[go: up one dir, main page]

WO2017185959A1 - Dérivés fusionnés d'imidazole présentant une activité inhibitrice de l'ido/la tdo et procédé pour leur préparation et utilisation correspondante - Google Patents

Dérivés fusionnés d'imidazole présentant une activité inhibitrice de l'ido/la tdo et procédé pour leur préparation et utilisation correspondante Download PDF

Info

Publication number
WO2017185959A1
WO2017185959A1 PCT/CN2017/079583 CN2017079583W WO2017185959A1 WO 2017185959 A1 WO2017185959 A1 WO 2017185959A1 CN 2017079583 W CN2017079583 W CN 2017079583W WO 2017185959 A1 WO2017185959 A1 WO 2017185959A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
unsubstituted
optionally substituted
imidazo
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2017/079583
Other languages
English (en)
Chinese (zh)
Inventor
包如迪
李元念
刘福萍
张静涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Original Assignee
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority to CN201780023049.0A priority Critical patent/CN109071550B/zh
Publication of WO2017185959A1 publication Critical patent/WO2017185959A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the invention belongs to the technical field of drug development, and particularly relates to a fused imidazole derivative having IDO/TDO inhibitory activity, a preparation method and application thereof.
  • Tryptophan is an essential amino acid that is essential for the synthesis of proteins, niacin and the neurotransmitter serotonin (serotonin). Tryptophan has two metabolic pathways in the body: the serotonin pathway and the kynurenine pathway. A small fraction of tryptophan produces serotonin by tryptophan hydroxylase, about 95% of tryptophan in indoleamine 2,3-dioxygenase (IDO) or tryptophan The kynurenine is produced by the action of 2,3-dioxygenase (TDO).
  • IDO indoleamine 2,3-dioxygenase
  • TDO 2,3-dioxygenase
  • kynurenine There are also two metabolic pathways in kynurenine, most of which produce 3-hydroxykyurine (3-hydroxykynurenine) under the action of kynurenine 3-hydroxylase, followed by kynurenine (kynureninase, KYNU) catalyzes the hydrolysis to form 3-hydroxyanthronic acid, and finally undergoes multi-stage enzymatic reaction to produce quinolinic acid, pyridine carboxylic acid and nicotinamide adenine dinucleotide (NAD).
  • Molecules participate in various physiological processes in the body; another pathway is the formation of kynurenic acid (KYNA) under the action of kynurenine aminitric oxide transferase I and II (KAT I/1I).
  • Indoleamine 2,3-dioxygenase is the rate-limiting enzyme of the tryptophan/kynurenine pathway and is widely found in mammalian IDO in tissue cells other than the liver, including astrocytes. , microglia, macrophages, and vascular endothelial cells, acting on a wider range of substrates containing guanamine than TDO. TDO is expressed almost exclusively in the liver and has a high selectivity for substrates.
  • IDO can be induced by pro-inflammatory factors, in which interferon gamma is the strongest inducer, and during the stimulation activation of high levels of interferon gamma, IDO is activated, promoting the metabolism of tryptophan.
  • IDO immunomodulatory enzyme
  • T cells are sensitive to tryptophan depletion. When tryptophan concentration is decreased, T cell proliferation stops in G1 phase. IDO inhibits T cell activation by degrading tryptophan.
  • IDO activation is closely related to the pathogenesis of various diseases. It is an important target in the fields of cancer, Alzheimer's disease, Parkinson's disease, depression and other related diseases. It can liberate the body's defense against IDO/TDO inhibitors. System and help T cells better attack tumors, thus having the potential to treat a wide range of tumors Force, IDO/TDO inhibitors have broad application prospects, but so far no IDO/TDO inhibitors have been marketed. Therefore, it is of great theoretical significance and application value to find and develop new and efficient IDO inhibitors.
  • indoleamine 2,3-dioxygenase inhibitors are in the early stages of development, including NewLink's Indoximod, NLG-919 (IDO/TDO bispecific), Incyte's Epacadostat (INCB024360), and BMS.
  • IDO or TDO inhibitors from companies such as Flexus, Iomet, Iteos, Curadev, etc.;
  • Example compounds of the invention have high inhibitory activity against indoleamine 2,3-dioxygenase (IDO) in enzymatic and cellular models It also has inhibitory activity against tryptophan 2,3-dioxygenase (TDO) and has a good exposure in the PK animal model.
  • the inventors discovered a class of fused imidazole derivatives having the structure of formula (I) during the research, which have high inhibitory activity on IDO/TDO and can be used alone or in combination.
  • the invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 5 , -C 0-8 - OR 6 , -C 0-8 -C(O)OR 6 , -C 0-8 -C(O)R 6 , -C 0-8 -OC(O)R 7 , -C 0-8 -NR 8 R 9 , -C 0-8 -C(O)NR 8 R 9 , -N(R 8 )-C(O)R 7 or -N(R 8 )-C(O)OR 6 ,
  • C 3-8 cycloalkyl groups selected from halogen, cyano, nitro, azide, optionally substituted or unsubstituted C 1-8 alkyl, optionally substituted or unsubstituted , optionally substituted or unsubstituted 3-8 membered heterocyclic group, optionally substituted or unsubstituted C 5-10 aryl, optionally substituted or unsubstituted 5-10 membered heteroaryl, -C 0-8 -S(O) r R 5 , -C 0-8 -OR 6 , -C 0-8 -C(O)OR 6 , -C 0-8 -C(O)R 6 , -C 0-8 - OC(O)R 7 , -C 0-8 -NR 8 R 9 , -C 0-8 -C(O)NR 8 R 9 , -N(R 8 )-C(O)R 7 or -N( Substi
  • R, R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, optionally substituted or unsubstituted C 1-8 alkyl, optionally substituted or unsubstituted C 2-8 alkenyl, optionally substituted or unsubstituted C 2-8 alkynyl, optionally substituted or unsubstituted C 3-8 cycloalkyl, optionally substituted or unsubstituted 3-8 membered heterocyclic ring , optionally substituted or unsubstituted C 5-10 aryl, optionally substituted or unsubstituted 5-10 membered heteroaryl, -C 0-8 -S(O) r R 5 , -C 0-8 -OR 6 , -C 0-8 -C(O)OR 6 , -C 0-8 -C(O)R 6 , -C 0-8 -OC(O)R 7 ,
  • R 5 and R 6 are each independently selected from hydrogen, hydrazine, optionally substituted or unsubstituted C 1-8 alkyl, optionally substituted or unsubstituted C 2-8 alkenyl, optionally substituted or unsubstituted C 2-8 alkynyl, optionally substituted or unsubstituted C 3-8 cycloalkyl, optionally substituted or unsubstituted 3-8 membered heterocyclic group, optionally substituted or unsubstituted C 5-10 aryl a optionally substituted or unsubstituted 5-10 membered heteroaryl, optionally substituted or unsubstituted amino group or optionally substituted or unsubstituted C 1-8 alkanoyl;
  • R 7 is selected from hydrogen, hydrazine, optionally substituted or unsubstituted C 1-8 alkyl, optionally substituted or unsubstituted C 2-8 alkenyl, optionally substituted or unsubstituted C 2-8 alkyne , optionally substituted or unsubstituted C 1-8 alkoxy, optionally substituted or unsubstituted C 3-8 cycloalkyl, optionally substituted or unsubstituted C 3-8 cycloalkoxy, optionally a substituted or unsubstituted 3-8 membered heterocyclic group, an optionally substituted or unsubstituted 3-8 membered heterocyclic oxy group, an optionally substituted or unsubstituted C 5-10 aryl group, optionally substituted or unsubstituted a C 5-10 aryloxy group, an optionally substituted or unsubstituted 5-10 membered heteroaryl group, an optionally substituted or unsubstituted 5
  • R 8 and R 9 are each independently selected from hydrogen, hydrazine, hydroxy, optionally substituted or unsubstituted C 1-8 alkyl, optionally substituted or unsubstituted C 2-8 alkenyl, optionally substituted or not Substituted C 2-8 alkynyl, optionally substituted or unsubstituted C 3-8 cycloalkyl, optionally substituted or unsubstituted 3-8 membered heterocyclyl, optionally substituted or unsubstituted C 5 10 aryl, optionally substituted or unsubstituted 5-10 membered heteroaryl, optionally substituted or unsubstituted C 1-8 alkanoyl or optionally substituted or unsubstituted amino;
  • the optionally substituted substituent is selected from the group consisting of hydrazine, halogen, hydroxy, decyl, cyano, nitro, acetylamino, azide, sulfonyl, methylsulfonyl, isopropylsulfonyl, phenylsulfonyl, aminosulfonyl , C 1-8 alkyl, trifluoromethyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 1-8 alkane Oxyl, C 1-8 alkoxycarbonyl, C 1-8 alkylcarbonyl, C 1-8 alkylcarbonyloxy, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroary
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3, 4 or 5;
  • r 0, 1, or 2.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof wherein R 1 is selected from the group consisting of a hydrogen atom, a halogen, and C 1- A 6 alkyl group or a C 1-6 haloalkyl group, preferably a hydrogen atom or a halogen.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof wherein R, R 3 and R 4 are each independently selected from the group consisting of A hydrogen atom, a halogen or a C 1-6 alkyl group; preferably a hydrogen atom.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a C 1-6 alkoxy group, a 3-6 membered heterocyclic group or a 5-8 membered heteroaryl group; wherein the C 1-6 alkoxy group, the 3-6 membered heterocyclic group and the 5-8 membered heteroaryl group; Further optionally further substituted by C 1-6 alkyl, -(CH 2 ) x R 5 , -(CH 2 ) x OR 5 , -(CH 2 ) x COR 5 , -(CH 2 ) x OCOR 5 , C 3 Substituted by one or more substituents of -8 cycloalkyl and 3-6 membered heterocyclyl, wherein said R 5 is selected from the group consisting of hydrogen, hydroxy, acyl
  • a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is selected from the group consisting of the compound of the formula (II):
  • R, R 1 , R 2 and n are as defined in formula (I);
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is characterized by the compound of the formula (III):
  • R a is selected from a hydrogen atom, a -C 1-6 alkyl group, a -C 3-8 cycloalkyl group or a 3-8 heterocyclic group; wherein the alkyl group, cycloalkyl group and heterocyclic group are optionally -C One of 1-6 alkyl, -C 3-8 cycloalkyl, -ORc, -CORc, -COORc, -OCORc, 3-8 heterocyclic, 5-8 heteroaryl and 5-8 aryl or Substituted by a plurality of substituents;
  • R b is selected from a hydrogen atom, a halogen or a -C 1-6 alkyl group
  • R c is selected from a hydrogen atom, a -C 1-6 alkyl group or a 3-8 heterocyclic group
  • R, R 1 to R 4 , m and n are as defined in formula (I);
  • x is an integer of 0, 1, or 2.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is characterized by the compound of the formula (IV) :
  • R 1 , R 2 , R a , R b , R c , x and n are as defined in the formula (III).
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient .
  • the present invention provides a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for the preparation of a pathological feature for the treatment of a disorder of tryptophan metabolism mediated by IDO/TDO Use of the drug for the disease;
  • the disease characterized by the pathology of the IDO/TDO-mediated disorder of tryptophan metabolism is preferably selected from cancer or tumor, viral infection, depression, neurodegenerative disorder, trauma, age-related cataract, Organ transplant rejection or autoimmune disease.
  • C 1-8 alkyl means a straight-chain alkyl group having 1 to 8 carbon atoms and a branched alkyl group, the alkyl group means a saturated aliphatic hydrocarbon group, and C 0-8 means no carbon atom or C.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, Cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thio group, C 5-10 aryl group, C 5-10 aryloxy group, C 5-10 aryl group Substituted with a substituent of a thio group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, and a 5-10 membered heteroarylthio group;
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C 3-8 cycloalkyl” refers to a cycloalkyl group of from 3 to 8 carbon atoms, “C 5-10 .
  • Cycloalkyl means a cycloalkyl "C 5-6 cycloalkyl” comprising a cycloalkyl group of 5 to 10 carbon atoms, preferably 5 to 6 carbon atoms, for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • the "5-10 membered heterocyclic group” means a ring group containing 5 to 10 ring atoms
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms, preferably a "5-6 membered heterocyclic ring”.
  • Base means a ring group containing 5 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, propylene oxide, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably a ring Oxypropane, piperazinyl and morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused heterocyclyl refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon.
  • r is an integer of 0, 1, 2
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:
  • Bridge heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups.
  • Non-limiting examples of bridged cycloalkyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group
  • C 5-10 aryl means an all-carbon aryl group having 5 to 10 carbons
  • 5-10 membered aryl group means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group can be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 Heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5 Substituted with a substituent of a 10-membered heteroaryloxy group and a 5-10 membered heteroarylthio group;
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O) r (where r is an integer 0, 1, 2), 5-
  • a 6-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms
  • a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl,
  • a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group or the like is preferably a pyrazolyl group.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxy, thiol, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3- 8-membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl Substituted with a substituent of 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio;
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like are examples of the alkenyl group.
  • Alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 Heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5 Substituted with a substituent of a 10-membered heteroaryloxy group or a 5-10 membered heteroarylthio group;
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from halogen, hydroxy, mercapto, cyano, nitro, azido group, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 Heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5 Substituted with a substituent of a 10-membered heteroaryloxy group or a 5-10 membered heteroarylthio group;
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above.
  • the C 1-8 alkoxy group means an alkyloxy group having 1-8 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, azide a group, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a halogen-substituted C 1-8 alkyl group, a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered Substituted with an aryl group, a 5-10 membered heteroaryloxy group or a 5-10 membered heteroarylthio group;
  • Halo-substituted C 1-8 alkyl means a hydrogen on the alkyl group optionally substituted with 1-8 carbon alkyl groups substituted by fluorine, chlorine, bromine or iodine atoms, such as difluoromethyl, dichloromethyl Base, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • Halo-substituted C 1-8 alkoxy refers to a hydrogen on the alkyl group optionally substituted with 1-8 carbon alkoxy groups substituted with fluorine, chlorine, bromine or iodine atoms.
  • fluorine chlorine, bromine or iodine atoms.
  • difluoromethoxy dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
  • Halogen means fluoro, chloro, bromo or iodo.
  • DMSO dimethyl sulfoxide
  • LDA lithium diisopropylamide
  • DIAD diisopropyl azodicarboxylate
  • DMF N,N-dimethylformamide
  • DPPA diphenyl azide
  • Pd(dppf)Cl 2 means [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • THF tetrahydrofuran
  • Optionally substituted refers to one or more hydrogen atoms in the group independently of each other by the corresponding number of hydrazine, halogen, hydroxy, thiol, cyano, nitro, azide, C1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylthio, C 5-10 aryl, C 5-10 aryloxy, C 5-10 arylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryl Substituted by an oxy group or a substituent of a 5-10 membered heteroarylthio group; preferably an anthracene, a halogen, a hydroxy group, a decyl group, a cyano group, a nitro group, an acetyla
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an olefin.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ) internally labeled as tetramethylsilane (TMS).
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • Hydrogen atmosphere It means that the reaction flask is connected to a hydrogen balloon of about 1L volume.
  • the solution in the examples means an aqueous solution unless otherwise specified.
  • the temperature of the reaction is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • TLC thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • Column chromatography eluent system includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and ethyl acetate system, D: ethyl acetate and methanol, solvent
  • A dichloromethane and methanol system
  • B n-hexane and ethyl acetate system
  • C dichloromethane and ethyl acetate system
  • D ethyl acetate and methanol
  • solvent The volume ratio is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of ammonia water and acetic acid.
  • Step 6 Preparation of 1-((5H-imidazo[5,1-a]isoindol-5-yl)methyl)-3-(4-cyanophenyl)urea
  • the second step preparation of 6-fluoro-5H-imidazo[5,1-a]isoindole
  • 6-Fluoro-5H-imidazo[5,1-a]isoindole 200 mg, 1.148 mmol was dissolved in dry tetrahydrofuran (2 mL), cooled to -78 ° C under N2, and LDA (0.86 mL, 2M) In THF). Slowly rise to room temperature, stir for 3 hours, add water, extract with dichloromethane, dry, and purify by column chromatography to give 2-(6-fluoro-5H-imidazo[5,1-a]isoindole-5-yl)acetate Butyl ester (245 mg).
  • Step 5 Preparation of 1-(4-cyanophenyl)-3-((6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)methyl)urea
  • Step 2 1-((6-Fluoro-5H-imidazo[5,1-a]isoindol-5-yl)methyl)-3-(4-(1-methyl-1H-pyrazole) -4- Preparation of phenyl)urea
  • the second step preparation of 6-(trifluoromethyl)-5H-imidazo[5,1-a]isoindole
  • the preparation method was the same as in Example 5.
  • the second step preparation of 7-fluoro-5H-imidazo[5,1-a]isoindole
  • Step 5 Preparation of 1-(4-cyanophenyl-3-((7-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)methyl)urea
  • the second step preparation of 8-fluoro-5H-imidazo[5,1-a]isoindole
  • Step 5 Preparation of 1-(4-cyanophenyl-3-((8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)methyl)urea
  • the preparation method was the same as in Example 18.
  • the preparation method was the same as in Example 28.
  • the preparation method was the same as in Example 27.
  • the preparation method was the same as in Example 28.
  • the preparation method was the same as in Example 39.
  • the preparation method was the same as in Example 40.
  • the third step 1-((5H-imidazo[5,1-a]isoindol-5-yl)methyl)-3-(5-chloro-2-fluoro-4-(1-cyclobutyl) Preparation of methyl-1H-pyrazol-4-yl)phenyl)urea
  • Examples 52 and 53 2-(4-(4-(3-(5H-imidazo[5,1-a]isoindol-5-yl)methyl)ureido)-2-fluorobenzene -1H-pyrazol-1-yl)ethyl acetate and 1-((5H-imidazo[5,1-a]isoindol-5-yl)methyl)-3-(3- Fluoro-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)phenyl)urea
  • the reaction was carried out at 104 ° C for 1 hour under a nitrogen atmosphere.
  • the reaction was completed by LC-MS.
  • the reaction mixture was concentrated and the residue was purifiedjjjjjjjjjj Methyl)-3-(4-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)-3-fluorophenyl)urea (5.7 mg).
  • the reaction was carried out at 104 ° C for 1 hour under a nitrogen atmosphere.
  • the reaction was completed by LC-MS.
  • the reaction mixture was concentrated and the residue was purifiedjjjjjjjjjj Methyl)-3-(3-fluoro-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)phenyl)urea (5.8 mg).
  • the preparation method was the same as in Example 54.
  • the reaction was carried out at 104 ° C for 1 hour under nitrogen.
  • the reaction was completed by LC-MS.
  • the reaction mixture was concentrated and the residue was purifiedjjjjjjjjjj Methyl)-3-(3-fluoro-4-(1-(2-(2-carbonylpyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)urea (8.5 mg ).
  • the reaction was carried out at 104 ° C for 1 hour under nitrogen.
  • the reaction was completed by LC-MS.
  • the reaction mixture was concentrated and the residue was purifiedjjjjjjjjjj Methyl)-3-(5-chloro-2-fluoro-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)urea (3.5 mg).
  • the preparation method was the same as in Example 64.
  • the preparation method was the same as in Example 64.
  • the preparation method was the same as in Example 54.
  • the preparation method was the same as in Example 64.
  • the preparation method was the same as in Example 54.
  • the preparation method was the same as in Example 64.
  • the preparation method was the same as in Example 54.
  • the preparation method was the same as in Example 54.
  • the preparation method was the same as in Example 64.
  • the preparation method was the same as in Example 54.
  • the preparation method was the same as in Example 80.
  • the preparation method was the same as in Example 80.
  • the preparation method was the same as in Example 80.
  • the preparation method was the same as in Example 80.
  • the preparation method was the same as in Example 81.
  • IDO Human indoleamine 2,3-dioxygenase
  • the idoleamine 2,3-dioxygenase (IDO) enzymatic reaction was carried out in a 96-well plate with a reaction volume of 20 ⁇ L.
  • the reaction conditions were: 40 nM IDO enzyme, 0.2 mM L-tryptophan, 50 mM KPB. (pH 6.5) buffer, 20 mM L-ascorbate, 10 ⁇ M methylene blue, 0.2 mg/mL catalase, different concentrations of compound, ⁇ 1% dimethyl sulfoxide.
  • test compound stock solution was prepared as 10 mM with dimethyl sulfoxide.
  • the experiment was diluted with dimethyl sulfoxide to the highest concentration of the test, then subjected to a 1:3 gradient dilution, generally diluted to 8 to 10 concentration points, each A multi-well was set at the concentration point, and each test contained one reference compound.
  • the original data of absorbance at 490 nm was read by the microplate reader, and the inhibition of IDO enzyme activity was calculated at different concentration points of the test compound.
  • the half-inhibitory concentration IC 50 value of the compound was obtained by nonlinear fitting analysis of the inhibition percentage data by GraphPad Prism software.
  • Example 39 twenty three Example 72 ⁇ 1 Example 40 twenty three Example 73 75 Example 41 16 Example 74 46 Example 45 19 Example 75 44 Example 46 11 Example 76 46 Example 47 29 Example 77 19 Example 48 45 Example 79 19 Example 49 17 Example 80 ⁇ 1 Example 50 1 Example 81 19 Example 51 ⁇ 1 Example 83 28 Example 52 twenty four Example 84 3 Example 53 17 Example 85 26 Example 54 2
  • test data indicates that the compounds of the examples of the present invention have a strong IDO inhibition.
  • Interferon gamma induces expression of IDO in Hela cells, a model used to test compounds for inhibitory activity against indoleamine 2,3-dioxygenase (IDO) activity.
  • the culture medium of Hela cells ATCC
  • the test compound storage solution was prepared as 10 mM with dimethyl sulfoxide.
  • the experiment was diluted with dimethyl sulfoxide to the highest concentration in the experiment.
  • the experiment was carried out with a medium serial dilution of 3 times, usually diluted to 8 to 10 concentration points. Multiple holes are provided for each concentration point.
  • the final concentration of DMSO was 0.5% and each experiment contained an internal reference compound.
  • the procedure was as follows: 20,000 HeLa cells (ATCC) were added to each well in a 96-well culture plate overnight, and interferon gamma (final concentration 50 ng/mL) and different concentrations of the test compound and internal reference were administered 24 hours later. The compound is added to the cultured cells. After 24:00, 140 ⁇ L of supernatant/well was transferred to a new 96-well plate, 10 ⁇ L of 6.1 N trichloroacetic acid was added to each well, and incubation was carried out at 50 ° C for 30 minutes to hydrolyze N-formyl-kynurenine into dogs. Urinine.
  • reaction mixture was centrifuged (2500 rpm for 10 minutes) to remove the precipitate, and 100 ⁇ L of the supernatant was transferred to another new 96-well plate, and 100 ⁇ L of 2% (w/v) p-(dimethylamino)benzaldehyde was added to each well.
  • p-DMBA glacial acetic acid solution
  • absorbance at 490 nm was read with a BioTek Synergy H1 plate reader (Molecular Devices).
  • the original data of absorbance at 490 nm was read by the microplate reader, and the inhibition of IDO enzyme activity was calculated at different concentration points of the test compound.
  • the half-inhibitory concentration IC 50 value of the compound was obtained by nonlinear fitting analysis of the inhibition percentage data by GraphPad Prism software.
  • Example number IC 50 (uM) Example number IC 50 (uM)
  • Example 1 0.842 Example 54 0.322 Example 12 0.991 Example 56 0.483 Example 16 0.899 Example 57 0.233 Example 21 0.609 Example 58 0.666 Example 22 0.441 Example 60 0.321 Example 23 0.249 Example 61 0.453 Example 24 0.388 Example 62 0.293 Example 25 0.955 Example 64 0.322 Example 27 0.724 Example 65 0.571 Example 28 0.298 Example 66 0.872 Example 31 0.363 Example 67 0.278 Example 37 0.637 Example 68 0.426 Example 38 0.717 Example 69 0.309 Example 39 0.409 Example 70 0.640 Example 40 0.152 Example 71 0.305 Example 41 0.144 Example 72 0.324 Example 45 0.208 Example 73 0.735 Example 46 0.290 Example 74 0.564 Example 47 0.526 Example 75 0.627 Example 48 0.604 Example 76 0.310 Example 49 0.436 Example 77 0.464 Example 50 0.354 Example 79 0.587 Example 51 0.388 Example 80 0.578 Example 52 0.950 Example 81 0.788 Example 53 0.957 Example 82
  • Test data indicates that the compounds of the examples of the invention have strong cellular activity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés fusionnés d'imidazole présentant une activité d'inhibition de l'IDO/la TDO et présentant la structure de formule (I) et un procédé pour leur préparation et utilisation correspondante. La série de dérivés fusionnés d'imidazole présente un degré élevé d'activité inhibitrice contre l'IDO/la TDO et peut être largement appliquée pour traiter ou prévenir des cancers ou des tumeurs, des infections virales, la dépression, des maladies neurodégénératives, un traumatisme, des cataractes liées à l'âge, un rejet de greffe d'organe ou des maladies auto-immunes et peut également être utilisée pour inhiber une immunosuppression chez un patient et présente le potentiel d'être développé en une nouvelle génération d'immunosuppresseurs.
PCT/CN2017/079583 2016-04-27 2017-04-06 Dérivés fusionnés d'imidazole présentant une activité inhibitrice de l'ido/la tdo et procédé pour leur préparation et utilisation correspondante Ceased WO2017185959A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780023049.0A CN109071550B (zh) 2016-04-27 2017-04-06 具有ido/tdo抑制活性的稠合咪唑衍生物及其制备方法和应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610273075.6A CN107312005B (zh) 2016-04-27 2016-04-27 具有ido/tdo抑制活性的稠合咪唑衍生物及其制备方法和应用
CN201610273075.6 2016-04-27

Publications (1)

Publication Number Publication Date
WO2017185959A1 true WO2017185959A1 (fr) 2017-11-02

Family

ID=60161886

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/079583 Ceased WO2017185959A1 (fr) 2016-04-27 2017-04-06 Dérivés fusionnés d'imidazole présentant une activité inhibitrice de l'ido/la tdo et procédé pour leur préparation et utilisation correspondante

Country Status (2)

Country Link
CN (2) CN107312005B (fr)
WO (1) WO2017185959A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106478634B (zh) * 2015-09-01 2020-05-22 尚华医药科技(江西)有限公司 稠合咪唑化合物、其制备方法、药物组合物和用途
WO2018045966A1 (fr) * 2016-09-12 2018-03-15 广州必贝特医药技术有限公司 Composés tricycliques fusionnés contenant de l'imidazole et leurs applications

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103547579A (zh) * 2011-04-15 2014-01-29 新联基因公司 用作ido抑制剂的稠合咪唑衍生物
WO2016037026A1 (fr) * 2014-09-05 2016-03-10 Merck Patent Gmbh Composés diaza et triaza tricycliques à substitution cyclohexyl-éthyle utilisés comme antagonistes de l'indoleamine-2,3-dioxygénase (ido) pour le traitement du cancer
CN105884780A (zh) * 2015-02-16 2016-08-24 上海迪诺医药科技有限公司 多环化合物、其药物组合物及应用
CN106478634A (zh) * 2015-09-01 2017-03-08 上海璎黎药业有限公司 稠合咪唑化合物、其制备方法、药物组合物和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103547579A (zh) * 2011-04-15 2014-01-29 新联基因公司 用作ido抑制剂的稠合咪唑衍生物
WO2016037026A1 (fr) * 2014-09-05 2016-03-10 Merck Patent Gmbh Composés diaza et triaza tricycliques à substitution cyclohexyl-éthyle utilisés comme antagonistes de l'indoleamine-2,3-dioxygénase (ido) pour le traitement du cancer
CN105884780A (zh) * 2015-02-16 2016-08-24 上海迪诺医药科技有限公司 多环化合物、其药物组合物及应用
CN106478634A (zh) * 2015-09-01 2017-03-08 上海璎黎药业有限公司 稠合咪唑化合物、其制备方法、药物组合物和用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Also Published As

Publication number Publication date
CN107312005B (zh) 2021-12-17
CN109071550A (zh) 2018-12-21
CN109071550B (zh) 2021-04-06
CN107312005A (zh) 2017-11-03

Similar Documents

Publication Publication Date Title
CN111757878B (zh) 一种哒嗪类衍生物抑制剂、其制备方法和应用
CN109963854B (zh) 杂芳基并[4,3-c]嘧啶-5-胺类衍生物、其制备方法及其在医药上的应用
CN105636953B (zh) 1,4‑二取代的哒嗪衍生物及其用于治疗与smn缺乏相关的病症的用途
CN106220644B (zh) 稠环嘧啶氨基衍生物﹑其制备方法、中间体、药物组合物及应用
KR20210135561A (ko) 피라진 유도체 및 shp2 억제에서의 그의 적용
CN113173924B (zh) 一种作为cdk抑制剂的吡啶乙酰胺类衍生物、其制备方法及用途
CN105503827B (zh) Egfr抑制剂及其制备方法和用途
WO2020200158A1 (fr) Dérivés d'amide n-hétéroaromatiques destinés au traitement du cancer
WO2020063792A1 (fr) Dérivé macrocyclique d'indole, son procédé de préparation et son application en médecine
CN118005656B (zh) Kras g12c突变蛋白嘧啶并噻喃二酮类抑制剂的制备及其应用
CN106187915A (zh) 具有alk与egfr双重活性的抑制剂及其制备方法和应用
WO2022166469A1 (fr) Inhibiteur de kinase fgfr et son utilisation
WO2016011979A1 (fr) Dérivé 7h-pyrrolo[2,3-d]pyrimidine 2,4-disubstituté, procédé de préparation et utilisation médicinale de ce dernier
WO2016169421A1 (fr) Dérivé imidazo isoindole, méthode de préparation correspondante et utilisation médicale correspondante
WO2024131777A1 (fr) Composé chimérique de kras-protac, son procédé de préparation et son utilisation
CN107438598A (zh) 喹唑啉和喹啉化合物及其用途
WO2020034987A1 (fr) Promédicament renfermant un dérivé de glucuronide en tant qu'inhibiteur jak, son procédé de préparation et ses applications
CN111094254B (zh) 杂芳基类衍生物、其制备方法及其在医药上的应用
WO2024149189A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation
CN115667246B (zh) 一种哒嗪类衍生物自由碱的晶型及其制备方法和应用
CN109071550B (zh) 具有ido/tdo抑制活性的稠合咪唑衍生物及其制备方法和应用
TW202430164A (zh) Pkmyt1抑制劑
WO2023116763A1 (fr) Composé pyridazine, composition pharmaceutique et leur utilisation
CN115215862A (zh) 嘧啶酮化合物及其用途
CN110105275B (zh) 酰胺类衍生物、其制法与医药上的用途

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

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

Ref document number: 17788611

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17788611

Country of ref document: EP

Kind code of ref document: A1