WO2019196780A1 - Nouvel inhibiteur de l'indoléamine 2,3-dioxygénase, son procédé de préparation et son utilisation - Google Patents
Nouvel inhibiteur de l'indoléamine 2,3-dioxygénase, son procédé de préparation et son utilisation Download PDFInfo
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- WO2019196780A1 WO2019196780A1 PCT/CN2019/081709 CN2019081709W WO2019196780A1 WO 2019196780 A1 WO2019196780 A1 WO 2019196780A1 CN 2019081709 W CN2019081709 W CN 2019081709W WO 2019196780 A1 WO2019196780 A1 WO 2019196780A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
Definitions
- the invention belongs to the field of medicinal chemistry, relates to a novel compound having an effective indoleamine 2,3-dioxygenase inhibiting function and good pharmacokinetic properties, a preparation method thereof, a pharmaceutical composition comprising the same, and Its medical use.
- Indoleamine-2,3-dioxygenase is a monomeric enzyme containing heme found in the cell for the first time in 1967 by the Hayaishi group.
- the cDNA encodes a protein. 403 amino acids with a molecular weight of 45 kDa, a rate-limiting enzyme that is catabolized along the tryptophan-kynurenine pathway and widely expressed in many mammalian tissues (Hayaishi O. et al., Science, 1969, 164: 389-396).
- IDO-mediated tryptophan (Trp)-Kirurenine (Kyn) metabolic pathway is involved in tumor immune escape, and IDO also plays an important role in inducing tumor microenvironmental immune tolerance. The role.
- Tryptophan is one of the essential amino acids in mammals and needs to be ingested in large quantities from food to maintain cell activation and proliferation, as well as the synthesis of proteins and some neurotransmitters. Therefore, lack of tryptophan can cause dysfunction of some important cells. IDO can catalyze the conversion of tryptophan to N-formyl kynurenine in vivo, resulting in insufficient tryptophan content in the body, which in turn leads to tumorigenesis. In addition, immunohistological studies have shown that the kynurenine metabolic pathway can lead to an increase in the neurogenic excitotoxin, which can lead to a variety of serious neurological diseases such as Alzheimer's disease (Guillemin GJet al., Neuropathol. And Appl. Neurobiol., 2005, 31: 395-404).
- tryptophan metabolism rate-limiting enzymes There are two main types of tryptophan metabolism rate-limiting enzymes in mammals: tryptophan-2,3-dioxygenase (TDO) and IDO.
- TDO tryptophan-2,3-dioxygenase
- IDO IDO
- Kotake et al. purified proteins from rabbit intestines and found that TDO was mainly expressed in mammalian liver. It has not been found to be closely related to the immune system.
- TDO catalyzes the kynurenine metabolic pathway and converts tryptophan to N-formyl kynurenine (Higuchi K. et al., J. Biochem., 1937, 25:71-77; Shimizu T. et al ., J. Biol. Chem., 1978, 253: 4700-4706).
- IDO the enzyme purified from the intestinal tract of rabbits was identified as IDO containing heme.
- IDO is the only enzyme outside the liver that catalyzes the oxidative cleavage of purines in the tryptophan structure and catabolizes along the kynurenine pathway.
- IDO is usually expressed in organs with more mucosa (such as lung, small intestine and large intestine, rectum, spleen, kidney, stomach, brain, etc.) and is widely distributed (Hayaishi O. et al., Proceedings of the tenth FEBS meeting, 1975, 131-144).
- mucosa such as lung, small intestine and large intestine, rectum, spleen, kidney, stomach, brain, etc.
- pathological conditions such as pregnancy, chronic infection, organ transplantation, tumors, etc.
- the expression of IDO will increase significantly, and thus participate in mediating local immunosuppression.
- IDO can inhibit local T cell immune responses in the tumor microenvironment by: tryptophan depletion, toxic metabolism, and induction of regulatory T cell proliferation. In many cases, it is overexpressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, in culture conditions without tryptophan or kynurenine, T cells undergo proliferation inhibition, decreased activity, and even apoptosis. There is a regulatory point in T cells that is very sensitive to tryptophan levels, which can consume tryptophan under the action of IDO, and arrest T cell proliferation in the middle of G1 phase, thereby inhibiting T cell proliferation and immune response.
- T cells stop proliferating, they may not be stimulated again. This is the mechanism of immune function of IDO in vivo (Mellor A. et al., Biochem. Biophys. Res. Commun., 2005, 338(1): 20 -24; Le Rond S. et al., J. Exp. Med., 2002, 196(4): 447-457).
- IDO inhibitors As a new immunotargeting drug, small molecule IDO inhibitors combined with immunological checkpoint inhibitors (ICI) have shown significantly improved efficacy and response rates in a variety of solid tumors, opening up for tumor immunotherapy A new window.
- ICI immunological checkpoint inhibitors
- a number of IDO inhibitor drug candidates have been in clinical research, and many patents have been applied, such as CN102164902A, US20080047579A1, WO2016/073770A1, WO2017/213919A1 and the like.
- CN102164902A US20080047579A1, WO2016/073770A1, WO2017/213919A1
- IDO inhibitors there is still a need to find compounds that overcome the shortcomings of existing inhibitors, have improved stability, pharmacodynamics, pharmacokinetics, etc. over existing inhibitors, or have found novelty for IDO family targets.
- the present invention is directed to a novel series of compounds which have a modulatory or inhibitory effect on IDO activity, a process for the preparation of the series of compounds, a pharmaceutical composition comprising the series of compounds, and a pharmaceutical use of the series of compounds.
- the invention provides a compound having the structure of formula I:
- R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
- A is NR 6 , N-OH, S or O;
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
- R 5a and R 5b are each independently hydrogen, halogen, hydroxy (-OH) or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously hydroxy, both are dehydrated to form a carbonyl group;
- E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl; And each
- At least one of R 1 and R 2 is optionally substituted C 2 -C 4 alkynyl, -SF 5 , -NHSO 2 NH 2 , -P(O)(CH 3 ) 2 or dialkoxyphosphoryl;
- A is NR 6 , N-OH, S or O;
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
- R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
- E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
- R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
- R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
- E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
- R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
- E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
- R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
- A is optionally selected from NR 6 , N-OH, S or O;
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
- E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
- the present invention provides a compound of the above formula I, which comprises:
- the present invention provides a process for the preparation of a compound of the above formula I, which comprises the steps of:
- the acylating reagent used in the step 1) of the above preparation method includes, but is not limited to, glacial acetic acid, acetic anhydride (or acetic anhydride), acetyl chloride, benzoic anhydride, benzoyl chloride, etc.
- sulfonylation Reagents include, but are not limited to, formic acid anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, p-toluenesulfonic anhydride, p-toluenesulfonyl chloride, and the like.
- the introduction of the fragment E in the step 2) of the above production method is achieved by a coupling reaction.
- Common coupling reactions include, but are not limited to, Suzuki Reaction, Heck Reaction, Stille Reaction, Sogonoshira Coupling, and Xiongtian Coupling Reaction ( Kumada Coupling reaction, Negishi Coupling, Hiyama Coupling, and the like.
- the hydrogenation in the step 3) of the above production method is carried out by means of catalytic hydrogenation, metal hydride hydrogenation or hydroboration.
- Catalysts commonly used in catalytic hydrogenation reactions include, but are not limited to, nickel catalysts (eg, Raney nickel), palladium catalysts (eg, palladium on carbon), platinum catalysts (eg, platinum carbon); reagents commonly found in metal hydride hydrogenation reactions include (but Not limited to) lithium hydride (LiH), sodium hydride (NaH), lithium aluminum hydride (LiAlH 4 ), etc.; common reagents in the hydroboration reaction include, but are not limited to, diborane (B 2 H 4 ), hydroboration Sodium (NaBH 4 ) and the like.
- the present invention also provides a corresponding preparation method.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof, cis A reverse isomer, an isotope label, or a prodrug.
- composition further comprises a pharmaceutically acceptable carrier.
- the present invention provides a compound having the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label thereof Or a prodrug or a pharmaceutical composition as described above, which is used as an IDO inhibitor.
- the present invention provides a compound having the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label thereof Or the use of a prodrug or the above pharmaceutical composition as an IDO inhibitor.
- the present application provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-label thereof Or the use of a prodrug or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by IDO.
- the present invention provides a method for preventing and/or treating a disease mediated at least in part by IDO, comprising the steps of: treating a therapeutically effective amount of a compound having the above structure of Formula I or a pharmaceutically acceptable compound thereof Accepted salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or pharmaceutical compositions described above are administered to a patient in need thereof.
- IDO includes, but is not limited to, cancer (eg, cervical cancer), neurodegenerative diseases (eg, Alzheimer's disease), viral infection (eg, AIDS), bacterial infection (eg, chain Cocci infection), eye diseases (such as cataracts), autoimmune diseases (such as rheumatoid arthritis), depression, anxiety, and psychological disorders.
- cancer eg, cervical cancer
- neurodegenerative diseases eg, Alzheimer's disease
- viral infection eg, AIDS
- bacterial infection eg, chain Cocci infection
- eye diseases such as cataracts
- autoimmune diseases such as rheumatoid arthritis
- depression anxiety, and psychological disorders.
- the present invention provides a pharmaceutical combination comprising the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof, cis A trans isomer, an isotopic label or prodrug or a pharmaceutical composition as described above and at least one additional cancer therapeutic.
- the present invention provides a method for preventing and/or treating cancer comprising the steps of: administering a therapeutically effective amount of the above compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, hydrate thereof, Solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or the above pharmaceutical compositions and at least one additional cancer therapeutic are administered to a patient in need thereof.
- the above cancer includes, but is not limited to, brain cancer, liver cancer, gallbladder cancer, bronchial cancer, lung cancer, bladder cancer, ovarian cancer, cervical cancer, testicular cancer, lip cancer, tongue cancer, hypopharyngeal cancer, laryngeal cancer, esophagus Cancer, stomach cancer, intestinal cancer (eg colon cancer, rectal cancer), thyroid cancer, salivary gland cancer, pancreatic cancer, breast cancer, prostate cancer, blood cancer (or leukemia), lymphoma (or lymphoma), bone cancer and skin cancer.
- cancer therapeutic agents include, but are not limited to, antispasmodic drugs (such as pentastatin, etc.), antipyrimidine drugs (such as fluorouracil), antifolate drugs (such as methotrexate), DNA polymerase inhibitors (such as Cytarabine, alkylating agents (such as cyclophosphamide), platinum complexes (such as cisplatin), DNA-killing antibiotics (such as mitomycin), topoisomerase inhibitors (such as camptothecin) Embedding DNA interference nucleic acid synthetic drugs (such as epirubicin), blocking raw material supply drugs (such as asparaginase), interfering with tubulin forming drugs (such as paclitaxel), interfering with ribosome functional drugs (such as harringtonine) ), cytokines (eg, IL-1), thymosin, tumor cell proliferative viruses (eg, adenovirus ONYX-015), and the like.
- antispasmodic drugs
- the present invention provides a novel structure of the compound of formula I, which can be used as a highly effective IDO inhibitor, and has various pharmacological activities such as anti-tumor, anti-neurodegenerative diseases (such as Alzheimer's disease), anti-inflammatory and the like.
- the synthesis method is mild, the operation is simple and easy, and it is easy to derivatize, and is suitable for industrial scale production.
- Figure 1 is a synthetic route of the compound 2 of the present invention.
- “Pharmaceutically acceptable salt” refers to a salt of a compound of formula I having substantially no toxicity to an organism.
- Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or an inorganic/organic base, such salts being referred to as acid addition salts or Base addition salt.
- Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
- Common organic acids include, but are not limited to, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid.
- common inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide
- common organic bases include, but are not limited to, diethylamine, triethylamine, ethambutol and the like.
- hydrate means a substance formed by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with water by a non-covalent intermolecular force. Common hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, and the like.
- solvate means a substance formed by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule by a non-covalent intermolecular force.
- solvate includes “hydrates.” Common solvates include, but are not limited to, hydrates, ethanolates, acetonates, and the like.
- isomer refers to a compound having the same number of atoms and atom type and thus having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms.
- stereoisomer (also referred to as “an optical isomer”) means having a vertical asymmetric plane due to at least one chiral factor, including a chiral center, a chiral axis, a chiral surface, and the like. Thereby a stable isomer capable of rotating plane polarized light. Because of the presence of asymmetric centers and other chemical structures in the compounds of the invention that may result in stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention and salts thereof include asymmetric carbon atoms, they can exist as a single stereoisomeric form, a racemate, an enantiomer, and a mixture of diastereomers.
- these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds can be prepared or isolated to give the pure stereoisomers, ie, single enantiomers or diastereomers, or single stereoisomers (purity ⁇ A mixture of 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85% or ⁇ 80%).
- a single stereoisomer of a compound is prepared by synthesizing an optically active starting material having a desired chiral center, or by preparing a mixture of enantiomeric products, followed by separation or resolution.
- enantiomer refers to a pair of stereoisomers that have a mirror image that does not overlap each other.
- diastereomer or “diastereomer” refers to an optical isomer that does not form a mirror image of each other.
- racemic mixture or “racemate” refers to a mixture of aliquots of a single enantiomer (ie, an equimolar amount of a mixture of two R and S enantiomers).
- non-racemic mixture refers to a mixture of unequal portions of a single enantiomer. All stereoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
- tautomer refers to structural isomers having different energies that are mutually transformable by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
- proton tautomers include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization Isomerization of amide-imine alcohol, and the like. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
- cis-trans isomer refers to a stereoisomer formed by an atom (or group) located on either side of a double bond or ring system due to a position relative to a reference plane; an atom in the cis isomer ( Or a group) is located on the same side of the double bond or ring system in which the atom (or group) is located on the opposite side of the double bond or ring system. Unless otherwise indicated, all cis and trans isomer forms of the compounds of the invention are within the scope of the invention.
- isotopic label refers to a compound formed by replacing a particular atom in a structure with its isotope atom.
- the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.
- prodrug refers to a derivative compound that is capable of providing a compound of the invention, either directly or indirectly, after application to a patient.
- Particularly preferred derivatizing compounds or prodrugs are compounds which, when administered to a patient, increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system) compound of.
- site of action e.g., the lymphatic system
- the term "independently” means that at least two groups (or ring systems) having the same or similar range of values present in the structure may have the same or different meanings in a particular situation.
- substituent X and the substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl
- substituent Y when the substituent X is hydrogen, the substituent Y may be either hydrogen or halogen. Hydroxy, cyano, alkyl or aryl;
- the substituent Y is hydrogen, the substituent X may be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl.
- optionally substituted means that the group (or ring system) is present unsubstituted or substituted with at least one substituent (or substituted ring system).
- substituents or substituted ring systems
- halogen means four atoms of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
- sulfonyl refers to a monovalent group formed by the loss of a hydroxy group of a sulfonic acid and attached to the parent nucleus via a single bond to the sulfur atom; common sulfonyl groups include, but are not limited to, methyl sulfonate An acyl group (-SO 2 CH 3 ), a trifluoromethylsulfonyl group (-SO 2 CF 3 ), a phenylsulfonyl group (-SO 2 Ph), an aminosulfonyl group (-SO 2 NH 2 ), or the like.
- sulfonylamino refers to a monovalent group formed by the loss of a hydrogen atom on the amino group by a sulfonamide and attached to the parent nucleus via a single bond to the nitrogen atom; common sulfonylamino groups include (but Not limited to) methylsulfonylamino (-NHSO 2 CH 3 ), trifluoromethylsulfonylamino (-NHSO 2 CF 3 ), phenylsulfonylamino (-NHSO 2 Ph), sulfamoylamino (-NHSO) 2 NH 2 ) and so on.
- phosphoroacyl refers to a monovalent group formed by the loss of a hydroxyl group by hypophosphorous acid and attached to the parent nucleus via a single bond to the phosphorus atom; common hypophosphoryl groups include, but are not limited to, two Methylphosphoryl (-P(O)(CH 3 ) 2 ), diphenylphosphoryl (-P(O)Ph 2 ), methylphenylphosphoryl (-P(O)(Ph) (CH 3 )), dialkoxyphosphoryl (-P(O)(OR) 2 ), and the like.
- phosphoryl refers to a monovalent group formed by the loss of a hydroxyl group by a phosphoric acid and attached to a parent core through a single bond to a phosphorus atom.
- alkyl refers to a monovalent straight or branched alkane group consisting of a carbon atom and a hydrogen atom, containing no unsaturation, and attached to the parent core through a single bond, preferably C 1 -C 6 alkyl, more preferably C 1 -C 4 alkyl; common alkyl groups include, but are not limited to, methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), sec-butyl (-CH(CH 3 )CH 2 CH 3 ), Butyl (-CH 2 CH(CH 3 ) 2 ), tert-butyl (-C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), neopentyl (-CH) 2 C(CH
- alkynyl refers to a monovalent straight or branched alkyne group consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond, and attached to the parent core through a single bond, preferably C 2 - C 6 alkynyl; common alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propyn-1-yl (ie propynyl) (-C ⁇ C-CH 3 ), 1- Butyn-1-yl (ie butynyl) Pentyn-1-yl 1,3-butadiyn-1-yl (-C ⁇ CC ⁇ CH), 1,4-pentadiyn-1-yl Wait.
- alkoxy refers to a monovalent straight or branched chain which consists solely of carbon atoms, hydrogen atoms and oxygen atoms and which may contain unsaturation and which are linked by a single bond to the oxygen atom.
- a C 1 -C 4 alkoxy group common alkoxy groups include, but are not limited to, methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy ( -OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 ) CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), n-pentyloxy (-OCH 2 CH 2 CH 2 CH 3 ), neopentyloxy (-OCH 2 CH 2 CH 2 CH 3
- carbonyl refers to a divalent group consisting of only one carbon atom and one oxygen atom, a carbon atom and an oxygen atom are bonded by a double bond, and the carbon atoms in the structure are also bonded to each other through a single bond. The other two fragments.
- alkanoyl refers to a monovalent straight or branched chain group consisting of only a carbon atom, a hydrogen atom and an oxygen atom, containing no unsaturation other than the carbonyl group in its structure, and passing through a carbonyl group.
- a linked single bond is attached to the parent core, preferably a C 1 -C 4 alkanoyl group; common alkanoyl groups include, but are not limited to, formyl (-(O)CH), acetyl (-(O)CCH 3 ), positive Propionyl (-(O)CCH 2 CH 3 ), n-butyryl (-(O)CCH 2 CH 2 CH 3 ), isobutyryl (-(O)CCH(CH 3 ) 2 ), n-pentanoyl (- (O) CCH 2 CH 2 CH 2 CH 3 ), pivaloyl (-(O)CC(CH 3 ) 3 ), and the like.
- common alkanoyl groups include, but are not limited to, formyl (-(O)CH), acetyl (-(O)CCH 3 ), positive Propionyl (-(O)CCH 2 CH 3 ), n-butyryl (-(O)CCH 2 CH 2 CH 3 ), iso
- cycloalkyl refers to a monovalent monocyclic or polycyclic (including bridged and spiro form) non-aromatic ring system consisting of only carbon and hydrogen atoms, no unsaturation, and A single bond to the parent core; common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl (also known as decalinyl, naphthyl) ), adamantyl and the like.
- heterocyclyl refers to a monovalent monocyclic or polycyclic (including bridged and spiro form) non-aromatic ring system consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus.
- common heterocyclic groups include, but are not limited to, oxiranyl, oxetane-3-yl, azetidin-3-yl, tetrahydrofuran- 2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidine Acridine-4-yl and the like.
- aryl refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system which consists of only carbon and hydrogen atoms and is attached to the parent nucleus by a single bond;
- the group includes, but is not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthryl, fluorenyl, fluorenyl, fluorenyl, fluorenyl and the like.
- heteroaryl refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus, and Single bond to the parent core; common heterocyclic groups include, but are not limited to, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, anthracene Pyridyl, carbazolyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyridazinyl, fluorenyl , quinolyl, isoquinolyl, phenazinyl, phenoxazinyl, phenothiazine,
- the present invention provides a compound of formula I:
- R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
- A is NR 6 , N-OH, S or O;
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
- R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
- E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
- R 1 and R 2 in the above compounds of formula I are each independently hydrogen, halo, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl
- An optionally substituted C 3 -C 6 cycloalkyl group, an optionally substituted 3 to 6 membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group Or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or hydrogen on the phenyl ring linking R 1 , R 2 may be optionally substituted by deuterium,
- R 1 and R 2 in the above compound of formula I are each on two adjacent carbon atoms of the phenyl ring, R 1 and R 2 are bonded to each other to form a saturated 5-membered ring, a saturated 5-membered ring, a saturated 6-membered ring or an unsaturated 6-membered ring containing 0, 1 or 2 heteroatoms including O, N and S, wherein: a saturated 5-membered ring is a ring Pentane, pyrrolidine (ie tetrahydropyrrole), furan (ie tetrahydrofuran), thiophene (ie tetrahydrothiophene), imidazolidine (ie tetrahydroimidazole), pyrazolidine (ie tetrahydropyrazole), oxazole Alkane (ie tetrahydrooxazole), isooxazolidine (ie tetrahydro
- a in the above formula I is NR 6 , N-OH, S or O;
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl , optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl
- the hydrogen in R 3 , R 6 is optionally substituted by deuterium, wherein: the optionally substituted C 1 -C 6 alkyl group is methyl, ethyl, hydroxymethyl, cyanomethyl, fluoromethyl, difluoro Methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, a-naphthylmethyl or ⁇ -naphthylmethyl; optionally substituted C 1 -C 6
- R 3a and R 5b in the above compounds of formula I are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously In the case of a hydroxyl group, the two are dehydrated to form a carbonyl group, wherein the optionally substituted C 1 -C 6 alkyl group is a methyl group, an ethyl group, a methylol group, a cyanomethyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group. .
- E in the above formula I compound is one of the following fragments optionally substituted with at least one R 7 :
- Each R 7 is each independently halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl , -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 Independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl, wherein: for R 7 , the optionally substituted C 1 -C 6 alkyl is methyl, ethyl, hydroxymethyl, cyanide Methy
- R 1 and R 2 in the compound of formula I above is optionally substituted C 2 -C 4 alkynyl, -SF 5 , -NHSO 2 NH 2 , -P(O (CH 3 ) 2 or dialkoxyphosphoryl;
- A is NR 6 , N-OH, S or O;
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl , optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl
- the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
- R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously When it is a hydroxy group, the two are dehydrated to form
- R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1- C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclic, optionally substituted C 1 -C 4 alkoxy, optionally substituted C a 1- C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, a hydrogen in R 1 , R 2 and/or a hydrogen on the phenyl ring linking R 1 , R 2 may be optionally substituted by deuter
- a in the above formula I is N-OH, and R 5a and R 5b are not simultaneously hydrogen;
- R 1 and R 2 are each independently hydrogen, halogen, cyano, - (CH 2 ) n SF 5 , —(CH 2 ) n NHSO 2 NH 2 , —(CH 2 ) n P(O)(CH 3 ) 2 , a sulfonyl group, a sulfonylamino group, an optionally substituted hypophosphoryl group, Optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkanoyl or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or benzene linking R 1 , R 2 and/
- R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 Group, optionally substituted C 3 -C 6 cycloalkyl, and R 3, R 6 is optionally substituted by deuterium hydrogen;
- E is optionally substituted with at least one R 7 5 to 12-membered aryl, heteroaryl, Aryl, cycloalkyl or heterocyclic; each R 7 is independently hydrogen, halo, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 ene , optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 )
- R 5a and R 5b in the above formula I formula form a carbonyl group
- R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , (CH 2 ) n NHSO 2 NH 2 , —(CH 2 ) n P(O)(CH 3 ) 2 , a sulfonyl group, a sulfonylamino group, an optionally substituted hypophosphoryl group, an optionally substituted phosphoryl group, optionally Substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclyl, optionally substituted C 1 -C 4 alkoxy, optionally Substituted C 1 -C 4 alkanoyl or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or hydrogen on the
- E in the above formula I compound is one of the following:
- the above compound of formula I is a compound of formula Ia:
- R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group).
- Phosphoryl optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
- the compound of formula I above is a compound of formula Ia-1 or a compound of formula Ia-2:
- R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group).
- Phosphoryl optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
- the above compound of formula I is a compound of formula Ib:
- R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group).
- Phosphoryl optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
- the compound of formula I above is a compound of formula Ib-1 or a compound of formula Ib-2:
- R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group).
- Phosphoryl optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
- the above compound of formula I is a compound of formula Ic:
- fragment E and the substituents R 1 , R 2 , R 3 , R 5a , R 5b and R 6 are as defined above.
- the compound of formula I above is a compound of formula Ic-1 or a compound of formula Ic-2:
- fragment E and the substituents R 1 , R 2 , R 3 , R 5a , R 5b and R 6 are as defined above.
- the above compound of formula I is a compound of formula Id:
- R 5a and R 5b are not hydrogen, and the fragment E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as defined above.
- the compound of formula I above is a compound of formula Id-1 or a compound of formula Id-2:
- R 5a and R 5b are not hydrogen, and the fragment E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as defined above.
- the present invention provides a process for the preparation of a compound of formula I above, which comprises the steps of:
- the acylating reagent used in the step 1) of the above preparation method includes, but is not limited to, glacial acetic acid, acetic anhydride (or acetic anhydride), acetyl chloride, benzoic anhydride, and benzoic acid.
- the sulfonylating reagents include, but are not limited to, formic acid anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, p-toluenesulfonic anhydride, p-toluenesulfonyl chloride, and the like. .
- the introduction of Fragment E in step 2) of the above preparation process is achieved by a coupling reaction.
- Common coupling reactions include, but are not limited to, Suzuki Reaction, Heck Reaction, Stille Reaction, Sogonoshira Coupling, and Xiongtian Coupling Reaction ( Kumada Coupling reaction, Negishi Coupling, Hiyama Coupling, and the like. It will be appreciated that those skilled in the art are familiar with the experimental conditions of the above coupling reactions.
- the hydrogenation in step 3) of the above preparation process is achieved by catalytic hydrogenation, metal hydride hydrogenation or hydroboration.
- Catalysts commonly used in catalytic hydrogenation reactions include, but are not limited to, nickel catalysts (eg, Raney nickel), palladium catalysts (eg, palladium on carbon), platinum catalysts (eg, platinum carbon); reagents commonly found in metal hydride hydrogenation reactions include (but Not limited to) lithium hydride (LiH), sodium hydride (NaH), lithium aluminum hydride (LiAlH 4 ), etc.; common reagents in the hydroboration reaction include, but are not limited to, diborane (B 2 H 4 ), hydroboration Sodium (NaBH 4 ) and the like.
- the present invention also provides a corresponding preparation method comprising the following steps:
- the above preparation method further comprises the following steps:
- the chiral fragment R chiral is introduced into the compounds III-1 and III-2 obtained in the step 4), respectively, to obtain the compounds III'-1 and III'-2; the compound III'-1 is chirally resolved to obtain the compound III.
- '-1-a and III'-1-b, compound III'-2 was chiralized to give compounds III'-2-a and III'-2-b; and then the chiral fragment R chiral was removed separately.
- the chiral fragment R chiral is provided by a chiral auxiliary
- the chiral auxiliary is a 4-substituted oxazolidinone compound, including but not limited to (S)-4-phenyl-2-oxazolidine Ketone, (R)-4-phenyl-2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone, (R)-4-benzyl-2-oxazolidinone, (S)-4-isopropyl-2-oxazolidinone, (R)-4-isopropyl-2-oxazolidinone, (S)-4-tert-butyl-2-oxazolidinone And (R)-4-tert-butyl-2-oxazolidinone.
- the chiral auxiliary group R chiral is introduced into the compounds III-1' and III-2', respectively, to obtain the compounds III'-1' and III'-2'; the compound III'-1' is induced by the chiral auxiliary group, and R 5b is introduced.
- the group gives the compounds III'-1'-a and III'-1'-b, and the compound III'-2' is induced by a chiral auxiliary group, and the R 5b group is introduced to obtain the compound III'-2'-a and III.
- '-2'-b; the chiral fragment R chiral is removed separately, and the compounds III"-1'-a and III"-1'-b and III" for reacting with the aniline compound in step 5) are obtained.
- the chiral auxiliary group R chiral is a 4-substituted oxazolidinone compound, including but not limited to (S)-4-phenyl-2-oxazolidinone, (R)-4-phenyl -2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone, (R)-4-benzyl-2-oxazolidinone, (S)-4-isopropyl- 2-oxazolidinone, (R)-4-isopropyl-2-oxazolidinone, (S)-4-tert-butyl-2-oxazolidinone, (R)-4-tert-butyl -2-oxazolidinone and the like.
- pharmaceutical composition refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.
- pharmaceutically acceptable carrier refers to a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and is not deleterious to the subject, including but not limited to diluents (or fillers), binders, disintegration Agents, lubricants, wetting agents, thickeners, glidants, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, solubilizers, surfactants, and the like.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label thereof Or prodrug.
- the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
- the present invention provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or The use of a pharmaceutical composition as an IDO inhibitor.
- the present application also provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or Use of the above pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by IDO.
- IDO at least partially mediated by IDO
- diseases in which at least a portion of IDO-related factors are involved in the pathogenesis including but not limited to cancer (eg, cervical cancer), neurodegenerative diseases (eg, Alz Haimo disease), viral infections (such as AIDS), bacterial infections (such as streptococcal infections), ocular diseases (such as cataracts), autoimmune diseases (such as rheumatoid arthritis), depression, anxiety, and psychological disorders .
- cancer eg, cervical cancer
- neurodegenerative diseases eg, Alz Haimo disease
- viral infections such as AIDS
- bacterial infections such as streptococcal infections
- ocular diseases such as cataracts
- autoimmune diseases such as rheumatoid arthritis
- depression anxiety, and psychological disorders .
- the present invention provides a method for preventing and/or treating a disease mediated at least in part by IDO, comprising the steps of: administering a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable salt, hydrate thereof, Solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or pharmaceutical compositions described above are administered to a patient in need thereof.
- terapéuticaally effective amount refers to a dose of a pharmaceutically active ingredient that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., a patient).
- administering means applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (for example, a pharmaceutical composition of the present invention) to a patient or a cell, tissue, organ, biological fluid or the like.
- a pharmaceutically active ingredient such as a compound of the present invention
- a pharmaceutical composition comprising a pharmaceutically active ingredient (for example, a pharmaceutical composition of the present invention)
- Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.
- the term "required for it” refers to the judgment of a doctor or other caregiver that the patient needs or will benefit from the prevention and/or treatment process, based on the judgment of the doctor or other caregiver in his area of expertise. Factors.
- patient refers to a human or non-human animal (eg, a mammal).
- the present invention provides a pharmaceutical combination comprising the above compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis and trans isomer thereof, isotope label Or a prodrug or a pharmaceutical composition as described above and at least one additional cancer therapeutic.
- cancer refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, undesired ability to invade surrounding tissues, and/or the ability to establish new growth in ectopic.
- Common cancers include (but are not limited to) brain cancer, liver cancer, gallbladder cancer, bronchial cancer, lung cancer, bladder cancer, ovarian cancer, cervical cancer, testicular cancer, lip cancer, tongue cancer, hypopharyngeal cancer, laryngeal cancer, esophageal cancer, Gastric cancer, intestinal cancer (eg colon cancer, rectal cancer), thyroid cancer, salivary gland cancer, pancreatic cancer, breast cancer, prostate cancer, blood cancer (or leukemia), lymphoma (or lymphoma), bone cancer and skin cancer.
- cancer therapeutic agent refers to a pharmaceutical or pharmaceutical formulation that is effective in controlling and/or combating cancer.
- Common cancer therapeutics include, but are not limited to, anticonvulsants (such as pentastatin, etc.), antipyrimidines (such as fluorouracil), antifolates (such as methotrexate), DNA polymerase inhibitors (such as arabinose).
- Cytidine alkylating agents (such as cyclophosphamide), platinum complexes (such as cisplatin), DNA-killing antibiotics (such as mitomycin), topoisomerase inhibitors (such as camptothecin), embedding DNA interferes with nucleic acid synthesis drugs (such as epirubicin), prevents the supply of raw materials (such as asparaginase), interferes with tubulin-forming drugs (such as paclitaxel), interferes with ribosome-functional drugs (such as harringtonine), Cytokines (eg, IL-1), thymosin, tumor cell proliferative viruses (eg, adenovirus ONYX-015), and the like.
- alkylating agents such as cyclophosphamide
- platinum complexes such as cisplatin
- DNA-killing antibiotics such as mitomycin
- topoisomerase inhibitors such as camptothecin
- embedding DNA interferes with nucleic acid synthesis drugs
- the present invention provides a method for preventing and/or treating cancer comprising the steps of: administering a therapeutically effective amount of a compound of the above formula I or a pharmaceutically acceptable salt, hydrate, solvate thereof, or stereoisomer thereof A construct, tautomer, cis-trans isomer, isotopic label or prodrug or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent are administered to a patient in need thereof.
- Example 1 Synthesis of Compounds 1 to 7 and 70 to 71.
- S4 The product in S3 is separated and purified by silica gel column chromatography, and the mobile phase is petroleum ether/ethyl acetate (V/V: 10:1 to 1:1) to obtain the target compound 2-(cis-4-( Ethyl 6-fluoroquinolin-4-yl)cyclohexyl)propanoate.
- S7 The product of S6 was purified by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate (V/V: 10:1 to 1:1) to obtain the target compound (4R)-3-((2S) -2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4-phenyloxazolidin-2-one.
- S8 The product of S7 (1.0 eq.) was dissolved in THF (0.25M) and water (1M), and aqueous solution of hydrogen peroxide (35 wt%, 4 eq.) was slowly added at 0 ° C, then lithium hydroxide (1.6 eq) was added.
- the target compound isolated and purified in S7 is (S)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propionic acid, it can be obtained by a method similar to the above method ( S,Z)-N-(4-Chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 3).
- the target compound isolated and purified in S4 is ethyl 2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propionate
- a method similar to the above method can be used to obtain (R, Z)-N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 4) and (S, Z)-N-(4-Chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 5).
- N-(4-chlorophenyl)-2-(4-(6-fluoroquinoline) can be obtained by a method similar to the above.
- 4-yl)cyclohexyl)propanoid compound 6
- (R)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl) Propionin Compound 70.
- ESI-MS m/z 410.17, [M+H] + .
- the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-pentafluoroanisole.
- the mass spectrometric data of the specific compound were as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-ethynylaniline.
- the mass spectrometric data of the specific compound were as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-dimethylphosphoranilide.
- the mass spectrometric data of the specific compound were as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-aminosulfonamidoaniline.
- the mass spectrometric data of the specific compound were as follows:
- the target compounds in each step were prepared by the method described in Example 6, and the target compounds were obtained by substituting the corresponding enantiomers.
- the mass spectrometric data of the specific compounds were as follows:
- the target compound in each step was prepared by the method described in Example 4 except that the target compound (amide compound) in S9 was not subjected to the carbonyl derivatization reaction in S10, and the mass spectrometric data of the specific compound were as follows:
- the target compound in each step was prepared by the method described in Example 9, and the target compound was obtained by substituting each corresponding enantiomer.
- the mass spectrometric identification data of the specific compound is as follows:
- the target compounds in each step were prepared by the method described in Example 11, and the target compounds were obtained by substituting the corresponding enantiomers.
- the mass spectrometric identification data of the specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 3-bromo-4-fluoroaniline.
- the mass spectrometric data of the specific compound were as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl.
- Dimethyl borate, replacing p-chloroaniline in S9 with 3-chloro-4-fluoroaniline, the mass spectrometric identification data of specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl.
- Dimethyl borate, replacing p-chloroaniline in S9 with m-chloroaniline, the mass spectrometric identification data of specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with benzo[b]thiophen-5-ylborate.
- the ester replace the p-chloroaniline in S9 with 3-chloro-4-fluoroaniline.
- the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 2-oxo-2H-chromene-6-yl.
- Dimethyl borate, replacing p-chloroaniline in S9 with 3-chloro-4-fluoroaniline, the mass spectrometric identification data of specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl. Dimethyl borate, replacing p-chloroaniline in S9 with 3,4-methylenedioxyaniline.
- the mass spectrometric data of specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-chloro-2,3,5,6-deuterated aniline.
- the mass spectrometric data of the specific compound were as follows. :
- the target compound in each step was prepared by the method described in Example 8, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid B.
- the mass spectrometric identification data of esters and specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 7, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid.
- the mass spectrometric identification data of esters and specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid
- the mass spectrometric identification data of esters and specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid The ester is replaced by methylamine in S10.
- the mass spectrometric data of the specific compound are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid
- the ester, the p-chloroaniline in S9 is replaced by N-methyl-p-chloroaniline, and the target compound (amide compound) in S9 is obtained, and the carbonyl derivatization reaction in S10 is not performed.
- the mass spectrometric identification data of the specific compound are as follows:
- Example 25 Synthesis of compounds 83 to 84.
- the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid
- the ester, the p-chloroaniline in S9 is replaced by N-tridecylmethyl-p-chloroaniline, and the target compound (amide compound) in S9 is obtained, and the carbonyl derivatization reaction in S10 is not carried out, and the specific compound is identified by mass spectrometry.
- Data are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-propargylaniline or N-methyl-4-propargylaniline.
- the identification data is as follows:
- the target compound in each step was prepared by the method described in Example 23, except that 4-propargyl phenylamine or N-methyl-4-propargyl phenylamine in S9 was replaced with 4-pentafluorothiol.
- aniline or N-methyl-4-pentafluorothiomethylaniline is as follows:
- Example 28 Synthesis of compounds 97-100.
- the target compound in each step was prepared by the method described in Example 2 except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-oxo-2-(4-oxo).
- Ethyl acetate of cyclohexyl) the mass spectrometric identification data of specific compounds are as follows:
- the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-oxo-2-(4-oxo).
- Ethyl acetate of cyclohexyl the mass spectrometric identification data of specific compounds are as follows:
- Example 30 Investigation of the inhibitory activity of the compound against the indoleamine-2,3-dioxygenase (IDO) of HeLa cells.
- HeLa (ATCC CCL-2) cells were obtained from ATCC and supplemented with 4.5 g/L glucose, 4.5 g/L L-glutamine and 4.5 g/L sodium L-pyruvate, 2 mM L-alanyl -L-glutamine dipeptide, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin and 10% fetal bovine serum.
- the cells were maintained in a humidified incubator at 37 ° C, 5% CO 2 .
- Interferon gamma induces expression of IDO in Hela cells, a model used to test the inhibitory activity of compounds on indoleamine 2,3-dioxygenase (IDO).
- the culture medium of Hela cells was RPMI-1640 containing 100 ⁇ M of L-tryptophan but no phenol red.
- the stock solution of the test compound was prepared with dimethyl sulfoxide at a concentration of 10 mM. During the experiment, it was diluted with dimethyl sulfoxide to the highest concentration of the test, and then serially diluted with the medium for 3 times, generally diluted to 8 to 10 concentration points, and duplicate holes were set at each concentration point.
- the final concentration of dimethyl sulfoxide was 0.5%, and each experiment contained the internal reference compound Epacadostat (INCB024360).
- the specific procedure of the assay was as follows: 20,000 HeLa cells were added to each well in a 96-well culture plate and cultured overnight. After 24 h, interferon gamma (final concentration 50 ng/mL) and various concentrations of test compound and internal reference compound were added to the cultured cells. After 24 h, transfer 140 ⁇ L of supernatant/well to a new 96-well plate, add 10 ⁇ L of each of 6.1 N trichloroacetic acid per well, incubate at 50 ° C for 30 min to hydrolyze N-formyl-kynurenine to canine urine. Amino acid. The reaction mixture was centrifuged (2500 rpm, 10 min) to remove the precipitate.
- A indicates ⁇ 10 nM
- B indicates ⁇ 100 nM
- C indicates ⁇ 1000 nM.
- the novel structure of the compound of the formula I provided by the present invention can inhibit the indoleamine-2,3-dioxygenase (IDO) of HeLa cells, and the IC50 value can reach 100 nM or less. Individually even below 10nM, the effect is more significant, can be used as a highly effective IDO inhibitor for the prevention and / or treatment of diseases mediated at least in part by IDO, with anti-tumor and anti-neurodegenerative diseases (such as Alzhai Silent disease, anti-inflammatory and many other intended uses.
- IDO indoleamine-2,3-dioxygenase
- Example 31 Inhibitory activity of compounds against indoleamine-2,3-dioxygenase (IDO) of HeLa cells.
- HeLa (ATCC CCL-2) cells were obtained from ATCC and cultured in EMEM (Eagle's Minimum Essential Medium; In 30-2003 TM medium, the medium contains Earle's balanced salt solution, non-essential amino acids, 2 mM L-glutamine, 1 mM sodium pyruvate and 1500 mg/L sodium bicarbonate, as follows:
- Ave HC contains 10 ng/mL of IFN- ⁇ , no average reading of compounds
- Cpd well contains 10 ng/mL of IFN- ⁇ and contains the reading value of the test compound
- the compound 47 has an excellent inhibitory effect against HeLa cell guanamine-2,3-dioxygenase (IDO).
- the IC 50 value reached below 1 nM;
- Compound 52 had comparable HeLa cell indole-2,3-dioxygenase (IDO) inhibition compared to the control compound Epacadostat.
- IDO HeLa cell indole-2,3-dioxygenase
- These compounds are useful as potent IDO inhibitors for the prevention and/or treatment of diseases mediated at least in part by IDO, with anti-tumor, anti-neurodegenerative diseases (such as Alzheimer's disease), anti-inflammatory, etc. The intended use.
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Abstract
La présente invention se rapporte au domaine de la chimie pharmaceutique. L'invention concerne un nouvel inhibiteur de l'indoléamine 2,3-dioxygénase (IDO), son procédé de préparation et son utilisation. L'inhibiteur d'IDO selon la présente invention a une structure représentée par la formule (I) et a de multiples activités pharmacologiques telles que la prévention de cancers, de maladies neurodégénératives et de l'inflammation.
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