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WO2019141095A1 - Dérivé d'amidine et de guanidine, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé d'amidine et de guanidine, son procédé de préparation et son utilisation médicale Download PDF

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Publication number
WO2019141095A1
WO2019141095A1 PCT/CN2019/070339 CN2019070339W WO2019141095A1 WO 2019141095 A1 WO2019141095 A1 WO 2019141095A1 CN 2019070339 W CN2019070339 W CN 2019070339W WO 2019141095 A1 WO2019141095 A1 WO 2019141095A1
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alkyl
group
cycloalkyl
alkoxy
compound
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English (en)
Chinese (zh)
Inventor
李桂英
蔡家强
游泽金
韩润丰
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/16—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring
    • C07C13/18—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring with a cyclohexane ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel terpenoids and anthraquinone derivatives as IDO inhibitors, a process for the preparation thereof, and pharmaceutical compositions containing the same, and their use in medicine.
  • Tumor immunotherapy is to control and kill tumor cells by modulating the immune system of the body to enhance the anti-tumor immunity of the tumor microenvironment (such as inhibiting IDO-mediated tumor immune escape mechanism). Because of its safety, effectiveness, and low adverse reactions, it has become a new treatment for cancer treatment after surgery, radiotherapy and chemotherapy.
  • IDO is one of the most promising small molecule drug targets for cancer immunotherapy currently entering clinical research.
  • the Hayaishi group (Hayaishi O. et al., Science, 1969, 164, 389–396) first discovered IDO in cells. It is a monomeric enzyme containing heme.
  • the cDNA encoded protein is composed of 403 amino acids. It is 45kDa, the rate-limiting enzyme that catalyzes the catabolism of tryptophan by the kynurenine pathway. It is widely distributed in tissues other than the liver of humans and other mammals (such as rabbits and mice). It is the only catalyzed color ammonia outside the liver. The rate-limiting enzyme for acid catabolism.
  • T cell (Treg) mediated immunosuppression promotes immune surveillance of tumor escape.
  • IDO In addition to tumors, IDO is associated with the development of diseases such as depression, senile dementia, and cataracts. In addition, IDO is also involved in neurological and psychiatric disorders (such as mood disorders) and other chronic diseases caused by IDO activation leading to degradation of tryptophan, such as viral infections (such as AIDS), autoimmune diseases, bacterial infections such as Lyme disease and Streptococcal infection, etc. Therefore, inhibition of IDO activity has enormous therapeutic value.
  • diseases such as depression, senile dementia, and cataracts.
  • IDO is also involved in neurological and psychiatric disorders (such as mood disorders) and other chronic diseases caused by IDO activation leading to degradation of tryptophan, such as viral infections (such as AIDS), autoimmune diseases, bacterial infections such as Lyme disease and Streptococcal infection, etc. Therefore, inhibition of IDO activity has enormous therapeutic value.
  • the IDO small molecule inhibitor Epacadostat developed by Incyte is currently used in combination with the PD-1 antibody keytruda or the PD-L1 antibody avelumab in clinical I/II trials to treat a variety of cancers, such as advanced or metastatic solid tumors, relapsing gelatinous mothers. Cell tumors, etc.
  • Nivolumab for the treatment of a variety of cancers, such as advanced renal cell carcinoma, untreated metastatic or unresectable melanoma;
  • Nivolumab and the LAG-3 antibody relatlimab were used in the treatment of advanced malignancies.
  • NewLink Genetics is also conducting clinical trials of multiple indoximod (NLG-8189) in combination with other drugs, such as in the clinical phase II/III trial with PD-1 antibody keytruda or Nivolumab for the treatment of metastatic melanoma.
  • IDO inhibitor patent applications include WO2016073770, WO2016073734, WO2016073738, and the like. However, there are currently no IDO inhibitors listed. In order to achieve better therapeutic effects and better meet market demand, it is urgent to develop new high-efficiency and low-toxic IDO inhibitors.
  • the IDO inhibitor is a compound of formula I, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, eutectic, polymorph or solvent of the compound. Or a stable isotope derivative, metabolite or prodrug of the compound:
  • n 0 or 1;
  • R 1 is selected from a C 6 -C 14 aryl group, a 5-14 membered heteroaryl group, or a 9-10 membered arylheterocyclyl group; said C 6 -C 14 aryl group, 5-14 membered heteroaryl group
  • the 9-10 membered arylheterocyclyl group may be optionally substituted by the following substituents: OH, halogen, CN, NO 2 , CO 2 H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl.
  • R 2 and R 3 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl-OC 1- C 6 alkyl, C 1 -C 6 hydroxyalkyl may be optionally substituted by OH, halogen, CN, C(O)NH 2 , NH 2 , NHMe, NMe 2 , 4-7 Heterocyclyl, the 4-7 membered heterocyclyl is optionally substituted by OH, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkane An oxy group, a
  • R 4 and R 5 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl may be optionally
  • the ground is substituted by the following substituents: OH, halogen, C 1 -C 6 haloalkyl, CN, CO 2 H, -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 9 C(O)R 10 ;
  • R 6 is selected from C 6 -C 14 aryl, 5-14 membered heteroaryl, -CH 2 -C 6 -C 14 aryl, -CH 2 -5-14 membered heteroaryl, C 3 -C 7 ring Alkyl, 3-14 membered heterocyclyl, 9-12 membered arylheterocyclyl; said C 6 -C 14 aryl, 5-14 membered heteroaryl, -CH 2 -C 6 -C 14 An aryl group, a -CH 2 -5-14 membered heteroaryl group, a C 3 -C 7 cycloalkyl group, a 3-14 membered heterocyclic group, a 9-12 membered arylheterocyclyl group may be optionally substituted by the following substituents Substitution: OH, halogen, CN, NO 2 , CO 2 H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 al
  • R 7 , R 8 and R 9 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1- C 6 hydroxyalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl, 4-7 membered heterocyclyl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy , C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl and 4-7 membered heterocyclyl are optionally substituted by the following substituents : OH, CN, halogen, NH 2 , NHMe, NMe 2 , CO 2 H, or R 7 , R 8 together with the N atom to which they are attached form a 4-7 membered heterocyclic group; when a
  • R 10 is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 - C 6 alkyl-OC 1 -C 6 alkyl, 4-7 membered heterocyclic group, said C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 3 -C 6 cycloalkyl group, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl and 4-7 membered heterocyclyl can be optionally substituted by OH, CN, halogen, NH 2 , NHMe, NMe 2 , CO 2 H, or R 9 , R 10 and the N and C or S atoms to which they are attached form a 4-7 membered heterocyclic group; when a plurality of R 10 are present simultaneously,
  • X is NR 11 or CHNO 2 ;
  • R 11 is selected from the group consisting of hydrogen, OH, CN, NH 2 , NHMe, NMe 2 , -SO 2 R 12 , -C(O)R 13 ,
  • R 12 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl is optionally substituted by the following substituent: OH , OC 1 -C 6 alkyl, NH 2 , NHMe, NMe 2 , 4-7 membered heterocyclic group;
  • R 13 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-OC 1 - C 6 alkyl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-
  • the OC 1 -C 6 alkyl group may be optionally substituted by the following substituents: OH, halogen, C 1 -C 6 haloalkyl, CN, C(O)NH 2 , NH 2 , NHMe, NMe 2 , 4-7 Heterocyclic group.
  • the compound has the structure of Formula II, III, IV or V:
  • R 1 , R 5 , R 6 and X are as defined above for formula I;
  • R 1 , R 2 , R 3 , R 5 , R 6 and X are as defined above for formula I; preferably, R 2 and R 3 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl;
  • R 1 , R 4 , R 5 , R 6 and X are as defined above for formula I; preferably, R 4 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C The 1- C 6 alkyl-OC 1 -C 6 alkyl group may be optionally substituted by the following substituents: OH, halogen, C 1 -C 6 haloalkyl, CN, CO 2 H, -NR 7 R 8 , -C (O)NR 7 R 8 , -NR 9 C(O)R 10 ;
  • R 1 , P ring, R 5 , R 6 and X are as defined in the above formula I.
  • the compound has the structure of Formula II-1, II-2, III-1, III-2, IV-1, IV-2, V-1 or V-2:
  • R 1 , R 5 , R 6 and X are as defined above for formula I;
  • R 1 , R 2 , R 3 , R 5 , R 6 and X are as defined above for formula I; preferably, R 2 and R 3 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl;
  • R 1 , R 4 , R 5 , R 6 and X are as defined above for formula I; preferably, R 4 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1- C 6 alkyl-OC 1 -C 6 alkyl may be optionally substituted by OH, halogen, C 1 -C 6 haloalkyl, CN, CO 2 H, -NR 7 R 8 , C ( O) NR 7 R 8 , -NR 9 C(O)R 10 ;
  • R 1 , P ring, R 5 , R 6 and X are as defined in the above formula I.
  • R 1 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C 6 -C 10 aryl
  • the 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl can be optionally substituted with OH, halogen, CN, NO 2 , CO 2 H, C 1 -C 6 alkyl, C 3- C 6 cycloalkyl, C 1 -C 6 alkoxy, -OC 1 -C 6 alkyl-OC 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, -C(O)OR 7 , -C(O)NR 7 R 8 , -NR 9 C(O)R 10 , -NR 9 SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 7 R 8 , -C(O)R 10 , -SO 2 R 10 , C 6 -
  • R 1 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C 6 -C 10 aryl,
  • the 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl can be optionally substituted with the following substituents: OH, halogen, CN, NO 2 , CO 2 H, C 1 -C 4 alkyl, C 3- C 6 cycloalkyl, C 1 -C 4 alkoxy, -OC 1 -C 4 alkyl-OC 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, -C(O)OR 7 , -C(O)NR 7 R 8 , -NR 9 C(O)R 10 , -NR 9 SO 2 R 10 , -SO 2 NR 7 R 8 , -NR 7 R 8 , -C(O)R 10 , -SO 2
  • R 1 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl; said C 6 -C 10 aryl,
  • the 5-10 membered heteroaryl or 9-10 membered benzoheterocyclyl can be optionally substituted with a halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 - C 4 alkoxy, C 1 -C 4 hydroxyalkyl, -C(O)NR 7 R 8 ; C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6
  • the cycloalkyl group may be optionally substituted by the following substituents: OH, -NR 7 R 8 ; R 7 , R 8 are as defined above.
  • R 1 is selected from the group consisting of phenyl, quinolyl, pyridyl, oxazolyl, The phenyl group, quinolyl group, pyridyl group, carbazolyl group, It may be optionally substituted by the following substituents: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy, - C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -OCH 2 CH 2 OH, -OCH 2 CH 2 NH(CH 3 ), -OCH 2 CH 2 N(CH 3 ) 2 .
  • R 1 is selected from the group consisting of phenyl, quinolyl, pyridyl, and the phenyl, quinolyl, pyridyl group may be optionally substituted with the following substituents: fluorine, chlorine, Methyl, ethyl, propyl, isopropyl, n-butyl, methoxy, ethoxy, propoxy, isopropoxy.
  • R 1 is selected from the group consisting of phenyl, p-methoxyphenyl, quinolyl, pyridyl,
  • n 1.
  • n 0.
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 1 - C 4 alkyl-OC 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, said C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl may be optionally substituted by OH, halogen, CN, C(O)NH 2 , NH 2 , NHMe, NMe 2 , 4-7 membered heterocyclic group, which may be optionally substituted by the following substituents: OH, halogen, CN, C 1 -C 4 alkyl, C 1 -C a 4- haloalkyl group
  • R 2 and R 3 are each independently selected from hydrogen, C 1 -C 4 alkyl or R 2 , R 3 and the C atom to which they are attached form a P ring, said P The ring is selected from a C 3 -C 5 cycloalkyl group.
  • R 2 and R 3 are each independently selected from hydrogen, methyl, ethyl, propyl, or R 2 , R 3 and the C atom to which they are attached form a P ring,
  • the P ring is selected from cyclopropane, cyclobutane or cyclopentane.
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; preferably, R 2 and R 3 are each independently selected from hydrogen, methyl.
  • R 4 and R 5 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkoxy, C 2 -C 4 hydroxyalkyl, C 2 -C 4 alkyl-OC 2 -C 4 alkyl, said C 1 -C 4 alkyl, C 2 -C 4 alkoxy, C 2 -C 4 hydroxyalkyl, C 2 -C 4 alkyl- OC 2 -C 4 alkyl may be optionally substituted by OH, halogen, C 1 -C 4 haloalkyl, CN, CO 2 H, -NR 7 R 8 , C(O)NR 7 R 8 , -NR 9 C(O)R 10 ; R 7 , R 8 , R 9 , R 10 are as defined above.
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 2 -C 4 hydroxyalkyl, said C 1 -C 4 alkyl It is optionally substituted by the halogen: -NR 7 R 8 , R 7 , R 8 as defined above.
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, -CH 2 CH 2 NH (CH 3 ), -CH 2 CH 2 N(CH 3 ) 2 .
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; preferably, R 4 and R 5 are each hydrogen.
  • R 6 is selected from the group consisting of C 6 -C 10 aryl, 5-10 membered heteroaryl, -CH 2 -C 6 -C 10 aryl, -CH 2 -5-10 a heteroaryl group, a C 3 -C 7 cycloalkyl group, a 3-10 membered heterocyclic group, a 9-12 membered benzoheterocyclyl group; said C 6 -C 10 aryl group, 5-10 membered heteroaryl group, -CH 2 -C 6 -C 10 aryl, -CH 2 -5-10 membered heteroaryl, C 3 -C 7 cycloalkyl, 3-10 membered heterocyclic, 9-12 membered benzoheterocyclyl Cocoa may be optionally substituted by the following substituents: OH, halogen, CN, NO 2 , CO 2 H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl
  • R 6 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, -CH 2 -C 6 -C 10 aryl optionally substituted by a substituent , -CH 2 -5-10 membered heteroaryl, 3-10 membered heterocyclic group, 9-12 membered benzoheterocyclyl, said C 6 -C 10 aryl, 5-10 membered heteroaryl, 3
  • the -10 membered heterocyclyl, 9-12 membered benzoheterocyclylcocoa is optionally substituted with the following substituents: OH, halogen, CN, NO 2 , CO 2 H, C 1 -C 4 alkyl, C 3- C 5 cycloalkyl, C 1 -C 4 alkoxy, C 2 -C 4 hydroxyalkyl, -OC 2-4 alkyl-OH, -OC 2-4 alkyl-NR 7 R 8 , 4-7
  • R 6 is selected from the group consisting of phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridyl, thiazolyl, pyrrolidinyl, 2,3-dihydrobenzene And [b][1,4]dioxanyl, the phenyl, piperidinyl, oxopiperidinyl, tetrahydropyranyl, pyridyl, thiazolyl, pyrrolidinyl, 2 , 3-dihydrobenzo[b][1,4]dioxenyl can be optionally substituted by the following substituents: fluoro, chloro, methyl, ethyl, propyl, isopropyl, Oxy, ethoxy, propoxy, isopropoxy, CN, hydroxyethyl, hydroxypropyl, -OCH 2 CH 2 OH, -
  • R 6 is phenyl, which is optionally fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, C. Oxy, isopropoxy or CN substituted; preferably, R 6 is phenyl which is optionally substituted by fluorine, chlorine, methoxy or CN.
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 hydroxyalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl, 4-7 membered heterocyclyl, said C 1 -C 4 alkane a C 2 -C 4 alkoxy group, a C 3 -C 6 cycloalkyl group, a C 2 -C 4 hydroxyalkyl group, a C 1 -C 4 alkyl-OC 1 -C 4 alkyl group and a 4-7 membered hetero
  • the cyclic group may be optionally substituted by the following substituents: OH, CN, halogen, NH 2 , NHMe, NMe 2 , CO 2 H, or R 7 ,
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 hydroxyalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl, 4-6 membered heterocyclyl, said C 1 -C 4 alkane , C 1 -C 4 haloalkyl, C 2 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 hydroxyalkyl, C 1 -C 4 alkyl-OC 1 -C 4
  • the alkyl, 4-6 membered heterocyclyl can be optionally substituted with OH, CN, halogen, NH 2 , NHMe, NMe 2 , CO 2 H, or R 7 , R 8 and the N
  • R 7 , R 8 and R 9 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkoxy, said C 1 -C 4
  • the alkyl, C 2 -C 4 alkoxy group can be optionally substituted with NH 2 , NHMe, NMe 2 with the following substituents.
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl.
  • R 10 is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 hydroxyalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl, 4-7 membered heterocyclic group, said C 1 -C 4 alkyl group, C 2 -C 4 alkoxy group, C 3 -C 6 cycloalkyl, C 2 -C 4 hydroxyalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl and 4-7 membered heterocyclyl can be optionally substituted by the following substituents : OH, CN, halogen, NH 2 , NHMe, NMe 2 , CO 2 H, or R 9 , R 10 and the N and C or S atoms to which they are attached form a 4-7 member
  • R 10 is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 hydroxyalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl, 4-6 membered heterocyclyl, said C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2- C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 hydroxyalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl, 4-6 membered heterocyclic group Optionally substituted with OH, CN, halogen, NH 2 , NHMe, NMe 2 , CO 2 H, or R 9 , R 10 and the N and C atoms to which they are attached form a 4-7 membered heterocyclic group
  • R 10 is selected from C 1 -C 4 alkyl, C 2 -C 4 alkoxy, said C 1 -C 4 alkyl, C 2 -C 4 alkoxy It may be optionally substituted with the following substituents: NH 2 , NHMe, NMe 2 .
  • R 10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl.
  • X is NR 11 or CHNO 2 ; preferably, X is NR 11 ;
  • R 11 is selected from the group consisting of hydrogen, OH, CN, NH 2 , NHMe, NMe 2 , -SO 2 R 12 , -C(O)R 13 ,
  • R 12 is selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl; said C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl may be optionally substituted by the following substituents: OH, OC 1 -C 4 alkyl, NH 2 , NHMe, NMe 2 , 4-7 membered heterocyclic group;
  • R 13 is selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl, said C 1 -C 4 alkyl, C 3 - C 6 cycloalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl may be optionally substituted by OH, halogen, C 1 -C 6 haloalkyl, CN, C(O)NH 2 , NH 2 , NHMe, NMe 2 , 4-7 membered heterocyclic group;
  • X is selected from NR 11 or CHNO 2 ; preferably, X is NR 11 ;
  • R 11 is selected from the group consisting of hydrogen, OH, CN, NH 2 , NHMe, NMe 2 , -SO 2 R 12 , -C(O)R 13 ,
  • R 12 is selected from C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl;
  • R 13 is selected from C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl, said C 1 -C 4 alkyl, C 3 - C 5 cycloalkyl, C 1 -C 4 alkyl-OC 1 -C 4 alkyl may be optionally substituted by OH, halogen, C 1 -C 4 haloalkyl, CN, C(O)NH 2 , NH 2 , NHMe, NMe 2 , 4-6 membered heterocyclic group.
  • X is selected from NR 11 or CHNO 2 , preferably X is NR 11 ; wherein R 11 is selected from CN, -SO 2 R 12 ; R 12 is selected from C 1 -C 4 Alkyl, C 3 -C 5 cycloalkyl.
  • X is selected from NR 11 or CHNO 2 , preferably X is NR 11 ; wherein R 11 is selected from CN, -SO 2 R 12 ; R 12 is selected from methyl, ethyl, propyl , isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane; preferably, X is selected from NR 11 or CHNO 2 , more preferably, X is NR 11 ; wherein R 11 is selected from CN, -SO 2 Me, -SO 2 Et, -SO 2 Pr, -SO 2 -i-Pr, -SO 2 -cyclopropane, -SO 2 -cyclobutane; further preferably, X is selected from N-SO 2 Me, N-CN, CH-NO 2 ; Still more preferably, X is selected from the group consisting of N-SO 2 Me, N-CN.
  • the compound of the invention is selected from, but not limited to:
  • One aspect of the invention provides a method of making a compound of the invention, the method comprising:
  • R 1 is as defined in the above formula I.
  • Compound A-1 forms enolization intermediate A-2 under the action of a base and PhNTf 2 or Tf 2 O and 2,6-di-tert-butyl-4-methylpyridine.
  • the base used is LiHMDS, LDA, NaHMDS, KHMDS, t BuOK, NaH or NaOH, etc.
  • the solvent is THF, CH 3 CN, DCM or DCE, etc.
  • the temperature is -78 ° C to 25 ° C;
  • the second step the compound A-2 is reacted with an R 1 -boric acid or a boronic ester by a coupling reaction (for example, Suzuki reaction) to form an intermediate A-3.
  • a coupling reaction for example, Suzuki reaction
  • the catalyst used is Pd(PPh 3 ) 4 or Pd(dppf)Cl 2 , etc.
  • the base used is Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 or K 2 CO 3 , etc.
  • the solvent is Dioxane. /H 2 O, DMF / H 2 O, DMSO / H 2 O or CH 3 CN / H 2 O, etc., the temperature is 60 ° C to 120 ° C;
  • the catalyst used is Pd / C, PtO 2 or Pd (OH) 2 / C, etc.
  • the solvent is MeOH or EtOH, etc.
  • the temperature is rt to 80 ° C;
  • the acid used is a Dioxane solution of HCl or a DCM solution of TFA, etc., at a temperature of 0 ° C to rt.
  • R 1 is as defined above for formula I, and R 2 and R 3 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 - C 6 alkyl-OC 1 -C 6 alkyl.
  • Compound B-1 forms enolization intermediate B-2 under the action of a base and PhNTf 2 or Tf 2 O and 2,6-di-tert-butyl-4-methylpyridine.
  • reaction conditions are as described in the first step of the preparation method of Intermediate A.
  • Second step Compound B-2 is reacted with R 1 -boric acid or a boronic ester by a coupling reaction (for example, Suzuki reaction) to give intermediate B-3.
  • a coupling reaction for example, Suzuki reaction
  • reaction conditions are as described in the second step of the preparation method of Intermediate A.
  • reaction conditions are as described in the third step of the preparation method of Intermediate A.
  • the fourth step the alkylation of the compound B-4 in the presence of a base to form the intermediate B-5.
  • the alkylating agent used is R 2 -L 1 and/or R 3 -L 1 (L 1 is -Cl, -Br, -I or -OMs, etc.), undergoing one and/or two alkylation, the base used Is BuLi, LiHMDS, LDA, t BuOK, NaH, Cs 2 CO 3 , K 2 CO 3 or NaOH, etc., the solvent is THF, CH 3 CN, DCM, DMF, DMSO, DCE or Acetone, etc., the temperature is -78 ° C to Rt;
  • Step 5 Compound B-5 is hydrolyzed in the presence of a base to give Intermediate B-6.
  • the base used is LiOH, NaOH or KOH, etc.
  • the solvent is MeOH / H 2 O or EtOH / H 2 O, etc.
  • the temperature is 0 to 80 ° C;
  • the sixth step the Curtius rearrangement reaction of compound B-6 produces intermediate B-7.
  • the base used is Et 3 N, DIPEA, etc.
  • the reagent is DPPA or the like
  • the solvent is t BuOH, toluene, DCM, a mixed solvent of t BuOH and toluene, and the like, and the temperature is 40 to 110 °C.
  • Step 7 Compound B-7 is hydrolyzed under basic conditions to form product B.
  • the base used is NaOH, LiOH or KOH, etc.
  • the solvent used is Dioxane/H 2 O, MeOH/H 2 O, EtOH/H 2 O, etc., at a temperature of rt to 80 °C.
  • R 1 is as defined above for formula I
  • R 4 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-OC 1 -C 6 alkyl, said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-OC 1 -C 6 alkyl may be optionally substituted by the following substituents: OH, CN, -NR 7 R 8 , -C(O)NR 7 R 8 , -NR 9 C(O)R 10 .
  • the base used for alkylation is BuLi, LiHMDS, LDA, t BuOK, NaH, Cs 2 CO 3 , K 2 CO 3 or NaOH, etc.
  • the solvent is THF, CH 3 CN, DCM, DMF, DMSO, DCE or Acetone, etc., temperature Is -78 ° C to 60 ° C; if Mitsunobu reaction occurs, the reagent used is generally DIAD or DEAD, etc., the solvent is THF, DCM or DCE, etc., the temperature is 0 ° C to 80 ° C;
  • intermediate C-1 removes the Boc protecting group to form intermediate C under the action of an acid.
  • reaction conditions are as described in the fourth step of the preparation method of Intermediate A.
  • R 1 is as defined above for formula I, and the P ring is a C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group.
  • Second step Compound R 1 -L 2 (L 2 is Cl, Br, I or OTf, etc.) is coupled to D-1a or D-1b by a coupling reaction (for example, Suzuki reaction) to give intermediate D-2.
  • a coupling reaction for example, Suzuki reaction
  • reaction conditions are as described in the second step of the preparation method of Intermediate A.
  • reaction conditions are as described in the third step of the preparation method of Intermediate A.
  • the acid used is HCl, H 2 SO 4 , p-toluenesulfonic acid or methanesulfonic acid, etc.
  • the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH 3 CN, Dioxane, Acetone or Toluene, etc., temperature is rt To 100 ° C;
  • the fourth step-A Compound D-4 and Compound D-5 form Intermediate D-6 under basic conditions.
  • the base used is LDA, n-BuLi, t BuOK, NaOH, NaH, LiHMDS, NaHMDS or KHMDS
  • the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, CH 3 CN, Dioxane or Toluene, and the temperature is -78. °C to rt;
  • Step 4 - B Reductive amination of compound D-4 with an amine can also give intermediate A
  • the amine source used is ammonium chloride, ammonium acetate, an aqueous solution of NH 3 or a MeOH solution
  • the reducing agent is NaBH 3 CN, NaBH 4 , NaBH(OAc) 3 , etc.
  • the solvent is THF, DCM, DCE, MeOH, EtOH, DMF. , CH 3 CN, Dioxane or Toluene, etc., the temperature is 0 ° C to 80 ° C.
  • the dehydrating reagent used is an acid such as HCl, H 2 SO 4 or TFA, or the Burgess dehydrating agent, and the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, CH 3 CN, Dioxane or Toluene.
  • Step 6 Compound D-7 produces intermediate D-8 under reducing conditions.
  • reaction conditions are as described in the third step of the preparation method of Intermediate A.
  • Step 7 Compound D-8 is hydrolyzed under basic/acidic conditions to give intermediate D-9.
  • the acid used is HCl, H 2 SO 4 , p-toluenesulfonic acid or methanesulfonic acid, etc.
  • the base is LiOH, NaOH or KOH, etc.
  • the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH 3 CN, Dioxane Or Toluene, etc., at a temperature of rt to 100 ° C;
  • Step 8 Compound D-9 is rearranged by Curtius to form intermediate D-10.
  • reaction conditions are as described in the sixth step of the preparation method of Intermediate B.
  • Step 9 Compound D-10 is hydrolyzed to intermediate D under basic conditions.
  • reaction conditions are as described in the seventh step of the preparation method of Intermediate B.
  • R 5 and R 6 are as defined in the above formula I.
  • Compounds E-1 and E-2 form intermediate E under the action of a base.
  • the base used is LiHMDS, LDA, NaHMDS, KHMDS, TEA, DIPEA, t BuOK, NaH or Cs 2 CO 3 , etc.
  • the solvent used is THF, DCM, DCE, DMF, DMSO, CH 3 CN, Dioxane, MeOH, EtOH or Toluene. Etc., the temperature is -10 ° C to 140 ° C.
  • R 5 , R 6 and R 12 are as defined in the above formula I.
  • reaction conditions are as described in the first step of the preparation process of Intermediate E.
  • R 5 and R 6 are as defined in the above formula I.
  • reaction conditions are as described in the first step of the preparation process of Intermediate E.
  • R 1 , R 5 , R 6 , R 12 are as defined in the above formula I
  • R 4 is as defined in the above intermediate C
  • R 2 and R 3 are as defined in the above intermediate B
  • the P ring and the above intermediate D The definitions are the same
  • X is N-CN, N-SO 2 R 12 or CH-NO 2 .
  • intermediate A is reacted with intermediates E, F, G, respectively, under basic conditions to form a compound of formula II.
  • intermediate B is reacted with intermediates E, F, and G, respectively, under basic conditions to form a compound of formula III.
  • intermediate C is reacted with intermediates E, F, and G, respectively, under basic conditions to form a compound of formula IV.
  • intermediate D is reacted with intermediates E, F, and G, respectively, under basic conditions to form a compound of formula V.
  • reaction conditions are as described in the first step of the preparation process of Intermediate E.
  • R 1 , R 5 , R 6 , R 12 are as defined in the above formula I
  • R 4 is as defined in the above intermediate C
  • R 2 and R 3 are as defined in the above intermediate B
  • the P ring and the above intermediate D The definitions are the same
  • X is N-CN, N-SO 2 R 12 or CH-NO 2
  • X' is PhO or MeS.
  • intermediate A is reacted with intermediates E-1, F-1, and G-1 under basic conditions to form intermediate A'.
  • the intermediate B is reacted with the intermediates E-1, F-1, and G-1 under basic conditions to form the intermediate B'.
  • the intermediate C is reacted with the intermediates E-1, F-1, and G-1 under basic conditions to form an intermediate C'.
  • the intermediate D is reacted with the intermediates E-1, F-1, and G-1 under basic conditions to form the intermediate D'.
  • reaction conditions are as described in the first step of the preparation process of Intermediate E.
  • Step Two Intermediate A ', B', C 'or D' Intermediate R 5 -NH-R 6 Formula II, Formula III, Formula IV, and a compound of Formula V were reacted under basic conditions.
  • intermediate D 'Intermediate R 5 -NH-R 6 of the compound of formula V under basic conditions.
  • reaction conditions are as described in the first step of the preparation process of Intermediate E.
  • composition preparation, preparation method and treatment method of pharmaceutical composition
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph of the compound A eutectic or solvate, or a stable isotope derivative, metabolite or prodrug of said compound, further comprising one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is for treating a disease associated with IDO activity or IDO mediated immunosuppression.
  • Another aspect of the invention provides a method of preparing a pharmaceutical composition, the method comprising administering a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, the compound being pharmaceutically Accepted salts, polymorphs, eutectics or solvates, or stable isotope derivatives, metabolites or prodrugs of the compounds, in combination with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is for treating a disease associated with IDO activity or IDO mediated immunosuppression.
  • Another aspect of the invention provides a pharmaceutical formulation comprising a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph of the compound a conjugate, a eutectic or a solvate, or a stable isotope derivative, metabolite or prodrug of the compound, or a pharmaceutical composition of the invention.
  • Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvent of the compound , or a stable isotope derivative, metabolite or prodrug of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention, prepared for the prevention or treatment of IDO activity-related or IDO-mediated immunity Use in drugs that inhibit related diseases.
  • Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvent of the compound , or a stable isotope derivative, metabolite or prodrug of the compound, a pharmaceutical composition of the invention or a pharmaceutical formulation of the invention for use in preventing or treating IDO activity-related or IDO-mediated immunosuppression Related diseases.
  • Another aspect of the invention provides a method of preventing or treating a disease associated with IDO activity or IDO mediated immunosuppression, comprising administering to a subject in need thereof an effective amount of a compound of the invention, a stereoisomer of the compound a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, Or a pharmaceutical composition of the invention or a pharmaceutical preparation of the invention, and optionally comprising administering to an individual in need thereof other drugs for treating diseases such as cancer.
  • Another aspect of the invention provides a method of preventing or treating a disease associated with IDO activity or IDO mediated immunosuppression, comprising administering to a subject in need thereof an effective amount of a compound of the invention, a stereoisomer of the compound a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, Or a pharmaceutical composition of the invention or a pharmaceutical preparation of the invention, and comprises administering a PD-1 antibody or a PD-L1 antibody to an individual in need thereof.
  • Diseases associated with IDO activity or IDO mediated immunosuppression according to the invention include, but are not limited to, tumors, depression, Alzheimer's disease and the like.
  • the tumor includes, but is not limited to, brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer.
  • the "individuals in need thereof” include mammals such as bovine, equine, porcine, canine, feline, rodent, primate; for example, human .
  • Another aspect of the invention provides a formulation comprising a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph of the compound a eutectic or solvate, or a stable isotope derivative, metabolite or prodrug of said compound, which is used to modulate (e.g., reduce or inhibit) an individual (e.g., a mammal, such as a bovine, a horse)
  • an individual e.g., a mammal, such as a bovine, a horse
  • Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvent of the compound Or a use of a stable isotopic derivative, metabolite or prodrug of said compound for the preparation of a formulation for modulating (e.g., reducing or inhibiting) an individual cell (e.g., a mammal, such as a bovine, The activity of IDO in equines, porcines, canines, felines, rodents, primates; for example, humans.
  • an individual cell e.g., a mammal, such as a bovine
  • Another aspect of the invention provides a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, a pharmaceutically acceptable salt, polymorph, eutectic or solvent of the compound Or a stable isotope derivative, metabolite or prodrug of said compound for use in regulating (eg, reducing or inhibiting) an individual (eg, a mammal, such as a bovine, equine, porcine, dog)
  • an individual eg, a mammal, such as a bovine, equine, porcine, dog
  • a modulator eg, reducing or inhibiting
  • an individual eg, a mammal, such as a bovine, equine, porcine, canine, feline, rodent, primate
  • a method of the activity of an IDO in an animal comprising administering to said cell an effective amount of a compound of the invention, a stereoisomer, a tautomer or a mixture thereof, said compound A pharmaceutically acceptable salt, polymorph, eutectic or solvate, or a stable isotope derivative, metabolite or prodrug of the compound.
  • the formulation is administered to an individual to modulate (eg, reduce or inhibit) the activity of the IDO in the cells of the subject; or the formulation is administered to an in vitro cell (eg, a cell line or a cell from an individual) ) to modulate (eg, reduce or inhibit) the activity of IDO in cells.
  • an in vitro cell eg, a cell line or a cell from an individual
  • alkyl is defined as a straight or branched saturated aliphatic hydrocarbon group.
  • an alkyl group has from 1 to 6, such as from 1 to 4 carbon atoms.
  • C 1 -C 6 alkyl refers to a straight or branched chain group having from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl) , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which may be optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen ( At this time, the group is referred to as "haloalkyl” such as CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl or CH 2 CH 2 CF
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridging systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.) , which is optionally substituted by one or more (such as 1 to 3) suitable substituents.
  • bicyclic hydrocarbon ring eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,
  • the cycloalkyl group has, for example, 3 to 7 carbon atoms, for example 3 to 6 carbon atoms.
  • C 3 -C 7 cycloalkyl refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having from 3 to 7 ring-forming carbon atoms (eg, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl), which may be optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • alkoxy refers to an alkyl group, as defined above, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of C 1 -C 6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutyl Oxyl, tert-butoxy, pentyloxy, hexyloxy and the like.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C 6 -C 14 aryl means an aromatic group containing from 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • the aryl group may be optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1 -C 6 alkyl, etc.).
  • arylheterocyclyl refers to a cyclic group formed by the aryl and heterocyclyl groups sharing two adjacent carbon atoms with each other, the point of attachment to other groups being on the aryl group. .
  • aryl or heterocyclic is as defined herein.
  • the term “9-12 membered arylheterocyclyl” means a group containing an arylheterocyclyl group of a total of 9 to 12 ring atoms, particularly phenyl and 5-8.
  • heteroaryl refers to a monocyclic heteroaryl or a bicyclic or polycyclic ring system containing at least one heteroaromatic ring (heteroaromatic ring means an aromatic ring system containing at least one heteroatom).
  • the point of attachment to other groups on the heteroaryl ring having, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5, 6, 7, 8, 9 or 10 ring atoms, and which contain one or more (eg 1, 2, 3, 4 or 5) heteroatoms (eg, oxygen, nitrogen or sulfur) which may be the same or different, and, in each case
  • the aryl group, the heterocyclic group or the cycloalkyl group may be shared with two adjacent atoms to form a cyclic group.
  • the term "5-10 membered heteroaryl” means a heteroaryl group containing 5 to 10 ring atoms (including a 5-6 membered heteroaryl group, examples of which include, but are not limited to, thienyl, Furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridine a pyridyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group, and the like, and a cyclo- and derivative thereof, and a cyclo-derivative is not limited to a heteroaryl-heteroaryl group, a heteroaryl-aryl group, a heteroaryl group.
  • heterocyclyl, or heteroarylcycloalkyl especially 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl phenyl, 5-6 membered heteroaryl And a 5-6 membered heterocyclic group, or a 5-6 membered heteroaryl and C 4-6 cycloalkyl group (especially a 5-6 membered heteroarylcyclobutyl group, a 5-6 membered heteroarylcyclopentylene group) a group, a 5-6 membered heteroarylcyclohexylene group, examples of which include, but are not limited to, anthracenyl, isodecyl, oxazolyl, benzimidazole, quinolyl, isoquinolyl, Wait.
  • 3-14 membered heterocyclyl as used herein means a heterocyclic group containing 3 to 14 ring atoms (including a 3-7 membered heterocyclic group, examples of which include, but are not limited to, ethylene oxide) , aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholine a base, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, a trithianyl group, and the like, and a cyclo- and derivative thereof, and a cyclic derivative includes, but not limited to, a heterocyclic heterocyclic group.
  • heterocyclyl-aryl, heterocyclylheteroaryl, heterocyclylcycloalkyl especially 3-7 membered heterocyclyl 3-7 membered heterocyclic, 3-7 membered heterocyclyl Aryl, 3-7 membered heterocyclylheteroaryl, 3-7 membered heterocyclylcycloalkyl, especially 3-7 membered heterocyclylphenyl, 3-7 membered heterocyclyl 5- 10-membered heteroaryl, 3-7 membered heterocyclyl and C 4-6 cycloalkyl, examples of which include, but are not limited to, pyrrolidino-cyclopropyl, cyclopentyl-azacyclopropyl, pyrrolidinyl Cyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinyl Piperazinyl, morpholinyl and pyrrolidinyl, piperidinyl and morpholinyl,
  • paracyclic refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
  • hydroxyalkyl as used herein means that the hydrogen atom of the alkyl group is substituted by one or more (eg, 1, 2, 3 or 4) hydroxyl groups
  • C 1 -6 hydroxyalkyl means that the hydrogen atom of the C 1 -C 6 alkyl group is substituted by one or more (for example, 1, 2, 3 or 4) hydroxyl groups. Examples thereof include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyhexyl, and the like.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded.
  • the normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be unsubstituted (1) or (2) substituted with one or more (eg 1, 2, 3 or 4) substituents. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • the present invention also encompasses all pharmaceutically acceptable isotopic compounds (stable isotope derivatives) which are identical to the compounds of the present invention except that one or more atoms are of the same atomic number but differ in atomic mass or mass number in nature.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g.
  • isotope of fluorine eg 18 F
  • isotopes of iodine eg 123 I and 125 I
  • isotopes of nitrogen eg 13 N and 15 N
  • isotopes of oxygen eg 15 O, 17 O and 18 O
  • isotope of phosphorus eg, 32 P
  • isotope of sulfur eg, 35 S.
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • asymmetric center which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • nitroso-oxime can be present in solution in the following tautomeric forms:
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio. It will also be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs which, after administration to a patient in need thereof, can be directly or indirectly A compound of the invention or a metabolite or residue thereof is provided.
  • a compound of the invention it is also intended to encompass the various derivative forms described above for the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • acid addition salts for example, hexafluorophosphate, meglumine salt, and the like.
  • suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association).
  • Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • ⁇ is used herein to mean a bond in the structural formula which represents a cis or trans isomer, or a mixture of cis and trans isomers in any ratio.
  • the compound of the present invention has high inhibitory activity against IDO in cells, and has excellent properties such as good pharmacokinetic properties and good safety.
  • the structure of the compound was confirmed by nuclear magnetic resonance spectroscopy ( 1 H NMR) and/or mass spectrometry (MS). The reaction was monitored by silica gel thin layer chromatography (TLC) (GF 254 as the stationary phase) or LCMS.
  • TLC silica gel thin layer chromatography
  • the microwave reaction was carried out using a Biotage Initiator microwave reactor.
  • the temperature of the reaction was room temperature (15 ° C to 30 ° C) unless otherwise specified.
  • the reagents used in the present application were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.
  • Second step 4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yltrifluoromethanesulfonate 2e
  • the third step synthesis of (2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)carbamic acid tert-butyl ester 2f
  • the fourth step the synthesis of (4-phenylcyclohexyl)carbamic acid tert-butyl ester 2g
  • Step 6 N-(((4-Chlorophenyl)amino)((4-phenylcyclohexyl)amino)methylene)methanesulfonamide (Compound 2)
  • Pd(dppf)Cl 2 1000 mg, 1.4 mmol
  • 3a 6.5 g, 29.0 mmol
  • B 2 pin 2 9.6 g, 38.0 mmol
  • AcOK 8.5 g, 87.0 mmol
  • Step 5 1-(4-Chlorophenyl)-2-cyano-3-(4-(6-fluoroquinolin-4-yl)cyclohexyl)anthracene (Compound 3)
  • compound 2c is used to synthesize the cis or trans isomer of compound 6 according to the synthesis of compound 5.
  • 6A (6 mg, relatively polar isomer); 6B (5 mg, relatively polar isomer).
  • Step 7 1-(4-(2-Methylpyridin-4-yl)cyclohexyl)ethylamine hydrochloride 7i
  • Step 8 Phenyl N-(4-chlorophenyl)-N'-cyanooxyaminoimidate phenyl 7k
  • Step 9 1-(4-Chlorophenyl)-2-cyano-3-(1-(4-(2-methylpyridin-4-yl)cyclohexyl)ethyl)indole (Compound 7)
  • Example 8 1-(4-Chlorophenyl)-2-cyano-3-(1-(4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)indole (Compound 9)
  • Pd(dppf)Cl 2 500 mg, 0.7 mmol
  • 3b 4.0 g, 14.0 mmol
  • 7b 4.2 g, 14.0 mmol
  • K 2 CO 3 5.8 g, 42.0 mmol
  • Step 7 1-(4-Chlorophenyl)-2-cyano-3-(1-(4-(6-fluoroquinolin-4-yl)cyclohexyl)ethyl)anthracene (Compound 9)
  • Step 5 N-(((4-chlorophenyl)amino)((4-(2-methylpyridin-4-yl)cyclohexyl)amino)methylene)methanesulfonamide 35
  • the third step (4-(2,6-dimethylpyridin-4-yl)cyclohexyl)carbamic acid tert-butyl ester 37d.
  • the fourth step the synthesis of 4-(2,6-dimethylpyridin-4-yl)cyclohexylamine hydrochloride 37e
  • Step 5 N-(((4-chlorophenyl)amino)((4-(2,6-dimethylpyridin-4-yl)cyclohexyl)amino)methylene)methanesulfonamide 37
  • Step 5 4-(4-(2-(Dimethylamino)ethoxy)phenyl)cyclohexylamine 42g
  • Step 6 N-(((4-chlorophenyl)amino)((4-(4-(2-(dimethylamino)ethoxy)phenyl)cyclohexyl)amino)methylene) Sulfonamide 42
  • DIPEA (518.74 mg, 4.01 mmol) was added to a solution of compound 2h (175.87 mg, 1.00 mmol) and 2b (200 mg, 1.00 mmol) in acetonitrile (5 mL) and then warmed to 90 ° C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated.
  • 86b 50 mg, 173.38 ⁇ mol,), 2 h (30.39 mg, 173.38 ⁇ mol), and DIPEA (44.81 mg, 346.76 ⁇ mol) were dissolved in DMF (2.50 mL), and heated to 125 ° C to stir the reaction for 6 h.
  • LCMS was used to monitor the complete conversion of the starting materials. After the reaction was completed, it was cooled to room temperature, diluted with water, and then extracted with EA. The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure and purified by Prep-HPLC. Cis or trans isomer.
  • 86A peak 1, 25 mg, collection time 9.7-9.9 min
  • 86B peak 2, 7 mg, collection time 9.9-10.1 min
  • Step 5 N-((4-chlorophenyl)amino)((4-(2,3-dimethylpyridin-4-yl)cyclohexyl)amino)methylene)sulfonamide 87
  • the effect of the compound on intracellular IDO enzyme activity was determined by the NFK Green method.
  • NFK Green fluorescent dye NTRC
  • L-tryptophan Sigma-Aldrich
  • R&D systems Recombinant Human IFN-gamma Protein
  • Cell culture Tumor cells were cultured in vitro in a single layer.
  • the culture conditions were: Hela cells, DMEM plus 10% fetal bovine serum, and cultured in an incubator containing 5% CO 2 at 37 °C. Digestion treatment with trypsin-EDTA was performed 2-3 times a week. When the cells are in the exponential growth phase, the cells are harvested, counted, and plated. The cell concentration (10,000 cells/well of HeLa cells) was adjusted, and the cells were seeded at 70 ⁇ L/well into the corresponding wells of a 96-well plate. Label the 96-well plate and place it in the incubator for 24 hours. A test well without cells was set as a negative control group.
  • test compound preparation The test compound is dissolved in DMSO to prepare a mother liquid, and an appropriate amount of the mother liquid is aspirated into the culture solution to be mixed, and the drug solution is prepared into a corresponding incubation concentration. 10 ⁇ L of the prepared compound solution was added to each well, and the cells were further incubated for 1 h.
  • IDO stimulation and substrate addition Add 10 ⁇ L of 500 ng/mL IFN- ⁇ (Recombinant Human IFN-gamma Protein) (dissolved in complete medium) while adding 10 ⁇ L of sterile 0.5 mM L-tryptophan solution (dissolved in 20 mM) Hepes), incubated for 48 h.
  • IFN- ⁇ Recombinant Human IFN-gamma Protein
  • sterile 0.5 mM L-tryptophan solution dissolved in 20 mM
  • NFK Green was added to each well, and incubated at 37 ° C for 4 hours.
  • Compound inhibition rate (%) (1-Savg / Cavg) ⁇ 100%; Savg average fluorescence reading for the test compound, Cavg is the average fluorescence reading the negative control group, IC 50 is calculated by the GraphPad Prism software.
  • the compounds of the present invention have a significant inhibitory effect on the IDO enzyme in Hela cells.
  • CYP450 is the most important enzyme system in drug metabolism, and enzymes involved in metabolism interact with drugs, the most important of which are CYP1A2, CYP2D6 and CYP3A4.
  • P450-Glo TM CYP1A2 Screening System, CYP2D6Cyan Screening Kit and The CYP3A4Red Screening Kit was assayed for inhibitory activity against CYP1A2, CYP2D6 and CYP3A4 according to the kit instructions at 1 ⁇ M and 10 ⁇ M. The test results are shown in Table 3.

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Abstract

L'invention concerne un composé représenté par la formule (I), une composition pharmaceutique, une formulation pharmaceutique et l'utilisation du composé dans la préparation d'un médicament pour la prévention ou le traitement de maladies associées à l'activité d'IDO ou à l'immunosuppression médiée par l'IDO.
PCT/CN2019/070339 2018-01-19 2019-01-04 Dérivé d'amidine et de guanidine, son procédé de préparation et son utilisation médicale Ceased WO2019141095A1 (fr)

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CN107021929A (zh) * 2016-01-29 2017-08-08 苏州国匡医药科技有限公司 一类新型ido抑制剂、制备方法、药物组合物及其用途
CN107205970A (zh) * 2014-11-05 2017-09-26 弗莱塞斯生物科学公司 免疫调节剂
WO2017192840A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs méthodes d'utilisation
WO2017192844A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoleamine 2,3-dioxygénase et leurs méthodes d'utilisation
CN107427499A (zh) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 免疫调节剂

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EP2493862B1 (fr) * 2009-10-28 2016-10-05 Newlink Genetics Corporation Dérivés imidazole comme inhibiteurs de l'ido
NO2694640T3 (fr) * 2011-04-15 2018-03-17
MX366875B (es) * 2013-07-11 2019-07-29 Bristol Myers Squibb Co Inhibidores de indoleamina 2,3-dioxigenasa (ido).
UY36391A (es) * 2014-11-05 2016-06-01 Flexus Biosciences Inc Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido1), sus métodos de síntesis y composiciones farmacèuticas que las contienen
GB201602934D0 (en) * 2016-02-19 2016-04-06 Cancer Res Inst Royal Compounds

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CN107205970A (zh) * 2014-11-05 2017-09-26 弗莱塞斯生物科学公司 免疫调节剂
CN107427499A (zh) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 免疫调节剂
CN107021929A (zh) * 2016-01-29 2017-08-08 苏州国匡医药科技有限公司 一类新型ido抑制剂、制备方法、药物组合物及其用途
WO2017192840A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoléamine 2,3-dioxygénase et leurs méthodes d'utilisation
WO2017192844A1 (fr) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibiteurs d'indoleamine 2,3-dioxygénase et leurs méthodes d'utilisation

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