Nitrogen-containing ternary condensed ring derivative and application thereof

Abstract

The invention discloses a nitrogen-containing ternary fused ring derivative and structural forms such as a prodrug, an isomer, a solvate or a pharmaceutically acceptable salt form thereof. Methods for preparing such compounds; compositions comprising such compounds and therapeutic uses thereof. The derivative is an NLRP3 agonist, can increase the expression of NLRP3, is used for treating tumors, pathogen infection and alopecia, and has a great clinical application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to nitrogen-containing three-membered fused ring derivatives represented by formula (I) and their prodrugs, isomers, solvates or pharmaceutically acceptable salts. Such compounds are NLRP3 agonists and can be used to treat diseases, including tumors, pathogen infections and hair loss. Background Art

[0002] NLRP3 belongs to the NOD-like receptor family and is the most studied intracellular pattern recognition receptor in recent years. After recognizing pathogen-associated molecular patterns (PAMPs) or host-derived danger signal molecular patterns (DAMPs), it recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to assemble into inflammasomes and induce cell pyroptosis. NLRP3 is expressed in large quantities in innate immune cells such as macrophages and monocytes, participates in the body's innate immunity, resists pathogen infection and stress damage, and can also promote CD8 + T cells are activated to exert effective anti-tumor immune effects. Predicting the prognosis of cancer patients through gene sets shows that patients with liver cancer and skin melanoma with higher NLRP3 expression have a lower risk of death. This shows that NLRP3 plays an important role in the tumor microenvironment and can be used as a key target for tumor immunotherapy and as a tumor prognosis marker.

[0003] Hair loss is one of the common diseases in modern people. The incidence of hair loss is increasing and showing a trend of younger people. It often causes troubles to patients' work and life, and affects the mental health of patients with hair loss. The pathogenic factors of hair loss include genetic factors, endocrine disorders, taking certain drugs, diseases, excessive mental stress, etc., and currently only two drugs are approved for marketing: minoxidil and finasteride. No innovative drugs have been approved for marketing in the past 20 years. Existing therapeutic drugs have shortcomings such as limited response rate, obvious side effects, and recurrence after discontinuation of drugs. Therefore, new drugs are urgently needed to meet clinical needs.

[0004] After searching, there is no prior art application of NLRP3 agonists as drugs for treating hair loss. Summary of the invention

[0005] The present invention aims to provide a nitrogen-containing three-membered fused ring derivative with a novel structure, which can be used as an NLRP3 agonist for preventing or treating hair loss, promoting hair growth, etc.

[0006] A nitrogen-containing three-membered fused ring derivative, which is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] In the formula,

[0009] X 1 and X 2 are independently selected from N or C, and at least one is N;

[0010] Ring A is selected from 5 Substituted C 6-10 Aryl, 5-10 membered heteroaryl, 4-7 membered heterocyclyl;

[0011] R 1 Selected from H, halogen, -CN, -NO2, C 1-8 Alkyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)OR 6 、-C(O)NR 6 R 7 、-NR 6 R 7 ; C 1-8 Alkyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, one or more R 8 replace;

[0012] R 2 are independently selected from H, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group;

[0013] m is 0, 1, 2 or 3;

[0014] R 3 and R 4 are independently selected from H, C 1-8 Alkyl, C 2-8 Heteroalkyl, or R 3 , R 4 Together with the nitrogen atoms to which they are attached, they form a 4-8 membered heterocyclic group;

[0015] L is -(L 1 ) n -(L 2 ) p -, where L 1 and L 2 The same or different and each independently selected from C1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylidene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -N(R 6 )-, -S(O)-, -S(O)2-, -C(O)-;C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylidene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 12 Arylene, 5-10 membered heteroarylene, optionally substituted by one or more R 8 replace;

[0016] n and p are each independently 0, 1, 2 or 3;

[0017] R 5 Selected from H, halogen, -CN, -OH, -NH2, -NO2, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)OR 6 、-C(O)NR 6 R 7 、-NR 6 C(O)R 7 、-NR 6 R 7 、-OR 6 、-SR 6 、-C(O)R 6 、-OC(O)R 6 、-OC(O)NR 6 R 7 、-NR 6 C(O)NR 7 R 9 、-NR 6 C(O)OR 7 、-POR 6 、-P(O)R 6 R 7 、-P(O)OR 6 OR 7 、-S(O)R 6 、-S(O)2R 6 、-S(O)NR 6 R7 、-S(O)2NR 6 R 7 ; C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, one or more R 8 replace;

[0018] R 6 , R 7 , R 9 are independently selected from H, C 1-8 Alkyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl;

[0019] R 8 Selected from H, halogen, -CN, -OH, -NH2, -NO2, C 1-4 Alkyl, C 2-4 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)OR 6 、-C(O)NR 6 R 7 、-NR 6 C(O)R 7 、-NR 6 R 7 、-OR 6 、-SR 6 、-C(O)R 6 、-OC(O)R 6 、-OC(O)NR 6 R 7 、-NR 6 C(O)NR 7 R 9 、-NR 6 C(O)OR 7 、-POR 6 OR 7 、-P(O)R 6 R 7 、-P(O)OR 6 OR 7 、-S(O)R 6 、-S(O)2R 6 、-S(O)NR 6 R7 、-S(O)2NR 6 R 7 ;

[0020] The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O.

[0021] Preferably, in the general structural formula I, R 1 Selected from -Br, -CH3,

[0022] Preferably, in the general structural formula I, R 2 Each is independently preferably selected from H, -F, -Cl, -CN, -NO2, -CF3, -OCH3.

[0023] Preferably, in the general structural formula I, R 3 and R 4 are each independently selected from H, -CH3, or R 3 , R 4 Together with the nitrogen atoms to which they are attached, they form a morpholine ring.

[0024] Preferably, in the general formula I, L is selected from -C(O)-, -C(O)-NH-, -C(O)-NH-CH2C(CH3)2-, -C(O)-NH-(CH2)2-, -CH2-, -CH2-NH-, -CH2-O-, -CH2-O-(CH2)2-, -CH2-NH-(CH2)2-, -CH2-NH-CH2C(CH3)2-, -CH2-O-CH2C(CH3)2-, -(CH2)2-O-CH2-, -(CH2)2-, -NH-(CH2)2C(CH3)2-, -(CH2)3-O-, -O-(CH2)3O-, -CH2-N(CH2CH3)-CO-, -CH2-N(CH2CH3)- CH2-, -CH2-NH-C(O)-O-, -CH2-NH-S(O)2-, -CH2-NH-CH2-C(O)-, -CH2-NH-(CH2)3-, -CH2-O-(CH2)2-O-, -CH2-NH-C(O)-, -CH2-N(CH2CH3)-C(O)-, -NH-C(O)- CH2-, -CH2-O-(CH2)2-NH-C(O)-, -CH2-NH-CH2-, -CH2-NH-(CH2)3-, -CH2-N(CH2CH3)-C(O)-O-, -NH-C(O)-O-(CH2)2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)-NH-,

[0025] Preferably, in the general structural formula I, R 5 is selected from H, methyl, ethyl, methoxy, tert-butoxy, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, -OH, -NH2, dimethylamino, methylsulfonyl, acetyl, benzoyl, difluoromethyl,

[0026] Preferably, it is a compound having the following structural formula (II) or a pharmaceutically acceptable salt thereof:

[0027]

[0028] In the formula,

[0029] X 1 , X 2 are each independently selected from N or C;

[0030]

[0031] -CH3 or

[0032] L is selected from -C(O)-, -CH2-, -C(O)-NH-(CH2)2-, -CH2-NH-(CH2)2-, -CH2-NH-CH2-, -CH2-O-(CH2)2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)-, -CH2-NH-C(O)-O-, -CH2-NH-, -(CH2)3-O-, -CH2-N(CH2CH3)-CO-, -CH2-NH-C(O)-NH- or -CH2-O-;

[0033] R 5 Selected from H, OH, C 1-6 Alkyl, -OR 6 、NH2、 -NR 6 R 7 , Methyl sulfone, or difluoromethyl;

[0034] R 3 and R 4 are independently selected from H or C 1-6 alkyl;

[0035] or R 3 , R 4 Together with the nitrogen atoms to which they are attached, they form a 4-8 membered heterocyclic group;

[0036] R 6, R 7 Each independently selected from C 1-6 alkyl.

[0037] Preferably, it is a compound having the following structural formula (III) or a pharmaceutically acceptable salt thereof:

[0038]

[0039] In the formula,

[0040] X 2 Selected from N or C;

[0041] R 1 Selected from

[0042] -L- is selected from -C(O)-, -CH2-, -CH2-NH-(CH2)2-, -CH2-O-(CH2)2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)-O-, -CH2-NH-, -CH2-NH-C(O)- or -CH2-NH-CH2-;

[0043] R 5 Selected from H, OH, -OR 6 、NH2、-NR 6 R 7 , Methyl sulfone,

[0044]

[0045] R 6 , R 7 Each independently selected from C 1-6 alkyl.

[0046] Preferably, it is a compound having the following structural formula (IV) or a pharmaceutically acceptable salt thereof:

[0047]

[0048] In the formula,

[0049] R 1 Selected from

[0050] -L- is selected from -C(O)-, -CH2-, -CH2-O-(CH2)2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)-, -CH2-NH-C(O)-O- or -CH2-NH-;

[0051] R5 Selected from H, OH, C 1-6 Alkyl, -OR 6 , Methyl sulfone,

[0052] R 6 Selected from C 1-6 alkyl.

[0053] Preferably, it is a compound having the following structural formula (V) or a pharmaceutically acceptable salt thereof:

[0054]

[0055] In the formula,

[0056] -L- is selected from -CH2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)- or -CH2-NH-C(O)-O-;

[0057] R 5 Selected from C 1-6 alkyl,

[0058] The present invention also provides a nitrogen-containing three-membered fused ring derivative selected from the following characteristic compounds numbered 1 to 72 or their pharmaceutically acceptable salts:

[0059]

[0060]

[0061]

[0062] The “compounds” of the present invention include, but are not limited to, the following forms of the compounds: free base, stereoisomers, geometric isomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters), etc.

[0063] The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.

[0064] The "pharmaceutically acceptable salt" in the present invention refers to the salt of the compound of the present invention, which is a compound with a specific substituent found by the present invention and 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, malic acid, When the compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium or organic amines. For example: alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts.

[0065] In the present invention, "isotope" means that unless otherwise specified, the compounds of the present invention may exist in an isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest amount of atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotope labels are: hydrogen isotopes, including but not limited to 2 H and 3 H; Carbon isotopes: including but not limited to 13 C and 14 C; Chlorine isotopes: including but not limited to 35 Cl and 37 Cl; Fluorine isotopes: including but not limited to 18 F; Iodine isotopes: including but not limited to 123 I and 125 I; Nitrogen isotopes: including but not limited to 13 N and 15 N; oxygen isotopes: including but not limited to 15 O. 17 O and 18 O; Sulfur isotopes: including but not limited to 35 S. These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues, especially 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2H) substitution can enhance metabolic stability and prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and use known synthesis techniques to complete their synthesis like non-isotope-labeled compounds.

[0066] In the present invention, "isomer" means, unless otherwise specified, including stereoisomers or tautomers. Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include, but are not limited to, enantiomers, diastereomers, conformers (rotational isomers), geometric isomers (cis / trans) isomers, and atropisomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in a solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0067] The term "prodrug" in the present invention refers to a prodrug of a compound of the present invention that is easily converted into a compound of the present invention by chemical changes under physiological conditions. In addition, a prodrug can be converted into a compound of the present invention by chemical or biochemical methods in an in vivo environment.

[0068] The terms used in this document have the following meanings:

[0069] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0070] The term "alkyl" refers to a hydrocarbon chain containing the specified number of carbon atoms, which may be straight or branched. 1-8 The indicated group may have 1 to 8 (including the end point) carbon atoms, for example, C 1-6 Alkyl, including but not limited to methyl, ethyl, isopropyl, tert-butyl, n-hexyl. The term "alkylene" refers to a corresponding divalent group, for example, -CH2-.

[0071] The term "heteroalkyl" refers to an optionally substituted alkyl group containing two or more carbon atoms, which has one or more backbone chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus or a combination thereof, and the numerical ranges given refer to the number of carbons in the chain, such as C 2-8Assorted alkyl groups contain 2-8 carbon atoms. For example, -CH2OCH2CH3, -CH2NHCH2CH3 or -CH2N(Me)CH2CH3 are referred to as C3 assorted alkyl groups. Wherein, the point of attachment of assorted alkyl groups to other groups is on a carbon in the assorted alkyl backbone chain. The term "assorted alkylene" refers to the corresponding divalent group, for example, -CH2OCH2CH2-.

[0072] The term "haloalkyl" refers to an alkyl group substituted by one or more (eg, 1 to 3) the same or different halogen atoms, such as -CF3, -C2F5, -CHF2, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0073] The term "alkoxy" refers to an -O-alkyl group, for example, -OCH3.

[0074] The term "hydroxyalkyl" refers to a group formed by replacing the hydrogen atoms of an alkyl group with one or more hydroxy groups, including but not limited to hydroxymethyl, hydroxyethyl, and -CH(OH)CH3.

[0075] The term "haloalkoxy" refers to a -O-haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, "C 1-4 The "haloalkoxy group" includes C1, C2, C3, C4, C5 and C6 haloalkoxy groups, and specific examples include trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.

[0076] The term "alkenyl" refers to a hydrocarbon group having one or more carbon-carbon double bonds, which may be straight or branched, such as -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3. The alkenyl group may be optionally substituted with one or more (e.g., 1 to 3) identical or different substituents. The term "alkenylene" refers to a corresponding divalent group, such as -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, and the alkenylene group may be optionally substituted with one or more (e.g., 1 to 3) identical or different substituents.

[0077] The term "alkynyl" refers to a linear or branched hydrocarbon group having one or more carbon-carbon triple bonds, such as ethynyl, 2-propynyl, 1,3-butadiynyl, which may be optionally substituted with one or more (e.g., 1 to 3) identical or different substituents. The term "alkynylene" refers to a corresponding divalent group, such as An alkynylene group may be optionally substituted with one or more (eg, 1 to 3) substituents which may be the same or different.

[0078] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic group having a conjugated π electron system, wherein the ring of the monocyclic group is aromatic and at least one of the fused rings of the bicyclic or tricyclic group is aromatic, such as tetrahydronaphthyl. Examples of aryl groups also include phenyl, naphthyl and the like. The aryl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents (such as halogen, OH, CN, NO2, C 1-4 The term "arylene" refers to the corresponding divalent group.

[0079] 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) and bicyclic alkyl, including but not limited to spirocyclic alkyl, cyclo (condensed ring) alkyl or bridged cycloalkyl (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl). In the present invention, the cycloalkyl group may be optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl group are optionally oxo (i.e., forming C=O). The term "cycloalkylene" represents the corresponding divalent group.

[0080] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing one or more (e.g., 1, 2, 3, 4) identical or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl group are optionally oxidized (e.g., to form C=O, S(=O) or S(=O)2). The ring containing the monocyclic group is aromatic and at least one of the fused rings containing the bicyclic or tricyclic group is aromatic (but not necessarily a ring containing a heteroatom), such as Examples of heteroaryl groups also include, but are not limited to, pyridyl, furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl. The term "heteroarylene" refers to the corresponding divalent radical.

[0081] The term "heterocyclyl" refers to a monocyclic or polycyclic (e.g., cyclic, spirocyclic or bridged) group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms, wherein the heteroatoms are selected from O, N or S, and the carbon atoms and heteroatoms on the heterocyclyl are optionally oxidized (e.g., forming C=O, S(=O) or S(=O)2). Examples of heterocyclyl include piperazinyl, pyrrolidinyl, dioxane, dithianyl, thiomorpholinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, The term "heterocycloalkylene" refers to a corresponding divalent radical.

[0082] The present invention also provides a method for preparing the compound of formula (I), including but not limited to the following method:

[0083] Route 1: When -LR in formula (I) 5 Selected from Ring A is selected from When, compound I-A1 can be prepared by the following reaction:

[0084]

[0085] Among them, R 1 , R 2 , R 3 , R 4 and m are as defined above.

[0086] The specific reaction process is as follows:

[0087] Compound I-1 is substituted under alkaline conditions to generate compound I-2, compound I-2 is reduced to generate compound I-3, compound I-3 is chlorinated to generate compound I-4, compound I-4 is subjected to Buchwald coupling to generate compound I-5, compound I-5 and Compound I-A1 was generated by Suzuki coupling.

[0088] Route 2: When -LR in formula (I) 5 Selected from Ring A is selected from When, compound I-A2 can be prepared by the following reaction:

[0089]

[0090] Among them, R 1 , R 2 , R 3 , R 4and m are as defined above.

[0091] The specific reaction process is as follows:

[0092] Compound I-6 is substituted under alkaline conditions to generate compound I-7, compound I-7 is reduced to generate compound I-8, compound I-8 is chlorinated to generate compound I-9, compound I-9 is subjected to Buchwald coupling to generate compound I-10, compound I-10 and Compound I-A2 was generated by Suzuki coupling.

[0093] Route 3: When -LR in formula (I) 5 Selected from Ring A is selected from When, compound I-A3 can be prepared by the following reaction:

[0094]

[0095] Among them, R 1 , R 2 , R 3 , R 4 and m are as defined above.

[0096] The specific reaction process is as follows:

[0097] Compound I-11 is cyclized with urea to generate compound I-12, compound I-12 is chlorinated to generate compound I-13, compound I-13 is aminolyzed to generate compound I-14, compound I-14 is substituted to generate compound I-15, compound I-15 is cyclized with ethyl 3-bromopyruvate to generate compound I-16, compound I-16 is oxidized to generate compound I-17, compound I-17 is substituted to generate compound I-18, compound I-18 ...8, compound I-18 is cyclized with ethyl 3-bromopyruvate to generate compound I-16, compound Compound I-A3 was generated by Suzuki coupling.

[0098] Route 4: When ring A in formula (I) is selected from When, compound I-A4 can be prepared by the following reaction:

[0099]

[0100] Among them, R 1 , R 2 , R 3 , R 4 , m, L and R 5 As defined above.

[0101] The specific reaction process is as follows:

[0102] Compound I-19 is condensed to form compound I-20, compound I-20 is substituted to form compound I-21, compound I-21 undergoes intramolecular cyclization under alkaline conditions to form compound I-22, compound I-22 is chlorinated to form compound I-23, compound I-23 is substituted to form compound I-24, compound I-24 is brominated to form compound I-25, and compound I-25 is subjected to a palladium-catalyzed coupling reaction to form compound I-A4.

[0103] Route 5: When ring A in formula (I) is selected from When, compound I-A5 can be prepared by the following reaction:

[0104]

[0105] Among them, R 1 , R 2 , R 3 , R 4 , m, L and R 5 As defined above.

[0106] The specific reaction process is as follows:

[0107] Compound I-26 is condensed to form compound I-27, compound I-27 undergoes substitution to form compound I-28, compound I-28 undergoes intramolecular cyclization under alkaline conditions to form compound I-29, compound I-29 is substituted to form compound I-30, and compound I-30 undergoes substitution reaction under the action of n-BuLi to form compound I-A5.

[0108] Route 6: When -(L 1 ) n When - is selected from -C(O)-, compound IB can be prepared by the following reaction:

[0109]

[0110] Among them, R 1 , R 2 , R 3 , R 4 ,m,-(L 2 ) p -、R 5 , X 1 , X 2 and Ring A are as defined above.

[0111] The specific reaction process is as follows:

[0112] Compound IA is hydrolyzed under alkaline conditions to generate compound I-31, and compound I-31 undergoes amine acid condensation to generate compound IB.

[0113] Route 7: When -(L 1 ) n When - is selected from -CH2-, compound IC can be prepared by the following reaction:

[0114]

[0115] Among them, R 1 , R 2 , R 3 , R 4 ,m,-(L 2 ) p -、R 5 , X 1 , X 2 and Ring A are as defined above.

[0116] The specific reaction process is as follows:

[0117] Compound IA is reduced to generate compound I-32, which is then oxidized to generate compound I-33, and compound I-33 is subjected to reductive amination to generate compound IC.

[0118] Route 8: When -(L 1 ) n When - is selected from -CH2-NH-, compound ID can be prepared by the following reaction:

[0119]

[0120] Among them, -(L 2 ) p - is carbonyl or sulfonyl, R 1 , R 2 , R 3 , R 4 , R 5 , m, X 1 , X 2 and Ring A are as defined above.

[0121] The specific reaction process is as follows:

[0122] Compound I-32 is subjected to Mitsunobu reaction to generate compound I-34, which is then deprotected to generate compound I-35. Compound I-9 is subjected to substitution reaction to generate compound ID.

[0123] Route 9: When -(L 1 ) n When - is selected from -CH2-O-, compound IE can be prepared by the following reaction:

[0124]

[0125] Where X is CH or N, R 1 , R 2 , R 3 , R 4 ,m,-(L 2 ) p -、R 5 , X 1 , X 2 and Ring A are as defined above.

[0126] The specific reaction process is as follows:

[0127] Compound I-32 is subjected to substitution reaction to generate compound IE.

[0128] Route 10: When R in formula (I) 3 and R 4 When each is H, compound IF can be prepared by the following reaction:

[0129]

[0130] Among them, R 1 , R 2 ,m,-L-,R 5 , X 1 , X 2 and Ring A are as defined above.

[0131] The specific reaction process is as follows:

[0132] Compound I-36 is deprotected under acidic conditions to generate compound IF.

[0133] The present invention also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0134] Furthermore, the pharmaceutical composition also includes one or more pharmaceutically acceptable carriers.

[0135] The term "pharmaceutical composition" in the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier generally accepted in the art for delivering biologically active compounds to an organism (such as a human). The purpose of a pharmaceutical composition is to facilitate administration and delivery to an organism.

[0136] In the present invention, "pharmaceutically acceptable carrier" refers to a substance that is co-administered with an active ingredient and is conducive to the administration of the active ingredient, including but not limited to any pharmaceutically acceptable glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier for humans or animals (such as livestock). Non-limiting examples of "pharmaceutically acceptable carrier" include but are not limited to calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol, etc.

[0137] The pharmaceutical composition provided by the present invention can be manufactured by methods well known in the art, including but not limited to mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying, freeze-drying, etc.

[0138] The pharmaceutical composition provided by the present invention can be formulated into solid, semisolid, liquid or gas preparations, including but not limited to tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, etc.

[0139] The pharmaceutical composition provided by the present invention has administration routes including but not limited to oral administration, injection, inhalation, transdermal administration, mucosal administration, topical administration, intracavitary administration, etc., and administration sites including but not limited to oral cavity, sublingual administration, intravenous administration, intramuscular administration, lung, gastrointestinal tract administration, epidermal administration, subcutaneous administration, intranasal administration, intraocular administration, intraauricular administration, intraperitoneal administration, intravaginal administration, rectal administration, acupuncture points, etc. The preferred administration route is oral administration.

[0140] The present invention also provides a use of the compound or pharmaceutical composition as described above in the preparation of a drug for preventing or treating a disease associated with abnormal expression of the NLRP3 signaling pathway.

[0141] Preferably, the aforementioned compound or pharmaceutical composition provided by the present invention can achieve the prevention or treatment effect on the following diseases by regulating the activity of NLRP3: tumor, pathogen infection or hair loss.

[0142] Preferably, the tumor includes, but is not limited to, myeloid leukemia, adrenocortical carcinoma, lymphoma, bladder cancer, bone cancer, brain cancer, breast cancer, colon cancer, rectal cancer, small intestine cancer, stomach cancer, pharyngeal cancer, esophageal cancer, bile duct cancer, laryngeal cancer, endometrial cancer, cervical cancer, kidney cancer, liver cancer, pancreatic cancer, chronic myeloid leukemia, lung cancer, melanoma, osteosarcoma, ovarian cancer, pharyngeal cancer, prostate cancer, skin cancer, soft tissue sarcoma, testicular cancer.

[0143] Preferably, pathogen infection includes, but is not limited to, infection caused by bacteria, fungi, viruses, mycoplasmas, spirochetes, protozoa or helminths.

[0144] Compared with the prior art, the present invention has the following beneficial effects:

[0145] ① The inhibitory effect test on hERG ion channel shows that most of the compounds in this patent have no obvious inhibitory effect on hERG.

[0146] ② The hair growth and promotion test showed that the patented compound has the effect of promoting hair growth and can be used to treat hair loss.

[0147] In conclusion, the compounds of the present application have significant anti-tumor activity and / or good activity in promoting hair growth, and have promising prospects for clinical application.

[0148] Instruction Manual

[0149] Figure 1 The graph shows the effect of compound 33 on hair growth and promotion. One-way ANOVA, **, P<0.01. DETAILED DESCRIPTION

[0150] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0151] In addition, all operations involving raw materials that are easily oxidized or hydrolyzed are carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be used directly without further purification.

[0152] Explanation of the abbreviations of the chemical reagents involved:

[0153] K2CO3: potassium carbonate; DMAc: N,N-dimethylacetamide; Fe: iron powder; AcOH: acetic acid; POCl3: phosphorus oxychloride; PMBNH2: p-methoxybenzylamine; Pd(OAc)2: palladium acetate; PPh3: triphenylphosphine; t-BuOK: potassium tert-butoxide; dioxane: dioxane; Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; Na2SO4: sodium sulfate; NaCl: sodium chloride; Cs2CO3: cesium carbonate; LiOH·H2O: lithium hydroxide monohydrate; T HF: tetrahydrofuran; MeOH: methanol; EA: ethyl acetate; Tf2O: trifluoromethanesulfonic anhydride; TFA: trifluoroacetic acid; NH4Cl: ammonium chloride; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; HOBt: 1-hydroxybenzotriazole; LiAlH4: lithium aluminum hydride; MnO2: manganese dioxide; DCM: Dichloromethane; NaBH(OAc)3: sodium triacetoxyborohydride; Boc2O: di-tert-butyl dicarbonate; DMAP: N,N-dimethylaminopyridine; NaH: sodium hydride; DPPA: diphenylphosphoryl azide; TEA: triethylamine; toluene: toluene; DIAD: diisopropyl azodicarboxylate; N2H4·H2O: hydrazine hydrate; Ms2O: methanesulfonic anhydride; Py: pyridine; Triphosgene: triphosgene; CuI: cuprous iodide; DMSO: dimethyl sulfoxide; SOCl2: dichlorothionyl; NaHMDS: di( trimethylsilyl)amide; EtOH: ethanol; NBS: N-bromosuccinimide; Pd(PPh3)4: tetrakistriphenylphosphine palladium; ACN: acetonitrile; MeSNa: sodium methyl mercaptan; m-CPBA: m-chloroperbenzoic acid; KHMDS: potassium bis(trimethylsilyl)amide; PyBOP: 1H-benzotriazol-1-yloxytripyrrolidinophosphate; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; MeI: methyl iodide; EtI: ethyl iodide; n-BuLi: n-butyllithium; K3PO4: potassium phosphate.

[0154] The reaction starting materials and common intermediates involved in the embodiments of the present invention can be purchased from the market or prepared by themselves. The preparation process of the common intermediates that need to be prepared by themselves is described in detail as follows:

[0155] Preparation of common intermediate Int4

[0156]

[0157] Step 1: Synthesis of diethyl 1-(4-bromo-2-nitrophenyl)-1H-pyrrole-2,4-dicarboxylate (Int1)

[0158] Compound I-1: 1H-pyrrole-2,4-dicarboxylic acid diethyl ester (4.2 g, 19.89 mmol) and compound M1: 4-bromo-1-fluoro-2-nitrobenzene (5.25 g, 23.86 mmol) were dissolved in DMAc (30 mL), K2CO3 (4.13 g, 29.90 mmol) was added, and the mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature and quenched with water. It was extracted with EA three times (25 mL × 3), the combined organic phase was washed with water (15 mL), washed with saturated NaCl (15 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA: petroleum ether = 0-18%) to obtain intermediate Int1 (7.99 g) with a yield of 97.7% as a white solid.

[0159] MS (m / z): 412.0 [M+H] + .

[0160] Step 2: Synthesis of ethyl 7-bromo-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-2-carboxylate (Int2)

[0161] Dissolve the intermediate Int1 (7.98 g, 19.41 mmol) and iron powder (2.17 g, 38.88 mmol) in AcOH (50 mL). Heat the mixture to 100 ° C and stir for 2 hours. The reaction solution is cooled to room temperature and adjusted to pH 2-3 with hydrochloric acid (6 M). A large amount of solid precipitates and is filtered under reduced pressure. Collect the filter cake, concentrate under reduced pressure, and dry to obtain the intermediate Int2 (5.68 g) with a yield of 87.3%, which is a gray-green solid.

[0162] MS (m / z): 336.0 [M+H] + .

[0163] Step 3: Synthesis of ethyl 7-bromo-4-chloropyrrolo[1,2-a]quinoxaline-2-carboxylate (Int3)

[0164] The intermediate Int2 (5.67 g, 16.92 mmol) was dissolved in POCl3 (10 mL), and the reaction solution was stirred at 105 ° C for 8 hours. After the mixture was cooled to room temperature, it was concentrated under reduced pressure to remove most of the solvent, and the remaining concentrated solution was added dropwise to room temperature water for quenching. After the dropwise addition, it was extracted with EA three times (20 mL × 3), and the combined organic phase was washed with water (10 mL), washed with saturated NaCl (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the intermediate Int3 (4.98 g) with a yield of 83.2%, as a white solid.

[0165] MS (m / z): 353.0 [M+H] + .

[0166] Step 4: Synthesis of ethyl 7-bromo-4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-2-carboxylate (Int4)

[0167] The intermediate Int3 (1.05 g, 2.97 mmol), PMBNH2 (815 mg, 5.94 mmol), PPh3 (156 mg, 0.59 mmol), Pd(OAc)2 (67 mg, 0.30 mmol), and t-BuOK (428 mg, 4.45 mmol) were dissolved in dioxane (10 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 100 ° C for 3 hours. After the mixture was cooled to room temperature, it was quenched with water and extracted with EA three times (20 mL × 3). The combined organic phase was washed with water (10 mL), washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA: petroleum ether = 0-35%) to obtain the intermediate Int4 (978 mg) with a yield of 72.5% as a yellow solid.

[0168] MS (m / z): 454.0 [M+H] + .

[0169] 1 H NMR (400MHz, DMSO-d6) δ8.81(d,J=1.6Hz,1H),8.31(t,J=6.0Hz,1H),8.20(d,J=8.8Hz,1H),7.58(dd,J=4.8,1.6Hz,2H) ,7.37-7.29(m,3H),6.92–6.83(m,2H),4.67(d,J=6.0Hz,2H),4.30(q,J=7.2Hz,2H),3.72(s,3H),1.33(t,J=7.2Hz,3H).

[0170] Preparation of common intermediate Int6:

[0171]

[0172] Step 1: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (Int5)

[0173] The common intermediate Int4 (970 mg, 2.14 mmol), compound M2: 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester (1198 mg, 4.31 mmol), Pd(dppf)Cl2 (156 mg, 0.22 mmol) and Cs2CO3 (1403 mg, 4.31 mmol) were dissolved in a mixed solvent of dioxane / water (10 mL / 1 mL). The nitrogen atmosphere was replaced three times, and the reaction solution was stirred at 100°C for 2 hours. After the mixed solution was cooled to room temperature, it was quenched with water and extracted with EA three times (20 mL×3). The combined organic phase was washed with water (10 mL), washed with saturated NaCl (10 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (EA: petroleum ether = 0-50%) to obtain the intermediate Int5 (991 mg) with a yield of 88.3% as a white solid.

[0174] MS (m / z): 526.0 [M+H] + .

[0175] Step 2: Synthesis of 4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylic acid (Int6)

[0176] The intermediate Int5 (200 mg, 0.38 mmol) was dissolved in a mixed solvent of THF / MeOH / water (2 mL / 2 mL / 1 mL), LiOH·H2O (32 mg, 0.76 mmol) was added, and the mixture was stirred at room temperature for 6 h. The mixture was quenched with water, pH 6-7 was adjusted with citric acid (1 M solution), and extracted with EA three times (20 mL×3), the combined organic phase was washed with water (10 mL), washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (DCM: MeOH = 5%) to obtain the intermediate Int6 (180 mg) with a yield of 95.1% as a white solid.

[0177] MS (m / z): 498.0 [M+H] + .

[0178] Example 1: Preparation of ethyl 4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (1)

[0179]

[0180] Step 1: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (Int5)

[0181] Referring to the “Preparation method of common intermediate Int4”, the common intermediate Int4 is first prepared.

[0182] The common intermediate Int4 (970.0 mg, 2.14 mmol), compound M2 (1198.0 mg, 4.31 mmol), Pd(dppf)Cl2 (156.0 mg, 0.22 mmol) and Cs2CO3 (1403.0 mg, 4.31 mmol) were dissolved in a mixed solvent of dioxane / water (10 mL / 1 mL). The nitrogen atmosphere was replaced three times, and the reaction solution was stirred at 100 ° C for 2 hours. After the mixed solution was cooled to room temperature, it was quenched with water, extracted with EA (20 mL × 3), the combined organic phase was washed with water (10 mL), washed with saturated NaCl (10 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (eluent EA: petroleum ether = 0-50%) to obtain the intermediate Int5 (991.0 mg) with a yield of 88.3% as a white solid.

[0183] MS (m / z): 526.0 [M+H] + .

[0184] Step 2: Synthesis of ethyl 4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (1)

[0185] The intermediate Int5 (100.0 mg, 0.19 mmol) was dissolved in TFA (1 mL), Tf2O (0.1 mL) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (eluent ACN: 0.1% formic acid aqueous solution = 70-80%) to obtain the target compound 1 (35.0 mg) with a yield of 57.4% as a white solid.

[0186] MS (m / z): 322.0 [M+H] + .

[0187] 1H NMR (400MHz, DMSO-d6) δ8.80(d,J=1.6Hz,1H),8.26(d,J=8.5Hz,1H),7.83(d,J=1.9Hz,1H),7.72(s,1H),7.63(dd,J1=8.4 Hz,J2=1.9Hz,1H),7.51(d,J=1.5Hz,1H),7.16(s,2H),6.78(d,J=2.2Hz,1H),4.32(q,J=7.1Hz,3H),1.35(t,J=7.0Hz,3H).

[0188] Example 2: Preparation of ethyl 4-amino-7-phenylpyrrolo[1,2-a]quinoxaline-2-carboxylate (2)

[0189]

[0190] Step 1: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-phenylpyrrolo[1,2-a]quinoxaline-2-carboxylate (2-1)

[0191] Referring to the “Preparation method of common intermediate Int4”, the common intermediate Int4 is first prepared.

[0192] Referring to the synthesis of compound Int5 in step 1 of Example 1, only "compound M2" was replaced with "phenylboronic acid", and the rest of the method was the same. Compound 2-1 (30.0 mg) was prepared from Int4 (40.0 mg, 0.09 mmol) with a yield of 75.0%, as a light yellow oil.

[0193] MS (m / z): 452.0 [M+H] + .

[0194] Step 2: Synthesis of ethyl 4-amino-7-phenylpyrrolo[1,2-a]quinoxaline-2-carboxylate (2)

[0195] Referring to the synthesis of the target compound 1 in step 2 of Example 1, only "Compound Int5" was replaced with "Compound 2-1", and the rest of the method was the same to prepare the target compound 2 (3.50 mg) with a yield of 23.8% as a white solid.

[0196] MS (m / z): 332.0 [M+H] + .

[0197] 1H NMR (400MHz, DMSO-d6) δ8.84(d,J=1.2Hz,1H),8.32(d,J=8.4Hz,1H),7.77-7.72(m,2H),7.66(d,J=2.0Hz,1H),7.5 3(d,J=1.6Hz,1H),7.52-7.47(m,3H),7.41-7.35(m,1H),7.17(s,2H),4.33(q,J=7.2Hz,2H),1.35(t,J=7.2Hz,3H).

[0198] Example 3: Preparation of ethyl 4-amino-7-(1-methyl-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (3)

[0199]

[0200] Step 1: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-(1-methyl-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (3-1)

[0201] Referring to the “Preparation method of common intermediate Int4”, the common intermediate Int4 is first prepared.

[0202] Referring to the synthesis of compound Int5 in step 1 of Example 1, only "compound M2" was replaced with "1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole", and the rest of the method was the same. Compound 3-1 (80.0 mg) was prepared from Int4 (100.0 mg, 0.22 mmol) with a yield of 80.0%, as a light yellow solid.

[0203] MS (m / z): 456.0 [M+H] + .

[0204] Step 2: Synthesis of ethyl 4-amino-7-(1-methyl-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (3)

[0205] Referring to the synthesis of the target compound 1 in step 2 of Example 1, only "Compound Int5" was replaced with "Compound 3-1", and the rest of the method was the same to prepare the target compound 3 (35.0 mg) with a yield of 59.4% as a white solid.

[0206] MS (m / z): 336.0 [M+H] + .

[0207] 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.41(d,J=8.4Hz,1H),7.87(brs,2H),7.72(s,1H),7.58(d,J=2.0Hz,1H),7.50(d ,J=1.6Hz,1H),7.44(d,J=8.4Hz,1H),6.50(d,J=1.6Hz,1H),4.34(q,J=7.2Hz,2H),3.92(s,3H),1.35(t,J=7.2Hz,3H).

[0208] Example 4: Preparation of ethyl 4-amino-7-(pyridin-2-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (4)

[0209]

[0210] Step 1: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-(pyridin-2-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (4-1)

[0211] Refer to “Preparation method of common intermediate Int4” to first prepare intermediate Int4.

[0212] Referring to the synthesis of compound Int5 in step 1 of Example 1, only "compound M2" was replaced with "2-pyridineboronic acid", and the rest of the method was the same. Compound 4-1 (18.0 mg) was prepared from Int4 (200.0 mg, 0.44 mmol) with a yield of 9.0% as a white solid.

[0213] MS (m / z): 453.0 [M+H] + .

[0214] Step 2: Synthesis of ethyl 4-amino-7-(pyridin-2-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (4)

[0215] Referring to the synthesis of the target compound 1 in step 2 of Example 1, only "Compound Int5" was replaced by "Compound 4-1", and the rest of the method was the same to prepare the target compound 4 (6.3 mg) with a yield of 63.4% as a white solid.

[0216] MS (m / z): 333.0 [M+H] + .

[0217] 1H NMR (400MHz, DMSO-d6) δ8.96 (d, J=1.6Hz, 1H), 8.70 (dd, J1=4.8Hz, J2=1.0Hz, 1H), 8. 41(d,J=8.4Hz,1H),8.22(d,J=2.0Hz,1H),8.07(dt,J=8.0,1.0Hz,1H),8.01(dd,J1=8 .4Hz,J2=2.0Hz,1H),7.92(td,J=7.6,2.0Hz,1H),7.83(brs,2H),7.71(s,1H),7.39(d dd, J1=7.5Hz, J2=4.8Hz, J3=1.0Hz, 1H), 4.34 (q, J=7.2Hz, 2H), 1.36 (t, J=7.2Hz, 3H).

[0218] Example 5: Preparation of ethyl 4-amino-7-(thiophen-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (5)

[0219]

[0220] Step 1: Synthesis of ethyl 4-amino-7-bromopyrrolo[1,2-a]quinoxaline-2-carboxylate (5-1)

[0221] The intermediate Int4 (300.0 mg, 0.66 mmol) was dissolved in TFA (3 mL), Tf2O (1 mL) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated and the residue was separated by column chromatography (EA: petroleum ether = 0-30%) to obtain compound 5-1 (150.0 mg) with a yield of 68.2% as a pale white solid.

[0222] MS (m / z): 336.0 [M+H] + .

[0223] Step 2: Synthesis of ethyl 4-amino-7-(thiophen-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (5)

[0224] Compound 5 (50.0 mg, 0.15 mmol) was dissolved in 1,4-dioxane (1 mL), and water (0.1 mL), 3-thiopheneboronic acid (38.3 mg, 0.30 mmol), Pd(dppf)Cl2 (10.9 mg, 0.02 mmol) and K2CO3 (41.36 mg, 0.30 mmol) were added, and the reaction mixture was stirred at 100°C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (eluent ACN: 10 mmol / L ammonium bicarbonate aqueous solution = 80-90%) to obtain the target compound 5 (10.8 mg) with a yield of 21.4% as a brown solid.

[0225] MS (m / z): 338.0 [M+H] + .

[0226] 1 H NMR (400MHz, DMSO-d6) δ8.83(d,J=1.6Hz,1H),8.26(d,J=8.4Hz,1H),7.99-7.93(m,1H),7.73(d,J=2.0Hz,1H),7.68-7.63( m, 2H), 7.57 (dd, J1 = 8.4Hz, J2 = 2.0Hz, 1H), 7.52 (d, J = 1.6Hz, 1H), 7.14 (s, 2H), 4.32 (q, J = 7.2Hz, 2H), 1.35 (t, J = 7.2Hz, 3H).

[0227] Example 6: Preparation of ethyl 4-amino-7-(furan-2-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (6)

[0228]

[0229] Step 1: Synthesis of ethyl 4-amino-7-(furan-2-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (6)

[0230] Referring to the preparation method of compound 5-1 in Example 5, compound 5-1 was prepared.

[0231] Referring to the synthesis of the target compound 5 in step 2 of Example 5, only the compound "3-thiopheneboronic acid" was replaced by "2-furanboronic acid", and the rest of the method was the same to prepare the target compound 6 (6.0 mg) with a yield of 12.5%, as a gray solid.

[0232] MS (m / z): 322.0 [M+H] + .

[0233] 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.27(d,J=8.4Hz,1H),7.77(s,1H),7.69(s,1H),7.53(d,J=8. 4Hz,1H),7.51(s,1H),7.18(s,2H),7.02(s,1H),6.62(s,1H),4.36-4.29(m,2H),1.44-1.24(m,3H).

[0234] Example 7: Preparation of ethyl 4-amino-7-(pyridazin-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (7)

[0235]

[0236] Step 1: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-(pyridazin-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (7-1)

[0237] Refer to “Preparation method of common intermediate Int4” to first prepare intermediate Int4.

[0238] Referring to the synthesis of compound Int5 in step 1 of Example 1, only "compound M2" was replaced with "3-pyridazine boronic acid", and the rest of the method was the same. Compound 7-1 (16.0 mg) was prepared from Int4 (200.0 mg, 0.44 mmol) with a yield of 8.0% as a white solid.

[0239] MS (m / z): 454.0 [M+H] + .

[0240] Step 2: Synthesis of ethyl 4-amino-7-(pyridazin-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (7)

[0241] Referring to the synthesis of the target compound 1 in step 2 of Example 1, only "Compound Int5" was replaced with "Compound 7-1", and the rest of the method was the same to prepare the target compound 7 (4.4 mg) with a yield of 44.0% as a white solid.

[0242] MS (m / z): 334.0 [M+H] + .

[0243] 1 H NMR (400MHz, DMSO-d6) δ9.23(dd,J1=4.9Hz,J2=1.5Hz,1H),8.93(d,J=1.5Hz,1H),8.44(d,J=8.6Hz,1H),8.34(dd,J1=8.7Hz,J2=1.6Hz,1H),8.23(d,J=2 .0Hz,1H),8.02(dd,J1=8.6Hz,J2=2.1Hz,1H),7.80(dd,J1=8.7Hz,J2=4.9Hz ,1H),7.62(s,1H),7.47(s,2H),4.34(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0244] Example 8: Preparation of ethyl 4-amino-7-(cyclopent-1-en-1-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (8)

[0245]

[0246] Step 1: Synthesis of ethyl 4-amino-7-(cyclopent-1-en-1-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (8)

[0247] Referring to the preparation method of compound 5-1 in Example 5, compound 5-1 was prepared.

[0248] Referring to the synthesis of the target compound 5 in step 2 of Example 5, only the compound "3-thiopheneboronic acid" was replaced by "cyclopent-1-ene-1-ylboronic acid", and the rest of the method was the same to prepare the target compound 8 (6.00 mg) with a yield of 12.5% ​​as a gray solid.

[0249] MS (m / z): 322.0 [M+H] + .

[0250] 1 H NMR(400MHz,DMSO-d6)δ8.78(d,J=1.6Hz,1H),8.17(d,J=8..8Hz,1H),7.50(s,1H),7.44-7.35(m,2H),7.1 4(s,2H),6.35(s,1H),4.31(q,J=7.2Hz,2H),2.76-2.66(m,2H),2.03-1.95(m,2H),1.34(t,J=7.2Hz,3H).

[0251] Example 9: Preparation of 4-amino-7-methyl-pyrrolo[1,2-a]quinoxaline-2-carboxylic acid ethyl ester (9)

[0252]

[0253] Step 1: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-methylpyrrolo[1,2-a]quinoxaline-2-carboxylate (9-1)

[0254] Refer to “Preparation method of common intermediate Int4” to first prepare intermediate Int4.

[0255] Referring to the synthesis of compound Int5 in step 1 of Example 1, only "compound M2" was replaced with "methylboronic acid", and the rest of the method was the same to prepare compound 9-1 (16.0 mg) with a yield of 8.0% as a white solid.

[0256] MS (m / z): 454.0 [M+H] + .

[0257] Step 2: Synthesis of ethyl 4-amino-7-methylpyrrolo[1,2-a]quinoxaline-2-carboxylate (9)

[0258] Referring to the synthesis of the target compound 1 in step 2 of Example 1, only "Compound Int5" was replaced with "Compound 9-1", and the rest of the method was the same to prepare the target compound 9 (21.7 mg) with a yield of 52.9% as a white solid.

[0259] MS (m / z): 270.0 [M+H] + .

[0260] 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.19(d,J=8.4Hz,1H),8.14(s,1H),7.87(s,1H),7.71(s,1H ), 7.29 (s, 1H), 7.13 (d, J = 8.3Hz, 1H), 4.32 (q, J = 7.1Hz, 2H), 2.39 (s, 3H), 1.34 (t, J = 7.1Hz, 3H).

[0261] Example 10: Preparation of 4-amino-7-(1H-pyrazol-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (10)

[0262]

[0263] Step 1: Synthesis of 4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (10-1)

[0264] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0265] The intermediate Int6 (160.0 mg, 0.32 mmol), NH4Cl (34.0 mg, 0.64 mmol), HATU (183.0 mg, 0.48 mmol) and DIPEA (125.0 mg, 0.97 mmol) were dissolved in DMF (5 mL), and the mixture was stirred at room temperature for 3 h. The mixture was quenched with water, extracted with EA three times (20 mL × 3), the combined organic phase was washed with water (10 mL), washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (MeOH: DCM = 0-12%) to obtain compound 10-1 (81.0 mg) with a yield of 50.6% as a white solid.

[0266] MS (m / z): 497.0 [M+H] + .

[0267] Step 2: Synthesis of 4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (10)

[0268] Compound 10-1 (61.0 mg, 0.12 mmol) was dissolved in TFA (2 mL), Tf2O (0.2 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixed solution was concentrated under reduced pressure, and the concentrate was purified by preparative thin layer chromatography (MeOH: DCM = 5-15%) to obtain the target compound 10 (22.3 mg) with a yield of 61.9% as a white solid.

[0269] MS (m / z): 293.0 [M+H] + .

[0270] 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),8.71(d,J=1.6Hz,1H),7.92(d,J=8.4Hz,1H),7.82(d,J=1 7.1Hz,2H),7.66(s,2H),7.38(d,J=1.5Hz,1H),7.18(s,1H),7.08(s,2H),6.77(d,J=2.2Hz,1H).

[0271] Example 11: Preparation of 4-amino-N-(2-hydroxyethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (11)

[0272]

[0273] Step 1: Synthesis of 4-((4-methoxybenzyl)amino)-N-(2-hydroxyethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (11-1)

[0274] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0275] The intermediate Int6 (80.0 mg, 0.16 mmol), ethanolamine (15.0 mg, 0.24 mmol), HOBt (33.0 mg, 0.24 mmol), EDCI (46.0 mg, 0.24 mmol) and DIPEA (62.0 mg, 0.48 mmol) were dissolved in DMF (5 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water. It was extracted with EA three times (20 mL × 3), and the combined organic phase was washed with water (10 mL), saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-1 (53.0 mg).

[0276] MS (m / z): 541.0 [M+H] + .

[0277] Step 2: Synthesis of 4-amino-N-(2-hydroxyethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (11)

[0278] Compound 11-1 (49.0 mg) was dissolved in TFA (2 mL), Tf2O (0.2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the concentrate was purified by preparative thin layer chromatography (MeOH: DCM = 5-15%) to obtain the target compound 11 (8.9 mg) with a yield of 29.2% as a white solid.

[0279] MS (m / z): 337.0 [M+H] + .

[0280] 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),9.57(s,1H),9.05(d,J=1.6Hz,1H),8.35(q,J=5.3,4.8Hz,1H),8.14(d,J=8.6Hz,1H),8.09(d,J=1.8Hz,1H) ,8.01(d,J=1.4Hz,1H),7.96(dd,J1=8.6Hz,J2=1.8Hz,1H),7.85(d,J=2. 3Hz, 1H), 6.87-6.79 (m, 1H), 3.55 (t, J = 6.1Hz, 2H), 3.37 (q, J = 5.9Hz, 2H).

[0281] Example 12: Preparation of 4-amino-7-(1H-pyrazol-5-yl)-N-(2-(pyridin-2-yl)ethyl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (12)

[0282]

[0283] Step 1: Synthesis of 4-((4-methoxybenzyl)amino)-N-(2-(pyridin-2-yl)ethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (12-1)

[0284] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0285] Referring to the synthesis of compound 11-1 in step 1 of Example 11, only the compound "ethanolamine" was replaced with "2-(2-aminoethyl)pyridine", and the rest of the method was the same, and compound 12-1 (53.0 mg) was prepared from Int6 (60.0 mg, 0.12 mmol).

[0286] MS (m / z): 602.0 [M+H] + .

[0287] Step 2: Synthesis of 4-amino-7-(1H-pyrazol-5-yl)-N-(2-(pyridin-2-yl)ethyl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (12)

[0288] Referring to the synthesis of the target compound 11 in step 2 of Example 11, only "compound 11-1" was replaced by "compound 12-1". The rest of the method was the same to prepare the target compound 12 (10.0 mg) with a yield of 28.6% as a white solid.

[0289] MS (m / z): 398.0 [M+H] + .

[0290] 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.73(s,1H),8.54(d,J=5.2Hz,1H),8.37(t,J=5.7Hz,1H),7.99(d,J=8.5Hz,1H),7.89(s,1H),7.81-7.64(m ,3H),7.50(s,1H),7.32(d,J=7.8Hz,1H),7.24(dd,J1=7.6Hz,J2=5.0Hz,1H),6.78(d,J=2.1Hz,1H),3.65(q,J=6.9Hz,2H),3.03(t,J=7.4Hz,2H).

[0291] Example 13: Preparation of 4-amino-N,N-dimethyl-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (13)

[0292]

[0293] Step 1: Synthesis of 4-((4-methoxybenzyl)amino)-N,N-dimethyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (13-1)

[0294] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0295] Referring to the synthesis of compound 11-1 in step 1 of Example 11, only the compound "ethanolamine" was replaced with "dimethylamine hydrochloride", and the rest of the method was the same to prepare compound 13-1 (51 mg, crude product).

[0296] MS (m / z): 525.0 [M+H] + .

[0297] Step 2: Synthesis of 4-amino-N,N-dimethyl-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (13)

[0298] Referring to the synthesis of the target compound 11 in step 2 of Example 11, only "compound 11-1" was replaced by "compound 13-1". The rest of the method was the same to prepare the target compound 13 (8.3 mg) with a yield of 32.4% as a white solid.

[0299] MS (m / z): 321.0 [M+H] + .

[0300] 1 H NMR (400MHz, DMSO-d6) δ12.95(s,1H),8.62(s,1H),8.23(d,J=8.5Hz,1H),7.89(s,1H),7. 80-7.66(m,2H),7.48(s,1H),6.79(d,J=2.2Hz,1H),3.21(d,J=33.2Hz,3H),3.05(s,3H).

[0301] Example 14: Preparation of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-yl)(3,3-difluoroazetidine-1-yl)methanone (14)

[0302]

[0303] Step 1: Synthesis of (3,3-difluoroazetidin-1-yl)(4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methanone (14-1)

[0304] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0305] Referring to the synthesis of compound 11-1 in step 1 of Example 11, only the compound "ethanolamine" was replaced with "3,3-difluorotrimethyleneimine hydrochloride", and the rest of the method was the same. Compound 14-1 (90.0 mg) was prepared from Int6 (90.0 mg, 0.18 mmol) as a light yellow oil.

[0306] MS (m / z): 573.0 [M+H] + .

[0307] Step 2: Synthesis of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)(3,3-difluoroazetidin-1-yl)methanone (14)

[0308] Referring to the synthesis of the target compound 11 in step 2 of Example 11, only "compound 11-1" was replaced by "compound 14-1". The rest of the method was the same to prepare the target compound 14 (17.0 mg) with a yield of 29.4% as a white solid.

[0309] MS (m / z): 369.0 [M+H] + .

[0310] 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=1.6Hz,1H),8.24(d,J=8.8Hz,1H),8.17(s,1H),7.84(d,J=2.0Hz,1H),7.73(s,1H),7 .66(dd,J1=8.4Hz,J2=2.0Hz,1H),7.45(d,J=1.6Hz,1H),7.12(s,2H),6.79(d,J=2.0Hz,1H),4.98(s,2H),4.52(s,2H).

[0311] Example 15: Preparation of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-yl)(3-hydroxyazetidin-1-yl)methanone (15)

[0312]

[0313] Step 1: Synthesis of (3-hydroxyazetidin-1-yl)(4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methanone (15-1)

[0314] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0315] Referring to the synthesis of compound 10-1 in step 1 of Example 10, only the compound "NH4Cl" was replaced with "3-hydroxyazetidine hydrochloride", and the rest of the method was the same to prepare compound 15-1 (60.0 mg, crude) as a yellow oil.

[0316] MS (m / z): 553.0 [M+H] + .

[0317] Step 2: Synthesis of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)(3-hydroxyazetidin-1-yl)methanone (15)

[0318] Referring to the synthesis of the target compound 10 in step 2 of Example 10, only "compound 10-1" was replaced by "compound 15-1". The rest of the method was the same to prepare the target compound 15 (35.0 mg) with a yield of 92.5% as a white solid.

[0319] MS (m / z): 349.0 [M+H] + .

[0320] 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),8.75(s,1H),8.50(brs,2H),8.41(d,J=8.4Hz,1H),7.99(br s,1H),7.81(d,J=7.8Hz,3H),6.82(d,J=2.4Hz,1H),5.84(d,J=6.0Hz,1H), 4.73-4.66(m,1H),4.63-4.55(m,1H),4.41-4.15(m,2H),3.95-3.65(m,1H).

[0321] Example 16: Preparation of 4-amino-N-(2-(1,1-dioxythiomorpholinyl)ethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (16)

[0322]

[0323] Step 1: Synthesis of N-(2-(1,1-dioxythiomorpholinyl)ethyl)-4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (16-1)

[0324] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0325] Referring to the synthesis of compound 10-1 in step 1 of Example 10, only the compound "NH4Cl" was replaced with "4-(2-aminoethyl)thiomorpholine-1,1-dioxide", and the rest of the method was the same to prepare compound 16-1 (77.4 mg, crude product).

[0326] MS (m / z): 658.0 [M+H] + .

[0327] Step 2: Synthesis of 4-amino-N-(2-(1,1-dioxythiomorpholinyl)ethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (16)

[0328] Referring to the synthesis of the target compound 10 in step 2 of Example 10, only "compound 10-1" was replaced by "compound 16-1". The rest of the method was the same to prepare the target compound 16 (46.3 mg) with a yield of 85.2% as a white solid.

[0329] MS (m / z): 454.0 [M+H] + .

[0330] 1 H NMR (400MHz, DMSO-d6) δ13.0(brs,1H),8.82(s,1H),8.24(d,J=6.7Hz,1H),8.07(d,J=8.6Hz,1H),7.96(s,1H),7.79(s,2H) ,7.66(s,1H),6.80(d,J=2.3Hz,1H),3.41(d,J=6.2Hz,2H),3.11(t,J=5.0Hz,4H),3.06-2.94(m,4H),2.70(t,J=6.7Hz,2H).

[0331] Example 17: Preparation of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-yl)(morpholinyl)methanone (17)

[0332]

[0333] Step 1: Synthesis of (4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)(morpholinyl)methanone (17-1)

[0334] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0335] Referring to the synthesis of compound 11-1 in step 1 of Example 11, only the compound "ethanolamine" was replaced by "morpholine", and the rest of the method was the same to prepare compound 17-1 (50.0 mg, crude product) as a light yellow oil.

[0336] MS (m / z): 567.0 [M+H] + .

[0337] Step 2: Synthesis of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)(morpholinyl)methanone (17)

[0338] Referring to the synthesis of the target compound 11 in step 2 of Example 11, only "compound 11-1" was replaced by "compound 17-1". The rest of the method was the same to prepare the target compound 17 (10.0 mg) with a yield of 31.2% as a white solid.

[0339] MS (m / z): 363.0 [M+H] + .

[0340] 1 H NMR (400MHz, DMSO-d6) δ12.97(brs,1H),8.69(s,1H),8.27(d,J=8.4Hz,1H),7.95( s,1H),7.77(d,J=9.0Hz,2H),7.57(s,1H),6.80(s,1H),3.69(s,4H),3.67(s,4H).

[0341] Example 18: Preparation of 4-amino-N-(2-(morpholinoethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (18)

[0342]

[0343] Step 1: Synthesis of 4-((4-methoxybenzyl)amino)-N-(2-(morpholinoethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (18-1)

[0344] Refer to “Preparation method of common intermediate Int6” to first prepare intermediate Int6.

[0345] Referring to the synthesis of compound 10-1 in step 1 of Example 10, only the compound "NH4Cl" was replaced with "N-(2-aminoethyl)morpholine", and the rest of the method was the same to prepare compound 18-1 (68.6 mg, crude product).

[0346] MS (m / z): 610.0 [M+H] + .

[0347] Step 2: Synthesis of 4-amino-N-(2-(morpholinoethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxamide (18)

[0348] Referring to the synthesis of the target compound 10 in step 2 of Example 10, only "compound 10-1" was replaced by "compound 18-1". The rest of the method was the same to prepare the target compound 18 (30.6 mg) with a yield of 75.5% as a white solid.

[0349] MS (m / z): 398.0 [M+H] + .

[0350] 1 H NMR (400MHz, DMSO-d6) δ12.94(brs,1H),8.68(s,1H),8.13(t,J=5.7Hz,1H),7.97(d,J=8.5Hz,1H),7.84(d,J=1.9Hz,1H),7.81-7.59(m,2H),7. 38(d,J=1.5Hz,1H),7.07(s,2H),6.77(d,J=2.2Hz,1H),3.59(t,J=4.6Hz,4H),3.41(q,J=6.5Hz,2H),2.50-2.47(m,2H),2.44(t,J=4.6Hz,4H).

[0351] Example 19: Preparation of 2-(((4-amino-7-(1H-pyrazol-3-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)amino)ethan-1-ol (19)

[0352]

[0353] Step 1: Synthesis of (4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methanol (19-1)

[0354] Referring to steps 1 to 4 of “the preparation method of common intermediate Int6”, intermediate Int5 was prepared.

[0355] The intermediate Int5 (1.05 g, 2.0 mmol) was dissolved in ultra-dry THF (15 mL), and LiAlH4 (167.2 mg, 4.40 mmol) was added under ice bath, and the reaction mixture was stirred for 3 h. Then, an aqueous Na2CO3 solution was added to quench, and the mixture was extracted with EA three times (20 mL×3). The combined organic phase was washed with water (20 mL), saturated NaCl (20 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 19-1 (940.0 mg) with a yield of 97.3%.

[0356] MS (m / z): 484.0 [M+H] + .

[0357] Step 2: Synthesis of 4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carbaldehyde (19-2)

[0358] Compound 19-1 (940 mg, 1.94 mmol) and active MnO2 (1.70 g, 19.41 mmol) were dissolved in DCM (20 mL) and stirred at room temperature for 16 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain compound 19-2 (750.0 mg) with a yield of 80.1%.

[0359] MS (m / z): 482.0 [M+H] + .

[0360] Step 3: Synthesis of 2-(((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)amino)ethan-1-ol (19-3)

[0361] Compound 19-2 (50.0 mg, 0.10 mmol) was dissolved in THF (3 mL), 2-aminoethyl-1-ol (12.0 mg, 0.20 mmol) and NaBH(OAc)3 (42.0 mg, 0.2 mmol) were added at 0°C, and the reaction was stirred at 30°C for 16 hours. The mixture was quenched with water (15 mL), extracted with EA (10 mL×3), and the combined organic phase was washed with water (20 mL×2) and then dried and concentrated to obtain compound 19-3 (59.1 mg, crude product) as a light yellow liquid.

[0362] MS (m / z): 527.0 [M+H] + .

[0363] Step 4: Synthesis of 2-(((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)amino)ethan-1-ol (19)

[0364] Compound 19-3 (55 mg) was dissolved in TFA (5 mL), Tf2O (0.5 mL) was added, and the reaction was stirred at 30° C. for 3 hours. The mixture was dried and concentrated, and the residue was separated by preparative liquid phase separation (eluent ACN: 0.1% formic acid aqueous solution = 70-80%) to obtain the target compound 19 (16.2 mg) with a yield of 50.3% as a light yellow solid.

[0365] MS (m / z): 323.0 [M+H] + .

[0366] 1 H NMR (400MHz, DMSO-d6) δ13.08(s,1H),10.12(s,1H),9.67(s,1H),8.86(s,1H),8.74(s,1H),8.20(d,J=8.8Hz,1H),8.11(s,1H),7.9 5(dd,J1=8.4Hz,J2=2.0Hz,1H),7.86(s,2H),6.82(d,J=2.4Hz,1H),5.47(s,1H),4.54(d,J=18.4Hz,2H),3.89(s,2H),3.17(s,2H).

[0367] Example 20: Preparation of 1-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)amino)-2-methylpropan-2-ol (20)

[0368]

[0369] Step 1: Synthesis of 1-(((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)amino)-2-methylpropan-2-ol (20-1)

[0370] Referring to the synthesis of compound 19-3 in step 3 of Example 19, only the compound "2-aminoethane-1-ol" was replaced with "1-amino-2-methylpropan-2-ol", and the rest of the method was the same to prepare compound 20-1 (58.5 mg, crude product).

[0371] MS (m / z): 555.0 [M+H] + .

[0372] Step 2: Synthesis of 1-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)amino)-2-methylpropan-2-ol (20)

[0373] Referring to the synthesis of the target compound 19 in step 4 of Example 19, only "compound 19-3" was replaced by "compound 20-1". The rest of the method was the same to prepare the target compound 20 (20 mg) with a yield of 57.1% as a white solid.

[0374] MS (m / z): 351.0 [M+H] + .

[0375] 1 H NMR (400MHz, DMSO-d6) δ12.98(s,1H),8.65(s,2H),8.47(s,1H),8.08(d,J=8.4Hz,1H),7.96(s,1H), 7.79(s,2H),7.41(s,1H),6.79(d,J=2.2Hz,1H),5.18(s,1H),4.24(s,2H),2.89(s,2H),1.20(s,6H).

[0376] Example 21: Preparation of 2-((dimethylamino)methyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (21)

[0377]

[0378] Step 1: Synthesis of 2-((dimethylamino)methyl)-N-(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinolin-4-amine (21-1)

[0379] Referring to the synthesis of compound 19-3 in step 3 of Example 19, only the compound "2-aminoethane-1-ol" was replaced with "dimethylamine hydrochloride", and the rest of the method was the same to prepare compound 21-1 (61.7 mg, crude product) as a light yellow liquid.

[0380] MS (m / z): 511.0 [M+H] + .

[0381] Step 2: Synthesis of 2-((dimethylamino)methyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (21)

[0382] Referring to the synthesis of target compound 19 in step 4 of Example 19, only "compound 19-3" was replaced by "compound 21-1". The rest of the method was the same to prepare target compound 21 (23.9 mg) with a yield of 71.0% as a light yellow solid.

[0383] MS (m / z): 307.0 [M+H] + .

[0384] 1 H NMR(400MHz,DMSO-d6)δ13.0(s,1H),8.53(s,1H),8.15(s,1H),8.0(s,1H),7. 88-7.74(m,2H),7.49(s,1H),6.80(d,J=2.4Hz,1H),4.37(s,2H),2.80(s,6H).

[0385] Example 22: N 1 -((4-amino)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)-N 2 ,N 2 - Preparation of dimethylethane-1,2-diamine (22)

[0386]

[0387] Step 1: N 1 -((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)-N 2 ,N 2 -Synthesis of dimethylethane-1,2-diamine (22-1)

[0388] Referring to the synthesis of compound 19-3 in step 3 of Example 19, only the compound "2-aminoethane-1-ol" was replaced with "N 1 ,N 1 -dimethylethane-1,2-diamine", and the rest of the method was the same to prepare compound 22-1 (59.3 mg, crude product).

[0389] MS (m / z): 554.0 [M+H] + .

[0390] Step 2: N 1 -((4-amino)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)-N 2 ,N 2-Synthesis of dimethylethane-1,2-diamine (22)

[0391] Referring to the synthesis of target compound 19 in step 4 of Example 19, only "compound 19-3" was replaced by "compound 22-1". The rest of the method was the same to prepare target compound 22 (28.0 mg) with a yield of 77.1% as a white solid.

[0392] MS (m / z): 350.0 [M+H] + .

[0393] 1 H NMR (400MHz, DMSO-d6) δ13.04(s,1H),9.48(s,1H),9.02(s,2H),8.60(s,1H),8.20(d,J=8.6Hz,1H),8.11(s,1H) ,7.95(d,J=8.6Hz,1H),7.86(s,1H),7.70(s,1H),6.83(d,J=2.3Hz,1H),4.33(s,2H),3.36(s,4H),2.88(s,6H).

[0394] Example 23: Preparation of 2-(morpholinomethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-4-amine (23)

[0395]

[0396] Step 1: Synthesis of N-(4-methoxybenzyl)-2-(morpholinomethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (23-1)

[0397] Referring to the synthesis of compound 19-3 in step 3 of Example 19, only the compound "2-aminoethane-1-ol" was replaced with "morpholine", and the rest of the method was the same to prepare compound 23-1 (28.9 mg, crude product).

[0398] MS (m / z): 553.0 [M+H] + .

[0399] Step 2: Synthesis of 2-(morpholinomethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (23)

[0400] Referring to the synthesis of target compound 19 in step 4 of Example 19, only "compound 19-3" was replaced by "compound 23-1". The rest of the method was the same to prepare target compound 23 (10 mg) with a yield of 57.1% as a white solid.

[0401] MS (m / z): 349.0 [M+H] + .

[0402] 1 H NMR(400MHz,DMSO-d6)δ13.03(s,1H),8.54(s,1H),8.17(s,1H),8.02(s,1H),7.83(s,2H) ,7.55(s,1H),6.81(d,J=2.3Hz,1H),4.44(s,2H),3.99(s,2H),3.64(s,4H),3.15(s,2H).

[0403] Example 24: Preparation of 2-(((Morpholinethyl)amino)methyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (24)

[0404]

[0405] Step 1: Synthesis of N-(4-methoxybenzyl)-2-(((morpholinethyl)amino)methyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (24-1)

[0406] Referring to the synthesis of compound 19-3 in step 3 of Example 19, only the compound "2-aminoethane-1-ol" was replaced with "2-morpholinoethylamine", and the rest of the method was the same to prepare compound 24-1 (32.4 mg, crude product).

[0407] MS (m / z): 553.0 [M+H] + .

[0408] Step 2: Synthesis of 2-(((morpholinoethyl)amino)methyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (24)

[0409] Referring to the synthesis of target compound 19 in step 4 of Example 19, only "compound 19-3" was replaced by "compound 24-1". The rest of the method was the same to prepare target compound 24 (8.0 mg) with a yield of 40.9% as a white solid.

[0410] MS (m / z): 392.0 [M+H] + .

[0411] 1H NMR (400MHz, DMSO-d6) δ13.03(s,1H),9.66(s,1H),8.94(d,J=75.2Hz,2H),8.62(s,1H),8.20(d,J=8.7Hz,1H),8.13(d,J=10.1Hz,1H),7. 96(dd,J1=8.6Hz,J2=1.8Hz,1H),7.86(d,J=2.2Hz,1H),7.72(s,1H),6.83(d,J=2.3Hz,1H),4.33(s,2H),4.01(s,2H),3.73-3.03(m,10H).

[0412] Example 25: Preparation of 2-((3,3-difluoroazetidin-1-yl)methyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (25)

[0413]

[0414] Step 1: Synthesis of 2-((3,3-difluoroazetidin-1-yl)methyl)-N-(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (25-1)

[0415] Referring to the synthesis of compound 19-3 in step 3 of Example 19, only the compound "2-aminoethane-1-ol" was replaced with "3,3-difluoroazetidine hydrochloride", and the rest of the method was the same to prepare compound 25-1 (58.8 mg, crude product).

[0416] MS (m / z): 559.0 [M+H] + .

[0417] Step 2: Synthesis of 2-((3,3-difluoroazetidin-1-yl)methyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (25)

[0418] Referring to the synthesis of target compound 19 in step 4 of Example 19, only "compound 19-3" was replaced by "compound 25-1". The rest of the method was the same to prepare target compound 25 (20.0 mg) with a yield of 56.8% as a white solid.

[0419] MS (m / z): 355.0 [M+H] + .

[0420] 1H NMR (400MHz, Methanol-d4) δ8.39(s,1H),8.14(d,J=8.6Hz,1H),7.95(d,J=1.8Hz,1H),7.92(dd,J1=8.6Hz,J 2=1.8Hz,1H),7.77(d,J=2.4Hz,1H),7.57(s,1H),6.79(d,J=2.4Hz,1H),3.98(s,2H),3.83(t,J=12.0Hz,4H).

[0421] Example 26: Preparation of 7-(1H-pyrazol-5-yl)-2-(((2-(pyridin-2-yl)ethyl)amino)methyl)pyrrolo[1,2-a]quinoxalin-4-amine (26)

[0422]

[0423] Step 1: Synthesis of N-(4-methoxybenzyl)-2-(((2-(pyridin-2-yl)ethyl)amino)methyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (26-1)

[0424] Referring to the synthesis of compound 19-3 in step 3 of Example 19, only the compound "2-aminoethane-1-ol" was replaced with "2-(pyridin-2-yl)ethylamine", and the rest of the method was the same to prepare compound 26-1 (30.8 mg, crude product).

[0425] MS (m / z): 553.0 [M+H] + .

[0426] Step 2: Synthesis of 7-(1H-pyrazol-5-yl)-2-(((2-(pyridin-2-yl)ethyl)amino)methyl)pyrrolo[1,2-a]quinoxalin-4-amine (26)

[0427] Referring to the synthesis of target compound 19 in step 4 of Example 19, only "compound 19-3" was replaced by "compound 26-1". The rest of the method was the same to prepare target compound 26 (9.2 mg) with a yield of 48.0% as a white solid.

[0428] MS (m / z): 384.0 [M+H] + .

[0429] 1H NMR (400MHz, DMSO-d6) δ13.08(s,1H),9.02(s,2H),8.64(s,1H),8.55(d,J=5.0Hz,1H),8.20(s,1H), 8.09(s,1H),7.93(s,1H),7.86(s,1H),7.83-7.76(m,1H),7.73(s,1H),7.37(d,J=7.7Hz,1H),7.34-

[0430] 7.30(m,1H),6.82(s,1H),4.35(s,2H),3.16(t,J=7.5Hz,2H).

[0431] Example 27: Preparation of 1-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)azetidin-3-ol (27)

[0432]

[0433] Step 1: Synthesis of 1-((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)azetidin-3-ol (27-1)

[0434] Referring to the synthesis of compound 19-3 in step 3 of Example 19, only the compound "2-aminoethane-1-ol" was replaced with "azetidine-3-ol hydrochloride", and the rest of the method was the same to prepare compound 27-1 (56.6 mg, crude product).

[0435] MS (m / z): 539.0 [M+H] + .

[0436] Step 2: Synthesis of 1-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)azetidin-3-ol (27)

[0437] Referring to the synthesis of target compound 19 in step 4 of Example 19, only "compound 19-3" was replaced by "compound 27-1". The rest of the method was the same to prepare target compound 27 (15.0 mg) with a yield of 44.9% as a white solid.

[0438] MS (m / z): 335.0 [M+H] + .

[0439] 1H NMR (400MHz, Methanol-d4) δ8.56(s,1H),8.17(d,J=8.7Hz,1H),7.99(d,J=1.7Hz,1H),7.96(dd,J1=8.6Hz,J2=1.8Hz,1H),7.78(d,J=2.4Hz,1H), 7.68 (s, 1H), 6.81 (d, J = 2.4Hz, 1H), 4.70 (p, J = 6.0Hz, 1H), 4.57 (s, 2H), 4.44 (dd, J1 = 11.3Hz, J2 = 6.7Hz, 2H), 4.06 (dd, J1 = 11.5Hz, J2 = 5.3Hz, 2H).

[0440] Example 28: Preparation of 4-amino-7-(1H-pyrazol-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylic acid (28)

[0441]

[0442] 4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylic acid (41.6 mg, 0.084 mmol) was dissolved in TFA (1.0 mL), Tf2O (0.1 mL) was added dropwise, and the mixture was reacted at room temperature for 16 hours. The reaction was completed by MS monitoring, and the reaction solution was concentrated under reduced pressure and purified by preparative liquid phase (eluent ACN: 0.1% formic acid aqueous solution = 80-90%) to obtain compound 28 (15.8 mg) with a yield of 64.4% as a white solid.

[0443] MS (m / z): 294.0 [M+H] + .

[0444] 1 H NMR (400MHz, DMSO-d6) δ12.82(s,2H),8.80(s,1H),8.26(d,J=8.4Hz,1H),7.87(d,J=2. 0Hz,1H),7.74(s,1H),7.67(d,J=8.4Hz,1H),7.63-7.22(m,3H),6.79(d,J=2.0Hz,1H).

[0445] Example 29: Preparation of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methanol (29)

[0446]

[0447] Step 1: Synthesis of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methanol (29)

[0448] Referring to the preparation method of compound 19-1 in step 1 of Example 19, compound 19-1 was prepared.

[0449] Compound 19-1 (41.6 mg, 0.086 mmol) was dissolved in TFA (1.0 mL) and reacted for 24 hours, then Tf2O (0.1 mL) was added dropwise and reacted at room temperature for 1 hour. The reaction was complete as monitored by MS, and the reaction solution was concentrated under reduced pressure and purified by preparative liquid phase (eluent ACN: 10 mmol / L ammonium bicarbonate aqueous solution = 80-90%) to obtain the target compound 29 (6.60 mg) with a yield of 27.8% as a yellow solid.

[0450] MS (m / z): 280.0 [M+H] + .

[0451] 1 H NMR(400MHz,DMSO-d6)δ12.84(s,1H),8.10(s,1H),7.99(s,1H),7.85-7.48(m,3H), 7.0(s,1H),6.89(s,2H),6.74(s,1H),5.06(t,J=5.2Hz,1H),4.58(d,J=5.2Hz,2H).

[0452] Example 30: Preparation of 2-(ethoxymethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-4-amine (30)

[0453]

[0454] Step 1: Synthesis of ethyl 4-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (30-1)

[0455] Referring to steps 1 to 4 of “the preparation method of common intermediate Int6”, intermediate Int5 was prepared.

[0456] The intermediate Int5 (1.70 g, 3.23 mmol), Boc2O (1.40 g, 6.47 mmol), and DMAP (118.54 mg, 0.97 mmol) were dissolved in ACN (30.0 mL) and reacted at 30° C. for 48 hours. MS monitored that the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA: petroleum ether = 0-50%) to obtain compound 30-1 (1.60 g) with a yield of 79.2% as a yellow solid.

[0457] MS (m / z): 626.0 [M+H] + .

[0458] Step 2: Synthesis of tert-butyl (2-(hydroxymethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-yl)(4-methoxybenzyl)carbamate (30-2)

[0459] At 0°C, compound 30-1 (850.0 mg, 1.36 mmol) was dissolved in ultra-dry THF (4.0 mL), nitrogen was protected, and then LiAlH4 (103.11 mg, 2.72 mmol) was slowly added. After the addition, the reaction was continued for 20 minutes. MS monitored that the raw material reaction was complete. Saturated Na2CO3 was added for extraction and quenching, and the reaction solution was dissolved in EA (20.0 mL), washed with water (20.0 mL) and saturated NaCl (20.0 mL) in turn, and the organic phase was dried over anhydrous Na2SO4 and concentrated to obtain compound 30-2 (600.0 mg) with a yield of 75.7% as a yellow solid.

[0460] MS (m / z): 584.0 [M+H] + .

[0461] Step 3: Synthesis of tert-butyl (2-(ethoxymethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-yl)(4-methoxybenzyl)carbamate (30-3)

[0462] At 0°C, compound 30-2 (200 mg, 0.343 mmol) and NaH (27 mg, 60% stored in kerosene) were added to ultra-dry THF (4.0 mL), followed by EtI (106.0 mg, 0.685 mmol). The reaction was slowly warmed to room temperature and continued to stir for 24 hours. MS monitored that the raw material reaction was complete, and water was added to extract and quench. The reaction solution was dissolved in EA (20.0 mL), washed with water (20.0 mL) and saturated NaCl (20.0 mL) in turn, and the organic phase was dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (EA: petroleum ether = 0-30%) to obtain compound 30-3 (60.0 mg) with a yield of 28.7% as a yellow oily liquid.

[0463] MS (m / z): 612.0 [M+H] + .

[0464] Step 4: Synthesis of 2-(ethoxymethyl)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (30)

[0465] Compound 30-3 was dissolved in TFA (1.0 mL), Tf2O (0.1 mL) was added, and the mixture was reacted at room temperature for 3 days. MS monitored the reaction of the raw material to be complete. The reaction solution was concentrated under reduced pressure and purified by preparative liquid phase (eluent ACN: 0.1% formic acid aqueous solution = 80-90%) to obtain the target compound 30 (12.0 mg) with a yield of 39.8% as a white solid.

[0466] MS (m / z): 308.0 [M+H] + .

[0467] 1 H NMR(600MHz,DMSO-d6)δ13.01(s,1H),8.45(s,1H),8.19(d,J=8.4Hz,1H),7.98(s,1H),7.80(s,2 H),7.45(s,1H),6.79(d,J=2.4Hz,1H),4.55(s,2H),3.54(q,J=7.2Hz,2H),1.18(t,J=7.2Hz,3H).

[0468] Example 31: Preparation of (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methylpyridin-2-ylcarbamate (31)

[0469]

[0470] Step 1: Synthesis of tert-butyl 4-methoxybenzyl-(2-(((pyridin-2-ylcarbamoyl)oxy)methyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-yl)carbamate (31-1)

[0471] Referring to step 1 and step 2 of Example 30, compound 30-2 was prepared.

[0472] Compound 30-2 (150.0 mg, 0.257 mmol), DPPA (282.89 mg, 1.03 mmol), TEA (156.03 mg, 1.03 mmol) were dissolved in toluene (10.0 mL), heated to 100°C, 2-pyridine carboxylate (126.6 mg, 1.03 mmol) was added, and the mixture was reacted at 100°C for 1.5 hours. The reaction was complete as monitored by MS, and the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA: petroleum ether = 0-50%) to obtain compound 31-1 (90.0 mg) with a yield of 49.8%, as a yellow oily liquid.

[0473] MS (m / z): 704.0 [M+H] + .

[0474] Step 2: Synthesis of methyl pyridin-2-ylcarbamate (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)

[0475] Compound 31-1 (90.0 mg, 0.128 mmol) was dissolved in TFA (1.0 mL), and Tf2O (0.1 mL) was added and reacted at room temperature for 5 hours. MS monitored that the raw material reaction was complete. The reaction solution was concentrated under reduced pressure and purified by preparative liquid phase (eluent ACN: 0.1% formic acid aqueous solution = 90-100%) to obtain the target compound 31 (8.60 mg) with a yield of 16.9% as a yellow solid.

[0476] MS (m / z): 400.0 [M+H] + .

[0477] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),10.19(s,1H),8.34(s,1H),8.26(d,J=4.4Hz,1H),8.04( d,J=8.4Hz,1H),7.89-7.75(m,4H),7.64(s,1H),7.16-7.03(m,4H),6.76(s,1H),5.26(s,2H).

[0478] Example 32: Preparation of 2-(aminomethyl)-7-(1H-pyrrol-5-yl)pyrrolo[1,2-a]quinoxaline-4-amine (32)

[0479]

[0480] Step 1: Synthesis of 2-((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)isoindoline-1,3-dione (32-1)

[0481] Referring to step 1 in Example 19, compound 19-1 was prepared.

[0482] Compound 19-1 (670.0 mg, 1.4 mmol) was dissolved in THF (5 mL), PPh3 (1.70 g, 6.5 mmol), DIAD (1.31 g, 6.5 mmol) and phthalimide (380.0 mg, 2.6 mmol) were added, and the reaction was stirred at 20°C for 16 hours. The mixture was dried and concentrated at low temperature, and the residue was purified by column chromatography (100% EA) to obtain compound 32-1 (360.0 mg) with a yield of 42.4% as a light yellow solid.

[0483] MS (m / z): 613.0 [M+H] + .

[0484] Step 2: Synthesis of 2-(aminomethyl)-N-(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (32-2)

[0485] Compound 32-1 (340.0 mg, 0.6 mmol) was added to hydrazine hydrate (3 mL), and the reaction was stirred at 80°C for 16 hours. The mixture was dried and concentrated, quenched with water (15 mL), extracted with EA (10 mL × 3), the organic phases were combined, washed with water (20 mL × 2), dried and concentrated to obtain compound 32-2 (130.0 mg), with a yield of 48.5%, as a light yellow liquid.

[0486] MS (m / z): 483.0 [M+H] + .

[0487] Step 3: Synthesis of 2-(aminomethyl)-7-(1H-pyrrol-5-yl)pyrrolo[1,2-a]quinoxalin-4-amine (32)

[0488] Compound 32-2 (13.0 mg, 0.03 mmol) was dissolved in TFA (3 mL), Tf2O (0.3 mL) was added, and the reaction was stirred at 20°C for 3 hours. The mixture was dried and concentrated at low temperature, and the residue was separated by preparative liquid phase (eluent ACN: 0.1% formic acid aqueous solution = 70-80%) to obtain the target compound 32 (3.3 mg) with a yield of 39.5% as a light yellow solid.

[0489] MS (m / z): 279.0 [M+H] + .

[0490] 1 H NMR(400MHz,DMSO-d6)δ13.04(s,1H),8.57(s,1H),8.07(s,1H),7.91(s,1H),7.84(s,1H),7.67 (s,1H),7.33-7.24(m,1H),7.18(s,1H),6.80(d,J=2.3Hz,1H),6.64(s,1H),4.17-4.10(m,2H).

[0491] Example 33: Preparation of N-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)acetamide (33)

[0492]

[0493] Step 1: Synthesis of N-((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)acetamide (33-1)

[0494] Referring to steps 1 and 2 in Example 32, compound 32-2 was prepared.

[0495] Compound 32-2 (30.0 mg, 0.10 mmol) was dissolved in DCM (5 mL), TEA (9.0 mg, 0.10 mmol) was added, and acetyl chloride (7.0 mg, 0.10 mmol) was added under ice bath. The reaction mixture was stirred for 2 h. The mixture was quenched with water, extracted with EA (20 mL×3), the organic phases were combined and washed with water (10 mL), saturated NaCl (10 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 33-1 (32.0 mg).

[0496] MS (m / z): 525.0 [M+H] + .

[0497] Step 2: Synthesis of N-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)acetamide (33)

[0498] Compound 33-1 (30.0 mg, 0.06 mmol) was dissolved in TFA (2 mL), Tf2O (0.2 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by preparative thin layer chromatography (MeOH: DCM = 5-15%) to obtain the target compound 33 (8.4 mg) with a yield of 45.9% as a white solid.

[0499] MS (m / z): 321.0 [M+H] + .

[0500] 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.29(t,J=5.7Hz,1H),8.10(s,1H),7.99(d,J=8.5Hz,1H),7.81(s,1H),7.72 (s,1H),7.60(d,J=8.4Hz,1H),6.96(s,1H),6.93(s,2H),6.74(d,J=2.0Hz,1H),4.32(d,J=5.6Hz,2H),1.88(s,3H).

[0501] Example 34: Preparation of ethyl (4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)carbamate (34)

[0502]

[0503] Step 1: Synthesis of ethyl (4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)carbamate (34-1)

[0504] Referring to steps 1 and 2 in Example 32, compound 32-2 was prepared.

[0505] Compound 32-2 (35 mg, 0.10 mmol), diethyl pyrocarbonate (15 mg, 0.10 mmol) and TEA (13.0 mg, 0.13 mmol) were dissolved in DCM (5 mL), and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water, extracted with DCM (20 mL×3), and the organic phases were combined and washed with water (10 mL), saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 34-1 (32.0 mg, crude product).

[0506] MS (m / z): 555.0 [M+H] + .

[0507] Step 2: Synthesis of ethyl ((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)carbamate (34)

[0508] Compound 34-1 (32.0 mg) was dissolved in TFA (2 mL), Tf2O (0.2 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixed solution was concentrated under reduced pressure, and the concentrate was purified by preparative thin layer chromatography (MeOH: DCM = 5-15%) to obtain the target compound 34 (8.8 mg) with a yield of 43.6% as a white solid.

[0509] MS (m / z): 351.0 [M+H] + .

[0510] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.24(s,1H),8.08(d,J=8.5Hz,1H),7.91(s,1H),7.75(s,1H),7.72(d,J=8.4Hz,1H),7 .62(t,J=5.9Hz,1H),7.24(s,1H),6.76(d,J=2.2Hz,1H),4.26(d,J=6.0Hz,2H),4.03(q,J=7.1Hz,2H),1.19(t,J=7.1Hz,3H).

[0511] Example 35: Preparation of N-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)methanesulfonamide (35)

[0512]

[0513] Step 1: Synthesis of N-((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)methanesulfonamide (35-1)

[0514] Referring to steps 1 and 2 in Example 32, compound 32-2 was prepared.

[0515] Compound 32-2 (35.0 mg, 0.10 mmol), Ms2O (25.0 mg, 0.15 mmol) and pyridine (29.0 mg, 0.36 mmol) were dissolved in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with DCM (20 mL×3), and the organic phases were combined and washed with water (10 mL), saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 35-1 (93.0 mg, crude product).

[0516] MS (m / z): 561.0 [M+H] + .

[0517] Step 2: Synthesis of N-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)methanesulfonamide (35)

[0518] Compound 35-1 (93.0 mg) was dissolved in TFA (2 mL), Tf2O (0.2 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixed solution was concentrated under reduced pressure. The concentrate was purified by preparative thin layer chromatography (MeOH: DCM = 5-15%) to obtain the target compound 35 (31.8 mg) with a yield of 54.1% as a white solid.

[0519] MS (m / z): 357.0 [M+H] + .

[0520] 1 H NMR (400MHz, DMSO-d6) δ12.89(brs,1H),8.21(s,1H),8.03(d,J=8.5Hz,1H),7.84(s,1H),7.76(brs,1H),7.64(s, 1H), 7.50 (t, J = 6.1Hz, 1H), 7.18 (brs, 2H), 7.11 (s, 1H), 6.75 (d, J = 2.2Hz, 1H), 4.24 (d, J = 6.0Hz, 2H), 2.93 (s, 3H).

[0521] Example 36: Preparation of N-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)picolinamide (36)

[0522]

[0523] Step 1: Synthesis of N-((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)picolinamide (36-1)

[0524] Referring to step 1 to step 2 in Example 32, compound 32-2 was prepared.

[0525] Compound 32-2 (55.0 mg, 0.11 mmol), 2-picolinic acid (28.0 mg, 0.23 mmol), HATU (65.0 mg, 0.17 mmol) and DIPEA (44.0 mg, 0.32 mmol) were dissolved in DMF (2 mL), and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water, extracted with EA (20 mL×3), and the combined organic phase was washed with water (10 mL), washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 36-1 (61.0 mg, crude product).

[0526] MS (m / z): 588.0 [M+H] + .

[0527] Step 2: Synthesis of N-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)picolinamide (36)

[0528] Compound 36-1 (61.0 mg, 0.10 mmol) was dissolved in TFA (2 mL), Tf2O (0.2 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixed solution was concentrated under reduced pressure. The concentrate was purified by preparative thin layer chromatography (MeOH: DCM = 5-15%) to obtain the target compound 36 (23.1 mg) with a yield of 60.3% as a white solid.

[0529] MS (m / z): 384.0 [M+H] + .

[0530] 1H NMR (400MHz, DMSO-d6) δ12.98 (s, 1H), 9.33 (s, 1H), 8.67 (dt, J = 4.7, 1.2Hz, 1H), 8.3 8(s,1H),8.14(d,J=8.6Hz,1H),8.10(dt,J=7.9,1.2Hz,1H),8.03(td,J=7.7,1.8Hz ,1H),7.98(s,1H),7.83(s,1H),7.79(s,1H),7.63(ddd,J1=7.5Hz,J2=4.8Hz,J3=1. 4Hz,1H),7.42(s,1H),7.23(s,1H),7.10(s,1H),6.78(s,1H),4.60(d,J=6.2Hz,2H).

[0531] Example 37: Preparation of 3-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)oxazolidin-2-one (37)

[0532]

[0533] Step 1: Synthesis of 3-((4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)oxazolin-2-one (37-1)

[0534] Referring to the synthesis of compound 19-1 in step 1 of Example 19, compound 19-1 was prepared.

[0535] Compound 19-1 (100 mg, 0.19 mmol) was dissolved in ultra-dry DCM (5 mL), TEA (115 mg, 1.14 mmol) was added, and the mixture was stirred at room temperature for 15 minutes, triphosgene (28.0 mg, 0.10 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with EA (20 mL×3), and the combined organic phase was washed with water (10 mL), washed with saturated NaCl (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain compound 37-1 (43.0 mg, crude product).

[0536] MS (m / z): 553.0 [M+H] + .

[0537] Step 2: Synthesis of 3-((4-amino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxalin-2-yl)methyl)oxazolidin-2-one (37)

[0538] Compound 37-1 (43.0 mg) was dissolved in TFA (2 mL), Tf2O (0.2 mL) was added, and the mixture was stirred at room temperature for 2 h. The mixed solution was concentrated under reduced pressure. The concentrate was purified by preparative thin layer chromatography (MeOH: DCM = 5-15%) to obtain the target compound 37 (19.3 mg) with a yield of 55.4% as a white solid.

[0539] MS (m / z): 349.0 [M+H] + .

[0540] 1 H NMR(600MHz,DMSO-d6)δ12.86(s,1H),8.21(s,1H),8.03(d,J=8.6Hz,1H),7.82(s,2H),7.62(s,1H),7 .01(s,1H),6.96(s,2H),6.76(d,J=2.2Hz,1H),4.44(s,2H),4.35-4.22(m,2H),3.52(t,J=8.0Hz,2H).

[0541] Example 38: Preparation of ethyl 4-amino-7-(1H-pyrazol-1-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (38)

[0542]

[0543] Step 1: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-(1H-pyrazol-1-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (38-1)

[0544] Referring to the preparation method of intermediate Int4, intermediate Int4 was prepared.

[0545] At 20°C, the intermediate Int4 (100.0 mg, 0.22 mmol) was dissolved in DMSO (2 mL), and pyrazole (30.0 mg, 0.44 mmol), sodium carbonate (93.0 mg, 0.88 mmol), N,N'-dimethylethylenediamine (58.0 mg, 0.66 mmol), and CuI (84.0 mg, 0.44 mmol) were added in sequence. After nitrogen replacement three times, the reaction solution was heated to 120°C and stirred for 24 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, diluted with water (10 mL), extracted with EA (20 mL×3), the combined organic phase was washed with water (20 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography (EA: petroleum ether = 0-20%), compound 38-1 (86.0 mg) was obtained with a yield of 88.7% as a white solid.

[0546] MS (m / z): 442.0 [M+H] + .

[0547] Step 2: Synthesis of ethyl 4-amino-7-(1H-pyrazol-1-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (38)

[0548] At 20°C, compound 38-1 (86.0 mg, 0.19 mmol) was dissolved in TFA (2 mL), Tf2O (0.20 mL, 1.19 mmol) was added, and the mixture was stirred at 20°C for 6 hours. The reaction solution was concentrated to dryness and purified by preparative liquid phase (eluent ACN: 0.1% formic acid aqueous solution = 80-90%) to obtain the target compound 38 (35.8 mg) with a yield of 57.7% as a white solid.

[0549] MS (m / z): 322.0 [M+H] + .

[0550] 1 H NMR (400MHz, DMSO-d6) δ8.90(d,J=1.6Hz,1H),8.61(d,J=2.4Hz,1H),8.40(d,J=9.2Hz,1H),7.89(d,J=2.4Hz,1H),7.78(d,J=1 .6Hz, 1H), 7.73 (dd, J1 = 8.8Hz, J2 = 2.4Hz, 1H), 7.64 (s, 1H), 6.57 (t, J = 2.0Hz, 1H), 4.33 (q, J = 7.2Hz, 2H), 1.35 (t, J = 7.2Hz, 3H).

[0551] Example 39: Preparation of 4-(1-(hex-1-yn-1-yl)-7-phenylimidazo[1,2-a]quinoxalin-4-yl)morpholine (39)

[0552]

[0553] Step 1: Synthesis of 5H,10H-diimidazole[1,2-a:1',2'-d]pyrazine-5,10-dione (I-20)

[0554] 1H-imidazole-2-carboxylic acid (3.0 g, 26.76 mmol) was dissolved in SOCl2 (200 mL) and stirred at 80°C for 24 hours under nitrogen protection. The reaction solution was cooled and filtered, and the filter cake was washed with DCM (20 mL × 2) and dried to obtain compound I-20 (2.7 g) as a yellow solid.

[0555] Step 2: Synthesis of N-(4-fluoro-[1,1'-biphenyl]-3-yl)-1H-imidazole-2-carboxamide (39-1)

[0556] Under nitrogen protection, 4-fluoro-[1,1'-biphenyl]-3-amine (3.0 g, 15.96 mmol) was added to a three-necked flask, and then NaHMDS THF solution (1M, 23.92 mL, 23.92 mmol) was added to the reaction flask under an ice-salt bath. After stirring for 1 hour, compound I-20 (2.0 g, 10.64 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and 10 mL of water was added, extracted with EA (10 mL × 3), the organic phases were combined, dried, and then spin-dried. The residue was separated by column chromatography (EA: petroleum ether = 0-20%) to obtain compound 39-1 (900.0 mg), with a yield of 30.0%, as a gray-brown solid.

[0557] MS (m / z): 189.0 [M+H] + .

[0558] Step 3: Synthesis of 7-phenylimidazo[1,2-a]quinoxalin-4(5H)-one (39-2)

[0559] Compound 39-1 (700.0 mg, 2.49 mmol) was dissolved in DMAc (15 mL), and NaH (119.4 mg, 4.98 mmol) was added, and the reaction was carried out at 120°C for 48 hours under nitrogen protection. After the reaction solution was cooled, it was dropped into water (20 mL), the product was precipitated and filtered, and the filter cake was washed with water (20 mL × 2) and dried to obtain compound 39-2 (700.0 mg, crude product) as a gray-brown solid.

[0560] MS (m / z): 262.0 [M+H] + .

[0561] Step 4: Synthesis of 4-chloro-7-phenylimidazo[1,2-a]quinoxaline (39-3)

[0562] Compound 39-2 (640.0 mg) was dissolved in POCl3 (8 mL), and the reaction solution was stirred at 120°C for 3 hours. After the reaction solution was cooled, it was concentrated in vacuo, and the residue was dissolved in DCM (2 mL) and added dropwise to water (10 mL), extracted with DCM (10 mL×3), the organic phases were combined, dried and spin-dried, and the residue was separated by column chromatography (EA: petroleum ether = 0-45%) to obtain compound 39-3 (330.0 mg) with a yield of 36.7%, as a white solid.

[0563] MS (m / z): 280.0 [M+H] + .

[0564] Step 5: Synthesis of 4-(7-phenylimidazo[1,2-a]quinoxalin-4-yl)morpholine (39-4)

[0565] Compound 39-3 (330.0 mg, 1.18 mmol) was dissolved in DMF (5 mL), morpholine (411.0 mg, 4.72 mmol) was added, and the reaction solution was stirred at 27°C for 4 hours. Water (10 mL) was added to the reaction solution, and it was extracted with EA (10 mL×3). The organic phases were combined, washed with water (10 mL×2), dried and concentrated to obtain compound 39-4 (480.0 mg, crude product) as a yellow solid.

[0566] MS (m / z): 331.0 [M+H] + .

[0567] Step 6: Synthesis of 4-(1-bromo-7-phenylimidazo[1,2-a]quinoxalin-4-yl)morpholine (39-5)

[0568] Compound 39-4 (480.0 mg) was dissolved in DCM (5 mL), NBS (284.4 mg, 1.60 mmol) was added, and the reaction was stirred at 40° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (EA: petroleum ether = 0-10%) to obtain compound 39-5 (450.0 mg, yield 76%) as a white solid.

[0569] MS (m / z): 411.0 [M+H] + .

[0570] Step 7: Synthesis of 4-(1-(hex-1-yn-1-yl)-7-phenylimidazo[1,2-a]quinoxalin-4-yl)morpholine (39)

[0571] Compound 39-5 (100.0 mg, 0.24 mmol) was dissolved in ACN (2 mL), replaced with nitrogen three times, and then 1-hexyne (40.1 mg, 0.49 mmol), Pd(PPh3)4 (28.2 mg, 0.24 mmol), CuI (9.3 mg, 0.49 mmol) and TEA (101.2 mg, 1.0 mmol) were added, and the reaction solution was stirred at 75°C for 16 hours. After the reaction solution was cooled, it was filtered with diatomaceous earth, the filter cake was washed with EA (20 mL×2), the filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid phase (eluent ACN: 0.1% formic acid aqueous solution = 15-20%) to obtain the target compound 39 (8.0 mg) with a yield of 8.0% as a white solid.

[0572] MS (m / z): 411.0 [M+H] + .

[0573] 1H NMR(400MHz,DMSO-d6)δ9.13(d,J=8.8Hz,1H),7.89(d,J=2.0Hz,1H),7.88(s, 1H),7.82-7.78(m,2H),7.67(dd,J1=8.8Hz,J2=2.0Hz,1H),7.51(t,J=7.6Hz, 2H),7.41(t,J=7.2Hz,1H),4.28(t,J=4.8Hz,4H),3.79(t,J=4.8Hz,4H),2.71 (t,J=7.2Hz,2H),1.78-1.62(m,2H),1.60-1.48(m,2H),0.99(t,J=7.2Hz,3H).

[0574] Example 40: Preparation of ethyl 5-amino-8-(1H-pyrazol-5-yl)imidazo[1,2-c]quinazoline-2-carboxylate (40)

[0575]

[0576] Step 1: Synthesis of 7-bromoquinazoline-2,4(1H,3H)-dione (40-2)

[0577] Compound 40-1: 2-amino-4-bromobenzoic acid (2.90 g, 13.42 mmol) and urea (12.09 g, 201.36 mmol) were added to a sealed tube and stirred at 160°C for 6 hours. After the reaction solution was cooled to 100°C, 100 mL of water was slowly added, the product was precipitated and filtered, the filter cake was washed with water twice and then vacuum dried to obtain compound 40-2 (2.73 g) with a yield of 84.3%, as a gray solid.

[0578] MS (m / z): 243.0 [M+H] + .

[0579] Step 2: Synthesis of 7-bromo-2,4-dichloroquinazoline (40-3)

[0580] Compound 40-2 (1.28 g, 5.31 mmol) was dissolved in POCl3 (20 mL) and stirred at 120°C for 46 hours. The reaction solution was concentrated in vacuo and the residue was separated by column chromatography (EA: petroleum ether = 0-10%) to obtain compound 40-3 (350.0 mg) with a yield of 23.6% as a white solid.

[0581] MS (m / z): 279.0 [M+H] + .

[0582] Step 3: Synthesis of 7-bromo-2-chloroquinazolin-4-amine (40-4)

[0583] Compound 40-3 (350.0 mg, 1.26 mmol) was dissolved in THF (5 mL), and aqueous ammonia (0.15 mL, 3.78 mmol) was added, and the reaction was allowed to react at room temperature for 3 hours. The reaction solution was concentrated in vacuo to obtain compound 40-4 (300 mg, crude product) as a white solid.

[0584] MS (m / z): 258.0 [M+H] + .

[0585] Step 4: Synthesis of 7-bromo-2-(methylthio)quinazolin-4-amine (40-5)

[0586] Compound 40-4 (300.0 mg, 1.16 mmol) was dissolved in DMSO (3 mL), MeSNa (122.0 mg, 1.74 mmol) was added, and the reaction was stirred at 80°C for 16 hours. After the reaction solution was cooled, 5 mL of water was added, and it was extracted with EA (5 mL×3), the organic phases were combined, washed with water twice, dried and concentrated under reduced pressure, and the residue was separated by column chromatography (EA: petroleum ether = 0-10%) to obtain compound 40-5 (190.0 mg) with a yield of 60.5% as a white solid.

[0587] Step 5: Synthesis of ethyl 8-bromo-5-(methylthio)imidazo[1,2-c]quinazoline-2-carboxylate (40-6)

[0588] Compound 40-5 (100.0 mg, 0.22 mmol) was dissolved in toluene (5 mL), ethyl 3-bromo-2-oxopropanoate (274.31 mg, 1.41 mmol) was added, and the mixture was stirred at 150°C for 16 hours. After the reaction solution was cooled, 5 mL of water was added, and the mixture was extracted with EA (10 mL × 3). The organic phases were combined, dried, and concentrated, and the residue was separated by column chromatography (EA: petroleum ether = 0-25%) to obtain compound 40-6 (50.0 mg) with a yield of 19.5% as a white solid.

[0589] MS (m / z): 366.0 [M+H] + .

[0590] Step 6: Synthesis of ethyl 8-bromo-5-(methylsulfonyl)imidazo[1,2-c]quinazoline-2-carboxylate (40-7)

[0591] Compound 40-6 (150.0 mg, 0.41 mmol) was dissolved in DCM (5 mL), and m-CPBA (155.49 mg, 0.90 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (EA: petroleum ether = 0-50%) to obtain compound 40-7 (20.0 mg) with a yield of 12.3% as a white solid.

[0592] MS (m / z): 398.0 [M+H] +

[0593] Step 7: Synthesis of ethyl 8-bromo-5-((4-methoxybenzyl)amino)imidazo[1,2-c]quinazoline-2-carboxylate (40-8)

[0594] Compound 40-7 (100.0 mg, 0.19 mmol) was dissolved in dioxane (2 mL), and PMBNH2 (10.33 mg, 0.08 mmol) and DIPEA (19.47 mg, 0.15 mmol) were added, and the reaction was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated in vacuo to obtain compound 40-8 (20.0 mg, crude product) with a yield of 74.5% as a yellow oil.

[0595] MS (m / z): 457.0 [M+H] + .

[0596] Step 8: Synthesis of ethyl 5-((4-methoxybenzyl)amino)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-c]quinazoline-2-carboxylate (40-9)

[0597] Compound 40-8 (100.0 mg, 0.19 mmol) was dissolved in dioxane (1 mL), and water (0.1 mL), compound M2 (13.44 mg, 0.05 mmol), K3PO4 (18.65 mg, 0.09 mmol) and Pd(dppf)Cl2 (3.19 mg, 4.39 μmol) were added, and the reaction solution was stirred at 100°C for 5 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (EA: petroleum ether = 0-60%) to obtain compound 40-9 (22.0 mg) with a yield of 95.1% as a white solid.

[0598] MS (m / z): 527.0 [M+H] + .

[0599] Step 9: Synthesis of ethyl 5-amino-8-(1H-pyrazol-5-yl)imidazo[1,2-c]quinazoline-2-carboxylate (40)

[0600] Compound 40-9 (22.0 mg, 0.04 mmol) was dissolved in TFA (3 mL), Tf2O (0.1 mL) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (eluent ACN: 0.1% formic acid aqueous solution = 80-90%) to obtain the target compound 40 (1.10 mg) with a yield of 8.35% as a white solid.

[0601] MS (m / z): 323.0 [M+H] + .

[0602] 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),8.81(s,1H),8.25(d,J=8.0Hz,1H),7.90(d,J=1.2Hz,1H),7 .89-7.74(m,4H),7.80(s,2H),6.87(d,J=2.4Hz,1H),4.37(q,J=7.2Hz,2H),1.36(t,J=7.2Hz,3H).

[0603] Example 41: Preparation of N,N-diethyl-4-morpholino-7-phenylimidazo[1,5-a]quinoxaline-1-carboxamide (41)

[0604]

[0605] Step 1: Synthesis of 5H,10H-diimidazole[1,5-a:1',5'-d]pyrazine-5,10-dione (I-27)

[0606] Compound I-26 (2.0 g, 17.84 mmol) was dissolved in SOCl2 (200 mL) and stirred at 80°C for 18 hours under nitrogen protection. The reaction solution was cooled and filtered, and the filter cake was slurried with DCM (20 mL) and filtered again to obtain a crude compound I-27 (2.0 g) as a gray-black solid.

[0607] MS (m / z): 189.0 [M+H] + .

[0608] Step 2: Synthesis of N-(4-fluoro-[1,1'-biphenyl]-3-yl)-1H-imidazole-5-carboxamide (41-1)

[0609] 4-Fluoro-[1,1'-biphenyl]-3-amine (2.99 g, 15.95 mmol) was dissolved in THF (10 mL), replaced with nitrogen three times, and then KHMDS THF solution (1M, 32 mL, 31.89 mmol) was added dropwise at -10°C, and compound I-27 was added after stirring for 1 hour, and the reaction was continued to stir at 27°C for 16 hours. The reaction solution was concentrated under reduced pressure, water (20 mL) was added, and extracted with EA (20 mL×3), the organic phases were combined, dried, and concentrated under reduced pressure, and the residue was separated by column chromatography (methanol: DCM = 0-10%) to obtain compound 41-1 (770.0 mg) with a yield of 25%, as a reddish brown solid.

[0610] MS (m / z): 282.0 [M+H] + .

[0611] Step 3: Synthesis of 7-phenylimidazo[1,5-a]quinoxalin-4(5H)-one (41-2)

[0612] Compound 41-1 (1.07 g, 3.80 mmol) was dissolved in DMAc (10 mL), and NaH (182.57 mg, 7.61 mmol) was added, and the reaction was carried out under the protection of nitrogen at 180 ° C for 3 hours in a microwave oven. After the reaction mixture was cooled, 10 mL of water was added, and it was extracted with EA (10 mL × 3). The organic phases were combined and washed with water (10 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 41-2 (900.0 mg) as a yellow solid.

[0613] MS (m / z): 262.0 [M+H] + .

[0614] Step 4: Synthesis of 4-(7-phenylimidazo[1,5-a]quinoxalin-4-yl)morpholine (41-3)

[0615] Compound 41-2 (850.0 mg, 3.25 mmol) was dissolved in DMF (10 mL), and morpholine (566.85 mg, 6.51 mmol), PyBOP (6.77 g, 13.01 mmol), and DBU (2.97 mg, 19.52 mmol) were added, and the mixture was stirred at 27°C for 2 hours. Water (10 mL) was added to the reaction solution, and it was extracted with EA (10 mL × 3), and the organic phases were combined and washed with water (10 mL × 2), and the residue was separated by column chromatography (EA: petroleum ether = 0-25%) to obtain compound 41-3 (560.0 mg) with a yield of 52% as a white solid.

[0616] MS (m / z): 331.0 [M+H] + .

[0617] 1 H NMR(400MHz, DMSO-d6)δ8.08(s,1H),7.85(d,J=1.6Hz,1H),7.83-7.75(m,3H),7.66-7.60(m,1H),7.49(t,J=7.6Hz,2H),7.40( t,J=7.2Hz,1H),3.88-3.77(m,8H),3.65(q,J=7.2Hz,2H),3.23(q,J=7.2Hz,2H),1.32(t,J=6.8Hz,3H),1.06(t,J=6.8Hz,3H).

[0618] Step 5: Synthesis of N,N-diethyl-4-morpholino-7-phenylimidazo[1,5-a]quinoxaline-1-carboxamide (41)

[0619] Compound 41-3 (150.0 mg, 0.45 mmol) was dissolved in THF (2 mL), replaced with nitrogen three times, and then n-BuLi (0.36 mL, 0.91 mmol, 2 mol / L) was added dropwise at -78 °C. After the addition was completed, N,N-diethylformyl chloride (1123.12 mg, 0.91 mmol) was added after stirring for 30 minutes, and stirring was continued for 1 hour. The reaction solution was warmed to room temperature, saturated NH4Cl solution 5 mL was added, and washed with EA (5 mL × 3), the organic phases were combined and dried, and the residue was separated by column chromatography (EA: petroleum ether = 0-25%) to obtain the target compound 41 (46.0 mg) with a yield of 76.7%, as a light yellow oil.

[0620] MS (m / z): 430.0 [M+H] + .

[0621] 1 H NMR(400MHz, DMSO-d6)δ8.08(s,1H),7.85(d,J=1.6Hz,1H),7.83-7.75(m,3H),7.66-7.60(m,1H),7.49(t,J=7.6Hz,2H),7.40( t,J=7.2Hz,1H),3.88-3.77(m,8H),3.65(q,J=7.2Hz,2H),3.23(q,J=7.2Hz,2H),1.32(t,J=6.8Hz,3H),1.06(t,J=6.8Hz,3H).

[0622] Example 42: Preparation of ethyl 4-(methylamino)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (42)

[0623]

[0624] Step 1: Synthesis of ethyl 7-bromo-4-(((4-methoxybenzyl)methyl)amino)pyrrolo[1,2-a]quinoxaline-2-carboxylate (42-1)

[0625] Referring to the preparation method of common intermediate Int4, common intermediate Int4 was prepared.

[0626] The common intermediate Int4 (80.0 mg, 0.18 mmol) was dissolved in DMF (2 mL), NaH (8.45 mg, 0.35 mmol) was added under ice bath and stirred for 5 minutes, then MeI (50.0 mg, 0.35 mmol) was added, and the reaction was stirred at room temperature for 2 hours. 5 mL of water was added to the reaction solution, extracted with EA (5 mL × 3), the organic phases were combined and washed with water (5 mL × 2), dried and spin-dried, and the residue was separated by column chromatography (EA: petroleum ether = 0-15%) to obtain compound 42-1 (60.0 mg), with a yield of 73.2%, as a white solid.

[0627] MS (m / z): 468.0 [M+H] + .

[0628] Step 2: Synthesis of ethyl 4-((4-methoxybenzyl)(methyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (42-2)

[0629] Compound 42-1 (60.0 mg, 0.13 mmol) was dissolved in 1,4-dioxane (2 mL), 0.2 mL of water and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (71.27 mg, 0.26 mmol), Pd(dppf)Cl2 (9.30 mg, 0.01 mmol) and Cs2CO3 (83.48 mg, 0.26 mmol) were added, and the reaction was stirred at 100°C for 3 hours under nitrogen protection. The reaction solution was dried by rotary evaporation, and the residue was separated by column chromatography (EA: petroleum ether = 0-50%) to obtain compound 42-2 (56.0 mg) with a yield of 81.2% as a white solid.

[0630] MS (m / z): 540.0 [M+H] + .

[0631] Step 3: Synthesis of ethyl 4-(methylamino)-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (42)

[0632] Compound 42-2 (54.0 mg, 0.10 mmol) was dissolved in TFA (1 mL), 0.3 mL Tf2O was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase (ACN: 0.1% formic acid aqueous solution = 70-80%) to obtain the target compound 42 (30.0 mg) with a yield of 89.4% as a white solid.

[0633] MS (m / z): 336.0 [M+H] + .

[0634] 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.83(s,1H),8.29(d,J=8.4Hz,1H),7.98(s,1H),7.73(s,1H),7.69(d,J=7.6Hz,1H),7.52(br s,1H),6.83(d,J=2.4Hz,1H),4.32(q,J=7.2Hz,2H),3.06(s,3H),1.35(t,J=7.2Hz,3H).

[0635] Example 43: Preparation of ethyl 4-amino-7-(1H-pyrazol-5-yl)pyrazolo[1,2-a]quinoxaline-2-carboxylate (43)

[0636]

[0637] Step 1: Synthesis of diethyl 1-(4-bromo-2-nitrophenyl)-1H-pyrazole-2,4-dicarboxylate (43-1)

[0638] Dissolve 1H-pyrazole-2,4-dicarboxylic acid diethyl ester (2.0 g, 9.42 mmol) in DMAc (15 mL), add compound M1 (2.07 g, 9.42 mmol) and Cs2CO3 (7.68 g, 23.56 mmol), and stir the reaction at 40°C for 3 hours. After cooling the reaction solution, add 30 mL of water, extract with EA (10 mL × 3), combine the organic phases, wash twice with saturated NaCl (30 mL × 2), dry with anhydrous magnesium sulfate, filter and concentrate to obtain compound 43-1 (3.5 g, crude product) as a light yellow solid.

[0639] MS (m / z): 413.0 [M+H] + .

[0640] Step 2: Synthesis of ethyl 7-bromo-4-oxo-4,5-dihydropyrazolo[1,2-a]quinoxaline-2-carboxylate (43-2)

[0641] Compound 43-1 (1.0 g, crude product) was dissolved in glacial acetic acid (15 mL), iron powder (338.7 mg, 6.07 mmol) was added, and the reaction was stirred at 100°C for 5 hours. After the reaction cooled to room temperature, it was placed in an ice-water bath, and concentrated hydrochloric acid was added to completely dissolve the iron powder, and solids were precipitated. After stirring for 10 minutes, the precipitate was filtered, and the filter cake was washed with water (10 mL × 2), glacial EtOH (20 mL), and petroleum ether (20 mL), and dried to obtain compound 43-2 (512 mg) with a yield of 62.78%, as a gray-green solid.

[0642] MS (m / z): 337.0 [M+H] + .

[0643] Step 3: Synthesis of ethyl 7-bromo-4-chloropyrazolo[1,2-a]quinoxaline-2-carboxylate (43-3)

[0644] Compound 43-2 (512.0 mg, 1.52 mmol) was dissolved in POCl3 (5 mL) and reacted at 120°C for 3 hours. After the reaction solution was cooled, POCl3 was transferred in vacuo, DCM (10 mL) was added to the residue, and the mixture was slowly added to 10 mL of ice water, extracted with DCM (10 mL × 3), the organic phases were combined and washed once with 30 mL of saturated NaCl solution, and the organic phases were dried and concentrated to obtain compound 43-3 (352 mg, crude product) as an off-white solid.

[0645] MS (m / z): 354.0 [M+H] + .

[0646] Step 4: Synthesis of ethyl 7-bromo-4-((4-methoxybenzyl)amino)pyrazolo[1,2-a]quinoxaline-2-carboxylate (43-4)

[0647] Compound 43-3 (352 mg) and PMBNH2 (292.5 mg, 2.13 mmol) were dissolved in dioxane (10 mL), and sodium tert-butoxide (102.4 mg, 1.07 mmol), PPh3 (37.3 mg, 0.14 mmol) and Pd(OAc)2 (10.3 mg, 0.07 mmol) were added, and the reaction was stirred at 100°C for 5 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was separated by column chromatography (EA: petroleum ether = 0-16%) to obtain compound 43-4 (141.0 mg) with a yield of 43.5% as an off-white solid.

[0648] MS (m / z): 455.0 [M+H] + .

[0649] Step 5: Synthesis of ethyl 4-((4-methoxybenzyl)amino)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,2-a]quinoxaline-2-carboxylate (43-5)

[0650] Compound 43-4 (130.0 mg, 0.29 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (103.22 mg, 0.37 mmol) were dissolved in a mixed solvent (5 mL) of dioxane: water = 8:1, and then Cs2CO3 (231.3 mg, 0.71 mmol) and Pd(dppf)Cl2 (13 mg, 0.03 mmol) were added, and the reaction was stirred at 100°C for 2 hours under nitrogen protection. After the reaction solution was cooled, 5 mL of water was added, and it was extracted with EA (5 mL×3), the organic phases were combined, dried and concentrated, and the residue was separated by column chromatography (EA: petroleum ether = 0-25%) to obtain compound 43-5 (172 mg, crude product) as an off-white solid.

[0651] MS (m / z): 527.0 [M+H] + .

[0652] Step 6: Synthesis of ethyl 4-amino-7-(1H-pyrazol-5-yl)pyrazolo[1,2-a]quinoxaline-2-carboxylate (43)

[0653] Compound 43-5 (172.0 mg) was dissolved in TFA (3 mL), Tf2O (0.3 mL) was added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase purification (eluent ACN: 0.1% formic acid aqueous solution = 80-90%) to obtain the target compound 43 (33.5 mg) with a yield of 36.5% as an off-white solid.

[0654] MS (m / z): 323.0 [M+H] + .

[0655] 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.26(d,J=8.5Hz,1H),7.98(d,J=1.8Hz,1H),7.82(dd,J1=8.5Hz,J2=1.9Hz,1H) ,7.77(d,J=2.2Hz,1H),7.73(s,1H),7.55(s,2H),6.83(d,J=2.2Hz,1H),4.41(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[0656] Example 44: Preparation of ethyl 4-dimethylamino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (44)

[0657]

[0658] Step 1: Synthesis of ethyl 7-bromo-4-(dimethylamino)pyrrolo[1,2-a]quinoxaline-2-carboxylate (44-1)

[0659] Int3 was prepared by referring to steps 1 to 2 of the preparation method of the common intermediate Int4.

[0660] Dissolve 7-bromo-4-chloropyrrolo[1,2-a]quinoxaline-2-carboxylic acid ethyl ester (123.0 mg, 0.35 mmol) in 1,4-dioxane (10 mL), add dimethylamine hydrochloride (85.1 mg, 1.04 mmol), Pd(OAc)2 (7.9 mg, 0.035 mmol), PPh3 (18.4 mg, 0.07 mmol) and potassium phosphate (113.6 mg, 0.535 mmol), and stir at 100°C for 16 hours. After cooling, add 10 mL of water to the reaction solution, extract with EA (10 mL × 3), wash the combined organic phases with 20 mL of water twice, dry and concentrate, and separate the residue by column chromatography (EA: petroleum ether = 0-20%) to obtain compound 44-1 (90.0 mg), with a yield of 70.8%, as a light yellow solid.

[0661] MS (m / z): 363.0 [M+H] + .

[0662] Step 2: Synthesis of ethyl 4-dimethylamino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (44-2)

[0663] Compound 44-1 (72.5 mg, 0.20 mmol) was dissolved in dioxane (2 mL), 0.2 mL of water and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (166.9 mg, 0.60 mmol), Cs2CO3 (195.6 mg, 0.60 mmol) and Pd(dppf)Cl2 (14.5 mg, 0.02 mmol) were added, and the reaction was stirred at 100°C for 3 hours under nitrogen protection. After the reaction solution was cooled, 5 mL of water was added, and it was extracted with EA (5 mL×3), the organic phases were combined, dried and concentrated, and the residue was separated by column chromatography (EA: petroleum ether = 0-50%) to obtain compound 44-2 (50 mg) with a yield of 86.2% as a white solid.

[0664] MS (m / z): 434.0 [M+H] + .

[0665] Step 3: Synthesis of ethyl 4-dimethylamino-7-(1H-pyrazol-5-yl)pyrrolo[1,2-a]quinoxaline-2-carboxylate (44)

[0666] Compound 44-2 (43.0 mg, 0.10 mmol) was dissolved in DCM (1 mL), 0.1 mL TFA was added, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase (eluent ACN: 0.1% formic acid aqueous solution = 70-80%) to obtain the target compound 44 (20.0 mg) with a yield of 57.31% as a white solid.

[0667] MS (m / z): 350.0 [M+H] + .

[0668] 1 H NMR (400MHz, DMSO-d6) δ12.96(brs,1H),8.87(d,J=1.4Hz,1H),8.27(d,J=8.5Hz,1H),7.87(d,J=1.9Hz,1H),7.71(s,1H),7.65(dd ,J1=8.6Hz, J2=2.0Hz,1H),7.34(d,J=1.4Hz,1H),6.82(d,J=2.2Hz,1H),4.33(q,J=7.1Hz,2H),3.38(s,6H),1.35(t,J=7.1Hz,3H).

[0669] Control compound 1:

[0670]

[0671] Prepared by referring to the preparation method of Example 439 in CN112074516A.

[0672] Control compound 2:

[0673]

[0674] Prepared by referring to the preparation method of Example 443 in CN112074516A.

[0675] Example 45: Activation of IL-1β expression in THP-1 cells induced by PMA

[0676] THP-1 cells were purchased from Wuhan Pronocell Life Science Co., Ltd. The complete culture medium used was RPMI1640 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-streptomycin and a final concentration of 0.05 mM β-mercaptoethanol. Cells were cultured according to the supplier's instructions, and the cell density was maintained in the logarithmic phase before the experiment began. The cell concentration was diluted to 5×10 5 Phorbol 12-myristate 13-acetate (PMA, 300 ng / mL) was added to the cell suspension, and 100 μL of the cell suspension was plated in each well of a 96-well plate. The number of cells in each well was 5×10 4 After 24 hours of cell induction culture, the culture medium was discarded and the cells were washed twice with phosphate buffered saline (PBS). The derivatives of the present invention were dissolved in DMSO, diluted 3 times with culture medium to the required concentration and added to 96-well plates respectively. The cells were incubated with the compounds for 6 hours. The cell-free supernatant was collected and the IL-1β level was evaluated according to the instructions of the ELISA detection kit (Hangzhou Lianke Biotechnology Co., Ltd.). The solvent was blank. EC 50 The results are shown in Table 1.

[0677] Table 1. Agonist activity of compounds on hNLRP3

[0678]

[0679]

[0680]

Note

[0681] “++” represents ≤50 μM, but >5 μM; “+” represents >50 μM.

[0682] The results show that the compounds provided by the present invention all have significant effects on stimulating hNLRP3 activity, and some of the compounds are even more effective than the positive control compound BMS986299.

[0683] Example 46: Inhibitory effect of compounds on hERG ion channels

[0684] The inhibitory effect of the compound on the human hERG ion channel stably expressed in HEK293 cells was tested using conventional patch clamp. The compound was prepared at a concentration of 10 μM. Each cell was used as a control. The compound was perfused using a perfusion system that utilized its own gravity. After the current of each cell stabilized, the hERG current size before and after the addition of the compound was compared, and the blocking effect of the compound on the hERG current was calculated. The results are shown in Table 2.

[0685] Table 2. Blocking rate of compounds on hERG ion channels

[0686] Compound No. hERG Inhibition % 1 DD 10 D 13 D 20 D 21 D 23 DD 25 D 27 D 29 DD 33 D 43 D Control compound 1 DDD Control compound 2 DDD

[0687]

Note

[0688] The results show that the compounds provided by the present invention have significantly lower blocking effects on hERG current than control compound 1 and control compound 2, and have good safety, such as compounds 1, 10, 13, 20, 27, 29 and 43.

[0689] Example 47: Agonistic effect of compounds on hTLR7 / 8

[0690] Cells: HEK293-hTLR7 or 8 / Nano-Luc-NF-κB-Luciferase gene cells.

[0691] 1) The above cells in the logarithmic growth phase were trypsinized and resuspended in culture medium to 2×10 6 50 μL / well of cell resuspension was added to a 96-well plate, with 1×10 cells per well. 6 The DMSO solution of the test compound was diluted 3 times in series, and prepared into 2× test concentration with culture medium, and 50 μL / well was added to the cells in the 96-well plate, and cultured in a 37°C, 5% CO2 incubator for 16 hours. The culture medium was DMEM (High glucose) containing 10% FBS.

[0692] 2) After the cell incubation, add 100 μL / well Bright-GloTM Luciferase detection reagent, incubate at room temperature for 5 minutes, and read the relative luciferase activity unit (RLU) with a microplate reader.

[0693] 3) Stimulation of hTLR7 / 8 by the tested compounds 50The results are shown in Table 3 using the four-parameter method of log(agonist) vs. response--Variable slope using GraphPad software.

[0694] Table 3. Agonist activity of compounds on hTLR7 / 8

[0695]

[0696] Example 48: Effects of Compounds on Hair Growth and Promotion

[0697] Male C57BL / 6J mice in the resting stage of hair growth were selected. After isoflurane inhalation anesthesia, the hair on the back of the mice was removed with a depilatory cream. The depilatory area was 2cm×3cm. The mice were randomly divided into 3 groups, with 4 mice in each group. After depilation, the test solution was applied once a day, with the concentrations of 0.5mM and 5mM respectively. The Model group was applied with a blank solvent, and the application volume was 300μL. The application lasted for 14 days. The hair at the medication site was cut and weighed 24 hours after the last administration. The results are shown in Figure 1 .

[0698] from Figure 1 It can be seen that the compound 33 provided by the present invention has a significant effect of promoting hair growth compared with the model group (Model).

Claims

1. A nitrogen-containing three-membered fused ring derivative, which is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof: In the formula, X 1 and X 2 are independently selected from N or C, and at least one is N; Ring A is selected from 5 Substituted C 6-10 Aryl, 5-10 membered heteroaryl, 4-7 membered heterocyclyl; R 1 Selected from H, halogen, -CN, -NO2, C 1-8 Alkyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)OR 6 、-C(O)NR 6 R 7 、-NR 6 R 7 ; said C 1-8 Alkyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, one or more R 8 replace; R 2 are independently selected from H, halogen, -CN, -NO2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic group; m is 0, 1, 2 or 3; R 3 and R 4 are independently selected from H, C 1-8 Alkyl, C 2-8 Heteroalkyl, or R 3 , R 4 Together with the nitrogen atoms to which they are attached, they form a 4-8 membered heterocyclic group; L is -(L 1 ) n -(L 2 ) p -, where L 1 and L 2 The same or different and each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylidene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -N(R 6 )-, -S(O)-, -S(O)2-, -C(O)-; the C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylidene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 12 Arylene, 5-10 membered heteroarylene, optionally substituted by one or more R 8 replace; n and p are each independently 0, 1, 2 or 3; R 5 Selected from H, halogen, -CN, -OH, -NH2, -NO2, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)OR 6 、-C(O)NR 6 R 7 、-NR 6 C(O)R 7 、-NR 6 R 7 、-OR 6 、-SR 6 、-C(O)R 6 、-OC(O)R 6 、-OC(O)NR 6 R 7 、-NR 6 C(O)NR 7 R 9 、-NR 6 C(O)OR 7 、-POR 6 、-P(O)R 6 R 7 、-P(O)OR 6 OR 7 、-S(O)R 6 、-S(O)2R 6 、-S(O)NR 6 R 7 、-S(O)2NR 6 R 7 ; said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, one or more R 8 replace; R 6 , R 7 , R 9 are independently selected from H, C 1-8 Alkyl, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; R 8 Selected from H, halogen, -CN, -OH, -NH2, -NO2, C 1-4 Alkyl, C 2-4 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)OR 6 、-C(O)NR 6 R 7 、-NR 6 C(O)R 7 、-NR 6 R 7 、-OR 6 、-SR 6 、-C(O)R 6 、-OC(O)R 6 、-OC(O)NR 6 R 7 、-NR 6 C(O)NR 7 R 9 、-NR 6 C(O)OR 7 、-POR 6 OR 7 、-P(O)R 6 R 7 、-P(O)OR 6 OR 7 、-S(O)R 6 、-S(O)2R 6 、-S(O)NR 6 R 7 、-S(O)2NR 6 R 7 ; The heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O.

2. The nitrogen-containing three-membered fused ring derivative according to claim 1, characterized in that: In the general structural formula I, R 1 Selected from -Br, -CH3, 3. The nitrogen-containing three-membered fused ring derivative according to claim 1, characterized in that: In the general structural formula I, R 2 Each is independently preferably selected from H, -F, -Cl, -CN, -NO2, -CF3, -OCH3.

4. The nitrogen-containing three-membered fused ring derivative according to claim 1, characterized in that: In the general structural formula I, R 3 and R 4 are each independently selected from H, -CH3, or R 3 , R 4 Together with the nitrogen atoms to which they are attached, they form a morpholine ring.

5. The nitrogen-containing three-membered fused ring derivative according to claim 1, characterized in that: In the general structural formula I, L is selected from -C(O)-, -C(O)-NH-, -C(O)-NH-CH2C(CH3)2-, -C(O)-NH-(CH2)2-, -CH2-, -CH2-NH-, -CH2-O-, -CH2-O-(CH2)2-, -CH2-NH-(CH2)2-, -CH2-NH-CH2C(CH3)2-, -CH2-O-CH2C(CH3)2-, -(CH2)2-O-CH2-, -(CH2)2-, -NH-(CH2)2C(CH3)2-, -(CH2)3-O-, -O-(CH2)3O-, -CH2-N(CH2CH3)-CO-, -CH2-N(CH2CH3)-C H2-, -CH2-NH-C(O)-O-, -CH2-NH-S(O)2-, -CH2-NH-CH2-C(O)-, -CH2-NH-(CH2)3-, -CH2-O-(CH2)2-O-, -CH2-NH-C(O)-, -CH2-N(CH2CH3)-C(O)-, -NH-C(O)- CH2-, -CH2-O-(CH2)2-NH-C(O)-, -CH2-NH-CH2-, -CH2-NH-(CH2)3-, -CH2-N(CH2CH3)-C(O)-O-, -NH-C(O)-O-(CH2)2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)-NH-, 6. The nitrogen-containing three-membered fused ring derivative according to claim 1, characterized in that: In the general structural formula I, R 5 is selected from H, methyl, ethyl, methoxy, tert-butoxy, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, OH, NH2, dimethylamino, methylsulfonyl, acetyl, benzoyl, difluoromethyl, 7. The nitrogen-containing three-membered fused ring derivative according to any one of claims 1 to 6, characterized in that: It is a compound having the following structural formula (II) or a pharmaceutically acceptable salt thereof: In the formula, X 1 , X 2 are each independently selected from N or C; R 1 Selected from -CH3 or L is selected from -C(O)-, -CH2-, -C(O)-NH-(CH2)2-, -CH2-NH-(CH2)2-, -CH2-NH-CH2-, -CH2-O-(CH2)2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)-, -CH2-NH-C(O)-O-, -CH2-NH-, -(CH2)3-O-, -CH2-N(CH2CH3)-CO-, -CH2-NH-C(O)-NH- or -CH2-O-; R 5 Selected from H, OH, C 1-6 Alkyl, -OR 6 、NH2、 -NR 6 R 7 , Methyl sulfone, or difluoromethyl; R 3 and R 4 are independently selected from H or C 1-6 alkyl; or R 3 , R 4 Together with the nitrogen atoms to which they are attached, they form a 4-8 membered heterocyclic group; R 6 , R 7 Each independently selected from C 1-6 alkyl.

8. The nitrogen-containing three-membered fused ring derivative according to any one of claims 1 to 7, characterized in that: A compound having the following general structural formula (III) or a pharmaceutically acceptable salt thereof: In the formula, X 2 Selected from N or C; R 1 Selected from -L- is selected from -C(O)-, -CH2-, -CH2-NH-(CH2)2-, -CH2-O-(CH2)2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)-O-, -CH2-NH-, -CH2-NH-C(O)- or -CH2-NH-CH2-; R 5 Selected from H, OH, -OR 6 、NH2、-NR 6 R 7 , Methylsulfone, or R 6 , R 7 Each independently selected from C 1-6 alkyl.

9. The nitrogen-containing three-membered fused ring derivative according to any one of claims 1 to 8, characterized in that: A compound having the following general structural formula (IV) or a pharmaceutically acceptable salt thereof: In the formula, R 1 Selected from -L- is selected from -C(O)-, -CH2-, -CH2-O-(CH2)2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)-, -CH2-NH-C(O)-O- or -CH2-NH-; R 5 Selected from H, OH, C 1-6 Alkyl, -OR 6 , Methyl sulfone, R 6 Selected from C 1-6 alkyl.

10. The nitrogen-containing three-membered fused ring derivative according to any one of claims 1 to 9, characterized in that: A compound having the following structural formula (V) or a pharmaceutically acceptable salt thereof: In the formula, -L- is selected from -CH2-, -CH2-OC(O)-NH-, -CH2-NH-C(O)- or -CH2-NH-C(O)-O-; R 5 Selected from C 1-6 alkyl, 11. The nitrogen-containing three-membered fused ring derivative according to any one of claims 1 to 10, characterized in that: Selected from the following characteristic compounds or their isomers or pharmaceutically acceptable salts:

12. A pharmaceutical composition comprising at least one active ingredient as described in any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier or excipient.

13. A method for preparing a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for preventing or treating a disease associated with the NLRP3 signaling pathway, preferably a NLRP3 agonist.

14. The use according to claim 13, characterized in that The NLRP3 agonist is used to prevent or treat tumors, pathogen infection or hair loss.

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