WO2020108516A1 - Nitrogen-containing heteroaryl derivative regulator, preparation method therefor, and uses thereof - Google Patents
Nitrogen-containing heteroaryl derivative regulator, preparation method therefor, and uses thereof Download PDFInfo
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- WO2020108516A1 WO2020108516A1 PCT/CN2019/121205 CN2019121205W WO2020108516A1 WO 2020108516 A1 WO2020108516 A1 WO 2020108516A1 CN 2019121205 W CN2019121205 W CN 2019121205W WO 2020108516 A1 WO2020108516 A1 WO 2020108516A1
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- substituted
- unsubstituted
- amino
- heteroaryl
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- 0 C*(C)c1c[s]c(C)n1 Chemical compound C*(C)c1c[s]c(C)n1 0.000 description 14
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- SKDBPVURZPQUOE-PHZGNYQRSA-N Cc1cnc(Nc2nc(N[C@H]3C[C@H](CCC4)N(CCC#N)[C@H]4C3)nc(OC)c2)[s]1 Chemical compound Cc1cnc(Nc2nc(N[C@H]3C[C@H](CCC4)N(CCC#N)[C@H]4C3)nc(OC)c2)[s]1 SKDBPVURZPQUOE-PHZGNYQRSA-N 0.000 description 1
- MPBPVACPFBSAFW-UHFFFAOYSA-N Cc1n[s]c(C)n1 Chemical compound Cc1n[s]c(C)n1 MPBPVACPFBSAFW-UHFFFAOYSA-N 0.000 description 1
- CNFZDIJRXJPIAG-OSYLJGHBSA-N N#CCCN([C@H](CC1)C2)[C@@H]1C[C@@H]2Nc1nc(N(CC2)CCS2(=O)=O)cc(Nc2ncc(CO)[s]2)n1 Chemical compound N#CCCN([C@H](CC1)C2)[C@@H]1C[C@@H]2Nc1nc(N(CC2)CCS2(=O)=O)cc(Nc2ncc(CO)[s]2)n1 CNFZDIJRXJPIAG-OSYLJGHBSA-N 0.000 description 1
- CKVUEBJLZPKCRK-OSYLJGHBSA-N N#CCCN([C@H](CC1)C2)[C@@H]1C[C@@H]2Nc1nc(N2CCOCC2)cc(Nc2ncc(CO)[s]2)n1 Chemical compound N#CCCN([C@H](CC1)C2)[C@@H]1C[C@@H]2Nc1nc(N2CCOCC2)cc(Nc2ncc(CO)[s]2)n1 CKVUEBJLZPKCRK-OSYLJGHBSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
Definitions
- the invention belongs to the field of drug synthesis, and in particular relates to a JAK inhibitor, its preparation method and application.
- Janus kinase is an intracellular non-receptor tyrosine kinase that mediates signaling and activation of various cytokines.
- the JAK kinase family contains four subfamily members of JAK1, JAK2, JAK3 and TYK2. Members of each subfamily mediate different types of cytokine signaling pathways. JAK1, JAK2 and TYK2 are expressed in various tissues and cells of the human body, and JAK3 is mainly expressed In each hematopoietic tissue cell.
- the common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for tyrosine kinase JAK.
- the cytokine receptor When the cytokine receptor binds to its ligand, it activates JAKs coupled to the receptor, which in turn causes the receptor to be phosphorylated.
- the phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain, thereby causing STAT Receptors are recruited and phosphorylated by JAKs.
- Phosphotyrosine mediates STAT dimerization.
- the activated STAT dimer is transferred into the nucleus and activates the transcription of its target gene, thereby regulating the growth, activation, and Differentiation and other functions.
- the JAK/STAT signaling pathway mediates the signaling of most cytokines in cells and plays a key role in biological processes such as immune regulation and immune cell proliferation.
- the JAK/STAT signaling pathway has a wide range of functions and participates in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation.
- JAK/STAT signaling pathway is closely related to neoplastic diseases such as myelofibrosis, polycythemia vera, and primary thrombocythemia, mutation of JAK molecule itself It can also cause tumor diseases such as acute myeloid cell leukemia (AML), acute lymphocytic leukemia (ALL), breast ductal carcinoma, and non-small cell lung cancer (NSCLC).
- AML acute myeloid cell leukemia
- ALL acute lymphocytic leukemia
- NSCLC non-small cell lung cancer
- Inflammatory bowel disease is a chronic intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn' disease (CD).
- the drugs for treating inflammatory bowel disease mainly include aminosalicylic acid preparations, glucocorticoids, immunosuppressive agents, antibiotics, and the like.
- the main principle of UC treatment is to regulate immune response and suppress inflammation.
- sulfasalazine is mainly used in the treatment of mild to moderate UC.
- the current commonly used drugs for moderate to severe UC include glucocorticoids, but because the risk is greater than the benefit, it will not be used as a long-term treatment.
- Monoclonal antibodies have drugs, high costs, the production of drug antibodies affects the safety and effectiveness of drugs, and the inconvenient way of intravenous administration. There are still unmet medical needs in this field. Many patients who have received treatment have not yet been relieved, and up to 80% of Crohn's disease patients and 30% of UC patients will eventually need surgery.
- Tofacitinib (Xeljanz) is the first oral JAK inhibitor for the treatment of moderate to severely active UC adult patients. It has significant inhibitory activity against JAK 1, 2, and 3 subtypes, which increases the efficacy of tofacitinib, but it also brings More serious side effects. Adverse reactions include infection, tuberculosis, tumor, anemia, liver damage, and increased cholesterol. Tofacitinib's manual has many black box signs: serious infections (tuberculosis, bacteria, fungi, viruses) and malignant tumors (lymphomas, etc.). Due to the wide range of JAK-mediated functions, these side effects are caused by the drug inhibiting multiple JAKs simultaneously. Because JAK is widely involved in the regulation of immune cells, JAK inhibitors inevitably cause side effects related to immunosuppression, such as serious infections and even tumors. Even with many highly selective inhibitors currently under study, such side effects caused by the inhibition of targets are inevitable.
- the object of the present invention is to provide a compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by the general formula (I) is as follows:
- L is selected from the group consisting of a bond, an alkylene group, an alkenylene group, an alkynyl group, a cycloalkyl group, a heterocyclic group, -(CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
- G is selected from NR aa or CR aa ;
- M is selected from S or CR 4 ;
- Ring A is selected from heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, halogen, hydroxyl group, substituted or unsubstituted amino group, oxo group, nitrate Group, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted, unsubstituted heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR
- R 2 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group or alkynyl group;
- R 3 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, ring Alkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2
- R 4 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group or alkynyl group;
- R aa , R bb , R cc and R dd are the same or different, and are independently selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, Halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy Group, hydroxyalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, Halogen, hydroxyl, substituted or unsubstituted amino, o
- R aa and R bb are linked to form a cycloalkyl, heterocyclic group, aryl group and heteroaryl group, wherein the cycloalkyl, heterocyclic group, aryl group and heteroaryl group are optionally further selected from deuterium Atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, Hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Heterocyclic group, substituted or unsubstituted aryl
- n is an integer of 0, 1, 2 or 3;
- n is an integer of 0, 1, 2, 3, 4 or 5;
- n 1 is an integer of 0, 1, or 2;
- n 2 is an integer of 0, 1, or 2;
- n 1 is an integer of 0, 1, 2, 3, 4, or 5.
- the present invention also relates to a preferred embodiment, wherein the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) and its stereoisomer Body or its pharmaceutically acceptable salt:
- Rings A, L, R 1 to R 5 , m and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
- L is selected from bond, C 0-8 alkylene, C 2-8 alkenylene, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -, the hetero atom in the heterocyclic group is selected from one or more of N, O, S, P;
- Ring A is selected from C 5-12 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 0-8 alkoxy, Substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 heterocyclic, substituted or unsubstituted C 5-12 aryl And substituted or unsubstituted C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa ,
- R 2 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 hydroxyalkyl, C 0-8 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
- R 3 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR a
- R 4 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
- the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
- L is selected from the group consisting of bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -the hetero atom in the heterocyclic group is selected from one or more of N, O, and S;
- Ring A is selected from C 5-10 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 1-3 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-3 alkenyl, substituted or unsubstituted C 2-3 alkynyl, substituted or unsubstituted C 1-3 alkoxy, Substituted or unsubstituted C 1-3 hydroxyalkyl, substituted or unsubstituted C 1-3 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic, substituted or unsubstituted C 5-10 aryl And substituted or unsubstituted C 5-10 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2
- R 2 is selected from hydrogen atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl or C 2-3 alkynyl;
- R 3 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb ,
- R 4 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl or C 2-3 alkynyl;
- the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
- L is selected from bond, C 1-3 alkylene, (CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
- Ring A is selected from C 5-6 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, methyl, ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo Group, nitro group, cyano group, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2
- R 1 is selected from a hydrogen atom, C 1-3 alkyl, amino, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , (CH 2 ) n1 C(O)R aa , --(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb or -(CH 2 ) n1 C(O)NR aa R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O and S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from amino, cyano, -(CH 2 ) n1 R cc or -(CH 2
- R 2 is selected from hydrogen atom, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, halo Ethoxy, F, Cl, Br, amino, nitro, hydroxyl, cyano, vinyl, propenyl, ethynyl, propynyl
- R 3 is selected from hydrogen atom, C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) one or more of n1 C(O)NR aa R bb , optionally substituted by one or more substituents, heterocyclic and heteroaryl Is selected from one or more of N, O, S;
- R 4 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, Br, amino, nitro, hydroxy, cyano, vinyl or ethynyl ;
- the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
- L is selected from bond, methylene, -(CH 2 ) 2 -or -S(O) 2 -;
- Ring A is selected from
- R 1 is selected from cyano
- R 2 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, amino, hydroxy, cyano, vinyl, propenyl, ethynyl, propylene Alkynyl
- R 3 is selected from hydrogen atom, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, azetidine, oxetane, phenyl, benzyl, pyridine, -C (O)NH2;
- R 4 is selected from hydrogen atom, methyl, ethyl, methoxy, hydroxymethyl, F, Cl, amino, hydroxyl, cyano, vinyl or ethynyl;
- R5 is selected from methyl, methoxy, hydroxy, hydroxymethyl, F,
- n 0, 1 or 2;
- n 0, 1, or 2.
- the present invention also relates to a preferred embodiment.
- the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) and its stereoisomer Body or its pharmaceutically acceptable salt:
- Rings A, L, R 1 to R 5 , m and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
- L is selected from bond, C 0-8 alkylene, C 2-8 alkenylene, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -, the hetero atom in the heterocyclic group is selected from one or more of N, O, S, P;
- Ring A is selected from C 5-12 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 0-8 alkoxy, Substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 heterocyclic, substituted or unsubstituted C 5-12 aryl And substituted or unsubstituted C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa ,
- R 2 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 hydroxyalkyl, C 0-8 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
- R 3 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR a
- the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
- L is selected from bond, C 1-3 alkylene, (CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
- Ring A is selected from C 5-6 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, methyl, ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo Group, nitro group, cyano group, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2
- R 1 is selected from a hydrogen atom, C 1-3 alkyl, amino, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , (CH 2 ) n1 C(O)R aa , --(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb or -(CH 2 ) n1 C(O)NR aa R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O and S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from amino, cyano, -(CH 2 ) n1 R cc or -(CH 2
- R 2 is selected from hydrogen atom, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, halo Substituted ethoxy, F, Cl, Br, amino, nitro, hydroxyl, cyano, vinyl, propenyl, ethynyl, propynyl;
- R 3 is selected from hydrogen atom, C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) one or more of n1 C(O)NR aa R bb , optionally substituted by one or more substituents, heterocyclic and heteroaryl Is selected from one or more of N, O, S;
- the present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
- L is selected from bond, methylene, -(CH 2 ) 2 -or -S(O) 2 -;
- Ring A is selected from
- R 1 is selected from cyano
- R 2 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, amino, hydroxy, cyano, vinyl, propenyl, ethynyl, propylene Alkynyl
- R 3 is selected from hydrogen atom, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, azetidine, oxetane, phenyl, benzyl, pyridine, -C (O)NH2;
- R5 is selected from methyl, methoxy, hydroxy, hydroxymethyl, F,
- n 0, 1 or 2;
- n 0, 1, or 2.
- the present invention also relates to a preferred embodiment.
- the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) and its stereoisomer Body or its pharmaceutically acceptable salt:
- Ring A, R 2 to R 5 , m and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment.
- the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is represented by the general formulas (IV-A) and (IV-B)
- Ring A, R 2 to R 5 , m and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment.
- the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) and its stereoisomer Body or its pharmaceutically acceptable salt:
- Ring A, R 2 to R 5 and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VA) and (VB), Its stereoisomer or its pharmaceutically acceptable salt:
- Ring A, R 2 to R 5 and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VI) and (VIA), Its stereoisomer or its pharmaceutically acceptable salt:
- E, W and G are the same or different, each independently selected from a nitrogen atom or a carbon atom;
- R 2 to R 5 and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment.
- the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VII) and (VIIA), Its stereoisomer or its pharmaceutically acceptable salt:
- L, R 2 to R 5 , m and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VIII) and (VIIIA), Its stereoisomer or its pharmaceutically acceptable salt:
- L, R 1 to R 5 , m and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IX) and (IXA), Its stereoisomer or its pharmaceutically acceptable salt:
- R 2 to R 5 , m and n are as described in the general formula (I).
- the present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (X) and (XA), Its stereoisomer or its pharmaceutically acceptable salt:
- R 2 to R 5 and n are as described in the general formula (I).
- the present invention also relates to a preferred solution, wherein the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IX) and its stereoisomer Body or its pharmaceutically acceptable salt:
- J 1 and J 2 are the same or different, and are independently selected from carbon atom, nitrogen atom, oxygen atom and sulfur atom;
- R 3 to R 5 and n are as described in the general formula (I).
- the present invention also relates to a preferred solution, each of the general formulas, stereoisomers or pharmaceutically acceptable salts thereof according to any one of the claims, characterized in that
- Ring A is selected from the following groups:
- the present invention also relates to a preferred solution, each of the general formulas, stereoisomers or pharmaceutically acceptable salts thereof according to any one of the claims, characterized in that
- L is -(CH 2 ) n1 -or-(CH 2 ) n1 S(O) m1 -;
- R 1 is a cyano group or a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from a hydrogen atom and a cyano group;
- R 2 hydrogen atom or C 1-6 alkyl group; preferably hydrogen atom or C 1-3 alkyl group; more preferably hydrogen atom or methyl group;
- R 3 is selected from hydrogen atom, cyano group, halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, -(CH 2 ) n1 OR aa or -C(O)NR aa R bb ;
- R 4 is selected from hydrogen atom or halogen
- R 5 is selected from a hydrogen atom, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered heterocyclic group, 5-10 membered heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 P(O) m1 R aa R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , where the Heterocyclic group and heteroaryl group are optionally further substituted by hydrogen atom, C 1-6
- R aa , R bb , R cc and R dd are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group, an amino group, or a 3-8 membered heterocyclic group; wherein the C 1-6 alkane
- the group, the amino group, and the 3-8 membered heterocyclic group are optionally further substituted with one or more substituents among a hydrogen atom, a hydroxyl group, and a 5-10 membered heteroaryl group.
- the invention further relates to the use of any compound of the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of JAK kinase inhibitors.
- the present invention also relates to a method for the treatment of prevention and/or treatment of pre-prepared treatment of conditions mediated by JAK kinase inhibitors, which comprises administering to the patient a therapeutically effective dose of a compound represented by general formula (I) and its stereoisomer Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective dose of a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable Accepted carriers, diluents or excipients.
- the present invention also relates to the use of the compound of general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of drugs for treating inflammatory diseases and tumor diseases.
- the invention also relates to a method for treating inflammatory diseases and a method for treating tumor diseases, which comprises administering to the patient a therapeutically effective dose of a pharmaceutical composition.
- the inflammatory diseases mentioned above are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and the neoplastic diseases are selected from myelofibrosis and true Polycythemia and primary thrombocythemia, sex myeloid leukemia (AML), acute lymphocytic leukemia (ALL), breast ductal carcinoma, and non-small cell lung cancer (NSCLC), in which gastrointestinal inflammation is chronic intestinal disease Inflammatory diseases are more preferably ulcerative colitis and Crohn's disease.
- alkyl refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms
- the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
- lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
- the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point.
- the substituent is preferably one or more of the following groups, which are independently selected from Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate groups, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , Deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
- alkylene means that a hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” refers to -(CH 2 ) 4 -and so on.
- alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. The alkenyl group may be substituted or unsubstituted.
- the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
- the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 Carbon atoms, most preferably containing 3 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, more preferably cyclopropyl Group, cyclobutyl and cyclopentyl.
- spirocycloalkyl refers to a polycyclic group that shares a carbon atom (called a spiro atom) between 5- to 20-membered monocycles, which may contain one or more double bonds, but none of the rings is fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and dispirocycloalkyl groups. More preferably, it is 4 member/4 member, 4 member/5 member, 4 member/6 member, 5 member/5 member, or 5 member/6 member monospirocycloalkyl.
- Non-limiting examples of spirocycloalkyl include:
- a spirocyclic alkyl group that also contains a single spirocyclic alkyl group and a heterocyclic alkyl group sharing a spiro atom non-limiting examples include:
- fused ring alkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or Multiple double bonds, but no ring has a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cyclic alkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 4 members/4 members, 5 members/5 members or 5 members/6 members Bicycloalkyl.
- fused cycloalkyl include:
- bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
- bridged cycloalkyls include:
- the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl, etc.
- the cycloalkyl group may be optionally substituted or unsubstituted.
- the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
- heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, boron, phosphorus S(O) m (where m is an integer from 0 to 2) or P(O) n (where n is an integer from 0 to 2) heteroatom, but does not include the ring portion of -OO-, -OS- or -SS- ,
- the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably 3 to 8 ring atoms.
- Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, Dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl, oxetanyl Alkyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl and pyranyl.
- Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally linked to other groups through a single bond or through a ring Any two or more atoms of the above are further connected to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups in parallel.
- spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 3 and 20 membered single rings, where one or more ring atoms are nitrogen, oxygen, boron, phosphorus, S (O) m (where m is an integer from 0 to 2) or a hetero atom of P(O) n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
- Spiro heterocyclic groups are classified into mono-spiro heterocyclic groups, di-spiro heterocyclic groups or poly-spiro heterocyclic groups according to the number of spiro atoms shared between the rings, preferably mono-spiro heterocyclic groups and di-spiro heterocyclic groups. More preferably, it is 3 member/5 member, 4 member/5 member, 4 member/6 member, 5 member/5 member, or 5 member/6 member monospiro heterocyclic group.
- Non-limiting examples of spiro heterocyclic groups include:
- fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
- One or more rings may contain one or more Double bond, but none of the rings has a completely conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining rings
- the atom is carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
- bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3 member/5 member, 4 member/5 member or 5 member/6 member Bicyclic fused heterocyclic group.
- fused heterocyclic groups include:
- bridged heterocyclic group refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common
- one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
- bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
- bridged heterocyclic groups include:
- the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:
- the heterocyclic group may be optionally substituted or unsubstituted.
- the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
- aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl.
- the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
- the aryl group may be substituted or unsubstituted.
- the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate groups.
- heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
- the heteroaryl group is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, imidazolyl, pyridyl, pyrazine Group, pyrimidinyl, pyrazolyl, thiazole, thiadiazole, pyrazolyl, pyrazolyl
- the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
- the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above.
- alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
- the alkoxy group may be optionally substituted or unsubstituted.
- the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
- Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
- Haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
- Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.
- alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl can be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
- Alkynyl means (CH ⁇ C- or -C ⁇ C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio Group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate groups.
- Halogen means fluorine, chlorine, bromine or iodine.
- Amino refers to -NH 2 .
- Niro refers to -NO 2 .
- Carboxy refers to -C(O)OH.
- THF tetrahydrofuran
- EtOAc means ethyl acetate
- MeOH refers to methanol
- DMF N,N-dimethylformamide
- DIPEA diisopropylethylamine
- TFA trifluoroacetic acid
- DMA refers to N,N-dimethylacetamide.
- Et 2 O refers to diethyl ether
- DCE 1,2 dichloroethane
- DIPEA N,N-diisopropylethylamine
- NBS N-bromosuccinimide
- NIS N-iodosuccinimide
- Cbz-Cl refers to benzyl chloroformate
- Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
- HATU refers to 2-(7-benzobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
- KHMDS refers to potassium hexamethyldisilazide
- LiHMDS refers to lithium bistrimethylsilylamine.
- MeLi refers to methyl lithium
- N-BuLi refers to n-butyl lithium
- X is selected from A, B, or C
- X is selected from A, B, and C
- X is A, B, or C
- X is A, B, and C
- other different terms all express the same Meaning, that is, X can be any one or more of A, B, and C.
- the hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the examples involved in the present invention can also be replaced by deuterium atoms.
- heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
- Substituted refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.
- “Pharmaceutical composition” means a mixture containing one or more compounds described herein or a physiological/pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
- the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert the biological activity.
- “Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has proper biological activity.
- the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm). The measurement of NMR was performed by Bruker AVANCE-400 nuclear magnetic instrument. The solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). Methylsilane (TMS).
- Liquid chromatography-mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
- Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.
- the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized using or following methods known in the art.
- reaction solution was extracted with EA (15mL ⁇ 3), washed with saturated aqueous sodium chloride solution (15mL ⁇ 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to give the title compound as a pale yellow solid (200mg, 93 %).
- Step 4 3-((3-exo)-3-((4-methoxy-6-((5-methyl-1hydro-pyrazol-3-yl)amino)pyrimidin-2-yl) Preparation of amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
- Step 2 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino )-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
- Second step 2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-(( Preparation of 5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide
- Example 1 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1H-pyrazol-4-yl)
- the preparation of pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile is referred to Example 1.
- reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the title compound (50 mg , 6%).
- Step 3 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-2-morpholinopyrimidin-4-yl)amino )-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
- the second step (3-((2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl) methanol preparation
- the third step tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1-methyl- Preparation of 1H-pyrazol-4-yl)pyrimidin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
- Test compound inhibits JAK kinase activity
- Test Example 1 Determination of the inhibitory effect of the compounds of the present invention on JAK kinase activity
- the purpose of this test case is to test the activity of the compound against the inhibition of JAK kinase activity.
- centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf or Rainin company, microplate reader was purchased from American BioTek company, model is SynergyH1 full-function microplate reader.
- TR-FRET test fluorescence resonance energy transfer
- the kinase reaction was carried out in a white 384-well plate (PerkinElmer). 1-5 ⁇ L of compounds of different concentrations diluted with DMSO and ddH 2 O were added to each well. 1-5 ⁇ L of the corresponding vehicle was added to the positive control well, and then 1-5 ⁇ L was added to each well Kinase buffer (HEPES 50-250 mM, MgCl 2 5-20 mM, etc.) diluted 0.1-20 nM JAK kinase solution, add 1-5 ⁇ L of kinase buffer to the negative control well, add 1-5 ul of substrate containing peptide substrate and ATP Mix the solution and incubate at room temperature for 0.5 to 5 hours, add 10ul of EDTA and the detection solution containing the labeled antibody, incubate at room temperature for 1 to 24 hours, use the BioTek Synergy H1 microplate reader to measure the fluorescence signal value of each plate well at about 620nm and 665nm The
- Test Example 2 Determination of the inhibitory effect of compounds of the present invention on JAK-STAT signaling pathway
- the purpose of the experiment is to test the activity of the compound on the inhibition of JAK-STAT signaling pathway in cells.
- Microplate oscillator (88880024) was purchased from Thermo Scientific TM
- the centrifuge (5702R) was purchased from Eppendorf,
- the microplate reader was purchased from the United States BioTek company, the model is SynergyH1 full-function microplate reader.
- mice study compounds 1, 4, 7, 9, 12, 15, 16, 18, 21, 23, 27, 32, 33, 38, 42, 49, 53, 54, 57 , 58, 60, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 82, 83, 84, 88, 90, 92, 93, orally administered at a dose of 5 mg/kg in small Pharmacokinetic behavior in mice (plasma and colon, ileum tissue), by analyzing the drug concentration of colon and ileum, as well as colon/ileal drug concentration, colon/plasma drug concentration ratio, screening compounds with excellent PK for further research .
- mice There are 12 Balb/C mice in each group, male; p.o. after fasting overnight, the dose is 5 mg/kg, and the administration volume is 10 mL/kg.
- mice were sacrificed with CO 2 at 0 , 0.5, 1, 2 , 3, 5 and 7 hours, and 0.2 mL of blood was collected from the heart, placed in an EDTA-K 2 test tube, and centrifuged at 6000 rpm at 4°C. 6 Plasma is separated in minutes and stored at -80°C; the ileum is taken close to the cecum end with a length of about 4-5cm; the colon is also taken close to the cecum end with a length of about 2-3cm, taken out and weighed, placed in a 2mL centrifuge tube Store at °C.
- Plasma samples were precipitated by adding 160uL of acetonitrile to 40uL, and centrifuged at 3500 ⁇ g for 5-20 minutes after mixing.
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Abstract
Disclosed are a nitrogen-containing heteroaryl derivative compound as shown in the general formula (I), a preparation method thereof, and a pharmaceutical composition containing the same. The compound can be used as a JAK inhibitor and can be used in preparing drugs for treating inflammatory diseases and tumor diseases. Nothing to translate.
Description
本申请要求申请日为2018年11月27日的中国专利申请201811430470.6和申请日为2019年11月22日的中国专利申请201911162976.8的优先权。本申请引用上述中国专利申请的全文。This application requires the priority of the Chinese patent application 201811430470.6 with the filing date of November 27, 2018 and the Chinese patent application 201911162976.8 with the filing date of November 22, 2019. This application cites the entire text of the aforementioned Chinese patent application.
本发明属于药物合成领域，具体涉及一种JAK抑制剂、其制备方法和应用。The invention belongs to the field of drug synthesis, and in particular relates to a JAK inhibitor, its preparation method and application.
Janus激酶(JAK)是一种胞内非受体酪氨酸激酶，介导各种细胞因子的信号传导和激活。JAK激酶家族含有JAK1、JAK2、JAK3和TYK2四个亚家族成员，各亚家族成员分别介导不同类型的细胞因子信号通路，JAK1、JAK2和TYK2在人体各组织细胞中均有表达，JAK3主要表达于各造血组织细胞中。细胞因子受体的共同特点是受体本身不具有激酶活性，但受体胞内段具有酪氨酸激酶JAK的结合位点。当细胞因子受体与其配体结合后，激活受体偶联的JAKs，进而使受体被磷酸化，磷酸化的酪氨酸位点可与含有SH2结构域的STAT蛋白结合，从而使STAT被募集到受体并通过JAKs磷酸化，随后磷酸酪氨酸介导STAT二聚化，激活的STAT二聚体转移到细胞核内并激活其靶点基因转录，进而调控多种细胞的生长、活化、分化等多种功能。Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates signaling and activation of various cytokines. The JAK kinase family contains four subfamily members of JAK1, JAK2, JAK3 and TYK2. Members of each subfamily mediate different types of cytokine signaling pathways. JAK1, JAK2 and TYK2 are expressed in various tissues and cells of the human body, and JAK3 is mainly expressed In each hematopoietic tissue cell. The common feature of cytokine receptors is that the receptor itself does not have kinase activity, but the intracellular segment of the receptor has a binding site for tyrosine kinase JAK. When the cytokine receptor binds to its ligand, it activates JAKs coupled to the receptor, which in turn causes the receptor to be phosphorylated. The phosphorylated tyrosine site can bind to the STAT protein containing the SH2 domain, thereby causing STAT Receptors are recruited and phosphorylated by JAKs. Phosphotyrosine mediates STAT dimerization. The activated STAT dimer is transferred into the nucleus and activates the transcription of its target gene, thereby regulating the growth, activation, and Differentiation and other functions.
JAK/STAT信号通路介导细胞内大多数细胞因子的信号传导，在参与免疫调节、免疫细胞增殖等生物学过程中起关键作用。JAK/STAT信号通路功能广泛，参与细胞的增殖、分化、凋亡以及免疫调节等许多重要的生物学过程，与多种炎症性疾病如类风湿性关节炎、皮炎、银屑病、炎症性肠病(溃疡性结肠炎及克罗恩病)等密切相关；同时JAK/STAT信号通路与肿瘤性疾病如骨髓纤维化、真性红细胞增多症及原发性血小板增多症密切相关，JAK分子自身的突变也会导致急性骨髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、乳腺导管癌及非小细胞肺癌(NSCLC)等肿瘤性疾病。The JAK/STAT signaling pathway mediates the signaling of most cytokines in cells and plays a key role in biological processes such as immune regulation and immune cell proliferation. The JAK/STAT signaling pathway has a wide range of functions and participates in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. Diseases (ulcerative colitis and Crohn's disease) are closely related; at the same time, JAK/STAT signaling pathway is closely related to neoplastic diseases such as myelofibrosis, polycythemia vera, and primary thrombocythemia, mutation of JAK molecule itself It can also cause tumor diseases such as acute myeloid cell leukemia (AML), acute lymphocytic leukemia (ALL), breast ductal carcinoma, and non-small cell lung cancer (NSCLC).
炎症性肠病是慢性肠道炎症性疾病，包括溃疡性结肠炎(ulcerative colitis，UC)和克罗恩病(Crohn’disease，CD)。目前治疗炎症性肠病的药物主要有氨基水杨酸制剂、糖皮质激素、免疫抑制剂、抗生素等。UC的治疗以调节免疫反应、抑制炎症为主要原则。目前在临床上，柳氮磺胺吡啶主要用于治疗轻度至中度的UC。而中度至重度的UC目前常用的药物包括糖皮质激素类，但是因为风险大于益处，所以不会作为长期的治疗手段。 单克隆抗体则存在药物，成本高昂、产生药物抗体影响药物安全性和有效性，以及静脉给药的方式不够方便等问题，该领域仍存在着远未满足的医疗需求。许多接受治疗的患者还没有得到缓解，高达80％的克罗恩病患者和30％的UC患者最终需要接受手术治疗。Inflammatory bowel disease is a chronic intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn' disease (CD). At present, the drugs for treating inflammatory bowel disease mainly include aminosalicylic acid preparations, glucocorticoids, immunosuppressive agents, antibiotics, and the like. The main principle of UC treatment is to regulate immune response and suppress inflammation. Currently, sulfasalazine is mainly used in the treatment of mild to moderate UC. The current commonly used drugs for moderate to severe UC include glucocorticoids, but because the risk is greater than the benefit, it will not be used as a long-term treatment. Monoclonal antibodies have drugs, high costs, the production of drug antibodies affects the safety and effectiveness of drugs, and the inconvenient way of intravenous administration. There are still unmet medical needs in this field. Many patients who have received treatment have not yet been relieved, and up to 80% of Crohn's disease patients and 30% of UC patients will eventually need surgery.
Tofacitinib(Xeljanz)是治疗中度至重度活动性UC成人患者的首个口服JAK抑制剂，对JAK1、2、3亚型均有显著的抑制活性，这增加了tofacitinib的疗效，但同时也带来了较为严重的副作用。不良反应包括感染、结核、肿瘤、贫血、肝损伤及胆固醇增加等。Tofacitinib的说明书上有诸多的黑框标识：严重感染(肺结核、细菌、真菌、病毒)和恶性肿瘤(淋巴瘤等)。由于各个JAK介导的功能广泛，这些副作用是该药物同时抑制多个JAK引起的。由于JAK广泛参与免疫细胞的调节，JAK抑制剂不可避免地会引起免疫抑制相关的副作用，如严重的感染，甚至肿瘤的发生等。即使是目前在研的众多高选择性抑制剂，这种由抑制靶点造成的副作用也不可避免。Tofacitinib (Xeljanz) is the first oral JAK inhibitor for the treatment of moderate to severely active UC adult patients. It has significant inhibitory activity against JAK 1, 2, and 3 subtypes, which increases the efficacy of tofacitinib, but it also brings More serious side effects. Adverse reactions include infection, tuberculosis, tumor, anemia, liver damage, and increased cholesterol. Tofacitinib's manual has many black box signs: serious infections (tuberculosis, bacteria, fungi, viruses) and malignant tumors (lymphomas, etc.). Due to the wide range of JAK-mediated functions, these side effects are caused by the drug inhibiting multiple JAKs simultaneously. Because JAK is widely involved in the regulation of immune cells, JAK inhibitors inevitably cause side effects related to immunosuppression, such as serious infections and even tumors. Even with many highly selective inhibitors currently under study, such side effects caused by the inhibition of targets are inevitable.
鉴于JAK抑制剂的良好疗效和多种靶点相关性严重副作用，开发一种安全性更高的JAK抑制剂药物成为目前急需解决的问题。由于炎症性肠道疾病发生在胃肠道的肠腔表面，不需要药物进入血液系统即可发挥作用，因此开发一种降低药物在血液循环中系统暴露量而提高药物在炎症部位的局部暴露量的药物成为提高安全性的良好策略。国际申请WO2017189822A1报道了Theravance公司合成一系列化合物，该类化合物具有极低的系统暴露量，而在肠道炎性部位形成富集，既能有效地治疗肠道炎症，又不会造成严重的副作用，表明该策略具有很大的可行性，可能产生重大的临床应用价值。In view of the good efficacy of JAK inhibitors and the serious side effects associated with multiple targets, the development of a safer JAK inhibitor drug has become an urgent problem to be solved. Inflammatory bowel disease occurs on the surface of the intestinal lumen of the gastrointestinal tract and does not require drugs to enter the blood system to function. Therefore, a system was developed to reduce the exposure of drugs in the blood circulation and increase the local exposure of drugs at the site of inflammation Medicines have become a good strategy to improve safety. International application WO2017189822A1 reported that Theravance Company has synthesized a series of compounds with very low system exposure, and the formation of enrichment in the intestinal inflammatory site, which can effectively treat intestinal inflammation without causing serious side effects , Indicating that the strategy has great feasibility and may have significant clinical application value.
发明内容Summary of the invention
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：The object of the present invention is to provide a compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by the general formula (I) is as follows:
其中：among them:
L选自键、亚烷基、亚烯基、炔基、环烷基、杂环基、-(CH
2)
n1-或-(CH
2)
n1S(O)
m1-；
L is selected from the group consisting of a bond, an alkylene group, an alkenylene group, an alkynyl group, a cycloalkyl group, a heterocyclic group, -(CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
G选自NR
aa或CR
aa；
G is selected from NR aa or CR aa ;
M选自S或CR
4；
M is selected from S or CR 4 ;
环A选自杂芳基，其中所述杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代、未取代的杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个取代基所取代；
Ring A is selected from heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, halogen, hydroxyl group, substituted or unsubstituted amino group, oxo group, nitrate Group, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted, unsubstituted heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa ,- (CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S( O) substituted by one or more substituents in m1 R bb ;
R
1选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1NR
ccC(O)R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代；
R 1 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, hydroxyalkyl group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group , Cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C (O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa ,- (CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb, wherein the cycloalkyl, heterocyclic, aryl and heteroaromatic The group is optionally further selected from deuterium atoms, alkyl groups, haloalkyl groups, halogens, amino groups, oxo groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 NR cc C(O)R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd Replaced by multiple substituents;
R
2氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基；
R 2 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group or alkynyl group;
R
3氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个取代基所取代；
R 3 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, ring Alkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb is substituted by one or more substituents;
R
4氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基；
R 4 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group or alkynyl group;
R
5选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、羟烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、- NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1P(O)
m2R
aaR
bb、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aa(CH
2)
m1R
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代、未取代的杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1S(O)
m1NR
ccR
dd、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1C(O)NR
ccS(O)
m1R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代；
R 5 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group , Hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C (O)(CH 2 ) n1 OR aa ,-NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa ,- (CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, thio, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted, unsubstituted heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O) R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd is substituted by one or more substituents;
R
aa、R
bb、R
cc和R
dd相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
R aa , R bb , R cc and R dd are the same or different, and are independently selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, Halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy Group, hydroxyalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, Halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Substituted by one or more of hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
或者，R
aa和R
bb链接形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基中的一个或多个取代基所取代；
Alternatively, R aa and R bb are linked to form a cycloalkyl, heterocyclic group, aryl group and heteroaryl group, wherein the cycloalkyl, heterocyclic group, aryl group and heteroaryl group are optionally further selected from deuterium Atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, Hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Heterocyclic group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group is substituted by one or more substituents;
m为0、1、2或3的整数；m is an integer of 0, 1, 2 or 3;
n为0、1、2、3、4或5的整数；n is an integer of 0, 1, 2, 3, 4 or 5;
m
1为0、1或2的整数；
m 1 is an integer of 0, 1, or 2;
m
2为0、1或2的整数；且
m 2 is an integer of 0, 1, or 2; and
n
1为0、1、2、3、4或5的整数。
n 1 is an integer of 0, 1, 2, 3, 4, or 5.
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, wherein the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) and its stereoisomer Body or its pharmaceutically acceptable salt:
其中：among them:
环A、L、R
1～R
5、m和n如通式(I)所述。
Rings A, L, R 1 to R 5 , m and n are as described in the general formula (I).
本发明还涉及一个优选方案，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
其中，among them,
L选自键、C
0-8亚烷基、C
2-8亚烯基、C
2-8炔基、C
3-8环烷基、C
3-8杂环基、-(CH
2)
n1-或-(CH
2)
n1S(O)
m1-，杂环基中的杂原子选自N、O、S、P中的一个或多个；
L is selected from bond, C 0-8 alkylene, C 2-8 alkenylene, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -, the hetero atom in the heterocyclic group is selected from one or more of N, O, S, P;
环A选自C
5-12杂芳基，其中所述杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C
0-8烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C
2-8烯基、取代或未取代的C
2-8炔基、取代或未取代的C
0-8烷氧基、取代或未取代的C
0-8羟烷基、取代或未取代的C
3-8环烷基、取代或未取代的C
3-8杂环基、取代或未取代的C
5-12芳基和取代或未取代的C
5-12杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个取代基所取代；
Ring A is selected from C 5-12 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 0-8 alkoxy, Substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 heterocyclic, substituted or unsubstituted C 5-12 aryl And substituted or unsubstituted C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa ,- (CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb Substituted by a substituent;
R
1选自氢原子、C
0-8烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-8卤代烷氧基、C
0-8羟烷基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基、C
2-8炔基、C
3-8环烷基、C
3-8杂环基、C
3-
8氧代杂环基、C
3-8硫代杂环基、C
5-12芳基、C
5-12杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，杂环基、杂芳基中的杂原子选自N、O、S、P中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自C
0-8烷基、C
0-8卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、C
2-8烯基、C
2-8炔基、C
0-
8烷氧基、C
0-8卤代烷氧基、C
0-8羟烷基、C
3-8环烷基、C
3-8杂环基、C
5-12芳基、C
5-12杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、 -(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1NR
ccC(O)R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代；杂环基、杂芳基中的杂原子选自N、O、S、P中的一个或多个；
R 1 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 haloalkoxy, C 0-8 hydroxyalkyl, halogen, amino, nitrate group, hydroxy, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 3- 8-oxo-heterocyclyl, C 3- 8 thioheterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C (O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one of N, O, S, P Or more; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from C 0-8 alkyl, C 0-8 haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, C 2-8 alkenyl, C 2-8 alkynyl groups, C 0- 8 alkoxy, C 0-8 haloalkoxy, C 0-8 hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O) OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 NR cc C(O)R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd is substituted by one or more substituents; heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O, S, P;
R
2选自氢原子、C
0-8烷基、C
0-8氘代烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-8羟烷基、C
0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基或C
2-8炔基；
R 2 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 hydroxyalkyl, C 0-8 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
R
3选自氢原子、氘原子、C
0-8烷基、C
0-8氘代烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-
8羟烷基、C
0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基、C
2-8炔基、C
3-8环烷基、C
3-8杂环基、C
5-12芳基、C
5-12杂芳基、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；
R 3 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb One or more, optionally substituted by one or more substituents, heterocyclic The hetero atom in the group or heteroaryl group is selected from one or more of N, O, and S;
R
4选自氢原子、氘原子、C
0-8烷基、C
0-8氘代烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-
8羟烷基、C
0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基或C
2-8炔基；
R 4 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
R
5选自氢原子、氘原子、C
0-8烷基、C
0-8氘代烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-
8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基、C
2-8炔基、C
3-8环烷基、C
0-8羟烷基、C
3-8杂环基、C
3-8氧代杂环基、C
3-8硫代杂环基、C
5-12芳基、C
5-12杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1P(O)
m2R
aaR
bb、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aa(CH
2)
m1R
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C
0-8烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的C
2-8烯基、取代或未取代的C
2-8炔基、取代或未取代的C
0-8烷氧基、取代或未取代的C
0-8羟烷基、取代或未取代的C
3-8环烷基、取代或未取代的C
3-8杂环基、取代或未取代的C
5-12芳基和取代或未取代的C
5-12杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1S(O)
m1NR
ccR
dd、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1C(O)NR
ccS(O)
m1R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个。
R 5 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 haloalkoxy, halogen, , Amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 0-8 hydroxyalkyl, C 3-8 heterocyclyl, C 3-8 oxoheterocyclyl , C 3-8 thioheterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C( O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -( CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkane Group, halogen, hydroxyl, substituted or unsubstituted amino, oxo, thio, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl , Substituted or unsubstituted C 0-8 alkoxy, substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 hetero Cyclic group, substituted or unsubstituted C 5-12 aryl group and substituted or unsubstituted C 5-12 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd It is substituted by one or more substituents, and the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, and S.
本发明还涉及一个优选方案，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
其中，among them,
L选自键、C
1-3亚烷基、C
2-3亚烯基、C
2-3炔基、C
3-6环烷基、C
3-6杂环基、-(CH
2)
n1-或-(CH
2)
n1S(O)
m1-杂环基中的杂原子选自N、O、S中的一个或多个；
L is selected from the group consisting of bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -the hetero atom in the heterocyclic group is selected from one or more of N, O, and S;
环A选自C
5-10杂芳基，其中所述杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C
1-3烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C
2-3烯基、取代或未取代的C
2-3炔基、取代或未取代的C
1-3烷氧基、取代或未取代的C
1-3羟烷基、取代或未取代的C
1-3环烷基、取代或未取代的C
3-6杂环基、取代或未取代的C
5-10芳基和取代或未取代的C
5-10杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个取代基所取代；
Ring A is selected from C 5-10 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 1-3 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-3 alkenyl, substituted or unsubstituted C 2-3 alkynyl, substituted or unsubstituted C 1-3 alkoxy, Substituted or unsubstituted C 1-3 hydroxyalkyl, substituted or unsubstituted C 1-3 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic, substituted or unsubstituted C 5-10 aryl And substituted or unsubstituted C 5-10 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa ,- (CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb Substituted by a substituent;
R
1选自氢原子、C
1-3烷基、C
1-3卤代烷基、C
1-3烷氧基、C
1-3卤代烷氧基、C
1-3羟烷基、卤素、氨基、硝基、羟基、氰基、C
2-3烯基、C
2-3炔基、C
3-6环烷基、C
3-6杂环基、C
3-
6氧代杂环基、C
3-6硫代杂环基、C
5-10芳基、C
5-10杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自C
1-3烷基、C
1-3卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、C
2-3烯基、C
2-3炔基、C
1-
3烷氧基、C
1-3卤代烷氧基、C
1-3羟烷基、C
1-3环烷基、C
3-6杂环基、C
5-10芳基、C
5-10杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1NR
ccC(O)R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；
R 1 is selected from hydrogen atom, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, halogen, amino, nitrate Group, hydroxyl group, cyano group, C 2-3 alkenyl group, C 2-3 alkynyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic group, C 3- 6 oxo heterocyclic group, C 3- 6 thioheterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C (O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from C 1-3 alkyl, C 1-3 haloalkyl, halogen, amino, oxo, nitro , cyano, hydroxy, C 2-3 alkenyl, C 2-3 alkynyl, C 1- 3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 cycloalkyl Group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 NR cc C(O)R dd or -(CH 2 ) n1 NR cc S (O) m1 R dd is substituted by one or more substituents, and the hetero atoms in the heterocyclic group and heteroaryl group are selected from one or more of N, O, and S;
R
2选自氢原子、C
1-3烷基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3烷氧基、C
1-3羟烷基、C
1-3卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-3烯基或C
2-3炔基；
R 2 is selected from hydrogen atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl or C 2-3 alkynyl;
R
3选自氢原子、氘原子、C
1-3烷基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3烷氧基、C
1-
3羟烷基、C
1-3卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-3烯基、C
2-3炔基、C
3-6环烷基、C
3-6杂环基、C
5-10芳基、C
5-10杂芳基、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；
R 3 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb One or more, optionally substituted by one or more substituents, heterocyclic The hetero atom in the group or heteroaryl group is selected from one or more of N, O, and S;
R
4选自氢原子、氘原子、C
1-3烷基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3烷氧基、C
1-
3羟烷基、C
1-3卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-3烯基或C
2-3炔基；
R 4 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl or C 2-3 alkynyl;
R
5选自氢原子、氘原子、C
1-3烷基、C
1-3氘代烷基、C
1-3卤代烷基、C
1-3烷氧基、C
1-
3卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-3烯基、C
2-3炔基、C
3-6环烷基、C
1-3羟烷基、C
3-6杂环基、C
3-6氧代杂环基、C
3-6硫代杂环基、C
5-10芳基、C
5-10杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1P(O)
m2R
aaR
bb、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aa(CH
2)
m1R
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C
1-3烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的C
2-3烯基、取代或未取代的C
2-3炔基、取代或未取代的C
1-3烷氧基、取代或未取代的C
1-3羟烷基、取代或未取代的C
3-6环烷基、取代或未取代的C
3-6杂环基、取代或未取代的C
5-10芳基和取代或未取代的C
5-10杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1S(O)
m1NR
ccR
dd、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1C(O)NR
ccS(O)
m1R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个。
R 5 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy, halogen, , Amino, nitro, hydroxyl, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 1-3 hydroxyalkyl, C 3-6 heterocyclyl, C 3-6 oxoheterocyclyl , C 3-6 thioheterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C( O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -( CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 1-3 alkane Group, halogen, hydroxyl, substituted or unsubstituted amino, oxo, thio, nitro, cyano, substituted or unsubstituted C 2-3 alkenyl, substituted or unsubstituted C 2-3 alkynyl , Substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 1-3 hydroxyalkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 hetero Cyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd It is substituted by one or more substituents, and the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, and S.
本发明还涉及一个优选方案，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
其中，among them,
L选自键、C
1-3亚烷基、(CH
2)
n1-或-(CH
2)
n1S(O)
m1-；
L is selected from bond, C 1-3 alkylene, (CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
环A选自C
5-6杂芳基，其中所述杂芳基任选进一步被选自氢原子、甲基、乙基、F、Cl、Br、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C
3-6杂环基、取代或未取代的C
5-10芳基和取代或未取代的C
5-10杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个取代基所取代；
Ring A is selected from C 5-6 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, methyl, ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo Group, nitro group, cyano group, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) One or more substituents in n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb ;
R
1选自氢原子、C
1-3烷基、氨基、氰基、C
2-3烯基、C
2-3炔基、C
3-6环烷基、C
3-6杂环基、C
5-10芳基、C
5-10杂芳基、-(CH
2)
n1R
aa、(CH
2)
n1C(O)R
aa、--(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb或-(CH
2)
n1C(O)NR
aaR
bb，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氨基、氰基、- (CH
2)
n1R
cc或-(CH
2)
n1NR
ccR
dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；
R 1 is selected from a hydrogen atom, C 1-3 alkyl, amino, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , (CH 2 ) n1 C(O)R aa , --(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb or -(CH 2 ) n1 C(O)NR aa R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O and S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from amino, cyano, -(CH 2 ) n1 R cc or -(CH 2 ) n1 NR cc R dd Substituted by one or more substituents, the heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O, S;
R
2选自氢原子、甲基、乙基、卤代甲基、卤代乙基、甲氧基、乙氧基、羟甲基、羟乙基、羟丙基、卤代甲氧基、卤代乙氧基、F、Cl、Br、氨基、硝基、羟基、氰基、乙烯基、丙烯基、乙炔基、丙炔基；
R 2 is selected from hydrogen atom, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, halo Ethoxy, F, Cl, Br, amino, nitro, hydroxyl, cyano, vinyl, propenyl, ethynyl, propynyl
R
3选自氢原子、C
1-3烷基、C
1-3羟烷基、C
3-6杂环基、C
5-10芳基、C
5-10杂芳基、-(CH
2)
n1C(O)R
aa或-(CH
2)
n1C(O)NR
aaR
bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；
R 3 is selected from hydrogen atom, C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) one or more of n1 C(O)NR aa R bb , optionally substituted by one or more substituents, heterocyclic and heteroaryl Is selected from one or more of N, O, S;
R
4选自氢原子、甲基、乙基、甲氧基、乙氧基、羟甲基、羟乙基、F、Cl、Br、氨基、硝基、羟基、氰基、乙烯基或乙炔基；
R 4 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, Br, amino, nitro, hydroxy, cyano, vinyl or ethynyl ;
R
5选自氢原子、甲基、乙基、丙基、甲氧基、乙氧基、F、Cl、Br、氨基、羟基、氰基、乙烯基、乙炔基、乙炔基、丙炔基、环丙基、环丁基、环戊基、环己基、羟甲基、羟乙基、羟丙基、C
3-6杂环基、C
3-6氧代杂环基、C
3-6硫代杂环基、C
5-6杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1P(O)
m2R
aaR
bb、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aa(CH
2)
m1R
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自取代或未取代的甲基、取代或未取代的乙基、F、Cl、Br、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的羟甲基、取代或未取代的羟乙基、取代或未取代的C
3-6环烷基、取代或未取代的C
3-6杂环基、取代或未取代的C
5-10芳基和取代或未取代的C
5-10杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1S(O)
m1NR
ccR
dd、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1C(O)NR
ccS(O)
m1R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个。
R 5 is selected from hydrogen atom, methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, Br, amino, hydroxyl, cyano, vinyl, ethynyl, ethynyl, propynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 3-6 heterocyclyl, C 3-6 oxoheterocyclyl , C 3-6 sulfur Heterocyclic group, C 5-6 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C (＝S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclyl , Aryl and heteroaryl are optionally further selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo, thio Group, nitro, cyano, substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyethyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic, substituted or unsubstituted C 5-10 aryl and substituted or unsubstituted C 5-10 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C (O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd It is substituted by multiple substituents, and the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, and S.
本发明还涉及一个优选方案，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, which is a compound represented by the general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof:
其中，among them,
L选自键、亚甲基、-(CH
2)
2-或-S(O)
2-；
L is selected from bond, methylene, -(CH 2 ) 2 -or -S(O) 2 -;
环A选自
Ring A is selected from
R
1选自氰基、
R 1 is selected from cyano,
R
2选自氢原子、甲基、乙基、甲氧基、乙氧基、羟甲基、羟乙基、F、Cl、氨基、羟基、氰基、乙烯基、丙烯基、乙炔基、丙炔基；
R 2 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, amino, hydroxy, cyano, vinyl, propenyl, ethynyl, propylene Alkynyl
R
3选自氢原子、甲基、乙基，丙基、羟甲基、羟乙基、羟丙基、氮杂环丁烷、氧杂环丁烷、苯基、苄基、吡啶、-C(O)NH2；
R 3 is selected from hydrogen atom, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, azetidine, oxetane, phenyl, benzyl, pyridine, -C (O)NH2;
R
4选自氢原子、甲基、乙基、甲氧基、羟甲基、F、Cl、氨基、羟基、氰基、乙烯基或乙炔基；
R 4 is selected from hydrogen atom, methyl, ethyl, methoxy, hydroxymethyl, F, Cl, amino, hydroxyl, cyano, vinyl or ethynyl;
R5选自甲基，甲氧基，羟基，羟甲基，F，
R5 is selected from methyl, methoxy, hydroxy, hydroxymethyl, F,
m为0、1或2；m is 0, 1 or 2;
n为0、1或2。n is 0, 1, or 2.
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(III)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment. The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) and its stereoisomer Body or its pharmaceutically acceptable salt:
其中：among them:
环A、L、R
1～R
5、m和n如通式(I)所述。
Rings A, L, R 1 to R 5 , m and n are as described in the general formula (I).
本发明还涉及一个优选方案，其为通式(III)所示的化合物、其立体异构体或其药学上可接受盐，The present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
其中，among them,
L选自键、C
0-8亚烷基、C
2-8亚烯基、C
2-8炔基、C
3-8环烷基、C
3-8杂环基、-(CH
2)
n1-或-(CH
2)
n1S(O)
m1-，杂环基中的杂原子选自N、O、S、P中的一个或多个；
L is selected from bond, C 0-8 alkylene, C 2-8 alkenylene, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -, the hetero atom in the heterocyclic group is selected from one or more of N, O, S, P;
环A选自C
5-12杂芳基，其中所述杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C
0-8烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C
2-8烯基、取代或未取代的C
2-8炔基、取代或未取代的C
0-8烷氧基、取代或未取代的C
0-8羟烷基、取代或未取代的C
3-8环烷基、取代或未取代的C
3-8杂环基、取代或未取代的C
5-12芳基和取代或未取代的C
5-12杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个取代基所取代；
Ring A is selected from C 5-12 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 0-8 alkoxy, Substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 heterocyclic, substituted or unsubstituted C 5-12 aryl And substituted or unsubstituted C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa ,- (CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb Substituted by a substituent;
R
1选自氢原子、C
0-8烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-8卤代烷氧基、C
0-8羟烷基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基、C
2-8炔基、C
3-8环烷基、C
3-8杂环基、C
3-
8氧代杂环基、C
3-8硫代杂环基、C
5-12芳基、C
5-12杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，杂环基、杂芳基中的杂原子选自N、O、S、P中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自C
0-8烷基、C
0-8卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、C
2-8烯基、C
2-8炔基、C
0-
8烷氧基、C
0-8卤代烷氧基、C
0-8羟烷基、C
3-8环烷基、C
3-8杂环基、C
5-12芳基、C
5-12杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1NR
ccC(O)R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代；杂环基、杂芳基中的杂原子选自N、O、S、P中的一个或多个；
R 1 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 haloalkoxy, C 0-8 hydroxyalkyl, halogen, amino, nitrate group, hydroxy, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 3- 8-oxo-heterocyclyl, C 3- 8 thioheterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C (O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one of N, O, S, P Or more; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from C 0-8 alkyl, C 0-8 haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, C 2-8 alkenyl, C 2-8 alkynyl groups, C 0- 8 alkoxy, C 0-8 haloalkoxy, C 0-8 hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O) OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 NR cc C(O)R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd is substituted by one or more substituents; heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O, S, P;
R
2选自氢原子、C
0-8烷基、C
0-8氘代烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-8羟烷基、C
0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基或C
2-8炔基；
R 2 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 hydroxyalkyl, C 0-8 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;
R
3选自氢原子、氘原子、C
0-8烷基、C
0-8氘代烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-
8羟烷基、C
0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基、C
2-8炔基、C
3-8环烷基、C
3-8杂环基、C
5-12芳基、C
5-12杂芳基、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；
R 3 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb One or more, optionally substituted by one or more substituents, heterocyclic The hetero atom in the group or heteroaryl group is selected from one or more of N, O, and S;
R
5选自氢原子、氘原子、C
0-8烷基、C
0-8氘代烷基、C
0-8卤代烷基、C
0-8烷氧基、C
0-
8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C
2-8烯基、C
2-8炔基、C
3-8环烷基、C
0-8 羟烷基、C
3-8杂环基、C
3-8氧代杂环基、C
3-8硫代杂环基、C
5-12芳基、C
5-12杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1P(O)
m2R
aaR
bb、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aa(CH
2)
m1R
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C
0-8烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的C
2-8烯基、取代或未取代的C
2-8炔基、取代或未取代的C
0-8烷氧基、取代或未取代的C
0-8羟烷基、取代或未取代的C
3-8环烷基、取代或未取代的C
3-8杂环基、取代或未取代的C
5-12芳基和取代或未取代的C
5-12杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1S(O)
m1NR
ccR
dd、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1C(O)NR
ccS(O)
m1R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个。
R 5 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 haloalkoxy, halogen, , Amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 0-8 hydroxyalkyl, C 3-8 heterocyclyl, C 3-8 oxoheterocyclyl , C 3-8 thioheterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C( O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -( CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkane Group, halogen, hydroxyl, substituted or unsubstituted amino, oxo, thio, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl , Substituted or unsubstituted C 0-8 alkoxy, substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 hetero Cyclic group, substituted or unsubstituted C 5-12 aryl group and substituted or unsubstituted C 5-12 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd It is substituted by one or more substituents, and the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, and S.
本发明还涉及一个优选方案，其为通式(III)所示的化合物、其立体异构体或其药学上可接受盐，The present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
其中，among them,
L选自键、C
1-3亚烷基、(CH
2)
n1-或-(CH
2)
n1S(O)
m1-；
L is selected from bond, C 1-3 alkylene, (CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;
环A选自C
5-6杂芳基，其中所述杂芳基任选进一步被选自氢原子、甲基、乙基、F、Cl、Br、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C
3-6杂环基、取代或未取代的C
5-10芳基和取代或未取代的C
5-10杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aaR
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb中的一个或多个取代基所取代；
Ring A is selected from C 5-6 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, methyl, ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo Group, nitro group, cyano group, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) One or more substituents in n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb ;
R
1选自氢原子、C
1-3烷基、氨基、氰基、C
2-3烯基、C
2-3炔基、C
3-6环烷基、C
3-6杂环基、C
5-10芳基、C
5-10杂芳基、-(CH
2)
n1R
aa、(CH
2)
n1C(O)R
aa、--(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1NR
aaR
bb或-(CH
2)
n1C(O)NR
aaR
bb，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氨基、氰基、-(CH
2)
n1R
cc或-(CH
2)
n1NR
ccR
dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；
R 1 is selected from a hydrogen atom, C 1-3 alkyl, amino, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , (CH 2 ) n1 C(O)R aa , --(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb or -(CH 2 ) n1 C(O)NR aa R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O and S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from amino, cyano, -(CH 2 ) n1 R cc or -(CH 2 ) n1 NR cc R dd Substituted by one or more substituents, the heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O, S;
R
2选自氢原子、甲基、乙基、卤代甲基、卤代乙基、甲氧基、乙氧基、羟甲基、羟乙基、羟丙基、卤代甲氧基、卤代乙氧基、F、Cl、Br、氨基、硝基、羟基、氰基、乙烯 基、丙烯基、乙炔基、丙炔基；
R 2 is selected from hydrogen atom, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, halo Substituted ethoxy, F, Cl, Br, amino, nitro, hydroxyl, cyano, vinyl, propenyl, ethynyl, propynyl;
R
3选自氢原子、C
1-3烷基、C
1-3羟烷基、C
3-6杂环基、C
5-10芳基、C
5-10杂芳基、-(CH
2)
n1C(O)R
aa或-(CH
2)
n1C(O)NR
aaR
bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；
R 3 is selected from hydrogen atom, C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) one or more of n1 C(O)NR aa R bb , optionally substituted by one or more substituents, heterocyclic and heteroaryl Is selected from one or more of N, O, S;
R
5选自氢原子、甲基、乙基、丙基、甲氧基、乙氧基、F、Cl、Br、氨基、羟基、氰基、乙烯基、乙炔基、乙炔基、丙炔基、环丙基、环丁基、环戊基、环己基、羟甲基、羟乙基、羟丙基、C
3-6杂环基、C
3-6氧代杂环基、C
3-6硫代杂环基、C
5-6杂芳基、-(CH
2)
n1R
aa、-(CH
2)
n1OR
aa、-NR
aaC(O)(CH
2)
n1OR
aa、-NR
aaC(＝S)(CH
2)
n1OR
bb、-(CH
2)
n1SR
aa、-(CH
2)
n1C(O)R
aa、-(CH
2)
n1C(O)OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1P(O)
m2R
aaR
bb、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aa(CH
2)
m1R
bb、-(CH
2)
n1NR
aaC(O)R
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自取代或未取代的甲基、取代或未取代的乙基、F、Cl、Br、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的羟甲基、取代或未取代的羟乙基、取代或未取代的C
3-6环烷基、取代或未取代的C
3-6杂环基、取代或未取代的C
5-10芳基和取代或未取代的C
5-10杂芳基、-(CH
2)
n1-、-(CH
2)
n1R
cc、-(CH
2)
n1OR
cc、-(CH
2)
n1SR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1S(O)
m1NR
ccR
dd、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1C(O)NR
ccS(O)
m1R
dd或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个。
R 5 is selected from hydrogen atom, methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, Br, amino, hydroxyl, cyano, vinyl, ethynyl, ethynyl, propynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 3-6 heterocyclyl, C 3-6 oxoheterocyclyl , C 3-6 sulfur Heterocyclic group, C 5-6 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C (＝S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclyl , Aryl and heteroaryl are optionally further selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo, thio Group, nitro, cyano, substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyethyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic, substituted or unsubstituted C 5-10 aryl and substituted or unsubstituted C 5-10 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C (O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd It is substituted by multiple substituents, and the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, and S.
本发明还涉及一个优选方案，其为通式(III)所示的化合物、其立体异构体或其药学上可接受盐，The present invention also relates to a preferred embodiment, which is a compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof,
其中，among them,
L选自键、亚甲基、-(CH
2)
2-或-S(O)
2-；
L is selected from bond, methylene, -(CH 2 ) 2 -or -S(O) 2 -;
环A选自
Ring A is selected from
R
1选自氰基、
R 1 is selected from cyano,
R
2选自氢原子、甲基、乙基、甲氧基、乙氧基、羟甲基、羟乙基、F、Cl、氨基、羟基、氰基、乙烯基、丙烯基、乙炔基、丙炔基；
R 2 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, amino, hydroxy, cyano, vinyl, propenyl, ethynyl, propylene Alkynyl
R
3选自氢原子、甲基、乙基，丙基、羟甲基、羟乙基、羟丙基、氮杂环丁烷、氧杂环丁烷、苯基、苄基、吡啶、-C(O)NH2；
R 3 is selected from hydrogen atom, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, azetidine, oxetane, phenyl, benzyl, pyridine, -C (O)NH2;
R5选自甲基，甲氧基，羟基，羟甲基，F，
R5 is selected from methyl, methoxy, hydroxy, hydroxymethyl, F,
m为0、1或2；m is 0, 1 or 2;
n为0、1或2。n is 0, 1, or 2.
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IV)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment. The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) and its stereoisomer Body or its pharmaceutically acceptable salt:
其中：among them:
环A、R
2～R
5、m和n如通式(I)所述。
Ring A, R 2 to R 5 , m and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IV-A)和(IV-B)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment. The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is represented by the general formulas (IV-A) and (IV-B) The compound shown, its stereoisomer or its pharmaceutically acceptable salt:
其中：among them:
环A、R
2～R
5、m和n如通式(I)所述。
Ring A, R 2 to R 5 , m and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(V)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment. The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) and its stereoisomer Body or its pharmaceutically acceptable salt:
其中：among them:
环A、R
2～R
5和n如通式(I)所述。
Ring A, R 2 to R 5 and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VA)和(VB)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VA) and (VB), Its stereoisomer or its pharmaceutically acceptable salt:
其中：among them:
环A、R
2～R
5和n如通式(I)所述。
Ring A, R 2 to R 5 and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VI)和(VIA)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VI) and (VIA), Its stereoisomer or its pharmaceutically acceptable salt:
其中：among them:
E、W和G相同或不相同，各自独立的选自氮原子或碳原子；E, W and G are the same or different, each independently selected from a nitrogen atom or a carbon atom;
R
2～R
5和n如通式(I)所述。
R 2 to R 5 and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VII)和(VIIA)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment. The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (VII) and (VIIA), Its stereoisomer or its pharmaceutically acceptable salt:
其中：among them:
L、R
2～R
5、m和n如通式(I)所述。
L, R 2 to R 5 , m and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VIII)和(VIIIA)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VIII) and (VIIIA), Its stereoisomer or its pharmaceutically acceptable salt:
其中：among them:
L、R
1～R
5、m和n如通式(I)所述。
L, R 1 to R 5 , m and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IX)和(IXA)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IX) and (IXA), Its stereoisomer or its pharmaceutically acceptable salt:
其中：among them:
R
2～R
5、m和n如通式(I)所述。
R 2 to R 5 , m and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(X)和(XA)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred embodiment, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (X) and (XA), Its stereoisomer or its pharmaceutically acceptable salt:
其中：among them:
R
2～R
5和n如通式(I)所述。
R 2 to R 5 and n are as described in the general formula (I).
本发明还涉及一个优选方案，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IX)所示的化合物、其立体异构体或其药学上可接受盐：The present invention also relates to a preferred solution, wherein the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IX) and its stereoisomer Body or its pharmaceutically acceptable salt:
其中：among them:
J
1和J
2相同或不相同，各自独立的选自碳原子、氮原子、氧原子和硫原子；
J 1 and J 2 are the same or different, and are independently selected from carbon atom, nitrogen atom, oxygen atom and sulfur atom;
R
3～R
5和n如通式(I)所述。
R 3 to R 5 and n are as described in the general formula (I).
本发明还涉及一个优选方案，任一项所述的各通式、其立体异构体或其药学上可接受的盐，其特征在于，The present invention also relates to a preferred solution, each of the general formulas, stereoisomers or pharmaceutically acceptable salts thereof according to any one of the claims, characterized in that
环A选自如下基团：Ring A is selected from the following groups:
本发明还涉及一个优选方案，任一项所述的各通式、其立体异构体或其药学上可接受的盐，其特征在于，The present invention also relates to a preferred solution, each of the general formulas, stereoisomers or pharmaceutically acceptable salts thereof according to any one of the claims, characterized in that
L为-(CH
2)
n1-或-(CH
2)
n1S(O)
m1-；
L is -(CH 2 ) n1 -or-(CH 2 ) n1 S(O) m1 -;
R
1选氰基或3-8元杂环基，其中所述的的杂环基任选进一步被选自氢原子和氰基中的一个或多个取代基所取代；
R 1 is a cyano group or a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from a hydrogen atom and a cyano group;
R
2氢原子或C
1-6烷基；优选氢原子或C
1-3烷基；更优选氢原子或甲基；
R 2 hydrogen atom or C 1-6 alkyl group; preferably hydrogen atom or C 1-3 alkyl group; more preferably hydrogen atom or methyl group;
R
3选自氢原子、氰基、卤素、C
1-6烷基、C
1-6卤代烷基、C
1-6羟烷基、C
3-8环烷基、3-8元杂环基、-(CH
2)
n1OR
aa或-C(O)NR
aaR
bb；
R 3 is selected from hydrogen atom, cyano group, halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, -(CH 2 ) n1 OR aa or -C(O)NR aa R bb ;
R
4选自氢原子或卤素；
R 4 is selected from hydrogen atom or halogen;
R
5选自氢原子、卤素、羟基、氨基、C
1-6烷基、C
1-6烷氧基、3-8元杂环基、5-10元杂芳基、-(CH
2)
n1OR
aa、-(CH
2)
n1S(O)
m1R
aa、-(CH
2)
n1P(O)
m2R
aaR
bb、-(CH
2)
n1NR
aaR
bb、-(CH
2)
n1C(O)NR
aa(CH
2)
m1R
bb、-(CH
2)
n1P(O)
m1R
aaR
bb或-(CH
2)
n1NR
aaS(O)
m1R
bb，其中所述的杂环基和杂芳基任选进一步被氢原子、C
1-6烷基、羟基、氨基、羧基、氧代基、硫代基、C
1-6烷氧基、C
1-6羟烷基、-(CH
2)
n1OR
cc、-(CH
2)
n1C(O)R
cc、-(CH
2)
n1C(O)OR
cc、-(CH
2)
n1S(O)
m1R
cc、-(CH
2)
n1S(O)
m1NR
ccR
dd、-(CH
2)
n1NR
ccR
dd、-(CH
2)
n1C(O)NR
ccR
dd、-(CH
2)
n1C(O)NR
ccS(O)
m1R
dd、或-(CH
2)
n1NR
ccS(O)
m1R
dd中的一个或多个取代基所取代；
R 5 is selected from a hydrogen atom, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered heterocyclic group, 5-10 membered heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 P(O) m1 R aa R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , where the Heterocyclic group and heteroaryl group are optionally further substituted by hydrogen atom, C 1-6 alkyl group, hydroxyl group, amino group, carboxyl group, oxo group, thio group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C( O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd is substituted by one or more substituents;
R
aa、R
bb、R
cc和R
dd相同或不同，且各自独立地选自氢原子、C
1-6烷基、氨基或3-8元杂环基；其中所述的C
1-6烷基、氨基和3-8元杂环基任选进一步被氢原子、羟基、5-10元杂芳基中的一个或多个取代基所取代。
R aa , R bb , R cc and R dd are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group, an amino group, or a 3-8 membered heterocyclic group; wherein the C 1-6 alkane The group, the amino group, and the 3-8 membered heterocyclic group are optionally further substituted with one or more substituents among a hydrogen atom, a hydroxyl group, and a 5-10 membered heteroaryl group.
本发明进一步涉及任一所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备JAK激酶抑制剂药物中的应用。The invention further relates to the use of any compound of the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of JAK kinase inhibitors.
本发明还涉及一种治疗预防和/或治疗预制备治疗由JAK激酶抑制剂介导的病症的 方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。The present invention also relates to a method for the treatment of prevention and/or treatment of pre-prepared treatment of conditions mediated by JAK kinase inhibitors, which comprises administering to the patient a therapeutically effective dose of a compound represented by general formula (I) and its stereoisomer Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
本发明还涉及一种药用组合物，其包括治疗有效剂量的的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。The present invention also relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable Accepted carriers, diluents or excipients.
本发明还涉及所述的通式(I)化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备治疗炎症性疾病和肿瘤疾病相关药物中的应用。The present invention also relates to the use of the compound of general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of drugs for treating inflammatory diseases and tumor diseases.
本发明还涉及一种治疗炎症性疾病的方法和一种治疗肿瘤疾病的方法，其包括向患者施用治疗有效剂量的药物组合物。The invention also relates to a method for treating inflammatory diseases and a method for treating tumor diseases, which comprises administering to the patient a therapeutically effective dose of a pharmaceutical composition.
以上所述的炎症性疾病选自类风湿性关节炎、皮炎、银屑病、炎症性肠病(溃疡性结肠炎及克罗恩病)，所述的肿瘤性疾病选自骨髓纤维化、真性红细胞增多症及原发性血小板增多症、性骨髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、乳腺导管癌及非小细胞肺癌(NSCLC)，其中胃肠发炎疾病是慢性肠道炎症性疾病，进一步优选溃疡性结肠炎和克罗恩氏病。The inflammatory diseases mentioned above are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and the neoplastic diseases are selected from myelofibrosis and true Polycythemia and primary thrombocythemia, sex myeloid leukemia (AML), acute lymphocytic leukemia (ALL), breast ductal carcinoma, and non-small cell lung cancer (NSCLC), in which gastrointestinal inflammation is chronic intestinal disease Inflammatory diseases are more preferably ulcerative colitis and Crohn's disease.
发明的详细说明Detailed description of the invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、 1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms The alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Amyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and its various branched isomers, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably one or more of the following groups, which are independently selected from Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate groups, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , Deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH
2-、“亚乙基”指-(CH
2)
2-、“亚丙基”指-(CH
2)
3-、“亚丁基”指-(CH
2)
4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
The term "alkylene" means that a hydrogen atom of the alkyl group is further substituted, for example: "methylene" means -CH 2 -, "ethylene" means -(CH 2 ) 2 -, "propylene" Refers to -(CH 2 ) 3 -, "butylene" refers to -(CH 2 ) 4 -and so on. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个碳原子，最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基，更优选环丙基、环丁基和环戊基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 Carbon atoms, most preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, more preferably cyclopropyl Group, cyclobutyl and cyclopentyl.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between 5- to 20-membered monocycles, which may contain one or more double bonds, but none of the rings is fully conjugated Π electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. According to the number of spiro atoms shared between rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups, preferably monospirocycloalkyl groups and dispirocycloalkyl groups. More preferably, it is 4 member/4 member, 4 member/5 member, 4 member/6 member, 5 member/5 member, or 5 member/6 member monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：A spirocyclic alkyl group that also contains a single spirocyclic alkyl group and a heterocyclic alkyl group sharing a spiro atom, non-limiting examples include:
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为4元/4元、5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused ring alkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or Multiple double bonds, but no ring has a completely conjugated π-electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cyclic alkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 4 members/4 members, 5 members/5 members or 5 members/6 members Bicycloalkyl. Non-limiting examples of fused cycloalkyl include:
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated π electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyls include:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧、硼、磷、S(O)
m(其中m是整数0至2)或P(O)
n(其中n是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优 选包含3至8个环原子。单环杂环基的非限制性实例包括氧杂环丁基、氮杂环丁烷基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选氧杂环丁基、氧杂环丁烷基、四氢呋喃基、吡唑烷基、吗啉基、哌啶基、哌嗪基和吡喃基。更优选氧杂环丁基、氧杂环丁烷基、吗啉基、哌啶基和哌嗪基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, boron, phosphorus S(O) m (where m is an integer from 0 to 2) or P(O) n (where n is an integer from 0 to 2) heteroatom, but does not include the ring portion of -OO-, -OS- or -SS- , The remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, Dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl, oxetanyl Alkyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperidinyl, piperazinyl and pyranyl. More preferred are oxetanyl, oxetanyl, morpholinyl, piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally linked to other groups through a single bond or through a ring Any two or more atoms of the above are further connected to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups in parallel.
术语“螺杂环基”指3至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为氮、氧、硼、磷、S(O)
m(其中m是整数0至2)或P(O)
n(其中n是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 3 and 20 membered single rings, where one or more ring atoms are nitrogen, oxygen, boron, phosphorus, S (O) m (where m is an integer from 0 to 2) or a hetero atom of P(O) n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spiro heterocyclic groups are classified into mono-spiro heterocyclic groups, di-spiro heterocyclic groups or poly-spiro heterocyclic groups according to the number of spiro atoms shared between the rings, preferably mono-spiro heterocyclic groups and di-spiro heterocyclic groups. More preferably, it is 3 member/5 member, 4 member/5 member, 4 member/6 member, 5 member/5 member, or 5 member/6 member monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)
m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/5元、4元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings has a completely conjugated π-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3 member/5 member, 4 member/5 member or 5 member/6 member Bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)
m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
The term "bridged heterocyclic group" refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common In the y electron system of the yoke, one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups with a conjugated π-electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate groups.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、噁二唑、吡嗪基等，优选为噁唑基、噁二唑、四氮唑、三氮唑基、噻吩基、咪唑基、吡啶基、吡嗪基、嘧啶基、吡唑基、噻唑、噻二唑、吡唑基、嘧啶基或噻唑基；更优选吡啶基、嘧啶基、哌啶基、吡嗪基、咪唑基、吡唑基、噻唑、三氮唑、噻二唑和噁二唑。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, imidazolyl, pyridyl, pyrazine Group, pyrimidinyl, pyrazolyl, thiazole, thiadiazole, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyridyl, pyrimidinyl, piperidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazole, Triazole, thiadiazole and oxadiazole. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkenyl" refers to alkenyl, also known as alkenyl, where the alkenyl can be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
“炔基”指(CH≡C-或-C≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkynyl" means (CH≡C- or -C≡C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio Group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate groups.
“羟基”指-OH基团。"Hydroxy" refers to the -OH group.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“氨基”指-NH
2。
"Amino" refers to -NH 2 .
“氰基”指-CN。"Cyano" means -CN.
“硝基”指-NO
2。
"Nitro" refers to -NO 2 .
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“THF”指四氢呋喃。"THF" means tetrahydrofuran.
“EtOAc”指乙酸乙酯。"EtOAc" means ethyl acetate.
“MeOH”指甲醇。"MeOH" refers to methanol.
“DMF”指N、N-二甲基甲酰胺。"DMF" refers to N,N-dimethylformamide.
“DIPEA”指二异丙基乙胺。"DIPEA" means diisopropylethylamine.
“TFA”指三氟乙酸。"TFA" means trifluoroacetic acid.
“MeCN”指乙晴。"MeCN" means Yiqing.
“DMA”指N,N-二甲基乙酰胺。"DMA" refers to N,N-dimethylacetamide.
“Et
2O”指乙醚。
"Et 2 O" refers to diethyl ether.
“DCE”指1,2二氯乙烷。"DCE" means 1,2 dichloroethane.
“DIPEA”指N，N-二异丙基乙胺。"DIPEA" means N,N-diisopropylethylamine.
“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.
“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.
“Cbz-Cl”指氯甲酸苄酯。"Cbz-Cl" refers to benzyl chloroformate.
“Pd
2(dba)
3”指三(二亚苄基丙酮)二钯。
"Pd 2 (dba) 3 "means tris(dibenzylideneacetone) dipalladium.
“Dppf”指1,1’-双二苯基膦二茂铁。"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。"HATU" refers to 2-(7-benzobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
“KHMDS”指六甲基二硅基胺基钾。"KHMDS" refers to potassium hexamethyldisilazide.
“LiHMDS”指双三甲基硅基胺基锂。"LiHMDS" refers to lithium bistrimethylsilylamine.
“MeLi”指甲基锂。"MeLi" refers to methyl lithium.
“n-BuLi”指正丁基锂。"N-BuLi" refers to n-butyl lithium.
“NaBH(OAc)
3”指三乙酰氧基硼氢化钠。
"NaBH(OAc) 3 "means sodium triacetoxyborohydride.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, and C" and other different terms all express the same Meaning, that is, X can be any one or more of A, B, and C.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the examples involved in the present invention can also be replaced by deuterium atoms.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不 稳定的。"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiological/pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert the biological activity.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has proper biological activity.
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention is further described below in conjunction with examples, but these examples do not limit the scope of the present invention.
实施例Examples
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d
6)，氘代甲醇(CD
3OD)和氘代氯仿(CDCl
3)，内标为四甲基硅烷(TMS)。
The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The measurement of NMR was performed by Bruker AVANCE-400 nuclear magnetic instrument. The solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). Methylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Liquid chromatography-mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications adopted by TLC are 0.15mm～0.20mm, and the specifications adopted by thin layer chromatography separation and purification products are 0.4mm～0.5mm. Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized using or following methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.
实施例1Example 1
3-((3-exo)-3-((4-甲氧基-6-((5-甲基-1氢-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-methoxy-6-((5-methyl-1hydro-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8 -Azabicyclo[3.2.1]octane-8-yl)propionitrile
第一步：2,4-二氯-N-(5-甲基-1氢-吡唑-3-基)嘧啶-4-氨基的制备Step 1: Preparation of 2,4-dichloro-N-(5-methyl-1hydro-pyrazol-3-yl)pyrimidine-4-amino
往2,4,6-三氯嘧啶(300mg,1.64mmol)的乙醇(5mL)溶液中，依次加入3-氨基-5-甲基吡唑(485mg,2.46mmol)，DIPEA(423mg,3.28mmol)，室温下搅拌反应2小时。反应结束向反应液中加入水(30mL)，室温下搅拌30分钟，过滤，干燥得到标题化合物白色固体(300mg,75％)。To a solution of 2,4,6-trichloropyrimidine (300mg, 1.64mmol) in ethanol (5mL), add 3-amino-5-methylpyrazole (485mg, 2.46mmol), DIPEA (423mg, 3.28mmol) The reaction was stirred at room temperature for 2 hours. After the reaction, water (30 mL) was added to the reaction solution, which was stirred at room temperature for 30 minutes, filtered, and dried to obtain the title compound as a white solid (300 mg, 75%).
MS m/z(ESI):244.1[M+H]
+.
MS m/z(ESI): 244.1[M+H] + .
第二步：叔丁基-(3-exo)-3-((4-氯-6-((5-甲基-1氢-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸的制备The second step: tert-butyl-(3-exo)-3-((4-chloro-6-((5-methyl-1hydro-pyrazol-3-yl)amino)pyrimidin-2-yl)amino ) Preparation of 8-azabicyclo[3.2.1]octane-8-carboxylic acid
往2,4-二氯-N-(5-甲基-1氢-吡唑-3-基)嘧啶-4-氨基(244mg,1mmol)的DMSO(5mL)的溶液中，依次加入N-Boc-exo-3-氨基托烷(271mg,1.2mmol)，DIPEA(258mg,2mmol)，搅拌均匀于后100℃反应过夜。反应液用EA萃取(15mL x 3)，饱和氯化钠水溶液洗涤(15mL x 3)，收集有机相用无水硫酸钠干燥，过滤，减压浓缩有机溶剂得到标题化合物黄色固体(400mg,93％)。To a solution of 2,4-dichloro-N-(5-methyl-1hydro-pyrazol-3-yl)pyrimidine-4-amino (244mg, 1mmol) in DMSO (5mL), N-Boc was added in sequence -exo-3-aminotropane (271mg, 1.2mmol), DIPEA (258mg, 2mmol), stir evenly and react overnight at 100°C. The reaction solution was extracted with EA (15mL×3), washed with saturated aqueous sodium chloride solution (15mL×3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to give the title compound as a yellow solid (400mg, 93%) ).
MS m/z(ESI):434.2[M+H]
+.
MS m/z(ESI): 434.2[M+H] + .
第三步：(3-exo)-3-((4-甲氧基-6-((5-甲基-1氢-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备The third step: (3-exo)-3-((4-methoxy-6-((5-methyl-1hydro-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)- Preparation of 8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
往(3-exo)-3-((4-氯-6-((5-甲基-1氢-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(217mg,0.5mmol)的MeOH(10mL)的溶液中，加入甲醇钠(270mg,5mmol)，搅拌均匀后于100℃加热回流反应过夜。反应液用EA萃取(15mL x 3)，饱和氯化钠水溶液洗涤(15mL x 3)，收集有机相用无水硫酸钠干燥，过滤，减压浓缩有机溶剂得到标题化合物淡黄色固体(200mg,93％)。To (3-exo)-3-((4-chloro-6-((5-methyl-1hydro-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8-azabicyclo [3.2.1] A solution of octane-8-carboxylic acid tert-butyl ester (217 mg, 0.5 mmol) in MeOH (10 mL) was added sodium methoxide (270 mg, 5 mmol), stirred uniformly, and heated at 100°C under reflux overnight. The reaction solution was extracted with EA (15mL×3), washed with saturated aqueous sodium chloride solution (15mL×3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to give the title compound as a pale yellow solid (200mg, 93 %).
MS m/z(ESI):430.2[M+H]
+.
MS m/z(ESI): 430.2[M+H] + .
第四步：3-((3-exo)-3-((4-甲氧基-6-((5-甲基-1氢-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-基)丙腈的制备Step 4: 3-((3-exo)-3-((4-methoxy-6-((5-methyl-1hydro-pyrazol-3-yl)amino)pyrimidin-2-yl) Preparation of amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
(3-exo)-3-((4-甲氧基-6-((5-甲基-1氢-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(100mg,0.23mmol)溶于盐酸乙酸乙酯溶液(4.0N,2mL)中，室温搅拌30分钟后将反应液浓缩，加入MeOH(10mL)将其溶解，缓慢滴加入DIPEA(148mg,1.15mmol)，室温下搅拌10分钟，加入丙烯腈(18mg,0.34mmol)后继续搅拌2小时。反应结束后将反应液浓缩，柱层析(DCM:MeOH＝10:1)分离，制备型HPLC进一步纯化得到标题化合物(7.5mg,9％)。(3-exo)-3-((4-methoxy-6-((5-methyl-1hydro-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8-aza Bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100mg, 0.23mmol) was dissolved in ethyl acetate hydrochloric acid solution (4.0N, 2mL), stirred at room temperature for 30 minutes, the reaction solution was concentrated, and MeOH ( 10mL) Dissolve it, slowly add DIPEA (148mg, 1.15mmol) dropwise, stir at room temperature for 10 minutes, add acrylonitrile (18mg, 0.34mmol) and continue stirring for 2 hours. After the reaction was completed, the reaction solution was concentrated, separated by column chromatography (DCM:MeOH=10:1), and further purified by preparative HPLC to obtain the title compound (7.5 mg, 9%).
MS m/z(ESI):383.2[M+H]
+.
MS m/z(ESI): 383.2[M+H] + .
1H NMR(400MHz,CD
3OD)δ5.97(s,1H),5.58(s,1H),4.44-4.33(m,1H),4.03(s,2H),3.85(s,3H),3.35(s,2H),3.02(t,J＝6.8Hz,2H),2.30(s,2H),2.26(s,3H),2.25-2.20(m,2H),2.15(d,J＝8.4Hz,2H),1.92(t,J＝12.6Hz,2H).
1 H NMR (400 MHz, CD 3 OD) δ 5.97 (s, 1H), 5.58 (s, 1H), 4.44-4.33 (m, 1H), 4.03 (s, 2H), 3.85 (s, 3H), 3.35 (s, 2H), 3.02 (t, J = 6.8Hz, 2H), 2.30 (s, 2H), 2.26 (s, 3H), 2.25-2.20 (m, 2H), 2.15 (d, J = 8.4Hz, 2H), 1.92 (t, J = 12.6 Hz, 2H).
实施例2Example 2
3-((3-exo)-3-((4-甲氧基-6-((5-甲硫基唑-2-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-methoxy-6-((5-methylthioazol-2-yl)amino)pyrimidin-2-yl)amino)-8-azadi Cyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-甲氧基-6-((5-甲硫基唑-2-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-methoxy-6-((5-methylthioazol-2-yl)amino)pyrimidin-2-yl)amino)-8-azadi Refer to Example 1 for the preparation of cyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):400.2[M+H]
+.
MS m/z(ESI): 400.2[M+H] + .
实施例3Example 3
3-((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-2-yl)amino)-8-nitrogen Heterobicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-2-yl)amino)-8-nitrogen The preparation of heterobicyclo[3.2.1]octan-8-yl)propionitrile refers to Example 1.
MS m/z(ESI):416.2[M+H]
+.
MS m/z(ESI): 416.2[M+H] + .
实施例4Example 4
3-((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino) -8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-8-氮杂 二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino) Refer to Example 1 for the preparation of -8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):430.2[M+H]
+.
MS m/z(ESI): 430.2[M+H] + .
实施例5Example 5
3-((3-exo)-3-((4-甲氧基-6-((5-甲硫基唑-2-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-methoxy-6-((5-methylthioazol-2-yl)amino)pyrimidin-2-yl)amino)-9-azadi Cyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-甲氧基-6-((5-甲硫基唑-2-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-methoxy-6-((5-methylthioazol-2-yl)amino)pyrimidin-2-yl)amino)-9-azadi Refer to Example 1 for the preparation of cyclo[3.3.1]nonane-9-yl)propionitrile.
MS m/z(ESI):414.2[M+H]
+.
MS m/z(ESI): 414.2[M+H] + .
实施例6Example 6
3-((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-2-yl)amino)-9-nitrogen Heterobicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-2-yl)amino)-9-nitrogen The preparation of heterobicyclo[3.3.1]nonane-9-yl)propionitrile refers to Example 1.
MS m/z(ESI):430.2[M+H]
+.
MS m/z(ESI): 430.2[M+H] + .
实施例7Example 7
1-(((3-exo)-3-((4-甲氧基-6-((5-甲硫基唑-2-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-methoxy-6-((5-methylthioazol-2-yl)amino)pyrimidin-2-yl)amino)-9-aza Bicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-甲氧基-6-((5-甲硫基唑-2-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-methoxy-6-((5-methylthioazol-2-yl)amino)pyrimidin-2-yl)amino)-9-aza Refer to Example 1 for the preparation of bicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile.
MS m/z(ESI):505.2[M+H]
+.
MS m/z(ESI): 505.2[M+H] + .
实施例8Example 8
1-(((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino )-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino )-9-Azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile Refer to Example 1.
MS m/z(ESI):414.2[M+H]
+.
MS m/z(ESI): 414.2[M+H] + .
实施例9Example 9
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino)-8- Azabicyclo[3.2.1]octane-8-yl)propionitrile
第一步：叔-丁基(3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯的制备The first step: tert-butyl(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl) Preparation of amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
将叔-丁基(3-exo)-3-((4-氯-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(50mg,0.115mmol)和吗啉(200mg,2.3mmol)加入1,4-环氧六环(3mL)中，微波合成仪加热至170℃反应2.5小时，减压浓缩除去溶剂，残余物直接用于下一步反应。Tert-Butyl(3-exo)-3-((4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8- Azabicyclo[3.2.1]octane-8-carboxylate (50mg, 0.115mmol) and morpholine (200mg, 2.3mmol) were added to 1,4-epoxy hexacyclic (3mL) and heated by microwave synthesizer The reaction was carried out at 170°C for 2.5 hours. The solvent was concentrated under reduced pressure to remove the solvent, and the residue was directly used in the next reaction.
MS m/z(ESI):485.2[M+H]
+.
MS m/z(ESI): 485.2[M+H] + .
第二步：3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备Step 2: 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino )-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
将叔-丁基(3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯溶解于4M HCl的1,4-环氧六环溶液(10mL)中,室温搅拌反 应15分钟。减压浓缩除去溶剂，残余物溶解于无水甲醇(10mL)中，依次加入二异丙基乙基胺(0.95mL,5.75mmol)和丙烯腈(0.38mL,5.75mmol),室温搅拌2.5小时，减压浓缩除去溶剂，残余物经prep-HPLC分离得到标题化合物(34mg,48％)。Tert-Butyl(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino)- 8-Azabicyclo[3.2.1]octane-8-carboxylate was dissolved in 4M HCl in 1,4-epoxy hexacyclic solution (10mL) and stirred at room temperature for 15 minutes. The solvent was concentrated under reduced pressure, the residue was dissolved in anhydrous methanol (10 mL), diisopropylethylamine (0.95 mL, 5.75 mmol) and acrylonitrile (0.38 mL, 5.75 mmol) were added in this order, and stirred at room temperature for 2.5 hours. The solvent was concentrated under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (34 mg, 48%).
MS m/z(ESI):438.2[M+H]
+.
MS m/z(ESI): 438.2[M+H] + .
1H NMR(400MHz,DMSO-d
6)δ11.69(s,1H),8.85(s,1H),6.30(s,1H),6.01(s,1H),5.53(s,1H),4.15-3.94(m,1H),3.63(s,4H),3.33(s,4H),3.26(s,2H),2.60(s,4H),2.15(s,3H),1.95-1.43(m,8H).
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.85 (s, 1H), 6.30 (s, 1H), 6.01 (s, 1H), 5.53 (s, 1H), 4.15 3.94(m,1H), 3.63(s,4H),3.33(s,4H),3.26(s,2H),2.60(s,4H),2.15(s,3H),1.95-1.43(m,8H) .
实施例10Example 10
3-((3-exo)-3-((4-(1,1-二羟基硫代吗啉代)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(1,1-dihydroxythiomorpholino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine -2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(1,1-二羟基硫代吗啉代)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(1,1-dihydroxythiomorpholino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine Refer to Example 1 for the preparation of -2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):486.2[M+H]
+.
MS m/z(ESI): 486.2[M+H] + .
实施例11Example 11
3-((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-morpholinopyrimidin-2-yl)amino)-8-nitrogen Heterobicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-8-氮杂二环 [3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-morpholinopyrimidin-2-yl)amino)-8-nitrogen The preparation of heterobicyclo[3.2.1]octan-8-yl)propionitrile refers to Example 1.
MS m/z(ESI):471.2[M+H]
+.
MS m/z(ESI): 471.2[M+H] + .
实施例12Example 12
3-((3-exo)-3-((4-(1,1-二羟基硫代吗啉代)-6-((5-(羟甲基)噻唑-2-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(1,1-dihydroxythiomorpholino)-6-((5-(hydroxymethyl)thiazol-2-yl)amino)pyrimidine- 2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(1,1-二羟基硫代吗啉代)-6-((5-(羟甲基)噻唑-2-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(1,1-dihydroxythiomorpholino)-6-((5-(hydroxymethyl)thiazol-2-yl)amino)pyrimidine- Refer to Example 1 for the preparation of 2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):519.2[M+H]
+.
MS m/z(ESI): 519.2[M+H] + .
实施例13Example 13
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(4-(甲磺酰)哌嗪-1-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(4-(methylsulfonyl)piperazin-1-yl )Pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(4-(甲磺酰)哌嗪-1-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(4-(methylsulfonyl)piperazin-1-yl )Pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile Refer to Example 1.
MS m/z(ESI):515.3[M+H]
+.
MS m/z(ESI): 515.3[M+H] + .
实施例14Example 14
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(哌嗪-1-基)嘧啶-2-基)氨基)-8-氮杂二 环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(piperazin-1-yl)pyrimidin-2-yl) Amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(哌嗪-1-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(piperazin-1-yl)pyrimidin-2-yl) Refer to Example 1 for the preparation of amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):437.3[M+H]
+.
MS m/z(ESI): 437.3[M+H] + .
实施例15Example 15
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(3-羰基哌嗪-1-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(3-carbonylpiperazin-1-yl)pyrimidine-2 -Yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(3-羰基哌嗪-1-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(3-carbonylpiperazin-1-yl)pyrimidine-2 -Yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile Refer to Example 1.
MS m/z(ESI):451.3[M+H]
+.
MS m/z(ESI): 451.3[M+H] + .
实施例16Example 16
1-(((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-(4-(甲磺酰)哌嗪-1-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-(4-(methylsulfonyl)piperazin-1-yl )Pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-((5-(羟甲基)噻唑-2-基)氨基)-6-(4-(甲磺酰)哌嗪-1-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-(4-(methylsulfonyl)piperazin-1-yl ) Pyrimidin-2-yl) (methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile is prepared according to Example 1.
MS m/z(ESI):667.2[M+H]
+.
MS m/z(ESI): 667.2[M+H] + .
实施例17Example 17
3-((3-exo)-3-((4-(4-羟基哌啶-1-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(4-hydroxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2 -Yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(4-羟基哌啶-1-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(4-hydroxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2 -Yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile Refer to Example 1.
MS m/z(ESI):452.3[M+H]
+.
MS m/z(ESI): 452.3[M+H] + .
实施例18Example 18
1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)哌啶-4-羧酸1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)piperidine-4-carboxylic acid
1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)哌啶-4-羧酸的制备参照实施例1。1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)piperidine-4-carboxylic acid Refer to Example 1.
MS m/z(ESI):480.3[M+H]
+.
MS m/z(ESI): 480.3[M+H] + .
实施例19Example 19
1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)哌啶-4-甲酰胺1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)piperidine-4-carboxamide
1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)哌啶-4-甲酰胺的制备参照实施例1。1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)piperidine-4-carboxamide Refer to Example 1.
MS m/z(ESI):479.3[M+H]
+.
MS m/z(ESI): 479.3[M+H] + .
实施例20Example 20
1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)-N-(甲磺酰)哌啶-4-甲酰胺1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-N-(methanesulfonyl)piperidine-4-carboxamide
1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)-N-(甲磺酰)哌啶-4-甲酰胺的制备参照实施例1。1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-N-(methanesulfonyl)piperidine-4-carboxamide Refer to Example 1.
MS m/z(ESI):557.3[M+H]
+.
MS m/z(ESI): 557.3[M+H] + .
实施例21Example 21
3-((3-exo)-3-((4-(吖丁啶-1-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(acridin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl )Amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(吖丁啶-1-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(acridin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl ) Amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile Refer to Example 1.
MS m/z(ESI):408.3[M+H]
+.
MS m/z(ESI): 408.3[M+H] + .
实施例22Example 22
3-((3-exo)-3-((4-(3-羟基吖丁啶-1-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(3-hydroxyazetin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine- 2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(3-羟基吖丁啶-1-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(3-hydroxyazetin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine- Refer to Example 1 for the preparation of 2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):424.2[M+H]
+.
MS m/z(ESI): 424.2[M+H] + .
实施例23Example 23
1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)吖丁啶-3-甲酰胺1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)azetidine-3-carboxamide
1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)吖丁啶-3-甲酰胺的制备参照实施例1。1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)azetidine-3-carboxamide Refer to Example 1.
MS m/z(ESI):451.3[M+H]
+.
MS m/z(ESI): 451.3[M+H] + .
实施例24Example 24
N-(1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)吖丁啶-3-基)甲磺酰胺N-(1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)azetin-3-yl)methanesulfonamide
N-(1-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)吖丁啶-3-基)甲磺酰胺的制备参照实施例1。N-(1-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6- The preparation of ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)azetin-3-yl)methanesulfonamide refers to Example 1.
MS m/z(ESI):501.2[M+H]
+.
MS m/z(ESI): 501.2[M+H] + .
实施例25Example 25
3-((3-exo)-3-((4-(二甲氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(dimethylamino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)- 8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(二甲氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(dimethylamino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation of 8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):396.3[M+H]
+.
MS m/z(ESI): 396.3[M+H] + .
实施例26Example 26
N-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)-N-甲基甲磺酰胺N-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-N-methylmethanesulfonamide
N-(2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)-N-甲基甲磺酰胺的制备参照实施例1。N-(2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5 -Methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)-N-methylmethanesulfonamide Refer to Example 1.
MS m/z(ESI):460.2[M+H]
+.
MS m/z(ESI): 460.2[M+H] + .
实施例27Example 27
3-((3-exo)-3-((4-(甲基(吡啶-3-基甲基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(methyl(pyridin-3-ylmethyl)amino)-6-((5-methyl-1H-pyrazol-3-yl)amino) Pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(甲基(吡啶-3-基甲基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(methyl(pyridin-3-ylmethyl)amino)-6-((5-methyl-1H-pyrazol-3-yl)amino) For the preparation of pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile, refer to Example 1.
MS m/z(ESI):473.3[M+H]
+.
MS m/z(ESI): 473.3[M+H] + .
实施例28Example 28
3-((3-exo)-3-((4-(((1H-吡唑-4-基)甲基)(甲基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(((1H-pyrazol-4-yl)methyl)(methyl)amino)-6-((5-methyl-1H-pyrazole -3-yl)amino)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(((1H-吡唑-4-基)甲基)(甲基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧 啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(((1H-pyrazol-4-yl)methyl)(methyl)amino)-6-((5-methyl-1H-pyrazole For the preparation of -3-yl)amino)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile refer to Example 1.
MS m/z(ESI):462.3[M+H]
+.
MS m/z(ESI): 462.3[M+H] + .
实施例29Example 29
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(吡啶-3-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(pyridin-3-yl)pyrimidin-2-yl)amino )-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(吡啶-3-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(pyridin-3-yl)pyrimidin-2-yl)amino )-8-azabicyclo[3.2.1]octan-8-yl)propionitrile is prepared according to Example 1.
MS m/z(ESI):430.2[M+H]
+.
MS m/z(ESI): 430.2[M+H] + .
实施例30Example 30
3-((3-exo)-3-((4-(6-羟基吡啶-3-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(6-hydroxypyridin-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2- Group) Amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(6-羟基吡啶-3-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(6-hydroxypyridin-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2- Yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile Refer to Example 1 for preparation.
MS m/z(ESI):446.2[M+H]
+.
MS m/z(ESI): 446.2[M+H] + .
实施例31Example 31
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1H-吡唑-4-基)嘧啶-2-基)氨基)-8-氮 杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1H-pyrazol-4-yl)pyrimidine-2- Group) Amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1H-吡唑-4-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1H-pyrazol-4-yl)pyrimidine-2- Yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile Refer to Example 1 for preparation.
MS m/z(ESI):419.2[M+H]
+.
MS m/z(ESI): 419.2[M+H] + .
实施例32Example 32
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl )Pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
第一步：叔-丁基(3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯的制备The first step: tert-butyl(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyridine Preparation of oxazol-4-yl)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
将叔-丁基(3-exo)-3-((4-氯-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二 环[3.2.1]辛烷-8-羧酸酯(150mg,0.35mmol)、(1-甲基-1H-吡唑-4-基)硼酸(65mg,0.5mmol)、Pd(dppf)Cl
2(30mg,0.04mmol)、碳酸钠(110mg,1.05mmol)加入1,4-二氧六环水溶液(V
1,4-
二氧六环:V
水＝4:1,5mL)中,反应液均匀混合后，在微波加热120℃条件下反应3小时，冷却至室温，减压浓缩，所得粗品用快速硅胶柱层析分离纯化得到标题化合物为白色固体(120mg,2％)。
Tert-Butyl(3-exo)-3-((4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8- Azabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.35mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (65mg, 0.5mmol), Pd(dppf ) Cl 2 (30mg, 0.04mmol), sodium carbonate (110mg, 1.05mmol) was added 1,4-dioxane aqueous solution (V 1,4- dioxane : V water = 4:1,5mL), After the reaction solution was uniformly mixed, the reaction was conducted under microwave heating at 120°C for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The obtained crude product was separated and purified by flash silica gel column chromatography to obtain the title compound as a white solid (120 mg, 2%).
MS m/z(ESI):480.2[M+H]
+
MS m/z(ESI): 480.2[M+H] +
第二步：3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备The second step: 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole -4-yl)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile
将叔-丁基(3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(120mg,0.25mmol)和1,4-二氧六环盐酸溶液(4N,5mL)加入甲醇(10mL)中,室温下搅拌1小时，反应液减压浓缩，所得粗品加入由DIPEA(0.2mL)和甲醇(10mL)组成的溶液中,丙烯腈(0.2mL)缓慢加入该溶液，混合均匀后，室温条件下搅拌1小时，减压浓缩，用prep-HPLC分离纯化得到标题化合物为白色固体(64mg,57％)。Tert-Butyl(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole-4 -Yl)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (120mg, 0.25mmol) and 1,4-dioxane hydrochloric acid solution (4N , 5mL) was added to methanol (10mL), stirred at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, the resulting crude product was added to a solution consisting of DIPEA (0.2mL) and methanol (10mL), acrylonitrile (0.2mL) was slowly added to the After the solution was mixed uniformly, it was stirred at room temperature for 1 hour, concentrated under reduced pressure, and separated and purified by prep-HPLC to obtain the title compound as a white solid (64 mg, 57%).
MS m/z(ESI):433.2[M+H]
+
MS m/z(ESI): 433.2[M+H] +
1H NMR(400MHz,DMSO-d
6)δ11.84(s,1H),9.35(s,1H),8.01(s,1H),7.74(s,1H),6.39-6.47(m,3H),4.16-4.17(m,1H),3.88(s,3H),3.29-3.31(m,2H),2.62(s,4H),2.20(s,3H),1.55-1.92(m,8H).
1 H NMR (400MHz, DMSO-d 6 ) δ 11.84 (s, 1H), 9.35 (s, 1H), 8.01 (s, 1H), 7.74 (s, 1H), 6.39-6.47 (m, 3H), 4.16-4.17(m, 1H), 3.88(s, 3H), 3.29-3.31(m, 2H), 2.62(s, 4H), 2.20(s, 3H), 1.55-1.92(m, 8H)
实施例33Example 33
2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-甲酰胺2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-((5-methyl -1H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide
第一步：叔-丁基(3-exo)-3-((4-氨基甲酰-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯的制备The first step: tert-butyl(3-exo)-3-((4-carbamoyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) Preparation of amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
将叔-丁基(3-exo)-3-((4-氯-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(200mg,0.5mmol)、氰化锌(100mg,0.75mmol)、Pd2(dba)3(50mg,0.05mmol)、Xant-phos(60mg,0.1mmol)加入DMF(2mL)中，反应液均匀混合后，在微波150℃条件下加热反应0.5小时，冷却至室温，减压浓缩，所得粗品用快速硅胶柱层析分离纯化得到标题化合物为白色固体(50mg,23％)。Tert-Butyl(3-exo)-3-((4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8- Azabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.5 mmol), zinc cyanide (100 mg, 0.75 mmol), Pd2(dba)3 (50 mg, 0.05 mmol), Xant-phos( 60mg, 0.1mmol) was added to DMF (2mL), after the reaction solution was evenly mixed, the reaction was heated under microwave at 150 ℃ for 0.5 hours, cooled to room temperature, concentrated under reduced pressure, the resulting crude product was separated and purified by flash silica gel column chromatography to obtain the title compound It is a white solid (50 mg, 23%).
MS m/z(ESI):443.2[M+H]
+.
MS m/z(ESI): 443.2[M+H] + .
第二步：2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-甲酰胺的制备Second step: 2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-6-(( Preparation of 5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide
将叔-丁基(3-exo)-3-((4-氨基甲酰-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(50mg,0.11mmol)、1,4-二氧六环盐酸溶液(4N,5mL)加入甲醇(10mL)中，反应液室温反应2小时，减压浓缩，所得粗品加入DIPEA(0.2mL)和甲 醇(10mL)混合的溶液中。将丙烯腈(0.2mL)液缓慢加入混合溶液中，室温下搅拌1小时，减压浓缩，用prep-HPLC分离纯化得到标题化合物为白色固体(5.2mg,8％)。Tert-Butyl(3-exo)-3-((4-carbamoyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)- 8-Azabicyclo[3.2.1]octane-8-carboxylate (50mg, 0.11mmol), 1,4-dioxane hydrochloric acid solution (4N, 5mL) was added to methanol (10mL), the reaction solution The mixture was reacted at room temperature for 2 hours, concentrated under reduced pressure, and the resulting crude product was added to a mixed solution of DIPEA (0.2 mL) and methanol (10 mL). Acrylonitrile (0.2 mL) solution was slowly added to the mixed solution, stirred at room temperature for 1 hour, concentrated under reduced pressure, and separated and purified by prep-HPLC to obtain the title compound as a white solid (5.2 mg, 8%).
MS m/z(ESI):396.2[M+H]
+.
MS m/z(ESI): 396.2[M+H] + .
1H NMR(400MHz,DMSO-d
6)δ11.95(br s,1H),9.87(s,1H),7.49-7.57(m,2H),6.54-6.64(m,2H),4.15(s,1H),3.29-3.51(m,2H),2.57-2.67(m,4H),2.21(s,3H),1.52-2.01(m,8H).
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (br s, 1H), 9.87 (s, 1H), 7.49-7.57 (m, 2H), 6.54-6.64 (m, 2H), 4.15 (s, 1H), 3.29-3.51(m, 2H), 2.57-2.67(m, 4H), 2.21(s, 3H), 1.52-2.01(m, 8H).
实施例34Example 34
2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-N-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-甲酰胺2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-6-( (5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide
2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-N-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-甲酰胺的制备参照实施例1。2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-methyl-6-( For the preparation of (5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide, refer to Example 1.
MS m/z(ESI):410.2[M+H]
+.
MS m/z(ESI): 410.2[M+H] + .
实施例35Example 35
2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-N-(2-羟基乙基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-甲酰胺2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-(2-hydroxyethyl )-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide
2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)氨基)-N-(2-羟基乙基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-甲酰胺的制备参照实施例1。2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)amino)-N-(2-hydroxyethyl )-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxamide Refer to Example 1.
MS m/z(ESI):440.2[M+H]
+.
MS m/z(ESI): 440.2[M+H] + .
实施例36Example 36
2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)(甲基)氨基)-N-(2-羟基乙基)-6-((5-甲硫基唑-2-基)氨基)嘧啶-4-甲酰胺2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-N-(2 -Hydroxyethyl)-6-((5-methylthioazol-2-yl)amino)pyrimidine-4-carboxamide
2-(((3-exo)-8-(2-氰基乙基)-8-氮杂二环[3.2.1]辛烷-3-基)(甲基)氨基)-N-(2-羟基乙基)-6-((5-甲硫基唑-2-基)氨基)嘧啶-4-甲酰胺的制备参照实施例1。2-(((3-exo)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-3-yl)(methyl)amino)-N-(2 -Hydroxyethyl)-6-((5-methylthioazol-2-yl)amino)pyrimidine-4-carboxamide Refer to Example 1.
MS m/z(ESI):471.2[M+H]
+.
MS m/z(ESI): 471.2[M+H] + .
实施例37Example 37
3-((3-exo)-3-((4-羟基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-hydroxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8-aza Bicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-羟基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-hydroxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8-aza Refer to Example 1 for the preparation of bicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):369.2[M+H]
+.
MS m/z(ESI): 369.2[M+H] + .
实施例38Example 38
3-((3-exo)-3-((4-(羟甲基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(hydroxymethyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)- 8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(羟甲基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(hydroxymethyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation of 8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):383.2[M+H]
+.
MS m/z(ESI): 383.2[M+H] + .
实施例39Example 39
3-((3-exo)-3-((4-(2-羟基乙氧基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(2-hydroxyethoxy)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) Amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(2-羟基乙氧基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(2-hydroxyethoxy)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) Refer to Example 1 for the preparation of amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):413.2[M+H]
+.
MS m/z(ESI): 413.2[M+H] + .
实施例40Example 40
1-(((3-exo)-3-((4-(2-羟基乙氧基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-(2-hydroxyethoxy)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl )(Methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-(2-羟基乙氧基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-(2-hydroxyethoxy)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl ) (Methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile Refer to Example 1.
MS m/z(ESI):532.2[M+H]
+.
MS m/z(ESI): 532.2[M+H] + .
实施例41Example 41
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(甲磺酰)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)pyrimidin-2-yl)amino)- 8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(甲磺酰)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation of 8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):431.2[M+H]
+.
MS m/z(ESI): 431.2[M+H] + .
实施例42Example 42
3-((3-exo)-3-((4-(二甲基磷基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(dimethylphosphino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino )-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(二甲基磷基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(dimethylphosphino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino )-8-azabicyclo[3.2.1]octan-8-yl)propionitrile is prepared according to Example 1.
MS m/z(ESI):429.2[M+H]
+.
MS m/z(ESI): 429.2[M+H] + .
实施例43Example 43
3-((3-exo)-3-((4-(吖丁啶-1-基磺酰)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8- 氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-(Azetidine-1-ylsulfonyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2 -Yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-(吖丁啶-1-基磺酰)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-(Azetidine-1-ylsulfonyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2 -Yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile Refer to Example 1.
MS m/z(ESI):472.2[M+H]
+.
MS m/z(ESI): 472.2[M+H] + .
实施例44Example 44
3-((3-exo)-3-((6-((5-甲基-1H-吡唑-3-基)氨基)-4-(1-甲基-1H-吡唑-4-基)吡啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-4-(1-methyl-1H-pyrazol-4-yl )Pyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((6-((5-甲基-1H-吡唑-3-基)氨基)-4-(1-甲基-1H-吡唑-4-基)吡啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-4-(1-methyl-1H-pyrazol-4-yl )Pyridin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile Refer to Example 1.
MS m/z(ESI):432.3[M+H]
+.
MS m/z(ESI): 432.3[M+H] + .
实施例45Example 45
3-((3-exo)-3-((6-甲氧基-2-((5-甲硫基唑-2-基)氨基)嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((6-methoxy-2-((5-methylthioazol-2-yl)amino)pyrimidin-4-yl)amino)-8-azadi Cyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((6-甲氧基-2-((5-甲硫基唑-2-基)氨基)嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((6-methoxy-2-((5-methylthioazol-2-yl)amino)pyrimidin-4-yl)amino)-8-azadi Refer to Example 1 for the preparation of cyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):400.2[M+H]
+.
MS m/z(ESI): 400.2[M+H] + .
实施例46Example 46
3-((3-exo)-3-((6-甲氧基-5-甲基-2-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((6-methoxy-5-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl) Amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((6-甲氧基-5-甲基-2-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((6-methoxy-5-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl) Refer to Example 1 for the preparation of amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):397.2[M+H]
+.
MS m/z(ESI): 397.2[M+H] + .
实施例47Example 47
3-((3-exo)-3-((4-甲氧基-5-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-methoxy-5-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) Amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((4-甲氧基-5-甲基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮 杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-methoxy-5-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) Refer to Example 1 for the preparation of amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):397.2[M+H]
+.
MS m/z(ESI): 397.2[M+H] + .
实施例48Example 48
3-((3-exo)-3-((5-甲基-2-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((5-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-4-yl) Amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((5-甲基-2-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((5-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-4-yl) Refer to Example 1 for the preparation of amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):452.2[M+H]
+.
MS m/z(ESI): 452.2[M+H] + .
实施例49Example 49
3-((3-exo)-3-((2-((5-甲基-1H-吡唑-3-基)氨基)噻唑-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)thiazol-4-yl)amino)-8-azabicyclo[3.2 .1] Octane-8-yl) propionitrile
3-((3-exo)-3-((2-((5-甲基-1H-吡唑-3-基)氨基)噻唑-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((2-((5-methyl-1H-pyrazol-3-yl)amino)thiazol-4-yl)amino)-8-azabicyclo[3.2 .1] Preparation of octane-8-yl) propionitrile Refer to Example 1.
MS m/z(ESI):358.2[M+H]
+.
MS m/z(ESI): 358.2[M+H] + .
实施例50Example 50
3-((3-exo)-3-((5-((5-甲基-1H-吡唑-3-基)氨基)-1,2,4-噻二唑-3-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)-1,2,4-thiadiazol-3-yl)amino) -8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((5-((5-甲基-1H-吡唑-3-基)氨基)-1,2,4-噻二唑-3-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)-1,2,4-thiadiazol-3-yl)amino) Refer to Example 1 for the preparation of -8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):359.2[M+H]
+.
MS m/z(ESI): 359.2[M+H] + .
实施例51Example 51
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)噻唑-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiazol-2-yl)amino)-8-azabicyclo[3.2 .1] Octane-8-yl) propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)噻唑-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiazol-2-yl)amino)-8-azabicyclo[3.2 .1] Preparation of octane-8-yl) propionitrile Refer to Example 1.
MS m/z(ESI):358.2[M+H]
+.
MS m/z(ESI): 358.2[M+H] + .
实施例52Example 52
3-((3-exo)-3-((3-((5-甲基-1H-吡唑-3-基)氨基)-1,2,4-噻二唑-5-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((3-((5-methyl-1H-pyrazol-3-yl)amino)-1,2,4-thiadiazol-5-yl)amino) -8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((3-((5-甲基-1H-吡唑-3-基)氨基)-1,2,4-噻二唑-5-基)氨基)-8-氮杂二环 [3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((3-((5-methyl-1H-pyrazol-3-yl)amino)-1,2,4-thiadiazol-5-yl)amino) Refer to Example 1 for the preparation of -8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):359.2[M+H]
+.
MS m/z(ESI): 359.2[M+H] + .
实施例53Example 53
3-((3-exo)-3-((5-((5-甲基-1H-吡唑-3-基)氨基)-1,2,4-噁二唑-3-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)-1,2,4-oxadiazol-3-yl)amino) -8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((5-((5-甲基-1H-吡唑-3-基)氨基)-1,2,4-噁二唑-3-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((5-((5-methyl-1H-pyrazol-3-yl)amino)-1,2,4-oxadiazol-3-yl)amino) Refer to Example 1 for the preparation of -8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):343.2[M+H]
+.
MS m/z(ESI): 343.2[M+H] + .
实施例54Example 54
3-((3-exo)-3-((1-甲基-5-((5-甲基-1H-吡唑-3-基)氨基)-1H-1,2,4-三唑-3-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((1-methyl-5-((5-methyl-1H-pyrazol-3-yl)amino)-1H-1,2,4-triazole- 3-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((1-甲基-5-((5-甲基-1H-吡唑-3-基)氨基)-1H-1,2,4-三唑-3-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((1-methyl-5-((5-methyl-1H-pyrazol-3-yl)amino)-1H-1,2,4-triazole- For the preparation of 3-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile, refer to Example 1.
MS m/z(ESI):356.2[M+H]
+.
MS m/z(ESI): 356.2[M+H] + .
实施例55Example 55
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基-5-甲基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxy-5-methylpyrimidine- 2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基-5-甲基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxy-5-methylpyrimidine- The preparation of 2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile refers to Example 1.
MS m/z(ESI):532.2[M+H]
+.
MS m/z(ESI): 532.2[M+H] + .
实施例56Example 56
1-(((3-exo)-3-((5-氟-4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((5-fluoro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidine-2 -Yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((5-氟-4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((5-fluoro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidine-2 -Yl) (methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile Refer to Example 1.
MS m/z(ESI):536.2[M+H]
+.
MS m/z(ESI): 536.2[M+H] + .
实施例57Example 57
3-((2-(((3-exo)-9-((3-氰基吖丁啶-1-基)磺酰)-9-氮杂二环[3.3.1]壬烷-3-基)(甲基)氨基)-6-甲氧基嘧啶-4-基)氨基)-1H-吡唑-5-甲酰胺3-((2-(((3-exo)-9-((3-cyanoazetin-1-yl)sulfonyl)-9-azabicyclo[3.3.1]nonane-3- Group) (methyl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide
3-((2-(((3-exo)-9-((3-氰基吖丁啶-1-基)磺酰)-9-氮杂二环[3.3.1]壬烷-3-基)(甲基)氨基)-6-甲氧基嘧啶-4-基)氨基)-1H-吡唑-5-甲酰胺的制备参照实施例1。3-((2-(((3-exo)-9-((3-cyanoazetin-1-yl)sulfonyl)-9-azabicyclo[3.3.1]nonane-3- Group) (methyl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazole-5-carboxamide Refer to Example 1.
MS m/z(ESI):531.2[M+H]
+.
MS m/z(ESI): 531.2[M+H] + .
实施例58Example 58
1-(((3-exo)-3-((4-甲氧基-6-((5-(噁丁环-3-基)-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-methoxy-6-((5-(oxbutylcyclo-3-yl)-1H-pyrazol-3-yl)amino)pyrimidine-2 -Yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-甲氧基-6-((5-(噁丁环-3-基)-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-methoxy-6-((5-(oxbutylcyclo-3-yl)-1H-pyrazol-3-yl)amino)pyrimidine-2 -Yl) (methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile Refer to Example 1.
MS m/z(ESI):544.2[M+H]
+.
MS m/z(ESI): 544.2[M+H] + .
实施例59Example 59
1-(((3-exo)-3-((5-氟-2-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基嘧啶-4-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((5-fluoro-2-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidine-4 -Yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((5-氟-2-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基嘧啶-4-基)(甲基)氨 基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((5-fluoro-2-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidine-4 -Yl) (methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile Refer to Example 1.
MS m/z(ESI):536.2[M+H]
+.
MS m/z(ESI): 536.2[M+H] + .
实施例60Example 60
1-(((3-exo)-3-((4-((4-氟-5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-((4-fluoro-5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidine-2 -Yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-((4-氟-5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-((4-fluoro-5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidine-2 -Yl) (methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile Refer to Example 1.
MS m/z(ESI):536.2[M+H]
+.
MS m/z(ESI): 536.2[M+H] + .
实施例61Example 61
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(1H-吡唑-4-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1H-pyrazol-4-yl) Pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(1H-吡唑-4-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1H-pyrazol-4-yl) The preparation of pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile is referred to Example 1.
MS m/z(ESI):554.2[M+H]
+.
MS m/z(ESI): 554.2[M+H] + .
实施例62Example 62
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(哌嗪-1-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(piperazin-1-yl)pyrimidine- 2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(哌嗪-1-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(piperazin-1-yl)pyrimidine- For the preparation of 2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile, refer to Example 1.
MS m/z(ESI):572.3[M+H]
+.
MS m/z(ESI): 572.3[M+H] + .
实施例63Example 63
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(噁丁环-3-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(oxbutan-3-yl)pyrimidine -2-yl) (methyl) amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(噁丁环-3-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(oxbutan-3-yl)pyrimidine -2-yl) (methyl) amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile is prepared according to Example 1.
MS m/z(ESI):544.2[M+H]
+.
MS m/z(ESI): 544.2[M+H] + .
实施例64Example 64
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(甲磺酰)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)pyrimidin-2-yl )(Methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(甲磺酰)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(methylsulfonyl)pyrimidin-2-yl ) (Methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile Refer to Example 1.
MS m/z(ESI):566.2[M+H]
+.
MS m/z(ESI): 566.2[M+H] + .
实施例65Example 65
3-((3-exo)-3-((2-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((2-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-4-yl)amino)-8-nitrogen Heterobicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-((2-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((2-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-4-yl)amino)-8-nitrogen The preparation of heterobicyclo[3.2.1]octan-8-yl)propionitrile refers to Example 1.
MS m/z(ESI):416.2[M+H]
+.
MS m/z(ESI): 416.2[M+H] + .
实施例66Example 66
1-(((3-exo)-3-((6-甲氧基-2-((5-甲硫基唑-2-基)氨基)嘧啶-4-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((6-methoxy-2-((5-methylthioazol-2-yl)amino)pyrimidin-4-yl)amino)-9-aza Bicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((6-甲氧基-2-((5-甲硫基唑-2-基)氨基)嘧啶-4-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((6-methoxy-2-((5-methylthioazol-2-yl)amino)pyrimidin-4-yl)amino)-9-aza Refer to Example 1 for the preparation of bicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile.
MS m/z(ESI):505.2[M+H]
+.
MS m/z(ESI): 505.2[M+H] + .
实施例67Example 67
1-(((3-exo)-3-((2-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-4-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((2-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-4-yl)(methyl)amino )-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((2-((5-(羟甲基)噻唑-2-基)氨基)-6-甲氧基嘧啶-4-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例1。1-(((3-exo)-3-((2-((5-(hydroxymethyl)thiazol-2-yl)amino)-6-methoxypyrimidin-4-yl)(methyl)amino )-9-Azabicyclo[3.3.1]nonane-9-yl)sulfonyl) azetidine-3-carbonitrile Refer to Example 1.
MS m/z(ESI):535.2[M+H]
+.
MS m/z(ESI): 535.2[M+H] + .
实施例68Example 68
3-((3-exo)-3-((6-((5-甲基-1H-吡唑-3-基)氨基)吡嗪-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)pyrazin-2-yl)amino)-8-azabicyclo[ 3.2.1)octane-8-yl)propionitrile
3-((3-exo)-3-((6-((5-甲基-1H-吡唑-3-基)氨基)吡嗪-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)pyrazin-2-yl)amino)-8-azabicyclo[ 3.2.1] Preparation of octan-8-yl) propionitrile Refer to Example 1.
MS m/z(ESI):353.2[M+H]
+.
MS m/z(ESI): 353.2[M+H] + .
实施例69Example 69
3-((3-exo)-3-((6-((5-甲基-1H-吡唑-3-基)氨基)-2-吗啉代嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-2-morpholinopyrimidin-4-yl)amino)-8- Azabicyclo[3.2.1]octane-8-yl)propionitrile
第一步：叔-丁基(3-exo)-3-((2-氯-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯的制备The first step: tert-butyl(3-exo)-3-((2-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino) Preparation of -8-azabicyclo[3.2.1]octane-8-carboxylate
将2,6-二氯-N-(5-甲基-1H-吡唑-3-基)嘧啶-4-胺(488mg,2.0mmol)、叔-丁基(3-exo)-3-氨基-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(475mg,2.1mmol)和三乙胺(0.7mL,5.0mmol)溶解于DMSO(5mL)中，加热至60℃搅拌反应23小时。冷却至室温，反应液用乙酸乙酯稀释，依次经过饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，残余物经硅胶柱层析分离得到标题化合物(50mg,6％)。2,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (488 mg, 2.0 mmol), tert-butyl(3-exo)-3-amino -8-Azabicyclo[3.2.1]octane-8-carboxylate (475mg, 2.1mmol) and triethylamine (0.7mL, 5.0mmol) were dissolved in DMSO (5mL), heated to 60°C and stirred Reaction for 23 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the title compound (50 mg , 6%).
MS m/z(ESI):434.2[M+H]
+.
MS m/z(ESI): 434.2[M+H] + .
第二步：叔-丁基(3-exo)-3-((6-((5-甲基-1H-吡唑-3-基)氨基)-2-吗啉代嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯的制备The second step: tert-butyl(3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-2-morpholinopyrimidin-4-yl) Preparation of amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
将叔-丁基(3-exo)-3-((2-氯-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(50mg,0.115mmol)和吗啉(500mg,5.75mmol)加入1,4-环氧六环(3mL)中，微波合成仪加热至170℃反应3小时，减压浓缩除去溶剂，残余物经制备TLC分离得到标题化合物(55.7mg,100％)。Tert-Butyl(3-exo)-3-((2-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-8- Azabicyclo[3.2.1]octane-8-carboxylate (50mg, 0.115mmol) and morpholine (500mg, 5.75mmol) were added to 1,4-epoxy hexacyclic (3mL) and heated by microwave synthesizer After reacting at 170°C for 3 hours, the solvent was concentrated under reduced pressure to remove the solvent, and the residue was separated by preparative TLC to obtain the title compound (55.7 mg, 100%).
MS m/z(ESI):485.3[M+H]
+.
MS m/z(ESI): 485.3[M+H] + .
第三步：3-((3-exo)-3-((6-((5-甲基-1H-吡唑-3-基)氨基)-2-吗啉代嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备Step 3: 3-((3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-2-morpholinopyrimidin-4-yl)amino )-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
将叔-丁基(3-exo)-3-((6-((5-甲基-1H-吡唑-3-基)氨基)-2-吗啉代嘧啶-4-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(55.7mg,0.115mmol)溶解于4M HCl的1,4-环氧六环溶液(10mL)中，室温搅拌反应20分钟。减压浓缩除去溶剂，残余物溶解于无水甲醇(10mL)中，依次加入二异丙基乙基胺(0.95mL,5.75mmol)和丙烯腈(0.38mL,5.75mmol)，室温搅拌80分钟，减压浓缩除去溶剂，残余物经prep-HPLC分离得到标题化合物(25.4mg,50.4％)。Tert-Butyl(3-exo)-3-((6-((5-methyl-1H-pyrazol-3-yl)amino)-2-morpholinopyrimidin-4-yl)amino)- 8-Azabicyclo[3.2.1]octane-8-carboxylate (55.7mg, 0.115mmol) was dissolved in 4M HCl in 1,4-epoxy hexacyclic solution (10mL), stirred at room temperature for 20 minutes . The solvent was concentrated under reduced pressure, the residue was dissolved in anhydrous methanol (10 mL), diisopropylethylamine (0.95 mL, 5.75 mmol) and acrylonitrile (0.38 mL, 5.75 mmol) were added in this order, and stirred at room temperature for 80 minutes, The solvent was concentrated under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (25.4 mg, 50.4%).
MS m/z(ESI):438.2[M+H]
+.
MS m/z(ESI): 438.2[M+H] + .
1H NMR(400MHz,DMSO-d
6)δ11.66(s,1H),8.50(s,1H),6.36(s,1H),5.88(s,1H),5.68(s,1H),4.03(s,1H),3.59(dd,J＝12.8,3.8Hz,8H),3.25(s,2H),2.58(dt,J＝16.4,5.5Hz,4H),2.16(s,3H),1.92-1.38(m,8H).
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.66 (s, 1H), 8.50 (s, 1H), 6.36 (s, 1H), 5.88 (s, 1H), 5.68 (s, 1H), 4.03 ( s, 1H), 3.59 (dd, J = 12.8, 3.8 Hz, 8H), 3.25 (s, 2H), 2.58 (dt, J = 16.4, 5.5 Hz, 4H), 2.16 (s, 3H), 1.92-1.38 (m,8H).
实施例70Example 70
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8-azabicyclo[3.2 .1] Octane-8-yl) propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例1。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8-azabicyclo[3.2 .1] Preparation of octane-8-yl) propionitrile Refer to Example 1.
MS m/z(ESI):353.2[M+H]
+.
MS m/z(ESI): 353.2[M+H] + .
实施例71Example 71
1-(((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-8 -Azabicyclo[3.2.1]octane-8-yl)sulfonyl)azetidine-3-carbonitrile
将叔-丁基(3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(215mg,0.5mmol)、1,4-二氧六环盐酸溶液(4N,10mL)加入甲醇(20mL)中，室温反应1小时后，反应液减压浓缩，所得粗品加入由DIPEA(0.5mL)和DMF(10mL)组成的溶液中,3-氰基吖丁啶-1-磺酰氯化(90mg,0.5mmol)缓慢加入该溶液中，混合均匀后，室温条件下搅拌1小时，减压浓缩，用prep-HPLC分离纯化得到标题化合物为白色固体(34.2mg,15％)。Tert-Butyl(3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)- 8-Azabicyclo[3.2.1]octane-8-carboxylate (215mg, 0.5mmol), 1,4-dioxane hydrochloric acid solution (4N, 10mL) was added to methanol (20mL), the reaction at room temperature After 1 hour, the reaction solution was concentrated under reduced pressure, and the resulting crude product was added to a solution consisting of DIPEA (0.5 mL) and DMF (10 mL). 3-cyanoazetidine-1-sulfonyl chloride (90 mg, 0.5 mmol) was slowly added After this solution was mixed uniformly, it was stirred at room temperature for 1 hour, concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound as a white solid (34.2 mg, 15%).
MS m/z(ESI):474.1[M+H]
+
MS m/z(ESI): 474.1[M+H] +
1H NMR(400MHz,DMSO-d
6)δ11.85(s,1H),9.15(s,1H),5.65-6.56(m,3H),3.72-4.24(m,11H),2.18(s,3H),1.61-1.97(m,8H).
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.85 (s, 1H), 9.15 (s, 1H), 5.65-6.56 (m, 3H), 3.72-4.24 (m, 11H), 2.18 (s, 3H ), 1.61-1.97 (m, 8H).
实施例72Example 72
1-(((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-9 -Azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例71。1-(((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-9 -For the preparation of azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile, refer to Example 71.
MS m/z(ESI):488.2[M+H]
+.
MS m/z(ESI): 488.2[M+H] + .
实施例73Example 73
6-甲氧基-N4-(5-甲基-1H-吡唑-3-基)-N2-((3-exo)-9-(吡啶-2-基磺酰)-9-氮杂二环[3.3.1]壬烷-3-基)嘧啶-2,4-二胺6-methoxy-N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-2-ylsulfonyl)-9-azadi Cyclo[3.3.1]nonane-3-yl)pyrimidine-2,4-diamine
6-甲氧基-N4-(5-甲基-1H-吡唑-3-基)-N2-((3-exo)-9-(吡啶-2-基磺酰)-9-氮杂二环[3.3.1]壬烷-3-基)嘧啶-2,4-二胺的制备参照实施例71。6-methoxy-N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-2-ylsulfonyl)-9-azadi The preparation of cyclo[3.3.1]nonane-3-yl)pyrimidine-2,4-diamine refers to Example 71.
MS m/z(ESI):485.2[M+H]
+.
MS m/z(ESI): 485.2[M+H] + .
实施例74Example 74
((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)(吡啶-2-基)甲酮((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-9-aza Bicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methanone
((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环 [3.3.1]壬烷-9-基)(吡啶-2-基)甲酮的制备参照实施例71。((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-9-aza For the preparation of bicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methanone, refer to Example 71.
MS m/z(ESI):449.2[M+H]
+.
MS m/z(ESI): 449.2[M+H] + .
实施例75Example 75
2-(二甲氨基)-1-((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)乙烷-1-酮2-(dimethylamino)-1-((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2 -Yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)ethane-1-one
2-(二甲氨基)-1-((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)乙烷-1-酮的制备参照实施例71。2-(dimethylamino)-1-((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2 -Yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)ethane-1-one Refer to Example 71 for the preparation.
MS m/z(ESI):429.2[M+H]
+.
MS m/z(ESI): 429.2[M+H] + .
实施例76Example 76
1-((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)-2-(甲基氨基)乙烷-1-酮1-((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-9- Azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one
1-((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)-2-(甲基氨基)乙烷-1-酮的制备参照实施例71。1-((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-9- Refer to Example 71 for the preparation of azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one.
MS m/z(ESI):415.2[M+H]
+.
MS m/z(ESI): 415.2[M+H] + .
实施例77Example 77
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino)-9- Azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例9。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino)-9- Refer to Example 9 for the preparation of azabicyclo[3.3.1]nonane-9-yl)propionitrile.
MS m/z(ESI):452.2[M+H]
+.
MS m/z(ESI): 452.2[M+H] + .
实施例78Example 78
3-((3-exo)-3-((4-(1H-咪唑-1-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-(1H-imidazol-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl )Amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-(1H-咪唑-1-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例9。3-((3-exo)-3-((4-(1H-imidazol-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl ) Amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile Refer to Example 9 for preparation.
MS m/z(ESI):433.2[M+H]
+.
MS m/z(ESI): 433.2[M+H] + .
实施例79Example 79
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(6-甲基吡啶-3-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(6-methylpyridin-3-yl)pyrimidine-2 -Yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(6-甲基吡啶-3-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例32。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(6-methylpyridin-3-yl)pyrimidine-2 -Yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile Refer to Example 32 for the preparation.
MS m/z(ESI):458.2[M+H]
+.
MS m/z(ESI): 458.2[M+H] + .
实施例80Example 80
3-((3-exo)-3-((4-(1-甲基-1H-咪唑-4-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-(1-methyl-1H-imidazol-4-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino) Pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-(1-甲基-1H-咪唑-4-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例32。3-((3-exo)-3-((4-(1-methyl-1H-imidazol-4-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino) For the preparation of pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile, refer to Example 32.
MS m/z(ESI):447.2[M+H]
+.
MS m/z(ESI): 447.2[M+H] + .
实施例81Example 81
3-((3-exo)-3-((4-(1-甲基-1H-吡唑-3-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-(1-methyl-1H-pyrazol-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino )Pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-(1-甲基-1H-吡唑-3-基)-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例32。3-((3-exo)-3-((4-(1-methyl-1H-pyrazol-3-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino )Pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile Refer to Example 32.
MS m/z(ESI):447.2[M+H]
+.
MS m/z(ESI): 447.2[M+H] + .
实施例82Example 82
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl )Pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例32。3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl )Pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile Refer to Example 32.
MS m/z(ESI):447.2[M+H]
+.
MS m/z(ESI): 447.2[M+H] + .
实施例83Example 83
1-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)-2-(甲基氨基)乙烷-1-酮1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl )Pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one
1-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)-2-(甲基氨基)乙烷-1-酮的制备参照实施例32。1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl )Pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one Refer to Example 32 for preparation.
MS m/z(ESI):465.2[M+H]
+.
MS m/z(ESI): 465.2[M+H] + .
实施例84Example 84
((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)(吡啶-2-基)甲酮((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine -2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methanone
((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)(吡啶-2-基)甲酮的制备参照实施例32。((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine -2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methanone was prepared according to Example 32.
MS m/z(ESI):499.2[M+H]
+.
MS m/z(ESI): 499.2[M+H] + .
实施例85Example 85
1-(((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈1-(((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(methyl) Amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile
1-(((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)磺酰)吖丁啶-3-甲腈的制备参照实施例71。1-(((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(methyl) For the preparation of amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azetidine-3-carbonitrile, refer to Example 71.
MS m/z(ESI):502.2[M+H]
+.
MS m/z(ESI): 502.2[M+H] + .
实施例86Example 86
6-甲氧基-N2-甲基-N4-(5-甲基-1H-吡唑-3-基)-N2-((3-exo)-9-(吡啶-2-基磺酰)-9-氮杂二环[3.3.1]壬烷-3-基)嘧啶-2,4-二胺6-methoxy-N2-methyl-N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-2-ylsulfonyl)- 9-azabicyclo[3.3.1]nonane-3-yl)pyrimidine-2,4-diamine
6-甲氧基-N2-甲基-N4-(5-甲基-1H-吡唑-3-基)-N2-((3-exo)-9-(吡啶-2-基磺酰)-9-氮杂二环[3.3.1]壬烷-3-基)嘧啶-2,4-二胺的制备参照实施例71。6-methoxy-N2-methyl-N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-2-ylsulfonyl)- The preparation of 9-azabicyclo[3.3.1]nonane-3-yl)pyrimidine-2,4-diamine refers to Example 71.
MS m/z(ESI):499.2[M+H]
+.
MS m/z(ESI): 499.2[M+H] + .
实施例87Example 87
((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)(吡啶-2-基)甲酮((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(methyl)amino)- 9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methanone
((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二 环[3.3.1]壬烷-9-基)(吡啶-2-基)甲酮的制备参照实施例71。((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(methyl)amino)- Refer to Example 71 for the preparation of 9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methanone.
MS m/z(ESI):463.2[M+H]
+.
MS m/z(ESI): 463.2[M+H] + .
实施例88Example 88
1-((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)-2-(甲基氨基)乙烷-1-酮1-((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(methyl)amino )-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one
1-((3-exo)-3-((4-甲氧基-6-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)-2-(甲基氨基)乙烷-1-酮的制备参照实施例71。1-((3-exo)-3-((4-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(methyl)amino )-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one Refer to Example 71 for preparation.
MS m/z(ESI):429.2[M+H]
+.
MS m/z(ESI): 429.2[M+H] + .
实施例89Example 89
3-((3-exo)-3-(甲基(4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino)- 8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-(甲基(4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例9。3-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino)- Refer to Example 9 for the preparation of 8-azabicyclo[3.2.1]octan-8-yl)propionitrile.
MS m/z(ESI):452.2[M+H]
+.
MS m/z(ESI): 452.2[M+H] + .
实施例90Example 90
3-((3-exo)-3-(甲基(4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino)- 9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-(甲基(4-((5-甲基-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例9。3-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)amino)- For the preparation of 9-azabicyclo[3.3.1]nonane-9-yl)propionitrile, refer to Example 9.
MS m/z(ESI):466.2[M+H]
+.
MS m/z(ESI): 466.2[M+H] + .
实施例91Example 91
3-((3-exo)-3-(甲基(4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole-4 -Yl)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
3-((3-exo)-3-(甲基(4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备参照实施例32。3-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole-4 -Yl)pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile Refer to Example 32.
MS m/z(ESI):447.2[M+H]
+.
MS m/z(ESI): 447.2[M+H] + .
实施例92Example 92
3-((3-exo)-3-(甲基(4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole-4 -Yl)pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-(甲基(4-((5-甲基-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例32。3-((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole-4 -Yl)pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile Refer to Example 32 for the preparation.
MS m/z(ESI):461.2[M+H]
+.
MS m/z(ESI): 461.2[M+H] + .
实施例93Example 93
3-((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)(甲基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole- 4-yl)pyrimidin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
第一步：2,4-二氯-6-(1-甲基-1H-吡唑-4-基)嘧啶的制备Step 1: Preparation of 2,4-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine
将2,4,6-三氯嘧啶(500mg,2.73mmol)、(1-甲基-1H-吡唑-4-基)硼酸(413mg,3.28mmol)、Pd(PPh3)4(311mg,0.27mmol)、碳酸钠(870mg,8.19mmol)加入溶剂中(20mL,V
1,4-二氧六环:V
水＝3:1),反应液在60℃条件下搅拌过夜。减压浓缩，所得粗品用快速硅胶柱层析分离纯化得到标题化合物为白色色固体(500mg,80％)。
Combine 2,4,6-trichloropyrimidine (500 mg, 2.73 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (413 mg, 3.28 mmol), and Pd(PPh3) 4 (311 mg, 0.27 mmol ), sodium carbonate (870mg, 8.19mmol) was added to the solvent (20mL, V 1,4-dioxane : V water = 3:1), the reaction solution was stirred at 60 ° C overnight. After concentration under reduced pressure, the obtained crude product was separated and purified by flash silica gel column chromatography to obtain the title compound as a white solid (500 mg, 80%).
MS m/z(ESI):229.1[M+H]
+.
MS m/z(ESI): 229.1[M+H] + .
第二步：(3-((2-氯-6-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)-1H-吡唑-5-基)甲醇的制备The second step: (3-((2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl) methanol preparation
将(3-氨基-1H-吡唑-5-基)甲醇(240mg,2.21mmol)、2,4-二氯-6-(1-甲基-1H-吡唑-4-基) 嘧啶(400mg,1.76mmol)、NaI(160mg,1.76mmol)、DIPEA(700mg,5.28mmol)加入DMF(10mL)中，反应液在90℃条件下反应两天，减压浓缩，所得粗品用快速硅胶柱层析分离纯化得到标题化合物为白色色固体(200mg,37％)。(3-Amino-1H-pyrazol-5-yl)methanol (240 mg, 2.21 mmol), 2,4-dichloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine (400 mg , 1.76mmol), NaI (160mg, 1.76mmol), DIPEA (700mg, 5.28mmol) was added to DMF (10mL), the reaction solution was reacted at 90 ℃ for two days, concentrated under reduced pressure, the crude product obtained by flash silica gel column chromatography Isolation and purification gave the title compound as a white solid (200 mg, 37%).
MS m/z(ESI):306.1[M+H]
+.
MS m/z(ESI): 306.1[M+H] + .
第三步：叔-丁基(3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)(甲基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯的制备The third step: tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1-methyl- Preparation of 1H-pyrazol-4-yl)pyrimidin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
将叔-丁基(3-exo)-3-(甲基氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(240mg,0.98mmol)、(3-((2-氯-6-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)-1H-吡唑-5-基)甲醇(200mg,0.66mmol)、DIPEA(250mg,1.98mmol)加入正丁醇(3mL)中，反应液均匀混合后，在微波加热165℃条件下反应10小时，冷却至室温，减压浓缩，所得粗品用快速硅胶柱层析分离纯化得到标题化合物为淡黄色固体(80mg,23％)。Tert-Butyl(3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate (240mg, 0.98mmol), (3-(( 2-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (200mg, 0.66mmol), DIPEA (250mg , 1.98mmol) was added to n-butanol (3mL), after the reaction solution was evenly mixed, the reaction was carried out under microwave heating at 165 ℃ for 10 hours, cooled to room temperature, concentrated under reduced pressure, the crude product obtained was separated and purified by flash silica gel column chromatography The compound was a light yellow solid (80 mg, 23%).
MS m/z(ESI):510.1[M+H]
+.
MS m/z(ESI): 510.1[M+H] + .
第四步：3-((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)(甲基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的制备Fourth step: 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H -Pyrazol-4-yl)pyrimidin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile
将叔-丁基(3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)(甲基)氨基)-8-氮杂二环[3.2.1]辛烷-8-羧酸酯(80mg,0.16mmol)、1,4-二氧六环盐酸溶液(2mL,4N)加入甲醇(10mL)中，室温下搅拌2小时，LCMS显示原料反应完全，减压浓缩，所得粗品加入由DIPEA(80mg,0.6mmol)和甲醇(10mL)混合的溶液中，在室温下 搅拌，将丙烯腈(21mg,0.4mmol)缓慢滴入溶液中，反应液反应1小时，减压浓缩，用prep-HPLC分离纯化得到标题化合物为淡黄色固体(3.3mg,5％)。Tert-Butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyridine Oxazol-4-yl)pyrimidin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (80mg, 0.16mmol), 1,4-di Oxyhexacyclohydrochloric acid solution (2mL, 4N) was added to methanol (10mL), stirred at room temperature for 2 hours, LCMS showed the raw material reaction was complete, concentrated under reduced pressure, the resulting crude product was added by DIPEA (80mg, 0.6mmol) and methanol (10mL) mixed The solution was stirred at room temperature, acrylonitrile (21mg, 0.4mmol) was slowly dropped into the solution, the reaction solution was reacted for 1 hour, concentrated under reduced pressure, and purified by prep-HPLC to obtain the title compound as a pale yellow solid (3.3mg , 5%).
MS m/z(ESI):463.2[M+H]
+.
MS m/z(ESI): 463.2[M+H] + .
1H NMR(400MHz,DMSO-d
6)δ12.06(s,1H),9.34(d,J＝6.4Hz,1H),8.13(s,1H),7.78(s,1H),6.32-6.49(m,2H),5.21(d,J＝1.6Hz,1H),4.70(d,J＝16Hz,2H),4.43(d,J＝5.6Hz,2H),3.88(s,3H),2.95-3.05(m,1H),2.55-2.67(m,4H),2.33(d,J＝2.8Hz,3H),1.21-2.11(m,8H).
1 H NMR (400 MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 9.34 (d, J=6.4 Hz, 1H), 8.13 (s, 1H), 7.78 (s, 1H), 6.32-6.49 ( m, 2H), 5.21 (d, J = 1.6 Hz, 1H), 4.70 (d, J = 16 Hz, 2H), 4.43 (d, J = 5.6 Hz, 2H), 3.88 (s, 3H), 2.95-3.05 (m, 1H), 2.55-2.67 (m, 4H), 2.33 (d, J=2.8Hz, 3H), 1.21-2.11 (m, 8H).
实施例94Example 94
3-((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole- 4-yl)pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-(1-甲基-1H-吡唑-4-基)嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例93。3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-(1-methyl-1H-pyrazole- Refer to Example 93 for the preparation of 4-yl)pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile.
MS m/z(ESI):477.2[M+H]
+.
MS m/z(ESI): 477.2[M+H] + .
实施例95Example 95
3-((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)(meth Group) amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile
3-((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-吗啉代嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)丙腈的制备参照实施例93。3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-morpholinopyrimidin-2-yl)(meth Yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile Refer to Example 93 for the preparation.
MS m/z(ESI):482.2[M+H]
+.
MS m/z(ESI): 482.2[M+H] + .
实施例96Example 96
((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)(吡啶-2-基)甲酮((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl) Amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methanone
((3-exo)-3-((4-((5-(羟甲基)-1H-吡唑-3-基)氨基)-6-甲氧基嘧啶-2-基)(甲基)氨基)-9-氮杂二环[3.3.1]壬烷-9-基)(吡啶-2-基)甲酮的制备参照实施例93。((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl) Refer to Example 93 for the preparation of amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methanone.
MS m/z(ESI):479.2[M+H]
+.
MS m/z(ESI): 479.2[M+H] + .
生物学测试评价Biological test evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The present invention is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.
1.测试化合物对JAK激酶活性抑制实验1. Test compound inhibits JAK kinase activity
测试例1、本发明化合物对JAK激酶活性抑制作用的测定Test Example 1. Determination of the inhibitory effect of the compounds of the present invention on JAK kinase activity
实验目的：该测试例的目的是测试化合物对JAK激酶活性抑制的活性。Purpose of the experiment: The purpose of this test case is to test the activity of the compound against the inhibition of JAK kinase activity.
实验仪器：离心机(5702R)购自Eppendorf公司，移液器购自Eppendorf或Rainin公司，酶标仪购自美国BioTek公司,型号为SynergyH1全功能酶标仪。Experimental instrument: centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf or Rainin company, microplate reader was purchased from American BioTek company, model is SynergyH1 full-function microplate reader.
实验方法：本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对JAK激酶活性的抑制作用，并得出化合物对JAK激酶活性的半数抑制浓度IC
50。
Experimental Method: The inhibitory effect of test fluorescence resonance energy transfer (TR-FRET) method of test compounds on the JAK kinase activity, and compounds obtained half JAK kinase activity inhibitory concentration IC 50.
具体实验操作如下：The specific experimental operations are as follows:
激酶反应在白色384孔板(PerkinElmer)中进行，每孔加入1-5μL用DMSO和ddH
2O稀释的不同浓度的化合物，阳性对照孔加入1-5μL相应溶媒，然后每孔加入1-5μL用激酶缓冲液(HEPES 50-250mM，MgCl
25-20mM等)稀释的0.1-20nM JAK激酶溶液，阴性对照孔加入1-5μL的激酶缓冲液，加入1～5ul包含多肽底物和ATP的底物混合液，室温孵育0.5～5小时，加入10ul EDTA和含标记抗体的检测液，室温孵育1～24小时，用BioTek Synergy H1酶标仪测定各板孔的约620nm和665nm荧光信号值，通过荧光信号值计算抑制率。根据不 同浓度的抑制率通过曲线拟合得出化合物的IC
50。
The kinase reaction was carried out in a white 384-well plate (PerkinElmer). 1-5 μL of compounds of different concentrations diluted with DMSO and ddH 2 O were added to each well. 1-5 μL of the corresponding vehicle was added to the positive control well, and then 1-5 μL was added to each well Kinase buffer (HEPES 50-250 mM, MgCl 2 5-20 mM, etc.) diluted 0.1-20 nM JAK kinase solution, add 1-5 μL of kinase buffer to the negative control well, add 1-5 ul of substrate containing peptide substrate and ATP Mix the solution and incubate at room temperature for 0.5 to 5 hours, add 10ul of EDTA and the detection solution containing the labeled antibody, incubate at room temperature for 1 to 24 hours, use the BioTek Synergy H1 microplate reader to measure the fluorescence signal value of each plate well at about 620nm and 665nm The signal value calculates the suppression rate. The IC 50 of the compound was obtained by curve fitting according to the inhibition rates at different concentrations.
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不添加激酶)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC
50值。
Calculate the percentage inhibition data of wells treated with compounds by positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition rate=100-[(test compound value-negative control value)]/ (Positive control value-negative control value) × 100}. GraphPad prism was used to fit the data of different concentration and corresponding percentage inhibition rate to the 4-parameter nonlinear logic formula to calculate the IC 50 value.
实验结论：Experimental results:
通过以上方案得出本发明所示的实施例化合物在JAK1/TYK2激酶活性试验中显示出如下表1的生物活性。According to the above scheme, it was found that the compounds of the examples shown in the present invention showed the biological activities in Table 1 below in the JAK1/TYK2 kinase activity test.
表1Table 1
由上表可知：以上实施例化合物都能显著抑制JAK1/TYK2激酶的酶学活性，部分化合物对JAK1/TYK2激酶表现出强效的抑制作用。From the above table, it can be seen that the compounds in the above examples can significantly inhibit the enzymatic activity of JAK1/TYK2 kinase, and some of the compounds show strong inhibitory effects on JAK1/TYK2 kinase.
测试例2、本发明化合物对细胞JAK-STAT信号通路抑制作用的测定Test Example 2. Determination of the inhibitory effect of compounds of the present invention on JAK-STAT signaling pathway
实验目的：该测试例的目的是测试化合物对细胞JAK-STAT信号通路抑制的活性。The purpose of the experiment: The purpose of this test case is to test the activity of the compound on the inhibition of JAK-STAT signaling pathway in cells.
实验仪器：laboratory apparatus:
微孔板振荡器(88880024)购自Thermo Scientific
TM公司
Microplate oscillator (88880024) was purchased from Thermo Scientific TM
离心机(5702R)购自Eppendorf公司，The centrifuge (5702R) was purchased from Eppendorf,
移液器购自Eppendorf公司，Pipettes were purchased from Eppendorf,
酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。The microplate reader was purchased from the United States BioTek company, the model is SynergyH1 full-function microplate reader.
实验方法：本实验采用U266细胞系，通过INF-α刺激激活JAK-STAT信号通路，检测化合物对其下游STAT3磷酸化的抑制活性，并得出化合物对JAK-STAT信号通路活性的半数抑制浓度IC
50。
Experimental method: In this experiment, U266 cell line was used to activate JAK-STAT signaling pathway through INF-α stimulation, and the inhibitory activity of the compound on its downstream STAT3 phosphorylation was detected, and the compound's half inhibitory concentration IC on JAK-STAT signaling pathway activity was obtained. 50 .
具体实验操作如下：The specific experimental operations are as follows:
384孔检测板中铺入U266细3-12μL，每孔细胞个数为100-300K，加入2μL梯度稀释好的化合物溶液，室温350rpm震荡孵育2小时。2小时后加入2μL INF-α，INF-α终浓度1000U/mL，室温震荡15分钟。加入2-5μL(5X)LANCE Ultra Lysis Buffer 2溶液，室温震荡2小时。2小时后加入5μL终浓度为0.5nM的LANCE Ultra Eu-labeled Anti-STAT3 Antibody(PerkinElmer)和终浓度为5nM的LANCE Ultra ULight-labeled Anti-STAT3 Antibody(PerkinElmer)溶液，室温孵育过夜。酶标仪测定各板孔的665nm荧光信号值，通过荧光信号值计算抑制率，根据不同浓度的抑制率通过曲线拟合得出化合物的IC
50。
Spread 3-12 μL of U266 fine in the 384-well detection plate, the number of cells per well is 100-300K, add 2 μL of the gradient diluted compound solution, and incubate at 350 rpm with shaking at room temperature for 2 hours. After 2 hours, add 2 μL of INF-α, the final concentration of INF-α is 1000U/mL, and shake at room temperature for 15 minutes. Add 2-5μL (5X) LANCE Ultra Lysis Buffer 2 solution and shake at room temperature for 2 hours. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 0.5 nM and LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 5 nM were added, and incubated overnight at room temperature. 665nm fluorescence signal then determined values of the respective plate hole, by a fluorescence inhibition rate signal value, the inhibition rate according to varying concentrations of IC 50 by curve fitting of the compound obtained.
实验数据处理方法：Experimental data processing method:
通过于板上阳性对照孔(DMSO对照孔)和阴性对照孔(不加细胞)计算使用化合物处理的孔的百分比抑制数据{％抑制率＝100-[(测试化合物值-阴性对照值)]/(阳性对照值-阴性对照值)×100}。使用GraphPad prism拟合不同浓度和相应百分比抑制率数据至4参数非线性逻辑公式计算出IC
50值。
Calculate the percentage inhibition data of wells treated with compounds by positive control wells (DMSO control wells) and negative control wells (without cells added) on the plate {% inhibition rate=100-[(test compound value-negative control value)]/ (Positive control value-negative control value) × 100}. GraphPad prism was used to fit the data of different concentration and corresponding percentage inhibition rate to the 4-parameter nonlinear logic formula to calculate the IC 50 value.
实验结论：Experimental results:
通过以上方案得出本发明所示的实施例化合物对U266细胞JAK-STAT信号通路活性中显示出如下表2的生物活性。Based on the above scheme, it can be concluded that the compounds of the examples shown in the present invention show the biological activities of Table 2 below in the activity of JAK-STAT signaling pathway in U266 cells.
表2Table 2
由上表可知：以上实施例化合物对人骨髓瘤细胞U266的JAK-STAT信号通路活性具有明显的抑制作用。It can be seen from the above table that the compounds of the above examples have a significant inhibitory effect on the activity of JAK-STAT signaling pathway of human myeloma cell U266.
测试3、Balb/C小鼠药代动力学测定Test 3. Determination of pharmacokinetics of Balb/C mice
1.研究目的：1. Research purpose:
以Balb/C小鼠为受试动物，研究化合物1、4、7、9、12、15、16、18、21、23、27、32、33、38、42、49、53、54、57、58、60、68、69、70、71、72、73、74、76、77、78、82、83、84、88、90、92、93，在5mg/kg剂量下口服给药在小鼠体内(血浆和结肠、回肠组织)的药代动力学行为，通过分析结肠和回肠的药物浓度，以及结肠/回肠药物浓度、结肠/血浆药物浓度比值，筛选PK优异的化合物用于下一步研究。Using Balb/C mice as test animals, study compounds 1, 4, 7, 9, 12, 15, 16, 18, 21, 23, 27, 32, 33, 38, 42, 49, 53, 54, 57 , 58, 60, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 82, 83, 84, 88, 90, 92, 93, orally administered at a dose of 5 mg/kg in small Pharmacokinetic behavior in mice (plasma and colon, ileum tissue), by analyzing the drug concentration of colon and ileum, as well as colon/ileal drug concentration, colon/plasma drug concentration ratio, screening compounds with excellent PK for further research .
2.试验方案2. Test plan
2.1试验药品：2.1 Test drugs:
本发明化合物1、4、7、9、12、15、16、18、21、23、27、32、33、38、42、49、53、54、57、58、60、68、69、70、71、72、73、74、76、77、78、82、83、84、88、90、 92、93，自制。Compounds of the invention 1, 4, 7, 9, 12, 15, 16, 18, 21, 23, 27, 32, 33, 38, 42, 49, 53, 54, 57, 58, 60, 68, 69, 70 , 71, 72, 73, 74, 76, 77, 78, 82, 83, 84, 88, 90, 92, 93, self-made.
2.2试验动物：2.2 Test animals:
Balb/C Mouse每组12只，雄性，上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006 N0.311620400001794)。Balb/CMouse 12 animals per group, male, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).
2.3给药：2.3 Administration:
Balb/C小鼠每组12只，雄性；禁食一夜后分别p.o.，剂量为5mg/kg，给药体积10mL/kg。There are 12 Balb/C mice in each group, male; p.o. after fasting overnight, the dose is 5 mg/kg, and the administration volume is 10 mL/kg.
2.4样品采集：2.4 Sample collection:
小鼠给药前和给药后，在0、0.5、1、2、3、5和7小时，采用CO
2处死，心脏采血0.2mL，置于EDTA-K
2试管中，4℃6000rpm离心6分钟分离血浆，于-80℃保存；回肠取靠近盲肠端，长度约4-5cm；结肠同样取靠近盲肠端，长度约2-3cm，取出称重后，置于2mL离心管中，于-80℃保存。
Before and after administration, the mice were sacrificed with CO 2 at 0 , 0.5, 1, 2 , 3, 5 and 7 hours, and 0.2 mL of blood was collected from the heart, placed in an EDTA-K 2 test tube, and centrifuged at 6000 rpm at 4°C. 6 Plasma is separated in minutes and stored at -80°C; the ileum is taken close to the cecum end with a length of about 4-5cm; the colon is also taken close to the cecum end with a length of about 2-3cm, taken out and weighed, placed in a 2mL centrifuge tube Store at ℃.
2.5样品处理：2.5 Sample processing:
1)血浆样品40uL加入160uL乙腈沉淀,混合后3500×g离心5～20分钟。1) Plasma samples were precipitated by adding 160uL of acetonitrile to 40uL, and centrifuged at 3500×g for 5-20 minutes after mixing.
2)血浆和肠匀浆样品30μL加入90μL含内标(100ng/mL)乙腈沉淀,混合后13000rpm离心8分钟。2) 30 μL of plasma and intestinal homogenate samples were added to 90 μL of acetonitrile containing internal standard (100 ng/mL) for precipitation. After mixing, they were centrifuged at 13000 rpm for 8 minutes.
3)取处理后上清溶液70uL加入70μL水，涡旋混合10分钟，随后取20μL进行LC/MS/MS分析待测化合物的浓度，LC/MS/MS分析仪器：AB Sciex API 4000 Qtrap。3) Take 70 μL of the supernatant solution after treatment, add 70 μL of water, vortex to mix for 10 minutes, and then take 20 μL for LC/MS/MS analysis of the concentration of the test compound. LC/MS/MS analysis instrument: AB Sciex API 4000Qtrap
2.6液相分析2.6 Liquid phase analysis
●液相条件：Shimadzu LC-20AD泵●Liquid phase condition: Shimadzu LC-20AD pump
●色谱柱：Agilent ZORBAX XDB-C18(50×2.1mm,3.5μm)移动相：A液为0.1％甲酸水溶液，B液为乙腈●Chromatography column: Agilent ZORBAX XDB-C18 (50×2.1mm, 3.5μm) Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile
●流速：0.4mL/min●Flow rate: 0.4mL/min
●洗脱时间：0-4.0分钟，洗脱液如下：●Elution time: 0-4.0 minutes, the eluent is as follows:
3.试验结果与分析3. Test results and analysis
药代动力学主要参数用WinNonlin 6.1计算得到，小鼠药代实验结果见下表3：The main parameters of pharmacokinetics are calculated by WinNonlin 6.1. The results of mouse pharmacokinetic experiments are shown in Table 3 below:
表3table 3
从表中小鼠药代动力学(PK)实验结果可以看出：本发明实施例化合物在结肠和回肠中表现出良好的暴露水平，血药浓度时间曲线下面积(AUC)和最大血药浓度(C
max)均达到筛选标准；并且部分化合物的结肠/回肠药物浓度、结肠/血浆药物浓度比值较高，表现出良好的选择性。
From the results of mouse pharmacokinetic (PK) experiments in the table, it can be seen that the compounds of the examples of the present invention show good exposure levels in the colon and ileum, the area under the blood concentration time curve (AUC) and the maximum blood concentration ( C max ) all meet the screening criteria; and some compounds have higher colon/ileal drug concentration and colon/plasma drug concentration ratio, showing good selectivity.
Claims (19)
- 一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：A compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:其中：among them:L选自键、亚烷基、亚烯基、炔基、环烷基、杂环基、-(CH 2) n1-或-(CH 2) n1S(O) m1-； L is selected from the group consisting of a bond, an alkylene group, an alkenylene group, an alkynyl group, a cycloalkyl group, a heterocyclic group, -(CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;G选自NR aa或CR aa； G is selected from NR aa or CR aa ;M选自S或CR 4； M is selected from S or CR 4 ;环A选自杂芳基，其中所述杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代、未取代的杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代； Ring A is selected from heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, halogen, hydroxyl group, substituted or unsubstituted amino group, oxo group, nitrate Group, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted, unsubstituted heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa ,- (CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S( O) substituted by one or more substituents in m1 R bb ;R 1选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1NR ccC(O)R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代； R 1 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, hydroxyalkyl group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group , Cycloalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C (O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa ,- (CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaromatic The group is optionally further selected from deuterium atoms, alkyl groups, haloalkyl groups, halogens, amino groups, oxo groups, nitro groups, cyano groups, hydroxy groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 NR cc C(O)R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd Replaced by multiple substituents;R 2氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、 卤素、氨基、硝基、羟基、氰基、烯基或炔基； R 2 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group or alkynyl group;R 3氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代； R 3 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, ring Alkyl, heterocyclic, aryl, heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb is substituted by one or more substituents;R 4氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基； R 4 hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, hydroxyalkyl group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group or alkynyl group;R 5选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、羟烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1P(O) m2R aaR bb、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aa(CH 2) m1R bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代、未取代的杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1S(O) m1NR ccR dd、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NR ccS(O) m1R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代； R 5 is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group , Hydroxyalkyl, heterocyclyl, oxoheterocyclyl, thioheterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C (O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa ,- (CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, thio, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl , Substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted, unsubstituted heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O) R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd is substituted by one or more substituents;R aa、R bb、R cc和R dd相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代； R aa , R bb , R cc and R dd are the same or different, and are independently selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, haloalkoxy group, Halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy Group, hydroxyalkyl group, haloalkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted alkyl group, Halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Substituted by one or more of hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;或者，R aa和R bb链接形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、取代或未取代的烷基、取代或未取代 的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基或取代或未取代的杂芳基中的一个或多个取代基所取代； Alternatively, R aa and R bb are linked to form a cycloalkyl, heterocyclic group, aryl group and heteroaryl group, wherein the cycloalkyl, heterocyclic group, aryl group and heteroaryl group are optionally further selected from deuterium Atom, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, Hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Heterocyclic group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group is substituted by one or more substituents;m为0、1、2或3的整数；m is an integer of 0, 1, 2 or 3;n为0、1、2、3、4或5的整数；n is an integer of 0, 1, 2, 3, 4 or 5;m 1为0、1或2的整数； m 1 is an integer of 0, 1, or 2;m 2为0、1或2的整数；且 m 2 is an integer of 0, 1, or 2; andn 1为0、1、2、3、4或5的整数。 n 1 is an integer of 0, 1, 2, 3, 4, or 5.
- 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：The compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by general formula (II), its stereoisomer or its pharmacy Acceptable salt:其中：among them:环A、L、R 1～R 5、m和n如权利要求1所述。 Rings A, L, R 1 to R 5 , m and n are as defined in claim 1.
- 根据权利要求2所述的通式(II)所示的化合物、其立体异构体或其药学上可接受盐：The compound represented by the general formula (II) according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof:其中：among them:L选自键、C 0-8亚烷基、C 2-8亚烯基、C 2-8炔基、C 3-8环烷基、C 3-8杂环基、-(CH 2) n1-或-(CH 2) n1S(O) m1-，杂环基中的杂原子选自N、O、S、P中的一个或多个； L is selected from bond, C 0-8 alkylene, C 2-8 alkenylene, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -, the hetero atom in the heterocyclic group is selected from one or more of N, O, S, P;环A选自C 5-12杂芳基，其中所述杂芳基任选进一步被选自氢原子、氘原子、取代或 未取代的C 0-8烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 0-8烷氧基、取代或未取代的C 0-8羟烷基、取代或未取代的C 3-8环烷基、取代或未取代的C 3-8杂环基、取代或未取代的C 5-12芳基和取代或未取代的C 5-12杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代； Ring A is selected from C 5-12 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 0-8 alkoxy, Substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 heterocyclic, substituted or unsubstituted C 5-12 aryl And substituted or unsubstituted C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa ,- (CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb Substituted by a substituent;R 1选自氢原子、C 0-8烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0-8卤代烷氧基、C 0-8羟烷基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、C 3-8杂环基、C 3- 8氧代杂环基、C 3-8硫代杂环基、C 5-12芳基、C 5-12杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，杂环基、杂芳基中的杂原子选自N、O、S、P中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自C 0-8烷基、C 0-8卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、C 2-8烯基、C 2-8炔基、C 0- 8烷氧基、C 0-8卤代烷氧基、C 0-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 5-12芳基、C 5-12杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1NR ccC(O)R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；杂环基、杂芳基中的杂原子选自N、O、S、P中的一个或多个； R 1 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 haloalkoxy, C 0-8 hydroxyalkyl, halogen, amino, nitrate group, hydroxy, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 3- 8-oxo-heterocyclyl, C 3- 8 thioheterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C (O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one of N, O, S, P Or more; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from C 0-8 alkyl, C 0-8 haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, C 2-8 alkenyl, C 2-8 alkynyl groups, C 0- 8 alkoxy, C 0-8 haloalkoxy, C 0-8 hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O) OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 NR cc C(O)R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd is substituted by one or more substituents; heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O, S, P;R 2选自氢原子、C 0-8烷基、C 0-8氘代烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0-8羟烷基、C 0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基或C 2-8炔基； R 2 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 hydroxyalkyl, C 0-8 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;R 3选自氢原子、氘原子、C 0-8烷基、C 0-8氘代烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0- 8羟烷基、C 0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、C 3-8杂环基、C 5-12芳基、C 5-12杂芳基、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 3 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb One or more, optionally substituted by one or more substituents, heterocyclic The hetero atom in the group or heteroaryl group is selected from one or more of N, O, and S;R 4选自氢原子、氘原子、C 0-8烷基、C 0-8氘代烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0- 8羟烷基、C 0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基或C 2-8炔基； R 4 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;R 5选自氢原子、氘原子、C 0-8烷基、C 0-8氘代烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0- 8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、C 0-8羟烷基、C 3-8杂环基、C 3-8氧代杂环基、C 3-8硫代杂环基、C 5-12芳基、C 5-12杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1P(O) m2R aaR bb、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aa(CH 2) m1R bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C 0-8烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 0-8烷氧基、取代或未取代的C 0-8羟烷基、取代或未取代的C 3-8环烷基、取代或未取代的C 3-8杂环基、取代或未取代的C 5-12芳基和取代或未取代的C 5-12杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1S(O) m1NR ccR dd、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NR ccS(O) m1R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个 R 5 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 haloalkoxy, halogen, , Amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 0-8 hydroxyalkyl, C 3-8 heterocyclyl, C 3-8 oxoheterocyclyl , C 3-8 thioheterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C( O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -( CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkane Group, halogen, hydroxyl, substituted or unsubstituted amino, oxo, thio, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl , Substituted or unsubstituted C 0-8 alkoxy, substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 hetero Cyclic group, substituted or unsubstituted C 5-12 aryl group and substituted or unsubstituted C 5-12 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd Substituted by one or more substituents, heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O and S条件是，当R2为H或甲基、R3为羟甲基时，R4不为氢或R5不为甲氧基或-L1-R1不为或n＝2。 The condition is that when R2 is H or methyl and R3 is hydroxymethyl, R4 is not hydrogen or R5 is not methoxy or -L1-R1 is notOr n=2.
- 根据权利要求3所述的通式(II)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：The compound represented by the general formula (II) according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:L选自键、C 1-3亚烷基、C 2-3亚烯基、C 2-3炔基、C 3-6环烷基、C 3-6杂环基、-(CH 2) n1-或-(CH 2) n1S(O) m1-杂环基中的杂原子选自N、O、S中的一个或多个； L is selected from the group consisting of bond, C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -the hetero atom in the heterocyclic group is selected from one or more of N, O, and S;环A选自C 5-10杂芳基，其中所述杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C 1-3烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C 2-3烯基、取代或未取代的C 2-3炔基、取代或未取代的C 1-3烷氧基、取代或未取代的C 1-3羟烷基、取代或未取代的C 1-3环烷基、取代或未取代的C 3-6杂环基、取代或未取代的C 5-10芳基和取代或未取代的C 5-10杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代； Ring A is selected from C 5-10 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 1-3 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-3 alkenyl, substituted or unsubstituted C 2-3 alkynyl, substituted or unsubstituted C 1-3 alkoxy, Substituted or unsubstituted C 1-3 hydroxyalkyl, substituted or unsubstituted C 1-3 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic, substituted or unsubstituted C 5-10 aryl And substituted or unsubstituted C 5-10 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa ,- (CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb Substituted by a substituent;R 1选自氢原子、C 1-3烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、卤素、氨基、硝基、羟基、氰基、C 2-3烯基、C 2-3炔基、C 3-6环烷基、C 3-6杂环基、C 3- 6氧代杂环基、C 3-6硫代杂环基、C 5-10芳基、C 5-10杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、- NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自C 1-3烷基、C 1-3卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、C 2-3烯基、C 2-3炔基、C 1- 3烷氧基、C 1-3卤代烷氧基、C 1-3羟烷基、C 1-3环烷基、C 3-6杂环基、C 5-10芳基、C 5-10杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1NR ccC(O)R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 1 is selected from hydrogen atom, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, halogen, amino, nitrate Group, hydroxyl group, cyano group, C 2-3 alkenyl group, C 2-3 alkynyl group, C 3-6 cycloalkyl group, C 3-6 heterocyclic group, C 3- 6 oxo heterocyclic group, C 3- 6 thioheterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa ,-NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C (O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from C 1-3 alkyl, C 1-3 haloalkyl, halogen, amino, oxo, nitro , cyano, hydroxy, C 2-3 alkenyl, C 2-3 alkynyl, C 1- 3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 cycloalkyl Group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 NR cc C(O)R dd or -(CH 2 ) n1 NR cc S (O) m1 R dd is substituted by one or more substituents, and the hetero atoms in the heterocyclic group and heteroaryl group are selected from one or more of N, O, and S;R 2选自氢原子、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3羟烷基、C 1-3卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-3烯基或C 2-3炔基； R 2 is selected from hydrogen atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl or C 2-3 alkynyl;R 3选自氢原子、氘原子、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1- 3羟烷基、C 1-3卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-3烯基、C 2-3炔基、C 3-6环烷基、C 3-6杂环基、C 5-10芳基、C 5-10杂芳基、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 3 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb One or more, optionally substituted by one or more substituents, heterocyclic The hetero atom in the group or heteroaryl group is selected from one or more of N, O, and S;R 4选自氢原子、氘原子、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1- 3羟烷基、C 1-3卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-3烯基或C 2-3炔基； R 4 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 hydroxyalkyl, C 1-3 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-3 alkenyl or C 2-3 alkynyl;R 5选自氢原子、氘原子、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、C 1- 3卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-3烯基、C 2-3炔基、C 3-6环烷基、C 1-3羟烷基、C 3-6杂环基、C 3-6氧代杂环基、C 3-6硫代杂环基、C 5-10芳基、C 5-10杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1P(O) m2R aaR bb、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aa(CH 2) m1R bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C 1-3烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的C 2-3烯基、取代或未取代的C 2-3炔基、取代或未取代的C 1-3烷氧基、取代或未取代的C 1-3羟烷基、取代或未取代的C 3-6环烷基、取代或未取代的C 3-6杂环基、取代或未取代的C 5-10芳基和取代或未取代的C 5-10杂芳基、-(CH 2) n1-、 -(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1S(O) m1NR ccR dd、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NR ccS(O) m1R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 5 is selected from a hydrogen atom, a deuterium atom, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy, halogen, , Amino, nitro, hydroxyl, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 1-3 hydroxyalkyl, C 3-6 heterocyclyl, C 3-6 oxoheterocyclyl , C 3-6 thioheterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C( O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -( CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 1-3 alkane Group, halogen, hydroxyl, substituted or unsubstituted amino, oxo, thio, nitro, cyano, substituted or unsubstituted C 2-3 alkenyl, substituted or unsubstituted C 2-3 alkynyl , Substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 1-3 hydroxyalkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 hetero Cyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd One or more substituents are substituted, and the hetero atoms in the heterocyclic group and heteroaryl group are selected from one or more of N, O, and S;条件是，当R2为H或甲基、R3为羟甲基时，R4不为氢或R5不为甲氧基或-L1-R1不为或n＝2。 The condition is that when R2 is H or methyl and R3 is hydroxymethyl, R4 is not hydrogen or R5 is not methoxy or -L1-R1 is notOr n=2.
- 根据权利要求4所述的通式(II)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：The compound represented by the general formula (II) according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:L选自键、C 1-3亚烷基、(CH 2) n1-或-(CH 2) n1S(O) m1-； L is selected from bond, C 1-3 alkylene, (CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;环A选自C 5-6杂芳基，其中所述杂芳基任选进一步被选自氢原子、甲基、乙基、F、Cl、Br、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C 3-6杂环基、取代或未取代的C 5-10芳基和取代或未取代的C 5-10杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代； Ring A is selected from C 5-6 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, methyl, ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo Group, nitro group, cyano group, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) One or more substituents in n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb ;R 1选自氢原子、C 1-3烷基、氨基、氰基、C 2-3烯基、C 2-3炔基、C 3-6环烷基、C 3-6杂环基、C 5-10芳基、C 5-10杂芳基、-(CH 2) n1R aa、(CH 2) n1C(O)R aa、--(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb或-(CH 2) n1C(O)NR aaR bb，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氨基、氰基、-(CH 2) n1R cc或-(CH 2) n1NR ccR dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 1 is selected from a hydrogen atom, C 1-3 alkyl, amino, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , (CH 2 ) n1 C(O)R aa , --(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb or -(CH 2 ) n1 C(O)NR aa R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O and S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from amino, cyano, -(CH 2 ) n1 R cc or -(CH 2 ) n1 NR cc R dd Substituted by one or more substituents, the heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O, S;R 2选自氢原子、甲基、乙基、卤代甲基、卤代乙基、甲氧基、乙氧基、羟甲基、羟乙基、羟丙基、卤代甲氧基、卤代乙氧基、F、Cl、Br、氨基、硝基、羟基、氰基、乙烯基、丙烯基、乙炔基、丙炔基； R 2 is selected from hydrogen atom, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, halo Ethoxy, F, Cl, Br, amino, nitro, hydroxyl, cyano, vinyl, propenyl, ethynyl, propynylR 3选自氢原子、C 1-3烷基、C 1-3羟烷基、C 3-6杂环基、C 5-10芳基、C 5-10杂芳基、-(CH 2) n1C(O)R aa或-(CH 2) n1C(O)NR aaR bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 3 is selected from hydrogen atom, C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) one or more of n1 C(O)NR aa R bb , optionally substituted by one or more substituents, heterocyclic and heteroaryl Is selected from one or more of N, O, S;R 4选自氢原子、甲基、乙基、甲氧基、乙氧基、羟甲基、羟乙基、F、Cl、Br、氨基、硝基、羟基、氰基、乙烯基或乙炔基； R 4 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, Br, amino, nitro, hydroxy, cyano, vinyl or ethynyl ;R 5选自氢原子、甲基、乙基、丙基、甲氧基、乙氧基、F、Cl、Br、氨基、羟基、氰基、乙烯基、乙炔基、乙炔基、丙炔基、环丙基、环丁基、环戊基、环己基、羟甲基、羟 乙基、羟丙基、C 3-6杂环基、C 3-6氧代杂环基、C 3-6硫代杂环基、C 5-6杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1P(O) m2R aaR bb、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aa(CH 2) m1R bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自取代或未取代的甲基、取代或未取代的乙基、F、Cl、Br、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的羟甲基、取代或未取代的羟乙基、取代或未取代的C 3-6环烷基、取代或未取代的C 3-6杂环基、取代或未取代的C 5-10芳基和取代或未取代的C 5-10杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1S(O) m1NR ccR dd、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NR ccS(O) m1R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 5 is selected from hydrogen atom, methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, Br, amino, hydroxyl, cyano, vinyl, ethynyl, ethynyl, propynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 3-6 heterocyclyl, C 3-6 oxoheterocyclyl , C 3-6 sulfur Heterocyclic group, C 5-6 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C (＝S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclyl , Aryl and heteroaryl are optionally further selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo, thio Group, nitro, cyano, substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyethyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic, substituted or unsubstituted C 5-10 aryl and substituted or unsubstituted C 5-10 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C (O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd Or substituted by multiple substituents, the hetero atoms in the heterocyclic group and heteroaryl group are selected from one or more of N, O, and S;条件是，当R2为H或甲基、R3为羟甲基时，R4不为氢或R5不为甲氧基或-L1-R1不为或n＝2。 The condition is that when R2 is H or methyl and R3 is hydroxymethyl, R4 is not hydrogen or R5 is not methoxy or -L1-R1 is notOr n=2.
- 根据权利要求5所述的通式(II)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：The compound represented by the general formula (II) according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:L选自键、亚甲基、-(CH 2) 2-或-S(O) 2-； L is selected from bond, methylene, -(CH 2 ) 2 -or -S(O) 2 -;环A选自Ring A is selected fromR 1选自氰基、R 1 is selected from cyano,R 2选自氢原子、甲基、乙基、甲氧基、乙氧基、羟甲基、羟乙基、F、Cl、氨基、羟 基、氰基、乙烯基、丙烯基、乙炔基、丙炔基； R 2 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, amino, hydroxy, cyano, vinyl, propenyl, ethynyl, propylene AlkynylR 3选自氢原子、甲基、乙基，丙基、羟甲基、羟乙基、羟丙基、氮杂环丁烷、氧杂环丁烷、苯基、苄基、吡啶、-C(O)NH2； R 3 is selected from hydrogen atom, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, azetidine, oxetane, phenyl, benzyl, pyridine, -C (O)NH2;R 4选自氢原子、甲基、乙基、甲氧基、羟甲基、F、Cl、氨基、羟基、氰基、乙烯基或乙炔基； R 4 is selected from hydrogen atom, methyl, ethyl, methoxy, hydroxymethyl, F, Cl, amino, hydroxyl, cyano, vinyl or ethynyl;R5选自甲基，甲氧基，羟基，羟甲基，F，R5 is selected from methyl, methoxy, hydroxy, hydroxymethyl, F,m为0、1或2；m is 0, 1 or 2;n为0、1或2。n is 0, 1, or 2.
- 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受 盐，其为通式(III)所示的化合物、其立体异构体或其药学上可接受盐：The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, which is the compound represented by the general formula (III), its stereoisomer or its pharmacy Acceptable salt:其中：among them:环A、L、R 1～R 5、m和n如权利要求1所述。 Rings A, L, R 1 to R 5 , m and n are as defined in claim 1.
- 根据权利要求7所述的通式(III)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：The compound represented by the general formula (III) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:L选自键、C 0-8亚烷基、C 2-8亚烯基、C 2-8炔基、C 3-8环烷基、C 3-8杂环基、-(CH 2) n1-或-(CH 2) n1S(O) m1-，杂环基中的杂原子选自N、O、S、P中的一个或多个； L is selected from bond, C 0-8 alkylene, C 2-8 alkenylene, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, -(CH 2 ) n1 -Or- (CH 2 ) n1 S(O) m1 -, the hetero atom in the heterocyclic group is selected from one or more of N, O, S, P;环A选自C 5-12杂芳基，其中所述杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C 0-8烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 0-8烷氧基、取代或未取代的C 0-8羟烷基、取代或未取代的C 3-8环烷基、取代或未取代的C 3-8杂环基、取代或未取代的C 5-12芳基和取代或未取代的C 5-12杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代； Ring A is selected from C 5-12 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, oxo, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 0-8 alkoxy, Substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 heterocyclic, substituted or unsubstituted C 5-12 aryl And substituted or unsubstituted C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa ,- (CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb Substituted by a substituent;R 1选自氢原子、C 0-8烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0-8卤代烷氧基、C 0-8羟烷基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、C 3-8杂环基、C 3- 8氧代杂环基、C 3-8硫代杂环基、C 5-12芳基、C 5-12杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，杂环基、杂芳基中的杂原子选自N、O、S、P中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自C 0-8烷基、C 0-8卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、C 2-8烯基、C 2-8炔基、C 0- 8烷氧基、C 0-8卤代烷氧基、C 0-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 5-12芳基、C 5-12杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、 -(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1NR ccC(O)R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；杂环基、杂芳基中的杂原子选自N、O、S、P中的一个或多个； R 1 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 haloalkoxy, C 0-8 hydroxyalkyl, halogen, amino, nitrate group, hydroxy, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 3- 8-oxo-heterocyclyl, C 3- 8 thioheterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C (O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one of N, O, S, P Or more; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from C 0-8 alkyl, C 0-8 haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, C 2-8 alkenyl, C 2-8 alkynyl groups, C 0- 8 alkoxy, C 0-8 haloalkoxy, C 0-8 hydroxyalkyl, C 3-8 Cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O) OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 NR cc C(O)R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd is substituted by one or more substituents; heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O, S, P;R 2选自氢原子、C 0-8烷基、C 0-8氘代烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0-8羟烷基、C 0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基或C 2-8炔基； R 2 is selected from a hydrogen atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0-8 hydroxyalkyl, C 0-8 Haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl or C 2-8 alkynyl;R 3选自氢原子、氘原子、C 0-8烷基、C 0-8氘代烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0- 8羟烷基、C 0-8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、C 3-8杂环基、C 5-12芳基、C 5-12杂芳基、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 3 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 hydroxyalkyl, C 0-8 haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -( CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb One or more, optionally substituted by one or more substituents, heterocyclic The hetero atom in the group or heteroaryl group is selected from one or more of N, O, and S;R 5选自氢原子、氘原子、C 0-8烷基、C 0-8氘代烷基、C 0-8卤代烷基、C 0-8烷氧基、C 0- 8卤代烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、C 0-8羟烷基、C 3-8杂环基、C 3-8氧代杂环基、C 3-8硫代杂环基、C 5-12芳基、C 5-12杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1P(O) m2R aaR bb、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aa(CH 2) m1R bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氢原子、氘原子、取代或未取代的C 0-8烷基、卤素、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 0-8烷氧基、取代或未取代的C 0-8羟烷基、取代或未取代的C 3-8环烷基、取代或未取代的C 3-8杂环基、取代或未取代的C 5-12芳基和取代或未取代的C 5-12杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1S(O) m1NR ccR dd、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NR ccS(O) m1R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个。 R 5 is selected from a hydrogen atom, a deuterium atom, C 0-8 alkyl, C 0-8 deuterated alkyl, C 0-8 haloalkyl, C 0-8 alkoxy, C 0- 8 haloalkoxy, halogen, , Amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 0-8 hydroxyalkyl, C 3-8 heterocyclyl, C 3-8 oxoheterocyclyl , C 3-8 thioheterocyclyl, C 5-12 aryl, C 5-12 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C(=S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C( O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -( CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from hydrogen atom, deuterium atom, substituted or unsubstituted C 0-8 alkane Group, halogen, hydroxyl, substituted or unsubstituted amino, oxo, thio, nitro, cyano, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl , Substituted or unsubstituted C 0-8 alkoxy, substituted or unsubstituted C 0-8 hydroxyalkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 3-8 hetero Cyclic group, substituted or unsubstituted C 5-12 aryl group and substituted or unsubstituted C 5-12 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd It is substituted by one or more substituents, and the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, and S.
- 根据权利要求8所述的通式(III)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：The compound represented by the general formula (III) according to claim 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:L选自键、C 1-3亚烷基、(CH 2) n1-或-(CH 2) n1S(O) m1-； L is selected from bond, C 1-3 alkylene, (CH 2 ) n1 -or -(CH 2 ) n1 S(O) m1 -;环A选自C 5-6杂芳基，其中所述杂芳基任选进一步被选自氢原子、甲基、乙基、F、Cl、Br、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的C 3-6杂环基、 取代或未取代的C 5-10芳基和取代或未取代的C 5-10杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代； Ring A is selected from C 5-6 heteroaryl, wherein the heteroaryl is optionally further selected from hydrogen atom, methyl, ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo Group, nitro group, cyano group, substituted or unsubstituted C 3-6 heterocyclic group, substituted or unsubstituted C 5-10 aryl group and substituted or unsubstituted C 5-10 heteroaryl group, -(CH 2 ) n1 -, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa R bb , -(CH 2 ) One or more substituents in n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb ;R 1选自氢原子、C 1-3烷基、氨基、氰基、C 2-3烯基、C 2-3炔基、C 3-6环烷基、C 3-6杂环基、C 5-10芳基、C 5-10杂芳基、-(CH 2) n1R aa、(CH 2) n1C(O)R aa、--(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb或-(CH 2) n1C(O)NR aaR bb，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个；其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氨基、氰基、-(CH 2) n1R cc或-(CH 2) n1NR ccR dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 1 is selected from a hydrogen atom, C 1-3 alkyl, amino, cyano, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 5-10 aryl, C 5-10 heteroaryl, -(CH 2 ) n1 R aa , (CH 2 ) n1 C(O)R aa , --(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 NR aa R bb or -(CH 2 ) n1 C(O)NR aa R bb , the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O and S Wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from amino, cyano, -(CH 2 ) n1 R cc or -(CH 2 ) n1 NR cc R dd Substituted by one or more substituents, the heteroatoms in heterocyclyl and heteroaryl are selected from one or more of N, O, S;R 2选自氢原子、甲基、乙基、卤代甲基、卤代乙基、甲氧基、乙氧基、羟甲基、羟乙基、羟丙基、卤代甲氧基、卤代乙氧基、F、Cl、Br、氨基、硝基、羟基、氰基、乙烯基、丙烯基、乙炔基、丙炔基； R 2 is selected from hydrogen atom, methyl, ethyl, halomethyl, haloethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, halomethoxy, halo Ethoxy, F, Cl, Br, amino, nitro, hydroxyl, cyano, vinyl, propenyl, ethynyl, propynylR 3选自氢原子、C 1-3烷基、C 1-3羟烷基、C 3-6杂环基、C 5-10芳基、C 5-10杂芳基、-(CH 2) n1C(O)R aa或-(CH 2) n1C(O)NR aaR bb中的一个或多个，可选的被一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个； R 3 is selected from hydrogen atom, C 1-3 alkyl group, C 1-3 hydroxyalkyl group, C 3-6 heterocyclic group, C 5-10 aryl group, C 5-10 heteroaryl group, -(CH 2 ) n1 C(O)R aa or -(CH 2 ) one or more of n1 C(O)NR aa R bb , optionally substituted by one or more substituents, heterocyclic and heteroaryl Is selected from one or more of N, O, S;R 5选自氢原子、甲基、乙基、丙基、甲氧基、乙氧基、F、Cl、Br、氨基、羟基、氰基、乙烯基、乙炔基、乙炔基、丙炔基、环丙基、环丁基、环戊基、环己基、羟甲基、羟乙基、羟丙基、C 3-6杂环基、C 3-6氧代杂环基、C 3-6硫代杂环基、C 5-6杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1P(O) m2R aaR bb、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aa(CH 2) m1R bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自取代或未取代的甲基、取代或未取代的乙基、F、Cl、Br、羟基、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的羟甲基、取代或未取代的羟乙基、取代或未取代的C 3-6环烷基、取代或未取代的C 3-6杂环基、取代或未取代的C 5-10芳基和取代或未取代的C 5-10杂芳基、-(CH 2) n1-、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1S(O) m1NR ccR dd、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NR ccS(O) m1R dd或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代，杂环基、杂芳基中的杂原子选自N、O、S中的一个或多个。 R 5 is selected from hydrogen atom, methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, Br, amino, hydroxyl, cyano, vinyl, ethynyl, ethynyl, propynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, C 3-6 heterocyclyl, C 3-6 oxoheterocyclyl , C 3-6 sulfur Heterocyclic group, C 5-6 heteroaryl, -(CH 2 ) n1 R aa , -(CH 2 ) n1 OR aa , -NR aa C(O)(CH 2 ) n1 OR aa , -NR aa C (＝S)(CH 2 ) n1 OR bb , -(CH 2 ) n1 SR aa , -(CH 2 ) n1 C(O)R aa , -(CH 2 ) n1 C(O)OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 NR aa C(O)R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , wherein the cycloalkyl, heterocyclyl , Aryl and heteroaryl are optionally further selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, F, Cl, Br, hydroxyl, substituted or unsubstituted amino, oxo, thio Group, nitro, cyano, substituted or unsubstituted methoxy, substituted or unsubstituted ethoxy, substituted or unsubstituted hydroxymethyl, substituted or unsubstituted hydroxyethyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocyclic, substituted or unsubstituted C 5-10 aryl and substituted or unsubstituted C 5-10 heteroaryl, -(CH 2 ) n1 -, -(CH 2 ) n1 R cc , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 SR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C (O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C(O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd It is substituted by multiple substituents, and the hetero atom in the heterocyclic group and heteroaryl group is selected from one or more of N, O, and S.
- 根据权利要求8所述的通式(III)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：The compound represented by the general formula (III) according to claim 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:L选自键、亚甲基、-(CH 2) 2-或-S(O) 2-； L is selected from bond, methylene, -(CH 2 ) 2 -or -S(O) 2 -;环A选自Ring A is selected fromR 1选自氰基、R 1 is selected from cyano,R 2选自氢原子、甲基、乙基、甲氧基、乙氧基、羟甲基、羟乙基、F、Cl、氨基、羟基、氰基、乙烯基、丙烯基、乙炔基、丙炔基； R 2 is selected from hydrogen atom, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, F, Cl, amino, hydroxy, cyano, vinyl, propenyl, ethynyl, propylene AlkynylR 3选自氢原子、甲基、乙基，丙基、羟甲基、羟乙基、羟丙基、氮杂环丁烷、氧杂环丁烷、苯基、苄基、吡啶、-C(O)NH2； R 3 is selected from hydrogen atom, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, azetidine, oxetane, phenyl, benzyl, pyridine, -C (O)NH2;R5选自甲基，甲氧基，羟基，羟甲基，F，R5 is selected from methyl, methoxy, hydroxy, hydroxymethyl, F,m为0、1或2；m is 0, 1 or 2;n为0、1或2。n is 0, 1, or 2.
- 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IV)所示的化合物、其立体异构体或其药学上可接受盐：The compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by general formula (IV), its stereoisomer or its pharmacy Acceptable salt:其中：among them:环A、R 2～R 5、m和n如权利要求1所述； Rings A, R 2 to R 5 , m and n are as described in claim 1;或者，其为通式(V)所示的化合物、其立体异构体或其药学上可接受盐：Alternatively, it is a compound represented by general formula (V), its stereoisomer, or a pharmaceutically acceptable salt thereof:其中：among them:环A、R 2～R 5和n如权利要求1所述； Ring A, R 2 to R 5 and n are as described in claim 1;或者，其为通式(VI)和(VIA)所示的化合物、其立体异构体或其药学上可接受盐：Alternatively, it is a compound represented by general formulas (VI) and (VIA), its stereoisomer or a pharmaceutically acceptable salt thereof:其中：among them:E、W和G相同或不相同，各自独立的选自氮原子或碳原子；E, W and G are the same or different, each independently selected from a nitrogen atom or a carbon atom;R 2～R 5和n如权利要求1所述； R 2 to R 5 and n are as claimed in claim 1;或者，其为通式(VII)和(VIIA)所示的化合物、其立体异构体或其药学上可接受盐：Alternatively, it is a compound represented by general formulas (VII) and (VIIA), its stereoisomer, or a pharmaceutically acceptable salt thereof:其中：among them:L、R 2～R 5、m和n如权利要求1所述。 L, R 2 to R 5 , m and n are as defined in claim 1.
- 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IV-A)和(IV-B)所示的化合物、其立体异构体或其药学上可接受盐：The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (IV-A) and (IV-B), Its stereoisomer or its pharmaceutically acceptable salt:其中：among them:环A、R 2～R 5、m和n如权利要求1所述； Rings A, R 2 to R 5 , m and n are as described in claim 1;或者，其为通式(VA)和(VB)所示的化合物、其立体异构体或其药学上可接受盐：Alternatively, it is a compound represented by general formulas (VA) and (VB), its stereoisomer, or a pharmaceutically acceptable salt thereof:其中：among them:环A、R 2～R 5和n如权利要求1所述。 Ring A, R 2 to R 5 and n are as defined in claim 1.
- 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VIII)和(VIIIA)所示的化合物、其立体异构体或其药学上可接受盐：The compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by general formula (VIII) and (VIIIA) and its stereoisomer Body or its pharmaceutically acceptable salt:其中：among them:L、R 1～R 5、m和n如权利要求1所述； L, R 1 to R 5 , m and n are as described in claim 1;或者，其为通式(IX)和(IXA)所示的化合物、其立体异构体或其药学上可接受盐：Alternatively, it is a compound represented by general formulas (IX) and (IXA), its stereoisomer, or a pharmaceutically acceptable salt thereof:其中：among them:R 2～R 5、m和n如权利要求1所述； R 2 to R 5 , m and n are as described in claim 1;或者，其为通式(X)和(XA)所示的化合物、其立体异构体或其药学上可接受盐：Alternatively, it is a compound represented by general formulas (X) and (XA), its stereoisomer, or a pharmaceutically acceptable salt thereof:其中：among them:R 2～R 5和n如权利要求1所述； R 2 to R 5 and n are as claimed in claim 1;或者，其为通式(IX)所示的化合物、其立体异构体或其药学上可接受盐：Or, it is a compound represented by the general formula (IX), its stereoisomer, or a pharmaceutically acceptable salt thereof:其中：among them:J 1和J 2相同或不相同，各自独立的选自碳原子、氮原子、氧原子和硫原子； J 1 and J 2 are the same or different, and are independently selected from carbon atom, nitrogen atom, oxygen atom and sulfur atom;R 3～R 5和n如权利要求1所述。 R 3 to R 5 and n are as defined in claim 1.
- 根据权利要求1-2、7中至少一项所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：The compound represented by each general formula according to at least one of claims 1-2 and 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that:环A选自如下基团：Ring A is selected from the following groups:
- 根据权利要求1～12中至少一项所述的各通式、其立体异构体或其药学上可接受的盐，其特征在于，The general formula, its stereoisomers or pharmaceutically acceptable salts thereof according to at least one of claims 1 to 12, characterized in thatL为-(CH 2) n1-或-(CH 2) n1S(O) m1-； L is -(CH 2 ) n1 -or-(CH 2 ) n1 S(O) m1 -;R 1选氰基或3-8元杂环基，其中所述的的杂环基任选进一步被选自氢原子和氰基中的一个或多个取代基所取代； R 1 is a cyano group or a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from a hydrogen atom and a cyano group;R 2氢原子或C 1-6烷基；优选氢原子或C 1-3烷基；更优选氢原子或甲基； R 2 hydrogen atom or C 1-6 alkyl group; preferably hydrogen atom or C 1-3 alkyl group; more preferably hydrogen atom or methyl group;R 3选自氢原子、氰基、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6羟烷基、C 3-8环烷基、3-8元杂环基、-(CH 2) n1OR aa或-C(O)NR aaR bb； R 3 is selected from hydrogen atom, cyano group, halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-8 membered heterocyclic group, -(CH 2 ) n1 OR aa or -C(O)NR aa R bb ;R 4选自氢原子或卤素； R 4 is selected from hydrogen atom or halogen;R 5选自氢原子、卤素、羟基、氨基、C 1-6烷基、C 1-6烷氧基、3-8元杂环基、5-10元杂芳基、-(CH 2) n1OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1P(O) m2R aaR bb、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aa(CH 2) m1R bb、-(CH 2) n1P(O) m1R aaR bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的杂环基和杂芳基任选进一步被氢原子、C 1-6烷基、羟基、氨基、羧基、氧代基、硫代基、C 1-6烷氧基、C 1-6羟烷基、-(CH 2) n1OR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1S(O) m1NR ccR dd、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NR ccS(O) m1R dd、或-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代； R 5 is selected from a hydrogen atom, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, 3-8 membered heterocyclic group, 5-10 membered heteroaryl, -(CH 2 ) n1 OR aa , -(CH 2 ) n1 S(O) m1 R aa , -(CH 2 ) n1 P(O) m2 R aa R bb , -(CH 2 ) n1 NR aa R bb , -(CH 2 ) n1 C(O)NR aa (CH 2 ) m1 R bb , -(CH 2 ) n1 P(O) m1 R aa R bb or -(CH 2 ) n1 NR aa S(O) m1 R bb , where the Heterocyclic group and heteroaryl group are optionally further substituted by hydrogen atom, C 1-6 alkyl group, hydroxyl group, amino group, carboxyl group, oxo group, thio group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl , -(CH 2 ) n1 OR cc , -(CH 2 ) n1 C(O)R cc , -(CH 2 ) n1 C(O)OR cc , -(CH 2 ) n1 S(O) m1 R cc , -(CH 2 ) n1 S(O) m1 NR cc R dd , -(CH 2 ) n1 NR cc R dd , -(CH 2 ) n1 C(O)NR cc R dd , -(CH 2 ) n1 C( O)NR cc S(O) m1 R dd or -(CH 2 ) n1 NR cc S(O) m1 R dd is substituted by one or more substituents;R aa、R bb、R cc和R dd相同或不同，且各自独立地选自氢原子、C 1-6烷基、氨基或3-8元杂环基；其中所述的C 1-6烷基、氨基和3-8元杂环基任选进一步被氢原子、羟基、5-10元杂芳基中的一个或多个取代基所取代。 R aa , R bb , R cc and R dd are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group, an amino group, or a 3-8 membered heterocyclic group; wherein the C 1-6 alkane The group, the amino group, and the 3-8 membered heterocyclic group are optionally further substituted with one or more substituents among a hydrogen atom, a hydroxyl group, and a 5-10 membered heteroaryl group.
- 根据权利要求1～15中至少一项所述任意通式所示化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：The compound of any general formula, its stereoisomer or a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 15, characterized in that it is selected from the following compounds:
- 一种药用组合物，其包括治疗有效剂量的权利要求1～16中至少一项所示的通式(I)化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective dose of a compound of general formula (I) shown in at least one of claims 1 to 16, a stereoisomer or a pharmaceutically acceptable salt thereof, and one or more A pharmaceutically acceptable carrier, diluent or excipient.
- 根据权利要求1～16中至少一项所述的通式(I)化合物、其立体异构体或其药学上可接受的盐，或权利要求17所述的药物组合物在制备JAK抑制剂药物中的应用。The compound of general formula (I) according to at least one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a JAK inhibitor drug Application.
- 根据权利要求1～16中至少一项所述的通式(I)化合物、其立体异构体或其药学上可接受的盐，或权利要求17所述的药物组合物在制备治疗炎症性疾病和肿瘤疾病相关药物中的应用，其中所述的炎症性疾病选自类风湿性关节炎、皮炎、银屑病、炎症性肠病(溃疡性结肠炎及克罗恩病)，所述的肿瘤性疾病选自骨髓纤维化、真性红细胞增多症及原发性血小板增多症、性骨髓细胞性白血病(AML)、急性淋巴细胞性白血病(ALL)、乳腺导管癌及非小细胞肺癌(NSCLC)，其中胃肠发炎疾病是慢性肠道炎症性疾病，进一步优选溃疡性结肠炎和克罗恩氏病。The compound of general formula (I) according to at least one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a treatment for inflammatory diseases The application of drugs related to tumor diseases, wherein the inflammatory diseases are selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), the tumor Sexual diseases are selected from myelofibrosis, polycythemia vera and primary thrombocythemia, myelocytic leukemia (AML), acute lymphocytic leukemia (ALL), breast ductal carcinoma and non-small cell lung cancer (NSCLC), Among them, gastrointestinal inflammatory diseases are chronic intestinal inflammatory diseases, and ulcerative colitis and Crohn's disease are further preferred.
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| WO2023011359A1 (en) * | 2021-08-05 | 2023-02-09 | 南京明德新药研发有限公司 | Bridged ring compound and use thereof |
| WO2023159307A1 (en) * | 2022-02-23 | 2023-08-31 | Repare Therapeutics Inc. | Polo-like kinase 4 (plk4) inhibitors, pharmaceutical compositions, methods of preparation and uses thereof |
| WO2023202706A1 (en) * | 2022-04-21 | 2023-10-26 | 南京明德新药研发有限公司 | Salt form and crystal form of selenium heterocyclic compound and application thereof |
Also Published As
| Publication number | Publication date |
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| TW202024069A (en) | 2020-07-01 |
| TWI740288B (en) | 2021-09-21 |
| CN111601804B (en) | 2024-06-04 |
| CN111601804A (en) | 2020-08-28 |
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