WO2020228823A1 - Nouveaux composés amides et leurs utilisations - Google Patents

Nouveaux composés amides et leurs utilisations Download PDF

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Publication number
WO2020228823A1
WO2020228823A1 PCT/CN2020/090598 CN2020090598W WO2020228823A1 WO 2020228823 A1 WO2020228823 A1 WO 2020228823A1 CN 2020090598 W CN2020090598 W CN 2020090598W WO 2020228823 A1 WO2020228823 A1 WO 2020228823A1
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Prior art keywords
alkyl
haloalkyl
pharmaceutically acceptable
acceptable salt
substituted
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PCT/CN2020/090598
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English (en)
Inventor
Wei-Guo Su
Guangxiu Dai
Weihan Zhang
Hong Jia
Haibin Yang
Huaqing CAI
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Hutchison Medipharma Limited
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Priority claimed from CN201910409909.5A external-priority patent/CN112047877A/zh
Application filed by Hutchison Medipharma Limited filed Critical Hutchison Medipharma Limited
Publication of WO2020228823A1 publication Critical patent/WO2020228823A1/fr

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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Definitions

  • the present invention relates to novel amide compounds, pharmaceutical compositions thereof, methods for preparing thereof, and uses thereof.
  • the amino acid L-tryptophan (L-Trp) is mainly catabolized via the so-called “kynurenine pathway” , i.e., the metabolic cascade that converts it into L-kynurenine.
  • the first step, from L-tryptophan to N-formyl-L-kynurenine is the rate-limiting step of the kynurenine metabolic pathway.
  • IDO1 indoleamine 2, 3-dioxygenase 1
  • IDO2 indoleamine 2, 3-dioxygenase 2
  • TDO tryptophan 2, 3-dioxygenase
  • IDO1 as a 45Kd monomer, is a cytosolic haem enzyme encoded by the INDO gene on human chromosome 8p22. It is expressed ubiquitously in various tissues and cells throughout the body, including immune cells, endothelial cells, and fibroblasts.
  • the expression of IDO1 is mainly regulated by inflammatory cues, such as IFN ⁇ , CpG-DNA, and LPS.
  • IDO2 is encoded by the INDOL1 gene, and is structurally very similar to IDO1 with about 42%similarity at the amino acid level, but is of very low enzymatic activity based on in vitro studies. In addition, the high incidence of genetic polymorphisms exist for human IDO2, abolishing the enzyme’s function.
  • TDO is encoded by the TDO2 gene, and expressed in high levels in the liver, and is functionally related to IDO1 and IDO2, but structural similarities at the amino acid level are only 10%.
  • TDO was thought to be mainly responsible for L-tryptophan homoeostasis in the body. More recently, studies have found that certain tumors mediate the tolerance of tumor cells to the host's immune system by highly expressing TDO. No TDO expression in host immune cells has been documented so far.
  • IDO1 expression is closely related to the occurrence and development of cancers.
  • some pro-inflammatory mediators such as IFN ⁇ can induce the expression of IDO1 in tumor cells or host immune cells (mainly antigen presenting cells, such as dendritic cells, macrophages, etc. ) .
  • IDO1 catalyze the metabolic reaction of L-tryptophan, through simultaneously reducing the concentration of L-tryptophan and increasing the production of L-kynurenine and its further metabolites (such as 3-hydroxykynurenine and 3-hydroxy-2-aminobenzoic acid, etc. ) to inhibit the proliferation of effector lymphocytes, such as T cells and NK cells, and induce their entry into cell cycle arrest and apoptosis.
  • effector lymphocytes such as T cells and NK cells
  • the immunosuppressive regulatory T cells are up-regulated, thereby helping the tumor cells to escape the host's immune surveillance and obtain a chance of malignant growth.
  • IDO1 small molecule inhibitors such as INCB024360 (Epacadostat) and NLG919 to inhibit IDO1 protein activity
  • IDO1 small molecule inhibitors such as INCB024360 (Epacadostat) and NLG919 to inhibit IDO1 protein activity
  • some IDO1 inhibitors such as INCB024360, BMS-986205, and Pf-06840003
  • IDO1/TDO small molecule inhibitors such as NLG919
  • IDO1 is a potential target for the treatment of malignancies (ESMO, 2016, Abstract 1110PD; ASCO, 2017, Abstract 4503; JCO. 2017.35 (15 suppl) : Abstract 1103; JCO. 2017.35 (15 suppl) : Abstract 3003; Cancer Res., 2017, 77 (13 Suppl) : Abstract CT116; Analyst and Investor Day Meeting, NewLink Genetics Corporation, October 25, 2016) .
  • IDO1 inhibitors may also be used to develop treatments for these diseases (Trends Immunol., 2013, 34 (3) : 137-143) .
  • IDO1 inhibitors currently entering clinical research have some drawbacks, and new IDO1 inhibitors are still needed to treat these diseases, especially cancer.
  • the present invention addresses these needs.
  • the present invention provides a compound of formula (I) :
  • X is N or CR 3 ;
  • Y is N or CR 4 ;
  • R 1 , R 2 , R 3 and R 4 are independently chosen from H, halo, -OH, -CN, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, -O (C 1-6 alkyl) , -NH (C 1-6 alkyl) , or -N (C 1-6 alkyl) 2 ;
  • Z is O, NR 5 , or CR 6 R 7 ;
  • R 5 is chosen from H, C 1-6 alkyl, or C 3-6 cycloalkyl
  • R 6 and R 7 are independently chosen from H, halo, -CN, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , -OH, C 1-6 alkyl, C 3-6 cycloalkyl, or -O (C 1-6 alkyl) ;
  • phenyl is phenyl, 5-6 membered heteroaryl, or indazolyl, each of which is optionally substituted with one or more groups chosen from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -O (C 1-6 alkyl) , or -O (C 1-6 haloalkyl) ;
  • pyridyl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with one or more groups chosen from halo, - (C 1-6 alkyl) n -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, - (C 1-6 alkyl) n -C 3-6 cycloalkyl, - (C 1-6 alkyl) n -phenyl, - (C 1-6 alkyl) n -4-6 membered heterocyclyl, - (C 1-6 alkyl) n -5-6 membered heteroaryl, - (C 1-6 alkyl) n -NR 1 ’R 2 ’, - (C 1-6 alkyl) n -CONR 1 ’R 2 ’,
  • n 0 or 1
  • n 1 or 2;
  • p is 0 or 1;
  • R 1 ’, R 2 ’, R 3 ’, R 4 ’, R 5 ’, R 6 ’, and R 7 ’ are independently chosen from H, C 1-6 alkyl, C 1-6 haloalkyl, - (C 1-6 alkyl) -O- (C 1-6 alkyl) , - (C 1-6 alkyl) -OH, - (C 1-6 alkyl) -CN, - (C 1-6 alkyl) -NH 2 , or C 3-6 cycloalkyl; or R 1 ’ and R 2 ’ together with the N atom they are attached to form a 4-6 membered heterocyclic ring.
  • compositions comprising the compounds of the present invention, and optionally comprising a pharmaceutically acceptable excipient.
  • a dash ( “-” ) that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -OR 3 refers to the attachment of R 3 to the rest of the molecule through an oxygen atom.
  • alkyl refers to a straight or branched saturated hydrocarbon radical containing 1-18 carbon atoms, preferably 1-10 carbon atoms, and more preferably 1-6 carbon atoms.
  • C 1-6 alkyl refers to an alkyl containing 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
  • alkyl located between two short dashes represents an alkylene linking group, for example, "- (C1-6 alkyl) -" refers to straight or branched C1-6 alkylene linking group.
  • alkylene refers to a straight or branced saturated divalent hydrocarbon radical containing 1-18 carbon atoms, preferably 1-10 carbon atoms, and more preferably 1-6 carbon atoms, and more preferably 1-4 carbon atoms.
  • - (C 1-6 alkyl) n - refers to a straight or branced alkylene containing 1-6 carbon atoms, wherein n is 0 or 1, such as -CH 2 -CH (CH 3 ) -CH 2 -, -CH (CH 3 ) -CH 2 -, -CH (CH 3 ) -CH 2 -CH 2 - etc.
  • the alkylene group is straight C 1-6 alkylene, more preferably -CH 2 -and -CH 2- CH 2 -.
  • C 2-6 alkenyl refers to an alkenyl containing 2-6 carbon atoms, preferably “C 2-4 alkenyl” , i.e. an alkenyl containing 2-4 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment for the alkenyl can be on or not on the double bonds.
  • alkynyl refers to a straight or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2, or 3, carbon-carbon triple bonds (C ⁇ C) and 2-10 carbon atoms, preferably 2-6 cabon atoms, more preferably 2-4 carbon atoms.
  • C 2-6 alkynyl refers to an alkynyl containing 2-6 carbon atoms, preferably “C 2-4 alkynyl” , i.e. an alkynyl containing 2-4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The point of attachment for the alkynyl can be on or not on the triple bonds.
  • halogen or “halo” as used herein means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro.
  • haloalkyl refers to an alkyl radical, as defined herein, in which one or more, for example 1, 2, 3, 4, or 5, hydrogen atoms are replaced with halogen atom, and when more than one hydrogen atoms are replaced with halogen atoms, the halogen atoms may be the same or different from each other.
  • haloalkyl refers to an alkyl radical, as defined herein, in which two or more, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are identical to each other.
  • haloalkyl refers to an alkyl radical, as defined herein, in which two or more hydrogen atoms, such as 2, 3, 4, or 5 hydrogen atoms are replaced with halogen atoms, wherein the halogen atoms are different from each other.
  • haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CH (CF 3 ) 2 , and the like.
  • cycloalkyl refers to saturated or partially unsaturated cyclic hydrocarbon radical having 3-12 ring carbon atoms, such as 3-8 ring carbon atoms, 5-7 ring carbon atoms, 4-7 ring carbon atoms or 3-6 ring carbon atoms, which may have one or more rings, such as 1, 2, or 3 rings, preferably 1 or 2 rings.
  • C 3-12 cycloalkyl refers to a cycloalkyl containing 3-12 carbon atoms in the ring
  • C 3-8 cycloalkyl refers to a cycloalkyl containing 3-8 carbon atoms in the ring.
  • Cycloalkyl also includes a fused or bridged ring, or a spirocyclic ring.
  • the rings of the cycle group may be saturated or has one or more, for example, one or two double bonds (i.e. partially unsaturated) , but not fully conjugated, and not an aryl as defined herein.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [4.1.0] heptyl, bicyclo [3.1.1] heptyl, spiro [3.3] heptyl, spiro [2.2] pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and bicyclo [3.1.1] hepta-2-ene.
  • heterocycle refers to saturated or partially unsaturated cyclic radicals having 3-12 ring atoms, such as 3-8 ring atoms, 5-7 ring atoms, 4-7 ring atoms, 4-6 ring atoms or 3-6 ring atoms, and containing one or more, for example 1, 2 or 3, preferably 1 or 2 heteroatoms independently chosen from N, O and S in the rings, with the remaining ring atoms being carbon; it may have one or more rings, for example 1, 2 or 3, preferably 1 or 2 rings.
  • the heterocycle group also includes those wherein the N or S heteroatom are optionally oxidized to various oxidation states.
  • heterocyclyl can be on the N heteroatom or carbon.
  • “3-12 membered heterocyclyl” refers to a heterocyclyl containing 3-12 ring atoms and containing at least one heteroatom independently chosen from N, O and S
  • “4-6 membered heterocyclyl” refers to a heterocyclyl containing 4-6 ring atoms and containing at least one heteroatom independently chosen from N, O and S.
  • the heterocycle group also includes a fused or bridged ring, or a spirocyclic ring.
  • the rings of the heterocycle group may be saturated or has one or more, for example, one or two double bonds (i.e.
  • heterocyclyl groups include, but are not limited to, 4-6 membered heterocyclyl, for example oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, pyrazolidinyl, and oxaspiro [3.3] heptanyl.
  • aryl or “aromatic ring” as used herein refers to carbocyclic hydrocarbon radical of 6 to 14 carbon atoms consisting of one ring or more fused rings, wherein at least one ring is an aromatic ring, for example phenyl, naphthalenyl, 1, 2, 3, 4-tetrahydronaphthalenyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthalenyl.
  • heteroaryl or “heteroaromatic ring” as used herein refers to: aromatic hydrocarbon radical having 5-12 ring atoms, such as having 5-10 ring atoms, 5-6 ring atoms, or 6 ring atoms, and containing one or more, for example, 1, 2, 3 or 4, preferably 1, 2 or 3 heteroatoms independently chosen from N, O, and S in the rings, with the remaining ring atoms being carbon; it may have one or more rings, for example, 1, 2 or 3, preferably have 1 or 2 rings; for example, said heteroaryl includes:
  • bicyclic aromatic hydrocarbon radical having 8-12 ring atoms, preferably having 9 or 10 ring atoms, and containing one or more, for example, 1, 2, 3 or 4, preferably 1, 2 or 3 heteroatoms independently chosen from N, O, and S (preferably N) in the rings, with the remaining ring atoms being carbon, wherein at least one of the rings is aromatic.
  • the bicyclic heteroaryl includes a 5-6 membered heterocyclic aromatic ring fused to a 5-6 membered cycloalkyl ring.
  • heteroaryl group examples include, but are not limited to, 5-6 membered heteroaryl, for example pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, triazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (such as 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, and 1, 3, 4-oxadiazolyl) , thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl, thienyl, furyl, pyranyl, pyrrolyl, pyridazinyl; and the bicyclic heteroaryl, for example benzodioxolyl, benzooxazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl,
  • Haldroxyl refers to the —OH radical.
  • asterisk “*” when a structure herein contains an asterisk “*” , it means that the chiral center of the compound marked by “*” is in either R-configuration or S-configuration, and the content of the compound with single configuration marked by “*” is at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 100%, or any value between those enumerated values) .
  • optionally substituted alkyl encompasses both “unsubstituted alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, chemically incorrect, synthetically non-feasible and/or inherently unstable.
  • substituted or “substituted with...” , as used herein, means that one or more hydrogens on the designated atom or group are replaced with one or more selections from the indicated group of substituents, provided that the designated atom's normal valence is not exceeded.
  • 2 hydrogens on a single atom are replaced by the oxo.
  • substituents and/or variables are permissible only if such combinations result in a chemically correct and stable compound.
  • a chemically correct and stable compound is meant to imply a compound that is sufficiently robust to survive sufficient isolation from a reaction mixture to be able to identify the chemical structure of the compound, and also sufficiently robust to allow subsequent formulation as an agent having at least one practical utility.
  • substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl) alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • substituted with one or more substituents means that one or more hydrogens on the designated atom or group are independently replaced with one or more selections from the indicated group of substituents. In some embodiments, “substituted with one or more substituents” means that the designated atom or group is substituted with 1, 2, 3, or 4 substituents independently chosen from the indicated group of substituents.
  • POSITA POSITA
  • some of the compounds of formula (I) may contain one or more chiral centers and therefore exist in two or more stereoisomeric forms.
  • the racemates of these isomers, the individual isomers and mixtures enriched in one enantiomer, as well as diastereomers when there are two chiral centers, and mixtures partially enriched with specific diastereomers are within the scope of the present invention.
  • the present invention includes all the individual stereoisomers (e.g. enantiomers) , racemic mixtures or partially resolved mixtures of the compounds of formula (I) and, where appropriate, the individual tautomeric forms thereof.
  • racemates can be used as such or can be resolved into their individual isomers.
  • the resolution can afford stereochemically pure compounds or mixtures enriched in one or more isomers.
  • Methods for separation of isomers are well known (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry” , Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using a chiral adsorbent.
  • Individual isomers can be prepared in chiral form from chiral precursors.
  • individual isomers can be separated chemically from a mixture by forming diastereomeric salts with a chiral acid, such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, fractionally crystallizing the salts, and then freeing one or both of the resolved bases, optionally repeating the process, so as obtain either or both substantially free of the other; i.e., in a form having an optical purity of >95%.
  • a chiral acid such as the individual enantiomers of 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, and the like, fractionally crystallizing the salts, and then free
  • racemates can be covalently linked to a chiral compound (auxiliary) to produce diastereomers which can be separated by chromatography or by fractional crystallization after which time the chiral auxiliary is chemically removed to afford the pure enantiomers, as is known to the POSITA.
  • auxiliary chiral compound
  • tautomer refers to constitutional isomers of compounds generated by rapid movement of an atom in two positions in a molecule. Tautomers readily interconvert into each other, e.g., enol form and ketone form are tipical tautomers.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound of Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject.
  • an acid addition salt includes such as a salt derived from an inorganic acid and an organic acid.
  • Said inorganic acid includes such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid;
  • said organic acid includes such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • the free base can be obtained by basifying a solution of the acid addition salt.
  • an acid addition salt particularly a pharmaceutically acceptable acid addition salt, may be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • the POSITA will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts.
  • solvates means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrates, for example, hemihydrate, monohydrate, and dihydrate.
  • group and “radical” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to other fragments of molecules.
  • an “active ingredient” is used to indicate a chemical substance which has biological activity.
  • an “active ingredient” is a chemical substance having pharmaceutical utility.
  • practical pharmaceutical activity can be established by appropriate pre-clinical assays, whether in vitro or in vivo. Pharmaceutical activity sufficient to be accepted by a regulatory agency, such as FDA in the U.S., is a higher standard than the pre-clinical assay. Such a higher standard of pharmaceutical activity, the success of which cannot generally be reasonably expected from the pre-clinical results, can be established by appropriate and successful randomized, double blind, controlled clinical trials in humans.
  • treating or “treatment” of a disease or disorder, in the context of achieving therapeutic benefit, refer to administering one or more pharmaceutical substances, especially a compound of formula (I) or a pharmaceutically acceptable salt thereof described herein to a subject that has the disease or disorder, or has a symptom of a disease or disorder, or has a predisposition toward a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disease or disorder, the symptoms of the disease or disorder, or the predisposition toward the disease or disorder.
  • the disease or disorder is cancer.
  • treating in the context of a chemical reaction, mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately lead to the formation of the indicated and/or the desired product.
  • effective amount refers to an amount or dose of an IDO inhibiting agent sufficient to generally bring about a therapeutic benefit in patients in need of treatment for a disease or disorder mediated by IDO or at least in part by IDO.
  • Effective amounts or doses of the active ingredient of the present disclosure may be ascertained by methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease or disorder, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the attending physician. In the United States, the determination of effective doses is generally difficult to predict from preclinical trials. In fact, the dose is completely unpredictable and the dose will develop a new unpredictable dosing regimen after initial use in a randomized, double-blind, controlled clinical trial.
  • An exemplary dose is in the range of from about 0.0001 to about 200 mg of active agent per kg of subject's body weight per day, such as from about 0.001 to 100 mg/kg/day, or about 0.01 to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided dosage units (e.g., BID, TID, QID) .
  • an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 5 g/day.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • inhibitors indicates a decrease in the baseline activity of a biological activity or process.
  • inhibitor of IDO activity is a practical pharmaceutical activity for purposes of this disclosure and refers to a decrease in the activity of IDO as a direct or indirect response to the presence of the compound of formula (I) and/or the pharmaceutically acceptable salt thereof described herein, relative to the activity of IDO in the absence of the compound of formula (I) and/or the pharmaceutically acceptable salt thereof.
  • the decrease in activity may be due to the direct interaction of the compound of formula (I) and/or the pharmaceutically acceptable salt thereof described herein with IDO, or due to the interaction of the compound of formula (I) and/or the pharmaceutically acceptable salt thereof described herein, with one or more other factors that in turn affect the IDO activity.
  • the presence of the compound of formula (I) and/or the pharmaceutically acceptable salt thereof described herein may decrease the IDO activity by directly binding to the IDO, by causing (directly or indirectly) another factor to decrease the IDO activity, or by (directly or indirectly) decreasing the amount of IDO present in the cell or organism.
  • subject means mammals and non-mammals.
  • Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like.
  • non-mammals include, but are not limited to, birds, and the like.
  • the term “subject” does not denote a particular age or sex. In some embodiments, the subject is a human.
  • X is N or CR 3 ;
  • Y is N or CR 4 ;
  • R 1 , R 2 , R 3 and R 4 are independently chosen from H, halo, -OH, -CN, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, -O (C 1-6 alkyl) , -NH (C 1-6 alkyl) , or -N (C 1-6 alkyl) 2 ;
  • Z is O, NR 5 , or CR 6 R 7 ;
  • R 5 is chosen from H, C 1-6 alkyl, or C 3-6 cycloalkyl
  • R 6 and R 7 are independently chosen from H, halo, -CN, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , -OH, C 1-6 alkyl, C 3-6 cycloalkyl, or -O (C 1-6 alkyl) ;
  • phenyl is phenyl, 5-6 membered heteroaryl, or indazolyl, each of which is optionally substituted with one or more groups chosen from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -O (C 1-6 alkyl) , or -O (C 1-6 haloalkyl) ;
  • pyridyl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with one or more groups chosen from halo, - (C 1-6 alkyl) n -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, - (C 1-6 alkyl) n -C 3-6 cycloalkyl, - (C 1-6 alkyl) n -phenyl, - (C 1-6 alkyl) n -4-6 membered heterocyclyl, - (C 1-6 alkyl) n -5-6 membered heteroaryl, - (C 1-6 alkyl) n -NR 1 ’R 2 ’, - (C 1-6 alkyl) n -CONR 1 ’R 2 ’,
  • n 0 or 1
  • n 1 or 2;
  • p is 0 or 1;
  • R 1 ’, R 2 ’, R 3 ’, R 4 ’, R 5 ’, R 6 ’, and R 7 ’ are independently chosen from H, C 1-6 alkyl, C 1-6 haloalkyl, - (C 1-6 alkyl) -O- (C 1-6 alkyl) , - (C 1-6 alkyl) -OH, - (C 1-6 alkyl) -CN, - (C 1-6 alkyl) -NH 2 , or C 3-6 cycloalkyl; or R 1 ’ and R 2 ’ together with the N atom they are attached to form a 4-6 membered heterocyclic ring.
  • X is CR 3 ; Y is CR 4 .
  • X is CH; Y is CH.
  • R 1 , R 2 , R 3 , R 4 , R 6 , and R 7 are independently chosen from H and halo (such as F) .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are all H.
  • X is CH; Y is N.
  • X is N; Y is N.
  • Z is CR 6 R 7 ;
  • R 6 and R 7 are independently chosen from H, halo, -CN, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , -OH, C 1-6 alkyl, C 3-6 cycloalkyl, or -O (C 1-6 alkyl) .
  • p is 0, Z is CHR 6 ; R 6 is chosen from H, -OH, C 1-6 alkyl, or -O (C 1-6 alkyl) .
  • p is 0, Z is CH 2 .
  • p is 1, Z is CR 6 R 7 ; R 6 and R 7 are independently chosen from H, halo, -CN, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , -OH, C 1-6 alkyl, C 3-6 cycloalkyl, or -O (C 1-6 alkyl) .
  • p is 1, Z is CHR 6 ; R 6 is chosen from H, -OH, C 1-6 alkyl, or -O (C 1-6 alkyl) .
  • p is 1, Z is NR 5 ; R 5 is chosen from H, C 1-6 alkyl, or C 3-6 cycloalkyl.
  • p is 1, Z is NR 5 ; R 5 is H or C 1-6 alkyl.
  • p is 1, Z is O.
  • the compound of formula (I) is phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with one or more groups chosen from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -O (C 1-6 alkyl) , or -O (C 1-6 haloalkyl) .
  • the compound of formula (I) is phenyl, pyridyl, pyrimidinyl, indazolyl, pyrrolyl, pyrazolyl, or thienyl, each of which is optionally substituted with one or more groups chosen from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , -O (C 1-6 alkyl) , or -O (C 1-6 haloalkyl) .
  • the compound of formula (I) is phenyl, which is optionally substituted with one or more groups chosen from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -NH 2 , -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is phenyl, which is optionally substituted with one or more groups chosen from halo, -CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is phenyl, which is optionally substituted with one or more groups chosen from F, Cl, Br, -CN, methyl, ethyl, ethynyl, -CF 3 , -OCF 3 , -OCHF 2 , or -OCH 3 .
  • the compound of formula (I) is phenyl, which is substituted with one or more groups chosen from F, Cl, Br, -CN, methyl, ethyl, -CF 3 , -OCF 3 , -OCHF 2 , or -OCH 3 .
  • the compound of formula (I) is phenyl, which is substituted with ethynyl.
  • the compound of formula (I) is phenyl, which is substituted with halo.
  • the compound of formula (I) is phenyl, which is substituted with -OCF 3 or -OCHF 2 .
  • the compound of formula (I) is phenyl, which is substituted with -CN.
  • the compound of formula (I) is pyridyl, which is optionally substituted with one or more groups chosen from C 2-6 alkynyl or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyrrolyl or thienyl, each of which is optionally substituted with halo or -CN.
  • the compound of formula (I) is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with one or more groups chosen from:
  • each of said 4-6 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with one or more groups chosen from C 1-6 alkyl, -O (C 1-6 alkyl) , or -NH (C 1-6 alkyl) ;
  • n 0 or 1
  • R 1 ’, R 2 ’, R 3 ’, R 4 ’, R 5 ’, and R 6 ’ are independently chosen from H, C 1-6 alkyl, C 1-6 haloalkyl, - (C 1-6 alkyl) -O- (C 1-6 alkyl) , - (C 1-6 alkyl) -OH, - (C 1-6 alkyl) -CN, - (C 1-6 alkyl) -NH 2 , or C 3-6 cycloalkyl; or R 1 ’ and R 2 ’ together with the N atom they are attached to form a 4-6 membered heterocyclic ring.
  • the compound of formula (I) is pyridyl, pyrimidinyl, or pyridazinyl, each of which is substituted with one, two, or three groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl substituted with -NH 2 , pyrimidinyl substituted with -NH 2 , or pyridazinyl substituted with -NH 2 , each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl substituted with - (C 1-6 alkyl) -OH, pyrimidinyl substituted with - (C 1-6 alkyl) -OH, or pyridazinyl substituted with - (C 1-6 alkyl) -OH, each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl or pyrimidinyl, each of which is optionally substituted with one or more groups chosen from:
  • each of said 4-6 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with one or more groups chosen from C 1-6 alkyl, -O (C 1-6 alkyl) , or -NH (C 1-6 alkyl) ;
  • n 0 or 1
  • R 1 ’, R 2 ’, R 3 ’, R 4 ’, R 5 ’, and R 6 ’ are independently chosen from H, C 1-6 alkyl, C 1-6 haloalkyl, - (C 1-6 alkyl) -O- (C 1-6 alkyl) , - (C 1-6 alkyl) -CN, or C 3-6 cycloalkyl; or R 1 ’ and R 2 ’ together with the N atom they are attached to form a 4-6 membered heterocyclic ring.
  • the compound of formula (I) is pyridyl or pyrimidinyl, each of which is substituted with one, two, or three groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl substituted with -NH 2 , or pyrimidinyl substituted with -NH 2 , each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl substituted with - (C 1-6 alkyl) -OH, or pyrimidinyl substituted with - (C 1-6 alkyl) -OH, each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl, which is optionally substituted with one or more groups chosen from:
  • each of said 4-6 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with one or more groups chosen from C 1-6 alkyl, -O (C 1-6 alkyl) , or -NH (C 1-6 alkyl) ;
  • n 0 or 1
  • R 1 ’, R 2 ’, R 3 ’, R 4 ’, R 5 ’, and R 6 ’ are independently chosen from H, C 1-6 alkyl, C 1-6 haloalkyl, - (C 1-6 alkyl) -O- (C 1-6 alkyl) , - (C 1-6 alkyl) -CN, or C 3-6 cycloalkyl; or R 1 ’ and R 2 ’ together with the N atom they are attached to form a 4-6 membered heterocyclic ring.
  • the compound of formula (I) is pyridyl, which is substituted with one, two, or three groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyridyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • each of said 4-6 membered heterocyclyl and 5-6 membered heteroaryl is optionally substituted with one or more groups chosen from C 1-6 alkyl, -O (C 1-6 alkyl) , or -NH (C 1-6 alkyl) ;
  • n 0 or 1
  • R 1 ’, R 2 ’, R 3 ’, R 4 ’, R 5 ’, and R 6 ’ are independently chosen from H, C 1-6 alkyl, C 1-6 haloalkyl, - (C 1-6 alkyl) -O- (C 1-6 alkyl) , - (C 1-6 alkyl) -CN, or C 3-6 cycloalkyl; or R 1 ’ and R 2 ’ together with the N atom they are attached to form a 4-6 membered heterocyclic ring.
  • the compound of formula (I) is each of which is optionally substituted with one or more groups chosen from -CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, -O (C 1-6 alkyl) , -O (C 1-6 haloalkyl) , -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or -NH (C 1-6 haloalkyl) .
  • the compound of formula (I) is each of which is substituted with one, two, or three groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is each of which is substituted with -NH 2 , and is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is each of which is substituted with - (C 1-6 alkyl) -OH, and is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is each of which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I) is pyrimidinyl, which is optionally substituted with one or more groups chosen from halo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, 4-6 membered heterocyclyl, -NR 1 ’R 2 ’, or -OR 5 ’; R 1 ’, R 2 ’, and R 5 ’ are independently chosen from H, C 1-6 alkyl, or C 1-6 haloalkyl.
  • the compound of formula (I) is pyrimidinyl, which is substituted with one, two, or three groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyrimidinyl, which is substituted with one, two, or three groups chosen from -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or C 1-6 haloalkyl.
  • the compound of formula (I) is pyrimidinyl substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyrimidinyl substituted with -NH 2 , which is also substituted with one or two groups chosen from -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or C 1-6 haloalkyl.
  • the compound of formula (I) is pyrimidinyl substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is pyrimidinyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I) is which is optionally substituted with one or more groups chosen from halo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, 4-6 membered heterocyclyl, -NR 1 ’R 2 ’, or -OR 5 ’; R 1 ’, R 2 ’, and R 5 ’ are independently chosen from H, C 1-6 alkyl, or C 1-6 haloalkyl.
  • the compound of formula (I) is which is optionally substituted with one or more groups chosen from -CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, -O (C 1-6 alkyl) , -O (C 1-6 haloalkyl) , -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or -NH (C 1-6 haloalkyl) .
  • the compound of formula (I) is which is substituted with one, two, or three groups chosen from halo, C 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is which is substituted with one, two, or three groups chosen from -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or C 1-6 haloalkyl.
  • -NH 2 is substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, C 1-6 alkyl, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • -NH 2 is substituted with -NH 2 , which is also substituted with one or two groups chosen from -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or C 1-6 haloalkyl.
  • the compound of formula (I) is substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I) is which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I) is formula (I-1) ,
  • X is N or CH; Y is N or CH.
  • X is CH; Y is CH.
  • X is CH; Y is N.
  • Z is NR 5 , CR 6 R 7 , or O; in which R 6 and R 7 are independently chosen from H, -OH, C 1-6 alkyl, or -O (C 1-6 alkyl) ; R 5 is H or C 1-6 alkyl.
  • Z is O.
  • Z is CH 2 .
  • Z is NH
  • R a is chosen from halo, -CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • R a is chosen from F, Cl, Br, -CN, methyl, ethyl, ethynyl, -CF 3 , -OCF 3 , or -OCH 3 .
  • R a is chosen from F, Cl, Br, -CN, methyl, ethyl, -CF 3 , -OCF 3 , or -OCH 3 .
  • R a is ethynyl
  • R a is halo
  • R a is -OCF 3 or -OCHF 2 .
  • R a is -CN.
  • the compound of formula (I-1) is pyridyl substituted with -NH 2 , pyrimidinyl substituted with -NH 2 , or pyridazinyl substituted with -NH 2 , each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is pyridyl substituted with -NH 2 , or pyrimidinyl substituted with -NH 2 , each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is pyridyl substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is each of which is substituted with -NH 2 , and is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is pyrimidinyl substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is pyrimidinyl substituted with -NH 2 , which is also substituted with one or two groups chosen from -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or C 1-6 haloalkyl.
  • -NH 2 is substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • -NH 2 is substituted with -NH 2 , which is also substituted with one or two groups chosen from -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or C 1-6 haloalkyl.
  • the compound of formula (I-1) is pyridyl substituted with - (C 1-6 alkyl) -OH, pyrimidinyl substituted with - (C 1-6 alkyl) -OH, or pyridazinyl substituted with - (C 1-6 alkyl) -OH, each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is pyridyl substituted with - (C 1-6 alkyl) -OH, or pyrimidinyl substituted with - (C 1-6 alkyl) -OH, each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is pyridyl substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is pyridyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I-1) is each of which is substituted with - (C 1-6 alkyl) -OH, and is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is each of which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I-1) is pyrimidinyl substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is pyrimidinyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I-1) is substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-1) is which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I) is formula (I-2) ,
  • X is N or CH; Y is N or CH.
  • X is CH; Y is CH.
  • X is CH; Y is N.
  • R a is chosen from halo, -CN, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • R a is chosen from F, Cl, Br, -CN, methyl, ethyl, ethynyl, -CF 3 , -OCF 3 , or -OCH 3 .
  • R a is chosen from F, Cl, Br, -CN, methyl, ethyl, -CF 3 , -OCF 3 , or -OCH 3 .
  • R a is ethynyl
  • R a is halo
  • R a is -OCF 3 or -OCHF 2 .
  • R a is -CN.
  • the compound of formula (I-2) is pyridyl substituted with -NH 2 , pyrimidinyl substituted with -NH 2 , or pyridazinyl substituted with -NH 2 , each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is pyridyl substituted with -NH 2 , or pyrimidinyl substituted with -NH 2 , each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is pyridyl substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is each of which is substituted with -NH 2 , and is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is pyrimidinyl substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is pyrimidinyl substituted with -NH 2 , which is also substituted with one or two groups chosen from -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or C 1-6 haloalkyl.
  • -NH 2 is substituted with -NH 2 , which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • -NH 2 is substituted with -NH 2 , which is also substituted with one or two groups chosen from -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , or C 1-6 haloalkyl.
  • the compound of formula (I-2) is pyridyl substituted with - (C 1-6 alkyl) -OH, pyrimidinyl substituted with - (C 1-6 alkyl) -OH, or pyridazinyl substituted with - (C 1-6 alkyl) -OH, each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is pyridyl substituted with - (C 1-6 alkyl) -OH, or pyrimidinyl substituted with - (C 1-6 alkyl) -OH, each of which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is pyridyl substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is pyridyl which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I-2) is each of which is substituted with - (C 1-6 alkyl) -OH, and is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is each of which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I-2) is pyrimidinyl substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is pyrimidinyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compound of formula (I-2) is substituted with - (C 1-6 alkyl) -OH, which is also substituted with one or two groups chosen from halo, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , - (C 1-6 alkyl) -OH, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , or -O (C 1-6 alkyl) .
  • the compound of formula (I-2) is which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  • the compounds of the present invention don’t include the following compounds:
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .
  • a pharmaceutically acceptable excipient e.g., a pharmaceutically acceptable carrier
  • a method of in vivo or in vitro inhibiting the activity of IDO comprising contacting IDO with an effective amount of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof e.g., any of the compounds described herein
  • a method of in vivo or in vitro inhibiting the activity of IDO comprising contacting IDO with an effective amount of a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .
  • a method of treating a disease mediated by IDO or at least in part by IDO in a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a method of treating cancer in a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof e.g., any of the compounds described herein
  • a method of treating a disease mediated by IDO or at least in part by IDO in a subject comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .
  • a method of treating cancer or an autoimmune disease in a subject comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof for treating a disease mediated by IDO or at least in part by IDO.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof for treating cancer or an autoimmune disease.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease mediated by IDO or at least in part by IDO.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, an autoimmune disease, obesity, or an obesity-related disease.
  • a combination comprising a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
  • said additional therapeutic agent is an anti-neoplastic agent.
  • said additional therapeutic agent is a chemotherapeutic agent.
  • said additional therapeutic agent is an immune checkpoint inhibitor.
  • a method of treating a disease mediated by IDO or at least in part by IDO in a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and an anti-neoplastic agent.
  • a compound of formula (I) e.g., any of the compounds described herein
  • an anti-neoplastic agent e.g., any of the compounds described herein
  • a method of treating cancer in a subject comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, a targeted therapeutic agent, or a chemotherapeutic agent.
  • a compound of formula (I) e.g., any of the compounds described herein
  • an immune checkpoint inhibitor e.g., any of the compounds described herein
  • a targeted therapeutic agent e.g., any of the compounds described herein
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof e.g., an anti-neoplastic agent
  • an anti-neoplastic agent in the manufacture of a combined medicament for treating a disease mediated by IDO or at least in part by IDO.
  • a compound of formula (I) e.g., any of the compounds described herein
  • a pharmaceutically acceptable salt thereof an immune checkpoint inhibitor, a targeted therapeutic agent, or a chemotherapeutic agent in the manufacture of a combined medicament for treating cancer or an autoimmune disease.
  • said immune checkpoint inhibitor is chosen from an anti-PD-1 inhibitor, a CTLA-4 inhibitor, or an OX-40 inhibitor.
  • said immune checkpoint inhibitor is chosen from pembrolizumab, nivolumab, and ipilimumab.
  • the disease mediated by IDO or at least in part by IDO is cancer or an autoimmune disease.
  • the cancer is solid tumor, or hematologic malignancy, such as leukemia, lymphoma, or myeloma.
  • the cancer is chosen from skin cancer (such as melanoma and basal carcinoma) , lung cancer, non-small cell lung cancer, renal cancer, head and neck cancer, urothelial carcinoma, pancreatic cancer, cervical cancer, bladder cancer, liver cancer, endometrial cancer, ovarian cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, brain tumor (including glioma and glioblastoma (GBM) ) , thyroid carcinoma, mesothelial carcinoma, choriocarcinoma, adrenal carcinoma, sarcoma (such as Kaposi's sarcoma) , leukemia, lymphoma, or myeloma.
  • skin cancer such as melanoma and basal carcinoma
  • lung cancer non-small cell lung cancer, renal cancer, head and neck cancer
  • urothelial carcinoma pancreatic cancer
  • cervical cancer bladder cancer
  • liver cancer endometrial cancer
  • ovarian cancer breast cancer
  • the cancer is chosen from melanoma, lung cancer, renal cell carcinoma, head and neck cancer, urothelial carcinoma, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular cancer, endometrial cancer, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, glioma, glioblastoma (GBM) , acute myeloid leukemia (AML) , human acute monocytic leukemia (M (5) ) , acute lymphocytic leukemia (ALL) , and diffuse large B-cell lymphoma (DLBCL) .
  • melanoma lung cancer, renal cell carcinoma, head and neck cancer, urothelial carcinoma, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular cancer, endometrial cancer, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, glioma, glioblastom
  • the autoimmune disease is chosen from arthritis, such as rheumatoid arthritis, collagen induced arthritis, and the like.
  • the obesity-related disease is chosen from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythms, arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, angina pectoris) , cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and the like.
  • condensation reaction of compound of formula (2-1) with compound of formula (2-2) , in the presence of a condensating agent (such as but not limited to HATU) gives compound of formula (2-3) ; then, coupling reaction of compound of formula (2-3) under the catalysis of a palladium reagent (such as but not limited to Pd (PPh 3 ) 4 ) , affords compound of formula (2-4) ; finally, further condensation reaction of compound of formula (2-4) with compound of formula (2-5) , under the catalysis of a palladium reagent (such as but not limited to Pd (PPh 3 ) 4 ) , gives compound of formula (2-6) .
  • R 1 , R 2 , X, Y, p are as defined herein; R a and R b are one or more substituents respectively; W is a leaving group.
  • R 1 , R 2 , X, Y, p are as defined herein; R a and R b are one or more substituents respectively; W is a leaving group; M is Sn substituted with C 1-6 alkyl, boric acid, or boronate.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.
  • a pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein; and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier) .
  • a pharmaceutically acceptable carrier refers to a carrier that is compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated.
  • solubilizing agents such as cyclodextrins (which form specific, more soluble complexes with the the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein)
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the art.
  • a pharmaceutical composition comprising a compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein can be administered in various known manners, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • a pharmaceutical composition described herein can be prepared in the form of tablet, capsule, sachet, dragee, powder, granule, lozenge, powder for reconstitution, liquid preparation, or suppository.
  • a pharmaceutical composition comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof is formulated for intravenous infusion, topical administration, or oral administration.
  • An oral composition can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions and solutions.
  • Commonly used carriers for tablets include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added to tablets.
  • useful diluents include lactose and dried corn starch.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be present in an amount of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg in a tablet. In some embodiments, the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be present in an amount of 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400 and 500 mg in a capsule.
  • a sterile injectable composition e.g., aqueous or oleaginous suspension
  • a sterile injectable composition can be formulated according to techniques known in the art using suitable dispersing or wetting agents (for example, Tween 80) and suspending agents.
  • the sterile injectable Intermediate can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • suitable dispersing or wetting agents for example, Tween 80
  • the sterile injectable Intermediate can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol.
  • the pharmaceutically acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono-or di-glycerides) .
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the Intermediate of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • An inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • a topical composition can be formulated in form of oil, cream, lotion, ointment, and the like.
  • suitable carriers for the composition include vegetable or mineral oils, white petrolatum (white soft paraffin) , branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C12) .
  • the pharmaceutically acceptable carrier is one in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers may be employed in those topical formulations. Examples of such enhancers can be found in U.S. Patents 3,989,816 and 4,444,762.
  • Creams may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed.
  • An example of such a cream is one which includes, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool.
  • An example of such an ointment is one which includes about 30%by weight almond oil and about 70%by weight white soft paraffin.
  • Suitable in vitro assays can be used to evaluate the practical utility of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein, in inhibiting the IDO activity.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can further be examined for additional practical utility in treating cancer by in vivo assays.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be administered to an animal (e.g., a mouse model) having cancer and its therapeutic effects can be accessed. If the pre-clinical results are successful, the dosage range and administration route for animals, such as humans, can be projected.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be shown to have sufficient pre-clinical practical utility to merit clinical trials hoped to demonstrate a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.
  • cancer refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites.
  • cancer includes, but is not limited to, solid tumors and hematologic malignancies.
  • cancer encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels.
  • cancer further encompasses primary and metastatic cancers.
  • Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; testicular cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC) , bronchioloalveolar carcinoma (BAC) , and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; endometrial cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; skin cancer, including, e.g., malignant melanoma, and basal carcinoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumor
  • Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML) ; chronic myelogenous leukemia (CML) , including accelerated CML and CML blast phase (CML-BP) ; acute lymphoblastic leukemia (ALL) ; chronic lymphocytic leukemia (CLL) ; Hodgkin's lymphoma; non-Hodgkin's lymphoma (NHL) ; follicular lymphoma; mantle cell lymphoma (MCL) ; B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL) ; multiple myeloma (MM) ; Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS) , including refractory anemia (RA) , refractory anemia with ringed siderblasts (RARS) , refractory anemia with excess blasts (RAEB)
  • solid tumors include melanoma, lung cancer (such as non-small cell lung cancer) , renal cell carcinoma, head and neck cancer (such as squamous cell carcinoma of the head and neck) , urothelial carcinoma, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular cancer, endometrial cancer, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, esophageal cancer, glioma, and glioblastoma (GBM) .
  • lung cancer such as non-small cell lung cancer
  • renal cell carcinoma such as squamous cell carcinoma of the head and neck
  • urothelial carcinoma pancreatic cancer
  • cervical cancer bladder cancer
  • hepatocellular cancer endometrial cancer
  • ovarian cancer breast cancer
  • colorectal cancer prostate cancer
  • gastric cancer esophageal cancer
  • glioma glioblastoma
  • GBM glioblastoma
  • exemplary hematologic malignancies include leukemia, such as acute lymphocytic leukemia (ALL) , acute myeloid leukemia (AML) , chronic lymphocytic leukemia (CLL) , and chronic myelogenous leukemia (CML) ; multiple myeloma (MM) ; and lymphoma, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL) , mantle cell lymphoma (MCL) , follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL) .
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • MM multiple myeloma
  • lymphoma such as Hodgkin's lymph
  • the compound of formula (I) and/or a pharmaceutically acceptable salt described herein can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with cancer.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt described herein can be used to achieve a beneficial therapeutic or prophylactic effect, for example, in subjects with an autoimmune disease.
  • autoimmune disease refers to a disease or disorder arising from and/or directed against an individual's own tissues or organs, or a co-segregate or manifestation thereof, or resulting condition therefrom.
  • autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD) , allergic rhinitis, lupus, myasthenia gravis, multiple sclerosis (MS) , rheumatoid arthritis (RA) , collagen induced arthritis, psoriasis, inflammatory bowel disease (IBD) , asthma and idiopathic thrombocytopenic purpura, and myeloproliferative disease, such as myelofibrosis, post-Polycythemia vera/Essential Thrombocythemia myelofibrosis (post-PV/ET myelofibrosis) .
  • COPD chronic obstructive pulmonary disease
  • MS multiple sclerosis
  • RA rheum
  • obesity-related disease refers to a disease or disorder that is associated with, caused by, or resulted from obesity.
  • obesity-related diseases include, but are not limited to, diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythms, arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, angina pectoris) , cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and the like.
  • the compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein may be used in combination with additional active ingredients in the treatment of cancer.
  • the additional active ingredients may be coadministered separately with the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein or included with such an ingredient in a pharmaceutical composition according to the disclosure, such as a fixed-dose combination drug product.
  • additional active ingredients are those that are known or discovered to be effective in the treatment of diseases mediated by IDO or at least in part by IDO, such as another IDO inhibitor or a compound active against another target associated with the particular disease.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein) , decrease one or more side effects, or decrease the required dose of the compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein.
  • the compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein is administered in conjunction with an anti-neoplastic agent.
  • an anti-neoplastic agent refers to any agent that is administered to a subject with cancer for purposes of treating the cancer.
  • the anti-neoplastic agents include, but are not limited to: radiotherapeutic agents, chemotherapeutic agents, immunotherapeutic agents, targeted therapeutic agents.
  • the compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein is administered in conjunction with an immune checkpoint inhibitor, a targeted therapeutic agent, or a chemotherapeutic agent.
  • Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 antibodies, such as pembrolizumab and nivolumab; anti-PD-L1 antibodies, such as atezolizumab, durvalumab, and avelumab; anti-CTLA-4 antibodies, such as ipilimumab; and BTLA antibodies, LAG-3 antibodies, TIM3 antibodies, TIGIT antibodies, VISTA antibodies.
  • anti-PD-1 antibodies such as pembrolizumab and nivolumab
  • anti-PD-L1 antibodies such as atezolizumab, durvalumab, and avelumab
  • anti-CTLA-4 antibodies such as ipilimumab
  • BTLA antibodies LAG-3 antibodies, TIM3 antibodies, TIGIT antibodies, VISTA antibodies.
  • Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin) ; topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin) ; alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide) ; DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin) ; DNA intercalators and free radical generators such as bleomycin; nucleoside mimetics
  • Non-limiting examples of targeted therapeutic agents include protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib) ; proteasome inhibitors (e.g., bortezomib) ; NF-kappa B inhibitors, including inhibitors of I kappa B kinase; antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab) ; and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication.
  • protein tyrosine kinase inhibitors e.g., imatinib mesylate and gefitinib
  • proteasome inhibitors e.g., bortezomib
  • the empty balance (s) is (are) the hydrogen atom (s) which is (are) omitted for convenience purpose.
  • the optically pure enantiomers compounds 219 and 220 were isolated from the corresponding racemic compounds by chiral HPLC.
  • the optically pure enantiomers compounds 230 and 231 were isolated from the corresponding racemic compounds by chiral HPLC.
  • the compound obtained by removing the solvent of the first fraction is Compound 230
  • the compound obtained by removing the solvent of the second fraction is Compound 231.
  • N- (1- (4-bromo-2-fluorophenyl) cyclopropyl) -4-fluorobenzamide 300 mg, , 0.852 mmol
  • bis (pinacolato) diboron 216.4 mg, 0.852 mmol
  • KOAc 162.7 mg, 1.704 mmol
  • Pd (dppf) Cl 2 ⁇ CH 2 Cl 2 69.4 mg, 0.085 mmol
  • 6-Bromonicotinonitrile (2.34 g, 12.8 mmol) was dissolved in Et 2 O (60 mL) , cooled to -78°C, and then was added Ti (OiPr) 4 (4.16 mL, 14.1 mmol) dropwise. The mixture was stirred for 5 min, and then EtMgBr (28.1 mL, 28.1 mmol, 1 mol/L) was added. The resulting mixture was stirred at -78°C for 30 min, then warmed to the room temperature slowly and stirred for 1h. Then BF 3 . Et 2 O (3.22 mL, 25.6 mmol) was added, and the mixture was stirred for 2h at room tempreture.
  • 1,4-Dibromobenzene (2.36 g, 10.0 mmol) was dissolved in THF (50 mL) and was cooled to -78°C. Then, n-BuLi (6.25 mL, 1.6 mol/L, in hexane ) was added dropwise. The reaction was stirred for 1h at this temperature, followed by the addition of tert-butyl 3-oxoazetidine-1-carboxylate (1.71 g, 10.0 mmol) in 5 mL of THF, and then was warmed to room temperature and stirred overnight. The reaction was quenched with 50 mL of aqeuous solution of NH 4 Cl, and extracted with 100 mL of EtOAC twice.
  • tert-Butyl 3- (4-bromophenyl) -3-hydroxyazetidine-1-carboxylate (1.0 g, 3.04 mmol) and DIEA (784 mg, 6.08 mmol) were dissolved in CH 2 Cl 2 (30 mL) , and cooled to 0°C. MsCl (521 mg, 4.57 mmol) was added, and then the mixture was warmed to the room temperature and stirred overnight. The mixture was quenched with 30 mL of saturated solution of NaOH, and then extracted with 100 mL of CH 2 Cl 2 twice .
  • N- (1- (4- (6-aminopyridin-3-yl) phenyl) cyclopropyl) -4-ethynylbenzamide (100 mg, 0.283 mmol) (prepared according to the procedure described in Example 1) was dissolved in 10 mL of THF, and cooled to 0°C. DIEA (0.140 mL, 0.849 mmol) and acetyl chloride (44.4 mg, 0.566 mmol) were added in sequence. The mixture was stirred for 1h at the room temperature.
  • SKOV-3 cells were purchased from American Standard Biological Collection Center ATCC Cell Bank, and were cultured at 37°C in a cell culture incubator supplied with 5%CO 2 with DMEM medium containing 3.7 g/L sodium bicarbonate and 4.5 g/L glucose, and supplemented 2 mM L-glutamine and 10 %fetal bovine serum;
  • DMEM GIBCO, Catalog number: 31053028;
  • Glutamine GIBCO, Catalog number: 35050061;
  • Fetal bovine serum (FBS) GIBCO, Catalog number: 10099-141;
  • L-tryptophan (L-Trp) Sigma-Aldrich, Catalog number: T0254;
  • L-Kynurenine Sigma-Aldrich, Catalog number: K8625;
  • Microplate reader SpectraMax M2, Molecular Devices
  • Standard curve stock solution was prepared by diluting a series of concentrations of L-Kynurenine with cell culture media DMEM. The final concentration is 240, 120, 60, 30, 15, 7.5, 3.75, and 1.87 ⁇ M, respectively.
  • SKOV-3 cells were seeded in a 96 well culture plate at a density of 1.0 x 10 4 per well, i.e. 180 ⁇ L per well, and incubated in a cell culture incubator at 5%CO 2 and 37°C.
  • the test compound was diluted 3 times in serum-free DMEM medium to the corresponding concentration on the same day, and then 10 ⁇ L/well of different concentrations of the diluted compound (the final concentration: 1.0, 0.33, 0.11, 0.037, 0.012, 0.0041, 0.0014, and 0.00046 ⁇ M, DMSO final concentration: 0.5%) or 10 ⁇ L/well control solution (0.5%DMSO) were added to the 180 ⁇ L/well cell culture system, then 10 ⁇ L/well of mixture of human IFN ⁇ (final concentration of 50 ng/mL) and L-Trp (final concentration of 50 ⁇ mol/L) diluted in serum-free DMEM medium were added into cells. The cells were incubated in a cell culture incubator at 5%CO 2 and 37°C for 48 hours.
  • the absorbance optical density signal was detected at a wavelength of 480 nm using a SpectraMax M2 microplate reader.
  • Serial concentrations of kynurenine standards were diluted in cell culture medium and the optical density values at each concentration point were measured after treatment as described above. Then, the optical density signal is taken as the ordinate, the kynurenine concentration is plotted on the abscissa, and the kynurenine standard curve is plotted using the EXCEL software.
  • the linear regression equation is fitted, and the concentration of kynurenine in test compound treated wells and human IFN- ⁇ control treated wells are calculated according to the equation.
  • the inhibition rate (%) of each concentration of compounds was calculated according to the concentration of kynurenine in each well, and then calculated by the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited) to obtain an IC 50 value.
  • the inhibition rate is calculated as follows:
  • ⁇ [kynurenine] Compound represents the concentration of kynurenine in the cell well containing human IFN- ⁇ and the test compound.
  • ⁇ [kynurenine] IFN- ⁇ represents the concentration of kynurenine in the cell well containing only human IFN- ⁇ .
  • Human peripheral blood routinely incubated at 37°C in cell incubator supplied with 5%CO 2
  • Salmonella typhimurium (LPS) Calbiochem, catalog number 437650
  • Tryptophan (L-Trp) Sigma-Aldrich, catalog number T0254
  • Kynurenine (L-Kynurenine) Sigma-Aldrich, catalog number K8625
  • DMSO Dimethyl sulfoxide
  • Standard Curve Solution 5 ⁇ L of the standard curve working solution was added to 45 ⁇ L of blank plasma from which endogenous canine urine amino acid was removed via activated carbon, and the Standard Curve Solution was obtained after vortex.
  • the final gradient concentration is 50, 20, 5.0, 2.0, 1.0, 0.50, 0.20, 0.10 and 0.050 ⁇ M.
  • the whole blood was seeded in a 96 well plates at 180 ⁇ L/well, and incubated in a cell incubator at 5%CO 2 and 37 °C.
  • the test compound was diluted 3 times in serum-free RPMI-1640 medium to the corresponding concentration, and then 10 ⁇ L/well of different concentrations of the diluted compound (the final concentration: 0.30, 0.10, 0.033, 0.011, 0.0037 and 0.0012 ⁇ M, and the final concentration of DMSO was 0.25%) or 10 ⁇ L/well control solution (0.25%DMSO) were added to the 180 ⁇ L/well human whole blood culture system, then 10 ⁇ L/well of mixture of human IFN ⁇ (final concentration of 150 ng/mL) , LPS (final concentration of 150 ⁇ mol/L) and L-Trp (final concentration of 50 ⁇ mol/L) diluted in serum-free DMEM medium were added into cells. The cells were incubated in a cell culture incubator at
  • LC-MS/MS was used to determine the concentration of Kynurenine in the sample.
  • the peak area of Kynurenine and internal standard compound is automatically collected and integrated by Software Analyst 1.6.2.
  • the standard curve forquantification is obtained by fitting the theoretical concentration of kynurenine to the peak area ratio of Kynurenine and internal standard compound using linear regression equation.
  • the inhibition rate (%) of each of the concentration of test compounds was calculated according to the concentration of kynurenine in each well, and then calculated by the 205 model in XL-Fit 5.3 software (ID Business Solutions Limited) to obtain an IC 50 value.
  • the inhibition rate is calculated as follows:
  • Inhibition rate (%) 100%- ⁇ (test compound well–control solution well) / (human IFN- ⁇ control well –control solution well) ⁇ ⁇ 100%, wherein:
  • Test compound well represents the concertration of Kynurenine in human whole blood containing human IFN- ⁇ and the test compound.
  • Human IFN- ⁇ control well represents the concertration of Kynurenine in human whole blood containing only human IFN- ⁇ .
  • Control solution well represents the concertration of Kynurenine in uncultured human whole blood plasma.
  • Test compounds diclofenac sodium, 4’-hydroxydiclofenac, dextromethorphan hydrobromic acid, dextrophan tartaric acid, quinidine anhydrous, sulfaphenazole, etc. were purchased from Sigma-Aldrich of the U.S. Pooled human liver microsomes (HLM) was purchased from CellzDirect, Life Technologies (U.S.A. ) .
  • Glucose-6-phosphate (G-6-P) , glucose-6-phosphate dehydrogenase (G-6PDH) , and nicotinamide adenine dinucleotide phosphate (NADP) were purchased from Sigma-Aldrich (U.S.A. ) .
  • the incubation conditions of different enzyme isoforms such as types and concentrations of substrates and positive inhibitors, protein content, incubation time, and internal standards were shown in Table 1.
  • the detailed constitution of the incubation system was shown in Table 2.
  • the microsomes solution, phosphate buffer and substrate working solutions were prepared using the reagents in the table based on the requirements of the experiment.
  • NADPH regenerating system included G-6-P (final concentration is 5 mM, pH 7.4) , G-6-PD (final concentration is 1U/mL, pH 7.4) , NADP (final concentration is 1 mM, pH 7.4) , MgCl 2 (Final concentration is 3 mM) , EDTA (final concentration is 1 mM) and phosphate buffer (final concentration is 50 mM, pH 7.4) .
  • the above solutions were mixed and incubated at 37°C in water bath for 10 min and then placed on ice for later use.
  • the test compound was dissolved in DMSO firstly to prepare a stock solution with a concentration of 10 mM, and then diluted with 80%acetonitrile to achieve a working solution of 1 mM.
  • the proportion of organic solvents contained in the final incubation system did not exceed 1%.
  • a vehicle control group (the blank vehicle does not contain the test compound or positive inhibitor) was set for both the test compound and each positive inhibitor. Each component was added as described in Table 2, and the total volume of the incubation system was 125 ⁇ L.
  • the test compound and the positive inhibitor were mixed with the microsomes solution in advance, and then added to the NDAPH regenerating system and placed at 37 °C in water bath to start the reaction. After incubation at 37 °C for 20 minutes, 125 ⁇ L of ice cold acetonitrile solution (containing internal standard with the corresponding concentration) was added to stop the reaction (see Table 1) . The terminated incubation solution was centrifuged at 4400 rpm and 4 °C for 10 min, and the supernatant was transferred and injected for LC-MS/MS analysis.
  • Percentage of remaining enzyme activity the amount of metabolite produced in the inhibitor group/the amount of metabolite produced in the vehicle control group ⁇ 100%
  • Caco-2 (Human colon adenocarcinoma) cell lines were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences (Shanghai, China) .
  • 1X Hank’s balanced salt solution (HBSS) and N-2-Hydroxyethylpiperazine-N’-2-ethanesulphonic acid (HEPES) were obtained from Life Technologies, USA.
  • Cortisone, propranolol hydrochloride, fluorescein sodium salt, and formic acid were purchased from Sigma-Aldrich, USA.
  • Methanol, acetonitrile (ACN) , isopropanol, and ethyl acetate were all HPLC grade and purchased from Fisher Scientific, USA.
  • DMSO Dimethyl sulfoxide
  • Deionized water (resistivity ⁇ 18 M ⁇ cm) was produced by purification system in house.
  • HTS 24-well cell culture system containing an array of 24 inserts with permeable supports (called A side below, polycarbonate membrane, pore size: 0.4 ⁇ m, membrane growth area: 0.33 cm 2 ) and a common 24-well cell culture plate (called B side below) was provided by Corning Corstar, USA.
  • fluorescein sodium stock solution a certain amount of fluorescein sodium salt was weighed and dissolved with DMSO to get 10 mM stock solution.
  • cortisone stock solution (internal standard for negative mode) : a certain amount of cortisone was weighed and dissolved with DMSO to get 50 mM stock solution.
  • Dilution 1 400 mL deionized water + 400 mL ACN+ 8 ⁇ L 10 mM propranolol stock solution + 16 ⁇ L 50 mM cortisone stock solution.
  • test solution 4.99 mL Solution 1+ 5 ⁇ L 10 mM stock solution of test compound + 5 ⁇ L 10 mM fluorescein sodium stock solution.
  • the pre-incubation solution in A side was replaced by 0.3 mL of the test solution; vice versa, the pre-incubation solution in B side was substituted by 1.0 mL of the test solution to determine the B ⁇ A transport.
  • 10 ⁇ L of samples in donor side were immediately collected after dosing and labeled as 0 h samples. Then the culture system was put into the shaker and incubated for 60 min, after which the samples of both sides were collected and the TEER values were measured again.
  • samples and samples from donor side were diluted to 1/20 with Solution 1, and 200 ⁇ L of the diluted samples and 150 ⁇ L undiluted samples from receiver side were further diluted to 1/2 with Dilution 1. Finally, 150 ⁇ L of the samples were transferred for concentration determination and detection of fluorescence intensity.
  • the compound concentration of the sample was determined using LC-MS/MS analytical method.
  • the peak area ratio of the test compound to the internal standard was used as relative concentration to calculate the parameters.
  • Fluorescence intensity was detected by PerkinElmer Victor3 TM 1420 Multilabel Counter. 150 ⁇ L of above pre-treated samples were added to a 96-well plate, and the fluorescence intensity was detected at excitation wavelength of 485 nm and emission wavelength of 535 nm.
  • B ⁇ A apparent permeability coefficient of B ⁇ A
  • V r receiver side volume (1 mL for A ⁇ B; 0.3 mL for B ⁇ A) ;
  • V d donor side volume (0.3 mL for A ⁇ B; 1 mL for B ⁇ A) ;
  • RFU r, t The relative fluorescence units (RFU) of receiver side at time t;
  • RFU blank The relative fluorescence units of blank solution
  • RFU d, 0 The relative fluorescence units of donor side at time zero.

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Abstract

La présente invention concerne de nouveaux composés amides de formule (I), des compositions pharmaceutiques de ceux-ci, des procédés de préparation de ceux-ci, et leurs utilisations, les symboles étant tels que définis dans la description.
PCT/CN2020/090598 2019-05-16 2020-05-15 Nouveaux composés amides et leurs utilisations WO2020228823A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022037585A1 (fr) * 2020-08-18 2022-02-24 Hutchison Medipharma Limited Composés de pyrimidinone et leurs utilisations

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009073620A2 (fr) * 2007-11-30 2009-06-11 Newlink Genetics Inhibiteurs de l'ido
WO2015150097A1 (fr) * 2014-04-04 2015-10-08 Iomet Pharma Ltd Dérivés indolés destinés à être utilisés dans le domaine de la médecine
WO2016054804A1 (fr) * 2014-10-10 2016-04-14 Merck Sharp & Dohme Corp. Pyrimidines substituées utilisées comme inhibiteurs de la hif prolyl hydroxylase
WO2019099294A1 (fr) * 2017-11-14 2019-05-23 Merck Sharp & Dohme Corp. Nouveaux composés biaryles substitués utilisés en tant qu'inhibiteurs de l'indoléamine 2,3-dioxygénase (ido)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009073620A2 (fr) * 2007-11-30 2009-06-11 Newlink Genetics Inhibiteurs de l'ido
WO2015150097A1 (fr) * 2014-04-04 2015-10-08 Iomet Pharma Ltd Dérivés indolés destinés à être utilisés dans le domaine de la médecine
WO2016054804A1 (fr) * 2014-10-10 2016-04-14 Merck Sharp & Dohme Corp. Pyrimidines substituées utilisées comme inhibiteurs de la hif prolyl hydroxylase
WO2019099294A1 (fr) * 2017-11-14 2019-05-23 Merck Sharp & Dohme Corp. Nouveaux composés biaryles substitués utilisés en tant qu'inhibiteurs de l'indoléamine 2,3-dioxygénase (ido)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022037585A1 (fr) * 2020-08-18 2022-02-24 Hutchison Medipharma Limited Composés de pyrimidinone et leurs utilisations

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