WO2018024188A1 - Composé polycyclique et procédé de fabrication, composition pharmaceutique et application de celui-ci - Google Patents

Composé polycyclique et procédé de fabrication, composition pharmaceutique et application de celui-ci Download PDF

Info

Publication number
WO2018024188A1
WO2018024188A1 PCT/CN2017/095396 CN2017095396W WO2018024188A1 WO 2018024188 A1 WO2018024188 A1 WO 2018024188A1 CN 2017095396 W CN2017095396 W CN 2017095396W WO 2018024188 A1 WO2018024188 A1 WO 2018024188A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
compound
group
unsubstituted
synthesis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2017/095396
Other languages
English (en)
Chinese (zh)
Inventor
陈寿军
利群
刘胜洋
郭洪利
刘凤涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai de Novo Pharmatech Co Ltd
Original Assignee
Shanghai de Novo Pharmatech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai de Novo Pharmatech Co Ltd filed Critical Shanghai de Novo Pharmatech Co Ltd
Publication of WO2018024188A1 publication Critical patent/WO2018024188A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 present invention relates to a polycyclic compound, a process for its preparation, a pharmaceutical composition and use.
  • Indoleamine 2,3-dioxygenase is an immunomodulatory enzyme produced by some alternative activated macrophages and other immunoregulatory cells (also used by many tumors as a strategy to destroy immunity) in humans.
  • the middle is encoded by the IDO gene. Its role is to break down the essential L-tryptophan to kynurenine. The depletion of tryptophan and its metabolites lead to a strong inhibition of the immune response, causing the cessation of T cell growth, blocking the activation of T cells, inducing T cell apoptosis and increasing the production of regulatory T cells.
  • the metabolic pathway from tryptophan to kynurenine has now been established as a key regulatory pathway for innate and adaptive immunity.
  • IDO inhibitors can activate T cells to enhance the body's immune function
  • IDO inhibitors have therapeutic effects on many diseases, including tumor resistance and rejection, chronic infections, HIV infection and AIDS, autoimmune diseases or conditions, such as Rheumatoid arthritis, immune tolerance and prevention of fetal rejection in the uterus.
  • Inhibitors of IDO can also be used to treat neurological or neuropsychiatric diseases or disorders, such as depression (Protula et al, 2005, Blood, 106: 238290; Munn et al, 1998, Science 281:11913).
  • IDO inhibition can enhance the body's immunity and significantly improve the anti-tumor efficacy of various chemotherapeutic drugs and the efficacy of other immunosuppressive diseases (CJDAustin and LMRendina, Drug Discovery Today 2014, 1-9).
  • IDO-/- mouse knockout is feasible and the mice are healthy, which means that IDO inhibition may not cause serious toxicity by the mechanism of action.
  • IDO small molecule inhibitors currently under development to treat and prevent the above-mentioned IDO-related diseases
  • PCT Patent Application WO 99/29310 discloses a method of altering T cell-mediated immunity, including by administering a certain amount of 1-methyl DL. Tryptophan or p-(3 benzofuranyl)-DL-alanine alters the extracellular concentration of local tryptophan and tryptophan metabolites (Munn, 1999).
  • Compounds capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO) are disclosed in WO2004/0234623; U.S. Patent Application No. 2004/0234623 discloses the treatment of cancer by administering an IDO inhibitor in combination with other treatments or The method of infecting patients.
  • IDO inhibitors have good treatment and prevention for immunosuppression, tumor suppression, chronic infection, viral infection including HIV infection, autoimmune diseases or disorders and intrauterine fetal rejection
  • a method of inhibiting IDO activity to inhibit inhibition of tryptophan.
  • an IDO inhibitor can be used to enhance the activity of T cells.
  • IDO chemistry has been well studied and its x-ray crystal structure has also been resolved, which has helped to better use structure-based drug design and structural optimization of drugs. IDO is currently a very attractive target for therapeutic intervention.
  • the technical problem to be solved by the present invention is to provide a novel polycyclic compound, a preparation method thereof, a pharmaceutical composition and use thereof.
  • the polycyclic compound of the present invention has a good IDO inhibitory action, and can effectively treat, alleviate and/or prevent various related diseases caused by immunosuppression, such as tumors, infectious diseases, and autoimmune diseases.
  • IDO inhibitors in the present invention may include the following meanings: IDO inhibitors, TDO inhibitors, or dual inhibitors of IDO and TDO.
  • the present invention provides a polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • ring A is a benzene ring or a 5-6 membered heteroaryl ring
  • the B ring is a 5-membered heteroaryl ring, and A 1 , A 2 , A 3 and A 4 are any combination of the following:
  • a 1 is C
  • a 2 is NR 4 , O or S
  • a 3 is CR 5
  • a 4 is CH or N;
  • a 1 is C
  • a 2 is CR 5 or N
  • a 3 is NR 4 , O or S
  • a 4 is CR 5a or N
  • a 1 is C
  • a 2 is CH or N
  • a 3 is CR 5
  • a 4 is NR 4 , O or S;
  • a 1 is N
  • a 2 is CR 5 or N
  • a 3 is CR 5a or N
  • a 4 is N or CR 5b ;
  • a 1 is CR 5
  • a 2 is C
  • a 3 is NR 4 , O or S
  • a 4 is NR 4 or CR 5a ;
  • a 1 is CR 5
  • a 2 is C
  • a 3 is CR 5a
  • a 4 is NR 4 , O or S;
  • X 1 is a linkage, -O-, -NR 4 - or -CR 6 R 6a -;
  • X 2 is -C(O)- or -S(O) 1-2 -;
  • X 3 is a linkage, -NR 4 - or -CR 6 R 6a -; and, when X 1 is -NR 4 -, X 2 is -C(O)-, X 3 is -NR 4 -;
  • Y is a bond or -(CR 6 R 6a ) p -;
  • U and V are each independently selected from N or CR 3 ;
  • Z and W are each independently selected from CHR 3 , NR 3 , O, C(O) or S(O) 2 ;
  • L is a linkage, C 2-6 alkenylene, C 2-6 alkynylene or -(CR 6 R 6a ) m -;
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl, -SH, -CN, -NO 2 , -OR b , -OC(O)R a , -OC(O)OR b , -OC(O)N(R b ) 2 , -C(O)OR b , -C(O)R a , -C(O)N(R b ) 2 , -NR b C(O)R a , -N(R b )C(O)OR b , -N(R b )C(O)N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 0-2 R a , -S(O) 2 N(
  • R 2 or R 3 are each independently selected from the group consisting of hydrogen, -NO 2 , -CN, -OH, -NH 2 , -SH, -OR 8 , -OC(O)R 8 , -OC(O)NR 7 R 8 , -OC(O)OR 8 , -OP(O)(OR 7 ) 2 , -OS(O) 2 (OH), -OS(O) 1-2 R 8 , -S(O) 1-2 OR 8 , -S(O) 2 NR 7 R 8 , -S(O) 0-2 R 8 , -S(O) 2 N(R 7 )C(O)NR 7 R 8 , -C(O)OR 8, -C (O) R 8 , -C (O) N (OH) R 8, -C (O) NR 7 R 8, -NR 7 R 8, -N (R 7) C (O) OR 8 , -N(R 7 )C(O)N(R
  • R 4 is H, C 1-6 alkyl or C 3-8 cycloalkyl
  • R 5 , R 5a and R 5b are each independently selected from H or C 1-6 alkyl;
  • R 6 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted alkoxy; substituted An alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, or a substituted alkoxy group is substituted at any position by one or more of the following groups: halogen, hydroxy, alkyl, heterocycloalkyl, cycloalkyl , alkoxy, amino, aryl, heteroaryl, -SR a , -N(R b ) 2 , -S(O) 2 N(R b ) 2 , -NR b C(O)N(R b 2 , -NR b C(O)R a , -C(O)R a , -S(O) 0
  • R 6a is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, -SR a , -OR b , -N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 2 N (R b ) 2 , -(CH 2 ) m S(O) 0-2 CH 3 , -OS(O) 3 H, -OP(O)(OR b ) 2 , -OC(O)R a ,- OC(O)N(R b ) 2 , -C(O)N(R b ) 2 , -(CH 2 ) m C(O)OH, -(CH 2 ) m OH, -(CH 2 ) m N (R b ) 2 or -(CH 2 ) m C(O)N(R b ) 2 ;
  • R 6 and R 6a together with the C atom to which they are attached form a 3-8 membered monocyclic cycloalkyl group
  • R 7 or R 8 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl When the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl group is substituted, It may be further substituted at any position by 1 to 3 substituents selected from a halogen, a hydroxyl group, an amino group,
  • R a and R b are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkylalkyl, cycloalkylalkyl, arylalkane Or a heteroarylalkyl group, or two R b together with the N atom to which they are attached together form a 3-8 membered monocyclic heterocycloalkyl group;
  • n, m and p are independently 1, 2 or 3;
  • q and t are independently 0, 1, or 2, respectively.
  • the 5-6 membered heteroaryl group is preferably a thienyl group, a pyridyl group or a pyrimidinyl group.
  • the R 1 is preferably hydrogen, halogen, hydroxy, decyl, cyano, C 1-3 alkoxy, C 1-3 alkylthio, C 1-4 alkyl (eg, methyl, ethyl, n-propyl) Or isopropyl), halo C 1-3 alkyl (eg, trifluoromethyl, difluoromethyl) and halo C 1-3 alkoxy (eg, trifluoromethoxy, difluoromethyl) One or more of oxy), -C(O)OH, -C(O)NH 2 , -S(O) 2 CH 3 .
  • R 1 is one of H, F, Cl, Br, -CH 3 , -CN, -OH, -OCH 3 , -OCF 3 , -OCHF 2 and -C(O)NH 2 or A variety.
  • the R 4 is preferably H, methyl, ethyl, isopropyl or cyclopropyl.
  • the R 5 is preferably H, methyl, ethyl, n-propyl or isopropyl
  • the R 5a is preferably H, methyl, ethyl, n-propyl or isopropyl.
  • the R 5b is preferably H.
  • the R 6 is preferably hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, A substituted or unsubstituted 3-8 membered heterocycloalkyl group, or a substituted or unsubstituted C 1-4 alkoxy group.
  • the substituted alkyl group, substituted cycloalkyl group, substituted heterocycloalkyl group, or substituted alkoxy group is substituted at any position by one or more of the following groups: halogen, hydroxy, alkyl, Heterocycloalkyl, cycloalkyl, alkoxy, amino, aryl, heteroaryl, -SR a , -N(R b ) 2 , -S(O) 2 N(R b ) 2 , -NR b C (O) N (R b ) 2, -NR b C (O) R a, -C (O) R a, -S (O) 0-2 R a, -C (O) OR b, - ( CH 2 ) m OH or -(CH 2 ) m N(R b ) 2 .
  • the R 6a is preferably hydrogen, deuterium, halogen, hydroxyl, amino, C 1-4 alkyl, -SR a , -OR b , -N(R b ) 2 , -NR b S(O) 2 R a , -S(O) 2 N(R b ) 2 , -(CH 2 ) m S(O) 0-2 CH 3 , -OS(O) 3 H,- OP(O)(OR b ) 2 , -OC(O)R a , -OC(O)N(R b ) 2 , -C(O)N(R b ) 2 , -(CH 2 ) m C( O) OH, -(CH 2 ) m OH, -(CH 2 ) m N(R b ) 2 or -(CH 2 ) m C(O)N(R
  • R 6 or R 6a is H, -CH 3 , -CF 3 , -CH 2 CH 3 or F.
  • X 1 is preferably a linkage.
  • the X 2 is preferably -C(O)-, or -S(O) 1-2 -.
  • the X 3 is preferably a linkage, or -NH-.
  • the X 1 , X 2 and X 3 are preferably any combination of the following:
  • X 1 is a linkage, X 2 is -C(O)-, and X 3 is -NH-;
  • X 1 is a linkage
  • X 2 is -S(O) 2 -
  • X 3 is -NH-;
  • X 1 is -NH-
  • X 2 is -S(O) 2 -
  • X 3 is -NH-
  • X 1 is -NH-
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • X 1 , X 2 and X 3 are more preferably any combination of the following: X 1 is a linking bond, X 2 is -C(O)-, and X 3 is -NH-.
  • the Y is preferably a linkage, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -CHF- Or -CF 2 -.
  • the L is preferably a linkage, -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -C(CH 3 ) 2 -, -CHF- or -CF 2 -.
  • L is a linkage or -O-.
  • the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-4 alkyl group, more preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, or a substituted group. Or unsubstituted propyl, substituted or unsubstituted isopropyl;
  • the substituted or unsubstituted aryl group is preferably a substituted or unsubstituted C 6-10 aryl group, more preferably a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group;
  • the substituted or unsubstituted heteroaryl group is preferably a substituted or unsubstituted 5-10 membered heteroaryl group, more preferably a substituted or unsubstituted pyridyl group, a substituted or unsubstituted N- group.
  • the substituted or unsubstituted cycloalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl group, more preferably a substituted or unsubstituted C 3-8 monocyclic cycloalkyl group;
  • the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted 5-8 membered heterocycloalkyl group, more preferably a substituted or unsubstituted 5-8 membered monoheterocycloalkane. base;
  • R 2 or R 3 is a substituted alkyl group, a substituted cycloalkyl group, a substituted heterocycloalkyl group, a substituted aryl group or a substituted heteroaryl group, the following 1 to 3 R A groups may be used.
  • the halogen is preferably F, Cl, Br, I; more preferably F or Cl;
  • the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-4 alkyl group; more preferably a methyl group, an ethyl group, a n-propyl group or a different group.
  • the substituted or unsubstituted alkyl group is preferably a substituted or unsubstituted C 1-4 alkyl group; more preferably a methyl group, an ethyl group, a n-propyl group or a different group.
  • the substituted or unsubstituted alkoxy group is preferably a substituted or unsubstituted C 1-4 alkoxy group; more preferably a methoxy group or an ethoxy group.
  • the substituted or unsubstituted alkylthio group is preferably a substituted or unsubstituted C 1-4 alkylthio group; more preferably a methylthio group or an ethylthio group.
  • the substituted or unsubstituted aryl group is preferably a substituted or unsubstituted phenyl group.
  • the substituted or unsubstituted heteroaryl group is preferably a substituted or unsubstituted 5-6 membered heteroaryl group.
  • the substituted or unsubstituted cycloalkyl group is preferably a substituted or unsubstituted C 3-8 cycloalkyl group.
  • the substituted or unsubstituted heterocycloalkyl group is preferably a substituted or unsubstituted 5-8 membered heterocycloalkyl group.
  • R 2 or R 3 in the R A , when the alkyl group, the alkoxy group, the aryl group, the heteroaryl group, the cycloalkyl group or the heterocycloalkyl group is substituted, it may be further selected from 1 to 3 Substituents from a halogen, a hydroxyl group, an amino group, a C 1-3 alkyl group, or a halogenated C 1-3 alkoxy group are substituted at any position.
  • R 7 or R 8 are each independently preferably hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted a 3-8 membered heterocycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted C 3-8 cycloalkyl C 1-3 alkyl group, Substituted or unsubstituted 3-8 membered heterocycloalkyl C 1-3 alkyl, substituted or unsubstituted phenyl C 1-3 alkyl, or substituted or unsubstituted 5-6 membered heteroaryl C 1- 3 alkyl; or, R 7 and R 8 together with the N atom to which they are attached form a 3-8 membered monoheterocycloalkyl
  • the alkylalkyl group when the alkyl group, the aryl group, the heteroaryl group, the cycloalkyl group, the heterocycloalkyl group, the arylalkyl group, the heteroarylalkyl group, the cycloalkylalkyl group or the heterocyclic ring
  • the alkylalkyl group when substituted, it may be further substituted at any position by 1 to 3 substituents selected from a halogen, a hydroxyl group, an amino group, a C 1-4 alkyl group, or a halogenated C 1-3 alkoxy group.
  • R 3 is hydrogen, fluorine, hydroxy, cyano, C 1-4 alkyl, or C 1-3 alkoxy.
  • R 2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-10 membered heteroaryl group.
  • the R a and R b are each independently preferably from hydrogen, C 1-4 alkyl, halo C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl C 1-3 alkyl, C 3-8 cycloalkyl C 1-3 alkyl, phenylalkyl, or 5-6 membered heteroaryl C 1-3 alkyl, or two R b together with the N atom to which they are attached form a 3-8 membered monocyclic heterocycloalkyl group.
  • R a is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • R b is hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • the definitions of the A ring, the B ring, R 1 , R 2 , A 1 to A 4 , X 1 to X 3 , L, Y, U, W, Z, V, q, t and n are as described above.
  • the A 1 -A 4 are any combination of the following:
  • a 1 is C
  • a 2 is NR 4 , O or S
  • a 3 is CR 5
  • a 4 is CH or N;
  • a 1 is C
  • a 2 is CR 5 or N
  • a 3 is NR 4 , O or S
  • a 4 is CR 5a or N
  • a 1 is C
  • a 2 is CH or N
  • a 3 is CR 5
  • a 4 is NR 4 , O or S.
  • the A 1 -A 4 are in any combination of the following:
  • a 1 is C
  • a 2 is NR 4
  • a 3 is CR 5
  • a 4 is CH or N;
  • a 1 is C
  • a 2 is CR 5 or N
  • a 3 is NR 4
  • a 4 is CR 5a or N;
  • a 1 is C
  • a 2 is CH or N
  • a 3 is CR 5
  • a 4 is NR 4 .
  • the B ring Is any of the following structures:
  • the B ring Is any of the following structures
  • X 1 is a linkage
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • t is 1 and q is 1.
  • U is CR 3 and V is CH.
  • Z is CH 2 and W is CH 2 .
  • L is a linkage
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of: methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • a ring the B ring
  • the B ring Preferably, it is any of the following structures;
  • X 1 is a linkage
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • t is 1 and q is 1.
  • U is CH and V is CH.
  • Z is CH 2 and W is CH 2 .
  • L is a linkage
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • W is N or CH
  • a 2 , A 3 and A 4 are the following combinations:
  • a 2 is CR 5 , A 3 is NR 4 , and A 4 is N;
  • a 2 is N
  • a 3 is NR 4
  • a 4 is CR 5a ;
  • a 2 is CR 5
  • a 3 is NR 4
  • a 4 is CR 5a ;
  • a 2 is N
  • a 3 is NR 4
  • a 4 is N
  • a 2 is N, A 3 is O or S, and A 4 is CH;
  • R 1 , R 2 , R 4 , R 5 , R 5a , L, X 1 to X 3 , Y, U, V, q and n are as described above.
  • a 2 is CR 5
  • a 3 is NR 4
  • a 4 is CR 5a .
  • X 1 is a linkage
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • q is one.
  • U is CR 3 and V is CH.
  • L is a linkage
  • R 3 is H or hydroxy
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • W is N or CH;
  • R 4 is H or -CH 3 ;
  • R 5 is H, methyl, ethyl or isopropyl;
  • R 5a is H, methyl, ethyl or isopropyl;
  • R 1 , R 2 , R 3 , L, Y and n are as described above.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • L is a linkage
  • R 3 is H or hydroxy
  • R 5 is H or methyl.
  • R 5a is H or methyl.
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • a 2 , A 3 and A 4 are the following combinations:
  • a 2 is NR 4 , A 3 is CR 5 , and A 4 is CH;
  • a 2 is NR 4 , A 3 is N, and A 4 is CH;
  • a 2 is S, A 3 is CH, and A 4 is N;
  • a 2 is O, A 3 is CH, and A 4 is N;
  • R 1 , R 2 , R 4 , R 5 , L, X 1 , X 2 , X 3 , Y, U, V, W, n and q are as described above.
  • X 1 is a linkage
  • X 2 is -C(O)-
  • X 3 is -NH-.
  • Y is -CH 2 -.
  • Y is -CH 2 CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • q is one.
  • U is CR 3
  • V is CH
  • R 3 is H or hydroxy
  • L is a linkage
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • W is N or CH
  • R 1 , R 2 , R 3 , R 5 , L, Y and n are as described above.
  • Y is -CH 2 -.
  • Y is -CH (CH 3) -.
  • Y is -C (CH 3) 2 -.
  • L is a linkage
  • R 3 is H or hydroxy
  • R 5 is H, methyl, ethyl, or isopropyl.
  • R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted N-oxidized pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted Isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl;
  • the substituted R 2 may be substituted at any position by 1 to 3 R A groups as follows: C 1-3 alkyl (eg methyl, ethyl, isopropyl), C 1-3 alkoxy (eg One or more of methoxy, ethoxy), F, Cl, Br, I, -OH, -NH 2
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • a 2 , A 3 and A 4 are the following combinations:
  • a 2 is CH
  • a 3 is CH
  • a 4 is NR 4 ;
  • a 2 is CH, A 3 is N, and A 4 is CH;
  • a 2 is N, A 3 is CH, and A 4 is CH;
  • a 2 is N, A 3 is N, and A 4 is CH;
  • a 2 is N
  • a 3 is N
  • a 4 is NR 4 ;
  • R 1 , R 2 , L, X, Y, U, V and W are as described above.
  • the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt preferably has a structural formula of:
  • a ring R 1 , R 2 , L, X 1 , X 2 , X 3 , Y, A 1 , A 2 , A 3 , A 4 and n are as described above.
  • the polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt is preferably one of the following structures:
  • the present invention also provides a process for the preparation of the polycyclic compound (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, which is any of the following methods:
  • the compound of the formula Ia can be obtained by the reaction formula 1 shown in the method 1, wherein the ring A, the ring B, the R 1 , the R 2 , the L, the X 1 , the A 1 , the A 2 , the A 3 , the A 4 , the U, V and n are defined as described above.
  • the method 1 comprises the steps of: subjecting the compound represented by 1a and 1b to a compound represented by Ia under a basic condition, and the conditions and steps of the condensation reaction may be the conditions and steps of a conventional condensation reaction in the art, and the present invention is particularly preferred.
  • the solvent is preferably dichloromethane
  • the condensing agent is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
  • the base is preferably N, N-diisopropylethylamine (DIPEA) or triethylamine (TEA)
  • the reaction temperature is preferably 0 ° C to room temperature, in order to accelerate the reaction rate, a catalytic amount of 4-dimethylaminopyridine can also be added to the reaction system.
  • the compound of the formula Ib can be obtained by the reaction formula 2 shown in the method 2, wherein the ring A, the ring B, the R 1 , the R 2 , the L, the X 1 , the A 1 , the A 2 , the A 3 , the A 4 , the U, V and n are defined as described above.
  • the method 2 comprises the steps of: obtaining a compound represented by Ib by nucleophilic substitution reaction under basic conditions, and the conditions and steps of the reaction may be conventional conditions and steps in the art, and the following reactions are particularly preferred in the present invention.
  • the solvent is preferably dichloromethane (DCM);
  • the base is preferably N,N-diisopropylethylamine (DIPEA) or triethylamine (TEA), in general, in order to catalyze the progress of the reaction, in the reaction system
  • DIPEA N,N-diisopropylethylamine
  • TEA triethylamine
  • a catalytic amount of 4-dimethylaminopyridine is added, and the reaction temperature is preferably from 0 ° C to room temperature.
  • Boc is used as a protecting group
  • subsequent deprotection reactions can be carried out under standard conditions, for example, p-toluenesulfonic acid/methanol system, dichloromethane/trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonate
  • the pharmaceutically acceptable salt of the polycyclic compound (I) can be synthesized by a general chemical method.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent chemical equivalent or an excess of an acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprising a polycyclic compound (I), an isomer thereof, a prodrug, a solvent
  • the active ingredient comprising a polycyclic compound (I), an isomer thereof, a prodrug, a solvent
  • a compound, a hydrate, a stable isotope derivative, and a pharmaceutically acceptable salt One or more of a compound, a hydrate, a stable isotope derivative, and a pharmaceutically acceptable salt.
  • the active ingredient may also include other therapeutic agents for cancer, viral infection or autoimmune diseases.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment.
  • dosage unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quatern
  • any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
  • a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be added.
  • the content of the composition in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 80% by mass. %.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.
  • injectable solutions eg, glucose solutions and amino acid solutions
  • suppositories are given Drug to the rectum.
  • the present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is used in the preparation of hydrazine Use in indoleamine 2,3-dioxygenase inhibitors.
  • the indoleamine 2,3-dioxygenase inhibitor (IDO inhibitor) refers to inhibiting IDO activity or expression (including abnormal activity or overexpression of IDO) and reversing IDO-mediated immunosuppression. Compound.
  • the IDO inhibitor can inhibit IDO.
  • the present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for stimulation Application in T cell proliferation drugs.
  • the present invention also provides the polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for treatment
  • a medicament for alleviating and/or preventing a disease associated with guanamine 2,3-dioxygenase.
  • the N-hydroxy steroid compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition may also be a Or a variety of other types of therapeutic agents and/or therapeutic methods for treating cancer in combination for treating, ameliorating and/or preventing a disease associated with guanamine 2,3-dioxygenase.
  • the 2,3-dioxygenase-mediated related disease refers to a disease caused by 2,3-dioxygenase-mediated immunosuppression, which may include: a virus or other infection (eg, : skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.), cancer, or autoimmune diseases (eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).
  • a virus or other infection eg, : skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.
  • cancer eg. rheumatoid arthritis, lupus erythematosus, psoriasis, etc.
  • autoimmune diseases eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.
  • the other kind of therapeutic agent for treating cancer may be a therapeutic form for single administration with the polycyclic compound (I), or a therapeutic dosage form for sequential administration.
  • the other types of therapeutic agents and/or therapeutic methods for treating cancer may include, but are not limited to, tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, platinum compounds, antimetabolites, Hormone and hormone analogs, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies (eg, specific kinase inhibitors), immunotherapeutics, pro-apoptotic agents, cell cycle signaling pathway inhibitors, and radiotherapy One or more.
  • the tubulin inhibitor may be selected from, but not limited to, a vinblastine series (eg, vinblastine, vincristine, vinorelbine, vindesine), a taxane (docetaxel, paclitaxel), and a One or more of eribulin sulfonate.
  • a vinblastine series eg, vinblastine, vincristine, vinorelbine, vindesine
  • a taxane docetaxel, paclitaxel
  • eribulin sulfonate eribulin sulfonate
  • the alkylating agent may be selected from one or more of the group consisting of nitrogen mustard, ethyleneimine derivative, methanesulfonate, nitrosourea, and triazene.
  • the topozyme I/II inhibitor may be selected from, but not limited to, one or more of irinotecan, topotecan, doxorubicin, and dexrazoxane.
  • the platinum compound may be selected from, but not limited to, cisplatin and/or carboplatin.
  • the anti-metabolites may be selected from, but not limited to, folic acid antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, for example: methotrexate, 5-fluorouracil, fluorouridine, arabinose One or more of cytidine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentastatin, and gemcitabine.
  • the immunotherapeutic agent can be selected from, but not limited to, anti-tumor vaccines (eg, synthetic peptides, DNA vaccines, and recombinant viruses), oncolytic viruses, immunostimulatory antibodies, novel adjuvants, cytokine treatments (eg, IL2 and GM- One or more of CSF), chimeric antigen receptor T cell therapy (CAR-T), small molecule immunomodulator, tumor microenvironmental modulator, and anti-angiogenic factor.
  • anti-tumor vaccines eg, synthetic peptides, DNA vaccines, and recombinant viruses
  • oncolytic viruses immunostimulatory antibodies
  • novel adjuvants eg, IL2 and GM- One or more of CSF
  • CAR-T chimeric antigen receptor T cell therapy
  • small molecule immunomodulator eg, tumor microenvironmental modulator, and anti-angiogenic factor.
  • the immunostimulatory antibodies can include, but are not limited to, 1) protein antagonists that inhibit T cell activity (eg, immunological checkpoint inhibitors): CTLA4 (eg, ipilimumab and tremelimumab), PD-1 (eg, pembrolizumab and nivolumab) ), PD-L1 (eg durvalumab, avelumab and atezolizumab), LAG3 And one or more of TIM3; 1) a protein agonist that stimulates T cell activity: one or more of GITR, OX40, OX40L, 4-1BB (CD137), CD27, and CD40.
  • CTLA4 eg, ipilimumab and tremelimumab
  • PD-1 eg, pembrolizumab and nivolumab
  • PD-L1 eg durvalumab, avelumab and atezolizumab
  • the signal transduction pathway inhibitor may be selected from, but not limited to, a BCR/ABL kinase inhibitor, an epidermal growth factor receptor inhibitor, a her-2/neu receptor inhibitor, an AKT family kinase inhibitor, PI3K Signal pathway inhibitors, and cell cycle checkpoint inhibitors.
  • the angiogenesis inhibitor can be selected from, but not limited to, one or more of a VEGF/VEGFR signaling pathway inhibitor, a Src family kinase inhibitor, a Src signaling pathway inhibitor, and a c-Fes kinase inhibitor.
  • the viral infection may include: from influenza, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, chickenpox - Infections caused by viruses such as herpes zoster virus, Coxsackie virus, or human immunodeficiency virus (HIV).
  • HCV hepatitis C virus
  • HPV human papillomavirus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • poliovirus chickenpox - Infections caused by viruses such as herpes zoster virus, Coxsackie virus, or human immunodeficiency virus (HIV).
  • the cancer may include, but is not limited to, bone cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, One or more of head and neck cancer, lymphoma, leukemia and skin cancer.
  • the autoimmune diseases may include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease (MCTD), systemic scleroderma (including: CREST syndrome), dermatomyositis, knot Segmental vasculitis, nephropathy (including: pulmonary hemorrhagic nephritis syndrome, acute glomerulonephritis, primary membrane proliferative glomerulonephritis, etc.), endocrine-related diseases (including: type I diabetes, gonadal insufficiency, malignancy) Anemia (including anemia, hyperthyroidism, etc.), liver disease (including: primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, etc.) and autoimmune reactions due to infection (eg One or more of AIDS, malaria, etc.
  • MCTD mixed connective tissue disease
  • the present invention also provides a polycyclic compound (I), an isomer thereof, a prodrug, a solvate, a hydrate, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition
  • a method of inhibiting tryptophan degradation in a system comprising the steps of inhibiting degradation of tryptophan in a mammal by administering to a mammal a therapeutically effective amount of a compound of formula (I); said system being IDO-expressing Tissue, mammal or cell tissue.
  • Said mammal preferably a human.
  • substituent name is not preceded by the definition of "substituted or unsubstituted”, and is meant to mean unsubstituted, for example, "alkyl” means unsubstituted alkyl, “cycloalkyl” "" means an unsubstituted cycloalkyl group.
  • substituted at one position by one or more groups means that any one or more of the hydrogen atoms of one or more atoms specified on the group are represented by the specified group. Substituted, provided that the normal valence of the specified atom is not exceeded, the substitutions are all reasonable substitutions that are common in the art. For example, substitution of 1 to 3 groups at any position means that one, two or three identical or different substituents may be reasonably substituted at any position.
  • alkyl refers to a saturated straight or branched chain hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8 carbon atoms, and representative examples of alkyl groups include, but are not limited to, : methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, 4, 4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof.
  • cycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) containing from 3 to 20 carbon atoms. Monocyclic or polycyclic groups. "monocyclic cycloalkyl” is preferably a 3-10 membered monocycloalkyl group, more preferably a 5-8 membered monocycloalkyl group, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ring Octyl, cyclodecyl, cyclododecyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “fused cycloalkyl” and “spirocycloalkyl", and “fused cycloalkyl” includes a monocyclic ring fused to an aryl, cycloalkyl, or heteroaryl group.
  • Alkyl rings, fused bicyclic cycloalkyl groups include, but are not limited to, benzocyclobutene, 2,3-dihydro-1-H-indole, 2,3-cyclopentenopyridine, 5,6-dihydro -4H-cyclopentyl [B] thiophene, decalin, and the like.
  • “Spirocycloalkyl” refers to a bicyclic group formed by the sharing of one carbon atom by two cycloalkyl groups, including but not limited to: spiro[2.4]heptyl, spiro[4.5]decane, and the like.
  • a monocyclic cycloalkyl or bicyclic cycloalkyl group can be attached to the parent molecule through any carbon atom on the ring.
  • heterocycloalkyl refers to a 3-20 membered non-aromatic cyclic group consisting of a carbon atom and a saturated or partially unsaturated (containing 1 or 2 double bonds) consisting of a hetero atom selected from nitrogen, oxygen or sulfur.
  • the cyclic group may be a monocyclic or bicyclic group.
  • the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and a nitrogen, carbon or sulfur atom in the heterocycloalkyl group. It can optionally be oxidized.
  • the nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt.
  • the "monocyclic heterocycloalkyl group” is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 5-8 membered monocyclic heterocycloalkyl group.
  • monocyclic heterocycloalkyl group is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 5-8 membered monocyclic heterocycloalkyl group.
  • aziridine tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholine-S-oxide-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl and the like.
  • Polycycloheterocycloalkyl includes “fused heterocycloalkyl” and “spiroheterocyclyl”.
  • “Fused heterocycloalkyl” includes a monocyclic heterocycloalkyl ring fused to a phenyl, heterocycloalkyl, cycloalkyl or heteroaryl group, including but not limited to: 2,3 - dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, indanyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolinyl, Wait.
  • Spiroheterocyclyl means a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing one carbon atom, and spiroheterocyclyl groups include, but are not limited to: Wait.
  • Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl groups can be attached to the parent molecule through any ring atom on the ring.
  • the above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group.
  • cycloalkylalkyl embraces the definitions of alkyl and cycloalkyl as described above.
  • heterocycloalkylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heterocycloalkylalkyl embraces the definitions of alkyl and heterocycloalkyl as described above.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group.
  • alkoxy includes the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • alkylthio means that a cyclic or acyclic alkyl group is bonded to each other through a sulfur atom and a parent molecule, and includes an alkyl fluorenyl group, a cycloalkyl fluorenyl group, and a heterocycloalkyl fluorenyl group.
  • alkylthio embraces the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • hydroxyalkyl refers to an alkyl arbitrary one hydrogen atom is substituted with a hydroxyl group, including but not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C (CH 3) 2 OH.
  • alkenyl refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing at least one carbon to carbon double bond. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
  • C 2-4 alkenyl means having 2-4 carbon atoms, an alkenyl group
  • C 2-6 alkenyl means an alkenyl radical having 2-6 carbon atoms, include ethenyl, propenyl , butenyl, 2-methylbutenyl and cyclohexenyl.
  • the alkenyl group may be substituted.
  • alkynyl refers to a straight, branched or cyclic hydrocarbon radical containing at least one carbon to carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, and includes ethynyl, propynyl, butynyl and 3-methylbutynyl.
  • aryl refers to any stable 6-10 membered monocyclic or bicyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl.
  • heteroaryl refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-12 A bicyclic structure, preferably a 5-6 membered heteroaryl group.
  • the number of heteroatoms is preferably 1, 2 or 3, including but not limited to: pyridyl, pyrimidinyl, pyridazine-3(2H)-one, furyl, thienyl, thiazolyl, pyrrolyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1 , 2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolyl, isodecyl, benzofuranyl, benzothienyl, benzo[d][1 , 3] dioxolane, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolinyl and the like.
  • cyclo-heteroaryl refers to a group formed by a monocyclic heteroaryl group and a group selected from a monocyclic heteroaryl group or a monocyclic aryl group sharing two adjacent ring atoms, said "co-ring"
  • a heteroaryl group is a bicyclic group.
  • the cycloheteroaryl group is preferably a 8-12 membered bicyclic group including, but not limited to, carbazolyl, isoxazolyl, indolyl, isodecyl, benzofuranyl, benzothienyl, Benzothiazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 4-aza Sulfhydryl, 5-azaindolyl, 2-azaindolyl, 6-azaindolyl, 7-azaindolyl, 1H-pyrrolo[2,3-B]pyridinyl, 4-Azacarbazolyl, 7-azacarbazolyl, 6-azacarbazolyl, 1H-pyrazolo[3,4-C]pyridine, and the like.
  • arylalkyl refers to an alkyl linkage between the aryl group and the parent core structure.
  • arylalkyl embraces the definition of alkyl and aryl as defined above.
  • heteroarylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heteroarylalkyl embraces the definitions of alkyl and heteroaryl as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • haloalkyl refers to an alkyl group optionally substituted by halogen.
  • haloalkyl embraces the definitions of the above halo and alkyl.
  • haloalkoxy refers to an alkoxy group optionally substituted by halogen.
  • haloalkoxy includes the definitions of the above halo and alkoxy.
  • amino means -NH 2
  • alkylamino refers to at least one amino hydrogen atoms are substituted by alkyl groups, including but not limited to: -NHCH 2, -NHCH 2 CH 3 .
  • aminoalkyl means that any one of the hydrogen atoms on the alkyl group is replaced by an amino group, including but not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 .
  • alkylamino and aminoalkyl embrace the definitions of alkyl and amino groups described above.
  • alkylene refers to an alkyl, alkenyl or alkynyl group which may serve as a linking bond to the other two groups, which may be straight chain as well. It may be a branched structure such as -(CH 2 ) q -; the alkenylene or alkynylene group may be a branched, straight chain or cyclic structure.
  • Root temperature as used herein means 15-30 °C.
  • the isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms.
  • prodrug is meant that the compound is converted to the original active compound after metabolism in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.
  • “Pharmaceutically acceptable salts” as described herein are discussed in Berge, et al., “Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like.
  • the compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with an acid, for example, hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, citrate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,
  • the pharmaceutically acceptable salt thereof may further include: an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • “isomer” means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention.
  • a compound of the formula I or a salt thereof, in stereoisomeric form is a single stereoisomer (enantiomer and diastereomer). Isomers) and mixtures thereof are included within the scope of the invention.
  • the invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more chiral centers are inverted.
  • the scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures.
  • the invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers.
  • the invention includes all combinations and subsets of stereoisomers of all the specific groups defined above.
  • the invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.
  • the reagents and starting materials used in the present invention are commercially available.
  • the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • All of the compounds of the present invention can be separated by high performance liquid chromatography, silica gel column chromatography, thin layer silica gel plates, flash separators or by supercritical fluid chromatography (SFC).
  • SFC supercritical fluid chromatography
  • Flash column chromatography Flash system / Cheetah TM
  • Agela Technologies MP200 supporting the use of a separation column for Flash columm Silica-CS (80g) , Cat No.CS140080-0.
  • High performance liquid chromatography was carried out using Shimadzu LC-20 preparative liquid chromatography at a detection wavelength of 214 nm & 254 nm; flow rate: 9.0 mL / min.
  • the column is: waters xbridge Pre C18, 10um, 19mm x 260mm.
  • Elution conditions (acidic conditions): Condition 1: 30 to 65% mobile phase A and 70 to 35% mobile phase B; Condition 2: 40 to 60% mobile phase A and 60 to 40% mobile phase B; Condition 10: 80 ⁇ 40% mobile phase A and 20-60% mobile phase B; Condition 11: 15-30% mobile phase A and 85-70% mobile phase B; mobile phase A: 0.05% aqueous trifluoroacetic acid solution (percentage percent by volume) , mobile phase B: acetonitrile.
  • Elution conditions (basic conditions): Condition 3: 65 to 70% mobile phase A and 35 to 30% mobile phase B; Condition 4: 30 to 55% mobile phase A and 70 to 45% mobile phase B; Condition 5: 30-65% mobile phase A and 70-35% mobile phase B; Condition 6: 40-70% mobile phase A and 60-30% mobile phase B; Condition 7: 45-75% mobile phase A and 55-25% Mobile phase B; Condition 8: 70 to 25% mobile phase A and 30 to 75% mobile phase B; Condition 9: 70 to 30% mobile phase A and 30 to 70% mobile phase B; Condition 12: 30 to 45% flow Phase A and 70-55% mobile phase B; Condition 13: 20-40% mobile phase A and 80-60% mobile phase B; Condition 14: 20-35% mobile phase A and 80-65% mobile phase B; conditions 15:25-40% mobile phase A and 75-60% mobile phase B; Condition 16: 65-35% mobile phase A and 35-65% mobile phase B; Condition 17: 25-65% mobile phase A and 75 ⁇ 35% mobile phase B; Condition 18: 15 to 35% mobile phase A and 85 to 65% mobile phase B; Condition
  • Supercritical fluid chromatography used SFC-80 (Thar, Waters) at a flow rate of 80 g/min and a column temperature of 35 °C.
  • the detection wavelength is 214.
  • the chiral analysis was performed using a supercritical fluid chromatography analyzer SFC Method Station (Thar, Waters) at a flow rate of 4.0 mL/min, a column temperature of 35 ° C, and a detection wavelength of 214.
  • the thin layer silica gel plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
  • Step 3 Synthesis of Compound 1.3
  • Step 1 Synthesis of Compounds 2.1a and 2.1b:
  • Step 2 Synthesis of compounds 2.2a and 2.2b
  • N-phenylbis(trifluoromethanesulfonimide) (8.2 g, 23.1 mmol) of methyl tert-butyl ether (75 mL)
  • a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran 2.0 M, 11.5 mL, 23.1 mmol
  • EtOAc EtOAc
  • Step 1 Synthesis of Compound 7.1
  • Methyl cinnamate (1.0 g, 6.1 mmol) and p-toluenesulfonylmethyl isocyanide (TosMIC) (1.31 g, 6.71 mmol) were dissolved in tetrahydrofuran and dimethyl sulfoxide (25 mL, 4: In a mixed solution of 1), a suspension of sodium hydrogen (60%, 370 mg, 9.15 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture. After the completion of the dropwise addition, the reaction system was heated to 80 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, and then the mixture was evaporated. The combined organic layers were washed with brine brine and evaporated The residue was purified by silica gel chromatography chromatography elut elut elut elut elut elut elut
  • the methyl cinnamate in step 2 is replaced by the corresponding substituted methyl cinnamate, the substituted ethyl cinnamate or the substituted tert-butyl cinnamate to obtain the compound 8.3 to 8.31:
  • compound 8.33 was synthesized using 3-hydroxycinnamic acid as a starting material:
  • Step 1 Synthesis of Compound 10.1
  • the compound 10.1 (850 mg, 3.9 mmol) was added to a mixed solvent of anhydrous tetrahydrofuran (15 mL), ethanol (2 mL) and water (2 mL), and the mixture was stirred at 80 ° C for 12 hours, concentrated under reduced pressure, with hydrochloric acid (1.0 M) The pH was adjusted to 5 to 6. The solid was filtered, and the filter cake was dried to give Compound 10.2 (520 mg, yield: 71%) as a white solid.
  • Acetyl chloride (1.3 g, 16.5 mmol) was added dropwise to a solution of aminoacetaldehyde diethyl acetal (2 g, 15.0 mmol) and triethylamine (2.13 g, 21.0 mmol) in ethyl acetate (30 mL). .
  • the reaction mixture was stirred at room temperature for 1 hour, then ethanol (0.3 mL) was added to the reaction mixture, and the mixture was stirred for 1 hr. reaction.
  • Step 1 Synthesis of ethyl 3-(pyridin-3-yl)acrylate
  • the compound 200.3 is reacted with 1-bromo-3-methyl-2-butanone and ethyl benzoylacetate or ethyl 2-cyanobenzoylacetate to give the compound 20.17 to 20.18:
  • the compound 20.20 was obtained by the reaction of the compound 20.3 by the reaction of methyl 2-cyano-6-methoxybenzoylacetate.
  • Compound 20.20 160 mg, 0.59 mmol
  • sodium hydroxide 47 mg, 1.18 mmol
  • the reaction mixture was adjusted to pH 2-3 with hydrochloric acid (1.0M), ethyl acetate (20 mL ⁇ 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a mixture of compound 20.21. (95 mg, yield: 59%) was obtained as a white solid.
  • Compound 4-1 (187 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 1) to give compound 4-1a (20 mg, peak time: 18.5 to 20.0 minutes, single stereo configuration) and 4-1b ( 12 mg, peak time: 16.3 to 18.0 minutes, single stereo configuration), all white solids.
  • Compound 4-2 (187 mg, cis-trans isomer mixture) was subjected to prep-HPLC (separation condition 1) to give compound 4-2a (28 mg, peak time: 17.0 to 18.5 minutes, single stereo configuration) and 4-2b ( 16 mg, peak time: 18.7 to 19.0 minutes, single stereo configuration), all white solids.
  • the more polar compound 6-5b (2.6 mg, single stereo configuration) was a white solid.
  • the less polar compound 6-24b (26.5 mg, single stereo configuration) was a white solid.
  • the more polar compound, 6-32b (20.3 mg, single stereo configuration), was a white solid.
  • the less polar compound 6-44b (18.3 mg, single stereo configuration) was a white solid.
  • the configuration and the more polar compound 8-1b (40 mg, single stereo configuration) were both white solids.
  • the configuration and the more polar compound 8-2b (14 mg, single stereo configuration) were all white solids.
  • the compound 8-21a-8-23a was synthesized by the synthesis method of the compound 6-38a using the compound 8-13a, 8-12a or 8-16a as a starting material:
  • the more polar compound 9-1b (3.5 mg, single stereo configuration) was a white solid.
  • the configuration and the less polar compound 13-11b (23 mg, single stereo configuration) were both white solids.
  • Compound 14-12 (213 mg, cis and trans isomer mixture) was subjected to prep-HPLC (isolation condition 5) to give compound 14-12a (30 mg, peak time: 15.5 to 16.0 min, single stereo configuration) and 14-12b (40 mg, peak time: 16.2 to 16.6 minutes, single stereo configuration), all white-like solids.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un composé polycyclique et un procédé de fabrication, une composition pharmaceutique et une application de celui-ci. La structure du composé polycyclique et un isomère, un promédicament, un solvate, un hydrate, un dérivé isotopique stable ou un sel pharmaceutiquement acceptable de celui-ci sont représentés par la formule (I). Le composé polycyclique présente un excellent effet inhibiteur contre l'ID01, et peut efficacement traiter, atténuer et/ou prévenir diverses maladies provoquées par l'immunosuppression, y compris une maladie auto-immune provoquée par une tumeur ou une infection virale.
PCT/CN2017/095396 2016-08-02 2017-08-01 Composé polycyclique et procédé de fabrication, composition pharmaceutique et application de celui-ci Ceased WO2018024188A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN201610626450 2016-08-02
CN201610626450.0 2016-08-02
CN201611173686 2016-12-16
CN201611173686.X 2016-12-16
CN201710266483.3 2017-04-21
CN201710266483 2017-04-21

Publications (1)

Publication Number Publication Date
WO2018024188A1 true WO2018024188A1 (fr) 2018-02-08

Family

ID=61072485

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/095396 Ceased WO2018024188A1 (fr) 2016-08-02 2017-08-01 Composé polycyclique et procédé de fabrication, composition pharmaceutique et application de celui-ci

Country Status (2)

Country Link
CN (1) CN107674013B (fr)
WO (1) WO2018024188A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019120256A1 (fr) * 2017-12-22 2019-06-27 上海迪诺医药科技有限公司 Dérivé cyclique hétéroaryle à cinq chaînons, composition pharmaceutique le contenant et utilisations associées
CN110066236A (zh) * 2018-01-24 2019-07-30 上海迪诺医药科技有限公司 1h-吡咯衍生物、其制备方法、药物组合物及应用
CN110066271A (zh) * 2018-01-23 2019-07-30 上海迪诺医药科技有限公司 吡咯衍生物、其制备方法、药物组合物及应用
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109956929B (zh) * 2017-12-22 2023-09-19 上海迪诺医药科技有限公司 杂环衍生物、其制备方法、药物组合物及应用
CN110156656B (zh) * 2018-02-13 2023-04-07 上海迪诺医药科技有限公司 五元杂芳环衍生物、其制备方法、药物组合物及应用
CN109705109A (zh) * 2019-01-23 2019-05-03 东北农业大学 一种除草剂及其用途
CN111153846B (zh) * 2020-01-17 2021-08-31 中国药科大学 吡咯类化合物、其制备方法和药物组合物与用途
EP4110758A1 (fr) * 2020-02-25 2023-01-04 Tes Pharma S.r.l. Composés hétérocycliques pour la modulation de nr2f6
CN114344291B (zh) * 2022-02-16 2023-09-29 中南大学湘雅医院 4-苯基-1h-吡咯-3-羧酸在制备治疗骨质疏松药物中的应用、脂质体
CN118221635A (zh) * 2024-03-21 2024-06-21 沈阳药科大学 芳基噻吩类化合物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011005052A2 (fr) * 2009-07-10 2011-01-13 Green Gross Corporation Nouveaux dérivés imidazole-4-carboxamide contenant de l’arylpipérazine et composition pharmaceutique contenant ces dérivés
WO2016073774A2 (fr) * 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Agents immunorégulateurs

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200303304A (en) * 2002-02-18 2003-09-01 Astrazeneca Ab Chemical compounds
KR101152658B1 (ko) * 2009-04-30 2012-06-18 한국과학기술연구원 세로토닌 5-ｈｔ6 길항 활성 효과를 갖는 피페라진 화합물 함유 조성물
UY36390A (es) * 2014-11-05 2016-06-01 Flexus Biosciences Inc Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen
BR112017008809A2 (pt) * 2014-11-05 2017-12-19 Flexus Biosciences Inc agentes imunorreguladores

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011005052A2 (fr) * 2009-07-10 2011-01-13 Green Gross Corporation Nouveaux dérivés imidazole-4-carboxamide contenant de l’arylpipérazine et composition pharmaceutique contenant ces dérivés
WO2016073774A2 (fr) * 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Agents immunorégulateurs

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 14 April 2014, Columbus, Ohio, US; abstract no. RN1584366-54-0 *
CHEMICAL ABSTRACTS, 30 April 2014, Columbus, Ohio, US; abstract no. RN1593550-87-8 *
CHEMICAL ABSTRACTS, 30 April 2014, Columbus, Ohio, US; abstract no. RN1594335-16-6, "RN1594335-16-6" *
SEO, H.J. ET AL.: "Design and Synthesis of Novel Arylpiperazine Derivatives Containing the Imidazole Core Targeting 5-HT2A Receptor and 5-HT Transporter", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, 8 August 2011 (2011-08-08), pages 6305 - 6318, XP055461002 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
WO2019120256A1 (fr) * 2017-12-22 2019-06-27 上海迪诺医药科技有限公司 Dérivé cyclique hétéroaryle à cinq chaînons, composition pharmaceutique le contenant et utilisations associées
CN110066271A (zh) * 2018-01-23 2019-07-30 上海迪诺医药科技有限公司 吡咯衍生物、其制备方法、药物组合物及应用
CN110066271B (zh) * 2018-01-23 2023-04-07 上海迪诺医药科技有限公司 吡咯衍生物、其制备方法、药物组合物及应用
CN110066236A (zh) * 2018-01-24 2019-07-30 上海迪诺医药科技有限公司 1h-吡咯衍生物、其制备方法、药物组合物及应用
CN110066236B (zh) * 2018-01-24 2023-03-24 上海迪诺医药科技有限公司 1h-吡咯衍生物、其制备方法、药物组合物及应用
US12049466B2 (en) 2018-05-17 2024-07-30 Forma Therapeutics, Inc. Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors
US11535618B2 (en) 2018-10-05 2022-12-27 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11814386B2 (en) 2018-10-05 2023-11-14 Forma Therapeutics, Inc. Fused pyrrolines which act as ubiquitin-specific protease 30 (USP30) inhibitors
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

Also Published As

Publication number Publication date
CN107674013A (zh) 2018-02-09
CN107674013B (zh) 2022-05-24

Similar Documents

Publication Publication Date Title
CN107674013B (zh) 多环化合物、其制备方法、药物组合物及应用
JP7451765B2 (ja) Ｃｄｋ阻害剤としてのピリジンアセトアミド系誘導体、その調製方法及び用途
CN105884780B (zh) 多环化合物、其药物组合物及应用
TWI771630B (zh) 溴結構域(bromodomain)抑制劑
TWI865480B (zh) 抑制pge2/ep4信號傳導的化合物、其製備方法及其在醫藥上的應用
AU2016249273A1 (en) Bromodomain inhibitor
KR102345381B1 (ko) 키나제 억제제로서 유용한 카르바졸 카르복스아미드 화합물
KR102805503B1 (ko) Creb 결합 단백질(cbp)의 저해
EP3271361B1 (fr) Composés hétérocycliques tricycliques utiles comme inhibiteurs du tnf
CN107663159A (zh) 多环化合物、其药物组合物及应用
KR101760158B1 (ko) 축환 피리딘 화합물
CN109071548A (zh) 可用于治疗尤其是癌症的吡咯并咪唑衍生物或其类似物
WO2024114787A1 (fr) Composé amide ou urée
CN107207486A (zh) 用于抑制布罗莫结构域和末端外蛋白质的方法和组合
JP6859358B2 (ja) テトラヒドロインダゾール及びその医学的使用
CN110156656A (zh) 五元杂芳环衍生物、其制备方法、药物组合物及应用
CN113490668A (zh) 用于治疗与apj受体活性有关的疾病的化合物和组合物
JP2025508475A (ja) プロスタグランジンｅ２（ｐｇｅ２）受容体拮抗剤としてのアミド化合物
AU2015247575B2 (en) Polycyclic hERG activators
JP7406008B2 (ja) Ｃｄｋ９阻害剤としての多環式アミド系誘導体、その調製方法及び用途
CN110066236B (zh) 1h-吡咯衍生物、其制备方法、药物组合物及应用
JP2021116240A (ja) （ヘテロ）アリールイミダゾロン化合物
CN110066271B (zh) 吡咯衍生物、其制备方法、药物组合物及应用
WO2019120256A1 (fr) Dérivé cyclique hétéroaryle à cinq chaînons, composition pharmaceutique le contenant et utilisations associées
CN117412981A (zh) 氧化膦衍生物及其制备方法和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17836370

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17836370

Country of ref document: EP

Kind code of ref document: A1