP Deleted/Parental HCT116 cells were cultured in vitro in monolayers in 10% FBS+1% P/S MCCOYS 5A medium (Invitrogen) at 37°C and 5% CO ₂ . Cells in logarithmic growth phase were digested and the concentration was adjusted. 150 cells per well were seeded in a 384-well plate and cultured overnight. Pre-diluted compounds (10000 nM starting, 4-fold dilution, 10 points or 5000 nM starting, 5-fold dilution, 8 points) were added. DMSO was added to the negative control group and culture medium was added to the blank control group. After culturing in an incubator at 37°C and 5% CO ₂ for 10 days, 40 μL CellTiter-Glo (Promega) was added to each well and the relative chemiluminescence unit value was read in the chemiluminescence detection mode of the microplate reader.

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

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%

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 _IC50 value by the following formula:

y=Min+(Max-Min)/(1+(x/ _IC50 )^(-Hillslope)), wherein: y is the percentage inhibition rate; Max and Min are the maximum and minimum values of the fitting curve, respectively; x is the logarithmic concentration of the compound; and Hillslope is the slope of the curve.

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.

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

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

MTAP Deleted/Parental HCT116 cells were cultured in vitro in a monolayer in RPMI6140 medium (source culture) containing 10% FBS + 1% P/S at 37°C and 5% CO ₂ . The cells in the logarithmic growth phase were digested and the concentration was adjusted. 250 cells per well were inoculated in a 96-well plate and cultured overnight. Pre-diluted compounds (5000 nM starting, 4-fold dilution, 9 points) were added. DMSO was added to the negative control group and culture medium was added to the blank control group. After 7 days of culture in an incubator at 37°C and 5% CO ₂ , 50 μl CellTiter-Glo (Promega) was added to each well and lysed at room temperature in the dark for 10 minutes. The test solution was transferred to a 96-well opaque white plate, and then the relative chemiluminescence unit value was read in the chemiluminescence detection mode of the microplate reader.

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.

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

The experimental results show that the compounds of the present invention have a strong inhibitory effect on MTAP Deleted HCT116 cells, and have a certain selectivity for MTAP Parental HCT116 cells.

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

Claims

A compound having a 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 heterocyclyl, 5-6 membered heteroaryl 3-8 membered cycloalkyl, 5-6 membered heteroaryl 3-8 membered heterocyclyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

Ring B is selected from C 6-15 aromatic ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroaryl and C 6-10 aromatic 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, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

R 1 is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO 2 , -NR 10 R 11 , -CONR 10 R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, 3-8 membered heterocyclyl, C 6-10 aromatic ring and 5-10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR 7 R 8 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C substituted by C 3-6 cycloalkyl, C 3-8 cycloalkoxy, C 3-6 heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;

R 2 is LR 2 ';

L is independently a direct bond or -(CR 5 R 6 ) p - at each occurrence;

R 2 'at each occurrence 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 heterocyclyl, C 3-8 cycloalkyloxy , 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 and 3-8 membered cycloalkyl and 5-6 membered heteroaryl and 3-8 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl are optionally substituted with one or more halogen, OH, CN, -NR 7 R 8 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C substituted with 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy, C 3-6 heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl;

R3 is selected from H, OH, halogen, CN, NR10R11 , C1-6 alkyl, C1-6 alkoxy, C2-6 heteroalkyl, C3-8 cycloalkyl and 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more halogen, OH, CN, -NR7R8, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy , C1-4 haloalkoxy , C3-6 cycloalkyl, C3-8 cycloalkyloxy and C3-6 heterocyclyl;

R4 is independently selected at each occurrence from H, OH, oxo, halogen, CN, -NO2 , -SF5 , -NR7R8 , -NHCOC1-6alkyl , C1-6alkyl , -C2-6alkenyl , -C2-6alkynyl , C1-6haloalkyl , C1-6alkoxy , C2-6heteroalkyl , C1-6haloalkoxy, C3-8cycloalkyl, 3-8 membered heterocyclyl, C3-8cycloalkyloxy , C6-10aryl and 5-10 membered heteroaryl, said alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl , heterocyclyl, cycloalkyloxy, aryl, heteroaryl being optionally substituted with one or more halogen, CN, -NR5R6 , C1-4alkyl , C1-4haloalkyl, C1-4alkoxy , C1-4haloalkoxy , C3-6cycloalkyl , C 3-8- membered cycloalkoxy, 3-6-membered heterocyclic group substitution;

Alternatively, R 3 and R 4 together with the atoms to which they are attached form a 3-10 membered heterocyclic group;

R 9 is independently selected at each occurrence from H, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said alkyl, heteroalkyl, cycloalkyl, heterocyclyl being optionally substituted with one or more halogen, OH, CN, -NR 7 R 8 , C 1-4 alkyl , C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkyloxy, C 3-6 heterocyclyl;

R5 and R6 are each independently selected from H, OH, halogen, C1-6 alkyl, C1-6 alkoxy and C3-8 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more halogen, OH, CN, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, C3-8 cycloalkyloxy, 3-6 membered heterocyclyl; or

R5 and R6 , together with the carbon atom to which they are attached, form a C3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, wherein the cycloalkyl group or the heterocyclyl group is optionally substituted by one or more OH, halogen , CN, -NR5R6 , C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, C1-4 haloalkoxy group, C3-6 cycloalkyl group, C3-8 cycloalkoxy group or a 3-6 membered heterocyclyl group;

R 7 , R 8 , R 10 and R 11 are each independently selected from H, C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein 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 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy , C 3-6 cycloalkyl, C 3-8 cycloalkoxy, 3-6 membered heterocyclyl; or

R7 and R8 , R10 and R11 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, which is optionally substituted with one or more halogen, CN, -NR5R6 , C1-4 alkyl, C1-4 haloalkyl , C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, C3-8 cycloalkoxy, or a 3-6 membered heterocyclic group;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is 1 or 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 the group consisting of a C 6-15 aromatic ring, a 5-15 membered heteroaromatic ring, a benzo 3-8 membered cycloalkyl group, a benzo 3-8 membered heterocyclyl group, a 5-6 membered heteroaryl 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl 3-8 membered heterocyclyl group, and a 3-8 membered heterocyclyl group;

Ring B 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 3-8 membered cycloalkyl, 5-6 membered heteroaryl 3-8 membered heterocyclyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

R 1 is independently selected at each occurrence 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 haloalkyl, C 1-4 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl; said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy are optionally substituted with one or more halogen, OH, CN, -NR 7 R 8 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkyloxy, C 3-6 heterocyclyl; R 10 and R R 11 is each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

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

R 2 'is independently selected at each occurrence from Ci -6 alkyl, Ci-6 alkoxy, C 2-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 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, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, OH, CN, -NR 7 R 8 , Ci -4 alkyl, Ci -4 haloalkyl, Ci-4 alkoxy, Ci -4 haloalkoxy , C substituted by C 3-6 cycloalkyl, C 3-8 cycloalkoxy, C 3-6 heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;

R 3 is selected from H, OH, halogen, -NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl and C 3-6 cycloalkyl;

R 4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, -SF 5 , -NR 7 R 8 , -NHCOCH 3 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl being optionally substituted with one or more halogen, CN, -NR 5 R 6 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkyloxy and 3-6 membered heterocyclyl;

Alternatively, R 3 and R 4 together with the atoms to which they are attached form a 3-10 membered heterocyclic group;

R9 at each occurrence is independently selected from H, C1-4 alkyl and C3-8 cycloalkyl.
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 a C 6-10 aromatic ring and a 5-10 membered heteroaromatic ring;

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, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,

Preferably, ring A is selected from pyridyl,

Preferably, ring A is selected from

Preferably, Selected from

The wavy line It indicates the point of attachment of the group to the rest of the molecule.
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 ring, 5-15 membered heteroaromatic ring, 5-15 membered heteroarylphenyl and 3-8 membered heterocyclylphenyl;

Preferably, ring B is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring, a 5-6 membered heteroarylphenyl ring and a 5-6 membered heterocyclylphenyl ring;

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 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;

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 a benzene ring,

Preferably, Selected from

The wavy line It indicates the point of attachment of the group to the rest of the molecule.
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 is independently selected at each occurrence 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 haloalkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy and 3-8 membered heterocyclyl; said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy are optionally substituted with one or more halogen, OH, CN, -NR 7 R 8 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkyloxy, C 3-6 heterocyclyl; R 10 and R R 11 is each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

Preferably, R 1 is independently selected from H, OH, halogen, -NR 10 R 11 , -CONR 10 R 11 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 heteroalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-8 cycloalkyl at each occurrence; the alkyl, alkoxy, heteroalkyl, cycloalkyl are optionally substituted with one or more halogen, OH, -NR 7 R 8 , C 1-4 alkyl , C 1-4 haloalkyl , C 1-4 alkoxy, C 1-4 haloalkoxy; R 10 and R 11 are independently selected from H, C 1-6 alkyl , or R 10 and R 11 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl;

Preferably, R 1 at each occurrence is independently selected from H, OH, halogen, -NR 10 R 11 , -CONR 10 R 11 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 3-8 cycloalkyl; R 10 and R 11 are independently selected from H, C 1-6 alkyl, or R 10 and R 11 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic group;

Preferably, R 1 at each occurrence is independently selected from H, halogen, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , azetidinyl, pyrrolidinyl, piperidinyl, -NH 2 , -CONH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 3-8 cycloalkyl;

Preferably, R 1 at each occurrence is independently selected from H, -NH 2 , -CONH 2 , C 1-4 alkyl and C 1-4 alkoxy;

Preferably, R 1 at each occurrence is independently selected from H, -CH 3 , -NH 2 , -CONH 2 and -OCH 3 .
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.
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 at each occurrence from Ci -6 alkyl, Ci-6 alkoxy, C 2-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 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, said alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzocycloalkyl, benzoheterocyclyl, heteroaryl and heterocyclyl, heteroaryl and heteroaryl, heteroaryl and cycloalkyl are optionally substituted with one or more halogen, OH, CN, -NR 7 R 8 , Ci -4 alkyl, Ci -4 haloalkyl, Ci-4 alkoxy, Ci -4 haloalkoxy , C substituted by C 3-6 cycloalkyl, C 3-8 cycloalkoxy, C 3-6 heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl;

Preferably, R 2 'is independently selected at each occurrence 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 with one or more halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl;

Preferably, R 2 'is independently selected at each occurrence 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 with one or more halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl;

Preferably, R 2 'at each occurrence is independently selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrimidinyl, -CH 2 OCH 3 , morpholinyl, pyranyl, pyrazolyl, pyridinyl, pyrrolopyridinyl, The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, pyranyl, pyrazolyl, pyridyl, Optionally substituted with one or more halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

Preferably, R 2 'at each occurrence is independently selected from methyl, trifluoromethyl, isopropyl, isobutyl, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclohexyl, cyclopentyl, dimethylcyclopentyl, -CH 2 OCH 3 ,

Preferably, R2 at each occurrence is independently selected from methyl, isopropyl, trifluoroethyl, isobutyl,

The wavy line It indicates the point of attachment of the group to the rest of the molecule.
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 is selected from H, OH, halogen, -NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl and C 3-6 cycloalkyl;

Preferably, R 3 is selected from H and C 1-4 alkyl;

Preferably, R3 is selected from H and methyl.
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:

R4 is independently selected at each occurrence from H, oxo, OH, halogen, CN, -NR7R8 , -NHCOCH3 , C1-4 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C2-6 heteroalkyl, C1-4 haloalkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkyloxy, aryl, heteroaryl being optionally substituted with one or more halogen, CN, -NR5R6 , C1-4 alkyl, C1-4 haloalkyl , C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, C3-8 cycloalkyloxy and 3-6 membered heterocyclyl;

Preferably, R4 is independently selected at each occurrence from H, oxo, OH, halogen, CN , -NR7R8 , C1-4 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C2-6 heteroalkyl, C1-4 haloalkoxy, C3-8 cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl being optionally substituted with one or more halogen, CN, -NR5R6 , C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, C3-8 cycloalkyloxy and 3-6 membered heterocyclyl;

Preferably, R 4 is independently selected at each occurrence from H, oxo, CN, halogen, -NR 7 R 8 , C 1-4 haloalkyl, 3-8 heterocyclyl, C 1-4 haloalkoxy, C 3-8 cycloalkyl, C 1-6 alkoxy, C 2-6 heteroalkyl and 5-10 membered heteroaryl, said alkoxy, heteroalkyl, heteroaryl being optionally substituted with one or more halogen, -NR 5 R 6 , C 1-4 alkyl and C 1-4 haloalkyl;

Preferably, R 4 is independently selected at each occurrence from H, oxo, CN, F, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , azetidinyl, pyrrolidinyl, piperidinyl, CF 3 , C 3-8 cycloalkyl, C 1-6 alkoxy, C 2-6 heteroalkyl and 5-6 membered heteroaryl, wherein the alkoxy, heteroalkyl and heteroaryl are optionally substituted with one or more halogen, -NR 5 R 6 , C 1-4 alkyl and C 1-4 haloalkyl;

Preferably, R 4 is independently selected at each occurrence from H, oxo, F, -N(CH 3 ) 2 , CF 3 , CN, cyclopropyl, -SF 5 and -OCF 3 .
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 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more halogen, OH, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; or R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, wherein the alkyl, alkoxy and cycloalkyl are optionally substituted with one or more halogen, OH, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl; The connected carbon atoms form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclyl group, wherein the cycloalkyl group or the heterocyclyl group is optionally substituted by one or more halogen, OH, -NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl group or a 3-6 membered heterocyclyl group;

Preferably, R 5 and R 6 are each independently selected from H, C 1-4 alkyl; or R 5 and R 6 , together with the carbon atom to which they are connected, form a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group;

Alternatively, R3 and R4 together with the atoms to which they are attached form a 3-8 membered heterocyclic group.
The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein:

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

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

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

Where q is 0 or 1.
A compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein the compound is selected from:
A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled substance, polymorph, solvate, N-oxide, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.
Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-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.
The 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 NH 2 undergo reductive amination reaction 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, the fifth step is to remove the protecting group of the condensation product of the fourth step 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 to 15.