Ring-fused compound, pharmaceutical composition containing ring-fused compound, and preparation method and application of ring-fused compound

Abstract

The invention relates to a fused ring compound, a pharmaceutical composition containing the fused ring compound, a preparation method of the fused ring compound and application of the fused ring compound. Specifically, the invention relates to an imidazo [1, 5-a] quinoxaline derivative as shown in a formula I. The imidazo [1, 5-a] quinoxaline derivative has a good inhibition effect on tumor cells and has good pharmacokinetics and other properties. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a cyclopentadienyl compound, a pharmaceutical composition comprising the same, a method for preparing the same, and use thereof in preventing or treating diseases or conditions associated with PRMT5 activity. Background Art

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

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

[0004] MTAP is the gene encoding methylthioadenosine phosphorylase, located on chromosome 9p21, close to the tumor suppressor gene CDKN2A (which often undergoes homozygous deletion). Therefore, MTAP is often co-deleted with CDKN2A in tumors (Marjon K, Kalev P, Marks K., Cancer Dependencies: PRMT5 and MAT2A in MTAP / p16-DeletedCancers, Annual Review of Cancer Biology, 2021, 5(1): 371-390.). Approximately 15% of solid tumors suffer from MTAP deletion.

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

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

[0007] The present invention provides an imidazo[1,5-a]quinoxaline compound, which has a good inhibitory effect on MTAP-deficient tumor cells and has good pharmacokinetic properties.

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

[0009]

[0010] in:

[0011] Ring A is a 3-11 membered heterocyclic ring;

[0012] X 1 , X 2 , X 3 Each independently selected from CR 9 and N;

[0013] R 1 is independently selected at each occurrence from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl;

[0014] R 2 Selected from H, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group;

[0015] R 3 is independently selected at each occurrence from H, -OH, halogen, -CN, -NR 4 R 5 、-COCH3、-NHCOCH3、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl are each optionally substituted by one or more R 6 replace;

[0016] R 6 is independently selected at each occurrence from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more independently selected from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substitution of cycloalkoxy and 3-8 membered heterocyclic groups;

[0017] R 4 and R 5 Each independently selected from H and C 1-6 Alkyl; or

[0018] R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more independently selected from halogen, OH, CN, -NH2 and C 1-6 Substitution of alkyl groups;

[0019] R 9 is independently selected at each occurrence from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0020] m is 0, 1 or 2; and

[0021] n is 0, 1, 2 or 3.

[0022] 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.

[0023] Another aspect of the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a disease or condition associated with PRMT5 activity.

[0024] Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention for use in preventing or treating a disease or condition associated with PRMT5 activity.

[0025] Another aspect of the present invention provides a method for preventing or treating a disease or condition associated with PRMT5 activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention.

[0026] Another aspect of the present invention provides a process for preparing the compounds of formula I of the present invention.

[0027] definition

[0028] 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.

[0029] 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.").

[0030] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 Alkyl" and "C 1-4 "Alkyl" refers to a linear or branched group having 1-6 carbon atoms and 1-4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0031] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more backbone chain atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, in the main chain carbon atoms of the alkyl group. Numerical ranges (e.g., C 1-6 Assorted alkyl) refers to the number of carbons in the chain, including 1-6 carbon atoms in this example. For example, a -CH2OCH2CH3 group is referred to as a C3 assorted alkyl, and a -CH2OCH2CH2NHCH3 group is referred to as a C4 assorted alkyl. Connection to the rest of the molecule can be made through heteroatoms or carbon atoms in the assorted alkyl chain.

[0032] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-8 Haloalkyl", "C 1-6 "Haloalkyl" and "C 1-4 "Haloalkyl" refers to haloalkyl having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, for example, -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0033] As used herein, the term "hydroxyalkyl" refers to a group in which a hydrogen atom in an alkyl group is replaced by one or more hydroxyl groups, for example, 1-4 Hydroxyalkyl or C 1-3 Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, and the like.

[0034] As used herein, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group is as described above. The alkoxy group herein may contain 1 to 12 carbon atoms, preferably C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc., and the alkoxy is optionally substituted with one or more (such as 1 to 3) identical or different substituents. For example, the term "haloalkoxy" refers to that the hydrogen atoms of the alkoxy are substituted with one or more (such as 1 to 3) identical or different halogen atoms.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including but not limited to monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl, including spirocyclic, paracyclic (condensed) or bridged ring systems (i.e., spirocyclic alkyl, paracyclic (condensed) alkyl and bridged cycloalkyl, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.). In the present invention, the cycloalkyl is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl are optionally substituted with oxo (oxo) groups (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms, such as C 3-6 Cycloalkyl, which may be a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic alkyl, such as C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Fused cycloalkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl.

[0039] 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.

[0040] As used herein, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated aliphatic monocyclic or polycyclic (e.g., cyclic, 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, such as 3-11 membered heterocycle, 3-8 membered heterocycle, 5-7 membered heterocycle, 4-7 membered heterocycle, 3-8 membered nitrogen heterocycle, 5-7 membered nitrogen heterocycle, 5-6 membered nitrogen heterocycle, wherein the heteroatoms include, but are not limited to, oxygen atoms, nitrogen atoms and sulfur atoms, and the carbon atoms and heteroatoms on the heterocyclyl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or are optionally substituted with one or more (e.g., 1 to 3) independently selected from halogen and C 1-3 Preferably, the heterocycle is a 5-7 membered heterocycle, and the heterocycle contains at least one N atom and optionally one or two other heteroatoms independently selected from O and S that are the same or different.

[0041] The term "3-11 membered heterocyclyl" means a heterocyclyl containing 3-11 ring atoms, including but not limited to a 4-10 membered heterocyclyl, a 4-9 membered heterocyclyl, a 4-8 membered heterocyclyl, a 4-7 membered heterocyclyl, a 5-6 membered heterocyclyl, a 3-10 membered heterocyclyl, a 3-8 membered heterocyclyl, a 3-7 membered heterocyclyl, a 4-7 membered nitrogen-containing heterocyclyl, a 4-7 membered oxygen-containing heterocyclyl, a 4-7 membered sulfur-containing heterocyclyl, a 5-6 membered nitrogen-containing heterocyclyl, a 5-6 membered oxygen-containing heterocyclyl, a 5-6 membered sulfur-containing heterocyclyl, and the like, wherein the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 3-11 membered heterocyclic groups include, but are not limited to, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (e.g. ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl.

[0042] In the present invention, the heterocyclic group may also include a parallel ring structure formed with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other group may be on any heterocyclic group or on the cycloalkyl group. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic groups and heterocyclic groups, heterocyclic groups and cycloalkyl groups, monoheterocyclic groups and monoheterocyclic groups, and monoheterocyclic groups and monocycloalkyl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and (mono) cycloalkyl groups, 3-7 membered (mono) heterocyclic groups and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl-cyclopropyl, cyclopentyl-aziridine, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl,

[0043] In the present invention, the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.

[0044] 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.

[0045] 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

[0046] 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.

[0047] Examples of the group obtained by condensing a heterocyclic group with an aryl group include, but are not limited to:

[0048] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π electron system. 6-12 "Aryl (aromatic ring)" means an aromatic group (aromatic ring) containing 6 to 12 carbon atoms, preferably C 6-10 Aryl (aromatic ring), preferably phenyl (benzene ring) or naphthyl (naphthalene ring). Aryl is optionally substituted by one or more (such as 1 to 3) identical or different substituents (such as halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0049] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl and a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, such as 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0050] 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.

[0051] In the present invention, a heteroaryl group (e.g., a monoheteroaryl group) can share two adjacent atoms with an aryl group (e.g., a monocyclic aryl group, such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocyclic alkyl group) or another heteroaryl group (e.g., another monoheteroaryl group) to form a parallel ring structure, and the connection point can be on any heteroaryl ring or on other rings, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (monocyclic) aryl, (mono)heteroaryl and (mono)heterocyclic group and (mono)heteroaryl and (mono)cycloalkyl, such as a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heteroaryl, a 5-6-membered (mono)heteroaryl and phenyl group, a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heterocyclic group or a 5-6-membered (mono)heteroaryl and C 4-6 (Mono)cycloalkyl (e.g., 5-6 membered heteroarylcyclobutyl, 5-6 membered heteroarylcyclopentyl or 5-6 membered heteroarylcyclohexyl), examples of which are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, benzothiazole, quinolyl, isoquinolyl, wait.

[0052] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0053] The term "replacement" refers to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the replacement forms a stable compound. The combination of substituents and / or variables is permitted only when such a combination forms a stable compound. The compounds of the present invention can also be substituted by suitable substituents in suitable positions, and suitable substituents adopt the substituents described above in the application and the substituents adopted by those skilled in the art.

[0054] 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.

[0055] 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.

[0056] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0057] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0058] 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.

[0059] The present invention also includes all pharmaceutically acceptable isotope-labeled compounds, which are identical to the compounds of the present invention, except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g. 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); isotopes of oxygen (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (e.g. 32 P); and sulfur isotopes (e.g. 35S). Certain isotopically-labeled compounds of the invention (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F. 15 O and 13 N) can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotope-labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations by using appropriate isotope-labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0060] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a single diastereomer. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oxime can exist in the following tautomeric form equilibrium in solution:

[0061]

[0062] 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%).

[0063] 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).

[0064] 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.

[0065] 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.

[0066] 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.

[0067] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0068] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate, meglumine salt, etc. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002).

[0069] 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.

[0070] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0071] Those skilled in the art will appreciate that, since nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles can form N-oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. The synthetic method for preparing the N-oxide of heterocycles and tertiary amines is well known to those skilled in the art, including but not limited to oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ES G Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0072] 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.

[0073] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may have less pharmacological activity or no pharmacological activity themselves, and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moiety" (e.g., "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0074] The present invention also encompasses compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, those described in TW Greene & P.GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. Using methods known in the art, the protecting groups can be removed at an appropriate subsequent stage.

[0075] The term "about" means within ±10%, preferably within ±5%, more preferably within ±2% of the stated value. It should be noted that if there is a difference between the described structure and the name of the structure, the described structure will be given greater weight.

[0076] Compound

[0077] The present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof:

[0078]

[0079] in:

[0080] Ring A is a 3-11 membered heterocyclic ring;

[0081] X 1 , X2 , X 3 Each independently selected from CR 9 and N;

[0082] R 1 is independently selected at each occurrence from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl;

[0083] R 2 Selected from H, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group;

[0084] R 3 is independently selected at each occurrence from H, -OH, halogen, -CN, -NR 4 R 5 、-COCH3、-NHCOCH3、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl are each optionally substituted by one or more R 6 replace;

[0085] R 6 is independently selected at each occurrence from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more independently selected from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substitution of cycloalkoxy and 3-8 membered heterocyclic groups;

[0086] R 4 and R 5 Each independently selected from H and C 1-6 Alkyl; or

[0087] R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more independently selected from halogen, OH, CN, -NH2 and C 1-6 Substitution of alkyl groups;

[0088] R 9 is independently selected at each occurrence from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0089] m is 0, 1 or 2; and

[0090] n is 0, 1, 2 or 3.

[0091] In certain embodiments, in the compound of formula I provided by the present invention, ring A is a 5-7 membered saturated or partially saturated heterocyclic ring, wherein the heterocyclic ring contains at least one N atom and optionally 1 or 2 other heteroatoms independently selected from O or S that are the same or different.

[0092] In certain embodiments, in the compound of formula I provided by the present invention, ring A is a 5-7 membered saturated heterocyclic ring, wherein the heterocyclic ring contains at least one N atom and optionally 1 or 2 other heteroatoms independently selected from O or S that are the same or different.

[0093] In certain embodiments, in the compound of formula I provided by the present invention, ring A is a 5-7 membered saturated nitrogen heterocycle or a 5-7 membered saturated N- and O-containing heterocycle.

[0094] In certain embodiments, in the compound of formula I provided by the present invention, ring A is a 6-membered saturated nitrogen heterocycle or a 6-membered saturated N- and O-containing heterocycle.

[0095] In certain embodiments, in the compound of formula I provided by the present invention, ring A is a piperidine ring or a morpholine ring.

[0096] In certain embodiments, the present invention provides compounds of formula I in which R 2 Selected from H, halogen, CN, C 1-4Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups.

[0097] In certain embodiments, the present invention provides compounds of formula I in which R 2 Selected from H, halogen, CN, ethynyl, cyclopropane and 3-6 membered heterocyclyl.

[0098] In certain embodiments, the present invention provides compounds of formula I in which R 2 For H.

[0099] In certain embodiments, the present invention provides compounds of formula I in which R 4 and R 5 Each independently selected from H and C 1-4 Alkyl; or R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more independently selected from halogen, OH, CN, -NH2 and C 1-4 The alkyl group is substituted with a substituent.

[0100] In certain embodiments, the present invention provides compounds of formula I in which R 4 and R 5 Each is independently selected from H, methyl, ethyl, propyl and butyl.

[0101] In certain embodiments, the present invention provides compounds of formula I in which R 4 and R 5 are each independently selected from H and methyl.

[0102] In certain embodiments, the present invention provides compounds of formula I, wherein X 3 is N.

[0103] In certain embodiments, in the compound of formula I provided by the present invention, n is 0, 1 or 2, preferably, n is 1 or 2, for example, n is 2.

[0104] In some embodiments, the present invention provides a compound of Formula IA or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof:

[0105]

[0106] Among them, R 1 , R 3 , X 1 , X 2 , m are as defined above.

[0107] In some embodiments, the present invention provides a compound of Formula IB or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof:

[0108]

[0109] Among them, R 1 , R 3 , X 1 , X 2 , m are as defined above.

[0110] In some embodiments, the present invention provides a compound of formula IB-1 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof:

[0111]

[0112] Among them, R 1 , R 3 , X 1 , X 2 , m are as defined above.

[0113] In some embodiments, the present invention provides a compound of Formula IC or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof:

[0114]

[0115] Among them, R 1 , R 3 , X 1 , X 2 , m are as defined above.

[0116] In some embodiments, the present invention provides a compound of formula IC-1 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof:

[0117] R 3 Each occurrence is independently selected from methyl, phenyl, The methyl, phenyl, Each optionally represented by one or more R 6 replace.

[0118]

[0119] Among them, R 1 , R 3 , X 1 , X 2 , m are as defined above.

[0120] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 1 Each occurrence is independently selected from H and C 1-4 alkyl.

[0121] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 1 Each is independently selected from H, methyl, ethyl, propyl and butyl.

[0122] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 1 are each independently selected from H and methyl.

[0123] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 1 For H.

[0124] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 3 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl are each optionally substituted by one or more R 6 replace.

[0125] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 3 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, aryl or heteroaryl groups are each optionally substituted by one or more R 6 replace.

[0126] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 3Each occurrence is independently selected from C 1-6 Alkyl, C 6-10 Aryl and 6-9 membered heteroaryl, wherein the alkyl, aryl or heteroaryl groups are each optionally substituted by one or more R 6 replace.

[0127] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 3 Each occurrence is independently selected from C 1-6 alkyl, phenyl, pyridyl, pyridazinyl and benzothiazolyl, wherein the phenyl, pyridyl, pyridazinyl or benzothiazolyl is each optionally substituted by one or more R 6 replace.

[0128] In certain embodiments, the present invention provides compounds of formula I, formula IA, formula IB, formula IB-1, formula IC or formula IC-1,

[0129] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 6 is independently selected at each occurrence from halogen, -CN, -NR 4 R 5 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more independently selected from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 The substituents of the cycloalkoxy group and the 3- to 8-membered heterocyclic group are substituted.

[0130] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 6 is independently selected at each occurrence from halogen, -NR 4 R 5 , C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 2-6 heteroalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, heterocyclyl, phenyl or heteroaryl are each optionally substituted by one or more independently selected from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、C 1-6 Alkyl, C 1-6 The substituents of the haloalkyl group and the 4-6 membered heterocyclic group are substituted.

[0131] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 6 Each occurrence is independently selected from -NR 4 R 5 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 4-7 membered heterocyclyl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, heterocyclyl and heteroaryl are each optionally substituted by one or more independently selected from halogen, -NR 4 R 5 、-COCH3、C 1-6 Alkyl, C 1-6 The substituents of the haloalkyl group and the 4-6 membered heterocyclic group are substituted.

[0132] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 6 Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, wherein the alkyl, alkoxy, heterocyclyl and heteroaryl are each optionally substituted by one or more independently selected from halogen, C 1-6 Alkyl, C 1-6 The substituents of the haloalkyl group are substituted.

[0133] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 6 Each occurrence is independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, wherein the alkyl, alkoxy, heteroaryl and heterocyclyl are each optionally substituted by one or more independently selected from halogen, C 1-4 Alkyl, C 1-4 The substituents of the haloalkyl group are substituted.

[0134] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 6 Each occurrence is independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, wherein the alkyl, alkoxy, heteroaryl and heterocyclyl are each optionally substituted by one or more independently selected from F, Cl, Br, I, C 1-4 Alkyl, C 1-4 The substituents of the haloalkyl group are substituted.

[0135] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 3 Each occurrence is independently selected from methyl, phenyl, The methyl, phenyl, Each is optionally replaced by one or more independently selected from trifluoromethyl, methoxy, pentafluoroethoxy, difluoromethoxy, trifluoromethoxy, substituted by a substituent.

[0136] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, wherein X 1 and X 2 Each independently is CR 9 .

[0137] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 9 is independently selected at each occurrence from H, halogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

[0138] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 9 is independently selected at each occurrence from H, F, Cl, methyl and trifluoromethyl.

[0139] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, R 9 For H.

[0140] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, wherein X 1 Selected from CH, C(CH3), C(F), C(Cl) and C(CF3).

[0141] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, wherein X 1 For CH.

[0142] In certain embodiments, the present invention provides compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1, wherein X 2 For CH.

[0143] In certain embodiments, in the compounds of Formula I, Formula IA, Formula IB, Formula IB-1, Formula IC or Formula IC-1 provided herein, m is 0 or 1, preferably, m is 1.

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

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

[0146]

[0147]

[0148]

[0149] Preparation method

[0150] In certain embodiments, the present invention provides a method for preparing a compound of Formula I, comprising the steps of:

[0151] Route A

[0152] The first step: Compound I-1 and I-2 undergo condensation reaction to generate compound I-3;

[0153]

[0154] Step 2: Compound I-3 is deprotected to generate Compound I. Preferably, the deprotection is performed by heating under acidic conditions;

[0155]

[0156] Wherein: each group is as defined above;

[0157] The reaction conditions of each step are as follows:

[0158] Step 1: Compounds I-1 and I-2 are subjected to a condensation reaction (e.g., HATU and DIPEA; POCl3 and pyridine, etc.) to generate compound I-3;

[0159] Step 2: Compound I-3 is heated and deprotected under acidic conditions (trifluoroacetic acid or the like is used as the acid) to generate compound I.

[0160] Pharmaceutical compositions, preparations and methods of treatment

[0161] In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotopically labeled compound thereof and one or more pharmaceutically acceptable carriers.

[0162] In some embodiments, the present invention provides a pharmaceutical preparation selected from a solid preparation, a semisolid preparation, a liquid preparation and a gaseous preparation, 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.

[0163] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise one or more additional therapeutic agents.

[0164] In some embodiments, the pharmaceutical composition or pharmaceutical formulation is administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0165] In some embodiments, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention in the preparation of a medicament for preventing or treating a disease or condition associated with PRMT5 activity.

[0166] In some embodiments, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention in the preparation of a medicament for modulating (e.g., reducing or inhibiting) PRMT5 activity.

[0167] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention, for use in preventing or treating a disease or condition associated with PRMT5 activity.

[0168] In some embodiments, the present invention provides a method for preventing or treating a disease or condition associated with PRMT5 activity, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical preparation of the present invention.

[0169] In some embodiments, the disease or condition associated with PRMT5 activity is a cancer or tumor in which MTAP is deficient.

[0170] In some embodiments, the cancer or tumor is selected from esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, melanoma, gastric cancer, colon cancer, leukemia (B-CLL) and lymphoma.

[0171] 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.

[0172] 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).

[0173] The pharmaceutical compositions of the invention can act systemically and / or locally. For this purpose, they can be administered by a suitable route.

[0174] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] Unless otherwise indicated, as used herein, the term "prevention" refers to the pre-administration of a drug to avoid or prevent the appearance of one or more symptoms of a disease or condition. One of ordinary skill in the medical field recognizes that the term "prevention" is not an absolute term. In the medical field, it is understood that the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or the symptoms of a condition is a meaning intended in this disclosure. The Physician's Desk Reference, a standard text in the field, uses the term "prevention" hundreds of times. As used therein, the term "prevention" with respect to a condition or disease refers to avoiding the cause, effect, symptom, or progression of a disease or condition before the disease or condition fully manifests itself.

[0180] 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.

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

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

[0183] Example

[0184] The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention. The abbreviations used herein have the following meanings:

[0185]

[0186]

[0187] The compounds of the present invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography. 1 The reaction was confirmed by H NMR and / or MS. The reaction was monitored by TLC or LC-MS.

[0188] 1 H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).

[0189] LC / MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0190] TLC used silica gel GF 254 as the stationary phase.

[0191] Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0192] Flash column chromatography was performed using a Biotage flash column chromatograph.

[0193] Agilent 1260 and Waters 2489 were used for Prep-HPLC.

[0194] Microwave reactions were performed using a BiotageInitiator microwave reactor.

[0195] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0196] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Teber Chemical Company.

[0197] Synthesis Example:

[0198] Intermediate Int-A: 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid

[0199]

[0200] Step 1: Synthesis of intermediate N-(4-bromo-2-fluorophenyl)-1H-imidazole-5-carboxamide (Compound Int A-3)

[0201] Int A-1 (15 g, 133.83 mmol) was dissolved in anhydrous DMF (50 mL) under an ice-water bath, and DIPEA (34.59 g, 267.65 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (76.33 g, 200.74 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of Int A-2 (27.97 g, 147.21 mmol) was added dropwise. The temperature was naturally raised to 25 °C and reacted for 16 hours. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 40:60) to obtain the intermediate Int A-3 (16.00 g). MS (ESI, m / z): 284.0 [M+H] + .

[0202] Step 2: Synthesis of intermediate 8-bromoimidazo[1,5-a]quinoxaline-4(5H)-one (Compound Int A-4)

[0203] Int A-3 (2.27 g, 7.98 mmol) was dissolved in anhydrous DMAc (20 mL), and NaH (479.01 mg, 11.98 mmol) was added in batches under ice bath, and stirred for 10 min, and then reacted at 140 ° C for 48 hours under nitrogen protection. After the reaction was completed, most of the DMAc was dried under reduced pressure, cooled to room temperature, stirred with water, and filtered. The filter cake was rinsed with water twice to obtain the intermediate Int A-4 (2.0 g), which was used after drying. MS (ESI, m / z): 264.0 [M+H] + .

[0204] Step 3: Synthesis of intermediate 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (compound IntA-5)

[0205] Int A-4 (2.0 g, 7.57 mmol), TEA (2.30 g, 22.72 mmol), Pd(dppf)2Cl2 (613.90 mg, 757.35 μmol) were added to the autoclave and dissolved with methanol (30 mL). After CO substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 140°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature and filtered. The filter cake was the intermediate Int A-5 (700 mg), which was used after drying. MS (ESI, m / z): 244.1 [M+H]+.

[0206] Step 4: Synthesis of intermediate 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (Compound Int A-7)

[0207] In anhydrous DMF (20 mL) was added with Int A-5 (700 mg, 2.88 mmol) and PyBOP (2.25 g, 4.32 mmol) under ice bath, and DIPEA (1.12 g, 8.63 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (962.46 mg, 5.76 mmol) was added and reacted at 60 °C for 16 hr. After the reaction was completed, water was added and stirred, and EA was extracted and concentrated to obtain a crude product, which was purified by silica gel column chromatography (mobile phase DCM: MeOH = 95:5) to obtain the intermediate Int A-7 (904 mg). MS (ESI, m / z): 393.2 [M+H] + .

[0208] Step 5: Synthesis of intermediate 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int A)

[0209] Int A-7 (904 mg, 2.30 mmol) was dissolved in 30 mL of methanol under ice bath, and an aqueous solution (15 mL) of NaOH (552.90 mg, 13.82 mmol) was added dropwise, and the temperature was naturally raised to 25°C for 16 hours. After the reaction, the methanol was dried by spin drying, and dilute hydrochloric acid was added dropwise to the remaining part under ice bath until the solution was acidic, and the filter cake was washed with water twice to obtain the intermediate Int A (840 mg). MS (ESI, m / z): 379.2 [M+H] + .

[0210] Intermediate Int B: 2-(5-methylpiperidin-2-yl)-5-(trifluoromethyl)pyridine

[0211]

[0212] Step 1: Synthesis of 5-methylpiperidin-2-one (Compound Int B-2)

[0213] Int B-1 (5 g, 45.82 mmol) was dissolved in MeOH (40 mL), and then Pd(OH)2 / C (6.43 g, 4.58 mmol) was added, and the hydrogen was replaced three times. The autoclave was heated to 80°C and stirred for 12 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to obtain compound Int B-2 (5 g). MS (ESI, m / z): 114.2 [M+H] + .

[0214] Step 2: Synthesis of tert-butyl 5-methyl-2-oxopiperidine-1-carboxylate (Compound Int B-3)

[0215] Int B-2 (1 g, 8.84 mmol) and DMAP (107.97 mg, 883.73 μmol) were added to THF (10 mL), and (Boc)2O (2.12 g, 9.72 mmol) was slowly added, and stirred at 25°C for 16 hours. After the reaction was completed, the mixture was quenched with ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (PE:EA=9:1) to obtain compound Int B-3 (1.72 g).

[0216] Step 3: Synthesis of tert-butyl 3-methyl-6-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (Compound Int B-5)

[0217] Int B-3 (5 g, 23.44 mmol) was dissolved in THF (50 mL), cooled to -78 °C, and then LiHMDS (35.17 mmol, 1M THF solution, 35.17 mL) was slowly added. After the addition was completed, it was kept at -78 °C and stirred for 0.5 hr. Then, a THF (20 mL) solution of Int B-4 (10.05 g, 28.13 mmol) was added. After the addition was completed, the temperature naturally rose to 25 °C and the reaction was continued for 16 hr. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added under an ice bath to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (PE:EA=9:1) to obtain compound Int B-5 (7.5 g). MS (ESI, m / z): 363.1 [M+18] + .

[0218] Step 4: Synthesis of tert-butyl 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (Compound Int B-7)

[0219] Int B-5 (7.5 g, 21.72 mmol), Int B-6 (8.27 g, 32.58 mmol), PPh3 (341.78 mg, 1.30 mmol), Pd(PPh3)4 (752.90 mg, 651.54 μmol) and K2CO3 (7.50 g, 54.30 mmol) were weighed into a two-necked bottle, and then 1,4-dioxane (50 mL) was added. After replacing the nitrogen, the reaction temperature was raised to 90°C and stirred for 20 hours. The solvent was removed by concentration, and then extracted three times with dichloromethane. The organic phases were combined, concentrated, separated and purified by reverse phase column (H2O [0.05% NH4HCO3]: ACN = 10:90), concentrated, extracted with ethyl acetate, dried, filtered, and concentrated to obtain compound Int B-7 (1.55 g). MS (ESI, m / z): 324.2 [M+H] + .

[0220] Step 5: Synthesis of tert-butyl 5-methyl-5'-(trifluoromethyl)-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate (Compound Int B-9)

[0221] Int B-8 (2.17 g, 9.59 mmol), Int B-7 (1.55 g, 4.80 mmol), Pd(dppf)Cl2·DCM (391.60 mg, 479.53 μmol) were dissolved in 1,4-dioxane (50 mL), and then a solution of Na2CO3 (1.02 g, 9.59 mmol) in H2O (10 mL) was added. After replacing the nitrogen, the reaction system was heated to 90°C and reacted for 2 hours. The reaction was cooled to room temperature, directly concentrated, and extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound Int B-9 (1.6 g). MS (ESI, m / z): 343.1 [M+H] + .

[0222] Step 6: Synthesis of 5-methyl-5'-(trifluoromethyl)-3,4,5,6-tetrahydro-2,2'-bipyridine (Compound Int B-10)

[0223] Int B-9 (1.6 g, 4.67 mmol) was added to a 4N HCl 1,4-dioxane solution (10 mL) and reacted at 25°C for 2 hours. The mixture was directly concentrated to obtain compound Int B-10 (1 g). MS (ESI, m / z): 243.1 [M+H] + .

[0224] Step 7: Synthesis of 2-(5-methylpiperidin-2-yl)-5-(trifluoromethyl)pyridine (Compound Int B)

[0225] Int B-10 (1 g, 4.13 mmol) was added to THF (10 mL). After replacing nitrogen, NaBH4 (312.36 mg, 8.26 mmol) was added and the reaction was stirred at 25°C for 0.5 hr. After the reaction was completed, saturated ammonium chloride was added dropwise to quench the reaction. After concentration, the mixture was separated and purified by a reverse phase column (H2O [0.05% HCO2H]: ACN = 70: 30), and the target compound Int B (500 mg) was obtained after freeze-drying. MS (ESI, m / z): 245.1 [M+H] + .

[0226] Intermediate Int C: 5-(5-methylpiperidin-2-yl)benzo[d]thiazole

[0227]

[0228] Step 1: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (Compound Int C-2)

[0229] Int C-1 (500 mg, 2.34 mmol), Int B-6 (771.01 mg, 3.04 mmol), Pd(dppf)Cl2·DCM (190.73 mg, 233.56 μmol) and KOAc (687.63 mg, 7.01 mmol) were added to 1,4-dioxane (30 mL). After replacing nitrogen, the reaction system was heated to 80 ° C for 2 hours. The reaction solution was directly separated and purified by silica gel column chromatography (PE: EA = 98: 2), and the compound Int C-2 (580 mg) was obtained after concentration. MS (ESI, m / z): 262.1 [M+H] + .

[0230] Step 2: Synthesis of tert-butyl 6-(benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate (Compound Int C-3)

[0231] Int C-2 (100 mg, 382.93 μmol), Int B-5 (132.24 mg, 382.93 μmol), Pd(dppf)Cl2·DCM (31.27 mg, 38.29 μmol) and Na2CO3 (81.17 mg, 765.85 μmol) were added to a mixed solution of 1,4-dioxane (10 mL) and H2O (1 mL), and the reaction system was heated to 90°C for 2 hours. After cooling, the reaction system was directly concentrated to dryness, and the crude product was purified by silica gel column chromatography (PE:EA=20:1), and the target compound Int C-3 (580 mg) was obtained after concentration. MS (ESI, m / z): 331.1 [M+H] + .

[0232] Step 3: Synthesis of 5-(5-methyl-3,4,5,6-tetrahydropyridin-2-yl)benzo[d]thiazole (Compound Int C-4)

[0233] Add Int C-3 (600 mg, 1.82 mmol) to a 4N HCl solution of 1,4-dioxane (10 mL) and react at 25°C for 2 hours. Directly concentrate to dryness, add methanol and triethylamine and concentrate again to dryness, separate and purify by silica gel column chromatography (DCM:MeOH=98:2), and concentrate to obtain the target compound Int C-4 (385 mg). MS (ESI, m / z): 231.1 [M+H] + .

[0234] Step 4: Synthesis of 5-(5-methylpiperidin-2-yl)benzo[d]thiazole (Compound Int C)

[0235] Int C-4 (440 mg, 1.91 mmol) was added to THF (10 mL). After replacing nitrogen, NaBH4 (144.54 mg, 3.82 mmol) was added and the reaction was stirred at 25 °C for 0.5 hr. After the reaction was completed, saturated ammonium chloride was added dropwise to quench the reaction. After concentration to dryness, the mixture was separated and purified by silica gel column chromatography (DCM: MeOH = 97: 3). After concentration, the target compound Int C (400 mg) was obtained. MS (ESI, m / z): 233.1 [M+H] + .

[0236] Intermediate Int D: 3-(Benzo[d]thiazol-5-yl)-5-methylmorpholine

[0237]

[0238] Step 1: Synthesis of 5-methylmorpholin-3-one (Compound Int D-3)

[0239] Under ice bath, NaH (120 g, 3.00 mol) was slowly added to THF (1.00 L), and then Int D-1 (100 g, 1.33 mol) was slowly added dropwise. After the addition was completed, the mixture was kept at 0°C and stirred for 30 mins. Then the temperature was raised to 25°C, and Int D-2 (204 g, 1.66 mol) was slowly added to the reaction solution, and the reaction was kept at 25°C for 16 hrs. TLC (PE / EA=1 / 1, R f =0.15) and LCMS detected that the reaction was complete. Under ice bath, saturated NH4Cl aqueous solution (1.00 L) was slowly added dropwise to quench the reaction. It was extracted with ethyl acetate (6.00 L), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound Int D-3 (158 g). MS (ESI, m / z): 116.3 [M+H] + .

[0240] Step 2: Synthesis of tert-butyl 3-methyl-5-oxomorpholine-4-carboxylate (Compound Int D-4)

[0241] Compound Int D-3 (158 g, 1.37 mol) was dissolved in THF (1.00 L), and then DMAP (16.8 g, 137 mmol) and Boc2O (329 g, 1.51 mol) were added in sequence. The reaction solution was kept at 25 ° C and stirred for 16 hrs. LCMS detected that the reaction was complete. Then water (200 mL) was added to quench the reaction, and ethyl acetate (900 mL) was extracted. The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous Na2SO4, filtered, concentrated, separated and purified by silica gel column chromatography (PE / EA=1 / 0 to 6 / 1), and concentrated to obtain compound Int D-4 (55.0 g).

[0242] Step 3: Synthesis of tert-butyl 5-((diphenoxyphosphoryl)oxy)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (Compound Int D-6)

[0243] Int D-4 (54.9 g, 255 mmol) was dissolved in THF (800 mL), and after replacing nitrogen, the temperature was cooled to -70 °C and LiHMDS (1 M, 281 mL) was slowly added dropwise. After the addition was completed, the reaction was kept at -70 °C and stirred for 1 hr. Then Int D-5 (71.9 g, 268 mmol) was slowly added dropwise, and the reaction was stirred at -60 to -30 °C for 3 hrs. After the reaction was complete by LCMS, water (200 mL) was added at 0 °C to quench the reaction, and then extracted with ethyl acetate (300 mL x 3), the organic phases were combined, washed with saturated brine (600 mL), dried over anhydrous Na2SO4, filtered, concentrated, separated and purified by silica gel column chromatography (PE / EA=1 / 0 to 9 / 1), and concentrated to obtain compound Int D-6 (98.9 g). MS (ESI, m / z): 348.1 [M+H-Boc] + .

[0244] Step 4: Synthesis of tert-butyl 5-(benzo[d]thiazol-5-yl)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (Compound Int D-7)

[0245] Compound Int C-2 (700 mg, 2.68 mmol), Int D-6 (1.00 g, 2.24 mmol), XPhos Pd G3 (189 mg, 223 μmol) and KOAc (658 mg, 6.71 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10.0 mL) and H2O (2.50 mL). After replacing nitrogen, the reaction was stirred at 100 °C for 16 hrs. After LCMS detection, the reaction solution was concentrated and separated and purified by silica gel column chromatography (PE:EA = 100:1 to 1:1). After concentration, compound Int D-7 (350 mg) was obtained. MS (ESI, m / z): 333.2 [M+H] + .

[0246] Step 2: Synthesis of 5-(Benzo[d]thiazol-5-yl)-3-methyl-3,6-dihydro-2H-1,4-oxazine (Compound Int D-8)

[0247] Compound Int D-7 (350 mg, 1.05 mmol) was dissolved in DCM (2.00 mL), and then TFA (1.00 mL) was added. The reaction was stirred at 20 °C for 1 hr. LCMS detected that the reaction was complete, and the reaction solution was concentrated to obtain compound Int D-8 (350 mg). MS (ESI, m / z): 233.2 [M+H] + .

[0248] Step 3: Synthesis of 3-(Benzo[d]thiazol-5-yl)-5-methylmorpholine (Compound Int D)

[0249] Compound Int D-8 (468 mg, 2.01 mmol) was dissolved in MeOH (10.0 mL), cooled to 0°C in an ice bath, and then NaBH4 (381 mg, 10.0 mmol) was added. After the addition was completed, the reaction was naturally heated to 25°C and stirred for 1 hr. LCMS detected that the reaction was complete, and then saturated NH4Cl (aq, 5.00 mL) aqueous solution was added at 0°C to quench the reaction. DCM (10.0 mL) was added for dilution, and then extracted with DCM (10.0 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound Int D (130 mg). MS (ESI, m / z): 235.2 [M+H] + .

[0250] Intermediate Int E: 4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Int E)

[0251]

[0252] Step 1: Synthesis of N-(4-bromo-2-fluoro-5-methylphenyl)-1H-imidazole-5-carboxamide (Int E-2)

[0253] Int A-1 (3 g, 26.77 mmol) was dissolved in anhydrous DMF (50 mL) under an ice-water bath, and DIPEA (6.92 g, 53.53 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (15.27 g, 40.15 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of Int E-1 (6.01 g, 29.44 mmol) was added dropwise. The temperature was naturally raised to 25 °C and reacted for 16 hours. After the reaction was completed, water was added and stirred, and the crude product was extracted and concentrated with ethyl acetate. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 15: 85) to obtain compound Int E-2 (5.65 g). MS (ESI, m / z): 298.0 [M+H] + .

[0254] Step 2: Synthesis of 8-bromo-7-methylimidazo[1,5-a]quinoxaline-4(5H)-one (Int E-3)

[0255] Int E-2 (5.65 g, 18.95 mmol) was dissolved in anhydrous DMAc (35 mL), and NaH (1.14 g, 28.43 mmol) was added in batches under ice bath, and stirred for 10 min and reacted at 140 ° C for 48 hours. After the reaction was completed, it was cooled to room temperature and precipitated naturally. Compound Int E-3 (1.70 g) was obtained by suction filtration. The crude product was dried and used. MS (ESI, m / z): 278.0 [M+H] + .

[0256] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-7-methylimidazo[1,5-a]quinoxaline-4-amine (IntE-4)

[0257] In anhydrous DMF (20 mL) was added with Int E-3 (700 mg, 2.52 mmol) and PyBOP (1.96 g, 3.78 mmol) under ice bath, and DIPEA (975.91 mg, 7.55 mmol) was added dropwise and stirred for 10 min, and finally Int A-6 (841.72 mg, 5.03 mmol) was added and reacted at 60 °C for 16 hr. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H2O:ACN=20:80) to obtain compound Int E-4 (900 mg). MS (ESI, m / z): 427.0 [M+H] + .

[0258] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylate (Int E-5)

[0259] Int E-4 (800 mg, 1.87 mmol), TEA (568.36 mg, 5.62 mmol), Pd(dppf)2Cl2 (151.76 mg, 187.22 μmol) were added to the autoclave and dissolved with 30 mL of methanol. After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase DCM: MeOH = 96:4) to obtain compound Int E-5 (332 mg), which was used after drying. MS (ESI, m / z): 407.1 [M+H] + .

[0260] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Int E)

[0261] Int E-5 (332 mg, 816.86 μmol) was dissolved in methanol (10 mL) under ice bath, and an aqueous solution (2 mL) of NaOH (98.02 mg, 2.45 mmol) was added dropwise thereto, and the mixture was reacted at 55°C for 3 hours. After the reaction, the methanol was dried by spin drying, and dilute hydrochloric acid was added dropwise to the remaining portion under ice bath until the solution was acidic, and the mixture was filtered by suction, and the filter cake was washed with water twice to obtain compound Int E (236.80 mg), which was used without purification after drying. MS (ESI, m / z): 393.1 [M+H] + .

[0262] Intermediate Int F: 4-((2,4-dimethoxybenzyl)amino)-7-trifluoromethylimidazo[1,5-a]quinoxaline-8-carboxylic acid (Int F)

[0263]

[0264] Step 1: Synthesis of N-(4-bromo-2-fluoro-5-(trifluoromethyl)phenyl)-1H-imidazole-5-carboxamide (Int F-2)

[0265] Int A-1 (2.17 g, 19.38 mmol) was dissolved in anhydrous DMF (50 mL) under ice-water bath, DIPEA (3.76 g, 29.07 mmol) was slowly added dropwise, HATU (8.84 g, 23.25 mmol) was added after stirring evenly, stirring was continued for 1 h, and finally IntF-1 (5 g, 19.38 mmol) was added, and the temperature was naturally raised to 25 °C for 16 hours. After the reaction was completed, water was added and stirred, and EA was extracted and concentrated to obtain a crude product, which was purified by silica gel column chromatography (mobile phase PE: EA = 47:53) to obtain compound Int F-2 (1.55 g). MS (ESI, m / z): 351.9 [M+H] + .

[0266] Step 2: Synthesis of 8-bromo-7-(trifluoromethyl)imidazo[1,5-a]quinoxalin-4(5H)-one (Int F-3)

[0267] Int F-2 (1.55 g, 4.40 mmol) was dissolved in anhydrous DMAc (50 mL), sodium hydride (264.14 mg, 6.60 mmol) was added in batches under ice bath, stirred for 10 min and reacted at 100 °C for 12 hr. After the reaction was completed, it was cooled to room temperature, stirred with water, extracted with ethyl acetate and concentrated to obtain compound Int F-3 (1.40 g). MS (ESI, m / z): 332.0 [M+H] + .

[0268] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-7-(trifluoromethyl)imidazo[1,5-a]quinoxaline-4-amine (Int F-4)

[0269] In anhydrous DMF (5 mL) was added with Int F-3 (0.40 g, 1.20 mmol) and PyBOP (940.25 mg, 1.81 mmol) under ice bath, and DIPEA (467.03 mg, 3.61 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (302.11 mg, 302.11 mg) was added and reacted at 60°C for 16 hr. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H2O:ACN=36:64) to obtain compound Int F-4 (0.25 g). MS (ESI, m / z): 481.1 [M+H] + .

[0270] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)-7-(trifluoromethyl)imidazo[1,5-a]quinoxaline-8-carboxylate (Int F-5)

[0271] Int F-4 (0.25 g, 519.46 μmol), TEA (157.69 mg, 1.56 mmol), Pd(dppf)2Cl2 (42.11 mg, 51.95 μmol) were added to the autoclave, and dissolved with methanol (10 mL). After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, concentrated under reduced pressure, and separated and purified by Prep-TLC (PE:EA=8:2) to obtain compound Int F-5 (70 mg). MS (ESI, m / z): 461.1 [M+H] + .

[0272] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-7-(trifluoromethyl)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Int F)

[0273] Dissolve Int F-5 (70 mg, 152.04 μmol) in ethanol (10 mL) and H2O (2 mL), add NaOH (12.16 mg, 304.08 μmol), and react at 55°C for 3 hours. After the reaction is completed, concentrate under reduced pressure to remove the solvent to obtain compound Int F (65 mg). MS (ESI, m / z): 447.1 [M+H] + .

[0274] Intermediate Int G: 7-chloro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Int G)

[0275]

[0276] Step 1: Synthesis of N-(4-bromo-5-chloro-2-fluorophenyl)-1H-imidazole-5-carboxamide (Compound Int G-2)

[0277] Int A-1 (2.50 g, 22.28 mmol) was dissolved in anhydrous DMF (50 mL) under an ice-water bath, and DIPEA (8.64 g, 66.83 mmol) was slowly added dropwise. After stirring evenly, an anhydrous DMF solution of HATU (16.94 g, 44.55 mmol) was added dropwise. Stirring was continued for 1 h, and finally an anhydrous DMF solution of Int G-1 (5.0 g, 22.28 mmol) was added dropwise. The temperature was naturally raised to 80 °C for reaction for 16 h. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase PE: EA = 24:76) to obtain compound Int G-2 (3.94 g). MS (ESI, m / z): 317.9 [M+H] + .

[0278] Step 2: Synthesis of 8-bromo-7-chloroimidazo[1,5-a]quinoxaline-4(5H)-one (Compound Int G-3)

[0279] Int G-2 (3.94 g, 12.37 mmol) was dissolved in anhydrous DMAc (40 mL), sodium hydride (742.16 mg, 18.55 mmol) was added in batches under ice bath, stirred for 10 min and reacted at 140 °C for 48 hr. After the reaction was completed, it was cooled to room temperature, stirred with water, extracted with ethyl acetate and concentrated to obtain compound Int G-3 (2.59 g). MS (ESI, m / z): 298.0 [M+H] + .

[0280] Step 3: Synthesis of 8-bromo-7-chloro-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]quinoxaline-4-amine (Compound Int G-4)

[0281] In anhydrous DMF (20 mL) was added with Int G-3 (2.59 g, 8.68 mmol) and PyBOP (9.03 g, 17.35 mmol) under ice bath, and DIPEA (3.36 g, 26.03 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (4.35 g, 26.03 mmol) was added and reacted at 60 °C for 16 hr. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H2O:ACN=20:80) to obtain compound Int G-4 (1.00 g). MS (ESI, m / z): 447.1 [M+H] + .

[0282] Step 4: Synthesis of methyl 7-chloro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (Compound Int G-5)

[0283] Int G-4 (1.00 g, 2.23 mmol), TEA (678.05 mg, 6.70 mmol), Pd(dppf)2Cl2 (163.43 mg, 223.36 μmol) were added to the autoclave, and dissolved with methanol (30 mL). After carbon monoxide substitution, the pressure was increased to 1.2 atm and the reaction was carried out at 120°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature and directly concentrated to obtain compound Int G-5 (950 mg). MS (ESI, m / z): 427.2 [M+H] + .

[0284] Step 5: Synthesis of 7-chloro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int G)

[0285] Int G-5 (950 mg, 2.23 mmol) was dissolved in methanol (30 mL) under ice bath, and an aqueous solution (4 mL) of sodium hydroxide (267.07 mg, 6.68 mmol) was added dropwise, and the mixture was reacted at 55°C for 3 hours. After the reaction was completed, dilute hydrochloric acid was added dropwise under ice bath until the solution was acidic, and the solution was concentrated to obtain a crude product, which was purified by reverse phase HPLC column chromatography (mobile phase H2O:ACN=44:56) to obtain compound IntG (200 mg). MS (ESI, m / z): 413.0 [M+H] + .

[0286] Intermediate Int H: 7-Fluoro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (Int H)

[0287]

[0288] Step 1: Synthesis of N-(4-bromo-2,5-difluorophenyl)-1H-imidazole-5-carboxamide (Compound Int H-2)

[0289] Int A-1 (2.69 g, 24.04) was dissolved in anhydrous DMF (150 mL) under ice-water bath, DIPEA (4.66 g, 36.06 mmol) was slowly added dropwise, HATU (10.97 g, 28.85 mmol) was added after stirring evenly, stirring was continued for 1 h, and finally IntH-1 (5 g, 24.04) was added, and the temperature was raised to 80 °C for 48 hours. After the reaction was completed, water was added and stirred, and the crude product was extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by silica gel column chromatography (mobile phase PE: EA = 63: 37) to obtain compound Int H-2 (6.0 g). MS (ESI, m / z): 302.0 [M+H] + .

[0290] Step 2: Synthesis of 8-bromo-7-fluoroimidazo[1,5-a]quinoxaline-4(5H)-one (Compound Int H-3)

[0291] Int H-2 (6.0 g, 19.86 mmol) was dissolved in anhydrous DMAc (100 mL), sodium hydride (1.19 g, 29.79 mmol) was added in batches under ice bath, stirred for 10 min, and then heated to 140°C for 72 hr. After the reaction was completed, it was cooled to room temperature, stirred with water, extracted with ethyl acetate, and concentrated, and then separated and purified by reverse phase column chromatography (H2O [0.05% ammonium bicarbonate]: MeCN = 72:28) to obtain compound Int H-3 (0.5 g). MS (ESI, m / z): 282.0 [M+H] + .

[0292] Step 3: Synthesis of 8-bromo-N-(2,4-dimethoxybenzyl)-7-fluoroimidazo[1,5-a]quinoxaline-4-amine (Compound Int H-4)

[0293] In anhydrous DMF (30 mL) was added with Int H-3 (380 mg, 1.35 mmol) and PyBOP (1.05 g, 2.02 mmol) under ice bath, and DIPEA (522.33 mg, 4.04 mmol) was added dropwise and stirred for 10 min. Finally, Int A-6 (337.88 mg, 2.02 mmol) was added and reacted at 60°C for 16 hr. After the reaction was completed, water was added and stirred, and the mixture was extracted and concentrated with ethyl acetate to obtain a crude product, which was purified by reverse phase column chromatography (mobile phase H2O:ACN=36:64) to obtain compound Int H-4 (0.50 g). MS (ESI, m / z): 431.1 [M+H] + .

[0294] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylate (Compound Int H-5)

[0295] Int H-4 (0.50 g, 1.16 mmol), TEA (351.96 mg, 3.48 mmol), Pd(dppf)2Cl2 (93.98 mg, 115.94 μmol) were added to the autoclave, and dissolved with methanol (20 mL). After carbon monoxide substitution, the pressure was increased to 1.2 MPa and the reaction was carried out at 120°C for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, and concentrated under reduced pressure to obtain compound Int H-5 (70 mg). MS (ESI, m / z): 411.1 [M+H] + .

[0296] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int H)

[0297] Int H-5 (400 mg, 974.66 μmol) was dissolved in methanol (10 mL) and H2O (2 mL), sodium hydroxide (77.97 mg, 1.95 mmol) was added, and the temperature was raised to 60°C for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the compound Int H (320 mg) was obtained by purification by reverse phase column chromatography (mobile phase H2O [0.05% formic acid]: ACN = 65:35). MS (ESI, m / z): 397.1 [M+H] + .

[0298] Intermediate Int I: 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (Int I)

[0299]

[0300] Step 1: Synthesis of N-(4,6-dichloropyridin-3-yl)-1H-imidazole-5-carboxamide (Compound Int I-3)

[0301] Compound Int I-1 (8 g, 49.08 mmol) was dissolved in anhydrous THF (100 mL), cooled to -10 °C and NaHMDS (2M, 49.08 mL, 98.16 mmol) was added, stirred at -10 °C for 1 hour, and then Int I-2 (5.77 g, 24.54 mmol) THF solution (100 mL) was added, and the temperature was raised to 25 °C and the reaction was continued for 2 hours. After the reaction was completed, an appropriate amount of acetic acid was added to quench, and the reaction was concentrated under reduced pressure, and then a saturated sodium bicarbonate aqueous solution was added, filtered, and the solid product was collected, washed with water and hexane, and dried to obtain compound Int I-3 (10 g). MS (ESI, m / z): 257.0 [M+H] + .

[0302] Step 2: Synthesis of 8-chloroimidazo[1,5-a]pyrido[3,4-e]pyrazin-4(5H)-one (Compound Int I-4)

[0303] Compound Int I-3 (10 g, 38.90 mmol) was dissolved in anhydrous DMF (100 mL), and DBU (17.77 g, 116.70 mmol) was added. After the addition, the temperature was raised to 160°C and the mixture was reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, concentrated under reduced pressure, added with water, dissolved with saturated aqueous ammonium chloride solution, filtered, washed with water, the filter cake was collected, dried, and concentrated to obtain compound Int I-4 (8 g). MS (ESI, m / z): 221.0 [M+H] + .

[0304] Step 3: Synthesis of 8-chloro-N-(2,4-dimethoxybenzyl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-4-amine (Compound Int I-5)

[0305] Compound Int I-4 (5 g, 22.66 mmol), DIPEA (4.39 g, 34.00 mmol) and Int A-6 (5.68 g, 34.00 mmol) were dissolved in anhydrous DMF (300 mL), and PyBOP (12.97 g, 24.93 mmol) was added in batches under stirring. After the addition, the temperature was raised to 60°C and the reaction was continued for 5 hours. After the reaction was completed, the mixture was diluted with water, extracted and concentrated with EA to obtain a crude product, which was purified by reverse phase column chromatography (mobile phase H2O (0.05% ammonium bicarbonate): ACN = 36:64) to obtain compound Int I-5 (4.5 g). MS (ESI, m / z): 370.1 [M+H] + .

[0306] Step 4: Synthesis of methyl 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylate (Compound Int I-6)

[0307] Compound Int I-5 (4.50 g, 12.17 mmol), TEA (3.69 g, 36.51 mmol), Pd(dppf)Cl2·DCM (986.37 mg, 1.22 mmol) were added to the autoclave, and dissolved with methanol (20 mL). After carbon monoxide substitution, the pressure was increased to 1.2 MPa, and then the temperature was raised to 120°C for reaction for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, and concentrated under reduced pressure to obtain compound Int I-6 (4.7 g). MS (ESI, m / z): 394.1 [M+H] + .

[0308] Step 5: Synthesis of 4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (Compound Int I-7)

[0309] Compound Int I-6 (4.7 g, 11.95 mmol) was dissolved in methanol (150 mL) and H2O (30 mL), and sodium hydroxide (955.78 mg, 23.89 mmol) was added. After the addition, the temperature was raised to 60°C and the reaction was continued for 3 hours. After the reaction was completed, the methanol was removed by concentration under reduced pressure, and a small amount of water was added to dilute it. 1N hydrochloric acid was used to adjust the pH to about 6. Solids were precipitated, filtered, washed with water, and the filter cake was dried to obtain compound Int I-7 (4.3 g). MS (ESI, m / z): 380.2 [M+H] + .

[0310] Step 6: Synthesis of 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (Compound Int I)

[0311] Compound Int I-7 (4.3 g, 3.78 mmol) was dissolved in TFA (80 mL), and the temperature was raised to 90°C for reaction for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain compound Int I (3.8 g). MS (ESI, m / z): 230.0 [M+H] + .

[0312] Intermediate Int K: 3-(4-(trifluoromethyl)phenyl)morpholine (Int K)

[0313]

[0314] Step 1: Synthesis of tert-butyl (2-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethoxy)ethyl)carbamate (Compound Int K-3)

[0315] Int K-1 (13.5 g, 49.7 mmol, 7.30 mL) was dissolved in toluene (100 mL). After replacing nitrogen, the temperature was lowered to -20 °C, and iPrMgCl (2 M tetrahydrofuran solution, 37.3 mL) was slowly added dropwise. After the addition was completed, the reaction was kept at -20 °C and stirred for 2 hrs. Then Int K-2 (10.0 g, 49.7 mmol) was slowly added dropwise, and the reaction was kept at -20 °C and stirred for 2 hrs. LCMS and TLC (PE / EtOAc=3 / 1, R f =0.1) to detect the completion of the reaction, slowly drop saturated NH4Cl (200mL) in an ice bath to quench the reaction, then extract with CH2Cl2 (200mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, separate and purify by silica gel column chromatography (CH2Cl2 / MeOH=100 / 1 to 10 / 1), and concentrate to obtain compound Int K-3 (14.6g). MS (ESI, m / z): 248.1[M+H-Boc] + .

[0316] Step 2: Synthesis of 2-(2-aminoethoxy)-1-(4-(trifluoromethyl)phenyl)ethane-1-one (Compound Int K-4)

[0317] Int K-3 (14.6 g, 42.0 mmol) was dissolved in a 2M HCl aqueous solution (2M, 52.5 mL), and then the temperature was raised to 50°C and stirred for 2 hrs. LCMS detected that the reaction was complete, and a hydrochloric acid aqueous solution of compound Int K-4 was obtained. MS (ESI, m / z): 248.2 [M+H] + .

[0318] Step 3: Synthesis of 5-(4-(trifluoromethyl)phenyl)-3,6-dihydro-2H-1,4-oxazine (Compound Int K-5)

[0319] Add K2CO3 (13.9 g, 101 mmol) to a hydrochloric acid solution of compound Int K-4 (10.4 g, 42.0 mmol) and keep the mixture at 25°C for 1 hour. LCMS detected the reaction, and the filter cake was dried after filtration to obtain compound Int K-5 (9.63 g). MS (ESI, m / z): 230.1 [M+H] + .

[0320] Step 4: Synthesis of 3-(4-(trifluoromethyl)phenyl)morpholine (Compound Int K)

[0321] Compound Int K-5 (9.63 g, 42.0 mmol) was dissolved in THF (80 mL), and then NaBH3CN (10.6 g, 168 mmol) was added. The reaction temperature was raised to 60°C and stirred for 1 hr. LCMS detected that the reaction was complete, and H2O (200 mL) and EtOAc (200 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound Int K (7.51 g). MS (ESI, m / z): 232.1 [M+H] + .

[0322] Intermediate Int L: (3R,5S)-3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholine (Int L)

[0323]

[0324] Step 1: Synthesis of 5-methylmorpholin-3-one (Compound Int L-3)

[0325] NaH (120 g, 3.00 mol) was slowly added to THF (1.00 L), and then Int L-1 (100 g, 1.33 mol) was slowly added dropwise under ice bath, and stirred at 0°C for 30 mins, followed by Int L-2 (204 g, 1.66 mol). After the addition was completed, the reaction was kept at 25°C and stirred for 16 hrs. TLC (PE / EtOAc=1 / 1, R f =0.15) and LCMS detected that the reaction was complete, and then saturated NH4Cl (1.00L) was slowly added under ice bath to quench, and then extracted with ethyl acetate (6.00L), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound Int L-3 (158g). MS (ESI, m / z): 116.3[M+H] + .

[0326] Step 2: Synthesis of tert-butyl 3-methyl-5-oxomorpholine-4-carboxylate (Compound Int L-4)

[0327] Compound Int L-3 (158 g, 1.37 mol) was dissolved in THF (1.00 L), and then DMAP (16.8 g, 137 mmol) and Boc2O (329 g, 1.51 mol) were added in sequence, and the reaction was maintained at 25°C for 16 hrs. TLC (PE / EtOAc=5 / 1, R f=0.44) and LCMS showed that the reaction was complete, then H2O (200 mL) was added to quench, concentrated to remove the organic solvent, and then extracted with ethyl acetate (900 mL), combined organic phases, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE / EtOAc=1 / 0 to 6 / 1) to obtain compound Int L-4 (54.9 g). MS (ESI, m / z): 159.9 [M+H-56] + .

[0328] 1 H NMR (400MHz, CDCl3) δ4.31–4.14 (m, 3H), 3.81–3.79 (m, 2H), 1.56 (s, 9H), 1.40 (d, J = 6.4Hz, 3H).

[0329] Step 3: Synthesis of tert-butyl 5-((diphenoxyphosphoryl)oxy)-3-methyl-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (Compound Int L-5)

[0330] Compound Int L-4 (54.9 g, 255 mmol) was dissolved in THF (800 mL), and after replacing nitrogen, the temperature was lowered to -70°C, and LiHMDS (1 M, 281 mL) was slowly added dropwise. After the addition was completed, the mixture was kept at -70°C and stirred for 1 hr. Then Int D-5 (71.9 g, 268 mmol) was added dropwise. After the addition was completed, the reaction was continued at -60 to -30°C for 3 hrs. TLC (PE / EtOAc=3 / 1, R f =0.35) and LCMS detected that the reaction was complete, and water (200 mL) was added under ice bath to quench, then extracted with ethyl acetate (900 mL), the organic phases were combined, washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography (PE / EtOAc=1 / 0 to 9 / 1), and concentrated to obtain compound Int L-5 (98.9 g). MS (ESI, m / z): 348.1 [M+H-Boc] + .

[0331] Step 4: Synthesis of tert-butyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (Compound Int L-6)

[0332] Int L-5 (98.9 g, 221 mmol), B2Pin2 (84.2 g, 332 mmol), KOAc (65.1 g, 663 mmol) and XPhos Pd G3 (18.7 g, 22.1 mmol) were dissolved in 1,4-dioxane (1000 mL), and the temperature was raised to 100 °C for 2 hrs after replacing nitrogen. TLC (PE / EtOAc=5 / 1, R f =0.47) and LCMS detection reaction completion, then cooled to room temperature and filtered, the filter cake was washed with CH2Cl2 (1.0L), the organic phases were combined, concentrated by vacuum distillation, and separated and purified by silica gel column chromatography (PE / EtOAc=1 / 0 to 9 / 1), and concentrated to obtain compound Int L-6 (61.5g). MS (ESI, m / z): 269.7 [M+H-55] + .

[0333] Step 5: Synthesis of tert-butyl 3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate (Compound Int L-7)

[0334] Compound Int L-6 (20.9 g, 92.3 mmol), Int B-8 (30.0 g, 92.3 mmol), LiCl (7.04 g, 166 mmol), Na2CO3 (2 M, 415 mL) and Pd(PPh3)4 (10.7 g, 9.22 mmol) were dissolved in DME (750 mL), replaced with nitrogen, and heated to 80 °C for 12 hrs. TLC (PE / EtOAc=5 / 1, R f =0.33) and LCMS detected the reaction, cooled to room temperature and concentrated to remove the solvent, then extracted with water (300 mL) and dichloromethane (900 mL), combined the organic phases, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated, separated and purified by silica gel column chromatography (PE / EtOAc=1 / 0 to 17 / 3), and concentrated to obtain compound Int L-7 (11.9 g). MS (ESI, m / z): 345.0 [M+H] + .

[0335] 1 H NMR (400MHz, CDCl3) δ8.73(s,1H),7.81(dd,J=8.4,2.0Hz,1H),7.23(d,J=8.4Hz,1H),6.86(s,1 H), 4.73–4.69 (m, 1H), 4.16–4.13 (m, 1H), 4.04–4.01 (m, 1H), 1.26 (d, J = 7.2Hz, 3H), 1.18 (s, 9H).

[0336] Step 6: Synthesis of 3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-3,6-dihydro-2H-1,4-oxazine (Compound Int L-8)

[0337] Compound Int L-7 (8.40 g, 24.4 mmol) was dissolved in TFA (55.6 g, 488 mmol, 36.2 mL) and reacted at 20°C for 1 hr. LCMS detected that the reaction was complete and the mixture was directly concentrated to obtain compound Int L-8 (5.96 g). MS (ESI, m / z): 245.0 [M+H] + .

[0338] Step 7: Synthesis of (3R,5S)-3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholine (Compound Int L)

[0339] Compound Int L-8 (5.96 g, 24.4 mmol) was dissolved in THF (230 mL), and then NaBH3CN (6.13 g, 97.6 mmol) was added under ice bath, and the mixture was reacted at 20°C for 1.5 hrs. The reaction was complete after LCMS detection, and H2O (40.0 mL) was added for quenching, followed by extraction with CH2Cl2 (600 mL). The organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then chromatographed on a silica gel column (CH2Cl2 / MeOH = 100 / 0 to 95 / 5, containing 0.1% TFA, R f =0.33 & 0.24) was separated and purified, and then concentrated and separated by prep-SFC (chiral column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: 15% [0.1% NH3*H2O in MeOH solution] + 85% supercritical fluid CO2) to obtain compound Int L (3.67g, Rt=0.609min). MS (ESI, m / z): 247.0 [M+H] + .

[0340] 1 H NMR(400MHz, CDCl3)δ8.92–8.86(m,1H),8.09–8.00(m,1H),7.58–7.48(m,1H) ,4.53–4.38(m,1H),4.24–4.02(m,2H),3.68–3.42(m,4H),1.50–1.38(m,3H).

[0341] Example 1: (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)methanone

[0342]

[0343] Step 1: Synthesis of (2-(Benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)methanone (Compound 1-1)

[0344] Int A (100 mg, 211.43 μmol), pyridine (100 mg, 1.27 mmol) and DCM (5 mL) were added to the reaction flask, and POCl3 (97 mg, 634.28 μmol) was added after stirring and dissolving. The mixture was protected by nitrogen and reacted at room temperature for 30 min. Int C (49 mg, 211.43 μmol) was then added 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 (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 concentrated to obtain compound 1-1 (10 mg, 16.87 μmol). MS (ESI, m / z): 593.3 [M+H] + .

[0345] Step 2: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(2-(benzo[d]thiazol-5-yl)-5-methylpiperidin-1-yl)methanone (Compound 1)

[0346] Compound 1-1 (10 mg, 16.87 μmol) and TFA (1.5 mL) were added to the reaction flask, and the mixture was protected by nitrogen and reacted at 90 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated, diluted with saturated NaHCO3 solution, extracted with ethyl acetate (30 ml x 3), the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC and freeze-dried to obtain compound 1 (2.27 mg). MS (ESI, m / z): 443.2 [M+H] + .

[0347] 1H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 9.21 (s, 1H), 8.32 (d, J = 1.6Hz, 1H), 8.2 0(d,J=8.4Hz,1H),8.06(s,1H),7.90(s,1H),7.52(d,J=8.4Hz,1H),7.47–7.3 8(m,4H),5.63(br,1H),3.80(br,1H),3.19(d,J=13.6Hz,1H),2.32–2.19(m,2 H), 1.85 (s, 1H), 1.77–1.67 (m, 1H), 1.42–1.34 (m, 1H), 1.03 (d, J = 6.8Hz, 3H).

[0348] Example 2: (4-aminoimidazo[1,5-a]quinoxalin-8-yl)(3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone

[0349]

[0350] Step 1: Synthesis of (4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)(3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone (Compound 2-2)

[0351] Int A (46.10 mg, 121.84 μmol) was added to anhydrous THF (10 mL), and Py (38.55 mg, 487.35 μmol) and phosphorus oxychloride (46.70 mg, 304.60 μmol) were added dropwise in an ice bath, and 2-1 (30 mg, 121.84 μmol) was added after stirring for 10 min, and the temperature was raised to 60 ° C for 6 hours. After the reaction was completed, water was added to quench, and the crude intermediate compound 2-2 (20.00 mg) was obtained by extraction and concentration with ethyl acetate. MS (ESI, m / z): 607.2 [M+H] + .

[0352] Step 2: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone (Compound 2)

[0353] Compound 2-2 (20 mg, 32.97 μmol) was dissolved in TFA (10 mL) and reacted at 80°C for 2 hours. After the reaction was completed, the mixture was concentrated, washed with saturated sodium bicarbonate solution until alkaline, and then extracted with ethyl acetate and concentrated. The crude product was purified by reverse phase HPLC to obtain compound 2 (2.52 mg). MS (ESI, m / z): 457.3 [M+H] + .

[0354] 1 H NMR (400MHz, DMSO-d6) δ9.19(s,1H),9.02(s,1H),8.36(d,J=1.6Hz,1H),8.20(dd,J=8.4,2.0Hz,1H),7.91(s,1H),7.7 8(d,J=8.4Hz,1H),7.58–7.35(m,4H),5.66–4.80(m,2H),4.26–3.79(m,2H),3.79–3.51(m,2H),0.79(d,J=6.8Hz,3H).

[0355] Example 3: (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(5-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)methanone

[0356]

[0357] Step 1: Synthesis of (4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)(5-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)methanone (Compound 3-1)

[0358] Int B (20 mg, 81.88 μmol) and Int A (46.47 mg, 122.82 μmol) were dissolved in anhydrous DMF (2 mL), and then DIPEA (31.75 mg, 245.64 μmol) and HATU (62.27 mg, 163.76 μmol) were added in sequence. After the addition, the reaction system was heated to 60 ° C for 5 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate and concentrated to obtain a crude product. The crude product was separated and purified by Prep-TLC (DCM: MeOH = 20: 1) to obtain compound 3-1 (10 mg). MS (ESI, m / z): 605.3 [M + H] + .

[0359] Step 2: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(5-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)methanone (Compound 3)

[0360] Compound 3-1 (10 mg, 16.54 μmol) was dissolved in TFA (2 mL), and the temperature was raised to 90°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, washed with saturated sodium bicarbonate solution until alkaline, extracted with ethyl acetate and concentrated to obtain a crude product, which was purified by Prep-HPLC to obtain compound 3 (4.0 mg). MS (ESI, m / z): 455.1 [M+H]+ .

[0361] 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.30(s,1H),8.24–8.18(m,1H),7.75–7.66(m,1H),7.58–7.19(m,4H),5.62(s,2H),3.6 8–3.09(m,3H),2.45–2.35(m,1H),2.25–2.09(m,1H),1.92–1.78(m,1H),1.66–1.51(m,1H),1.42–1.31(m,1H),1.01(s,3H).

[0362] Example 4: (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-(benzo[d]thiazol-5-yl)-5-methylmorpholino)methanone

[0363]

[0364] Step 1: Synthesis of (3-(Benzo[d]thiazol-5-yl)-5-methylmorpholino)(4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)methanone (Compound 4-1)

[0365] Compounds Int D (20 mg, 85.35 μmol) and Int A (38.76 mg, 102.43 μmol) were dissolved in anhydrous THF (10 mL), and then Et3N (51.82 mg, 512.13 μmol) and CMPI (65.42 mg, 256.06 μmol) were added. After the addition, the reaction system was protected by N2 and the temperature was raised to 60 ° C for 12 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate and concentrated to obtain a crude product. The crude product was separated and purified by Prep-TLC (DCM: MeOH = 20: 1) to obtain compound 4-1 (20 mg). MS (ESI, m / z): 595.2 [M + H] + .

[0366] Step 2: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-(benzo[d]thiazol-5-yl)-5-methylmorpholino)methanone (Compound 4)

[0367] Compound 4-1 (20 mg, 33.63 μmol) was dissolved in TFA (2 mL), and the temperature was raised to 90°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, washed with saturated sodium bicarbonate solution until alkaline, extracted with ethyl acetate and concentrated to obtain a crude product, which was separated and purified by Prep-TLC (DCM: MeOH = 10: 1), and then purified again by Prep-HPLC to obtain compound 4 (12 mg). MS (ESI, m / z): 445.1 [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 9.23 (s, 1H), 8.36 (d, J = 1.6Hz, 1H), 8.27 (s ,1H),8.17(d,J=8.4Hz,1H),7.93(s,1H),7.69(d,J=1.6Hz,1H),7.57–7.38(m,4 H),5.71(s,1H),4.84(d,J=12.4Hz,1H),4.03(s,1H),3.95(dd,J=12.8,4.0Hz,1 H), 3.79 (dd, J = 11.6, 3.6Hz, 1H), 3.66 (d, J = 11.6Hz, 1H), 0.80 (d, J = 7.2Hz, 3H).

[0369] Example 14: (4-aminoimidazo[1,5-a]quinoxalin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone (Compound 14)

[0370]

[0371] Step 1: Synthesis of (4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone (Compound 14-1)

[0372] Int L (100 mg, 406 μmol) and Int A (153 mg, 406 μmol) were dissolved in THF (2 mL). After replacing nitrogen, the temperature was lowered to 0°C, and then pyridine (321 mg, 4.06 mmol, 327 μL) and POCl3 (186 mg, 1.22 mmol, 113 μL) were added. The reaction temperature was then raised to 60°C and stirred for 2 hrs. LCMS detected that the reaction was complete, and then H2O (50.0 mL) and EtOAc (30.0 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 14-1 (400 mg). MS (ESI, m / z): 607.4 [M+H] + .

[0373] Step 2: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone (Compound 14)

[0374] 14-1 (400 mg, 659.42 μmol) was dissolved in TFA (10.00 mL), and then heated to 80 ° C and stirred for 2 hours. LCMS detected that the reaction was complete, and after vacuum distillation and concentration, NaHCO3 (50.0 mL) and EtOAc (30.0 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated, and separated and purified by prep-HPLC, and then by SFC (chiral column: DAICELCHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: 45% [0.1% NH 3* H2O in MeOH solution] + 55% supercritical fluid CO2) to give compound 14 (10.8 mg, Rt = 1.822 min). MS (ESI, m / z): 457.0 [M+H] + .

[0375] 1 H NMR(400MHz, DMSO-d6)δ9.18(s,1H),9.02(s,1H),8.35(s,1H),8.14–8.26(m,1H),7.90(s,1H),7.78(d,J=8.4Hz,1H),7.44–7.52(m,2H),7.41(s, 2H),5.26–5.66(m,1H),4.94–5.08(m,1H),4.03–4.21(m,1H),3.82–3.90 (m,1H),3.70–3.76(m,1H),3.59(d,J=10.4Hz,1H),0.79(d,J=7.2Hz,3H).

[0376] Example 25: (4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone (Compound 25)

[0377]

[0378] Step 1: Synthesis of (4-((2,4-dimethoxybenzyl)amino)-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone (Compound 25-1)

[0379] Int L (100 mg, 406 μmol) and Int H (160.98 mg, 406 μmol) were dissolved in THF (3.00 mL). After replacing nitrogen, the temperature was lowered to 0°C, and then pyridine (321 mg, 4.06 mmol, 327 μL) and POCl3 (186 mg, 1.22 mmol, 113 μL) were added. The reaction temperature was then raised to 60°C and stirred for 12 hrs. LCMS detected that the reaction was complete, and then H2O (50.0 mL) and EtOAc (30.0 mL x3) were added for extraction. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 25-1 (99.0 mg). MS (ESI, m / z): 625.3 [M+H] + .

[0380] Step 2: Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)((3R,5S)-3-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)morpholino)methanone (Compound 25)

[0381] 25-1 (99.0 mg, 158 μmol) was dissolved in TFA (2.00 mL), then heated to 80°C and stirred for 0.5 hr. LCMS detected that the reaction was complete, and after vacuum distillation and concentration, NaHCO3 (50.0 mL) and EtOAc (30.0 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated, and separated and purified by prep-HPLC to obtain compound 25 (25.6 mg). MS (ESI, m / z): 475.2 [M+H] + .

[0382] 1H NMR (400MHz, DMSO-d6) δ9.16(s,1H),9.04(s,1H),8.40(d,J=5.6Hz,1H),8.12–8.33(m,1H),7.92(s,1H),7.75(d,J=4.0 Hz,1H),7.59(s,2H),7.11–7.37(m,1H),5.09–5.80(m,1H),4.41–5.00(m,1H),3.46–3.97(m,4H),0.77(d,J=6.8Hz,3H).

[0383] Example 32: (R)-(4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 32 Peak 1) and (S)-(4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 32 Peak 2)

[0384]

[0385] Step 1: Synthesis of 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int A')

[0386] Compound Int A (130 g, 343 mmol) was dissolved in TFA (383 g, 3.37 mol, 250 mL), the reaction temperature was raised to 80°C and stirred for 2 hrs. LCMS detected that the reaction was complete, and then the solvent was directly concentrated and removed. At room temperature, the compound Int A' (120 g) was recrystallized in MeOH (1000 mL). MS (ESI, m / z): 229.0 [M+H] + .

[0387] Step 2: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 32)

[0388] Int K (405 mg, 876 μmol) and Int A' (200 mg, 876 μmol) were dissolved in DMF (5 mL), and then TEA (231 mg, 2.28 mmol, 317 μL) and TBTU (338 mg, 1.05 mmol) were added. The reaction was stirred at 25 °C for 1 hr. LCMS and TLC (CH2Cl2 / MeOH=10 / 1, R f=0.4) to detect the formation of the product, then H2O (100 mL) and EtOAc (100 mL x3) were added for extraction, the organic phases were combined, dried over anhydrous Na2SO4, filtered, concentrated, and separated and purified by silica gel column chromatography (CH2Cl2 / MeOH=100 / 1 to 10 / 1), and concentrated to obtain compound 32 (110 mg). MS (ESI, m / z): 442.0 [M+H] + .

[0389] Step 3: Synthesis of (R)-(4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 32 Peak 1) and (S)-(4-aminoimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 32 Peak 2)

[0390] Compound 32 (1.20 g, 2.70 mmol) was purified by SFC (chiral column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: 50% [0.1% NH 3* H2O in MeOH solution] + 50% supercritical fluid CO2) to obtain compound 32 peak 1 (28.69 mg, Rt = 1.397 min) and compound 32 peak 2 (21.83 mg, Rt = 1.785 min). MS (ESI, m / z): 442.0 [M+H] + .

[0391] Compound 32 Peak 1: 1 H NMR(400MHz, DMSO-d6)δ9.17(br s,1H),8.30(d,J=1.1Hz,1H),7.91(s,1H),7.63–7.84(m,4H),7.38–7.50(m,4H),5.23–6.00(m,1H),4.49(br d,J=11.6Hz,1H),3.94(br d,J=10.0Hz,1H),3.75–3.85(m,1H),3.62(td,J=11.7,2.4Hz,1H),3.33–3.40(m,1H),3.06–3.29(m,1H).

[0392] Compound 32 Peak 2: 1H NMR(400MHz,DMSO-d6)δ9.18(br s,1H),8.30(s,1H),7.91(s,1H),7.66–7.82(m,4H),7.39–7.48(m,4H),5.24–6.03(m,1 H),4.44–4.54(m,1H),3.90–4.00(m,1H),3.76–3.87(m,1H),3.60–3.66(m,1H),3.39(br s,1H),3.13–3.30(m,1H).

[0393] Example 33: (R)-(4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 33 Peak 1) and (S)-(4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 33 Peak 2)

[0394]

[0395] Step 1: Synthesis of 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (Compound Int H')

[0396] Compound Int H (55 g, 138.76 mmol) was dissolved in TFA (153 g, 1.35 mol, 100 mL), and then the reaction temperature was raised to 60°C and stirred for 10 hrs. LCMS detected that the reaction was complete, and after concentration, the mixture was recrystallized in MeOH (200 mL) at room temperature to obtain compound Int H' (45.0 g). MS (ESI, m / z): 247.1 [M+H] + .

[0397] Step 2: Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 33)

[0398] Int K (400 mg, 865 μmol) and Int H' (284 mg, 865 μmol) were dissolved in DMF (5 mL), and then TEA (228 mg, 2.25 mmol, 313 μL) and TBTU (333 mg, 1.04 mmol) were added in sequence. The reaction was stirred at 25 °C for 1 hr. LCMS and TLC (CH2Cl2 / MeOH=10 / 1, R f=0.4) to detect the formation of the product, then H2O (100mL) and EtOAc (100mL x 3) were added for extraction, the organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated, and then separated and purified by silica gel column chromatography (CH2Cl2 / MeOH=100 / 1 to 10 / 1), and concentrated to obtain compound 33 (130mg). MS (ESI, m / z): 460.0[M+H] + .

[0399] Step 3: Synthesis of (R)-(4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 33 Peak 1) and (S)-(4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 33 Peak 2)

[0400] Compound 33 (130 mg, 283 μmol) was purified by SFC (chiral column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: 50% [0.1% NH 3* H2O in MeOH solution] + 50% supercritical fluid CO2) to obtain compound 33 peak 1 (51.01 mg, Rt = 0.976 min) and compound 33 peak 2 (46.11 mg, Rt = 1.237 min). MS (ESI, m / z): 460.0 [M+H] + .

[0401] Compound 33 Peak 1: 1 H NMR(400MHz,DMSO-d6)δ9.23(br s,1H),8.40(br s,1H),7.99(brs,1H),7.78–7.89(m,3H),7.67(br s,3H),7.31(br d,J=11.4Hz,1H),4.35–5.89(m,2H),3.76–4.05(m,2H),3.54–3.69(m,1H),3.42–3.49(m,1H),3.28–3.36(m,1H).

[0402] Compound 33 Peak 2: 1H NMR (400MHz, DMSO-d6) δ9.03–9.23(m,1H),8.35(br d,J=1.9Hz,1H),7.93(br s,1H),7.73–7.83(m,3H),7.62(br s,3H),7.19–7.31(m,1H),4.37–5.84(m,2H),3.75–3.97(m,2H),3.50–3.60(m,1H),3.37–3.42(m,1H),3.21–3.30(m,1H).

[0403] Example 34: (R)-(4-amino-7-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 34 Peak 1) and (S)-(4-amino-7-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 34 Peak 2)

[0404]

[0405] Step 1: Synthesis of (4-((2,4-dimethoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 34-1)

[0406] Int K (123 mg, 265 μmol) and Int E (130 mg, 331 μmol) were dissolved in DMF (10 mL), and then TEA (87.2 mg, 861 μmol, 120 μL) and TBTU (128 mg, 398 μmol) were added in sequence. After reacting at 25 °C for 1 hour, LCMS detected that the reaction was complete, and H2O (50 mL) and EtOAc (50 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 34-1 (320 mg). MS (ESI, m / z): 606.6 [M+H] + .

[0407] Step 2: Synthesis of (4-amino-7-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 34)

[0408] Compound 34-1 (320 mg, 528 μmol) was dissolved in TFA (10 mL) and kept at 80°C for 1 hr. LCMS and TLC (CH2Cl2 / MeOH=10 / 1, R f=0.4) to detect the completion of the reaction, add NaHCO3 aqueous solution (50 mL) and CH2Cl2 (50 mL x 3) to the reaction solution for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by silica gel column chromatography (CH2Cl2 / MeOH=100 / 1 to 10 / 1) to obtain compound 34 (80.0 mg). MS (ESI, m / z): 456.3 [M+H] + .

[0409] Step 3: Synthesis of (R)-(4-amino-7-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 34 Peak 1) and (S)-(4-amino-7-methylimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 34 Peak 2)

[0410] Compound 34 (80.0 mg, 176 μmol) was subjected to SFC (chiral column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 um); mobile phase: 35% [0.1% NH 3* After separation by H2O in MeOH solution [+65% supercritical fluid CO2], compound 34 peak 1 (4.83 mg, Rt = 1.447 min) and compound 34 peak 2 (5.82 mg, Rt = 1.887 min) were obtained. MS (ESI, m / z): 456.3 [M+H] + .

[0411] Compound 34 Peak 1: 1 H NMR (400MHz, DMSO-d6) δ8.81–9.19(m,1H),8.04–8.43(m,1H),7.78–7.91(m,4H),7.19–7.52(m ,4H),4.21–5.93(m,2H),3.85–3.98(m,1H),3.62(s,2H),3.14–3.21(m,2H),2.36–2.42(m,3H).

[0412] Compound 34 Peak 2: 1 H NMR(400MHz,DMSO-d6)δ8.99–9.27(m,1H),7.99–8.23(m,1H),7.79–7.89(m,4H),7.23–7.38(m,4H ),4.34–5.88(m,2H),3.86–3.98(m,1H),3.56–3.77(m,2H),3.16–3.25(m,2H),2.35–2.45(m,3H).

[0413] Example 35: (R)-(4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 35 Peak 1) and (S)-(4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 35 Peak 2)

[0414]

[0415] Step 1: Synthesis of (7-chloro-4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 35-1)

[0416] Int K (213 mg, 460 μmol) and Int G (380 mg, 920 μmol) were dissolved in DMF (10 mL), and then TEA (242 mg, 2.39 mmol, 333 μL) and TBTU (355 mg, 1.10 mmol) were added in sequence. After reacting at 25 ° C for 1 hour, LCMS detected that the reaction was complete, and H2O (50 mL) and EtOAc (50 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 35-1 (340 mg). MS (ESI, m / z): 626.7 [M+H] + .

[0417] Step 2: Synthesis of (4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 35)

[0418] Compound 35-1 (340 mg, 543 μmol) was dissolved in TFA (10 mL) and kept at 80°C for 1 hr. LCMS and TLC (CH2Cl2 / MeOH=10 / 1, R f =0.4) to detect the completion of the reaction, add NaHCO3 aqueous solution (50mL) and CH2Cl2 (50mL x 3) to the reaction solution for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by silica gel column chromatography (CH2Cl2 / MeOH=100 / 1 to 10 / 1) to obtain compound 35 (80.0mg). MS (ESI, m / z): 476.3[M+H] + .

[0419] Step 3: Synthesis of (R)-(4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 35 Peak 1) and (S)-(4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 35 Peak 2)

[0420] Compound 35 (20.0 mg, 40.8 μmol) was separated by SFC (chiral column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 um); mobile phase: 50% [0.1% NH3*H2O in MeOH solution] + 50% supercritical fluid CO2) to obtain compound 35 peak 1 (3.01 mg, Rt=1.739 min) and compound 35 peak 2 (1.90 mg, Rt=2.208 min). MS (ESI, m / z): 476.3 [M+H] + .

[0421] Compound 35 Peak 1: 1 H NMR(400MHz,DMSO-d6)δ8.93–9.25(m,1H),8.21–8.42(m,1H),7.77–7.97(m,4H),7.40–7.73 (m,4H),4.35–5.85(m,2H),3.86–4.00(m,1H),3.67–3.80(m,1H),3.53–3.65(m,1H),3.20(br dd,J=10.4,2.4Hz,2H).

[0422] Compound 35 Peak 2: 1 H NMR(400MHz,DMSO-d6)δ8.92–9.25(m,1H),8.18–8.44(m,1H),7.75–7.98(m,4H),7.38–7.74 (m,4H),4.35–5.86(m,2H),3.84–3.97(m,1H),3.67–3.81(m,1H),3.54–3.64(m,1H),3.19(br s,2H).

[0423] Example 36: (S)-(4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 36 Peak 1) and (R)-(4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 36 Peak 2)

[0424]

[0425] Step 1: Synthesis of (4-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrido[3,4-e]pyrazin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 36-1)

[0426] Int K (755 mg, 1.63 mmol) and Int I (570 mg, 1.63 mmol) were dissolved in DMF (10 mL), and then TEA (429 mg, 4.24 mmol, 590 μL) and TBTU (629 mg, 1.96 mmol) were added in sequence. After reacting at 25°C for 1 hour, the reaction was complete when detected by LCMS. H2O (50 mL) and EtOAc (50 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 36-1 (1.04 g). MS (ESI, m / z): 593.3 [M+H] + .

[0427] Step 2: Synthesis of (4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 36)

[0428] Compound 36-1 (1.04 g, 1.76 mmol) was dissolved in TFA (10 mL) and kept at 80°C for 1 hr. LCMS and TLC (CH2Cl2 / MeOH=10 / 1, R f =0.4) to detect the completion of the reaction, add NaHCO3 aqueous solution (50 mL) and CH2Cl2 (50 mL x 3) to the reaction solution for extraction, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by silica gel column chromatography (CH2Cl2 / MeOH=100 / 1 to 10 / 1) to obtain compound 36 (310 mg). MS (ESI, m / z): 443.2 [M+H] + .

[0429] Step 3: Synthesis of (S)-(4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 36 Peak 1) and (R)-(4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (Compound 36 Peak 2)

[0430] Compound 36 (310 mg, 701 μmol) was subjected to SFC (chiral column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um); mobile phase: 60% [0.1% NH 3* The mixture of H2O in CAN / MeOH (v / v=3 / 7) [+40% supercritical fluid CO2] was separated to obtain compound 36 peak 1 (100.34 mg, Rt=0.807 min) and compound 36 peak 2 (110.84 mg, Rt=1.534 min). MS (ESI, m / z): 443.4 [M+H] + .

[0431] Compound 36 Peak 1: 1 H NMR(400MHz,DMSO-d6)δ9.31(br s,1H),8.44–8.74(m,2H),7.98(s,1H),7.63–7.82(m,6H),5.59–5.80(m ,1H),4.34–4.62(m,1H),3.74–4.33(m,3H),3.52–3.65(m,1H),3.25(br s,1H).

[0432] Compound 36 Peak 2: 1 H NMR(400MHz,DMSO-d6)δ9.31(br s,1H),8.47–8.78(m,2H),7.98(s,1H),7.59–7.86(m,6H),5.55–5.84(m,1H) ,4.41–4.61(m,1H),3.72–4.37(m,3H),3.51–3.66(m,1H),2.88–3.30(m,1H).

[0433] Separation methods

[0434] The Prep-HPLC purification of the compounds in the examples was carried out using Aglient 1260 or Waters 2489 HPLC, and the separation column model was Waters SunFire Prep C 18 OBD(19mm×150mm×5.0μm), WatersXbridge Prep C 18 OBD (19mm×150mm×5.0μm) or YMC Actus Triart C 18(20mm×150mm×5.0μm), the column temperature was 25°C, the detection wavelength was 214nm, 254nm or 280nm, the mobile phase A was acetonitrile, the mobile phase B was 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, the volume ratio of the mobile phase was adjusted according to the polarity of the compound; the mobile phase flow rate was 28mL / min.

[0435] Biological evaluation

[0436] Experimental Example 1: Compounds inhibit proliferation of MTAP-deleted / parental HCT116 cells

[0437] MTAP-deficient / parental HCT116 cells (purchased from HORIZON) were cultured in vitro in monolayers under the conditions of RPMI6140 medium (source culture) containing 10% FBS + 1% P / S, 37°C, 5% CO2. The cells in the logarithmic growth phase were digested and the concentration was adjusted. 250 cells per well were inoculated in a 96-well plate and cultured overnight. The pre-diluted test compound (5000nM starting, 4-fold dilution, 9 points) was added. The negative control group was added with DMSO, and the blank control group was added with culture medium. After culturing in an incubator at 37°C, 5% CO2 for 8 days, 50μl CellTiter-Glo (Promega) was added to each well and lysed at room temperature in the dark for 10 minutes. The test solution was transferred to a 96-well opaque white plate, and then the relative chemiluminescence unit value was read in the chemiluminescence detection mode of the microplate reader.

[0438] The percentage inhibition rate of compounds at different concentrations was calculated according to the following formula:

[0439] Percent inhibition rate = (1 - (chemiluminescent signal value of the test compound - chemiluminescent signal value of the blank control) / (chemiluminescent signal value of the negative control - chemiluminescent signal value of the blank control)) x 100%.

[0440] The percentage inhibition rate of different concentrations of compounds was plotted against the compound concentration, and the curve was fitted according to the four-parameter model to calculate the IC 50 value:

[0441] y=Min+(Max-Min) / (1+(x / IC 50 )^(-Hillslope)), where: y is the percentage inhibition rate; Max and Min are the maximum and minimum values ​​of the fitting curve, respectively; x is the logarithmic concentration of the compound; and Hillslope is the slope of the curve.

[0442] The proliferation inhibitory activity of the compounds on MTAP-deficient / parental HCT116 cells was determined according to the above method. The results are shown in Table 1.

[0443] Table 1. Proliferation inhibitory activity of the compounds of the present invention on MTAP-deficient / parental HCT116 cells

[0444]

[0445] The experimental results show that the compound of the present invention has a strong inhibitory effect on MTAP-deficient HCT116 cells and has a certain selectivity relative to MTAP parent HCT116 cells.

[0446] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof: in: Ring A is a 3-11 membered heterocyclic ring; X 1 , X 2 , X 3 Each independently selected from CR 9 and N; R 1 is independently selected at each occurrence from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl; R 2 Selected from H, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic group; R 3 is independently selected at each occurrence from H, -OH, halogen, -CN, -NR 4 R 5 、-COCH3、-NHCOCH3、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl are each optionally substituted by one or more R 6 replace; R 6 is independently selected at each occurrence from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more independently selected from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-8 Substitution of cycloalkoxy and 3-8 membered heterocyclic groups; R 4 and R 5 Each independently selected from H and C 1-6 Alkyl; or R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more independently selected from halogen, OH, CN, -NH2 and C 1-6 Substitution of alkyl groups; R 9 is independently selected at each occurrence from H, halogen, C 1-4 Alkyl and C 1-4 Haloalkyl; m is 0, 1 or 2; and n is 0, 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein: Ring A is a 5-7 membered saturated or partially saturated heterocyclic ring, the heterocyclic ring contains at least one N atom and optionally 1 or 2 other heteroatoms independently selected from O or S which are the same or different; preferably, ring A is a 5-7 membered saturated heterocyclic ring; preferably, ring A is a 5-7 membered saturated nitrogen heterocyclic ring or a 5-7 membered saturated heterocyclic ring containing N and O, for example, ring A is a 6 membered saturated nitrogen heterocyclic ring or a 6 membered saturated heterocyclic ring containing N and O, and further, ring A is a piperidine ring and a morpholine ring.

3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein R 2 Selected from H, halogen, CN, C 1-4 Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein R 4 and R 5 Each independently selected from H and C 1-4 Alkyl; or R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more independently selected from halogen, OH, CN, -NH2 and C 1-4 The alkyl group is substituted with a substituent.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein X 3 is N.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein n is 0, 1 or 2, preferably, n is 1 or 2, for example, n is 2.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein the compound has the following structure: in, R 1 , R 3 , X 1 , X 2 , m as defined in any one of claims 1-6.

8. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein the compound has the following structure: in, R 1 , R 3 , X 1 , X 2 , m as defined in any one of claims 1-6.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein R 1 Each occurrence is independently selected from H and C 1-4 alkyl.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein R 3 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, hydroxyalkyl, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl are each optionally substituted by one or more R 6 replace.

11. The compound according to claim 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein R 6 is independently selected at each occurrence from halogen, -CN, -NR 4 R 5 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more independently selected from halogen, -OH, -CN, -NR 4 R 5 、-COCH3、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, C 3-8 The substituents of the cycloalkoxy group and the 3- to 8-membered heterocyclic group are substituted.

12. The compound according to claim 11 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein R 3 Each occurrence is independently selected from methyl, phenyl, The methyl, phenyl, Each is optionally replaced by one or more independently selected from trifluoromethyl, methoxy, pentafluoroethoxy, difluoromethoxy, trifluoromethoxy, substituted by a substituent.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein X 1 and X 2 Each independently is CR 9 , and R 9 is independently selected at each occurrence from H, halogen, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein m is 0 or 1, preferably, m is 1.

15. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, wherein the compound is selected from:

16. A pharmaceutical composition comprising a preventive or therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof and one or more pharmaceutically acceptable carriers; optionally, the pharmaceutical composition further comprises one or more other therapeutic agents.

17. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof, or the pharmaceutical composition according to claim 16 in the preparation of a medicament for preventing or treating a disease or condition associated with PRMT5 activity.

18. The use of claim 17, wherein the disease or condition associated with PRMT5 activity is a cancer or tumor in which MTAP is deficient; preferably, the cancer or tumor is selected from esophageal cancer, lung cancer, pancreatic cancer, glioblastoma, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, prostate cancer, melanoma, gastric cancer, colon cancer, leukemia (B-CLL) and lymphoma.

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