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WO2017140272A1 - Composé tricyclique servant d'immunomodulateur - Google Patents

Composé tricyclique servant d'immunomodulateur Download PDF

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Publication number
WO2017140272A1
WO2017140272A1 PCT/CN2017/074128 CN2017074128W WO2017140272A1 WO 2017140272 A1 WO2017140272 A1 WO 2017140272A1 CN 2017074128 W CN2017074128 W CN 2017074128W WO 2017140272 A1 WO2017140272 A1 WO 2017140272A1
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WIPO (PCT)
Prior art keywords
group
pharmaceutically acceptable
acceptable salt
cancer
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2017/074128
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English (en)
Chinese (zh)
Inventor
刘世岚
王大海
梁贵柏
胡国平
黎健
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
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Publication date
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd, Medshine Discovery Inc filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to CN201780011200.9A priority Critical patent/CN108884104B/zh
Publication of WO2017140272A1 publication Critical patent/WO2017140272A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application belongs to the field of medicine, and in particular to a tricyclic compound or a pharmaceutically acceptable salt thereof as an immunomodulator.
  • Tryptophan is an amino acid essential for the biosynthesis of proteins, niacin and neurotransmitter serotonin.
  • Indoleamine 2,3-dioxygenase also known as INDO or IDO
  • IDO IDO
  • IFN-y stimulation induces activation of IDO, leading to depletion of tryptophan, thereby preventing the growth of tryptophan-dependent cellular pathogens such as Toxoplasma gondii and Chlamydia trachomatis.
  • the activity of IDO also has anti-proliferative effects on many tumor cells. In the process of rejection of allogeneic tumors, IDO induction in vivo has been found, indicating that this enzyme may play a role in tumor rejection.
  • Small molecule inhibitors of IDO can be developed to treat or prevent IDO-related diseases.
  • PCT Publication WO 99/29310 reports a method of altering T cell mediated immunity comprising altering the local extracellular concentration of tryptophan and tryptophan metabolites, such as 1-A, using an IDO inhibitor.
  • -DL-tryptophan, p-(3-benzofuranyl)-DL-alanine, p-[3-benzo(b)thienyl]-DL-alanine and 6-nitro- L-tryptophan) (Munn, 1999).
  • a method for preparing antigen presenting cells for increasing or decreasing T cell tolerance is also reported in WO 03/087347 (Munn, 2003).
  • indoleamine-2,3-dioxygenase (IDO) inhibitory activity are also reported in WO 2004/094409, WO 2009/073620, WO 2009/132238, WO 2011/056652 and WO 2012/142237.
  • the compound of WO2012/142237 comprises a series of trycyclic imidazoisoindoles having strong IDO inhibitory activity, including NLG-919, having the structural formula shown below:
  • R 41 is selected from C 5-6 cycloalkyl, 5- to 12-membered heterocycloalkyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, optionally substituted by 1, 2 or 3 R.
  • R 42 R 43 ) and R 44 -LR 45 are selected from C 5-6 cycloalkyl, 5- to 12-membered heterocycloalkyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, optionally substituted by 1, 2 or 3 R.
  • R 42 R 43 and R 44 -LR 45 ;
  • R 42 and R 43 are each independently selected from C 1-3 alkyl, C 3-6 cycloalkyl and 5- to 6-membered aryl C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
  • R 44 is selected from the group consisting of a 5- to 6-membered cycloalkyl group optionally substituted by 1, 2 or 3 R, a 5- to 6-membered heterocycloalkyl group, a 5- to 6-membered aryl group, and a 5- to 9-membered heteroaryl group;
  • R 45 is selected from C 1-6 alkyl, 5- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered aryl, and 5 to 9 optionally substituted by 1, 2 or 3 R. Metaheteroaryl;
  • R is selected from the group consisting of OH, NH 2 , F, Cl, Br, I, CN, COOH, oxo, Me, Et, CH 2 F, CHF 2 , CF 3 , NHCH 3 , N(CH 3 ) 2 and
  • R41 is selected from C5-6 cycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 12-membered aromatic, optionally substituted by 1, 2 or 3 R a group of 5 to 12 membered heteroaryl, N(R 42 R 43 ) and R 44 -LR 45 .
  • R41 is selected from cyclopentyl, cyclohexyl, optionally substituted by 1, 2 or 3 R. Losing a hydrogen atom at any position
  • R 41 is selected from the group consisting of optionally substituted by 1, 2 or 3 R
  • R 41 is selected from the group consisting of optionally substituted by 1, 2 or 3 R
  • R 41 is selected from
  • R 41 is selected from
  • R 42 and R 43 are each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl optionally substituted by 1, 2 or 3 R. , cyclobutyl, cyclopentyl, cyclohexyl, phenyl CH 2 , phenyl CH 2 CH 2 , phenyl CH 2 CH 2 CH 2 and phenyl CH(CH 3 )CH 2 .
  • R 42 and R 43 are each independently selected from methyl, optionally substituted by 1, 2 or 3 R,
  • R 42 and R 43 are each independently selected from methyl
  • N(R 42 R 43 ) is selected from
  • R44 is selected from any of the positions that are optionally substituted by 1, 2 or 3 R to lose 2 hydrogen atoms. And benzene.
  • R44 is selected from phenylene and piperidinyl optionally substituted with 1, 2 or 3 R.
  • R 44 is selected from
  • R 44 is selected from
  • R 45 is selected from 5 to 6 membered cycloalkyl, 5 to 6 membered heterocycloalkyl, phenyl, and 5 to which are optionally substituted by 1, 2 or 3 R. 9-membered heteroaryl.
  • R 45 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl optionally substituted by 1, 2 or 3 R Base, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, piperazinyl, phenyl, pyrimidinyl, pyrazolyl, imidazolyl, thienyl, oxalic, which loses one hydrogen atom at any position Azolyl, isoxazolyl, thiazolyl and [1,2,4]triazolo[4,3-a]pyridinyl.
  • R 45 is selected from cyclohexyl, piperazinyl, phenyl, pyrimidinyl, pyrazolyl, imidazolyl, thienyl optionally substituted by 1, 2 or 3 R , oxazolyl, isoxazolyl, thiazolyl and [1,2,4]triazolo[4,3-a]pyridinyl.
  • R 45 is selected from the group consisting of t-butyl, cyclohexyl, optionally substituted with 1 R, phenyl, pyrimidinyl, pyridyl, at any position. Azyl and [1,2,4]triazolo[4,3-a]pyridinyl.
  • R 45 is selected from t-butyl groups optionally substituted with 1, 2 or 3 R,
  • R 45 is selected from the group consisting of optionally substituted by 1, 2 or 3 R
  • R 45 is selected from
  • R 45 is selected from
  • R 44 -LR 45 is selected from
  • R is selected from the group consisting of OH, NH 2 , F, Cl, Br, I, CN, COOH, Me, Et, CH 2 F, CHF 2 , CF 3 , NHCH 3 , N (CH 3 ) 2 and
  • R is selected from the group consisting of F, Cl, CN, oxo, Me, CF 3, and
  • One aspect of the present application is to provide a compound having the structure: or a pharmaceutically acceptable salt thereof:
  • Another aspect of the present application is to provide a compound having the structure: or a pharmaceutically acceptable salt thereof:
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the application provides a method of treating an immunosuppressive disorder mediated by guanidine 2,3-dioxygenase (IDO), the method comprising administering a compound of formula I, or a pharmaceutically acceptable compound thereof, to a subject in need thereof Accepted salt or a pharmaceutical composition thereof.
  • IDO guanidine 2,3-dioxygenase
  • the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment of an immunosuppressive disorder mediated by 2,3-dioxygenase (IDO) Use in.
  • IDO 2,3-dioxygenase
  • the application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of an immunosuppressive disorder mediated by 2,3-dioxygenase (IDO).
  • IDO 2,3-dioxygenase
  • the immunosuppressive disease is associated with an infectious disease or cancer.
  • the infectious disease is selected from the group consisting of influenza, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), poliovirus , herpes zoster virus, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV) or Coxsackie virus.
  • the cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head or neck cancer, lymphoma, leukemia or melanoma.
  • references to “one embodiment” or “an embodiment” or “in another embodiment” or “in some embodiments” throughout the specification are meant to include in the at least one embodiment The specific reference elements, structures or features described.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn means having mn carbon atoms in this moiety.
  • C 3-10 cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.
  • the "C 0-6 alkylene group” means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond. It is easy to understand that when a hetero atom is contained, mn represents the sum of the number of carbon atoms and hetero atoms.
  • C 1-10 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present application, and a pharmaceutically acceptable salt of the compound of the formula I, for example, a metal salt, an ammonium salt, a salt with an organic base, and a salt formed of an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, or the like.
  • metal salts include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.
  • Non-limiting examples of salts formed with organic bases include, but are not limited to, with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, A salt formed by dicyclohexylamine or the like.
  • Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting a compound of the free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of formula I of the present application may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present application.
  • the compounds of formula I of the present application may exist in polymorph or amorphous form.
  • the compounds of formula I of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and individual isomers are included within the scope of this application.
  • the compounds of formula I of the present application may exist in specific geometric or stereoisomeric forms. This application contemplates all such compounds, Including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers , (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are also included within the scope of the present application.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide purity. The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then known to those skilled in the art.
  • the diastereomeric resolution is carried out by fractional crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of formula I of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). All isotopic compositional changes of the compounds of Formula I of the present application, whether radioactive or not, are included within the scope of this application.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of the active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • halo or halogen, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is meant to include monohaloalkyl and polyhaloalkyl; for example, the term “halo (C 1 -C 4) alkyl” is meant to include, but are not limited to trifluoromethyl, 2,2,2 -Trifluoroethyl, 4-chlorobutyl and 3-bromopropyl, and the like.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • hydroxy refers to -OH.
  • cyano refers to -CN.
  • amino refers to -NH 2 , -NH(alkyl) and -N(alkyl) 2 , and specific examples of the amino group include, but are not limited to, -NH 2 , -NHCH 3 , -NHCH(CH 3 ) 2 , - N(CH 3 ) 2 , -NHC 2 H 5 , -N(CH 3 )C 2 H 5 and the like.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, ⁇ , ⁇ , etc.
  • the specific alkyl group includes all isomeric forms thereof, for example, the propyl group includes -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , for example, butyl includes -CH 2 CH 2 CH 2 CH 3 ,- CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 .
  • C 1-8 alkyl refers to an alkyl group having from 1 to 8 carbon atoms.
  • C1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • C 1-3 alkyl refers to an alkyl group having from 1 to 3 carbon atoms.
  • the "alkyl”, “C 1-8 alkyl”, “C 1-6 alkyl”, “C 1-4 alkyl” or “C 1-3 alkyl” may be unsubstituted or one Or a plurality of substituents selected from a hydroxyl group, a halogen or an amino group.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, such as a C3-20 cycloalkyl group, preferably a C3-6 cycloalkyl group, such as a cyclopropyl group, Cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the cycloalkyl group may be unsubstituted or substituted, and the substituent includes, but is not limited to, an alkyl group, an alkyloxy group, a cyano group, a carboxyl group, an aryl group, a heteroaryl group, an amino group, a halogen, a sulfonyl group. , sulfinyl group, phosphoryl group, hydroxyl group and the like.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • heteroalicyclic refers to a monocyclic or fused ring having from 3 to 12 ring atoms, having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1 or The two ring atoms are heteroatoms selected from N, O, S(O) n (where n is 0, 1, or 2), and the remaining ring atoms are C.
  • Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • Examples of 3-membered saturated heteroalicyclic rings include, but are not limited to Examples of 4-membered saturated heteroalicyclic rings include, but are not limited to, Examples of 5-membered saturated heteroalicyclic rings include, but are not limited to Examples of 6-membered saturated heteroalicyclic rings include, but are not limited to Examples of 7-membered saturated heteroalicyclic rings include, but are not limited to Examples of 5-membered unsaturated heteroalicyclic rings include, but are not limited to Examples of 6-membered unsaturated heteroalicyclic rings include, but are not limited to
  • heterocycloalkyl refers to a group remaining after the "heteroalicyclic" molecule has one hydrogen atom removed, and the heterocycloalkyl group may be unsubstituted or the hydrogen atom therein may be optionally substituted with a substituent.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by atoms such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • DBU 1,8-diazabicycloundec-7-ene
  • DMAP 4-dimethylaminopyridine
  • TBSCl t-butyldimethylchlorosilane
  • DMF stands for N,N-dimethylformamide
  • Pd(OAc) 2 represents palladium acetate
  • PPh 3 represents triphenylphosphine
  • SFC stands for chiral supercritical chromatography column
  • EtOAc represents ethyl acetate
  • t-Bu- represents tert-butyl m-CPBA stands for m-chloroperoxybenzoic acid
  • DCM stands for dichloromethane
  • CDI stands for carbonyl diimidazole
  • Boc- stands for t-butylcarbonyl
  • HATU stands for O-(7-azabenzotriazol-1-yl) -N,N,N',N'-te
  • Racemate Example 1 (160 mg, 564.63 mmol) was subjected to chiral separation (column: Chiralpak AD-3 150 x 4.6 mm ID, 3 um mobile phase: A: carbon dioxide B: methanol (0.05% diethylamine)) to afford isomer 1
  • Example 2 (20.00 mg, 12.50% yield) (retention time: 4.221 min) and isomer 2
  • Example 3 (40 mg, 25.00% yield) (retention time: 6.466 min).
  • LCMS (ESI) m/z: 301 (M+1). SFC ( RT 3.931 min).
  • Example 11E A solution of Example 11E (30 mg, 135.32 ⁇ mol) and CDI (24.14 mg, 148.85 ⁇ mol) in acetonitrile (1 mL) and DMF (1 mL) was stirred at 10 ° C for 2 hr. After completion of the reaction, DIEA (34.98 mg, 270.64 ⁇ mol) and dicyclohexylamine (135.32 ⁇ mol) were added, and stirring was continued at 10 ° C for 14 hours. The reaction mixture was purified by preparative HPLC to afford the title compound. The yield was 56.97%.
  • Examples 12-22 can be carried out by referring to the preparation method of Example 11, using different amines to obtain:
  • Example 11E (50 mg, 225.54 ⁇ mol) in DMF (1 mL) was added 2-cyclohexylacetic acid (225.54 ⁇ mol), HATU (85.76 mg, 225.54 ⁇ mol) and DIEA (58.30 mg, 451.08 ⁇ mol), at 12 ° C Stir for 30 minutes.
  • the reaction mixture was purified by preparative HPLC to afford the title compound. The yield was 59.83%.
  • Examples 24-46 were prepared according to the procedure of Example 23 using different amines:
  • the NFK green TM fluorescent molecule was used to detect changes in the formation of the IDO1 enzyme metabolite NFK, and the IC50 value of the compound was used as an index to evaluate the inhibitory effect of the compound on the recombinant human IDO1 enzyme.
  • IDO1 enzyme activity assay kit NTRC#NTRC-hIDO-10K
  • the compound was diluted to 1 mM in DMSO, diluted 3 fold, 10 gradients, double duplicate wells. 48 ⁇ L of 50 mM phosphate buffer pH 6.5 was transferred to the compound plate via a Bravo automated liquid handling platform. Then, 2 ⁇ L of the diluted compound DMSO solution was added, and after mixing, 10 ⁇ L was transferred to the enzyme reaction plate.
  • reaction buffer 50 mM phosphate buffer pH 6.5, 0.1% Tween-20, 2% glycerol, 20 mM ascorbic acid, 20 ⁇ g/ml catalase and 20 ⁇ M methylene blue
  • reaction buffer 50 mM phosphate buffer pH 6.5, 0.1% Tween-20, 2% glycerol, 20 mM ascorbic acid, 20 ⁇ g/ml catalase and 20 ⁇ M methylene blue
  • the reaction was started by adding 10 ⁇ L of 400 ⁇ M L-type tryptophan substrate and incubated at 23 ° C for 90 minutes.
  • 10 ⁇ L of NFK green TM fluorescent dye was added, sealed with a sealing plate, and placed at 37 ° C for 4 hours, and then read on an Envision multi-function plate reader (Ex 400 nm / Em 510 nm).
  • the reference well to which the IDO1 enzyme was added but no compound was added was determined to have a 0% inhibition rate, and the reference well to which the IDO1 enzyme was not added was determined to be 100% inhibition rate, and the IC50 value of the compound was calculated by analyzing the data with XLFit 5.
  • the change of kynurenine in Hela cells was detected by LC-MS method, and the inhibitory effect of the compound on IDO1 enzyme was evaluated by the IC50 value of the compound.
  • Cell line Hela cells
  • Precipitant 4 ⁇ M L-kynurenine-d4 dissolved in 100% acetonitrile, CacheSyn#CSTK008002;
  • Pre-heated medium trypsin, DPBS in a 37 ° C water bath. Aspirate the culture medium and wash it with 10 mL of DPBS; add pre-warmed trypsin to the flask, rotate the flask to cover the flask evenly, and place it in a 37 ° C, 5% CO 2 incubator for digestion 1 - 2 minutes; each T150 was suspended with 10-15 mL of medium, centrifuged at 800 rpm for 5 minutes, resuspended in 10 mL of medium, pipet 1 mL of cell suspension, counted with Vi-cell; diluted Hela cells with medium 5 ⁇ 10 5 /mL, 80 ⁇ L was added to a 96-cell plate, and cultured at 37 ° C for 5-6 hours in a 5% CO 2 incubator.
  • the compound was diluted to 1 mM with DMSO, diluted 3 fold, 9 gradients, double duplicate wells. 5 ⁇ L of the diluted compound DMSO solution was added to a compound plate containing 95 ⁇ L of the medium. After mixing, transfer 10 ⁇ L to the cell plate.
  • the reference well to which ⁇ -type interferon was added but no compound was added was determined to have a 0% inhibition rate, and the reference well to which Hela cells were not added was determined to be 100% inhibition rate, and the IC50 value of the compound was calculated by analyzing the data with XLFit 5.

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  • Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de formule (I) ou un sel correspondant pharmaceutiquement acceptable, et une composition pharmaceutique associée, le composé de formule (I) ou le sel pharmaceutiquement acceptable et la composition pharmaceutique associée assurant une activité inhibitrice de l'indole amine 2,3-dioxygénase (IDO) et étant capables de traiter les maladies immunosuppressives conditionnées par l'indole amine 2,3-dioxygénase (IDO), par exemple les maladies infectieuses ou le cancer.
PCT/CN2017/074128 2016-02-19 2017-02-20 Composé tricyclique servant d'immunomodulateur Ceased WO2017140272A1 (fr)

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WO2012142237A1 (fr) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
WO2013107164A1 (fr) * 2012-01-20 2013-07-25 辽宁思百得医药科技有限公司 Nouvel inhibiteur de l'indoléamine-2,3-dioxygénase, son procédé de fabrication et ses utilisations
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WO2006122150A1 (fr) * 2005-05-10 2006-11-16 Incyte Corporation Modulateurs de l'indolamine 2,3-dioxygenase et leurs procedes d'utilisation
WO2012142237A1 (fr) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Dérivés d'imidazole fusionnés pouvant être employés en tant qu'inhibiteurs d'ido
WO2013107164A1 (fr) * 2012-01-20 2013-07-25 辽宁思百得医药科技有限公司 Nouvel inhibiteur de l'indoléamine-2,3-dioxygénase, son procédé de fabrication et ses utilisations
WO2015031295A1 (fr) * 2013-08-27 2015-03-05 Bristol-Myers Squibb Company Inhibiteurs d'ido

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CN107383024A (zh) * 2016-09-12 2017-11-24 广州必贝特医药技术有限公司 含咪唑稠合三环类化合物及其应用
CN107383024B (zh) * 2016-09-12 2018-06-08 广州必贝特医药技术有限公司 含咪唑稠合三环类化合物及其应用

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