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WO2019120256A1 - Dérivé cyclique hétéroaryle à cinq chaînons, composition pharmaceutique le contenant et utilisations associées - Google Patents

Dérivé cyclique hétéroaryle à cinq chaînons, composition pharmaceutique le contenant et utilisations associées Download PDF

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Publication number
WO2019120256A1
WO2019120256A1 PCT/CN2018/122420 CN2018122420W WO2019120256A1 WO 2019120256 A1 WO2019120256 A1 WO 2019120256A1 CN 2018122420 W CN2018122420 W CN 2018122420W WO 2019120256 A1 WO2019120256 A1 WO 2019120256A1
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Prior art keywords
alkyl
group
compound
methyl
solvate
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English (en)
Chinese (zh)
Inventor
高大新
刘凤涛
李国成
郭洪利
杨伟
杨和平
王龙生
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Shanghai de Novo Pharmatech Co Ltd
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Shanghai de Novo Pharmatech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • 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
    • 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
    • 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
    • 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
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D247/00—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00
    • C07D247/02—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00 having the nitrogen atoms in positions 1 and 3
    • 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 five-membered heteroaryl ring derivative, a pharmaceutical composition thereof and use thereof.
  • 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 disorders or disorders such as depression (Protula et al, 2005, Blood, 106: 238290; Munn et al, 1998, Science 281: 11913).
  • 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 five-membered heteroaryl ring derivative, a pharmaceutical composition thereof and use thereof.
  • the five-membered heteroaryl ring derivative 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 five-membered heteroaryl ring derivative (I), an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • Cy is a pyrrole ring or an imidazole ring; when Cy is a pyrrole ring, X is NR, Y is CR 1 , Z is CR 2 , or X is CR 1 , Y is NR, Z is CR 2 '; When it is an imidazole ring, X is NR, Y is CR 1 , and Z is N;
  • A is ⁇ E.g ⁇ E.g ⁇ E.g ⁇ E.g ⁇ E.g
  • R is independently H, -C(O)N(R a ) 2 , -C(O)R a , -C(O)OR a , -S(O) 2 N(R a ) 2 , -S( O) 2 R a , C 1-6 alkyl ⁇ for example C 1-3 alkyl, for example methyl, ethyl, n-propyl or isopropyl, also for example methyl or isopropyl ⁇ , C 2- 6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl ⁇ eg C 3-5 cycloalkyl, again such as cyclopropyl, cyclobutyl or cyclopentyl, again such as cyclopropyl ⁇ , 3 -8 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, deuterated methyl (-CD 3 ) or 2-deuteropropene- 2-based ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 2 is independently hydrogen, deuterium, halogen ⁇ e.g., fluorine, chlorine, bromine or iodine, again such as bromine ⁇ , cyano, amido, ester, C 1-3 alkyl, C 3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; said phenyl or 5-6 membered heteroaryl is unsubstituted or optionally substituted with 1 to 3 groups at any position, Said group is one or more of hydrazine, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy and halogenated C 1-3 alkoxy;
  • halogen ⁇ e.g., fluorine, chlorine, bromine or iodine, again such as bromine ⁇ , cyano, amido, ester, C 1-3 alkyl, C 3-8 cycloalkyl, 3 -8 membered heterocycloalkyl,
  • R 2 ' is independently hydrogen, deuterium, halogen ⁇ eg fluorine, chlorine, bromine or iodine, again such as iodine ⁇ or C 1-3 alkyl ⁇ eg methyl, ethyl, n-propyl or isopropyl, for example methyl ⁇ ;
  • R 3 is independently
  • R 4 is independently methyl, cyano, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;
  • R 5 is independently hydrogen, deuterium, halogen ⁇ e.g., fluorine, chlorine, bromine or iodine, further such as fluorine ⁇ , amino, cyano, C 1-3 alkyl, C 1-3 alkoxy or halogen C 1- 3 alkoxy.
  • halogen e.g., fluorine, chlorine, bromine or iodine, further such as fluorine ⁇ , amino, cyano, C 1-3 alkyl, C 1-3 alkoxy or halogen C 1- 3 alkoxy.
  • the definition of the solvate can be as follows An undescribed group can be as described in any of the above schemes:
  • the solvate may be a hydrate and/or a methanolate, and may also be a hydrate or a water-methanol compound.
  • the molar ratio of the water to the five-membered heteroaryl ring derivative (I) may be from 1.0 to 1.5.
  • the molar ratio of the methanol to the five-membered heteroaromatic ring derivative (I) may be from 1.0 to 1.5.
  • the molar ratio of the water to the five-membered heteroaromatic ring derivative (I) may be from 1.0 to 1.5, and the methanol and the five-membered heteroaryl ring are The molar ratio of the derivative (I) may be from 1.0 to 1.5.
  • the molar ratio of the water to the five-membered heteroaryl ring derivative (I) may be 1.0, and the molar ratio of the methanol to the five-membered heteroaryl ring derivative (I) may be 1.0.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • Cy is a pyrrole ring.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • Cy is an imidazole ring.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R is independently H, C 1-6 alkyl or C 3-8 cycloalkyl; the C 1-6 alkyl or C 3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R is independently H.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R is independently C 1-6 alkyl or C 3-8 cycloalkyl; the C 1-6 alkyl or C 3-8 cycloalkyl is unsubstituted or alternatively substituted with one or more hydroxy groups Anywhere.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ .
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ .
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 1 is independently methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ .
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 1 is independently hydrogen, methyl, ethyl, propyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ .
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 1 is independently t-butyl.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 2 is independently hydrogen, deuterium, halogen or cyano.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 2 is independently hydrogen, deuterium or halogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 2 is independently hydrogen or deuterium.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 2 ' is independently hydrogen, deuterium or C 1-3 alkyl.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 3 is independently
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 3 is independently
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 4 is independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 4 is independently methoxy, trifluoromethoxy or difluoromethoxy.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 5 is independently hydrogen or halogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R 5 is independently hydrogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R is independently H, C 1-6 alkyl or C 3-8 cycloalkyl; the C 1-6 alkyl or C 3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 2 is independently hydrogen, deuterium, halogen or cyano
  • R 2 ' is independently hydrogen, deuterium, halogen or C 1-3 alkyl
  • R 3 is independently
  • R 4 is independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;
  • R 5 is independently hydrogen or halogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • Cy is a pyrrole ring
  • R is independently H
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 2 is independently hydrogen, deuterium, halogen or cyano
  • R 2 ' is independently hydrogen, deuterium, halogen or C 1-3 alkyl
  • R 3 is independently
  • R 4 is independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;
  • R 5 is independently hydrogen or halogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • Cy is a pyrrole ring
  • R is independently H
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 2 is independently hydrogen, deuterium or halogen
  • R 2 ' is independently hydrogen, deuterium, halogen or C 1-3 alkyl
  • R 3 is independently
  • R 4 is independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;
  • R 5 is independently hydrogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • Cy is a pyrrole ring
  • R is independently H
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 2 is independently hydrogen, deuterium or halogen
  • R 2 ' is independently hydrogen, deuterium, halogen or C 1-3 alkyl
  • R 3 is independently
  • R 4 is independently methoxy, trifluoromethoxy or difluoromethoxy
  • R 5 is independently hydrogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • Cy is a pyrrole ring, X is NR, Y is CR 1 , and Z is CR 2 ;
  • R is independently H
  • R 1 is independently methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 2 is independently hydrogen or deuterium
  • R 3 is independently
  • R 4 is independently methoxy, trifluoromethoxy or difluoromethoxy
  • R 5 is independently hydrogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • Cy is a pyrrole ring, X is CR 1 , Y is NR, and Z is CR 2 ';
  • R is independently H
  • R 1 is independently hydrogen, methyl, ethyl, propyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 2 ' is independently hydrogen, deuterium, halogen or C 1-3 alkyl
  • R 3 is independently
  • R 4 is independently methoxy, trifluoromethoxy or difluoromethoxy
  • R 5 is independently hydrogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • Cy is an imidazole ring
  • R is independently H, C 1-6 alkyl or C 3-8 cycloalkyl; the C 1-6 alkyl or C 3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 3 is independently
  • R 4 is independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;
  • R 5 is independently hydrogen or halogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R is independently C 1-6 alkyl or C 3-8 cycloalkyl; the C 1-6 alkyl or C 3-8 cycloalkyl is unsubstituted or alternatively substituted with one or more hydroxy groups Any position;
  • R 1 is independently hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ;
  • R 2 is independently hydrogen, deuterium, halogen or cyano
  • R 2 ' is independently hydrogen, deuterium, halogen or C 1-3 alkyl
  • R 3 is independently
  • R 4 is independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;
  • R 5 is independently hydrogen or halogen.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • R is independently H, C 1-6 alkyl or C 3-8 cycloalkyl; the C 1-6 alkyl or C 3-8 cycloalkyl is unsubstituted or optionally substituted by one or more hydroxy groups Replace at any position;
  • R 1 is independently t-butyl
  • R 2 is independently hydrogen, deuterium, halogen or cyano
  • R 2 ' is independently hydrogen, deuterium, halogen or C 1-3 alkyl
  • R 3 is independently
  • R 4 is independently methyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy;
  • R 5 is independently hydrogen or halogen.
  • Cy is a pyrrole ring
  • X is NH
  • Y is CR 1
  • Z is CR 2 .
  • Cy is a pyrrole ring
  • X is CR 1
  • Y is NH
  • Z is CR 2 .
  • R 1 is methyl, ethyl, propyl, isopropyl, deuterated methyl (-CD 3 ) or 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ .
  • R 1 is t-butyl
  • R 1 is trifluoromethyl or difluoromethyl.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • the present invention provides a five-membered heteroaryl ring derivative (II), an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • Z is N or CR 2 ;
  • R is H, -C(O)N(R a ) 2 , -C(O)R a , -C(O)OR a , -S(O) 2 N(R a ) 2 , -S(O) 2 R a , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5 a 6-membered heteroaryl group; the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group or 3-8 membered heterocycloalkyl group is unsubstituted or Optionally substituted at any position by one or more groups selected from the group consisting of: hydrazine, halogen, hydroxy, thiol, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, C
  • R 1 is methyl, ethyl, propyl, isopropyl, tert-butyl, deuterated methyl (-CD 3 ), 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ; , R 1 is a trifluoromethyl group, or a difluoromethyl group;
  • R 2 is hydrogen, deuterium, halogen, cyano, amide, ester, C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted or optionally substituted with 1 to 3 groups at any position, the group being an anthracene, a halogen, an amino group, a cyano group, C One or more of 1-3 alkyl, C 1-3 alkoxy and halogenated C 1-3 alkoxy;
  • R 4 is methyl, cyano, methoxy, ethoxy, trifluoromethoxy, or difluoromethoxy;
  • R 5 is hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • said Z is N.
  • said Z is CR 2 .
  • said R is H.
  • R is a substituted or unsubstituted methyl group.
  • R is a substituted or unsubstituted ethyl group.
  • R is substituted or unsubstituted isopropyl.
  • R is a substituted or unsubstituted cyclopropyl group.
  • R is a substituted or unsubstituted tert-butyl group.
  • the five-membered heteroaryl ring derivative (III), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, has a structural formula The best place is:
  • A is Or
  • A is Or
  • A is
  • R 1 is methyl, ethyl or isopropyl; or, R 1 is propyl, trifluoromethyl, difluoromethyl; or R 1 is deuterated methyl (-CD 3 ); or, R 1 Is 2-deutero-2-yl ⁇ -CD(CH 3 ) 2 ⁇ ; or, R 1 is a tert-butyl group;
  • R 2 is hydrogen, deuterium, halogen, cyano, amide, ester, C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C 1-3 alkyl, C 1- a substituent of a 3 -alkoxy group or a halogenated C 1-3 alkoxy group at any position;
  • R 4 is methyl, methoxy, cyano or trifluoromethoxy; or R 4 is ethoxy or difluoromethoxy;
  • R 5 is hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • the A is Wherein R 4 and R 5 are as defined above.
  • the A is Wherein R 4 and R 5 are as defined above.
  • the A is Wherein R 4 and R 5 are as defined above.
  • the A is Among them, the definition of R 4 is as described above.
  • the A is Among them, the definition of R 4 is as described above.
  • the A is Among them, the definition of R 4 is as described above.
  • the A is Among them, the definition of R 4 is as described above.
  • the A is Among them, the definition of R 4 is as described above.
  • R 1 is methyl
  • R 1 is ethyl
  • R 1 is isopropyl.
  • R 1 is t-butyl
  • said R 2 is hydrogen
  • said R 2 is deuterium.
  • said R 2 is chloro
  • said R 2 is bromine.
  • said R 2 is iodine.
  • said R 2 is cyano
  • said R 2 is methyl.
  • said R 4 is methyl.
  • R 4 is methoxy
  • said R 4 is difluoromethoxy.
  • said R 4 is trifluoromethoxy.
  • R 4 is cyano
  • said R 5 is hydrogen
  • said R 5 is fluoro
  • said R 5 is chloro
  • said R 5 is bromo
  • R 5 is cyano
  • R 5 is amino
  • said R 5 is methyl.
  • said R 5 is methoxy
  • R 5 is trifluoromethoxy
  • A, R, R 1 and R 2 are as defined above.
  • A, R and R 1 are as defined above.
  • A, Z, R, R 1 and R3 are as defined above.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, has a structural formula The best place is:
  • A, R 1 and R 2 are as defined above.
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention provides a five-membered heteroaryl ring derivative (IV), an isomer, a solvate thereof, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • R is H, -C(O)N(R a ) 2 , -C(O)R a , -C(O)OR a , -S(O) 2 N(R a ) 2 , -S(O) 2 R a , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or a 5-6 membered heteroaryl group; said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group, or 3-8 membered heterocycloalkyl group; Substituted or selectively 1 to 3 are selected from the group consisting of: hydrazine, halogen, hydroxy, decyl, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyla
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, deuterated methyl, or 2-deutero-2-yl;
  • R 2 ' is hydrogen, deuterium, halogen, or C 1-3 alkyl
  • R 4 is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;
  • R 5 is hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • said R is H.
  • R is a substituted or unsubstituted methyl group.
  • R is a substituted or unsubstituted ethyl group.
  • R is substituted or unsubstituted isopropyl.
  • R is a substituted or unsubstituted cyclopropyl group.
  • R is a substituted or unsubstituted tert-butyl group.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, has a structural formula The best place is:
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, deuterated methyl (-CD 3 ), or 2-deutero-2-yl ⁇ - CD(CH 3 ) 2 ⁇ ; or, R 1 is a tert-butyl group;
  • R 2 ' is hydrogen, deuterium, halogen, or C 1-3 alkyl
  • R 4 is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;
  • R 5 is hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • the A is Wherein R 4 and R 5 are as defined above.
  • the A is Among them, the definition of R 4 is as described above.
  • the A is Among them, the definition of R 4 is as described above.
  • the A is Among them, the definition of R 4 is as described above.
  • the A is Among them, the definition of R 4 is as described above.
  • R 1 is methyl
  • R 1 is isopropyl.
  • R 1 is deuterated methyl.
  • R 1 is 2-deutero-2-yl.
  • said R 2 ' is hydrogen.
  • said R 2 ' is deuterium.
  • said R 2 ' is chloro.
  • said R 2 ' is bromine.
  • said R 2 ' is iodine.
  • said R 2 ' is methyl.
  • said R 4 is methyl.
  • said R 4 is methoxy
  • said R 4 is difluoromethoxy.
  • said R 4 is trifluoromethoxy.
  • said R 4 is cyano
  • said R 5 is hydrogen
  • said R 5 is fluoro
  • said R 5 is chloro
  • said R 5 is bromo
  • R 5 is cyano
  • said R 5 is amino
  • said R 5 is methyl
  • said R 5 is methoxy
  • said R 5 is trifluoromethoxy.
  • the pyrrole derivative (I), an isomer thereof, a solvate, a crystal form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt preferably have a structural formula:
  • A, R, R 1 and R 2 ' are as defined above.
  • A, R, R 1 , R 2 ' and R 3 are as defined above.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, has a structural formula The best place is:
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 1 is methyl, isopropyl, deuterated methyl or 2-deutero-2-yl.
  • R 2 ' is H or D.
  • R 1 , R 2 ' and R 3 are as defined above.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 1 is methyl, isopropyl, deuterated methyl or 2-deutero-2-yl.
  • R 2 ' is H or D.
  • R 3 is
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • A is Or
  • A is Or
  • A is
  • R 1 is methyl, ethyl or isopropyl; or, R 1 is propyl, trifluoromethyl, difluoromethyl; or R 1 is deuterated methyl (-CD 3 );
  • R 2 is hydrogen, deuterium, halogen, cyano, amino, acyl, amide, ester, C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or a 5-6 membered heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C 1-3 alkyl , C 1-3 alkoxy, halo or a C 1-3 alkoxy group substituted at any position;
  • R 4 is methyl, methoxy, cyano or trifluoromethoxy; or R 4 is ethoxy or difluoromethoxy;
  • R 5 is hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • A is Or
  • A is Or
  • A is
  • R 1 is methyl, ethyl or isopropyl; or, R 1 is propyl, trifluoromethyl, difluoromethyl; or R 1 is deuterated methyl (-CD 3 ); or, R 1 Is 2-deutero-2-yl (-CD(CH 3 ) 2 );
  • R 2 is hydrogen, deuterium, halogen, cyano, amide, ester, C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C 1-3 alkyl, C 1- a substituent of a 3 -alkoxy group or a halogenated C 1-3 alkoxy group at any position;
  • R 4 is methyl, methoxy, cyano or trifluoromethoxy; or R 4 is ethoxy or difluoromethoxy;
  • R 5 is hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • A is Or
  • A is Or
  • A is
  • R 1 is methyl, ethyl or isopropyl; or, R 1 is propyl; or, R 1 is deuterated methyl (-CD 3 ); or R 1 is 2-deutero-2-yl (-CD(CH 3 ) 2 ); or, R 1 is a tert-butyl group;
  • R 2 is hydrogen, deuterium, halogen, cyano, amide, ester, C 1-3 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 a heteroaryl group; the phenyl group, or a 5-6 membered heteroaryl group, which is unsubstituted, or optionally 1 to 3, selected from the group consisting of hydrazine, halogen, amino, cyano, C 1-3 alkyl, C 1- a substituent of a 3 -alkoxy group or a halogenated C 1-3 alkoxy group at any position;
  • R 4 is methyl, methoxy, cyano or trifluoromethoxy; or R 4 is ethoxy or difluoromethoxy;
  • R 5 is hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative, or a pharmaceutically acceptable The definition of certain groups in the salt can be as follows, and the undescribed groups can be as described in any of the above schemes:
  • A is Or, A is
  • R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, deuterated methyl (-CD 3 ), or 2-deutero-2-yl ⁇ - CD(CH 3 ) 2 ⁇ ;
  • R 2 ' is hydrogen, deuterium, halogen, or C 1-3 alkyl
  • R 4 is methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy;
  • R 5 is hydrogen, deuterium, halogen, amino, cyano, C 1-3 alkyl, C 1-3 alkoxy, or halogenated C 1-3 alkoxy.
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) is preferably one of the following structures:
  • the heteroaromatic ring derivative (I) may be any of the following structures:
  • the heteroaromatic ring derivative (I) may be any of the following structures:
  • the solvate of the five-membered heteroaryl ring derivative (I) is any of the following structures:
  • the solvate of the five-membered heteroaryl ring derivative (I) may be the following compound:
  • the solvate of the five-membered heteroaryl ring derivative (I) may be the following compound:
  • the present invention also provides the five-membered heteroaryl ring derivative (II), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt.
  • the preparation method is any one of the following methods.
  • Method 1 in a solvent, a compound I-b and a compound X-1 are subjected to a condensation reaction under the action of a base;
  • A, Z, R, R 1 and R 3 are as defined above.
  • the conditions and steps of the condensation reaction may be the conditions and steps of the condensation reaction conventional in the art, and the present invention particularly preferably the following reaction conditions:
  • the solvent is preferably dichloromethane or N. N-dimethylformamide;
  • the solvent is preferably used in an amount of 5 to 20 mL / mmol of the compound Ib;
  • the base is preferably N, N-diisopropylethylamine, N-methylmorpholine or triethylamine;
  • the molar ratio of the base to the compound Ib is preferably 1:1 to 5:1; to accelerate the reaction rate, a catalytic amount of 4-dimethylaminopyridine, the 4-dimethylaminopyridine and the 4-dimethylaminopyridine may be added to the reaction system.
  • the molar ratio of the compound Ib is preferably from 0.05:1 to 0.2:1.
  • the condensing agent in the condensation reaction is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N'-diisopropylcarbodiimide (DIC), more preferably EDCI
  • the molar ratio of the condensing agent to the compound Ib is preferably 1:1 to 3:1; the temperature of the reaction is preferably 0 to 30 ° C
  • the reaction can be detected by TLC, generally as the end point of the reaction when the compound Ib disappears, preferably 0.5 to 24 hours; after the end of the reaction, the product can be further purified by post-treatment, preferably including the following steps: After quenching with ice water, the reaction system is diluted with a solvent, the organic phase is separated, the organic phase is dried, the organic solvent is removed under
  • the preparation method of the compound I-b can be a conventional method for such a reaction in the art, and preferably includes the following steps: deprotecting the compound I-a in a solvent;
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl group or an ethyl group; and A, R, R 1 and Z are as defined above.
  • the deprotection of Compound I-a can be carried out under acidic or basic conditions.
  • the acidic conditions are preferably a hydrochloric acid/alcohol system or a hydrogen chloride/alcohol system, preferably methanol or ethanol.
  • the solvent may be a solvent commonly used in such reactions in the art, preferably ethanol, methanol, tetrahydrofuran, water, or a mixed solvent of any two to four kinds of ethanol, methanol, tetrahydrofuran and water, more preferably ethanol.
  • Water mixed solvent wherein the volume ratio of ethanol to water is preferably 1:0.5 to 2:1.
  • the amount of the solvent generally does not affect the progress of the reaction, and preferably 5 to 15 mL/mmol of the compound I-a.
  • the base is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, more preferably sodium hydroxide, and the molar ratio of the base to the compound Ia is preferably from 2:1 to 10:1, and the base is usually used.
  • An aqueous solution of a base is prepared by first dissolving in water in a mixture solvent.
  • the temperature of the deprotection reaction is preferably 20 to 100 ° C, more preferably 60 to 100 ° C, still more preferably 80 to 100 ° C.
  • the progress of the reaction can be detected by TLC, and is generally the end point of the reaction when the compound I-a disappears, preferably 10 minutes to 2 hours.
  • the product may be further purified by post-treatment, preferably including the following steps: after removing the organic solvent under reduced pressure, the residue is sufficiently acidified, the obtained solid is filtered, and the filter cake is dried in vacuo to give compound I-b.
  • Method 2 performing amine transesterification of compound I-a and compound X-1 under the action of trimethylaluminum in a solvent;
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl group or an ethyl group; and A, R, R 1 and Z are as defined above.
  • the conditions and steps of the condensation reaction may be the conditions and steps of the conventional amine transesterification reaction in the art, and the present invention particularly preferably the following reaction conditions:
  • the solvent is preferably toluene,
  • the solvent is preferably used in an amount of 5 to 20 mL/mmol of compound Ia;
  • the molar ratio of trimethylaluminum to compound X-1 is preferably 2:1 to 3:1.
  • the molar ratio of the compound X-1 to the compound Ia is preferably 1:1 to 3:1; the temperature of the reaction is preferably room temperature to solvent reflux; the temperature of the reaction is more preferably 90 to 110 ° C; the reaction can be passed
  • the TLC is detected, generally as the end point of the reaction when the compound Ia disappears, preferably 1 to 24 hours; after the end of the reaction, the product may be further purified by post-treatment, the purification method includes silica gel column chromatography, flash column layer Purification by precipitation or prep-HPLC.
  • the steps and conditions for the silica gel column chromatography, flash column chromatography or prep-HPLC purification may be the steps and conditions conventionally purified in the art.
  • Compound I-a can be synthesized by the methods shown in Reaction Schemes 4 to 8, and Compound 1-b can also be synthesized by the method shown in Reaction Scheme 6:
  • Pg is a carboxy protecting group, preferably a C 1 - 6 alkyl, more preferably methyl or ethyl;
  • a and R 1 are defined as described above in.
  • Step 1 Solvent (preferably tetrahydrofuran), Compound I-a-2 is reacted with Y-3 in the presence of a base (preferably sodium hydrogen) to give Compound 1-a-3.
  • Step 2 In a solvent (preferably ethanol), the compound I-a-3 and ammonium acetate are heated under reflux and stirred for 2 to 4 hours, and after workup, the compound I-a (H/NH) is obtained.
  • solvent preferably ethanol
  • Pg is a carboxy protecting group, preferably a C 1 - 6 alkyl, more preferably methyl or ethyl;
  • R 1 (D) is a deuterated or 2- deutero-2-yl, A, and
  • the definition of R 1 is as described above.
  • Step 1 Compound I-a-3 and ammonium acetate are heated under reflux in deuterated methanol for 2 to 4 hours, and post-treated to give compound I-a (D/D).
  • Step 2 I-a (D/D) was stirred at room temperature for 1 to 3 hours in a trifluoroacetic acid / dichloromethane system to afford compound I-a (H/D).
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl group or an ethyl group; and A and R 1 are as defined above.
  • Step 1 Solvent (preferably tetrahydrofuran), Compound Ia (H/NH) or Ib (H/NH) is reacted with N-bromosuccinimide to obtain a compound.
  • Step 2 Condition (1), the compound obtained in Step 1 and cuprous cyanide are reacted in N,N-dicarboximide to obtain Compound Ia(CN) or Ib(CN); or Condition (2), Step 1 The obtained compound is reacted with a deuterated carboxylic acid/triethylamine/tetratriphenylphosphine palladium system or a heavy water/cerium carbonate/tetratriphenylphosphine palladium system in a deuterated dimethyl sulfoxide solution to obtain a compound Ia(D) or Ib. (D).
  • Pg is a carboxy protecting group, preferably a C 1 - 6 alkyl, more preferably methyl or ethyl;
  • a and R 1 are defined as described above in.
  • Step 1 Compound I-a-2 and pyridine are reacted with Dess-Martin oxidizing agent to obtain Compound I-a-4 in a solvent (preferably dichloromethane).
  • Step 2 The reaction of the solvent (preferably acetic acid), 1-a-4, ammonium acetate and Y-4 under microwave heating gives compound I-a (N/NH).
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl or ethyl group;
  • L is a bromine, iodine, boric acid or boronic acid ester;
  • R is a C 1-6 alkyl group;
  • the present invention also provides the five-membered heteroaryl ring derivative (IV), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt.
  • the preparation method is any one of the following methods.
  • Method 1 in a solvent, a compound II-b and a compound X-1 are subjected to a condensation reaction under the action of a base;
  • R 1 , R 2 and R 3 are as defined above.
  • the conditions and steps of the condensation reaction may be the conditions and steps of the condensation reaction conventional in the art, and the present invention particularly preferably the following reaction conditions:
  • the solvent is preferably dichloromethane or N. N-dimethylformamide;
  • the solvent is preferably used in an amount of 5 to 20 mL/mmol of compound II-b;
  • the base is preferably N,N-diisopropylethylamine, N-methylmorpholine or triethylamine
  • the molar ratio of the base to the compound II-b is preferably 1:1 to 5:1; to accelerate the reaction rate, a catalytic amount of 4-dimethylaminopyridine may also be added to the reaction system, the 4-di
  • the molar ratio of methylaminopyridine to compound II-b is preferably from 0.05:1 to 0.2:1.
  • the condensing agent in the condensation reaction is preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N'-diisopropylcarbodiimide (DIC), more preferably EDCI, the molar ratio of the condensing agent to the compound II-b is preferably 1:1 to 3:1; the temperature of the reaction is preferably 0 to 30 ° C; the reaction can be detected by TLC, generally as the end of the reaction when the compound II-b disappears, preferably 0.5 to 24 hours; after the end of the reaction, the product can be further purified by post-treatment, preferably including The following steps: the reaction system is quenched with ice water, diluted with a solvent, the organic phase is separated, the organic phase is dried, the organic solvent is removed under reduced pressure, and the residue is purified by conventional purification means, for example, silica gel column chromatography,
  • the preparation method of the compound II-b can be a conventional method of such a reaction in the art, and preferably comprises the steps of: deprotecting the compound II-a in a solvent;
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl group or an ethyl group; and A, R 1 and R 2 are as defined above.
  • the deprotection of the compound II-a can be carried out under acidic or basic conditions.
  • the acidic conditions are preferably a hydrochloric acid/alcohol system, a hydrogen chloride/alcohol system or a trifluoroacetic acid/dichloromethane system, preferably methanol or ethanol.
  • the solvent may be a solvent commonly used in such reactions in the art, preferably ethanol, methanol, tetrahydrofuran, water, or a mixed solvent of any two to four kinds of ethanol, methanol, tetrahydrofuran and water, more preferably ethanol.
  • the volume ratio of ethanol to water is preferably 1:0.5 to 2:1.
  • the amount of the solvent generally does not affect the progress of the reaction, and preferably 5 to 15 mL/mmol of the compound II-a.
  • the base is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, more preferably sodium hydroxide, and the molar ratio of the base to the compound II-a is preferably from 2:1 to 10:1, usually under normal conditions.
  • An aqueous solution of a base is prepared by dissolving a base in water in a solvent of the mixture.
  • the temperature of the deprotection reaction is preferably 20 to 100 ° C, more preferably 60 to 100 ° C, still more preferably 80 to 100 ° C.
  • the progress of the reaction can be detected by TLC, and is generally used as the end point of the reaction when the compound II-a disappears, preferably 10 minutes to 2 hours.
  • the product may be further purified by post-treatment, preferably including the following steps: after removing the organic solvent under reduced pressure, the residue is sufficiently acidified, the obtained solid is filtered, and the filter cake is dried in vacuo to obtain compound II- b.
  • Method 2 performing amine transesterification of compound II-a and compound X-1 under the action of trimethylaluminum in a solvent;
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl group or an ethyl group; and A, R 1 , R 2 and R 3 are as defined above.
  • the conditions and steps of the condensation reaction may be the conditions and steps of the conventional amine transesterification reaction in the art, and the present invention particularly preferably the following reaction conditions:
  • the solvent is preferably toluene,
  • the solvent is preferably used in an amount of 5 to 20 mL/mmol of compound II-a;
  • the molar ratio of trimethylaluminum to compound X-1 is preferably 2:1 to 3:1.
  • the molar ratio of the compound X-1 to the compound II-a is preferably 1:1 to 3:1; the temperature of the reaction is preferably room temperature to solvent reflux; the temperature of the reaction is more preferably 90 to 110 ° C;
  • the product can be detected by TLC, generally as the end point of the reaction when the compound II-a disappears, preferably 1 to 24 hours; after the end of the reaction, the product can be further purified by post-treatment, the purification method includes silica gel column chromatography. , Flash column chromatography or prep-HPLC purification.
  • the steps and conditions for the silica gel column chromatography, flash column chromatography or prep-HPLC purification may be the steps and conditions conventionally purified in the art.
  • Pg is a carboxy protecting group, preferably a C 1 - 6 alkyl, more preferably methyl or ethyl; defined as above A, R and R 1 are the.
  • the following conditions are preferably employed, in which a compound II-a-3 and a compound Y-5 or Y-6 are obtained by a suzuki coupling reaction in a solvent (preferably a mixed solvent of dioxane and water).
  • a solvent preferably a mixed solvent of dioxane and water.
  • Compound II-a (H/H) the suzuki coupling reaction conditions are conventional conditions in the art, wherein the catalyst is preferably tetrakistriphenylphosphine palladium.
  • Compound II-a-3 can be synthesized by the method shown in Reaction Scheme 13:
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl group or an ethyl group; and R 1 is a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • Step 1 Solvent (preferably tetrahydrofuran), Compound II-a-1 in the presence of a base (preferably sodium ethoxide and diisopropylethylamine) and Y-7 The reaction gives the compound II-a-2.
  • Step 2 In a solvent (preferably a mixed solvent of methyl tert-butyl ether and dichloromethane), the compound II-a-2 is reacted with hydrobromic acid to give a compound II-a-3 after workup.
  • solvent preferably a mixed solvent of methyl tert-butyl ether and dichloromethane
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl, ethyl or t-butyl group;
  • R 1 is hydrogen, methyl, deuterated methyl, ethyl or isopropyl .
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl group or an ethyl group; and A and R 1 are as defined above.
  • Step 1 Solvent (preferably tetrahydrofuran), Compound II-a (H) or II-b (H) is reacted with N-bromosuccinimide to obtain a compound. II-a (Br) or II-b (Br), or reacted with N-iodosuccinimide to give compound II-a (I) or II-b (I), or with N-chlorobutane
  • the imide reaction gives compound II-a (Cl) or II-b (Cl).
  • Step 2 Compound II-a (Br or I) or II-b (Br or I) obtained in the previous step in deuterated dimethyl sulfoxide solution and deuterated formic acid / triethylamine / tetratriphenylphosphine palladium system Or heavy water / cesium carbonate / tetratriphenylphosphine palladium system reaction to give compound II-a (D) or II-b (D).
  • Pg is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl or ethyl group; and X is iodine or bromine;
  • the compound II-a (H/H) is subjected to a nucleophilic substitution reaction under a base to obtain a compound II-a (H) in a solvent (preferably acetone).
  • a nucleophilic substitution reaction is conventional conditions in the art, and the base is preferably potassium carbonate or cesium carbonate.
  • R 1 is methyl, ethyl, propyl or isopropyl; and A and R 3 are as defined above.
  • the conditions and steps of the deuteration reaction may be the conditions and steps of the deuteration reaction conventional in the art, and the present invention particularly preferably the following reaction conditions: the solvent is preferably deuterated two Sulfuric acid, the solvent is preferably used in an amount of 10 to 50 mL / mmol of compound IV (Br) or VI (I); the reaction is preferably the following reaction system: deuterated formic acid / triethylamine / tetratriphenylphosphine palladium system or Heavy water / cesium carbonate / tetratriphenylphosphine palladium system; the reaction temperature is preferably 100 ⁇ 130 ° C; the reaction can be detected by TLC, generally as the end of the reaction when the compound IV (Br) or IV (I) disappears Preferably, after 1 to 24 hours; after the end of the reaction, the product may be further purified by post-treatment, which comprises silica gel column chromatography, flash column chromatography
  • the pharmaceutically acceptable salt of the five-membered heteroaryl ring derivative (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 adjuvant; the active ingredient comprising the above-mentioned five-membered heteroaryl ring derivative (I), and isomer thereof Form, solvate, crystalline form of the solvate, prodrug, stable isotope derivative or 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 five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the use of the pharmaceutical composition in the preparation of a guanamine 2,3-dioxygenase inhibitor (IDO1 inhibitor).
  • IDO1 inhibitor refers to inhibition of IDO1 activity or expression (including abnormal activity or overexpression of IDO1, and abnormal activity of IDO pathway), and reverses IDO1 - a compound that mediates immunosuppression.
  • the IDO1 inhibitor can inhibit IDO1.
  • the present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the use of the pharmaceutical composition in the preparation of a medicament.
  • the present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the use of the pharmaceutical composition for the preparation of a medicament for stimulating T cell proliferation.
  • the present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the pharmaceutical composition is formulated to treat, alleviate and/or prevent "viral or other infections (eg, skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.), cancer, or autoimmune diseases (" For example: the application of drugs such as rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).
  • the five-membered heteroaryl ring derivative and/or pharmaceutically acceptable salt of the formula (I) as described in any of the embodiments described in the present invention, or the pharmaceutical composition is prepared for treatment and amelioration And/or use in a medicament for preventing a disease associated with IDO1, the use comprising administering to the individual (e.g., a patient) a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
  • the IDO1 mediated related disease means that any disease, condition or disorder can be treated, alleviated and/or prevented with an IDO1 inhibitor.
  • diseases caused by IDO1 mediated immunosuppression including but not limited to: viruses or other infections (eg, skin infections, gastrointestinal infections, genitourinary infections, systemic infections, etc.) ), cancer, or autoimmune diseases (eg rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).
  • viruses or other infections 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 present invention also provides the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate, a solvate crystal form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, Or the use of the pharmaceutical composition for the preparation of a medicament for the treatment, amelioration and/or prevention of a related disease mediated by indoleamine 2,3-dioxygenase.
  • the use comprises administering to the individual (e.g., a patient) a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
  • Therapeutic agents can also be used in combination with one or more other therapeutic agents and/or therapeutic methods for treating cancer for the treatment, alleviation and/or prevention of guanamine 2,3-dioxygenase-mediated correlation. disease.
  • 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 invention also provides a method of treating, ameliorating and/or preventing a related disease mediated by indoleamine 2,3-dioxygenase, comprising administering to a subject a therapeutically required amount of said five-membered heteroaryl ring Derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition.
  • a method of treating, ameliorating and/or preventing a related disease mediated by indoleamine 2,3-dioxygenase comprising administering to a subject a therapeutically required amount of said five-membered heteroaryl ring Derivative (I), an isomer thereof, a solvate, a crystalline form of a solvate, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition.
  • Therapeutic agents can also be used in combination with one or more other therapeutic agents and/or therapeutic methods for treating cancer for the treatment, alleviation and/or prevention of guanamine 2,3-dioxygenase-mediated correlation. disease.
  • 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 invention also provides a method of treating, ameliorating and/or preventing a viral or other infection, cancer, or autoimmune disease comprising administering to a subject a therapeutically required amount of the five-membered heteroaryl ring derivative (I) a form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, an isomer, a solvate thereof, a solvate, or the pharmaceutical composition.
  • a method of treating, ameliorating and/or preventing a viral or other infection, cancer, or autoimmune disease comprising administering to a subject a therapeutically required amount of the five-membered heteroaryl ring derivative (I) a form, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, an isomer, a solvate thereof, a solvate, or the pharmaceutical composition.
  • Therapeutic agents can also be used in combination with one or more other therapeutic agents and/or therapeutic methods for treating cancer for the treatment, alleviation and/or prevention of guanamine 2,3-dioxygenase-mediated correlation. disease.
  • the other kind of therapeutic agent for treating cancer may be a single-administered therapeutic dosage form with the five-membered heteroaryl ring derivative (I) or a therapeutic dosage form administered sequentially.
  • 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), PD-L2, LAG3, TIM1, TIM3, TIM4, CD73, Galectin9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA , one or more of 2B4, CD48, GARP, PD1H, and LAIR1; 2) Protein agonists that stimulate T cell activity: B7-1, B7-2, CD28, ICOS, ICOS-L, GITR, GITRL, CD70 One or more of DR3, CD28H, GITR, OX
  • 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 B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) ), infections caused by viruses such as poliovirus, varicella-zoster virus, coxsackie virus, or human immunodeficiency virus (HIV).
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • HPV human papillomavirus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • viruses such as poliovirus, varicella-zoster virus, coxsackie virus, or human immunodeficiency virus (HIV).
  • the cancer can include a solid tumor or a liquid tumor.
  • the solid tumor can include, but is not limited to, the eye, bone, lung, stomach, pancreas, breast, prostate, brain (including glioblastoma and medulloblastoma), ovaries (including those from Stromal cells produced by epithelial cells, germ cells and interstitial cells), bladder, testis, spinal cord, kidney (including adenocarcinoma, nephroblastoma), mouth, lips, throat, oral cavity (including squamous cell carcinoma), nasal cavity, Small intestine, colon, rectum, parathyroid gland, gallbladder, bile duct, cervix, heart, inferior gland, bronchus, liver, ureter, vagina, anus, larynx, thyroid (including thyroid cancer and medullary carcinoma), esophagus, nasopharynx Pituitary, salivary gland, adrenal gland, intraepithelial neoplasia of the head and neck (including Bowen's disease and Page
  • the liquid tumor can include, but is not limited to, lymphoid tissue (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, and lymphocytes). Lymphoma, T-cell and B-cell chronic lymphocytic leukemia), chronic lymphocytic leukemia, myeloid leukemia and AIDS-related leukemia and other related tumors.
  • lymphoid tissue including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, and lymphocytes.
  • Lymphoma T-cell and B-cell chronic lymphocytic leukemia
  • chronic lymphocytic leukemia myeloid leukemia
  • AIDS-related leukemia and other related tumors other related tumors.
  • 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 Pontic 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 crystalline form, a prodrug, a stable isotopic derivative or a pharmaceutically acceptable form of the five-membered heteroaryl ring derivative (I), an isomer thereof, a solvate or a solvate thereof.
  • a method of inhibiting tryptophan degradation in a pharmaceutical composition comprising the steps of inhibiting degradation of tryptophan in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I)
  • the system is a tissue, mammal or cell tissue that expresses IDO.
  • Said mammal preferably a human.
  • 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.
  • substituted at one position by one or more groups is preferably “substituted at any position by 1 to 4 groups", more preferably “substituted at any position by 1 to 3 groups”; for example: Substitution at any position by 1 to 3 groups 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 hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6, from 1 to 5, from 1-4, from 1-3, or 1 to 2 carbon atoms
  • representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl , hexyl, heptyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, and various isomers thereof.
  • alkylene refers to an alkyl group which may be attached as a linking bond to two other groups, which may be either straight-chain or branched.
  • cycloalkyl refers to a monocyclic or polycyclic group containing from 3 to 20 carbon atoms which is saturated or partially unsaturated (comprising 1 or 2 double bonds).
  • a 3-10 membered monocycloalkyl group is preferred, and a 3-8 membered monocycloalkyl group is more preferred, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, Cyclododecyl, cyclohexenyl.
  • the 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.
  • heterocycloalkyl group is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • monocyclic heterocycloalkyl group preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • the heterocycloalkyl group can be attached to the parent molecule through any ring atom on the ring.
  • 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.
  • 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.
  • aryl refers to any stable 6-20 membered monocyclic or polycyclic aromatic group, preferably a C6-10 aryl group; for example: phenyl, naphthyl, and the like.
  • the aryl group is unsubstituted or alternatively selected from 1 to 3 selected from the group consisting of hydrazine, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, cyano, hydroxy,
  • the substituent of the amino group, the halogenated C 1-4 alkyl group, or the halogenated C 1-4 alkoxy group is substituted at any position.
  • 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, quinolyl, isoquinolyl and the like.
  • the heteroaryl group is unsubstituted or alternatively selected from 1 to 3 selected from the group consisting of hydrazine, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, cyano, hydroxy
  • the substituent of the amino group, the halogenated C 1-4 alkyl group or the halogenated C 1-4 alkoxy group is substituted at any position.
  • 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.
  • C2-4 alkenyl refers to an alkenyl group having 2 to 4 carbon atoms
  • C2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, including vinyl and propenyl. , butenyl, 2-methylbutenyl and cyclohexenyl.
  • 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.
  • 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.
  • amido refers to -C(O)N(R) 2 wherein R is hydrogen or C 1-6 alkyl.
  • ester group refers to -C(O)OR, wherein R is hydrogen or C1-6 alkyl.
  • cyano refers to -CN.
  • amino refers to -NH 2 .
  • alkylamino means that at least one hydrogen atom on the amino group is substituted by an alkyl group, including but not limited to: -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 .
  • solvate means a substance which is formed by the compound I with a suitable solvent.
  • the solvent is preferably water and/or an organic solvent.
  • 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).
  • the 1 H NMR chemical shift ( ⁇ ) was recorded in PPM (10 -6 ).
  • 1 H NMR was performed on a Bruker AVANCE-400 spectrometer. Suitable solvents are deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), deuterated dimethyl sulfoxide (DMSO-d 6 ) or deuterated formic acid (DCOOD), tetramethylsilane (TMS) as internal Standard.
  • 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, and rapid separation machines.
  • Silica gel column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
  • the thin layer silica gel plate is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • 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.
  • All compounds of the present invention can be analyzed by ultra performance liquid chromatography (UPLC) using a Waters ACQUITY Hclass platform: Waters ACQUITY UPLC BEH Shield RP18 2.1mm*100mm, 1.7 ⁇ m, mobile phase A: acetonitrile, mobile phase B: 5 mm aqueous potassium dihydrogen phosphate solution (pH adjusted to 2.5 with phosphoric acid). Gradient elution time 15 min, flow rate: 0.4 mL/min, detection wavelength: 214 nm & 254 nm; column temperature: 40 ° C; injection volume 1 ⁇ L; gradient elution conditions are as follows:
  • Detector distance d 60.3mm, tube pressure 40kV, tube flow 30mA, scanning method: Scan, collect the total number of diffraction points, the number of independent diffraction points, and observe the number of points (
  • the direct structure (Shelxs97) is used to analyze the crystal structure to obtain all non-hydrogen atom positions.
  • the least squares method is used to correct the structural parameters and discriminate the atom types.
  • the geometric calculation method and the difference Fourier method are used to obtain the positions of all hydrogen atoms, and finally the stereo configuration of the compounds is determined. .
  • Step 1 Ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (2.8 g, 17.93 mmol) was suspended in tetrahydrofuran (30 mL). EtOAc (1. %), stirring for 30 minutes, adding methyl iodide (3.8 g, 26.9 mmol) dropwise, stirring at ambient temperature for 16 hours, then adding sodium hydrogen (1.1 g, 26.9 mmol, 60%), stirring for 30 minutes, adding methyl iodide dropwise (3.8g, 26.9mmol), the mixture was stirred at 25 ° C for additional 16 hours, then added with water (20 mL).
  • Step 3 Ethyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxylate (110 mg, 0.50 mmol) and lithium hydroxide monohydrate (42 mg, 1.0 mmol) Tetrahydrofuran (2.0 mL) and water (1.0 mL) were stirred at 50 ° C for 2 hours, then methanol (1.0 mL) was added, and the mixture was stirred at room temperature overnight, and most of the organic solvent was evaporated to dryness.
  • Ethyl ester (5 mL ⁇ 3), EtOAcjjjjjjjjjjjjj %) is a white solid. [M+H] + 193.0.
  • Step 1 -78 ° C, 1,4-dioxaspiro[4.5]decane-8-one (6.0 g, 38.4 mmol), N-phenylbis(trifluoromethanesulfonimide) under nitrogen atmosphere.
  • (16.5 g, 46.1 mmol) of methyl tert-butyl ether (95 mL) was added dropwise to a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2.0 M, 23 mL). hour. The reaction was then allowed to warm to room temperature and stirred overnight. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc /1) Purification gave Compound 1.1 (10.8 g, yield: 97%) as a yellow oil.
  • Step 2 Compound 1.1 (8.0 g, 27.8 mmol), bispinacol borate (9.17 g, 36.1 mmol), potassium acetate (8.18 g, 83.3 mmol), sodium bromide (1.14 g, 11.1 mmol) and Pd (dppf) Cl 2 (1.0g , 1.4mmol) in 1,4-dioxane (100 mL) was stirred at reflux overnight. The reaction system was cooled to room temperature, and the solvent was evaporated,jjjjjjjjjj .
  • Step 3 Compound 1.2 (3.22 g, 12.1 mmol), 4-chloro-6-fluoroquinoline (2.1 g, 13.8 mol), potassium carbonate (3.85 g, 27.3 mmol) and Pd (PPh 3 ). 4 (0.22 g, 0.19 mmol) of water / 1,4-dioxane (50 mL, 4 / 1) mixture was stirred under reflux overnight, then the mixture was concentrated and extracted with ethyl acetate (60 mL ⁇ 3) The organic layer was dried over anhydrous sodium sulfate (MgSO4)
  • Step 4 To a solution of compound 1.3 (2.0 g, 7.02 mmol) in isopropanol (30 mL) was added Pd / C (200 mg, 10%), under a hydrogen atmosphere (hydrogen balloon) at 55 ° C Stir overnight. Then, the reaction system was filtered through Celite to remove Pd/C, and the filtrate was concentrated under reduced pressure to give Compound 1.4 (1.9 g, yield: 90%) as a yellow oil. m/z: [M+H] + 288.0.
  • Step 6 Mixing compound 1.5 (750 mg, 3.09 mmol) and p-methylbenzenesulfonylmethyl isocyanide (784 mg, 4.02 mmol) in ethylene glycol dimethyl ether (20 mL) and ethanol (2 mL) under ice bath. Potassium tert-butoxide (943 mg, 7.73 mmol) was added to the solution. The reaction system was stirred at room temperature overnight, then quenched with EtOAc EtOAc (EtOAc) The organic layer was washed with brine, filtered and evaporated.
  • EtOAc EtOAc
  • Step 7 To a solution of the compound 1.6a (263 mg, 1.04 mmol) in tetrahydrofuran (10 mL) was added dropwise to a solution of lithium tetrahydroaluminum in tetrahydrofuran (0.85 mL, 2.5 M), and the mixture was stirred at 0 ° C. hour. Then, water (0.3 mL), 15% aqueous sodium hydroxide solution (0.3 mL), water (1.0 mL) was added dropwise, filtered, and the filter cake was rinsed with tetrahydrofuran. The obtained filtrate was dried over anhydrous sodium sulfate and evaporated. m/z: [M+H] + 259.0.
  • Step 1 Dissolve bromoacetone (2.0 g, 14.7 mmol), ethyl cyanoacetate (1.66 g, 14.7 mmol), sodium ethoxide (1 g, 14.7 mmol) and diisopropylethylamine (1.89 g, 14.7 mmol)
  • the reaction solution was stirred at room temperature overnight in anhydrous tetrahydrofuran (40 mL).
  • the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen sulfate.
  • the organic phase was separated and the organic phase dried with anhydrous sodium
  • the residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut
  • Step 3 Compound 4.2 (200 mg, 0.86 mmol), (2-methoxypyridin-3-yl)boronic acid (263 mg, 1.72 mmol), potassium carbonate (356 mg, 2.58 mmol), tetratriphenylphosphine palladium (92.4 A suspension of mg, 0.08 mmol) of 1,4 dioxane (3 mL) and water (1 mL) was subjected to microwave reaction at 120 ° C for 1 hour. The reaction solution was then filtered, and the filtrate was extracted with ethyl acetate. The residue was purified by flash column chromatography eluting elut elut elut elut elut m/z: [M+H] + 261.0.
  • Step 4 A solution of compound 4.3 (200 mg, 0.77 mmol) and aqueous sodium hydroxide (4M, 3 mL) in ethanol (3 mL) was stirred at 100 ° C for 6 hr. The mixture was extracted with EtOAc (2M). The residue was purified by flash column chromatography (60% ethyl acetate / petroleum ether) to afford 4-(2-methoxypyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxylic acid (Comp. , 53 mg, yield: 30%) as a yellow oil. m/z: [M+H] + 233.2.
  • Step 1 To a solution of Compound 4.3 (0.7 g, 2.68 mmol) in EtOAc (10 mL), EtOAc (EtOAc (EtOAc) Then, the reaction system was cooled to room temperature, and concentrated under reduced pressure to give Compound 9.1 (700 mg, yield: 95%) as a yellow liquid. m/z: [M+H] + 275.2.
  • Step 2 To a solution of the compound 9.1 (300 mg, 1.09 mmol) in MeOH (5 mL), EtOAc (EtOAc, EtOAc. Add methyl tert-butyl ether and aqueous sodium hydroxide solution (1M) to the mixture, and add hydrochloric acid (2M) to the aqueous phase to adjust the pH ⁇ 1. The aqueous phase is extracted with ethyl acetate. The organic phase is combined with saturated brine.
  • EtOAc EtOAc
  • EtOAc methyl tert-butyl ether and aqueous sodium hydroxide solution
  • 2M hydrochloric acid
  • Step 1 To a solution of compound 4.3 (1 g, 3.84 mmol) and cyclopropylboronic acid (0.66 g, 7.68 mmol) in 1,2-dichloroethane (10 mL), EtOAc (0.73 g, 3. Sodium carbonate (0.81 g, 7.68 mmol), 2,2-bipyridine (0.6 g, 3.84 mmol), the reaction system was replaced with nitrogen three times, then stirred at 100 ° C for 16 hours, then the reaction system was cooled to room temperature, filtered The filtrate was concentrated under reduced pressure. EtOAcjjjjjjj m/z: [M+H] + 301.2.
  • Step 2 To a solution of the compound 10.1 (150 mg, 0.55 mmol) in MeOH (5 mL), EtOAc (EtOAc, EtOAc. Add methyl tert-butyl ether and aqueous sodium hydroxide solution (1M) to the mixture, and add hydrochloric acid (2M) to the aqueous phase to adjust the pH ⁇ 1.
  • the aqueous phase is extracted with ethyl acetate.
  • the organic phase is combined with saturated brine. After washing, the organic phase is dried over anhydrous sodium sulfate, filtered and evaporated toield of ⁇ Compound 10, 50 mg, yield: 33%) was obtained as a brown solid.
  • Step 1 N,N'-carbonyldiimidazole (5.3 g, 0.03) was added to a mixed solution of 2-methoxynicotinic acid (5.0 g, 0.03 mol) in tetrahydrofuran (16 mL) and acetonitrile (80 mL). (mmol), the reaction system was stirred at room temperature for 0.5 hours. Then, a monomethyl malonate potassium salt (10.2 g, 0.06 mol), triethylamine (9.9 g, 0.09 mol) and magnesium chloride (13.9 g, 0.14 mol) were added to the reaction mixture, and the resulting mixture was stirred at room temperature 2 hour.
  • Step 2 Add sodium hydrogen (60%, 286 mg, 7.17 mmol) to a solution of compound 11.1 (1.0 g, 4.78 mmol) in tetrahydrofuran (15 mL) under ice-cooling. Stir for 0.5 hours. Then, 1-bromo-3-methyl-2-butanone (1.18 g, 7.17 mmol) was added to the reaction mixture, and the reaction mixture was heated to reflux for 0.5 hr. The reaction mixture was then poured into a saturated aqueous solution of ammonium chloride and the mixture was evaporated. The organic phases were combined and washed with brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated,363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363363
  • Step 3 Under a nitrogen atmosphere, compound 11.2 (400 mg, 1.36 mmol) and ammonium acetate (315 mg, 4.09 mol) were added to ethanol (15 mL) and refluxed for 3 hours, then the reaction mixture was concentrated and ethyl acetate was added to the residue, then Wash with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate.
  • Step 4 A solution of compound 11.3 (350 mg, 1.27 mmol) and aqueous sodium hydroxide (4M, 2.5 mL, 10.0 mmol) After the reaction system was cooled to room temperature, water (40 mL) was added to the reaction mixture, and the organic solvent was evaporated. The residue was adjusted to pH 5-6 with hydrochloric acid (1M), stirred for 30 min, filtered, and then filtered and dried under vacuum at 50 ° C to give 5-isopropyl-2-(2-methoxypyridin-3-yl) -1H-pyrrole-3-carboxylic acid (Compound 11, 340 mg, Yield: 100%) was a yellow solid. m/z: [M+H] + 261.0.
  • N-bromosuccinimide (109 mg, 0.61 mmol) was added to a solution of Compound 11 (160 mg, 0.61 mmol) in THF (5 mL), and the mixture was stirred at 0 ° C for 2 hours. It was then stirred at room temperature overnight. Water (20 mL) was added to the reaction mixture, followed by ethyl acetate (5 mL ⁇ 3). The organic phases were combined and washed with brine. The organic phase was then separated and concentrated to dryness to give a crude material.
  • 2-(2-(difluoromethoxy)pyridin-3-yl is obtained by substituting the 2-methoxynicotinic acid in step 1 with 2-(difluoromethoxy)nicotinic acid by the synthesis of compound 11.3. -5-Isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Compound 26). m/z: [M+H] + 311.1.
  • step 1 The 2-methoxynicotinic acid in step 1 was replaced with 2-bromonicotinic acid by the synthesis of compound 11.3, and the 1-bromo-3-methyl-2-butanone in step 2 was replaced with bromoacetone to obtain 2 Methyl (2-bromopyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxylate (Compound 27).
  • Step 1 Methyl 2-(6-chloro-2-(trifluoromethoxy)nicotinyl)-4-oxopentanoate (under the synthesis of compound 11.2, 2 in step 1 under nitrogen protection) - methoxynicotinic acid is replaced by 6-chloro-2-(trifluoromethoxy)nicotinic acid, and 1-bromo-3-methyl-2-butanone in step 2 is replaced by bromoacetone) (250 mg, 0.7 mmol) was dissolved in deuterated methanol (5 mL) and stirred at 100 ° C for 2 hours.
  • deuterated methanol 5 mL
  • Step 2 To a solution of compound 33 (147 mg, 388 ⁇ mol) in deuterated dimethyl sulfoxide (2 mL) was added succinic acid (93 mg, 1.9 mmol), triethylamine (236 mg, 2.3 mmol) and THF. Phenylphosphine palladium (45 mg, 2.3 ⁇ mol), the reaction system was replaced with nitrogen three times and stirred at 110 ° C for 4 hours. After filtration with celite, the mixture was washed with EtOAc (EtOAc (EtOAc)EtOAc.
  • Step 1 Compound 31 (260 mg, 1.04 mmol) was added to a mixed solution of trifluoroacetic acid (2 mL) and dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, ethyl acetate and aq. The organic phase was concentrated, and the residue was purified tojjjjjjjj
  • Step 1 Methyl 4-oxo-2-(3-(trifluoromethoxy)pyridine-2-formyl)pentanoate (under the synthesis of compound 11.2, 2 in step 1 under nitrogen protection) - methoxynicotinic acid is replaced by 3-(trifluoromethoxy)pyridine-2-carboxylic acid, and 1-bromo-3-methyl-2-butanone in step 2 is replaced by bromoacetone) (200 mg, 0.63 mmol) was dissolved in deuterated methanol (5 mL) and stirred at 100 ° C for 2 hours.
  • Step 3 N-bromosuccinimide (17.6 mg, 0.09 mmol) was added portionwise to a solution of compound 47 (22 mg, 0.07 mmol) in tetrahydrofuran (3 mL). Stir for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. 2-(3-(Trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Compound 48, 28 mg, yield: 100%) as a white solid. m/z: [M+H] + 368.0.
  • Step 1 Methyl 2-(6-chloro-3-(trifluoromethoxy)pyridine-2-formyl)-5-methyl-4-oxohexanoate (using compound 11.2)
  • the 2-methoxynicotinic acid in step 1 is replaced by 6-chloro-3-(trifluoromethoxy)pyridine-2-carboxylic acid (50 mg, 0.13 mmol) dissolved in deuterated methanol ( 2 mL) and stirred at 100 ° C for 2 hours.
  • the reaction system was cooled to room temperature, ammonium acetate (20 mg, 0.26 mmol) was added and stirred at 100 ° C for 16 hours.
  • the reaction system was cooled to room temperature and then evaporated to dryness.
  • Step 2 To a solution of the compound 49 (47 mg, 0.13 mmol) in methanol (5 mL), EtOAc (40 mg, 0.64 mmol) and palladium carbon (30 mg, 10%). The mixture was stirred under heating for 6 hours. The resulting mixture was filtered over EtOAc (EtOAc)EtOAc. The residue was dissolved with EtOAc (EtOAc) (EtOAc)
  • Step 3 A solution of compound 50 (30 mg, EtOAc) (EtOAc) The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered, and then evaporated. Pyrrole-3-carboxylic acid (Compound 51, crude, 50 mg) was obtained as a yellow oil. m/z: [M+H] + 316.2.
  • Step 1 Methyl 5-(tert-butyl)-2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylate (using compound 11 Synthetic method, replacing 2-methoxynicotinic acid in step 1 with 6-chloro-3-(trifluoromethoxy)pyridine-2-carboxylic acid, 1-bromo-3-methyl- in step 2 2-butanone was replaced by 1-bromo-3,3-dimethylbutan-2-one (48 mg, 0.13 mmol), ammonium formate (33 mg, 0.52 mmol) and palladium on carbon (10 mg, 10%) were added to methanol.
  • reaction system In (5 mL), the reaction system was replaced with hydrogen three times, and then refluxed under a hydrogen atmosphere for 1 hour. The reaction solution was cooled to room temperature, filtered over Celite, and evaporated. Ethyl acetate and water were added to the residue, and the organic layer was evaporated.
  • Step 2 A mixed solution of Compound 52 (46 mg, 0.13 mmol) in methanol (4 mL) The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered, and then evaporated. The acid (Compound 53, 30 mg, Yield: 71%) was obtained as a yellow oil. m/z: [M+H] + 329.2.
  • Step 1 To the methyl 2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxylate (using compound under ice bath) A method for synthesizing 11 by replacing 2-methoxynicotinic acid in step 1 with 6-chloro-3-(trifluoromethoxy)pyridine-2-carboxylic acid) (35 mg, 0.1 mmol) of N, N To the solution of dimethylformamide (2 mL) was added sodium hydrogen (8 mg, 0.2 mmol, 60%), and the mixture was stirred for 15 min. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The mixture was stirred with EtOAc EtOAc. %) is a yellow oil.
  • Steps 2 & 3 Using the synthesis of compound 53 and reacting with compound 54 to give 1,5-dimethyl-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (Compound 56) is a yellow oil. m/z: [M+H] + 349.0.
  • Step 1 To a solution of methyl 3-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-3-pyruvate (150 mg, 0.50 mmol) and pyridine (119 mg, 1.50) Dess-Martin oxidant (321 mg, 0.76 mmol) was slowly added to a solution of dichloromethane (8 mL). After the addition, the reaction was stirred at room temperature for 3 hours, then a saturated aqueous solution of sodium thiosulfate (2 mL) and Saturated aqueous sodium hydrogencarbonate (2 mL) was stirred at room temperature for 1 hour. The reaction system was extracted with ethyl acetate (30 mL ⁇ 3).
  • Step 2 Compound 58 (80 mg, 0.26 mmol), EtOAc (EtOAc (EtOAc,EtOAc) The residue was extracted with ethyl acetate (30 mL ⁇ 3). The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash column chromatography eluting elut elut elut elut elut m/z: [M+H] + 378.2.
  • Step 3 A mixture of compound 59 (50 mg, 0.13 mmol), palladium carbon (20 mg) and ammonium formate (33 mg, 0.52 mmol) in methanol (10 mL) was replaced with hydrogen three times, then the reaction was stirred under a hydrogen atmosphere for one hour. . The reaction system was cooled to room temperature, and the palladium carbon was removed by filtration over Celite, and then the filtrate was concentrated to afford compound 60 (45 mg, crude) as white solid. m/z: [M+H] + 344.2.
  • Step 4 A solution of compound 60 (45 mg, EtOAc) (EtOAc) The organic solvent was concentrated under reduced pressure, and the aqueous phase was adjusted to pH 4 to 5 with hydrochloric acid (1M), and solid was precipitated, and filtered under reduced pressure to give 2-(t-butyl)-5-(3-(trifluoromethoxy)pyridine. 2-yl)-1H-imidazole-4-carboxylic acid (Compound 61, 20 mg, two-step yield: 44%) as a white solid. m/z: [M+H] + 330.2.
  • Step 1 Drying to methyl 2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxylate (170 mg, 0.51 mmol) Cyclopropylboronic acid (131 mg, 1.52 mmol), copper acetate (139 mg, 0.77 mmol), 2,2-bipyridine (120 mg, 0.77 mmol) and sodium carbonate were added sequentially to 1,2-dichloroethane (10 mL). 162 mg, 1.52 mmol), the reaction system was replaced with nitrogen three times, and then heated to 120 ° C for 3 hours. The reaction was cooled to room temperature, and the mixture was evaporated. The residue was purified by flash column chromatography chromatography eluting elut elut elut elut elut elut
  • Steps 2 & 3 Using the synthesis of compound 53 and reacting with compound 63 to give 1-cyclopropyl-5-methyl-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3 - carboxylic acid (compound 65). m/z: [M+H] + 327.2.
  • Step 1 To a solution of methyl 2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxylate (280 mg, Sodium hydrogen (67.2 mg, 1.68 mmol, 60%) was added to a solution of 0.84 mmol) of N,N-dimethylformamide (5 mL). The reaction system was stirred at 0 ° C for 30 minutes and then added to the above reaction system ( 2-Bromoethoxy)(tert-butyl)dimethylsilane (402 mg, 1.68 mmol). The reaction system was further stirred at room temperature overnight, and the mixture was evaporated. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut
  • Steps 2 & 3 Using the synthesis of compound 53 and reacting with compound 66 to give 1-(2-hydroxyethyl)-5-methyl-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H Pyrrole-3-carboxylic acid (compound 68). m/z: [M+H] + 331.2.
  • Step 1 Methyl 5-(tert-butyl)-2-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxylate under ice-bath conditions (1 g, 2.7 mmol) of N,N-dimethylformamide (10 mL) was added portionwise sodium hydrogen (160 mg, 4.0 mmol), and the mixture was stirred for 0.5 hr. After the addition of the reaction mixture, the reaction mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous ammonium chloride. The aqueous phase was extracted with ethyl acetate. Concentrated Compound 69 (1.1 g, yield: 98%) was obtained as a pale creamy liquid.
  • Step 2 To a solution of compound 69 (300 mg, 0.72 mmol) in 1,4-dioxane (3mL), water (1. 5mL), potassium hydride (VI) dihydrate (118mg, 0.36mmol) N-methyl-N-oxidized morpholine (253 mg, 2.16 mmol). After stirring at room temperature for 3 hours, sodium periodate (766 mg, 3.6 mmol) was added to the reaction system, and the reaction was stirred at room temperature for 12 hours. The reaction was quenched with aq. EtOAc EtOAc (EtOAc)EtOAc. /1 to 5/1) Purification gave Compound 70 (82 mg, yield: 28%) as a pale creamy liquid.
  • EtOAc EtOAc EtOAc
  • Step 3 To a solution of compound 70 (80 mg, 0.19 mmol) elute The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated.
  • Steps 4 & 5 Using the synthesis of compound 53 and reacting with compound 71 to give 5-tert-butyl-1-(2-hydroxyethyl)-2-(3-(trifluoromethoxy)pyridin-2-yl)- 1H-pyrrole-3-carboxylic acid (compound 73).
  • Step 1 2-methoxy-3-pyridine aldehyde (1.0 g, 7.29 mmol) and ethoxycarbonylmethylenetriphenylphosphine (2.4 g, 7.29 mmol) were dissolved in tetrahydrofuran (20 mL). Stir at room temperature overnight. The reaction mixture was then concentrated, and the residue was purified mjjjjjjj
  • Step 2 To a solution of the compound 74.1 (500 mg, 2.41 mmol) and 1-decylmethyl-p-toluenesulfonylmethylisonitrile (1.0 g, 4.82 mmol) in THF (20 mL) 7.23 mmol), the reaction system was stirred at room temperature for 3 hours. After the reaction was quenched with water, EtOAc (EtOAc)EtOAc. Ethyl (2-methoxypyridin-3-yl)-5-deuteromethyl-1H-pyrrole-3-carboxylate (Compound 74, 0.1 g, yield: 16%) m/z: [M+H] + 264.2.
  • Step 1 To a solution of 2-bromo-6-methoxypyridine (1 g, 5.3 mmol) and tert-butyl acrylate (3.4 g, 26.6 mmol) in tetrahydrofuran (40 mL), palladium acetate (118 g, 0.53 mmol) Triethylamine (2.68 g, 2.65 mmol) and tris(2-methylphenyl)phosphorate (322 mg, 1.06 mmol) were reacted three times with nitrogen, and then the reaction was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjj Dry over sodium sulfate and concentrate under reduced pressure. The residue was purified by flash column chromatography (EtOAc:EtOAc: m/z: [M+H] + 236.2.
  • Step 2 Sodium hydrogen (60%, 688 mg, 17.2 mmol) was added portionwise to a solution of TosMIC (1.49 g, 7.7 mmol) in N, N-dimethylformamide (3 mL). After the addition, the reaction system was further stirred for 0.5 hours, and then Compound 76.1 (1 g, 4.3 mmol) was added to the reaction system. The reaction system was stirred to room temperature and stirred for 2 hours.
  • Step 1 To a solution of methyl 3-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)-3-oxopropanoate (2.2 g, 7.39 mmol) in tetrahydrofuran Sodium borohydride (84 mg, 2.22 mmol) was added portionwise in a mixture of 10 mL) and methanol (10 mL). The mixture was stirred at 0 ° C for 30 min then quenched with water (10 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to afford Compound 77.1 (2.2 g, yield: 99%). m/z: [M+H] + 300.0.
  • Step 3 Compound 77.2 (320 mg, 1.14 mmol) and 1-methyl-p-toluenesulfonylmethylisonitrile (356 mg, 1.70 mmol) were dissolved in tetrahydrofuran (5 mL).
  • Step 4 Compound 77.3 (190 mg, 0.57 mmol) was dissolved in MeOH (5 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc After stirring for 48 hours, the reaction solution was filtered through Celite, and then filtered and washed with ethyl acetate, and the filtrate was concentrated to give 5-methyl-4-(2-(trifluoromethoxy)pyridin-3-yl)- Methyl 1H-pyrrole-3-carboxylate (Compound 77, 130 mg, Yield: 76%) was an off white solid. m/z: [M+H] + 301.2.
  • Step 1 To a compound 78.1 at room temperature (3-(6-chloro-2-(trifluoromethoxy)pyridin-3-yl)-3-oxoprop in step 1 using the synthesis of compound 77.2 Replacement of methyl ester with methyl 3-(6-chloro-3-(trifluoromethoxy)pyridin-2-yl)-3-oxopropanoate) (155 mg, 0.9 mmol) and 1-methyl- Potassium tert-butoxide (155 mg, 1.4 mmol) was added to a solution of toluenesulfonylmethyl isocyanide (290 mg, 1.4 mmol) in tetrahydrofuran (5 mL).
  • Step 2 To a solution of the mixture of compound 78.2A and 78.2B (204 mg, 0.6 mmol) in methanol (10 mL), EtOAc (EtOAc (EtOAc) It was replaced three times and stirred at 66 ° C for 16 hours. It was filtered through Celite and washed with methanol (3 ⁇ 5 mL). It was dissolved in ethyl acetate (10 mL), EtOAc (EtOAc m.
  • Example 53 Using the synthesis method of 1-deuteromethyl-p-toluenesulfonylmethyl isocyanide in Example 53, substituting deuterated methyl iodide with 2-iodopropane to obtain 1-isopropyl-p-toluenesulfonylmethyl isocyanide .
  • Example 53 Using the synthesis method of 1-deuteromethyl-p-toluenesulfonylmethyl isocyanide in Example 53, the deuterated methyl iodide was replaced with ethyl iodide to give 1-ethyl-p-toluenesulfonylmethyl isocyanide.
  • Step 2 To a mixture of compound 1-29 (40 mg, 0.06 mmol) and tetrakistriphenylphosphine palladium (36 mg, 0.03 mmol) in deuterated dimethyl sulfoxide (3 mL) was added triethylamine (73 mg). , 0.72 mmol) and deuterated formic acid (28 mg, 0.6 mmol). The reaction system was subjected to microwave reaction at 110 ° C for 3 hours, and the reaction mixture was cooled to room temperature, then water (10 mL) The combined organic layers were washed with EtOAc EtOAc.
  • reaction solution was cooled to room temperature and then filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to prep-HPLC (basic method, elution gradient: mobile phase B: 80-35 % (v/v%)) was purified to give compound 4-6 (1.4 mg, yield: 6%) as a white solid.
  • Step 2 To a solution of compound 4-7 (80 mg, 0.17 mmol) in deuterated dimethyl sulfoxide (5 mL) was added EtOAc (1 mL), tetratriphenylphosphine palladium (39 mg, 0.03 mmol) ⁇ (166 mg, 0.51 mmol), the reaction was replaced with nitrogen three times and stirred at 130 ° C for 5 hours. After filtration with celite, EtOAc (3 mL, EtOAc) was evaporated. Degradation: Mobile phase B: 80 to 35% (v/v%)) Purified to give compound 4-8 (6.5 mg, yield: 10%) as a pink solid.
  • compound 4-10 By the synthesis of compound 4-10, compound 12 was replaced with a mixture of compounds 78A and 78B to give a mixture of compounds 4-12 and 4-13, followed by prep-HPLC (base method, elution gradient: mobile phase B: 45). ⁇ 65% (v/v%)) isolated compound 4-12 (single stereo configuration, peak time: 15.6 to 16.4 minutes) and compound 4-13 (single stereo configuration, peak time: 16.5 to 17.0 minutes) ), all white solids.
  • Step 2 Compound 4-15 (42 mg, 0.08 mmol), deuterated acid (36.8 mg, 0.8 mmol), tetratriphenylphosphine palladium (46.2 mg, 0.04 mmol) and triethylamine (97.1 mg, 0.96 mmol)
  • deuterated acid 36.8 mg, 0.8 mmol
  • tetratriphenylphosphine palladium 46.2 mg, 0.04 mmol
  • triethylamine 97.1 mg, 0.96 mmol
  • Compound 6-1 is reacted with compound 4-1 to obtain compound 6-1 (cis-trans isomer mixture), and compound 6-1 is subjected to prep-HPLC (basic conditions, elution gradient: mobile phase B). : 30 to 70% (v/v%)) Compound 6-1A was isolated (peak time: 17.2-17.8 min, single stereo configuration) and 6-1B (peak time: 18.0-18.5 min, single stereostructure) type).
  • Example 124 Single crystal diffraction experiment of compounds 1-32 and 4-1
  • Single crystal culture Compounds 1-32 (10 mg) and 4-1 (10 mg) were dissolved in anhydrous methanol (10 mL), respectively, and water (4 mL) was added, filtered, and the filtrate was added to two 100 mL single ports. In an Erlenmeyer flask, it was allowed to stand at 10-20 ° C for 20-30 days, and a single crystal was precipitated, and a single crystal was collected for single crystal diffraction test.
  • test parameters are shown in the following table:
  • Test results The configuration of compound 1-32 was determined by single crystal diffraction to be a cis configuration, and the chemical name was: 5-(tert-butyl)-N-((1s,4s)-4-(6- Fluoroquinolin-4-yl)cyclohexyl)methyl)-2-(3-(trifluoromethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide.
  • Compound 4-1 was determined by single crystal diffraction to be a cis configuration, and the chemical name was: N-(((1s, 4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)methyl )-4-(2-Methoxypyridin-3-yl)-5-methyl-1H-pyrrole-3-carboxamide.
  • the compounds of the present invention 1-1 to 1-37, 2-1 to 2-4, 3-1 to 3-2, 4-1 to 4-20 can be obtained.
  • 7-1, 8-1 ⁇ 8-2 are all cis configurations, and the chemical names of some compounds are shown in the following table (named by Chemdraw software):

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Abstract

La présente invention concerne un dérivé cyclique hétéroaryle à cinq chaînons (I), et un isomère, un solvate, une forme cristalline du solvate, un promédicament, un dérivé isotopique stable, ou un sel pharmaceutiquement acceptable de celui-ci. Le dérivé cyclique hétéroaryle à cinq chaînons selon la présente invention a un bon effet inhibiteur d'IDO, et peut traiter, soulager et/ou prévenir de manière efficace diverses maladies associées provoquées par une immunosuppression, telles que des tumeurs, des maladies infectieuses et des maladies auto-immunes.
PCT/CN2018/122420 2017-12-22 2018-12-20 Dérivé cyclique hétéroaryle à cinq chaînons, composition pharmaceutique le contenant et utilisations associées Ceased WO2019120256A1 (fr)

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CN201711404528.5 2017-12-22
CN201810062990.X 2018-01-23
CN201810062990 2018-01-23
CN201810103001 2018-02-01
CN201810102631.2 2018-02-01
CN201810102631 2018-02-01
CN201810103001.7 2018-02-01
CN201810148831 2018-02-13
CN201810148831.1 2018-02-13
CN201810182186.5 2018-03-06
CN201810182186 2018-03-06
CN201810256091 2018-03-27
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106999450A (zh) * 2014-11-05 2017-08-01 弗莱塞斯生物科学公司 免疫调节剂
WO2018024188A1 (fr) * 2016-08-02 2018-02-08 上海迪诺医药科技有限公司 Composé polycyclique et procédé de fabrication, composition pharmaceutique et application de celui-ci
WO2018209049A1 (fr) * 2017-05-12 2018-11-15 Bristol-Myers Squibb Company Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106999450A (zh) * 2014-11-05 2017-08-01 弗莱塞斯生物科学公司 免疫调节剂
WO2018024188A1 (fr) * 2016-08-02 2018-02-08 上海迪诺医药科技有限公司 Composé polycyclique et procédé de fabrication, composition pharmaceutique et application de celui-ci
WO2018209049A1 (fr) * 2017-05-12 2018-11-15 Bristol-Myers Squibb Company Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs procédés d'utilisation

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