WO2020011147A1 - ANTAGONISTE DE RORγ ET SON UTILISATION EN MÉDECINE - Google Patents

ANTAGONISTE DE RORγ ET SON UTILISATION EN MÉDECINE Download PDF

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Publication number
WO2020011147A1
WO2020011147A1 PCT/CN2019/095203 CN2019095203W WO2020011147A1 WO 2020011147 A1 WO2020011147 A1 WO 2020011147A1 CN 2019095203 W CN2019095203 W CN 2019095203W WO 2020011147 A1 WO2020011147 A1 WO 2020011147A1
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Prior art keywords
mmol
phenyl
trifluoromethyl
membered
disease
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PCT/CN2019/095203
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English (en)
Inventor
Bing Liu
Xue ZHONG
Feng Wang
Xuke Li
Wei He
Wei Pan
Jiuzhong HUANG
Yingjun Zhang
Changchun Zheng
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Sunshine Lake Pharma Co., Ltd.
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Priority to CN201980045075.2A priority Critical patent/CN112513021B/zh
Publication of WO2020011147A1 publication Critical patent/WO2020011147A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • each R 2 is independently and optionally substituted with 1, 2, 3, 4, 5 or 6 R f. .
  • each R a , R b , R c and R d is independently unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 R g .
  • a pharmaceutical composition comprising a compound having Formula (I) disclosed herein or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant or a combination thereof;
  • the pharmaceutical composition disclosed herein further comprises other medicaments for preventing or treating inflammatory syndrome or autoimmune disease or any combination thereof.
  • alkoxyalkylene used interchangeablely with “alkoxyalkyl” refers to an alkoxy group attached to the parent molecular moiety via alkyl group, wherein the alkoxy and alkyl group are as defined herein. Such examples include, but are not limited to, methoxymethylene, ethoxymethylene, isopropoxymethylene, and the like.
  • heterocycle refers to a saturated or partially unsaturated nonaromatic univalent or multivalent monocyclic ring containing 3-12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur and oxygen.
  • the heterocyclyl group having 3 to 12 ring atoms contains 2-9 carbon atoms.
  • the heterocyclyl group having 3 to 12 ring atoms contains 2-8 carbon atoms.
  • the heterocyclyl group having 3 to 12 ring atoms contains 2-6 carbon atoms.
  • amino or “NH 2 " refers to a amino group which can attached to other group.
  • attachment of a connecting bond to a ring system represents that the ring can be attached to the remainder of the molecule through the connecting bond at any attachable position on the ring system.
  • Formula d represents that the ring can be attached to the remainder of the molecule at any attachable position on the ring system, including but not limited to formula d1 -formula d8.
  • a “pharmaceutically acceptable salts” refers to organic or inorganic salts of a compound disclosed herein.
  • Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19, which is incorporated herein by reference.
  • salts formed by pharmaceutically acceptable and nontoxic acids include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange.
  • hydrate can be used when said solvent is water.
  • one solvent molecule is associated with one molecule of the compound disclosed herein, such as a hydrate.
  • more than one solvent molecule may be associated with one molecule of the compound disclosed herein, such as a dihydrate.
  • less than one solvent molecule may be associated with one molecule of the compound disclosed herein, such as a hemihydrate.
  • all the solvates of the invention retain the biological effectiveness of the non-hydrate form of the compounds disclosed herein.
  • treating refers to that all can slow, interrupt, prevent, control or stop the progression of a disease or condition, but does not necessarily mean that all symptoms of the disease or condition can completely disappeared, including prophylactic treatment of the symptoms, especially in patients susceptible to such diseases or disorders.
  • the “treat” , “treating” or “treatment” of any disease or disorder in some embodiments refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another embodiment “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • the term "therapeutically effective amount” refers to an effective amount of the compound of the invention while administering to a cell, or organ, or a non-cellular biological material, or a medium which is capable of at least partially reducing or inhibiting RORyt activity, or at least partially reducing or inhibiting RORyt expression.
  • each of R 3 and R 4 is independently hydrogen, hydroxymethyl, hydroxyethyl or hydroxy-n-propyl.
  • A is a 3-to 12-membered heterocyclic ring, and wherein the 3-to 12-membered heterocyclic ring is optionally substituted with 1, 2, 3, 4 or 5 R 2 ; wherein R 2 is as defined herein.
  • A is and A is further optionally substituted with 1, 2, 3, 4 or 5 R 2 ; wherein each of R 2 , Y 1 , Y 2 is as defined herein.
  • each m is independently 0, 1 or 2.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the scope of the invention, and as disclosed herein are included in the present invention.
  • stereochemistry is indicated by a solid wedge or dashed line indicating a particular configuration, then the stereoisomer of the structure is clearly defined.
  • Isotopically enriched compound has the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I respectively.
  • a substituent in a compound of this invention is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom) , at least 4000 (60%deuterium incorporation) , at least 4500 (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) , at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at least 6333.3 (95%deuterium incorporation) , at least 6466.7 (97%deuterium incorporation) , at least 6600 (99%deuterium incorporation) , or at least 6633.3 (99.5%deuterium incorporation) .
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, DMSO-d6
  • compositions of present invention can exist in free form for treatment, or if appropriate, as a pharmaceutically acceptable derivative thereof.
  • Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • “Pharmaceutically acceptable excipient” as used herein means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled, such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and would result in pharmaceutically unacceptable compositions are avoided. In addition, each excipient must of course be pharmaceutically acceptable, for example with sufficiently high purity.
  • the compounds disclosed herein can be prepared to oral. In the other embodiment, the compounds disclosed herein can be prepared to inhalation. In the still other embodiment, the compounds disclosed herein can be prepared to nasal administration. In the yet other embodiment, the compounds disclosed herein can be prepared to transdermal administration. In the still yet other embodiments, the compounds disclosed herein can be prepared to topical administration.
  • compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled-, targeted-, and programmed-release forms.
  • compositions provided herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable inner matrixes include polymethylmethacrylate, polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • compositions particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides.
  • the finely divided powder may be prepared by, for example, micronisation and milling.
  • the size-reduced (eg micronised) compound can be defined by a D 50 value of about 1 to about 10 microns (for example as measured using laser diffraction) .
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the patient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 318 (1986) , 318 (3) .
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
  • bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol.
  • these compounds and pharmaceutical compositions disclosed herein are also useful for veterinary treatment of pets, introduced species of animals, and mammals in farm animals.
  • the animals disclosed herein include horses, dogs, and cats.
  • the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.
  • the low resolution mass spectrometry (MS) was determined on an Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min) .
  • Mobile phase 5%-95% (0.1%formic acid in CH 3 CN) in (0.1%formic acid in H 2 O)
  • electrospray ionization (ESI) was used, and UV detection was performed at 210 nm /254 nm.
  • the purity of the compound was determined by high performance liquid chromatography (HPLC) using an Agilent 1260 HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by a DAD detector, and finally the purity of the compound was calculated by area normalization method.
  • X represents a halogen atom
  • PG represents an amino protecting group
  • T 1 and T 2 are selected from carboxy or amino
  • T 1 and T 2 can not be the same.
  • Step 1 synthesis of (S) -1-tert-butyl 2-methyl-4- ( ( (trifluoromethyl) sulfonyl) oxo) -2, 3-dihydro-1H-pyrrol-1, 2-dicarboxylate
  • Step 2 synthesis of (S) -1-tert-butyl 2-methyl 4- (4- (trifluoromethyl) phenyl) -1H-pyrrol-1, 2 (2H, 5H) -dicarboxylate
  • Step 3 synthesis of (S) -tert-butyl 2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenyl) -2, 5-dihyro-1H-pyrrol-1-carboxylate
  • Step 4 Synthesis of (2S) -tert-butyl 2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidine-1-carboxylate
  • Step 1 synthesis of (S) -1-tert-butyl 2-methyl 5-bromo-3, 4-dihydropyridin -1, 2 (2H) -dicarboxylate
  • Step 2 synthesis of (S) -1-tert-butyl 2-methyl 5- (4- (trifluoromethyl) phenyl) -3, 4-dihydropyridin-1, 2 (2H) -dicarboxylate
  • Step 3 synthesis of (2S) -1-tert-butyl 2-methyl 5- (4- (trifluoromethyl) phenyl) piperidin-1, 2-dicarboxylate
  • Step 3 synthesis of 1- (4-nitrophenyl) -3- (4- (trifluoromethyl) phenyl) pyrrolidine
  • Step 2 synthesis of benzyl 4- (4- ( (4- (ethylsulfonyl) benzyl) ) carbamoyl) phenyl -2, 3-dihydro-1H-pyrrole-1-carboxylate
  • Step 3 synthesis of N- (4- (ethylsulfonyl) benzyl) -4-pyrrolidin-3-yl) benzamide
  • Example 12 2- (4- (ethylsulfonyl) phenyl) -N- (2-methyl-4- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) phenyl) acetamide
  • Step 1 synthesis of 1- (3-methyl-4-nitrophenyl) -3- (4- (trifluoromethyl) phenyl) pyrrolidine
  • HATU 164 mg, 0.43 mmol
  • TEA 0.10 mL, 0.70 mmol
  • 2-methyl-4- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) aniline 93 mg, 0.29 mmol
  • 2- (4- (ethylsulfonyl) phenyl) acetic acid 79 mg, 0.35 mmol
  • Step 3 synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (3-methoxy-4- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) phenyl) acetamide
  • Step 2 synthesis of N- (4- (ethylsulfonyl) benzyl) -3- (methoxymethyl) -4- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) benzamide
  • Step 1 synthesis of 2-nitro-5- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyridine
  • Step 2 synthesis of 5- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyridin-2-amine
  • Step 1 synthesis of 5-nitro-2- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyridine
  • Step 3 synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (6- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyridin-3-yl) acetamide
  • Step 1 synthesis of benzyl 3- ( ( (trifluoromethyl) sulfonyl) oxy) -2, 5-dihyro -1H-pyrrol-1-carboxylate
  • reaction mixture was cooled to room temperature, concentrated in vacuo, and the residue was diluted with DCM (80 mL) .
  • Step 3 synthesis of 3- (4- (trifluoromethyl) phenyl) pyrrolidine
  • Step 5 synthesis of 2- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyrimidin-5-amine
  • Step 6 synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (2- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyrimidin-5-yl) acetamide
  • Step 3 synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (5-methoxy-6- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyridin-3-yl) acetamide
  • TEA TEA (0.10 mL, 0.70 mmol) was added into a solution of 5-methoxy-6- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) pyridin-3-amine (80 mg, 0.24 mmol) , 2- (4- (ethylsulfonyl) phenyl) acetic acid (85 mg, 0.37 mmol) and HATU (136 mg, 0.36 mmol) in DCM (6 mL) under nitrogen protection. The mixture was stirred at room temperature for 5 h.
  • Step 1 synthesis of methyl 5-methoxy-6- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) nicotinate
  • TEA (0.20 ml, 1.45 mmol) was added into a solution of 5-methoxy-6- (3- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) nicotinic acid (150 mg, 0.41 mmol) , (4- (ethylsulfonyl) phenyl) methylamine (160 mg, 0.80 mmol) and HATU (236 mg, 0.62 mmol) in DCM (6 mL) under nitrogen protection. The mixture was stirred at room temperature for 8 h.
  • Step 2 synthesis of methyl (2S) -1- (4-nitrophenyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-2-carboxylate
  • Step 3 synthesis of ( (2S) -1- (4-aminophenyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-2-yl) methanol
  • Step 2 synthesis of methyl (2R) -1- (4-nitrophenyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-2-carboxylate
  • Step 3 synthesis of ( (2R) -1- (4-aminophenyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-2-yl) methanol
  • Step 4 synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (4- ( (2R) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) phenyl) acetamide
  • Step 1 synthesis of (2S) -2- (methoxymethyl) -1- (4-nitrophenyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidine
  • Step 2 synthesis of 4- ( (2S) -2-methoxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) aniline
  • Step 3 synthesis of 2- (4- (ethylsulfonyl) phenyl) -N- (4- ( (2S) -2- (methoxymethyl) -4- (4 - (trifluoromethyl) phenyl) pyrrolidin-1-yl) phenyl) acetamide
  • Step 1 synthesis of tert-butyl (2S) -2- (methoxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidine-1-carboxylate
  • Step 2 synthesis of (2S) -2- (methoxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidine
  • Step 1 synthesis of tert-butyl (2R) -2- (methoxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-carboxylate
  • Example 26 4- ( (2S) -2- (ethoxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) -N- (4- (ethylsulfonyl) benzyl) benzamide
  • reaction mixture was diluted with DCM (50 mL) , and then washed with saturated NaHCO 3 solution (35 mL) .
  • Step 1 synthesis of 4- ( (2S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) benzonitrile
  • Step 2 synthesis of 4- ( (2S) -2- ( (2-fluoroethoxy) methyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) benzonitrile
  • Example 28 4- ( (2S) -2- ( (cyclopropylmethoxy) methyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) -N- (4- (ethylsulfonyl) benzyl) benzamide
  • Step 1 synthesis of 4- ( (2S) -2- ( (2-methoxyethoxy) methyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) benzonitrile
  • DIPEA (0.50 mL, 3.0 mmol) was added into a solution of (4- (ethylsulfonyl) phenyl) methylamine (80 mg, 0.40 mmol) , 4- ( (2S) -2- ( (2-methoxyethoxy) methyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) benzoic acid (120 mg, 0.28 mmol) and HATU (500 mg, 1.30 mmol) in DCM (15 mL) under nitrogen protection. The mixture was stirred at room temperature for 10 h.
  • Step 2 synthesis of (2R) -tert-butyl 4- (4- (trifluoromethyl) phenyl) -2-vinyl -pyrrolidin-1-carboxylate
  • Step 3 synthesis of (2S) -tert-butyl 2-ethyl -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-carboxylate
  • Step 4 synthesis of (2S) -2-ethyl-4- (4- (trifluoromethyl) phenyl) pyrrolidine
  • Step 5 synthesis of 4- ( (2S) -2-ethyl-4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) -N- (4- (ethylsulfonyl) benzyl) benzamide
  • Example 34 4- ( (2S) -2- (difluoromethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin -1-yl) -N- (4- (ethylsulfonyl) benzyl) benzamide
  • Step 1 synthesis of N- (4- (ethylsulfonyl) benzyl) -4- ( (2S) -2-formyl-4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) benzamide
  • Dess-Martin reagent 200 mg, 0.47 mmol was added into a solution of N- (4- (ethylsulfonyl) benzyl) -4- ( (2S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) benzamide (100 mg, 0.18 mmol) in DCM (42 mL) .
  • the mixture was stirred at room temperature for 12 h.
  • the reaction mixture was filtered, and to the filtrate was added slowly saturated aqueous NaHCO 3 (100 mL) under ice-bath condition.
  • Step 1 synthesis of tert-butyl 4-methyl-3- (4- (trifluoromethyl) phenyl) -2, 3-dihyro -1H-pyrrole-1-carboxylate
  • Step 2 synthesis of tert-butyl 3-methyl-4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-carboxylate
  • Step 3 synthesis of 3-methyl-4- (4- (trifluoromethyl) phenyl) pyrrolidine
  • Step 4 synthesis of N- (4- (ethylsulfonyl) benzyl) -4- (3-methyl-4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) benzamide
  • Example 36 4- ( (2S) -2- ( (dimethylamino) methyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidin-1-yl) -N- (4- (ethylsulfonyl) benzyl) benzamide
  • Step 1 synthesis of (2S) -1- (tert-butoxyformyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidine-2-carboxylic acid
  • Step 2 synthesis of (2S) -tert-butyl 2- (morpholin-4-formyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidine-1-carboxylate
  • DIPEA (0.70 mL, 3.94 mmol) was added into a solution of morpholine (0.80 mL, 9.00 mmol) , (2S) -1- (tert-butoxyformyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidine -2-carboxylic acid (1.54 g, 4.29 mmol) and HATU (2.25 g, 5.74 mmol) in DCM (55 mL) under nitrogen protection. The mixture was stirred at room temperature for 12 h.
  • Step 2 synthesis of (2S) -tert-butyl 2- (morpholinylmethyl) -4- (4- (trifluoromethyl) phenyl) pyrrolidine-1-carboxylate

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Abstract

L'invention concerne des composés utiles en tant qu'antagoniste de RORγ ayant la formule (I). Les composés ou la composition pharmaceutique de ceux-ci peuvent être utilisés pour réguler le récepteur orphelin apparenté au récepteur des rétinoïdes gamma t (RORγt) L'invention concerne également des procédés de préparation des composés et de la composition de ceux-ci, et leurs utilisations dans le traitement ou la prévention d'une inflammation à médiation par RORγt ou de maladies auto-immunes chez des mammifères, en particulier des êtres humains.
PCT/CN2019/095203 2018-07-10 2019-07-09 ANTAGONISTE DE RORγ ET SON UTILISATION EN MÉDECINE WO2020011147A1 (fr)

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Cited By (3)

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CN111658651A (zh) * 2020-06-08 2020-09-15 重庆医科大学附属第一医院 CQMU151在制备治疗Th17细胞介导自身免疫病药物中的应用
WO2021139595A1 (fr) * 2020-01-06 2021-07-15 东莞市东阳光新药研发有限公司 INHIBITEUR DE RORγT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
WO2021139599A1 (fr) * 2020-01-06 2021-07-15 东莞市东阳光新药研发有限公司 INHIBITEUR DE RORγT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION

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CN115521233B (zh) * 2021-06-08 2024-02-09 复旦大学 一种RORγ激动剂及其在制备治疗肿瘤疾病药物以及促进Type17细胞分化中的应用

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CN106061947A (zh) * 2014-01-06 2016-10-26 百时美施贵宝公司 环己基砜RORγ调节剂
WO2017024018A1 (fr) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma
WO2017157332A1 (fr) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier
WO2018116285A1 (fr) * 2016-12-23 2018-06-28 Glenmark Pharmaceuticals S.A. Dérivés de morpholine substitués en tant que modulateurs de ror gamma

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CN106061947A (zh) * 2014-01-06 2016-10-26 百时美施贵宝公司 环己基砜RORγ调节剂
WO2017024018A1 (fr) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma
WO2017157332A1 (fr) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier
WO2018116285A1 (fr) * 2016-12-23 2018-06-28 Glenmark Pharmaceuticals S.A. Dérivés de morpholine substitués en tant que modulateurs de ror gamma

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021139595A1 (fr) * 2020-01-06 2021-07-15 东莞市东阳光新药研发有限公司 INHIBITEUR DE RORγT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
WO2021139599A1 (fr) * 2020-01-06 2021-07-15 东莞市东阳光新药研发有限公司 INHIBITEUR DE RORγT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION
EP4089079A4 (fr) * 2020-01-06 2024-03-13 Sunshine Lake Pharma Co., Ltd. Inhibiteur de ror gamma t, son procédé de préparation et son utilisation
CN111658651A (zh) * 2020-06-08 2020-09-15 重庆医科大学附属第一医院 CQMU151在制备治疗Th17细胞介导自身免疫病药物中的应用
CN111658651B (zh) * 2020-06-08 2021-08-03 重庆医科大学附属第一医院 CQMU151在制备治疗Th17细胞介导自身免疫病药物中的应用

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