WO2020151232A1 - 1,2,3,4-四氢喹喔啉衍生物及其制备方法和应用 - Google Patents
1,2,3,4-四氢喹喔啉衍生物及其制备方法和应用 Download PDFInfo
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- WO2020151232A1 WO2020151232A1 PCT/CN2019/105557 CN2019105557W WO2020151232A1 WO 2020151232 A1 WO2020151232 A1 WO 2020151232A1 CN 2019105557 W CN2019105557 W CN 2019105557W WO 2020151232 A1 WO2020151232 A1 WO 2020151232A1
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- alkyl
- deuterium
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- VISOYHBXCUTZML-IJHRGXPZSA-N O=S(c1cc(C(F)(F)F)ccc1)(N1c2cc(-c3cc(OC(F)F)cc(F)c3)ccc2N(CCC(C2)F)[C@@H]2C1)=O Chemical compound O=S(c1cc(C(F)(F)F)ccc1)(N1c2cc(-c3cc(OC(F)F)cc(F)c3)ccc2N(CCC(C2)F)[C@@H]2C1)=O VISOYHBXCUTZML-IJHRGXPZSA-N 0.000 description 2
- 0 *CCOc1ncc(C(F)(F)F)cc1S(N1c2cc(-c3cc(O*)cc(F)c3)ccc2N(CCN(C*)C2)[C@@]2C1)(=O)=O Chemical compound *CCOc1ncc(C(F)(F)F)cc1S(N1c2cc(-c3cc(O*)cc(F)c3)ccc2N(CCN(C*)C2)[C@@]2C1)(=O)=O 0.000 description 1
- CHQZGOBNSPSJOA-FIWMFUAISA-N CC(C)(C)OC(N(CC1)C[C@@H](C2)N1c1ccc(/C=C(\C)/c(c(Cl)ccc3)c3F)cc1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O)=O Chemical compound CC(C)(C)OC(N(CC1)C[C@@H](C2)N1c1ccc(/C=C(\C)/c(c(Cl)ccc3)c3F)cc1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O)=O CHQZGOBNSPSJOA-FIWMFUAISA-N 0.000 description 1
- MYWZLRSIWKWDFM-NRFANRHFSA-N CC(N(CC1)C[C@@H](C2)N1c(ccc(-c1cc(OC(F)F)cc(F)c1)c1)c1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O)=O Chemical compound CC(N(CC1)C[C@@H](C2)N1c(ccc(-c1cc(OC(F)F)cc(F)c1)c1)c1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O)=O MYWZLRSIWKWDFM-NRFANRHFSA-N 0.000 description 1
- MVKDNXIKAWKCCS-UHFFFAOYSA-N CC1=CC=CNC1=O Chemical compound CC1=CC=CNC1=O MVKDNXIKAWKCCS-UHFFFAOYSA-N 0.000 description 1
- GEFOQUWDCJJBHI-UHFFFAOYSA-N CN(CC1)c(ccc(Br)c2)c2N1S(c1cc(C(F)(F)F)ccc1)(=O)=O Chemical compound CN(CC1)c(ccc(Br)c2)c2N1S(c1cc(C(F)(F)F)ccc1)(=O)=O GEFOQUWDCJJBHI-UHFFFAOYSA-N 0.000 description 1
- YRQSBSIUKYRIRM-UHFFFAOYSA-N CN(CCCl)c(ccc(Br)c1)c1N Chemical compound CN(CCCl)c(ccc(Br)c1)c1N YRQSBSIUKYRIRM-UHFFFAOYSA-N 0.000 description 1
- PUQLGGXJPBMECN-HNNXBMFYSA-N CN([C@@H](CCC(OC)=O)C1)c(ccc(Br)c2)c2N1S(c1cc(C(F)(F)F)ccc1)(=O)=O Chemical compound CN([C@@H](CCC(OC)=O)C1)c(ccc(Br)c2)c2N1S(c1cc(C(F)(F)F)ccc1)(=O)=O PUQLGGXJPBMECN-HNNXBMFYSA-N 0.000 description 1
- DXGACWBAFPNXOZ-UHFFFAOYSA-N CN1c(ccc(Br)c2)c2NCC1 Chemical compound CN1c(ccc(Br)c2)c2NCC1 DXGACWBAFPNXOZ-UHFFFAOYSA-N 0.000 description 1
- HPJVHIHPNTZESA-NRFANRHFSA-N COC(CN(CC1)C[C@@H](CN(c2c3)S(c4cc(C(F)(F)F)cnc4OCCO)(=O)=O)N1c2ccc3-c1cc(OC(F)F)cc(F)c1)=O Chemical compound COC(CN(CC1)C[C@@H](CN(c2c3)S(c4cc(C(F)(F)F)cnc4OCCO)(=O)=O)N1c2ccc3-c1cc(OC(F)F)cc(F)c1)=O HPJVHIHPNTZESA-NRFANRHFSA-N 0.000 description 1
- YWMQELDRJAZLAQ-HMTLIYDFSA-N CS(COC(CC1)C[C@@H](C2)N1c(ccc(-c1cc(OC(F)F)cc(F)c1)c1)c1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O)(=O)=O Chemical compound CS(COC(CC1)C[C@@H](C2)N1c(ccc(-c1cc(OC(F)F)cc(F)c1)c1)c1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O)(=O)=O YWMQELDRJAZLAQ-HMTLIYDFSA-N 0.000 description 1
- YFEDWJDVXFOHMU-BHWOMJMDSA-N CSCOC(CC1)C[C@@H](C2)N1c(ccc(Br)c1)c1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O Chemical compound CSCOC(CC1)C[C@@H](C2)N1c(ccc(Br)c1)c1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O YFEDWJDVXFOHMU-BHWOMJMDSA-N 0.000 description 1
- PKRXLVZZAMDSOA-PZGXJGMVSA-N C[C@@](CC1)(C[C@@H](C2)N1c(ccc(-c1cc(OC(F)F)cc(F)c1)c1)c1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O)OCCC(O)=O Chemical compound C[C@@](CC1)(C[C@@H](C2)N1c(ccc(-c1cc(OC(F)F)cc(F)c1)c1)c1N2S(c1cc(C(F)(F)F)ccc1)(=O)=O)OCCC(O)=O PKRXLVZZAMDSOA-PZGXJGMVSA-N 0.000 description 1
- ITQTTZVARXURQS-UHFFFAOYSA-N Cc1cccnc1 Chemical compound Cc1cccnc1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 1
- MCTBFCLSTNYWJN-AXDSSHIGSA-N FC(CC1)C[C@@H](CNc2c3)N1c2ccc3Br Chemical compound FC(CC1)C[C@@H](CNc2c3)N1c2ccc3Br MCTBFCLSTNYWJN-AXDSSHIGSA-N 0.000 description 1
- WKMUQYZYLGNYQE-CQSZACIVSA-N O=S(c1cc(C(F)(F)F)ccc1)(N(C1)c(cc(cc2)Br)c2N2[C@H]1COCC2)=O Chemical compound O=S(c1cc(C(F)(F)F)ccc1)(N(C1)c(cc(cc2)Br)c2N2[C@H]1COCC2)=O WKMUQYZYLGNYQE-CQSZACIVSA-N 0.000 description 1
- TUWWMUSDFDPKFO-IBGZPJMESA-N O=S(c1cccc(C(F)(F)F)c1)(N1c(cc(cc2)-c3cc(OC(F)F)cc(F)c3)c2N(CCNC2)[C@@H]2C1)=O Chemical compound O=S(c1cccc(C(F)(F)F)c1)(N1c(cc(cc2)-c3cc(OC(F)F)cc(F)c3)c2N(CCNC2)[C@@H]2C1)=O TUWWMUSDFDPKFO-IBGZPJMESA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- 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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- 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
- A61K31/499—Spiro-condensed pyrazines or piperazines
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention belongs to the field of drug synthesis, and specifically relates to 1,2,3,4-tetrahydroquinoxaline derivatives and preparation methods and applications thereof.
- the retinoic acid-related orphan receptor (ROR) family contains three members: ROR ⁇ , - ⁇ and - ⁇ .
- ROR ⁇ is indispensable in the development of the cerebellum, while ROR ⁇ is mainly expressed in the brain and the retina, both of which play important functions in the normal development of the retina.
- ROR ⁇ is divided into two subtypes, ROR ⁇ 1 and ROR ⁇ 2 (ROR ⁇ t) according to different transcriptional splicing positions.
- the former is mainly expressed in liver, skeletal muscle and kidney, while ROR ⁇ t is mainly expressed in immune organs.
- Mice lacking ROR ⁇ t lack lymph nodes and Peyer’s nodes and other lymphoid organs, and the development and maturation of T cells are also affected. The number of various T cells is lower than that of normal mice.
- T helper cells play an indispensable role.
- CD4-positive T helper cells can differentiate into a series of regulatory helper cells such as Th1, Th2, Th17 and Treg under the induction of different cytokines in the microenvironment.
- Th1 and Th2 play an important role in the process of antigen recognition, presentation and activation of T effector cells.
- Treg is a type of regulatory cell that promotes immune suppression.
- Th17 is a new type of T helper cells discovered in recent years, which is characterized by secreting interleukin 17 (IL-17) cytokine.
- Th17 cells were originally thought to play immune functions by recruiting granulocytes to resist bacterial and fungal infections.
- Th17 cell differentiation to treat autoimmune diseases and activating Th17 cell differentiation to treat malignant tumors has become a hot spot in immune and tumor basic research and translational medicine.
- ROR ⁇ t can directly affect the abundance and activity of Th17 cells by regulating the activity of ROR ⁇ t through small molecule compounds.
- the level of cytokines (such as IL-17A) secreted by Th17 cells increased significantly, and the survival and immune activation ability of Th17 cells themselves was greatly enhanced.
- enhanced Th17 cell activation can reduce the number of immunosuppressive Treg cells and reduce the expression of immunosuppressive receptors (such as PD-1) in tumor infiltrating lymphocytes.
- oral small molecule ROR ⁇ t agonists can activate Th17 cells to enhance the ability of the immune system to recognize and kill tumor cells, and may become a new class of antibodies following PD-1 and PD-L1 antibodies in clinical practice.
- Tumor small molecule drugs can activate Th17 cells to enhance the ability of the immune system to recognize and kill tumor cells, and may become a new class of antibodies following PD-1 and PD-L1 antibodies in clinical practice.
- the purpose of the present invention is to provide a ROR ⁇ t small molecule agonist.
- the first aspect of the present invention provides a compound of formula (I), its stereoisomer, prodrug, or pharmaceutically acceptable salt thereof:
- Ring A is selected from the following structures:
- Ring B is selected from the following structures: Where Y is -O- or -N(R 27 )-;
- R 1 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl , 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S(O) r R 28 , -C 0-8 -OR 29 , -C 0 - 8 -C (O) OR 29 , -C 0-8 -C (O) R 30, -C 0-8 -OC (O) R 30, -C 0-8 -NR 31 R 32, -C 0 -8 -C(O)NR 31 R 32 or -C 0-8 -N(R 31 )-C(O)R 30 , the above groups are optionally further selected from deuterium, halogen, cyano , Nitro, azido, C 1-10 alkyl,
- R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 28 , -C 0-8- OR 29 , -C 0-8 -C(O)OR 29 , -C 0-8 -C(O)R 30 , -C 0-8 -OC(O)R 30 , -C 0-8 -NR 31 R 32 , -C 0-8 -C(O)NR 31 R 32 or -C 0-8 -N(R 31 )-C(O)R 30 , or R 2 and R 3 and the carbon directly connected Atoms together form C(O), 3-10 membered cycloalkyl or 3
- R 4 and R 3 together with the carbon atom directly connected to it form a 5-10 membered heterocyclic group, and the 5-10 membered heterocyclic group is optionally further selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl group, a halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, O, -C 0-8 -S(O) r R 28 , -C 0- 8 -OR 29 , -C 0-8 -C(O)OR 29 , -C 0-8 -C(O)R 30 , -C 0-8 -C(S)R 30 , -C 0-8-OC(O)R 30 , -C
- Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, SF 5 , -C 0-8 -S(O) r R 28 , -C 0- 8 -OR 29 , -C 0-8 -C(O)OR 29 , -C 0-8 -C(O)R 30 , -C 0-8 -OC(O)R 30 , -C 0-8- NR 31 R 32 , -C 0-8 -C(O)NR 31 R 32 or -C 0-8 -N(R 31 )-C(O)R 30 , the above groups are optionally further substituted by one or more Selected from deuterium, halogen, cyano,
- Each R 6 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 28 , -C 0-8 -OR 29 , -C 0-8 -C(O)OR 29 , -C 0-8 -C(O)R 30 , -C 0-8 -OC(O)R 30 , -C 0-8 -NR 31 R 32 , -C 0-8 -C(O)NR 31 R 32 or -C 0-8 -N(R 31 )-C(O)R 30 , the above-mentioned groups are optionally further selected from deuterium , Halogen, cyano, nitro, azido,
- R 7 and R 8 are each independently selected from hydrogen, deuterium, fluorine, C 1-4 alkyl, deuterium substituted C 1-4 alkyl, or fluorine substituted C 1-4 alkyl;
- R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 21 , R 22 , R 23 , R 24 , R 25 , and R 26 are each independently selected from hydrogen, deuterium, Halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group , C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 28 , -C 0-8 -OR 29 , -C 0-8 -C(O)OR 29 , -C 0-8 -C(O)R 30 , -C 0-8 -OC(O)R 30 , -C 0-8 -NR 31 R 32 , -C 0-8 -C(O)NR 31 R 32 or -C
- R 15 , R 16 , R 19 , R 20 , R 27 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 28 , -C 0-8 -C(O )OR 29 or -C 0-8 -C(O)R 30 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group , C 5-10 aryl, 5-10 membered hetero
- Each R 28 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclic oxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered hetero Aryloxy or -NR 31 R 32 , the above-mentioned groups are optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered hetero Substituted by aryl, 5-10 membered heteroaryloxy
- Each R 29 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl Or a 5-10 membered heteroaryl group, the above groups are optionally further selected by one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3 -10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 Substituted by a heteroaryl group, a 5-10 membered heteroaryloxy group or a substituent of -NR 31 R 32 ;
- Each R 30 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered hetero Aryl, 5-10 membered heteroaryloxy or -NR 31 R 32 , the above groups are optionally further selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1- 10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 Substituted by aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy
- Each R 31 and R 32 are independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkyl Amino, dialkylamino or C 1-10 alkanoyl group, the above groups are optionally further selected from deuterium, halogen, hydroxyl, carboxyl, C 1-8 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C
- R 31 , R 32 and their directly connected nitrogen atoms together form a 4-10 membered heterocyclic group, and the above-mentioned groups may be further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C Substituted by substituents of 5-10 aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 alkanoyl;
- n is an integer from 0 to 3
- p is an integer from 0 to 5;
- n1, m3, m5, and m7 are each independently 1 or 2;
- n2, m4, m6 are each independently 0, 1 or 2;
- Each r is independently 0, 1, or 2.
- each R 6 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0- 4 -S (O) r R 28, -C 0-4 -OR 29 , -C 0-4 -C(O)OR 29 , -C 0-4 -C(O)R 30 , -C 0-4 -OC(O)R 30 , -C 0- 4 -NR 31 R 32 , -C 0-4 -C(O)NR 31 R 32 or -C 0-4 -N(R 31 )-C(O)R 30 , the above groups are optionally further divided by one or Multiple selected from deuterium, halogen, cyano, nitro, azido, C
- each R 6 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxy Heterobutyl, 3-azetidinyl, phenyl, pyridyl, diazole, triazole, methanesulfonyl, aminosulfonyl, methoxy, methoxy, carboxy, acetyl, acetoxy Group, amino, dimethylamino, aminoacyl or acetamido, the above-mentioned groups are optionally further selected from deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, benzene Substituted by substituents of hydroxy, pyridyl, mesyl, hydroxy, methoxy, carboxy, or amino.
- the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof have the following compound structure of formula (IIa):
- R 2 and R 3 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 28 , -C 0- 4 -OR 29 , -C 0-4 -C(O)OR 29 , -C 0-4 -C(O)R 30 , -C 0-4 -OC(O)R 30 , -C 0-4- NR 31 R 32 , -C 0-4 -C(O)NR 31 R 32 or -C 0-4 -N(R 31 )-C(O)R 30 , or R 2 and R 3 are directly connected The carbon atoms of together form C(O), 3-10 membered
- R 4 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, phenyl, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, carboxyl , Methoxycarbonyl, ethoxycarbonyl or acetyl, the C 1-4 alkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocyclic group, phenyl group is optionally further selected by one or more deuterium , Fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, cyclopropyl, oxetanyl, methoxy, carboxyl, methyl Substituted by substituents of oxycarbonyl, acetyl, amino, dimethylamino or acety
- Ring A, Ring B, L, R 1 , R 5 , R 28 , R 29 , R 30 , R 31 , R 32 , r, m, and p are as described for the compound of formula (I).
- R 2 and R 3 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -C 0-4 -OR 29 , -C 0-4 -C(O)OR 29 , -C 0-4 -C(O)R 30 or -C 0-4 -OC(O)R 30 , or, R 2 and R 3 and their directly connected carbon Atoms together form C(O), 3-6 membered cycloalkyl or 3-6 membered heterocyclic group;
- R 4 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, the C 1-4 alkyl, C 3-6 cycloalkyl, 3-
- the 6-membered heterocyclic group is optionally further substituted by one or more selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, ring Propyl, oxetanyl, methoxy, carboxy, methoxycarbonyl, acetyl, amino, dimethylamino or acetamino substituents;
- R 7 is selected from hydrogen, deuterium, fluorine, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteromethyl or dideuteromethyl;
- Ring A, R 1 , R 29 , R 30 , and m are as described in the compound of formula (I).
- the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof have the following compound structure of formula (IIb):
- Z is selected from bond, -O-, -S-, -S(O)-, -S(O) 2 -, -N(R 33 )- or -(CR 35 R 36 )-;
- R 33 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 28 , -C 0-4- OR 29 , -C 0- 4 -C(O)OR 29 , -C 0-4 -C(O)R 30 , -C 0-4 -C(S)R 30 , -C 0-4 -OC( O) R 30 or -C 0-4 -C(O)NR 31 R 32 , the above-mentioned groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1- 4 alkyl group, C
- Each R 34 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0 -4 -S(O) r R 28 , -C 0-4 -OR 29 , -C 0-4 -C(O)OR 29 , -C 0-4 -C(O)R 30 , -C 0- 4 -OC(O)R 30 , -C 0-4 -NR 31 R 32 , -C 0-4 -C(O)NR 31 R 32 or -C 0-4 -N(R 31 )-C(O ) R 30 , the above groups are optionally further substitute
- R 35 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 28 , -C 0- 4 -OR 29 , -C 0-4 -C(O)OR 29 , -C 0-4 -C(O)R 30 , -C 0-4 -C(S)R 30 or -C 0-4- OC(O)R 30 , the above-mentioned groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyny
- R 36 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 28 , -C 0- 4 -OR 29 , -C 0-4 -C(O)OR 29 , -C 0-4 -C(O)R 30 , -C 0-4 -C(S)R 30 or -C 0-4- OC(O)R 30 , the above-mentioned groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyny
- q is an integer from 0 to 4; ring A, ring B, L, R 1 , R 2 , R 5 , R 6 , R 28 , R 29 , R 30 , R 31 , R 32 , m, r, p have the formula (I) As described in the compound.
- Z is selected from bond, -O-, -S-, -S(O)-, -S(O) 2 -, -N(R 33 )- or -(CR 35 R 36 )-;
- R 7 is selected from hydrogen, deuterium, fluorine, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteromethyl or dideuteromethyl;
- R 33 is selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -C 0-4 -S(O) r R 28 , -C 0-4 -OR 29 , -C 0-4 -C(O)OR 29 , -C 0-4 -C(O)R 30 , -C 0-4 -C(S)R 30 , -C 0-4 -OC(O)R 30 or -C 0-4 -C(O) NR 31 R 32 , the above-mentioned groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 -alkyny
- R 36 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl Or C 3-6 cycloalkyl, the above groups are optionally further selected from deuterium, fluorine, chlorine, cyano, nitro, azido, methyl, ethyl, hydroxy, methoxy or Substituted by carboxyl substituents;
- Ring A, R 1 , R 28 , R 29 , R 30 , R 31 , R 32 , m are as described in the compound of formula (I).
- ring A and -(R 1 ) m together form the following structure:
- Each R 28 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl , 5-8 membered heteroaryl or -NR 31 R 32 , the above-mentioned groups are optionally further selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-4 alkyl, C 1-4 Substituted by alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy or 3-8 membered heterocyclic group;
- Each R 29 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5- 8 aryl group Or a 5-8 membered heteroaryl group, the above-mentioned groups are optionally further selected by one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3 -8 cycloalkyl, C 3-8 cycloalkoxy or 3-8 membered heterocyclic substituent;
- Each R 30 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, C 5-8 aryl group, C 5-8 aryloxy group, 5-8 membered heterocyclic group Aryl, 5-8 membered heteroaryloxy or -NR 31 R 32 , the above-mentioned groups are optionally further selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1- 4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, C 5-8 aryl group, C 5-8 Substituted by aryloxy, 5-8 membered heteroaryl,
- Each R 31 and R 32 are independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3 -8 membered heterocyclic group, amino, monoalkylamino or dialkylamino.
- the compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:
- the second aspect of the present invention provides a method for preparing the aforementioned compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, which comprises the following steps:
- ring A, ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n, p are as described in the compound of formula (I).
- the third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
- the fourth aspect of the present invention provides a compound of formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof for preparing and treating one or more tumors, cancers, metabolic diseases, and autoimmune diseases Or the application of disordered drugs.
- the metabolic disease, autoimmune disease or disorder described in the application is selected from atopic dermatitis, contact dermatitis, atopic dermatitis, acne, acne, cystic fibrosis, allogeneic Rejection syndrome, multiple sclerosis, scleroderma, systemic lupus erythematosus (SLE), psoriasis, Hashimoto's disease, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis , Juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriatic arthritis (PsA), autoimmune diabetes, type I diabetes, type II diabetes, obesity, fatty liver, fatty tissue-related inflammation, pancreas Inflammation, thyroiditis, autoimmune thyroid disease, biliary cirrhosis, liver fibrosis, non-alcoholic fatty liver (NAFLD), ulcerative colitis, Crohn's disease, regional
- the tumor or cancer in the application is selected from fallopian tube tumors, ovarian tumors, peritoneal tumors, stage IV melanomas, solid tumors, gliomas, glioblastomas, mastoid nephromas , Head and neck tumors, lymphoma, myeloma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, hepatocellular carcinoma, breast cancer, cervical cancer, colon cancer, lung cancer , Stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, leukemia or non-small cell lung cancer.
- the fifth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof, which are used for the treatment of one or more tumors, cancers, metabolic diseases, autoimmune Drugs for sexual diseases or disorders.
- the compound of the invention has a strong inhibitory effect on ROR ⁇ t kinase activity, can be widely used in the preparation of therapeutic drugs, and is expected to be developed into a new generation of ROR ⁇ t agonist drugs. On this basis, the present invention has been completed.
- Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group, for example, "C 1-8 alkyl” refers to a straight chain alkyl group including 1 to 8 carbon atoms and a branched chain alkyl group, including but Not limited to 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 Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl Butyl, 2-ethylbuty
- the alkyl group may be optionally substituted or unsubstituted.
- Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
- C 3-10 cycloalkyl refers to a cycloalkyl group consisting of 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, of which:
- Monocyclic cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and others.
- Polycyclic cycloalkyls include spirocyclic, condensed, and bridged cycloalkyls.
- “Spirocycloalkyl” refers to a polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated ⁇ electron system. According to the number of shared spiro atoms between rings, spirocycloalkyls are classified into single spirocycloalkyls, bispirocycloalkyls or polyspirocycloalkyls. Spirocycloalkyls include but are not limited to:
- “Fused cycloalkyl” refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings (preferably 1 or 2) may contain one Or multiple double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls. Condensed cycloalkyls include but are not limited to:
- Bridged cycloalkyl refers to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected. These may contain one or more double bonds (preferably 1, 2, or 3), but none of them The ring has a completely conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls. Bridged cycloalkyls include but are not limited to:
- the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl and tetrahydronaphthyl , Benzocycloheptanyl, etc.
- Cycloalkyl groups can be optionally substituted or unsubstituted.
- Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
- ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
- ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
- Monocyclic heterocyclic groups include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
- Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
- “Spiro heterocyclic group” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2, 3, or 4), but none of the rings have a fully conjugated ⁇ -electron system.
- the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group.
- Spiro heterocyclic groups include but are not limited to:
- “Fused heterocyclic group” refers to a 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 bonds (preferably 1, 2, or 3), but none of the rings have a fully conjugated ⁇ -electron system, where one or more (preferably 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon.
- the fused heterocyclic groups include but are not limited to:
- Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings A fully conjugated ⁇ -electron system, where one or more ring atoms (preferably 1, 2, 3 or 4) are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include but are not limited to:
- the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, including but not limited to:
- the heterocyclic group may be optionally substituted or unsubstituted.
- Aryl refers to an all-carbon monocyclic or fused polycyclic (that is, a ring that shares adjacent pairs of carbon atoms), a polycyclic ring with a conjugated ⁇ -electron system (that is, a ring with adjacent pairs of carbon atoms). ) Group, for example, “C 5-10 aryl” refers to an all-carbon aryl group containing 5-10 carbons, and “5-10 membered aryl” refers to an all-carbon aryl group containing 5-10 carbons, including but It is not limited to phenyl and naphthyl. 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, including but not limited to:
- Aryl groups may be substituted or unsubstituted.
- Heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen and S(O)r (where r is an integer of 0, 1, 2) heteroatoms, for example, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thiophene Group, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
- the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
- Heteroaryl groups may be optionally substituted or unsubstituted.
- Alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond.
- C 2-8 alkenyl refers to a straight or branched chain containing 2-8 carbons.
- Alkenyl Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
- Alkenyl groups may be substituted or unsubstituted.
- Alkynyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond.
- C 2-8 alkynyl refers to a straight or branched chain containing 2-8 carbons.
- Alkynyl Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
- the alkynyl group may be substituted or unsubstituted.
- Alkoxy refers to -O-(alkyl), where the definition of alkyl is as described above, for example, "C 1-8 alkoxy” refers to an alkyloxy group containing 1-8 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy, etc.
- the alkoxy group may be optionally substituted or unsubstituted.
- Cycloalkoxy refers to and -O- (unsubstituted cycloalkyl), wherein the definition of cycloalkyl is as described above, for example, “C 3-10 cycloalkoxy” refers to those containing 3-10 carbons Cycloalkyloxy includes but is not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
- Cycloalkoxy may be optionally substituted or unsubstituted.
- 3-10 membered heterocyclic oxy group refers to and -O- (unsubstituted 3-10 membered heterocyclic group), wherein the definition of 3-10 membered heterocyclic group is as described above, 3-10 membered heterocyclic oxy group It can be optionally substituted or unsubstituted.
- C 5-10 aryloxy refers to and -O- (unsubstituted C 5-10 aryl), wherein the definition of C 5-10 aryl is as described above, and C 5-10 aryloxy may optionally be Substituted or unsubstituted.
- 5-10 membered heteroaryloxy group refers to and -O- (unsubstituted 5-10 membered heteroaryl group), where 5-10 membered heteroaryl group is defined as above, 5-10 membered heteroaryloxy group It can be optionally substituted or unsubstituted.
- C 1-8 Alkanoyl refers to the monovalent atomic group remaining after removing the hydroxyl group from C 1-8 alkyl acid, and is usually expressed as "C 0-7 -C(O)-", for example, “C 1 -C (O)-” means acetyl; “C 2 -C(O)-” means propionyl; “C 3 -C(O)-” means butyryl or isobutyryl.
- Halogen-substituted C 1-8 alkyl refers to a 1-8 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, or iodine atoms on the hydrogen on the alkyl group, including but not limited to difluoromethyl, difluoromethyl, Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
- Halogen-substituted C 1-8 alkoxy The hydrogen on the alkyl group is optionally substituted with 1-8 carbon alkoxy groups with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
- Halogen refers to fluorine, chlorine, bromine or iodine.
- DCM dichloromethane.
- PE means petroleum ether.
- EA/EtOAc means ethyl acetate.
- Halogen means fluorine, chlorine, bromine or iodine.
- DCM means dichloromethane.
- THF means tetrahydrofuran.
- PE means petroleum ether.
- DMSO means dimethyl sulfoxide.
- MeCN means acetonitrile.
- DME means dimethyl ether.
- Pd(dppf)Cl 2 refers to [1,1'-bis(diphenylphosphorus)ferrocene]palladium dichloride.
- heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present.
- the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
- Substituted means that one or more hydrogen atoms in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an olefin).
- “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and 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, which is beneficial to the absorption of the active ingredient and thus the biological activity.
- the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS).
- NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
- NMR is measured with Bruker AVANCE-400 or Bruker AVANCE-500 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) ,
- the internal standard is tetramethylsilane (TMS).
- the liquid mass spectrometry LC-MS is measured with Agilent 6120 mass spectrometer.
- HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm column).
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- the starting materials in the examples of the present invention are known and can be bought on the market, or can be synthesized by using or following methods known in the art.
- the third step Synthesis of 4-bromo-N1-(2-chloroethyl)-N1-methylbenzene-1,2-diamine
- Step 5 Synthesis of 6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline
- the third step Synthesis of tert-butyl 6-bromo-3-carbonyl-3,4-dihydroquinoxaline-1(2H)-carboxylate
- the fifth step tert-butyl 6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate synthesis
- Step 2 Methyl (S)-3-(6-bromo-3-carbonyl-1,2,3,4-tetrahydroquinoxalin-2-yl)propionate and (S)-7-bromo Synthesis of -3,3a-dihydropyrrolo[1,2-a]quinoxaline-1,4(2H,5H)-dione
- the third step Synthesis of methyl(S)-3-(6-bromo-1-methyl-3-carbonyl-1,2,3,4-tetrahydroquinoxalin-2-yl)propionate
- the fourth step Synthesis of methyl(S)-3-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl)propionate
- the fifth step Methyl (S)-3-(6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetra Synthesis of Hydroquinoxalin-2-yl) Propionate
- Step 1 Synthesis of (S)-1-(4-bromo-2-nitrophenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid
- the tert-butyl(S)-8-bromo-5-carbonyl-1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxaline- The 3-carboxylate (325 mg, 0.85 mmol) was dissolved in tetrahydrofuran (15 mL), and borane dimethyl sulfide tetrahydrofuran solution (1.3 mL, 2M in THF) was added to it.
- reaction solution was stirred at 50°C for 16 hours, then cooled to 0°C, quenched with methanol, concentrated to remove the solvent, and the residue was separated by a fast silica gel column to obtain tert-butyl(R)-8-bromo-1,2,4 ,4a,5,6-Hexahydro-3H-pyrandiazo[1,2-a]quinoxaline-3-carboxylate (250mg, 80%).
- ESI-MS 312[M-55] + .
- reaction solution was diluted with methyl tert-butyl ether (100mL), washed with saturated sodium chloride aqueous solution (30mL*3), combined the organic phases, dried over anhydrous magnesium sulfate and filtered and concentrated to obtain crude 1-chloro-2- Ethynyl-3-trifluoromethylbenzene (3.471 g, 98%) was used directly in the next reaction.
- the first step tert-butyl(S)-8-bromo-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro Synthesis of -3H-pyrandiazo[1,2-a]quinoxaline-3-carboxylate
- Step 1 Synthesis of 3-bromo-2-(2-((tert-butyldimethylsilyl)oxo)ethoxy)-5-(trifluoromethyl)pyridine
- Step 2 Synthesis of 3-(phenylmethylthio)-2-(2-((tert-butyldimethylsilyl)oxo)ethoxy)-5-(trifluoromethyl)pyridine
- the third step Synthesis of 2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridine-3-sulfonyl chloride
- the fifth step tert-butyl(S)-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-( (Trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxaline-3- Synthesis of carboxylate
- Step 2 Methyl (S)-2-(8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro Synthesis of -3H-pyranazinyl[1,2-a]quinoxalin-3-yl)acetate
- Step 2 Synthesis of (S)-8-bromo-1,2,4,4a-tetrahydro-[1,4]oxazole[4,3-aquinoxaline]-5(6H)-one
- Step 1 Synthesis of (S)-1-(4-bromo-2-nitrophenyl)-4-oxopiperidine-2-carboxylic acid
- the fifth step (6aS)-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido [1,2-a] Synthesis of Quinoxaline-8-ol
- the first step tert-butyl 6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4 -Dihydroquinoxaline-1(2H)-carboxylate synthesis
- the second step 7-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4 -Synthesis of tetrahydroquinoxaline
- the first step Methyl(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-methyl-4-( Synthesis of (3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propionate
- Examples 4-6 The preparation of Examples 4-6 was prepared by referring to the synthesis method of Example 1 or 3.
- the first step tert-butyl(S)-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl) Synthesis of -1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxaline-3-carboxylate
- the third step (S)-1-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxalin-3-yl)ethane-1-one
- Example 8 (S)-8-(3-(Difluoromethoxy)-5-fluorophenyl)-3-(methylsulfonyl)-6-((3-(trifluoromethyl)phenyl) )Sulfonyl)-2,3,4,4a,5,6-hexahydro-1H-pyranazinyl[1,2-a]quinoxaline
- the first step Methyl(S)-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl )-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxalin-3-yl)acetate
- the second step (S)-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)- Synthesis of 1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxalin-3-yl)acetic acid
- the first step tert-butyl(S,E)-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluorophenyl) Synthesis of (methyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxaline-3-carboxylate
- Example 11 The preparation of Examples 11, 12, and 13 were prepared by referring to the synthesis method of Example 10:
- the nuclear magnetic data of the compounds prepared in Examples 14-16 are as follows:
- Example 21 1 H NMR (500MHz, CDCl 3 ) ⁇ 7.79-7.81 (m, 3H), 7.55-7.64 (m,, 2H), 7.15-7.23 (m, 3H), 7.02-6.99 (m, 1H) ), 6.72(s, 1H), 6.30(s, 1H), 4.24(s, 1H), 3.67(s, 2H), 3.43(s, 3H), 3.20(s, 3H), 2.63(s, 1H) , 2.35(s, 1H), 2.14(s, 3H).
- reaction solution is separated by a fast reverse phase column to obtain methyl 2-((S)-8-((E)-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)- 6-((3-(Trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxa Lin-3-yl)propionate (15 mg, 22%).
- ESI-MS 652[M+H] + .
- Example 24 was prepared by referring to the synthesis method of Example 23:
- Example 26 The preparation of Examples 26 and 27 was prepared by referring to the synthesis method of Example 25:
- Example 29 The preparation of Examples 29, 30, and 31 was prepared by referring to the synthesis method of Example 28:
- Examples 33 and 34 was prepared by referring to the synthesis method of Example 32:
- Examples 36-42 The preparation of Examples 36-42 was prepared by referring to the synthesis method of Example 35:
- the nuclear magnetic data of the compounds prepared in Examples 36-42 are as follows:
- Example 49 ((Isopropoxycarbonyl)oxo)methyl(S,E)-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-ene-1- Yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a ]Quinoxalin-3-yl)acetate
- Example 50 was prepared by referring to the synthesis method of Example 49: ESI-MS 776[M+1] + .
- Example 51 tert-butyl (S)-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl) Sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxalin-3-yl)-2-methylpropionate preparation
- Example 52 The preparation of Examples 52 and 53 was prepared by referring to the synthesis method of Example 51:
- Example 57 Ethyl (S,E)-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(tri (Fluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxalin-3-yl)-2 -Preparation of carbonyl acetate
- Example 58 Ethyl (S,E)-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl) Sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxalin-3-yl)-2-carbonyl acetate preparation
- Example 58 The preparation of Example 58 was prepared by referring to the synthesis method of Example 57: ESI-MS 702.2 [M+H] + .
- Example 61 The preparation of Examples 61 and 62 was prepared by referring to the synthesis method of Example 60:
- Example 64 The preparation of Examples 64 and 65 was prepared by referring to the synthesis method of Example 63:
- the first step (S,E)-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-3-(2,2-dimethyl-1, 3-Dioxan-5-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1H-pyran Synthesis of nitro[1,2-a]quinoxaline
- Example 70 was prepared by referring to the synthesis method of Example 69:
- the first step dimethyl(S,E)-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-( (Trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxalin-3-yl)- Synthesis of 2-methylmalonate
- the second step (S,E)-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl (Yl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxalin-3-yl)-2-methyl Synthesis of propyl propane-1,3-diol
- Example 72 was prepared by referring to the synthesis method of Example 71:
- the nuclear magnetic data of the compound prepared in Example 72 are as follows:
- Example 74 The preparation of Example 74 was prepared by referring to the synthesis method of Example 73. ESI-MS 657[M+1] + .
- Example 77 The preparation of Examples 77 and 78 was prepared by referring to the synthesis method of Example 76:
- Example 82 (S,E)-1-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl) (Yl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyrandiazo[1,2-a]quinoxalin-3-yl)-2-methyl
- the first step tert-butyl(R,E)-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfon (Acyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazino[1,2-a]quinoxaline-3-carboxylic acid ester
- the third step Methyl (R,E)-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl) Synthesis of sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxalin-3-yl)acetate
- Example 84 (S,E)-1-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfon (Acyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl [1,2-a]quinoxalin-3-yl) ethane-1-one
- Example 84 The preparation of Example 84 was prepared by referring to the synthesis method of Example 7 to obtain: ESI-MS 660 [M+H] + .
- Example 85 Methyl(S,E)-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl )Sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxalin-3-yl)acetate
- Example 85 was prepared by referring to the synthesis method of Example 44: ESI-MS 690[M+H] + .
- Example 86 (S,E)-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfon (Acyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxalin-3-yl)acetic acid
- Example 86 The preparation of Example 86 was prepared by referring to the synthesis method of Example 9 to obtain: ESI-MS 676 [M+H] + .
- Example 88 (S)-2-((3-((8-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1, 2,3,4,4a,5-hexahydro-6H-pyrandiazo[1,2-a]quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridine-2 -Yl)oxo)ethane-1-ol
- Example 88 The preparation of Example 88 was prepared by referring to the synthesis method of Example 87:
- the third step (S)-2-((3-((8-(3-(difluoromethoxy)-5-fluorophenyl)-3-(methylsulfonyl)-1,2,3, 4,4a,5-Hexahydro-6H-pyrandiazo[1,2-a]quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridin-2-yl)oxy Generation) Synthesis of ethane-1-ol
- Example 90 Methyl (S)-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5- (Trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxaline-3 -Preparation of Acetate
- the first step Methyl(S)-2-(6-((2-(2-((tert-butyldimethylsilyl)oxo)ethoxy)-5-(trifluoromethyl )Pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl)-1,2,4,4a,5,6-hexahydro-3H-pyran Synthesis of azido[1,2-a]quinoxalin-3-yl)acetate
- the second step methyl (S)-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5- (Trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxaline-3 -Yl) acetate synthesis
- the first step tert-butyl(S)-2-(6-((2-(2-((tert-butyldimethylsilyl)oxo)ethoxy)-5-(trifluoro (Methyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl)-1,2,4,4a,5,6-hexahydro-3H- Synthesis of Pyranazinyl[1,2-a]quinoxalin-3-yl)acetate
- Examples 92 and 93 2-((4aS)-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-carbonyl-5-(trifluoromethyl)- 2,3-Dihydropyridin-3-yl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxaline-3 -Yl)acetic acid and (S)-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-methoxy-5-(trifluoromethyl) (Pyridin-3-yl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3H-pyranazinyl[1,2-a]quinoxalin-3-yl)acetic acid
- Example 95 The preparation of Examples 95, 96, 97 was prepared by referring to the synthesis method of Example 94:
- Example 99 was prepared by referring to the synthesis method of Example 98:
- the nuclear magnetic data of the compound prepared in Example 99 are as follows:
- Example 100 8-(3-(Difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a Preparation of ,5,6-hexahydro-[1,4]thiazinyl[4,3-a]quinoxaline
- Example 101 8-(3-(Difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-Hexahydro-[1,4]thiazinyl[4,3-a]quinoxaline 3-oxidation and 8-(3-(difluoromethoxy)-5-fluorophenyl )-6-((3-(Trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]thiazinyl[4,3 -a] Preparation of quinoxaline 3,3-dioxide
- Example 102 8-(3-(Difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-Hexahydro-[1,4]thiazinyl[4,3-a]quinoxaline 3,3-dioxide
- Example 103 (6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-fluoro-5-((3-(trifluoromethyl)phenyl)sulfonyl) Preparation of -6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline
- the first step (6aS)-3-bromo-8-fluoro-7,8,9,10-tetrahydro-5H-pyrido[1,2-a]quinoxaline-6(6aH)-one synthesis
- reaction mixture was diluted with 15ml ethyl acetate, washed with brine (15ml*3), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was separated by a fast silica gel column After obtaining (6aS)-3-bromo-8-fluoro-7,8,9,10-tetrahydro-5H-pyrido[1,2-a]quinoxaline-6(6aH)-one (40mg, yield Rate 66.8%).
- ESI-MS 299, 300[M+H] + .
- Example 104 (6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a ,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-carbamate
- Example 105 (6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a ,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-ol
- Example 106 2-(((6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl) Preparation of -6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-oxo)acetic acid
- the first step tert-butyl 2-(((6aS)-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10- Synthesis of hexahydro-5H-pyrido[1,2-a]quinoxaline-8-)oxy)acetate
- reaction mixture was diluted with 15ml ethyl acetate, washed with water (15ml*3), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was separated by a rapid silica gel column to obtain tert-butyl 2-((( 6aS)-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2- a] Quinoline-8-)oxy)acetate (35mg, yield 72.3%).
- ESI-MS 605, 607 [M+H] + .
- the second step 2-(((6aS)-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- Synthesis of 5H-pyrido[1,2-a]quinoxaline-8)-oxy)acetic acid
- the third step 2-(((6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl) Synthesis of -6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8)-oxy)acetic acid
- Example 107 (6aS,8R)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl)phenyl) Sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-ol
- the first step (6aS,8R)-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10- Synthesis of hexahydro-5H-pyrido[1,2-a]quinoxaline-8-ol
- reaction mixture was diluted with 15ml ethyl acetate, washed with brine (15ml*3), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue After separation by a fast silica gel column, (6aS,8R)-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9 , 10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-ol (25mg, yield 50.0%).
- ESI-MS 505, 507 [M+H] + .
- the second step (6aS,8R)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl)phenyl) Sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-ol
- Example 108 was prepared by referring to the synthesis method of Example 107:
- Example 109 3-(((6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl) -6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-)oxy)propionic acid
- the first step tert-butyl 3-(((6aS)-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10- Synthesis of hexahydro-5H-pyrido[1,2-a]quinoline-8-)oxy)propionate
- the second step tert-butyl 3-(((6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl) Sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8)-oxy)propionate
- the third step 3-(((6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl) Synthesis of -6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-)oxy)propionic acid
- Example 110 (6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylsulfonyl)methoxy)-5-((3-(trifluoro (Methyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline
- the first step (6aS)-3-bromo-8-((methylsulfide)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8 Synthesis of ,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline
- reaction solution was diluted with 15ml ethyl acetate, washed with water (15ml*3), dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the residue was separated by rapid silica gel column to obtain (6aS)-3-bromo-8 -((Methylthio)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[ 1,2-a] Quinoxaline (60 mg, 90.7% yield).
- ESI-MS 551, 553 [M+H] + .
- the second step (6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylsulfide)methoxy)-5-((3-(trifluoromethyl) (Yl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline
- the third step (6aS)-3-(3-(difluoromethoxy)-5-f fluorophenyl)-8-((methylsulfonyl)methoxy)-5-((3-( ⁇ Synthesis of (fluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline
- Example 111 (6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylsulfonyl)ethoxy)-5-((3-(trifluoro (Methyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline
- the third step (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((6aS)-3-(3-(difluoromethoxy)-5-fluoro Phenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quine Synthesis of oxaline-8-yl)oxo)tetrahydro-2H-pyran-3,4,5-triyltriacetate
- the fourth step (2R,3R,4S,5S,6R)-2-(((6aS)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3- (Trifluoromethyl)phenyl 1)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-)oxy)- Synthesis of 6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
- Example 113 3-(((6aS,8R)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl )Phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxalin-8-yl)oxo)propionic acid
- the first step tert-butyl 3-((((6aS,8R)-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a, Synthesis of 7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxalin-8-yl)oxo)propionate
- the second step tert-butyl 3-(((6aS,8R)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-( (Trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxalin-8-yl)oxo)propane Synthesis of acid esters
- the third step 3-(((6aS,8R)-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl) )Phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxalin-8-yl)oxo)propionic acid
- Example 114 was prepared by referring to the synthesis method of Example 113:
- Example 115 was prepared by referring to the synthesis method of Example 109:
- Example 116 (6aS,8S)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6 ,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-carboxylic acid preparation
- the first step (6aS,8S)-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5H- Synthesis of pyrido[1,2-a]quinoxaline-8-carbonitrile
- the third step (6aS,8S)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6 Synthesis of ,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxaline-8-carboxylic acid
- Example 117 was prepared by referring to the synthesis method of Example 116:
- the first step Methyl (S)-3-(1-methyl-6-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)- Synthesis of 4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propionate
- Example 120 Methyl(S,E)-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-methyl-4-( Preparation of (3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propionate
- Example 121 was prepared by referring to the synthesis method of Example 113:
- Example 122 was prepared by referring to the synthesis method of Example 59:
- TR-FRET Time-resolved fluorescence resonance energy transfer detection
- This experiment is a TR-FRET compound screening experiment for ROR ⁇ t nuclear receptor agonists.
- His-labeled ROR ⁇ t-LBD receptor When the His-labeled ROR ⁇ t-LBD receptor is combined with a receptor agonist, it may increase the recruitment of biotin-labeled co-activator peptides.
- Europium-His-ROR ⁇ t-LBD is indirectly labeled by the donor (Eu) by binding to the Eu-anti-His antibody. Once Eu is activated by an energy source (such as a flash lamp or laser), the energy will be bound to the isophycocyanin-chain The method of allophycocyanin-streptavidin is transferred to the co-activator indirectly labeled with allophycocyanin.
Abstract
Description
Claims (14)
- 式(I)化合物、其立体异构体、前药或其药学上可接受盐:其中,L选自键、-C(R 7)=C(R 8)-、-(CR 9R 10) m1-、-(CR 11R 12) m2-O-、-O-(CR 13R 14) m3-、-N(R 15)-C(O)-、-C(O)-N(R 16)-、-(CR 17R 18) m4-N(R 19)-、-N(R 20)-(CR 21R 22) m5-、-(CR 23R 24) m6-S(O) r-或-S(O) r-(CR 25R 26) m7-;R 1选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0- 8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、=O、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30的取代基所取代;R 2、R 3各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30,或者,R 2与R 3和其直接相连的碳原子一起形成C(O)、3-10元环烷基或3-10元杂环基,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、=O、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30的取代基所取代;R 4选自氢、氘、羟基、C 1-4烷基、乙烯基、丙烯基、烯丙基、乙炔基、C 3-6环烷基、3-6元杂环基、苯基、苄基、二氮唑、三氮唑、甲磺酰基、异丙磺酰基、氨基磺酰基、羧 基、甲氧羰基、乙氧羰基或乙酰基,所述C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、苄基、二氮唑、三氮唑任选进一步被一个或多个选自氘、卤素、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、环丙基、氧杂环丁基、=O、甲氧基、羧基、甲氧羰基、乙酰基、氨基、二甲氨基或乙酰氨基的取代基所取代,或者,R 4与R 3和其直接相连的碳原子一起形成5-10元杂环基,所述5-10元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2- 10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、=O、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-C(S)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30的取代基所取代,上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1- 10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、=O、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-C(S)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30的取代基所取代;每个R 5各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、SF 5、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、=O、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30的取代基所取代;每个R 6各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、=O、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30的取代基所取代;R 7、R 8各自独立地选自氢、氘、氟、C 1-4烷基、氘取代C 1-4烷基或氟取代C 1-4烷基;R 9、R 10、R 11、R 12、R 13、R 14、R 17、R 18、R 21、R 22、R 23、R 24、R 25、R 26各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30,或者,R 9与R 10、R 11与R 12、R 13与R 14、R 17与R 18、R 21与R 22、R 23与 R 24、R 25与R 26各自独立地和其直接相连的碳原子一起形成C(O)、3-6元环烷基、3-6元杂环基,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、=O、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30的取代基所取代;R 15、R 16、R 19、R 20、R 27各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 28、-C 0-8-C(O)OR 29或-C 0-8-C(O)R 30,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、=O、-C 0-8-S(O) rR 28、-C 0-8-O-R 29、-C 0-8-C(O)OR 29、-C 0-8-C(O)R 30、-C 0-8-O-C(O)R 30、-C 0-8-NR 31R 32、-C 0-8-C(O)NR 31R 32或-C 0-8-N(R 31)-C(O)R 30的取代基所取代;每个R 28各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 31R 32,上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 31R 32的取代基所取代;每个R 29各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基,上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 31R 32的取代基所取代;每个R 30各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 31R 32,上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 31R 32的取代基所取代;每个R 31、R 32各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基,上述基团任选进一步被一个或多个选自氘、卤素、羟基、羧基、C 1-8烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10 元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代;或者,R 31、R 32和其直接相连的氮原子一起形成4-10元杂环基,上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代;m为0~5的整数;n为0~3的整数;p为0~5的整数;m1、m3、m5、m7各自独立地为1或2;m2、m4、m6各自独立地为0、1或2;每个r各自独立地为0、1或2。
- 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐,其特征在于,每个R 6各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 28、-C 0- 4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-O-C(O)R 30、-C 0-4-NR 31R 32、-C 0-4-C(O)NR 31R 32或-C 0-4-N(R 31)-C(O)R 30,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、=O、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-O-C(O)R 30、-C 0-4-NR 31R 32、-C 0-4-C(O)NR 31R 32或-C 0-4-N(R 31)-C(O)R 30的取代基所取代;R 28、R 29、R 30、R 31、R 32如权利要求1所述;优选的,每个R 6选自氢、氘、氟、氯、氰基、甲基、乙基、异丙基、乙烯基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、3-氮杂环丁基、苯基、吡啶基、二氮唑、三氮唑、甲磺酰基、氨基磺酰基、甲氧基、甲氧酰基、羧基、乙酰基、乙酰氧基、氨基、二甲基氨基、氨基酰基或乙酰氨基,上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、三氟甲基、环丙基、苯基、吡啶基、甲磺酰基、羟基、甲氧基、羧基或氨基的取代基所取代。
- 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐,其特征在于,选自式(Ⅱa)化合物:其中,R 2、R 3各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-O-C(O)R 30、-C 0-4-NR 31R 32、-C 0-4-C(O)NR 31R 32或-C 0-4-N(R 31)-C(O)R 30,或者,R 2与R 3和其直接相连的碳原子一起形成C(O)、3-10元环烷基或3-10元杂环基;R 4选自氢、氘、羟基、C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基、甲磺酰基、异丙磺酰基、氨基磺酰基、羧基、甲氧羰基、乙氧羰基或乙酰基,所述C 1-4烷基、C 3-6环烷基、3-6元杂环基、苯基任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、环丙基、氧杂环丁基、甲氧基、羧基、甲氧羰基、乙酰基、氨基、二甲氨基或乙酰氨基的取代基所取代;环A、环B、L、R 1、R 5、R 28、R 29、R 30、R 31、R 32、r、m、p如权利要求1所述。
- 根据权利要求3所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐,其特征在于,选自式(Ⅲa1)化合物、式(Ⅲa2)化合物、式(Ⅲa3)或化合物式(Ⅲa4):其中,R 2、R 3各自独立地选自氢、氘、C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30或-C 0-4-O-C(O)R 30,或者,R 2与R 3和其直接相连的碳原子一起形成C(O)、3-6元环烷基或3-6元杂环基;R 4选自氢、氘、C 1-4烷基、C 3-6环烷基或3-6元杂环基,所述C 1-4烷基、C 3-6环烷基、3-6元杂环基任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、环丙基、氧杂环丁基、甲氧基、羧基、甲氧羰基、乙酰基、氨基、二甲氨基或乙酰氨基的取代基所取代;每个R 5各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基或-O-R 29,上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、氧杂环丁基、=O、甲氧基或羧基的取代基所取代;R 7选自氢、氘、氟、甲基、乙基、三氟甲基、二氟甲基、三氘甲基或二氘甲基;环A、R 1、R 29、R 30、m如权利要求3所述。
- 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐,其特征在于,选自式(Ⅱb)化合物:其中,Z选自键、-O-、-S-、-S(O)-、-S(O) 2-、-N(R 33)-或-(CR 35R 36)-;R 33选自氢、氘、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0- 4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-C(S)R 30、-C 0-4-O-C(O)R 30或-C 0-4-C(O)NR 31R 32,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2- 4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、=O、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-C(S)R 30、-C 0-4-O-C(O)R 30或-C 0-4-C(O)NR 31R 32的取代基所取代;每个R 34各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-O-C(O)R 30、-C 0-4-NR 31R 32、-C 0-4-C(O)NR 31R 32或-C 0-4-N(R 31)-C(O)R 30,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、=O、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-O-C(O)R 30、-C 0-4-NR 31R 32、-C 0-4-C(O)NR 31R 32或-C 0-4-N(R 31)-C(O)R 30的取代基所取代;R 35选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-C(S)R 30或-C 0-4-O-C(O)R 30,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、=O、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-O-C(O)R 30、-C 0-4-NR 31R 32、-C 0-4-C(O)NR 31R 32或-C 0-4-N(R 31)-C(O)R 30的取代基所取代;R 36选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-C(S)R 30或-C 0-4-O-C(O)R 30,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、 =O、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-O-C(O)R 30、-C 0-4-NR 31R 32、-C 0-4-C(O)NR 31R 32或-C 0-4-N(R 31)-C(O)R 30的取代基所取代;q为0~4的整数;环A、环B、L、R 1、R 2、R 5、R 6、R 28、R 29、R 30、R 31、R 32、m、r、p如权利要求1所述。
- 根据权利要求5所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐,其特征在于,选自式(Ⅲb1)化合物、式(Ⅲb2)化合物、式(Ⅲb3)化合物、式(Ⅲb4)化合物或式(Ⅲb5)化合物:其中,Z选自键、-O-、-S-、-S(O)-、-S(O) 2-、-N(R 33)-或-(CR 35R 36)-;每个R 5各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基或-O-R 29,上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、氧杂环丁基、=O、甲氧基或羧基的取代基所取代;R 7选自氢、氘、氟、甲基、乙基、三氟甲基、二氟甲基、三氘甲基或二氘甲基;R 33选自氢、氘、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-C(S)R 30、-C 0-4-O-C(O)R 30或-C 0-4-C(O)NR 31R 32,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、=O、-C 0-4-S(O) rR 28、-C 0-4-O-R 29、-C 0-4-C(O)OR 29、-C 0-4-C(O)R 30、-C 0-4-O-C(O)R 30或-C 0-4-C(O)NR 31R 32的取代基所取代;R 35选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-O-R 29、-C(O)OR 29、-O-C(O)R 30或-C(O)NR 31R 32,上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷 基、C 3-6环烷基、3-6元杂环基、=O、-S(O) rR 28、-C 0-4-O-R 29、-C(O)OR 29、-C(O)R 30或-C(O)NR 31R 32的取代基所取代;R 36选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基或C 3-6环烷基,上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、硝基、叠氮基、甲基、乙基、羟基、甲氧基或羧基的取代基所取代;环A、R 1、R 28、R 29、R 30、R 31、R 32、m如权利要求5所述。
- 根据权利要求1-6任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐,其特征在于,环A与-(R 1) m一起形成如下结构:其中,每个R 1各自独立地选自氢、氘、卤素、氰基、C 1-4烷基、C 3-6环烷基、3-6元杂环基或-O-R 29,上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、二氟甲基、三氘甲基、二氘甲基、环丙基、氧杂环丁基、=O、甲氧基、羧基、甲氧羰基、乙酰基、氨基、二甲氨基或乙酰氨基的取代基所取代;每个R 28各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 5-8芳基、5-8元杂芳基或-NR 31R 32,上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基或3-8元杂环基的取代基所取代;每个R 29各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 5- 8芳基或5-8元杂芳基,上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基或3-8元杂环基的取代基所取代;每个R 30各自独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基或-NR 31R 32,上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基或-NR 31R 32的取代基所取代;每个R 31、R 32各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、氨基、单烷基氨基或二烷基氨基。
- 一种药物组合物,其包括权利要求1~8任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。
- 根据权利要求1~8任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐在制备治疗一种或多种肿瘤、癌症、代谢性疾病、自身免疫性疾病或紊乱药物中的应用。
- 根据权利要求11所述的应用,其特征在于,所述的代谢性疾病、自身免疫性疾病或紊乱选自特应性皮炎、接触性皮炎、过敏性皮肤炎、粉刺、痤疮、囊性纤维化、同种异体排斥反应症、多发性硬化症、硬皮病、***性红斑狼疮(SLE)、银屑病、桥本病、关节炎、类风湿关节炎、银屑病性关节炎、幼年特发性关节炎、幼年类风湿性关节炎、骨关节炎、强直性脊柱炎、银屑病关节炎(PsA)、自身免疫性糖尿病、I型糖尿病、Ⅱ型糖尿病、肥胖、脂肪肝、脂肪组织相关炎症、胰腺炎、甲状腺炎、自身免疫性甲状腺疾病、胆汁性肝硬化、肝纤维化、非酒精性脂肪肝(NAFLD)、溃疡性结肠炎、克罗恩病、区域性肠炎、炎症性肠病(IBD)、炎症肠综合征(IBS)、慢跑综合征(S慢跑综合征)、原发性硬化性胆管炎、自身免疫性多内分泌综合征I型、自身免疫性多内分泌综合征II型、腹腔疾病、神经炎、***性硬化症、子宫内膜异位症、贝赫切特综合征、白塞病、心肌炎、皮肌炎、多肌炎、移植物抗宿主病、结节病、心肌梗死、肺动脉高压、皮肤利什曼病、克隆氏病、自身免疫性眼病、视神经炎、视神经脊髓炎、干眼症、葡萄膜炎、抗胰岛素性、重症肌无力、年龄相关性黄斑变性、吉兰-巴利综合征、血管球性肾炎、巩膜炎、重度抑郁症、季节性情感障碍、创伤后精神紧张性(精神)障碍(PTSD)、双相障碍、孤独症、癫痫、阿兹海默症、哮喘、慢性阻塞性肺病(COPD)、支气管炎、变应性鼻炎、过敏性鼻炎、抗类固醇哮喘、毒性弥漫性甲状腺肿、阻塞性睡眠呼吸暂停综合征(OSAS)、鼻窦息肉或与睡眠和/或昼夜节律改变相关的中枢神经***紊乱。
- 根据权利要求11所述的应用,其特征在于,所述的肿瘤或癌症选自输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、乳突肾性瘤、头颈部肿瘤、淋巴瘤、骨髓瘤、非霍奇金淋巴瘤、弥漫大B细胞淋巴瘤、滤泡性淋巴瘤、滑膜肉瘤、肝细胞癌、乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、白血病或非小细胞肺癌。
- 根据权利要求1~8任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐,其用作治疗一种或多种肿瘤、癌症、代谢性疾病、自身免疫性疾病或紊乱的药物。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012064744A2 (en) * | 2010-11-08 | 2012-05-18 | Lycera Corporation | Tetrahydroquinoline and related bicyclic compounds for inhibition of rorϒ activity and the treatment of disease |
WO2015171610A2 (en) * | 2014-05-05 | 2015-11-12 | Lycera Corporation | Tetrahydroquinoline sulfonamide and related compounds for use as agonists of rory and the treatment of disease |
CN107980042A (zh) * | 2015-06-11 | 2018-05-01 | 莱斯拉公司 | 用作RORγ激动剂和用于治疗疾病的芳基二氢-2H-苯并[b][1,4]噁嗪磺酰胺和相关化合物 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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JP4949413B2 (ja) * | 2006-02-13 | 2012-06-06 | エフ.ホフマン−ラ ロシュ アーゲー | 糖尿病の処置用のヘテロ二環式スルホンアミド誘導体 |
US9809561B2 (en) * | 2013-12-20 | 2017-11-07 | Merck Sharp & Dohme Corp. | Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease |
JP2018515491A (ja) * | 2015-05-05 | 2018-06-14 | リセラ・コーポレイションLycera Corporation | RORγの作動薬及び疾患の療法として使用するジヒドロ−2H−ベンゾ[b][1,4]オキサジンスルホンアミド及び関連化合物 |
KR20180011267A (ko) * | 2015-05-29 | 2018-01-31 | 시오노기 앤드 컴파니, 리미티드 | Hiv 복제 저해 작용을 갖는 함질소 3환성 유도체 |
JP6689013B2 (ja) * | 2016-11-28 | 2020-04-28 | 塩野義製薬株式会社 | 含窒素3環性誘導体を含有する医薬組成物 |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012064744A2 (en) * | 2010-11-08 | 2012-05-18 | Lycera Corporation | Tetrahydroquinoline and related bicyclic compounds for inhibition of rorϒ activity and the treatment of disease |
WO2015171610A2 (en) * | 2014-05-05 | 2015-11-12 | Lycera Corporation | Tetrahydroquinoline sulfonamide and related compounds for use as agonists of rory and the treatment of disease |
CN107980042A (zh) * | 2015-06-11 | 2018-05-01 | 莱斯拉公司 | 用作RORγ激动剂和用于治疗疾病的芳基二氢-2H-苯并[b][1,4]噁嗪磺酰胺和相关化合物 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3915977A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021047406A1 (zh) * | 2019-09-10 | 2021-03-18 | 四川科伦博泰生物医药股份有限公司 | 一种三并环类化合物,包含其的药物组合物,其制备方法及其用途 |
CN114096533A (zh) * | 2019-09-10 | 2022-02-25 | 四川科伦博泰生物医药股份有限公司 | 一种三并环类化合物,包含其的药物组合物,其制备方法及其用途 |
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AU2019424628B2 (en) | 2022-08-04 |
US20220009894A1 (en) | 2022-01-13 |
KR102554782B1 (ko) | 2023-07-13 |
KR20210081369A (ko) | 2021-07-01 |
JP7290356B2 (ja) | 2023-06-13 |
AU2019424628A1 (en) | 2021-05-06 |
CN112839931B (zh) | 2023-12-01 |
EP3915977A1 (en) | 2021-12-01 |
CA3117113A1 (en) | 2020-07-30 |
JP2022509147A (ja) | 2022-01-20 |
CN112839931A (zh) | 2021-05-25 |
TW202029963A (zh) | 2020-08-16 |
EP3915977A4 (en) | 2022-10-12 |
WO2020151232A9 (zh) | 2020-09-10 |
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