WO2022117075A1 - Composé azacyclique, son procédé de préparation et son utilisation - Google Patents

Composé azacyclique, son procédé de préparation et son utilisation Download PDF

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WO2022117075A1
WO2022117075A1 PCT/CN2021/135357 CN2021135357W WO2022117075A1 WO 2022117075 A1 WO2022117075 A1 WO 2022117075A1 CN 2021135357 W CN2021135357 W CN 2021135357W WO 2022117075 A1 WO2022117075 A1 WO 2022117075A1
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alkyl
compound
membered
pharmaceutically acceptable
halogenated
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邱关鹏
邓代国
雷曾荣
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广州费米子科技有限责任公司
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Definitions

  • the present invention relates to the technical field of medicine, in particular to an aza-heterocyclic compound, a preparation method and use thereof.
  • the tyrosine kinase JAK (Janus kinase) is a family of intracellular non-receptor tyrosine kinases, which mediate the signals produced by cytokines and transmit them through the JAK-STAT signaling pathway.
  • the tyrosine kinase JAK can not only phosphorylate the cytokine receptors bound to it, but also phosphorylate multiple signaling molecules containing specific SH2 domains.
  • the JAK protein family includes 4 members: JAK1, JAK2, JAK3 and Tyk2. They have 7 JAK homology domains (JH) in structure, of which the JH1 domain is the kinase domain and the JH2 domain is the "JAK homology domain".
  • JH6 and JH7 are receptor binding domains.
  • the JAK3 and ⁇ c subunits are known to be involved in linked severe combined immunity (SCID).
  • JAK2 is essential for the production of red blood cells and platelets, and JAK2 mutations can also lead to myeloproliferative disorders.
  • JAK1 is associated with polycythemia vera.
  • the JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines and is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation.
  • the JAK-STAT signaling pathway is a rapid intracellular communication pathway between extracellular signal (cytokine) membrane receptors and the nucleus. Compared with other signaling pathways, the transmission process of JAK-STAT signaling pathway is relatively simple, and it is mainly composed of three components, namely tyrosine kinase-related receptor, tyrosine kinase JAK and transcription factor STAT.
  • the JAK-STAT signaling pathway is activated by more than 50 different cytokine receptors known to be derived from pro-inflammatory cytokines, anti-inflammatory cytokines, hematopoietic growth factors and metabolic factors.
  • inflammatory diseases mainly include rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis and Crohn's disease; while tumor diseases mainly involve myelofibrosis, polycythemia vera and essential platelets hyperplasia.
  • the present invention provides an azanocyclic compound, which has excellent tyrosine kinase JAK inhibitory activity and can be used as a tyrosine kinase JAK inhibitor to solve various JAK-STAT signaling pathways Associated inflammatory or neoplastic disease.
  • azacyclic compound having the structure represented by the general formula (I) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, and prodrugs:
  • L 0 is selected from single bond and NR 1 ;
  • X 1 is selected from CH and N;
  • X 2 is selected from CR 4 and N;
  • R 4 is cyano
  • R 1 is selected from -H and C 1 -C 3 alkyl, or R 1 can together with R 4 form a 5-6 membered saturated or unsaturated ring; the 5-6 membered saturated or unsaturated ring is optionally surrounded by R 6 replace;
  • X 3 is selected from CH and N;
  • n is selected from 1 and 2;
  • n 2;
  • two R 0 are substituted on the same carbon atom or on adjacent carbon atoms, and the two R 0 are connected to each other to form a 4- to 6-membered saturated nitrogen heterocycle or a 4- to 6-membered saturated carbocycle;
  • the 4-6 membered saturated nitrogen heterocycle and the 4-6 membered saturated carbocycle are independently optionally substituted by R 2 ;
  • R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN , -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -NH-C(O) CH 2 CN,
  • R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl);
  • q, p are independently selected from 0, 1, 2 and 3;
  • the condition is that when X 2 is N, R 2 is not -C(O)CH 2 CN; when X 2 is N, and two R 0 are substituted on adjacent carbon atoms, the two R 0 are connected to each other A 4- to 6-membered saturated carbocyclic ring is formed.
  • L 0 is selected from single bond and NR 1 ; R 1 is selected from -H and C 1 -C 3 alkyl. In another example, L 0 may also be selected from alkyl, cycloalkyl and heterocyclyl. In another example, R 1 can also be selected from other alkyl groups, cycloalkyl groups and heterocyclyl groups.
  • X 1 is selected from CH and N.
  • X 2 is selected from CR 4 and N. wherein R 4 is selected from cyano.
  • R 4 can also be selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the 5- to 6-membered unsaturated ring formed by R 1 and R 4 together includes but is not limited to one of the following groups:
  • X 5 , X 7 , X 9 , and X 10 are independently selected from NR 6 , CHR 6 and C(R 6 ) 2 ;
  • X 6 , X 8 , and X 11 are each independently selected from N and CR 6 .
  • X 3 is selected from CH and N.
  • m 2; two R 0 are substituted on the same carbon atom or on adjacent carbon atoms, and the two R 0 are connected to each other to form a 4- to 6-membered saturated A nitrogen heterocycle or a 4-6 membered saturated carbocycle.
  • the 4-6 membered saturated nitrogen heterocycle and the 4-6 membered saturated carbocyclic ring are selected from one of the following groups, and 1 or 2 carbon atoms in the ring atoms are with the group Shared carbon atoms:
  • 4-6 membered saturated nitrogen heterocycle and the 4-6 membered saturated carbocycle are independently substituted by R 2 ;
  • R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN , -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -NH-C(O) CH 2 CN and the following groups:
  • R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • the compound has the structural features shown in the following formula (I-1):
  • R 2 is selected from
  • R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy or -SC 1 -C 3 alkyl.
  • X 1 is selected from CH and N. Further, X 1 is selected from CH.
  • R 4 is selected from cyano.
  • R 1 is selected from -H and C 1 -C 3 alkyl. Further R 1 is selected from C 1 -C 2 alkyl. Still further, R 1 is selected from methyl. In another example, R 1 can also be selected from other alkyl groups, cycloalkyl groups and heterocyclyl groups.
  • R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN and the following groups:
  • R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkyl mercapto, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.
  • R 1 is selected from C 1 -C 2 alkyl.
  • X1 is selected from CH.
  • R 2 is selected from the following groups:
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • the compound has the following formula (I-2) or the structural features:
  • X 1 is selected from CH and N. Further, X 1 is selected from CH.
  • X 2 is selected from CR 4 and N. wherein R 4 is selected from cyano. In another example, R 4 can also be selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Further, X 2 is selected from C-CN. Further, X 2 is selected from N.
  • R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN and the following groups:
  • R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 alkyl mercapto, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.
  • X 2 is N; R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl) and wherein R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.
  • R 2 is selected from one of the following groups:
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • X 2 is CR 4 ;
  • R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl), -C(O)CH 2 CN and R 5 is selected from C 1 -C 3 alkoxy.
  • R 2 is selected from one of the following groups:
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • X1 is selected from CH.
  • the compound has the structural features described in the following formula (I-3):
  • X 1 is selected from CH and N. Further, X 1 is selected from CH.
  • X 2 is selected from CR 4 and N. wherein R 4 is selected from cyano. In another example, R 4 can also be selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Further, X 2 is N.
  • R 1 is selected from -H and C 1 -C 3 alkyl. In another example, R 1 can also be selected from other alkyl groups, cycloalkyl groups and heterocyclyl groups. Further, R 1 is selected from CH 3 .
  • R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN, -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3- 6-membered cycloalkyl), -NH-C(O)CH 2 CN and the following groups:
  • R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • X 2 is N
  • R 2 is selected from wherein R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.
  • R 2 is selected from the following groups:
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • R 1 is selected from CH 3 .
  • X1 is selected from CH.
  • the compound has the structural features described in the following formula (I-4):
  • X 1 is selected from CH and N. Further, X 1 is selected from CH.
  • X 2 is selected from CR 4 and N. wherein R 4 is selected from cyano. In another example, R 4 can also be selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Further, X 2 is N.
  • R 1 is selected from -H and C 1 -C 3 alkyl. In another example, R 1 can also be selected from other alkyl groups, cycloalkyl groups and heterocyclyl groups. Further, R 1 is selected from CH 3 .
  • R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN and the following groups:
  • R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • X 2 is N; R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl) or the following groups:
  • R 5 is selected from C 1 -C 3 alkoxy or -SC 1 -C 3 alkyl.
  • R 2 is selected from S(O) 2 -propyl and the following groups:
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • R 1 is selected from CH 3 .
  • X1 is selected from CH.
  • the compound has the structural features described in the following formula (I-5):
  • X 4 is selected from CH or N;
  • Ring A represents the 5- to 6-membered saturated or unsaturated ring.
  • Ring A is selected from one of the following groups:
  • X 5 , X 7 , X 9 and X 10 are independently selected from NR 6 , CHR 6 or C(R 6 ) 2 ;
  • X 6 , X 8 , and X 11 are each independently selected from N or CR 6 .
  • ring A is selected from
  • X 1 is selected from CH and N. Further, X 1 is selected from CH.
  • X 4 is selected from CH. In another embodiment, X4 is selected from N.
  • R 6 is selected from -H, -OH, C 1 -C 4 alkyl and C 1 -C 4 alkylhydroxy.
  • R 6 is selected from -H, -OH, C 1 -C 3 alkyl and C 1 -C 3 alkyl hydroxyl. Still further, R6 is selected from -H, -OH, methyl and -CH( CH3 ) OH.
  • R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN, -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3- 6-membered cycloalkyl), -NH-C(O)CH 2 CN and the following groups:
  • R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p- (3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl); q, p are independently selected from 0, 1, 2 and 3, respectively.
  • R 2 is selected from the following groups:
  • R 5 is selected from C 1 -C 3 alkoxy.
  • R 2 is selected from one of the following groups:
  • R 2 can also be selected from alkyl, cycloalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the aforementioned R 2 contains -S- or -S(O) 2 -, or is substituted with at least one cyano group or mercapto group.
  • R 6 is selected from -H, -OH, C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy.
  • R 2 is selected from the following groups:
  • R 5 is selected from C 1 -C 3 alkoxy or -SC 1 -C 3 alkyl.
  • X1 is selected from CH.
  • the azacyclic compound is selected from one of the following compounds:
  • the present invention also provides a method for preparing aza-heterocyclic compounds or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, and prodrugs.
  • the preparation method of described compound comprises the steps:
  • a compound of formula (I) is subjected to a substitution or condensation reaction with a compound comprising R 2 ;
  • R 1 in L 0 can form a 5- to 6-membered unsaturated ring together with R 4 in X 2 ; the 5- to 6-membered unsaturated ring is substituted by R 6 ;
  • X represents halogen
  • L 0 , R 1 , R 0 , R 2 , R 6 , X 1 , X 2 , R 4 , X 3 , n and m are as defined above.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, multiple Crystal form, prodrug.
  • the present invention also provides the compounds as described above or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs prepared with tyrosine kinases Use of drugs with JAK inhibitory activity.
  • the present invention also provides compounds as described above or their stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs in the preparation of prophylactic or therapeutic properties Use in medicaments for the efficacy of immune diseases, skin diseases, allergic diseases, organ rejection, cancer, dry eye disease, myelofibrosis, polycythemia.
  • the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease
  • Described skin disease is psoriasis, rash or atopic dermatitis
  • Described allergic disease is asthma or rhinitis disease
  • Described organ transplant rejection is allogeneic suppression rejection or graft-versus-host disease
  • Described cancer is kidney cancer, Liver, pancreatic, gastric, breast, prostate, head and neck, thyroid, lung, glioblastoma, melanoma, lymphoma or leukemia.
  • the present invention has one or more of the following beneficial effects:
  • the invention provides an azacyclic compound, which can be used as a novel tyrosine kinase JAK inhibitor, exert better tyrosine kinase JAK inhibitory activity, and can solve the inflammatory diseases related to various JAK-STAT signaling pathways disease or neoplastic disease.
  • the azanocyclic compound has a good selective inhibitory activity on JAK1.
  • the compounds of the present invention significantly reduced hind paw volume and arthritic index (AI) in CIA rats compared to controls.
  • the compounds of the present invention possess significant pharmacokinetic advantages.
  • Figure 1 Effects of compound administered by oral gavage once daily for 2 weeks on body weight in CIA rats.
  • Figure 4 Effects of compound administered by oral gavage once daily for 2 weeks on hind paw volume in CIA rats.
  • Figure 5 Effects of compound administered by oral gavage once a day for 2 weeks on arthritis index in CIA rats.
  • azacyclic compounds of the present invention their preparation methods and their uses will be described in further detail below with reference to specific examples.
  • the present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the present disclosure is provided.
  • optical isomer shall include one of all isomers or their mixtures, for example, double bonds, geometric isomers in rings (E, Z, cis ( cis), trans (trans)), optical isomers (R-type, S-type) produced by the presence of asymmetric carbon atoms in straight-chain alkyl groups and branched-chain alkyl groups, and mixtures thereof in any ratio. Racemic mixtures and all isomers resulting from tautomers are included in the present invention.
  • each compound structure can be different stereoisomers with the same molecular formula, among which stereoisomers also include enantiomers and diastereomers, and enantiomers are optical isomers Diastereomers are stereoisomers of achiral enantiomers, and different isomers with the same molecular formula as the compounds of the present invention are also within the protection scope of the present invention.
  • salts refers to compounds that can be converted by conventional methods into the corresponding salts which are chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and which are physiologically compatible with the receptor .
  • the salts may be acid and/or base salts of the compound with inorganic and/or organic acids and/or with inorganic and/or organic bases, including zwitterionic salts (inner salts), and also quaternary ammonium salts, such as Alkylammonium salts.
  • These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the compound of the present invention or its stereoisomer or solvate with a certain amount of acid or base.
  • the salt is preferably a water-soluble pharmaceutically acceptable non-toxic acid addition salt, exemplified by an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with an organic acid (such as acetic acid) , oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods conventional in the art such as ion exchange.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acid such as acetic acid
  • oxalic acid maleic acid, tartaric acid, citric acid, succinic acid or malonic acid
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonic acid Salt, Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobate, Lactate, Laurate, Lauryl sulfonate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bisulfate Hynaphate, pectate,
  • Additional pharmaceutically acceptable salts may also include salts derived from suitable bases, including alkali metal, alkaline earth metal, and ammonium salts, as appropriate.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Additional pharmaceutically acceptable salts include the use of counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates with nontoxic ammonium, as appropriate. , quaternary ammonium and salts of amine cations.
  • solvate may also be referred to as “solvate”, “solvate”, and refers to a compound containing solvent molecules, wherein the solvent molecules can include coordinate bonds, covalent bonds, van der Waals forces, ionic bonds, hydrogen bond to the compound molecule.
  • Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds described herein can be prepared, eg, in crystalline forms, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates.
  • the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • prodrug refers to any compound that, when administered to an organism, produces a drug, ie, an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions.
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
  • Suitable examples include, but are not limited to: carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compounds, carbamates, azo compounds, phosphoramides, glucosides of compounds , ether, acetal and other forms.
  • an aryl group is optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the term includes instances where the aryl group is substituted with an alkyl group and instances where the aryl group is not substituted with an alkyl group.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • pharmaceutically acceptable carrier includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents and absorption agents compatible with pharmaceutical administration Delays and the like. Each carrier must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient.
  • Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted beta-cyclodextrins; (3) cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; Formulations such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyvalent Alcohols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers such as magnesium hydroxide and hydrogen
  • metabolite refers to a substance including the products of the compounds of the present invention produced during metabolism in vivo, including intermediate metabolites and final metabolites.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) of a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature and other factors can cause one crystalline form to dominate. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • alkyl refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof.
  • Alkyl groups are preferably, for example, C 1 -C 6 -alkyl, C 1 -C 5 -alkyl, C 1 -C 4 -alkyl and C 1 -C 3 -alkyl groups.
  • C 1 -C 3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms, and each time it appears, it can be independently C 1 alkyl, C 2 alkyl, C 3 alkane base.
  • Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH( CH3 ) 2 ).
  • alkenyl is an alkyl group as defined herein containing at least one carbon-carbon double bond.
  • the alkenyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2 to 6 carbon atoms.
  • alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl or 4-decenyl and the like.
  • Alkynyl is an alkyl group as defined herein containing at least one carbon-carbon triple bond.
  • the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2-6 carbon atoms.
  • saturated or unsaturated ring includes carbocyclyl, heterocyclyl, aryl and heteroaryl groups as defined below.
  • Carbocyclyl or “cycloalkyl” refers to a saturated or partially unsaturated cyclic carbon-containing group, such as a 4-6 membered (eg, 5-6 membered) saturated carbocycle and a 5-6 membered partially Saturated carbocycle.
  • the carbocyclyl group is a 3- to 4-membered monocycle, a 3- to 5-membered monocycle, a 3- to 6-membered monocycle, a 3- to 8-membered monocycle, a 3- to 10-membered monocycle , 5 to 8 membered monocyclic, 5 to 6 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring systems.
  • Carbocycles include bridged or spiro rings.
  • Non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl or spiro[3.3]heptane Base et al. Carbocyclyl groups can be optionally substituted.
  • saturated cycloalkyl comprises a non-aromatic hydrocarbon containing ring carbon atoms and may be a monocycloalkyl or a bridged cycloalkyl.
  • 3-6 membered saturated cycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms, each occurrence of which may independently be C 3 cycloalkyl, C 4 -cycloalkyl, C5 -cycloalkyl or C6 -cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the saturated cycloalkyl is a 4-6 membered saturated carbocycle, more preferably a 5-6 membered saturated carbocycle.
  • saturated nitrogen heterocyclyl refers to a saturated cycloalkyl group in which at least one ring carbon atom is substituted with N.
  • halogen refers to -F, -Cl, -Br or -I.
  • haloalkyl refers to an alkyl group substituted with a halogen group, wherein the alkyl group is as defined above, preferably haloC1-6 alkyl, haloC1-5 alkyl, haloC1 -4 alkyl, halogenated C 1-3 alkyl and halogenated C 1-2 alkyl.
  • cyano refers to -CN.
  • mercapto refers to -SH.
  • hydroxy refers to -OH.
  • alkylhydroxy refers to an alkyl group substituted with a hydroxyl group, wherein the alkyl group is as defined above, preferably C1-6 alkylhydroxyl, C1-5 alkylhydroxyl, C1-4 alkylhydroxyl , C 1-3 alkyl hydroxyl and C 1-2 alkyl hydroxyl.
  • alkoxy refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom. Phrases containing this term, for example, "C 1 -C 5 alkoxy” means the alkyl moiety contains 1 to 5 carbon atoms, "C 1 -C 3 alkoxy” means the alkyl moiety contains 1 to 3 carbon atoms carbon atoms.
  • aryl refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing one hydrogen atom, which can be a monocyclic aryl group, a fused-ring aryl group, or a polycyclic aryl group, preferably a 6-10 membered aryl group base.
  • polycyclic ring species at least one is an aromatic ring system.
  • Phrases containing this term, for example, "5-6 membered aryl” means that the aromatic ring system contains 5-6 ring atoms.
  • the aryl group is phenyl.
  • heteroaryl refers to aryl groups containing heteroatoms, which may be monocyclic or fused, independently selected from N, O and S, preferably 5-12 membered heteroaryl groups, preferably is a 5-8-membered heteroaryl group, more preferably a 5-6-membered heteroaryl group, and more preferably a 5-membered heteroaryl group.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, Isoquinolinyl, triazolyl, tetrahydropyrrolyl and thiadiazolyl.
  • a 5-6 membered monocyclic heteroaryl group typically contains 1 or more, preferably 1-3 heteroatoms independently selected from N, O and S.
  • 5-membered heteroaryl is an exemplary 5-membered heteroaryl group containing one heteroatom including, but not limited to, pyrrolyl, furyl, and thienyl; exemplary groups containing two heteroatoms 5-membered heteroaryl groups include, but are not limited to, imidazolyl, pyrazolyl, oxazolinyl, isoxazolinyl, thiazolyl, and isothiazolyl; exemplary 5-membered heteroatoms containing three heteroatoms Aryl groups include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl; exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or partially unsaturated cyclic group containing a heteroatom selected from N, O and S. Further, the term “heterocyclyl” refers to a non-aromatic group of a stable 3-10 membered saturated heterocyclic ring system wherein one or more of the ring-constituting atoms are heteroatoms and the remainder is carbon.
  • the heteroatoms include, but are not limited to, nitrogen atoms, oxygen atoms, sulfur atoms, and the like.
  • the heterocyclyl group may be a 3- to 8-membered monocyclic ring, a 5- to 8-membered monocyclic ring, a 5- to 6-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic ring system, preferably a 3- to 10-membered ring system Heterocyclyl, and contains at least 1, preferably 1 to 4 heteroatoms selected from N, O or S.
  • a heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic or more cyclic ring system, which may include and Cyclic (fused), bridged (bridged), or spiro ring systems (eg, bicyclic ring systems ("bicyclic heterocycloalkyl").
  • the ring systems of bicyclic heterocycloalkyl groups may be in a and is saturated.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridyl, oxiranyl, and thiirane , or a stereoisomer thereof;
  • exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, propylene oxide, thietane, or isomers thereof and Stereoisomers;
  • exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidine radical, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, or isomers and stereoisomers thereof.
  • Exemplary 6-membered Heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, thiacyclohexyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, Triazinyl, or isomers and stereoisomers thereof;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiacycle Heptyl group, and diazepanyl group, or its isomers and stereoisomers.
  • a typical heterocyclic group contains 1 or more, preferably 1-4 , more preferably a 5-6 membered monocyclic heterocyclyl with 1-3 heteroatoms independently selected from N, O and S.
  • heterocycloalkyl is a 4-6 membered heterocycloalkyl , wherein the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • the alkyl group represents the alkylene group to which it is attached, eg, the group " -C1 - C3 haloalkyl" Alkyl in should be understood to mean alkylene.
  • the present invention adopts traditional methods such as mass spectrometry and nuclear magnetic resonance to identify compounds, and each step and condition can refer to the routine operation steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the description method "...respectively independently” used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups.
  • the description mode "...respectively independently” can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same symbols are The specific options expressed between them do not affect each other.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the present invention provides a compound having the structure represented by general formula (I) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph Type, prodrug:
  • L 0 is selected from single bond and NR 1 ;
  • X 1 is selected from CH and N;
  • X 2 is selected from CR 4 and N;
  • R 4 is cyano, R 1 is selected from -H and C 1 -C 3 alkyl, or R 1 and R 4 together form a 5-6 membered saturated or unsaturated ring; the 5-6 membered saturated or unsaturated ring replaced by R 6 ;
  • X 3 is selected from CH and N;
  • n is selected from 1 and 2;
  • the 4-6 membered saturated nitrogen heterocycle or the 4-6 membered saturated carbocycle is independently substituted by R 2 ;
  • R 2 is selected from -S(O) 2 (C 1 -C 6 alkyl), -S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -C(O)CH 2 CN , -NH-S(O) 2 (C 1 -C 6 alkyl), -NH-S(O) 2 (CH 2 ) q -(3-6 membered cycloalkyl), -NH-C(O) CH 2 CN,
  • R 5 is selected from C 1 -C 5 alkyl, cyano, 3-5 membered saturated cycloalkyl, C 1 -C 5 alkoxy, -SC 1 -C 5 alkyl, -O-(CH 2 ) p -(3-6 membered cycloalkyl) and -S-( CH2 ) p- (3-6 membered cycloalkyl);
  • q, p are independently selected from 0, 1, 2 and 3;
  • the condition is that when X 2 is N, R 2 is not -C(O)CH 2 CN; when X 2 is N, and two R 0 are substituted on adjacent carbon atoms, the two R 0 are connected to each other A 4- to 6-membered saturated carbocyclic ring is formed.
  • the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the 4- to 6-membered saturated nitrogen heterocyclic ring and the 4- to 6-membered saturated carbocyclic ring are selected from one of the following groups, and 1 or 2 carbon atoms in the ring atoms are associated with the group Shared carbon atoms:
  • the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the following formula (I-1) or the structural feature:
  • the present invention provides the compound represented by the above formula (I-1) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, characterized in that R 2 is selected from
  • R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.
  • the present invention provides the compound represented by the above formula (I-1) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that R 1 is selected from C 1 -C 2 alkyl.
  • the present invention provides the compound represented by the above formula (I-1) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.
  • the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the structural features described in the following formula (I-2):
  • the present invention provides a compound represented by the above formula (I-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterized in that, X is N ;
  • R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl) and wherein R 5 is selected from -S-(3-5 membered cycloalkyl), C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.
  • the present invention provides the compound represented by the above formula (I-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 2 is CR 4 ;
  • R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl), -S(O) 2 CH 2 -(3-4 membered cycloalkyl), -C(O)CH 2 CN and R 5 is selected from C 1 -C 3 alkoxy.
  • the present invention provides the compound represented by the above formula (I-2) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.
  • the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the structural features described in the following formula (I-3):
  • the present invention provides the compound represented by the above formula (I-3) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterized in that, X is N ;
  • R 2 is selected from
  • R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.
  • the present invention provides the compound represented by the above formula (I-3) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that R 1 is selected from CH 3 .
  • the present invention provides the compound represented by the above formula (I-3) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.
  • the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the structural features described in the following formula (I-4):
  • the present invention provides the compound represented by the above formula (I-4) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterized in that, X is N ;
  • R 2 is selected from -S(O) 2 (C 1 -C 3 alkyl) and the following groups:
  • R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.
  • the present invention provides the compound represented by the above formula (I-4) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that R 1 is selected from CH 3 .
  • the present invention provides the compound represented by the above formula (I-4) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.
  • the present invention provides compounds of formula (I) above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, A prodrug, characterized in that the compound has the structural features described in the following formula (I-5):
  • X 4 is selected from CH or N;
  • Ring A represents the 5- to 6-membered saturated or unsaturated ring.
  • the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterised in that ring A is selected from one of the following groups:
  • X 5 , X 7 , X 9 , and X 10 are independently selected from NR 6 , CHR 6 and C(R 6 ) 2 ;
  • X 6 , X 8 , and X 11 are each independently selected from N and CR 6 .
  • the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, characterized in that R 6 is selected from -H, -OH, C 1 -C 3 alkyl and C 1 -C 3 alkyl hydroxyl.
  • the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type, prodrug, it is characterised in that R 2 is selected from the following groups:
  • R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl.
  • the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph type and prodrug, characterized in that X 1 is selected from CH.
  • the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph Type, prodrug, is characterized in that:
  • X 4 is N
  • R 5 is selected from C 1 -C 3 alkoxy and -SC 1 -C 3 alkyl
  • X5 is each independently NR6 or CHR6 ;
  • X 6 is each independently N or CR 6 ;
  • R 6 is selected from -H, -OH, C 1 -C 3 alkyl and C 1 -C 3 alkylhydroxy.
  • the present invention provides the compound represented by the above formula (I-5) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph Type, prodrug, is characterized in that:
  • X 4 is N
  • R 5 is C 1 -C 3 alkoxy
  • One of X 6 is N and the other is CR 6 ;
  • R 6 is C 1 -C 3 alkyl.
  • the present invention provides a compound having the structure represented by general formula (a) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs Type, prodrug:
  • L is NR c or bond
  • Y 1 is selected from CH or N;
  • Y 2 is selected from CH or N;
  • Y 3 is selected from CH or N;
  • R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ;
  • R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ;
  • R c is H or C 1-6 alkyl
  • R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5-8 membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of: -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ;
  • R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;
  • R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • n1 0, 1, 2 or 3;
  • n2 0, 1, 2 or 3;
  • n1 is 1, 2 or 3;
  • n2 is 1, 2 or 3.
  • the present invention provides a compound having a structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs:
  • Y 1 is selected from CH and N, wherein when Y 1 is CH, it is substituted with R b ;
  • R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ;
  • R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ;
  • R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5-8 membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of: -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ;
  • R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;
  • n1 0, 1, 2 or 3;
  • n2 0, 1, 2 or 3;
  • n1 is 1, 2 or 3;
  • n2 is 1, 2 or 3.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • Y 1 is N
  • R a is selected from -C(O)NR 8 R 9 ;
  • R 9 is -H
  • R 8 is selected from 6-10 membered aryl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 heteroatoms independently selected from N, O and S 5-8 membered heterocyclyl of heteroatoms; each of said aryl, heteroaryl and heterocyclyl is optionally substituted with 1-3 substituents independently selected from: -H, -ORx , -SRx , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;
  • n1 0, 1, 2 or 3;
  • n2 0, 1, 2 or 3;
  • n1 is 1, 2 or 3;
  • n2 is 1, 2 or 3.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • Y 1 is N
  • R a is selected from -C(O)NR 8 R 9 ;
  • R 9 is -H
  • R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x and -CN;
  • R x is selected from C 1-6 alkyl and halogenated C 1-6 alkyl
  • n1 0, 1, 2 or 3;
  • n2 0, 1, 2 or 3;
  • n1 is 1, 2 or 3;
  • n2 is 1, 2 or 3.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • Y 1 is N
  • R a is selected from -C(O)NR 8 R 9 ;
  • R 9 is -H
  • R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-2 substituents independently selected from: -OR x and -SR x ;
  • R x is C 1-4 alkyl
  • n1 0, 1, 2 or 3;
  • n2 0, 1, 2 or 3;
  • n1 is 1, 2 or 3;
  • n2 is 1, 2 or 3.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (b), (b-1) or (b-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • Y 1 is N
  • R a is selected from -C(O)NR 8 R 9 ;
  • R 9 is -H
  • R 8 is a 5-membered heteroaryl containing 3 heteroatoms independently selected from N and S; the heteroaryl is substituted with substituents independently selected from: -ORx and -SRx ;
  • R x is C 1-4 alkyl, preferably methyl or ethyl
  • n1 0;
  • n1 2;
  • n2 1
  • the present invention provides a compound having the structure represented by general formula (c) or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph Type, prodrug:
  • R a is selected from -C(O)R 7 , -C(O)NR 8 R 9 , -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ;
  • R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ;
  • R 7 is a 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, optionally substituted with 1-3 substituents independently selected from the following: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5-8 membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 9 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R 10 is selected from C 1-6 alkyl, 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S and a 5-8 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O, and S; Substituted with substituents independently selected from the group consisting of: -H, -ORx , -SRx , -CN, halogen, C1-6alkyl , and halogenated C1-6alkyl ;
  • R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;
  • R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • n1 0, 1, 2 or 3;
  • n2 0, 1, 2 or 3;
  • n1 is 1, 2 or 3;
  • n2 is 1, 2 or 3.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (c) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, poly Crystalline forms, prodrugs, wherein:
  • Ra is selected from -S(O) 2 R 10 and -S(O) 2 NR 10 R 11 ;
  • R b is selected from -CN, halogen, -OR x and -SR x ;
  • R 10 is selected from C 1-6 alkyl and 5-8-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; the heteroaryl is optionally selected from 1-3 independently Substituted from the following substituents: -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 11 is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R x is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • n1 0, 1, 2 or 3;
  • n2 0, 1, 2 or 3;
  • n1 is 1, 2 or 3;
  • n2 is 1, 2 or 3.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (c) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, poly Crystalline forms, prodrugs, wherein:
  • Ra is selected from -S(O) 2 R 10 ;
  • R b is -CN
  • R 10 is C 1-6 alkyl
  • n1 0, 1, 2 or 3;
  • n2 0, 1, 2 or 3;
  • n1 is 1, 2 or 3;
  • n2 is 1, 2 or 3.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (c) or its stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, multiple Crystal form, prodrug, wherein: R a is -S(O) 2 R 10 ;
  • R b is -CN
  • R 10 is C 1-4 alkyl, preferably propyl
  • n1 0;
  • n2 2;
  • n1 2;
  • n2 1
  • the present invention provides a compound having a structure represented by general formula (d), (d-1) or (d-2) or its stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs,
  • Y 1 is selected from CH and N;
  • R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5-8 membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R b is selected from -H, -CN, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -NR'R", -OR x and -SR x ;
  • R c is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;
  • R' and R" are each independently selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • p1 is 0, 1 or 2;
  • p2 is 0, 1 or 2;
  • q1 0, 1 or 2;
  • q2 0, 1 or 2.
  • the present invention provides a compound having a structure represented by general formula (e), (e-1) or (e-2) or its stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs,
  • R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R c is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;
  • p1 is 0, 1 or 2;
  • p2 is 0, 1 or 2;
  • q1 0, 1 or 2;
  • q2 0, 1 or 2.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (e), (e-1) or (e-2) or its stereoisomers, N-oxides, hydrates, solvates , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x , -CN and halogen;
  • R c is selected from -H and C 1-6 alkyl
  • R d is selected from -H and C 1-6 alkyl
  • R e is selected from -H and C 1-6 alkyl
  • R x is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • p1 is 0, 1 or 2;
  • p2 is 0, 1 or 2;
  • q1 0, 1 or 2;
  • q2 0, 1 or 2.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (e), (e-1) or (e-2) or its stereoisomers, N-oxides, hydrates, solvates , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-3 substituents independently selected from: -OR x and -SR x ;
  • R c is selected from -H and C 1-4 alkyl
  • R d is selected from -H and C 1-4 alkyl
  • R e is selected from -H and C 1-4 alkyl
  • R x is C 1-4 alkyl
  • p1 is 1 or 2;
  • p2 is 1 or 2;
  • q1 is 1 or 2;
  • q2 is 1 or 2.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (e), (e-1) or (e-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • R 8 is a 5-membered heteroaryl group containing 3 heteroatoms independently selected from N and S; the heteroaryl group is substituted with -OR x ;
  • R c is C 1-4 alkyl, preferably methyl
  • R d is -H
  • Re is -H
  • R x is C 1-4 alkyl, preferably methyl
  • p1 is 1;
  • p2 is 1;
  • the present invention provides a compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate, Metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs,
  • R 8 is selected from 6-10 membered aryl, 5-8 membered cycloalkyl, 5-8 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 1-3 independently A 5- to 8-membered heterocyclic group of heteroatoms selected from N, O and S; the aryl, cycloalkyl, heteroaryl and heterocyclic groups are each optionally via 1-3 substituents independently selected from the following Substituted: -H, -OR x , -SR x , -CN, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • Rc and Rf together with the atoms to which they are attached form a 5-8 membered heteroaryl containing 1-2 heteroatoms independently selected from N, O and S or 1-3 heteroatoms independently selected from N, O and A 5-8 membered heterocyclyl of a heteroatom of S; the heteroaryl or heterocyclyl is substituted with a substituent independently selected from the group consisting of: -H, oxo, -ORx , -SRx , -CN, halogen , C 1-6 alkyl, halogenated C 1-6 alkyl and hydroxy substituted C 1-6 alkyl;
  • R d is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R e is selected from -H, C 1-6 alkyl and halogenated C 1-6 alkyl
  • R x is selected from -H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 2-6 alkenyl and -C 2-6 alkynyl;
  • p1 is 0, 1 or 2;
  • p2 is 0, 1 or 2;
  • q1 0, 1 or 2;
  • q2 0, 1 or 2.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • R 8 is selected from phenyl and 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S; each of said phenyl and heteroaryl is optionally independently selected from 1-3 Substituted from the following substituents: -OR x , -SR x , -CN and halogen;
  • Rc and Rf taken together with the atoms to which they are attached, form a 5-6 membered heteroaryl group containing 1-2 heteroatoms independently selected from N, O, and S; the heteroaryl group is independently selected from 1-2 Substituted from the following substituents: -OR x , -SR x , C 1-4 alkyl and hydroxy substituted C 1-4 alkyl;
  • R d is selected from -H and C 1-4 alkyl
  • R e is selected from -H and C 1-4 alkyl
  • R x is selected from -H, C 1-4 alkyl and halogenated C 1-4 alkyl
  • p1 is 0, 1 or 2;
  • p2 is 0, 1 or 2;
  • q1 0, 1 or 2;
  • q2 0, 1 or 2.
  • the present invention provides the above-mentioned compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • R 8 is a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N and S; the heteroaryl is optionally substituted with 1-3 -OR x ;
  • R c and R f taken together with the atoms to which they are attached form a 5-6 membered heteroaryl group containing 2 N atoms; the heteroaryl group is selected from -H, C 1-4 alkyl and hydroxy through 1-2 Substituent substitution of substituted C 1-4 alkyl;
  • R d is -H
  • Re is -H
  • R x is C 1-4 alkyl
  • p1 is 1;
  • p2 is 1;
  • the present invention provides the above-mentioned compound having the structure represented by general formula (f), (f-1) or (f-2) or its stereoisomer, N-oxide, hydrate, solvate , metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs, wherein:
  • R 8 is a 5-membered heteroaryl group containing 3 heteroatoms independently selected from N and S; the heteroaryl group is substituted with -OR x ;
  • R c and R f together with the atoms to which they are attached form a 5-membered heteroaryl group containing 2 N atoms; the heteroaryl group is substituted with C 1-4 alkyl, preferably methyl;
  • R d is -H
  • Re is -H
  • R x is C 1-4 alkyl, preferably methyl
  • p1 is 1;
  • p2 is 1;
  • the compound is selected from the following structures:
  • Embodiments of the present invention also provide a method for preparing the compound, comprising the steps of:
  • a compound of formula (I) is subjected to a substitution or condensation reaction with a compound comprising R 2 ;
  • R 1 in L 0 can form a 5- to 6-membered unsaturated ring together with R 4 in X 2 ; the 5- to 6-membered unsaturated ring is substituted by R 6 ;
  • X represents halogen
  • L 0 , R 1 , R 0 , R 2 , R 6 , X 1 , X 2 , R 4 , X 3 , n and m are as defined above.
  • the compound of formula (I) is subjected to a condensation reaction with the compound containing R 2 .
  • the reagent used may be N,N'-carbonyldiimidazole (CDI).
  • R 4 is -NH 2
  • R 1 is -H
  • R 1 in L 0 can form a 5- to 6-membered unsaturated ring together with R 4 in X 2 , which refers to a cyclization reaction.
  • An embodiment of the present invention also provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the above-mentioned compound or its stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutical Acceptable salts, polymorphs, prodrugs above.
  • Embodiments of the present invention also provide compounds as described above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs thereof prepared with phenol Use of a drug for the inhibitory activity of the amino-kinase JAK.
  • Embodiments of the present invention also provide compounds as described above, or stereoisomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, polymorphs, prodrugs thereof, prepared with prophylactic Or the application in the medicine of the efficacy of treating autoimmune disease, skin disease, allergic disease, organ rejection, cancer, dry eye disease, myelofibrosis, polycythemia.
  • Embodiments of the present invention also provide compounds as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, prodrug or as described above thereof A pharmaceutical composition for inhibiting the tyrosine kinase JAK.
  • Embodiments of the present invention also provide compounds as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph, prodrug or as described above thereof
  • the pharmaceutical composition for preventing or treating a disease selected from the group consisting of autoimmune disease, skin disease, allergic disease, organ rejection, cancer, dry eye disease, myelofibrosis and polycythemia.
  • Embodiments of the present invention also provide a method of inhibiting the tyrosine kinase JAK comprising administering a compound as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable compound thereof Accepted salts, polymorphs or prodrugs or pharmaceutical compositions as described above.
  • Embodiments of the present invention also provide a method of preventing or treating a disease selected from the group consisting of autoimmune disease, skin disease, allergic disease, organ rejection, cancer, dry eye disease, myelofibrosis and polycythemia, which This includes administering a compound as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or a pharmaceutical composition as described above.
  • the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or autoimmune thyroid disease;
  • the skin disease is psoriasis, rash or atopic dermatitis;
  • the allergic condition is asthma or rhinitis;
  • the organ transplant rejection is allogeneic suppression rejection or graft-versus-host disease;
  • the cancer is kidney cancer , liver cancer, pancreatic cancer, stomach cancer, breast cancer, prostate cancer, head and neck cancer, thyroid cancer, lung cancer, glioblastoma, melanoma, lymphoma or leukemia.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC measurement was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6 mm).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from Titan Technology, Annagy Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.
  • Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature.
  • Room temperature is the most suitable reaction temperature, which is 20°C to 30°C.
  • TBSOTf tert-butyldimethylsilyl triflate
  • DIEA N,N-diisopropylethylamine
  • TFA trifluoroacetic acid
  • CDI N,N'-carbonyldiimidazole
  • TsOH p-toluenesulfonic acid
  • TsCl 4-methylbenzenesulfonyl chloride
  • Pd/C palladium/carbon
  • 6-(5-Cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate tert-butyl ester 1B 400 mg, 1.13 mmol was dissolved in an ethyl acetate solution of hydrogen chloride (10 mL, 1.5 mol/L), and the solution was stirred at room temperature to react overnight.
  • Step 3 4-(1-(2-cyanoacetyl)-1,6-diazaspiro[3.4]octan-6-yl)-1H-pyrrolo[2,3-b]pyridine- 5-carbonitrile (compound 1)
  • Step 2 6-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6 - tert-butyl diazaspiro[3.4]octane-1-carboxylate 2C
  • 6-(5-Cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate tert-butyl ester 1B 400 mg, 1.13 mmol was dissolved in an ethyl acetate solution of hydrogen chloride (10 mL, 1.5 mol/L), and the solution was stirred at room temperature to react overnight.
  • Step 2 4-(1,6-Diazaspiro[3.5]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (5C)
  • 6-(7-Tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylate tert-butyl ester 5B 130 mg, 0.26 mmol was dissolved in a dichloromethane solution (10 mL), TBSOTf (103 mg, 0.39 mmol) was added, and the solution was stirred at room temperature and reacted overnight.
  • the third step 4-(1-(propylsulfonyl)-1,6-diazaspiro[3.5]nonan-6-yl)-7-toluenesulfonyl-7H-pyrrolo[2,3- d]pyrimidine 5D
  • tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate 500 mg, 2.4 mmol
  • methylamine aqueous solution 5 mL
  • NaBH 3 CN 630 mg, 10 mmol
  • reaction mixture was extracted with ethyl acetate (10 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 7-(methylamino)-2-azaspiro[3.5]nonane- 2-Carboxylic acid tert-butyl ester 6B (500 mg, crude).
  • Step 2 7-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino )-2-Azaspiro[3.5]nonane-2-carboxylate tert-butyl ester (6C)
  • Step 3 N-methyl-N-(2-azaspiro[3.5]nonan-7-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-Pyrrolo[2,3-d]pyrimidin-4-amine (6D)
  • Nonane-2-carboxamide 6E was a white solid (180 mg, 50.4% yield).
  • N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-7-(methyl(7-((2-(trimethylsilyl)ethoxy)methyl) yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxamide 6E 180 mg, 0.32 mmol was dissolved in DCM (4 mL) ), added TFA (2 mL), and reacted at room temperature for 2 hours.
  • reaction solution was concentrated, purified by preparative HPLC, and lyophilized to obtain N-(3-methoxy-1,2,4-thiadiazol-5-yl)-7-(methyl(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonane-2-carboxamide (compound 6) was a white solid (5 mg, 3.6% yield).
  • Step 4 N-(3-(Ethylthio)-1,2,4-thiadiazol-5-yl)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -1,6-Diazaspiro[3.5]nonane-1-carboxamide (Compound 8)
  • the white solid compound methanesulfonic acid (3aR,5s,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane ]-5-yl ester 9D (700 mg, 2.3 mmol) was dissolved in methanol (3 mL), then 30% methylamine ethanol solution (5 mL, 11.5 mmol) was added at 0 °C with stirring, and the mixture was stirred at room temperature for further reaction 16 Hour.
  • Step 7 (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopenta Dien-2-ol (9H)
  • Step 8 Methanesulfonic acid (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydro cyclopentadien-2-yl ester (9I)
  • Step 9 N-((2r,3aR,5s,6aS)-5-azidooctahydrocyclopentadien-2-yl)-N-methyl-7-toluenesulfonyl-7H-pyrrolo [2,3-d]pyrimidin-4-amine (9J)
  • Methanesulfonic acid (2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopenta Dien-2-yl ester 9I (80 mg, 0.198 mmol) was dissolved in acetonitrile (3 mL), then tetrabutylamine azide (112 mg, 0.396 mmol) was added with stirring. The mixture was stirred at 90°C for 3 hours under nitrogen protection.
  • Step 10 (2s,3aR,5r,6aS)-N2 - methyl - N2-(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydro Cyclopentadiene-2,5-diamine (9K)
  • Step 12 N-((2s,3aR,5r,6aS)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadiene -2-yl)propane-1-sulfonamide (compound 9)
  • the first step 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (10A)
  • Step 2 6-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )-1,6-diazaspiro[3.5]nonane-1-carboxylate tert-butyl ester (10B)
  • the third step 4-(1,6-diazaspiro[3.5]nonan-6-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- Pyrrolo[2,3-b]pyridine-5-carbonitrile (10C)
  • Step 4 6-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )-N-(3-Methoxy-1,2,4-thiadiazol-5-yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (10D)
  • Step 5 6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-N-(3-methoxy-1,2,4-thiadiazole-5 -yl)-1,6-diazaspiro[3.5]nonane-1-carboxamide (Compound 10)
  • the first step 4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (11A)
  • Step 2 (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino) Hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate tert-butyl ester (11B)
  • the third step 4-(methyl((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)amino)-1-toluenesulfonyl-1H-pyrrolo[2, 3-b]pyridine-5-carbonitrile (11C)
  • Step 4 (3aR,5s,6aS)-5-((5-cyano-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino) -N-(3-(Methylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (11D)
  • Step 5 (3aR,5s,6aS)-5-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N-(3- (Methylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 11)
  • Step 2 (3aR,5s,6aS)-5-((5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)(methyl)amino)-N-(3- (Ethylthio)-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 12)
  • Step 6 5-Nitro-N-((3aR,5s,6aS)-octahydrocyclopentadieno[c]pyrrol-5-yl)-1-(phenylsulfonyl)-1H-pyrrolo [2,3-b]pyridin-4-amine (13H)
  • the seventh step (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-((5-nitro-1-(benzenesulfonyl) Acyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (13I)
  • the ninth step (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(6-(benzenesulfonyl)imidazo[4] ,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (13K)
  • Step 10 (3aR,5s,6aS)-5-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-N-(3-methoxy yl-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (Compound 13)
  • the first step (3aR,5s,6aS)-5-(2-((R)-1-hydroxyethyl)-6-(benzenesulfonyl)imidazo[4,5-d]pyrrolo[2, 3-b]pyridin-1(6H)-yl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2 (1H)-Carboxamide (15A)
  • Step 2 (3aR,5s,6aS)-5-(2-((R)-1-hydroxyethyl)imidazo[4,5-d]pyrrolo[2,3-b]pyridine-1( 6H)-yl)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxamide (compound 15)
  • the first step 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2r,3aR,5s,6aS)-5-(methyl(7-toluene) Sulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea (16A)
  • Step 2 N-((2r,3aR,5r,6aS)-5-(methyl(7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydro cyclopentadien-2-yl)propane-1-sulfonamide 18B
  • the first step 1-(3-methoxy-1,2,4-thiadiazol-5-yl)-3-((2s,3aR,5s,6aS)-5-(methyl(7-toluene) Sulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)octahydrocyclopentadien-2-yl)urea 19A
  • Methanesulfonic acid (3aR,5s,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane]-5 -Base ester 9D (16 g, crude product) and tetrabutylammonium azide (22.4 g, 78.84 mmol) were dissolved in acetonitrile (30 mL) and reacted at 90 °C for 4 h under nitrogen protection.
  • the third step N-((3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[cyclopentadiene-2,2'-[1,3]dioxane ]-5-yl)-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 20C
  • N-((3aR,5r,6aS)-5',5'-dimethylhexahydro-1H-spiro[p-cyclopentadiene-2,2'-[1,3]dioxane]-5 -yl)-5-nitro-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine 20C (6.2 g, 11.7 mmol) was dissolved in acetone (30 mL), water was added (10 mL) and TsOH (203 mg, 1.18 mmol) and stirred at room temperature for 15 h.

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Abstract

L'invention concerne un composé azacyclique, son procédé de préparation et son utilisation. Le composé azacyclique a une structure telle que représentée par la formule générale (I). Le composé azacyclique a une excellente activité inhibitrice de janus kinase (JAK) et peut être utilisé en tant qu'inhibiteur de janus kinase (JAK) pour soulager diverses maladies inflammatoires ou maladies tumorales associées à la voie de signalisation JAK-STAT.
PCT/CN2021/135357 2020-12-04 2021-12-03 Composé azacyclique, son procédé de préparation et son utilisation WO2022117075A1 (fr)

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CN117586285B (zh) * 2024-01-19 2024-04-05 英矽智能科技(上海)有限公司 三并环类化合物

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1439010A (zh) * 2000-06-26 2003-08-27 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物作为免疫抑制剂
CN102510865A (zh) * 2009-07-31 2012-06-20 日本烟草产业株式会社 含氮螺环化合物及其药物用途
WO2013091539A1 (fr) * 2011-12-21 2013-06-27 江苏恒瑞医药股份有限公司 Dérivé pyrrole de cycle hétéroaryle à six chaînons, procédé de préparation de celui-ci, et ses utilisations médicinales
WO2017140254A1 (fr) * 2016-02-19 2017-08-24 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un inhibiteur de janus kinase (jak) ou un sel pharmaceutiquement acceptable de celui-ci
WO2018095320A1 (fr) * 2016-11-23 2018-05-31 江苏恒瑞医药股份有限公司 Procédé de préparation et intermédiaire d'un dérivé de noyau hétéroaromatique à six chaînons de pyrrolo
CN108570048A (zh) * 2017-03-10 2018-09-25 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
CN111662295A (zh) * 2019-03-05 2020-09-15 珠海宇繁生物科技有限责任公司 一种irak4激酶抑制剂及其制备方法
WO2020182159A1 (fr) * 2019-03-14 2020-09-17 上海华汇拓医药科技有限公司 Inhibiteur de kinase jak, son procédé de préparation et ses applications dans le domaine de la médecine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1439010A (zh) * 2000-06-26 2003-08-27 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物作为免疫抑制剂
CN102510865A (zh) * 2009-07-31 2012-06-20 日本烟草产业株式会社 含氮螺环化合物及其药物用途
WO2013091539A1 (fr) * 2011-12-21 2013-06-27 江苏恒瑞医药股份有限公司 Dérivé pyrrole de cycle hétéroaryle à six chaînons, procédé de préparation de celui-ci, et ses utilisations médicinales
WO2017140254A1 (fr) * 2016-02-19 2017-08-24 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un inhibiteur de janus kinase (jak) ou un sel pharmaceutiquement acceptable de celui-ci
WO2018095320A1 (fr) * 2016-11-23 2018-05-31 江苏恒瑞医药股份有限公司 Procédé de préparation et intermédiaire d'un dérivé de noyau hétéroaromatique à six chaînons de pyrrolo
CN108570048A (zh) * 2017-03-10 2018-09-25 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
CN111662295A (zh) * 2019-03-05 2020-09-15 珠海宇繁生物科技有限责任公司 一种irak4激酶抑制剂及其制备方法
WO2020182159A1 (fr) * 2019-03-14 2020-09-17 上海华汇拓医药科技有限公司 Inhibiteur de kinase jak, son procédé de préparation et ses applications dans le domaine de la médecine

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