WO2020228823A1 - Novel amide compounds and uses thereof - Google Patents

Novel amide compounds and uses thereof 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
Prior art date
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PCT/CN2020/090598
Other languages
French (fr)
Inventor
Wei-Guo Su
Guangxiu Dai
Weihan Zhang
Hong Jia
Haibin Yang
Huaqing CAI
Original Assignee
Hutchison Medipharma Limited
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Priority claimed from CN201910409909.5A external-priority patent/CN112047877A/en
Application filed by Hutchison Medipharma Limited filed Critical Hutchison Medipharma Limited
Publication of WO2020228823A1 publication Critical patent/WO2020228823A1/en

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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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    • 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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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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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.

Abstract

The present invention relates to novel amide compounds of formula (I), pharmaceutical compositions thereof, methods for preparing thereof, and uses thereof, wherein the symbols are as defined in the specification.

Description

Novel amide compounds and uses thereof Field of the Invention
The present invention relates to novel amide compounds, pharmaceutical compositions thereof, methods for preparing thereof, and uses thereof.
Background of the Invention
In mammalian cells, 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. The present study suggests that there are mainly three enzymes, namely, IDO1 (indoleamine 2, 3-dioxygenase 1) , IDO2 (indoleamine 2, 3-dioxygenase 2) , and TDO (tryptophan 2, 3-dioxygenase) , participated in the L-tryptophan metabolic reactions as shown in the figure below.
Figure PCTCN2020090598-appb-000001
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 IFNγ, 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. At present, the research on the biological function of IDO2 is still insufficient. 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. The studies found that in a variety of primary and metastatic human tumors, such as acute myeloid leukemia, lung cancer, melanoma, the high expression of IDO1 is correlated with tumor malignancy, metastasis and prognosis, suggesting that IDO1 may be a potential therapeutic target. In the tumor microenvironment, some pro-inflammatory mediators such as IFNγ can induce the expression of IDO1 in tumor cells or host immune cells (mainly antigen presenting cells, such as dendritic cells, macrophages, etc. ) . These induced expression of 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. At the same time, 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.
Preclinical animal experiments have shown the effectiveness of targeting IDO1. For example, using the gene knockout IDO1 protein, or using IDO1 small molecule inhibitors such as INCB024360 (Epacadostat) and NLG919 to inhibit IDO1 protein activity, can effectively reduce the level of kynurenine in animals, thereby relieves IDO1-mediated tumor tolerant to the host's immune system, activates effector cells such as T cells and NK cells, and thus acts to inhibit tumor growth. Now, some IDO1 inhibitors (such as INCB024360, BMS-986205, and Pf-06840003) or IDO1/TDO small molecule inhibitors (such as NLG919) have entered early clinical trials. Early clinical trials have shown that targeting IDO1 is a safe treatment and patients who participated in the trials showed good tolerance. In addition, after treatment with IDO1 small molecule inhibitors for a period of time, the decreasing kynurenine levels with varying degrees were observed in both patient plasma and tumor. Moreover, early efficacy data showed that IDO1 inhibitors combined with immune checkpoint CTLA4 or PD1 antibodies showed better efficacy in some tumors than single agents, for example, the phase 1/2 clinical trial of the IDO1 inhibitor INCB024360 combined PD-1 antibody Pembrolizumab in melanoma patients showed an objective response rate (ORR) of 58%, and was significantly better than the clinical trial data of Pembrolizumab alone (phase 3, ORR, 32.9%) . These results indicate that 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) .
In addition to tumors, other diseases such as chronic infection, HIV, multiple sclerosis, and neurological depression are also associated with IDO1 activity. Therefore, IDO1 inhibitors may also be used to develop treatments for these diseases (Trends Immunol., 2013, 34 (3) : 137-143) . There is  currently no approved targeting IDO1 drugs on the market, and 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.
Summary of the Invention
The present invention provides a compound of formula (I) :
Figure PCTCN2020090598-appb-000002
or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein
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 6R 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) ;
Figure PCTCN2020090598-appb-000003
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) ;
Figure PCTCN2020090598-appb-000004
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’, - (C 1-6 alkyl)  n-NR 1’R 2’C (O) R 3’, - (C 1-6 alkyl)  n-C (O) R 3’, - (C 1-6 alkyl)  n-C (O) OR 4’, - (C 1-6 alkyl)  n-OR 5’, - (C 1-6 alkyl)  n-S (O)  mNR 1’R 2’, - (C 1-6 alkyl)  n-NR 1’R 2’S (O)  mR 6’,  - (C 1-6 alkyl)  n-S (O)  mR 6’, and - (C 1-6 alkyl)  n-SR 7’; in which each of said phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with one or more groups chosen from halo, -CN, -OH, -NH 2, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , C 1-6 alkyl, -O (C 1-6 alkyl) , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl)  2, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
n is 0 or 1;
m is 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.
The above compounds and the active compounds disclosed in the context of the present invention, which are covered by the above scope, are collectively referred to as "compounds of the present invention" .
Also provided is a pharmaceutical composition, comprising the compounds of the present invention, and optionally comprising a pharmaceutically acceptable excipient.
Also provided is a method of in vivo or in vitro inhibiting the activity of IDO, comprising contacting IDO with an effective amount of the compounds of the present invention.
Also provided is a method of treating a disease mediated by IDO or at least in part by IDO, comprising administering to the subject in need thereof an effective amount of the compounds of the present invention.
Also provided is a method of treating cancer, comprising administering to the subject in need thereof an effective amount of the compounds of the present invention.
Also provided is a use of the compounds of the present invention for treating a disease mediated by IDO or at least in part by IDO.
Also provided is a use of the compounds of the present invention for treating cancer or an autoimmune disease.
Also provided is a use of the compounds of the present invention in the manufacture of a medicament for treating a disease mediated by IDO or at least in part by IDO.
Also provided is a use of the compounds of the present invention in the manufacture of a medicament for treating cancer or an autoimmune disease.
Detailed Description of the Invention
Definitions
As used in the present application, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
A dash ( “-” ) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -OR 3 refers to the attachment of R 3 to the rest of the molecule through an oxygen atom.
The term “alkyl” as used herein 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. For example, “C 1-6 alkyl” refers to an alkyl containing 1-6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
An 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. The term “alkylene” as used herein 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. For example, "- (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. Preferably, the alkylene group is straight C 1-6 alkylene, more preferably -CH 2-and -CH 2-CH 2-.
The term “alkenyl” as used herein refers to a straight or branched unsaturated hydrocarbon radical containing one or more, for example 1, 2, or 3 carbon-carbon double bonds (C=C) and 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2-4 carbon atoms. For example, “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. Examples of 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.
The term “alkynyl” as used herein 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. For example, “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. Examples of 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.
The term “halogen” or “halo” as used herein means fluoro, chloro, bromo, and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro.
The term “haloalkyl” as used herein 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. In certain embodiment, the term “haloalkyl” as used herein 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. In another embodiment, the term “haloalkyl” as used herein 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. Examples of haloalkyl groups include, but are not limited to, -CF 3, -CHF 2, -CH 2CF 3, -CH (CF 3)  2, and the like.
The term “cycloalkyl” as used herein 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. For example, “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. Examples of 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.
The term “heterocycle” , “heterocyclyl” or “heterocyclic” as used herein 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. The point of attachment of heterocyclyl can be on the N heteroatom or carbon. For example, “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. partially unsaturated) , but not fully conjugated, and not a heteroaryl as defined herein. Examples of 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.
The term “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.
The term “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:
- monocyclic aromatic hydrocarbon radical having 5, 6 or 7 ring atoms, preferably having 5 or 6 ring atoms, i.e. 5-6 membered heteroaryl, 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 and O) in the ring, with the remaining ring atoms being carbon; and
- 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. For example, the bicyclic heteroaryl includes a 5-6 membered heterocyclic aromatic ring fused to a 5-6 membered cycloalkyl ring.
When the total number of S and O atoms in the heteroaryl group exceeds 1, said S and O heteroatoms are not adjacent to one another.
Examples of the heteroaryl group 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, imidazopyridyl (such as imidazo [1, 2-a] pyridyl) , imidazopyridazinyl (such as imidazo [1, 2-b] pyridazinyl) , pyrrolopyridyl (such as 1H-pyrrolo [2, 3-b] pyridyl) , pyrrolopyrimidinyl (such as pyrrolo [3, 4-d] pyrimidinyl) , pyrazolopyridyl (such as 1H-pyrazolo [3, 4-b] pyridyl) , pyrazolopyrimidinyl (such as pyrazolo [1, 5-a] pyrimidinyl) , triazolopyridyl (such as [1, 2, 4] triazolo [4, 3-a] pyridyl and [1, 2, 4] triazolo [1, 5-a] pyridyl) , tetrazolopyridyl (such as tetrazolo [1, 5-a] pyridyl) , benzofuryl, benzoimidazolinyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, and quinazolinyl.
“Hydroxyl” as used herein refers to the –OH radical.
“Oxo” as used herein refers to the =O radical.
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) .
The term “optional” or “optionally” as used herein means that the subsequently described event or circumstance may or may not occur, and the description includes instances wherein the event or circumstance occur and instances in which it does not occur. For example, “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.
The term “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. When a substituent is oxo (i.e., =O) , then 2 hydrogens on a single atom are replaced by the oxo. Combinations of 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.
Unless otherwise specified, 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.
The term “substituted with one or more substituents” as used herein 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.
It will be appreciated by the person of ordinary skill in the art ( “POSITA” ) that 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. It will be further appreciated by the POSITA that 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.
The 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. Alternatively, 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%. Alternatively, the 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.
The term “tautomer” as used herein 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. For example, 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. For examples, see, generally, S.M. Berge, et al., “Pharmaceutical Salts” , J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.
In addition, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, 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.
The term “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 2O, such combination being able to form one or more hydrates, for example, hemihydrate, monohydrate, and dihydrate.
As used herein, the terms “group” and “radical” are synonymous and are intended to indicate functional groups or fragments of molecules attachable to other fragments of molecules.
The term “active ingredient” is used to indicate a chemical substance which has biological activity. In some embodiments, an “active ingredient” is a chemical substance having pharmaceutical utility. In the United States, 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.
The terms “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. In some embodiments, the disease or disorder is cancer.
The terms “treating” , “contacting” and “reacting, ” 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.
The term “effective amount” as used herein 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) . For a 70-kg human, 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. Once improvement of the patient's disease or disorder has occurred, the dose may be adjusted for maintenance treatment. For example, 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. Of course, if symptoms have been alleviated to  an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
The term “inhibition” or “inhibiting” indicates a decrease in the baseline activity of a biological activity or process. The term “inhibition 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. For example, 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.
The term “subject” as used herein 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. Examples of 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.
In general, the term “about” is used herein to modify a numerical value above or below the stated value by a variance of 20%.
Technical and scientific terms used herein and not specifically defined have the meaning commonly understood by the POSITA to which the present disclosure pertains.
Provided is a compound of formula (I) :
Figure PCTCN2020090598-appb-000005
or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein
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 6R 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) ;
Figure PCTCN2020090598-appb-000006
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) ;
Figure PCTCN2020090598-appb-000007
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’, - (C 1-6 alkyl)  n-NR 1’R 2’C (O) R 3’, - (C 1-6 alkyl)  n-C (O) R 3’, - (C 1-6 alkyl)  n-C (O) OR 4’, - (C 1-6 alkyl)  n-OR 5’, - (C 1-6 alkyl)  n-S (O)  mNR 1’R 2’, - (C 1-6 alkyl)  n-NR 1’R 2’S (O)  mR 6’, - (C 1-6 alkyl)  n-S (O)  mR 6’, and - (C 1-6 alkyl)  n-SR 7’; in which each of said phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with one or more groups chosen from halo, -CN, -OH, -NH 2, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , C 1-6 alkyl, -O (C 1-6 alkyl) , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl)  2, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
n is 0 or 1;
m is 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.
In some embodiments of the compound of formula (I) , X is CR 3; Y is CR 4.
In some embodiments of the compound of formula (I) , X is CH; Y is CH.
In some embodiments of the compound of formula (I) , R 1, R 2, R 3, R 4, R 6, and R 7 are independently chosen from H and halo (such as F) .
In some embodiments of the compound of formula (I) , R 1, R 2, R 3, R 4, R 5, R 6, and R 7 are all H.
In some embodiments of the compound of formula (I) , X is CH; Y is N.
In some embodiments of the compound of formula (I) , X is N; Y is N.
In some embodiments of the compound of formula (I) , p is 0, Z is CR 6R 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) .
In some embodiments of the compound of formula (I) , p is 0, Z is CHR 6; R 6 is chosen from H, -OH, C 1-6 alkyl, or -O (C 1-6 alkyl) .
In some embodiments of the compound of formula (I) , p is 0, Z is CH 2.
In some embodiments of the compound of formula (I) , p is 1, Z is CR 6R 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) .
In some embodiments of the compound of formula (I) , p is 1, Z is CHR 6; R 6 is chosen from H, -OH, C 1-6 alkyl, or -O (C 1-6 alkyl) .
In some embodiments of the compound of formula (I) , p is 1, Z is NR 5; R 5 is chosen from H, C 1-6 alkyl, or C 3-6 cycloalkyl.
In some embodiments of the compound of formula (I) , p is 1, Z is NR 5; R 5 is H or C 1-6 alkyl.
In some embodiments of the compound of formula (I) , p is 1, Z is O.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000008
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000009
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000010
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000011
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000012
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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000013
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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000014
is phenyl, which is substituted with ethynyl.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000015
is phenyl, which is substituted with halo.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000016
is phenyl, which is substituted with -OCF 3 or -OCHF 2.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000017
is phenyl, which is substituted with -CN.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000018
is pyridyl, which is optionally substituted with one or more groups chosen from C 2-6 alkynyl or -O (C 1-6 alkyl) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000019
is pyrrolyl or thienyl, each of which is optionally substituted with halo or -CN.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000020
is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with one or more groups chosen from:
1) halo;
2) -NO 2;
3) oxo;
4) - (C 1-6 alkyl)  n-CN;
5) C 1-6 alkyl;
6) C 1-6 haloalkyl;
7) C 3-6 cycloalkyl;
8) - (C 1-6 alkyl)  n-4-6 membered heterocyclyl;
9) 5-6 membered heteroaryl;
10) - (C 1-6 alkyl)  n-NR 1’R 2’;
11) -CONR 1’R 2’;
12) -NR 1’R 2’C (O) R 3’;
13) -C (O) OR 4’;
14) - (C 1-6 alkyl)  n-OR 5’;
15) -S (O)  2NR 1’R 2’; or
16) -NR 1’R 2’S (O)  2R 6’;
in which 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 is 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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000021
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000022
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000023
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000024
is pyridyl or pyrimidinyl, each of which is optionally substituted with one or more groups chosen from:
1) halo;
2) -NO 2;
3) oxo;
4) - (C 1-6 alkyl)  n-CN;
5) C 1-6 alkyl;
6) C 1-6 haloalkyl;
7) C 3-6 cycloalkyl;
8) - (C 1-6 alkyl)  n-4-6 membered heterocyclyl;
9) 5-6 membered heteroaryl;
10) - (C 1-6 alkyl)  n-NR 1’R 2’;
11) -CONR 1’R 2’;
12) -NR 1’R 2’C (O) R 3’;
13) -C (O) OR 4’;
14) - (C 1-6 alkyl)  n-OR 5’;
15) -S (O)  2NR 1’R 2’; or
16) -NR 1’R 2’S (O)  2R 6’;
in which 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 is 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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000025
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000026
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000027
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000028
is pyridyl, which is optionally substituted with one or more groups chosen from:
1) halo;
2) -NO 2;
3) - (C 1-6 alkyl)  n-CN;
4) oxo;
5) C 1-6 alkyl;
6) C 1-6 haloalkyl;
7) C 3-6 cycloalkyl;
8) - (C 1-6 alkyl)  n-4-6 membered heterocyclyl;
9) 5-6 membered heteroaryl;
10) - (C 1-6 alkyl)  n-NR 1’R 2’;
11) -CONR 1’R 2’;
12) -NR 1’R 2’C (O) R 3’;
13) -C (O) OR 4’;
14) - (C 1-6 alkyl)  n-OR 5’;
15) -S (O)  2NR 1’R 2’; or
16) -NR 1’R 2’S (O)  2R 6’;
in which 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 is 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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000029
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000030
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000031
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000032
is pyridyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000033
is
Figure PCTCN2020090598-appb-000034
each of which is optionally substituted with one or more groups chosen from:
1) halo;
2) -NO 2;
3) oxo;
4) - (C 1-6 alkyl)  n-CN;
5) C 1-6 alkyl;
6) C 1-6 haloalkyl;
7) C 3-6 cycloalkyl;
8) - (C 1-6 alkyl)  n-4-6 membered heterocyclyl;
9) 5-6 membered heteroaryl;
10) - (C 1-6 alkyl)  n-NR 1’R 2’;
11) -CONR 1’R 2’;
12) -NR 1’R 2’C (O) R 3’;
13) -C (O) OR 4’;
14) - (C 1-6 alkyl)  n-OR 5’;
15) -S (O)  2NR 1’R 2’; or
16) -NR 1’R 2’S (O)  2R 6’;
in which 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 is 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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000035
is
Figure PCTCN2020090598-appb-000036
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000037
is
Figure PCTCN2020090598-appb-000038
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000039
is
Figure PCTCN2020090598-appb-000040
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000041
is
Figure PCTCN2020090598-appb-000042
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000043
is
Figure PCTCN2020090598-appb-000044
each of which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000045
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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000046
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000047
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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000048
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000049
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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000050
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000051
is pyrimidinyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000052
is
Figure PCTCN2020090598-appb-000053
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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000054
is
Figure PCTCN2020090598-appb-000055
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000056
is
Figure PCTCN2020090598-appb-000057
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000058
is
Figure PCTCN2020090598-appb-000059
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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000060
is
Figure PCTCN2020090598-appb-000061
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000062
is
Figure PCTCN2020090598-appb-000063
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.
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000064
is
Figure PCTCN2020090598-appb-000065
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) .
In some embodiments of the compound of formula (I) , 
Figure PCTCN2020090598-appb-000066
is
Figure PCTCN2020090598-appb-000067
which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I) , the compound of formula (I) is formula (I-1) ,
Figure PCTCN2020090598-appb-000068
In some embodiments of the compound of formula (I-1) , X is N or CH; Y is N or CH.
In some embodiments of the compound of formula (I-1) , X is CH; Y is CH.
In some embodiments of the compound of formula (I-1) , X is CH; Y is N.
In some embodiments of the compound of formula (I-1) , X is N; Y is N.
In some embodiments of the compound of formula (I-1) , Z is NR 5, CR 6R 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.
In some embodiments of the compound of formula (I-1) , Z is O.
In some embodiments of the compound of formula (I-1) , Z is CH 2.
In some embodiments of the compound of formula (I-1) , Z is NH.
In some embodiments of the compound of formula (I-1) , 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) .
In some embodiments of the compound of formula (I-1) , R a is chosen from F, Cl, Br, -CN, methyl, ethyl, ethynyl, -CF 3, -OCF 3, or -OCH 3.
In some embodiments of the compound of formula (I-1) , R a is chosen from F, Cl, Br, -CN, methyl, ethyl, -CF 3, -OCF 3, or -OCH 3.
In some embodiments of the compound of formula (I-1) , R a is ethynyl.
In some embodiments of the compound of formula (I-1) , R a is halo.
In some embodiments of the compound of formula (I-1) , R a is -OCF 3 or -OCHF 2.
In some embodiments of the compound of formula (I-1) , R a is -CN.
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000069
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000070
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000071
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000072
is
Figure PCTCN2020090598-appb-000073
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000074
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000075
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.
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000076
is
Figure PCTCN2020090598-appb-000077
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000078
is
Figure PCTCN2020090598-appb-000079
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.
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000080
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000081
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000082
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000083
is pyridyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000084
is
Figure PCTCN2020090598-appb-000085
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000086
is
Figure PCTCN2020090598-appb-000087
each of which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000088
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000089
is pyrimidinyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000090
is
Figure PCTCN2020090598-appb-000091
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) .
In some embodiments of the compound of formula (I-1) , 
Figure PCTCN2020090598-appb-000092
is
Figure PCTCN2020090598-appb-000093
which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I) , the compound of formula (I) is formula (I-2) ,
Figure PCTCN2020090598-appb-000094
In some embodiments of the compound of formula (I-2) , X is N or CH; Y is N or CH.
In some embodiments of the compound of formula (I-2) , X is CH; Y is CH.
In some embodiments of the compound of formula (I-2) , X is CH; Y is N.
In some embodiments of the compound of formula (I-2) , X is N; Y is N.
In some embodiments of the compound of formula (I-2) , 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) .
In some embodiments of the compound of formula (I-2) , R a is chosen from F, Cl, Br, -CN, methyl, ethyl, ethynyl, -CF 3, -OCF 3, or -OCH 3.
In some embodiments of the compound of formula (I-2) , R a is chosen from F, Cl, Br, -CN, methyl, ethyl, -CF 3, -OCF 3, or -OCH 3.
In some embodiments of the compound of formula (I-2) , R a is ethynyl.
In some embodiments of the compound of formula (I-2) , R a is halo.
In some embodiments of the compound of formula (I-2) , R a is -OCF 3 or -OCHF 2.
In some embodiments of the compound of formula (I-2) , R a is -CN.
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000095
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000096
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000097
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000098
is
Figure PCTCN2020090598-appb-000099
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000100
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000101
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.
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000102
is
Figure PCTCN2020090598-appb-000103
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000104
is
Figure PCTCN2020090598-appb-000105
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.
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000106
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000107
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000108
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000109
is pyridyl which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000110
is
Figure PCTCN2020090598-appb-000111
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000112
is
Figure PCTCN2020090598-appb-000113
each of which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000114
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000115
is pyrimidinyl, which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000116
is
Figure PCTCN2020090598-appb-000117
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) .
In some embodiments of the compound of formula (I-2) , 
Figure PCTCN2020090598-appb-000118
is
Figure PCTCN2020090598-appb-000119
which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
Also provided is a compound chosen from Compounds 1-331, as numbered in the experimental section, and/or a pharmaceutically acceptable salt thereof.
In an embodiment, the compounds of the present invention don’t include the following compounds:
Figure PCTCN2020090598-appb-000120
Figure PCTCN2020090598-appb-000121
Figure PCTCN2020090598-appb-000122
In another aspect, provided is 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) .
In another aspect, provided is 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.
In another aspect, provided is 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) .
In another aspect, provided is 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.
In another aspect, provided is 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.
In another aspect, provided is 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) .
In another aspect, provided is 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) .
In another aspect, provided is a use of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof for treating a disease mediated by IDO or at least in part by IDO.
In another aspect, provided is a use of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof for treating cancer or an autoimmune disease.
In another aspect, provided is a use of a compound of formula (I) (e.g., any of the compounds described herein) and/or 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.
In another aspect, provided is a use of a compound of formula (I) (e.g., any of the compounds described herein) and/or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, an autoimmune disease, obesity, or an obesity-related disease.
In another aspect, provided is 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.
In some embodiments, said additional therapeutic agent is an anti-neoplastic agent.
In some embodiments, said additional therapeutic agent is a chemotherapeutic agent.
In some embodiments, said additional therapeutic agent is an immune checkpoint inhibitor.
In another aspect, provided is 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.
In another aspect, provided is 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.
In another aspect, provided is a use 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 in the manufacture of a combined medicament for treating a disease mediated by IDO or at least in part by IDO.
In another aspect, provided is a use 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 in the manufacture of a combined medicament for treating cancer or an autoimmune disease.
In some embodiments, said immune checkpoint inhibitor is chosen from an anti-PD-1 inhibitor, a CTLA-4 inhibitor, or an OX-40 inhibitor.
In some embodiments, said immune checkpoint inhibitor is chosen from pembrolizumab, nivolumab, and ipilimumab.
In some embodiments, the disease mediated by IDO or at least in part by IDO is cancer or an autoimmune disease.
In some embodiments, the cancer is solid tumor, or hematologic malignancy, such as leukemia, lymphoma, or myeloma.
In some embodiments, 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.
In some embodiments, 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) .
In some embodiments, the autoimmune disease is chosen from arthritis, such as rheumatoid arthritis, collagen induced arthritis, and the like.
In some embodiments, 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.
General Synthetic Methods for Disclosed Embodiments
The compound of formula (I) and/or a pharmaceutically acceptable salt thereof described herein can be synthesized from commercially available starting material by methods well known in the art, taken together with the disclosure in this patent application. The Schemes 1-3 illustrate general methods for preparation of the compounds disclosed herein.
Method 1:
Figure PCTCN2020090598-appb-000123
Scheme 1
As shown in Scheme 1, coupling reaction of compound of formula (1-1) with compound (1-2) , under the catalysis of a palladium reagent (such as but not limited to Pd (PPh 3)  4) , gives compound of formula (1-3) ; then, deprotection reaction of compound of formula (1-3) , in the presence of an acid  (such as but not limited to TFA) , affords compound of formula (1-4) ; finally, condensation reaction of compound of formula (1-4) with compound of formula (1-5) , in the presence of a condensating agent (such as but not limited to HATU) , gives compound of formula (1-6) . Wherein, R 1, R 2, X, Y, p, 
Figure PCTCN2020090598-appb-000124
are as defined herein; R a and R b are one or more substituents respectively; W is a leaving group.
Method 2:
Figure PCTCN2020090598-appb-000125
Scheme 2
As shown in Scheme 2, 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) . Wherein, R 1, R 2, X, Y, p, 
Figure PCTCN2020090598-appb-000126
are as defined herein; R a and R b are one or more substituents respectively; W is a leaving group.
Method 3:
Figure PCTCN2020090598-appb-000127
Scheme 3
As shown in Scheme 3, coupling reaction of compound of formula (3-1) with compound of formula (3-2) , gives compound of formula (3-3) ; then, deprotection reaction of compound of formula (3-3) , in the presence of an acid (such as but not limited to TFA) , affords compound of formula (3-4) ; finally, condensation reaction of compound of formula (3-4) with compound of formula (3-5) , in the presence of a condensating agent (such as but not limited to HATU) , gives compound of formula (3-6) . Wherein, R 1, R 2, X, Y, p, 
Figure PCTCN2020090598-appb-000128
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 substituents of the compounds thus obtained can be further modified to provide other desired compounds. Synthetic chemistry transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989) ; L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994) ; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.
Before use, 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.
Pharmceutical Compositions and Practical Utility
The compound of formula (I) (e.g., any of those described herein) and/or a pharmaceutically acceptable salt thereof described herein is used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions. 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. For example, 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) , can be utilized as pharmaceutical excipients for delivery of the active ingredients. 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. The term “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. In some embodiments, 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. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.
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 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) 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. Among the pharmaceutically acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, 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) . In some embodiments, 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. Additionally, 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. For example, 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.
As used herein, the term "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. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies. The term "cancer" encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels. The term "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 tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; sarcoma, including, e.g., Kaposi's sarcoma; adrenal carcinoma; mesothelial carcinoma; choriocarcinoma; muscle carcinoma; connective tissue carcinoma; and thyroid carcinoma.
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) , and RAEB in transformation (RAEB-T) ; and myeloproliferative syndrome.
In some embodiments, 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) .
In some embodiments, 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) .
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.
The term “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. Examples of 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) .
The term “obesity-related disease” refers to a disease or disorder that is associated with, caused by, or resulted from obesity. Examples of 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.
In addition, 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. In some embodiments, 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.
In some embodiments, 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. As used herein, the term "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.
In some embodiments, 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.
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 (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea) ; paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047) .
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.
EXAMPLES
The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc. ) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. All MS data were determined by agilent 6120 or agilent 1100. All NMR data were generated using a Varian 400-MR machine. All reagents, except intermediates, used in this invention are commercially available. All compound names except the reagents were generated by Chemdraw 16.0.
If there is any atom with empty valence (s) in any one of the structures disclosed herein, the empty balance (s) is (are) the hydrogen atom (s) which is (are) omitted for convenience purpose.
In the present application, in the case of inconsistency of the structure and name of a compound, when the two of which are both given for the compound, it is subject to the structure of the compound, unless the context shows that the structure of the compound is incorrect and the name is correct.
In the following examples, the abbreviations below are used:
BF 3. Et 2O                  boron trifluoride diethyl etherate
KOAc                       potassium acetate
DIEA                       N, N-diisopropylethylamine
DMF                        N, N-dimethylformamide
DMSO                      dimethyl sulfoxide
dppf                      1, 1'-bis (diphenylphosphino) ferrocene
EDTA                      ethylene diamine tetraacetic acid
EtMgBr                    ethylmagnesium bromide
Et 2O                      diethyl ether
HATU                      2- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium
                          hexafluorophosphate
MgCl 2                     magnesium chloride
MsCl                      methanesulfonyl chloride
Pd (dppf) Cl 2·CH 2Cl 2      [1, 1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) ,
                          dichloromethane complex
Pd (PPh 3)  4               tetrakis (triphenylphosphine) palladium
TEA                       triethylamine
TFA                       trifluoroacetic acid
Ti (OiPr)  4               titanium (IV) isopropoxide
Example 1:
Compound 1
N- (1- (4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) phenyl) cyclopropyl) -4-chlorobenzamide
Figure PCTCN2020090598-appb-000129
a) tert-Butyl (1- (4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) phenyl) cyclopropyl) carbamate
tert-Butyl (1- (4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) carbamate (359 mg, 1.0 mmol) , 2-bromo-5- (trifluoromethyl) pyridin-3-amine (241 mg, 1.0 mmol) , K 2CO 3 (276mg, 2.0 mmol) and Pd (dppf) Cl 2·CH 2Cl 2 (82 mg, 0.1 mmol) were dissolved in a mixture of 10 mL of dioxane and 3 mL of water. After purging with N 2, the reaction was refluxed overnight. The mixture was concentrated, the resulting residue was purified by flash column chromatography (mobile phase: EtOAc/petroleum ether = 0～100%) to give the target compound as a white solid, yield: 58.5%. MS (m/z) : 394.2 (M+1) +.  1H NMR (399 MHz, DMSO-d6) δ 8.14 (d, J = 0.8 Hz, 1H) , 7.74 (s, 1H) , 7.59 -7.56 (m, 2H) , 7.37 (d, J = 1.6 Hz, 1H) , 7.21 -7.18 (m, 2H) , 5.54 (s, 2H) , 1.37 (s, 9H) , 1.15 (brs, 4H) .
b) N- (1- (4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) phenyl) cyclopropyl) -4-chlorobenzamide
tert-Butyl (1- (4- (3-amino-5- (trifluoromethyl) pyridin-2-yl) phenyl) cyclopropyl) carbamate (230 mg, 0.58 mmol) was dissolved in 5 mL of TFA, and then was concentrated. The resulting residue was dissolved in 3 mL of DMF, to which were added 4-chlorobenzoic acid (92 mg, 0.58 mmol) , HATU (222 mg, 0.58 mmol) and DIEA (151 mg, 1.16 mmol) , the reaction was stirred for 30 min. After reaction, the target compound as a white solid (170 mg) was obtained via flash column chromatography (mobile pahse: MeOH/H 2O (0～100%) , yield: 67.5%. MS (m/z) : 432.1 (M+1) +.  1H NMR (399 MHz, DMSO-d6) δ 9.31 (s, 1H) , 8.14 -8.13 (m, 1H) , 7.92 –7.88 (m, 2H) , 7.59 –7.50 (m, 4H) , 7.36 (d, J = 2.0 Hz, 1H) , 7.28 –7.24 (m, 2H) , 5.55 (s, 2H) , 1.29 (brs, 4H) .
The following compounds were prepared according to the procedure of Compound 1 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:
Figure PCTCN2020090598-appb-000130
Figure PCTCN2020090598-appb-000131
Figure PCTCN2020090598-appb-000132
Figure PCTCN2020090598-appb-000133
Figure PCTCN2020090598-appb-000134
Figure PCTCN2020090598-appb-000135
Figure PCTCN2020090598-appb-000136
Figure PCTCN2020090598-appb-000137
Figure PCTCN2020090598-appb-000138
Figure PCTCN2020090598-appb-000139
Figure PCTCN2020090598-appb-000140
Figure PCTCN2020090598-appb-000141
Figure PCTCN2020090598-appb-000142
Figure PCTCN2020090598-appb-000143
Figure PCTCN2020090598-appb-000144
Figure PCTCN2020090598-appb-000145
Figure PCTCN2020090598-appb-000146
Figure PCTCN2020090598-appb-000147
Figure PCTCN2020090598-appb-000148
Figure PCTCN2020090598-appb-000149
Figure PCTCN2020090598-appb-000150
Figure PCTCN2020090598-appb-000151
Figure PCTCN2020090598-appb-000152
Figure PCTCN2020090598-appb-000153
Figure PCTCN2020090598-appb-000154
Figure PCTCN2020090598-appb-000155
Figure PCTCN2020090598-appb-000156
Figure PCTCN2020090598-appb-000157
Figure PCTCN2020090598-appb-000158
Figure PCTCN2020090598-appb-000159
Figure PCTCN2020090598-appb-000160
Figure PCTCN2020090598-appb-000161
Figure PCTCN2020090598-appb-000162
Figure PCTCN2020090598-appb-000163
Figure PCTCN2020090598-appb-000164
Figure PCTCN2020090598-appb-000165
Figure PCTCN2020090598-appb-000166
Figure PCTCN2020090598-appb-000167
Figure PCTCN2020090598-appb-000168
Figure PCTCN2020090598-appb-000169
Figure PCTCN2020090598-appb-000170
Figure PCTCN2020090598-appb-000171
Figure PCTCN2020090598-appb-000172
Figure PCTCN2020090598-appb-000173
Figure PCTCN2020090598-appb-000174
Figure PCTCN2020090598-appb-000175
Figure PCTCN2020090598-appb-000176
Figure PCTCN2020090598-appb-000177
Figure PCTCN2020090598-appb-000178
Wherein, the optically pure enantiomers compounds 219 and 220 were isolated from the corresponding racemic compounds by chiral HPLC. HPLC Conditions: column: CHIRALPAK IG 20*250 mm; mobile phase: EtOH/n-heptane =20%/80%; detector: UV 254 nm; flow rate = 15 mL/min. Under the above conditions, the compound obtained by removing the solvent of the first fraction is Compound 219, and the compound obtained by removing the solvent of the second fractionis Compound 220.
The optically pure enantiomers compounds 230 and 231 were isolated from the corresponding racemic compounds by chiral HPLC. HPLC Conditions: column: CHIRALPAK IG 20*250 mm; mobile phase: EtOH/n-heptane =20%/80%; detector: UV 254 nm; flow rate = 15 mL/min. Under the above conditions, the compound obtained by removing the solvent of the first fraction is  Compound 230, and the compound obtained by removing the solvent of the second fraction is Compound 231.
The optically pure enantiomers compounds 233 and 234 were isolated from the corresponding racemic compounds by chiral HPLC. Under the HPLC conditions (column: CHIRALPAK IG 4.6*250 mm; mobile phase: (n-heptane+0.1%diethylamine) / (EtOH+0.1%diethylamine) =8: 2; detector: UV 254 nm; flow rate = 1 mL/min; temperature: 30℃) , the retention time of compound 234 is 5.244 min; the retention time of compound 233 is 5.744 min.
Example 2:
Compound 300
N- (1- (4- (3-amino-5-chloropyridin-2-yl) -2-fluorophenyl) cyclopropyl) -4-fluorobenzamide
Figure PCTCN2020090598-appb-000179
a) 1- (4-Bromo-2-fluorophenyl) cyclopropan-1-amine
4-Bromo-2-fluorobenzonitrile (2.00 g, 10.0 mmol) and Ti (OiPr)  4 (2.84 g, 10.0 mmol) were dissolved in 100 mL of THF, cooled to -78℃, and then was added EtMgBr (6.67 g, 20.0 mmol) dropwise. The reaction was warmed to the room temperature, and stirred for 2h. The mixture was then cooled to 0℃, and added BF 3. Et 2O (2.84 g, 20.0 mmol) dropwise. The resulting mixture was warmed to the room temperature, and stirred for 5h. The reaction was quenched with aqueous solution of NaOH (2 mol/L) , filtered over diatomite, and washed with MeOH (100 mL) . The resulting filtrate was combined and concentrated. The resulting residue was purified by flash column chromatography (mobile phase: MeOH/CH 2Cl 2 = 0～10%) to give 1- (4-bromo-2-fluorophenyl) cyclopropan-1-amine as a yellow oil, yield: 13.0%. MS (m/z) : 230.0 (M+1)  +.
b) N- (1- (4-bromo-2-fluorophenyl) cyclopropyl) -4-fluorobenzamide
1- (4-Bromo-2-fluorophenyl) cyclopropan-1-amine (300 mg, , 1.304 mmol) , 4-fluorobenzoic acid (182.7 mg, 1.304 mmol) , HATU (743.7 mg, 1.956 mmol) and DIEA (505.6 mg, 3.912 mmol) were dissolved in DMF. The mixture was stirred overnight at RT. After reaction, the mixture was concentrated and the resulting residue was purified by flash column chromatography (mobile pahse: MeOH/H 2O = 0～100%) to give the target compound as a yellow solid, yield: 65.2%. MS (m/z) : 352.0 (M+1)  +.
c) 4-Fluoro-N- (1- (2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) benzamide
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) and Pd (dppf) Cl 2·CH 2Cl 2 (69.4 mg, 0.085 mmol) were dissolved in 40 mL of dioxane. The mixture was stirred for 4h at 80 ℃ under N 2. The mixture was cooled down after reaction, concentrated and the resulting reside was purified by flash column chromatography (mobile phase: MeOH/H 2O =0～100%) to give the target compound as a yellow solid (300 mg) , yield: 73.9%. MS (m/z) : 400.2 (M+1)  +.
d) N- (1- (4- (3-amino-5-chloropyridin-2-yl) -2-fluorophenyl) cyclopropyl) -4-fluorobenzamide
4-Fluoro-N- (1- (2-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) cyclopropyl) b enzamide (120 mg, 0.301 mmol) , 2-bromo-5-chloropyridin-3-amine (62.4 mg, 0.301 mmol) , K 2CO 3 (83.2 mg, 0.602 mmol) and Pd (dppf) Cl 2·CH 2Cl 2 (24.5 mg, 0.03 mmol) were dissolved in a mixture of 10 mL of dioxane and 2 mL of water. The mixture was refluxed overnight under N 2. The mixture was cooled down after reaction, concentrated and the resulting reside was purified by flash column chromatography (mobiled phase: MeOH/H 2O = 0～100%) to give the target compound as a yellow solid (66 mg) , yield: 56.5%. MS (m/z) : 400.1 (M+1)  +.
1H NMR (399 MHz, DMSO-d6) δ 9.23 (s, 1H) , 7.92-7.85 (m, 2H) , 7.83 (d, J = 2.2Hz, 1H) , 7.62 (t, J = 8.2Hz, 1H) , 7.39 (dd, J = 8.0, 1.7Hz, 1H) , 7.32 (dd, J = 12.2, 1.7Hz, 1H) , 7.27-7.21 (m, 2H) , 7.17 (d, J = 2.2Hz, 1H) , 5.51 (s, 2H) , 1.27-1.15 (m, 4H) .
The following compounds were prepared according to the procedure of Compound 300 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:
Figure PCTCN2020090598-appb-000180
Example 3:
Compound 318
N- (1- (5'-chloro- [2, 2'-bipyridinyl] -5-yl) cyclopropyl) -4-ethynylbenzamide
Figure PCTCN2020090598-appb-000181
a) 1- (6-Bromopyridin-3-yl) cyclopropan-1-amine
6-Bromonicotinonitrile (2.34 g, 12.8 mmol) was dissolved in Et 2O (60 mL) , cooled to -78℃, 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℃ for 30 min, then warmed to the room temperature slowly and stirred for 1h. Then BF 3. Et 2O (3.22 mL, 25.6 mmol) was added, and the mixture was stirred for 2h at room tempreture. The reaction mixture was quenched with aqueous solution of HCl (1 M) after reaction, and extracted with Et 2O. The pH of the separated water phase was adjusted to about 10 with saturated solution of Na 2CO 3, then was extracted with EtOAc. The organic layers were combined, dried over anhydrous Na 2SO 4, and concentrated to give the target compound as a yellow oil (1.6 g, 58.7%) . MS (m/z) : 212.9 [M+1]  +.
b) tert-Butyl (1- (6-bromopyridin-3-yl) cyclopropyl) carbamate
1- (6-Bromopyridin-3-yl) cyclopropan-1-amine (1.6 g, 7.51 mmol) was dissolved in CH 2Cl 2 (30 mL) . TEA (1.6 mL, 11.3 mmol) and Di-tert-butyl dicarbonate (1.97 g, 9.01 mmol) were added in sequence. The reaction was stirred overnight at room temperature. After concentration, the residue was purified by flash column chromatography (mobile phase: EtOAc/petroleum ether = 0～60%) to give the target compound as a yellow oil (950 mg) , yield: 40%. MS (m/z) : 313.0 [M+1]  +
c) tert-Butyl (1- (5'-chloro- [2, 2'-bipyridinyl] -5-yl) cyclopropyl) carbamate
tert-Butyl (1- (6-bromopyridin-3-yl) cyclopropyl) carbamate (313 mg, 1 mmol) was dissolved in toluene (6 mL) . 5-Chloro-2- (tributylstannyl) pyridine (563 mg, 1.4 mmol) and Pd (PPh 3)  4 (87 mg, 0.075 mmol) were added in sequence. The reaction mixture was stirred overnight under N 2 at 100℃. The mixture was filterted after reaction. The filtrate was concentrated and purified by flash column chromatography (mobile phase: EtOAc/petroleum ether = 0～70%) to give the target compound as a yellow solid (240 mg) , yield: 69%. MS (m/z) : 346.0 [M+1]  +.
d) N- (1- (5'-chloro- [2, 2'-bipyridinyl] -5-yl) cyclopropyl) -4-ethynylbenzamide
To a solution of tert-butyl (1- (5'-chloro- [2, 2'-bipyridinyl] -5-yl) cyclopropyl) carbamate (240 mg, 0.69 mmol) in CH 2Cl 2 (12 mL) , was added TFA (3 mL) dropwise. The reaction was stirred overnight at the room temperature. The mixture was concentrated after reaction; the pH was adjusted to about 10 with saturated solution of Na 2CO 3, and extracted with EtOAc. The organic layers were combined and dried over anhydrous Na 2SO 4 and concentrated to give a yellow solid.
The obtained solid was dissolved in DMF (8 mL) , and then 4-ethynylbenzoic acid (123 mg, 0.84 mmol) , DIEA (0.24 mL, 1.38 mmol) and HATU (340 mg, 0.9 mmol) were added in sequence.  The mixture was was stirred for 5 h at the room temperature. The reacation was added with water after reaction, and extracted with EtOAc. The organic layers were combined and dried over anhydrous Na 2SO 4, concentrated and purified by flash column chromatography (mobile phase: EtOAc/petroleum ether = 0～70%) to give the target compound as a yellow solid (175 mg) , yield: 68%. MS (m/z) : 374.0 [M+1] +.  1HNMR (399 MHz, DMSO-d6) δ 9.38 (s, 1H) , 8.68 (dd, J = 2.5, 0.6 Hz, 1H) , 8.50 (dd, J = 2.4, 0.6 Hz, 1H) , 8.32 (dd, J = 8.6, 0.6 Hz, 1H) , 8.23 (dd, J = 8.4, 0.6 Hz, 1H) , 8.02 (dd, J = 8.6, 2.5 Hz, 1H) , 7.93 –7.86 (m, 2H) , 7.71 (dd, J = 8.4, 2.5 Hz, 1H) , 7.61 –7.53 (m, 2H) , 4.37 (s, 1H) , 1.40 (t, J = 6.4 Hz, 2H) , 1.42-1.39 (m, 2H) , 1.35-1.32 (m, 2H) .
The following compounds were prepared according to the procedure of Compound 318 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:
Figure PCTCN2020090598-appb-000182
Figure PCTCN2020090598-appb-000183
*:using the corresponding borates instead of stannyl reagents.
Example 4:
Compound 325
N- (3- (4- (5-chloropyridin-2-yl) phenyl) azetidin-3-yl) -4-ethynylbenzamide
Figure PCTCN2020090598-appb-000184
a) tert-Butyl 3- (4-bromophenyl) -3-hydroxyazetidine-1-carboxylate
1,4-Dibromobenzene (2.36 g, 10.0 mmol) was dissolved in THF (50 mL) and was cooled to -78℃. 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 4Cl, and extracted with 100 mL of EtOAC twice. The organic layers were combined and dried over anhydrous Na 2SO 4,  concentrated and the resulting residue was purified by flash column chromatography (mobile phase: EtOAc/petroleum ether = 1/3) to give the target compound as a yellow solid (2.1 g, yield: 64%) . MS (m/z) : 272.0/274 (M-56+1)  +
b) tert-Butyl 3- (4-bromophenyl) -3- ( (methylsulfonyl) oxy) azetidine-1-carboxylate
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 2Cl 2 (30 mL) , and cooled to 0℃. 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 2Cl 2 twice . The organic layers were combined and dried over anhydrous Na 2SO 4 , concentrated to give the target product as a yellow oil (1.23 g, 3.04mmol) , which was used for the next step without further purification. MS (m/z) : 210.0/212.0 (M-195)  +
c) tert-Butyl 3-azido-3- (4-bromophenyl) azetidine-1-carboxylate
tert-Butyl 3- (4-bromophenyl) -3- ( (methylsulfonyl) oxy) azetidine-1-carboxylate (1.23 g, 3.04 mmol) and NaN 3 (392 mg, 6.04 mmol) were dissolved in 15 mL of DMF in sequence. The mixture was stirred at 60℃ overnight. Cooled to the room temperature after reaction, and 15 mL of water was added, then extracted with CH 2Cl 2 twice. The organic layers were combined, concentrated and the resulting reside was purified by flash column chromatography (mobile phase: EtOAc/petroleum ether = 1/20～1/1) to give the target compound as a yellow oil (700 mg) , yield: 65%. MS (m/z) : 210.0/212.0 (M-142)  +
d) tert-Butyl 3- (4-bromophenyl) -3- ( (triphenyl-λ 5-phosphaneylidene) amino) azetidine-1-carboxylate
tert-Butyl 3-azido-3- (4-bromophenyl) azetidine-1-carboxylate (700 mg, 1.97 mmol) and PPh 3 (774 mg, 2.96 mmol) were dissolved in 30 mL of THF, and then 1 mL of ammonia was added. The mixture was stirred overnight at the room temperature. After reaction, the mxiture was concentrated and the resulting reside was purified by flash column chromatography (mobile phase: EtOAc/petroleum ether = 1/10～1/1) to give the target compound as a white solid (500 mg) , yield: 43.1%. MS (m/z) : 587.2/589.2 (M+1)  +
e) tert-Butyl 3- (4- (5-chloropyridin-2-yl) phenyl) -3- ( (triphenyl-λ 5-phosphaneylidene) amino) azetidine-1-carboxylate
tert-Butyl 3- (4-bromophenyl) -3- ( (triphenyl-λ 5-phosphaneylidene) amino) azetidine-1-carboxylate (386 mg, 0.66 mmol) , 5-chloro-2- (tributylstannyl) pyridine (317 mg, 0.79 mmol) and Pd (PPh 3)  4 (76 mg, 0.066 mmol) were dissolved in 30 mL of dioxane and stirred at 110℃ overnight under N 2. After reaction, the mixture was cooled and quenched with 5 mL of aqeous solution of KF, and then oncentrated and the residue was purified by flash column chromatography (mobile phase: MeOH/H 2O=1～100%) to give the compound as a yellow solid (270 mg, yield: 66.0%) . MS (m/z) : 620.3 (M+1)  +.
f) tert-Butyl 3-amino-3- (4- (5-chloropyridin-2-yl) phenyl) azetidine-1-carboxylate
tert-Butyl 3- (4- (5-chloropyridin-2-yl) phenyl) -3- ( (triphenyl-λ 5-phosphaneylidene) amino) azetidine-1-carboxylate (270 mg, 0.44 mmol) was dissolved in MeOH (5 mL) , and 2 mL of aqueous solution of NaOH (2 mol/L) was added. The mixture was stirred overnight at the room temperature. After reaction, the mxiture was concentrated and the residue was purified by flash column chromatography (mobile phase: MeOH/H 2O=1～100%) to give the target compound as a yellow solid (140 mg, yield: 88.4%) . MS (m/z) : 360.1 (M+1)  +.
g) tert-Butyl 3- (4- (5-chloropyridin-2-yl) phenyl) -3- (4-ethynylbenzamido) azetidine-1-carboxylate
tert-Butyl 3-amino-3- (4- (5-chloropyridin-2-yl) phenyl) azetidine-1-carboxylate (140 mg, 0.39 mmol) was dissolved in DMF (5 mL) . 4-Ethynylbenzoic acid (57 mg, 0.39 mmol) , HATU (222 mg, 0.59 mmol) and DIEA (100 mg, 0.78 mmol) were added in sequence. The reaction was stirred overnight at the room temperature. After reaction, the mxiture was concentrated and the residue was purified by flash column chromatography (mobile phase: MeOH/H 2O=1～100%) to give the target compound as a yellow solid (100 mg) , yield: 53.8%. MS (m/z) : 488.0 (M+1)  + .
h) N- (3- (4- (5-chloropyridin-2-yl) phenyl) azetidin-3-yl) -4-ethynylbenzamide
tert-Butyl 3- (4- (5-chloropyridin-2-yl) phenyl) -3- (4-ethynylbenzamido) azetidine-1-carboxylate (100 mg, 0.21 mmol) was dissolved in 1mL of TFA. The mixture was stirred for 5 min at the room temperature, and then concentrated and the resiude was purified by flash column chromatography (mobile phase: MeOH/H 2O=1～100%) to give the target compound as a yellow solid (48 mg) , yield: 59.1%. MS (m/z) : 388.1 (M+1)  +.  1H NMR (399 MHz, CD 3OD) δ 8.57 (m, 1H) , 8.00 (m, 2H) , 7.89-7.83 (m, 4H) , 7.68 (m, 2H) , 7.56 (m, 2H) , 4.17 (dd, J = 34.1, 9.4Hz, 4H) , 3.69 (s, 1H) .
The following compounds were prepared according to the procedure of Compound 325 using the corresponding reagents and intermediates under appropriate conditions that will be recognized by one skilled in the art:
Figure PCTCN2020090598-appb-000185
Example 5:
Compound 327
N- (1- (4- (6-acetamidopyridin-3-yl) phenyl) cyclopropyl) -4-ethynylbenzamide
Figure PCTCN2020090598-appb-000186
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℃. 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. After reaction, the mixture was concentrated and the residue was purified by flash column chromatography (mobile phase: MeOH/H 2O =10～100%) to give the target compound as a yellow solid (60 mg) , yield: 53.7%. MS (m/z) : 396.2 (M+1)  +.  1H NMR (399 MHz, DMSO-d 6) δ 10.54 (s, 1H) , 9.30 (s, 1H) , 8.57 (d, J = 2.5 Hz, 1H) , 8.11 (d, J = 8.7 Hz, 1H) , 8.01 (dd, J = 8.7, 2.5 Hz, 1H) , 7.95-7.82 (m, 2H) , 7.64-7.50 (m, 4H) , 7.26 (d, J = 8.5 Hz, 2H) , 4.37 (s, 1H) , 2.08 (s, 3H) , 1.28 (s, 4H) .
Example 6
Determination of IDO1 activity in SKOV-3 cells
1. Reagents and materials
SKOV-3 cells: SKOV-3 cells were purchased from American Standard Biological Collection Center ATCC Cell Bank, and were cultured at 37℃ 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;
Human IFNγ: R&D Systems, Catalog number: 285-IF-100;
L-tryptophan (L-Trp) : Sigma-Aldrich, Catalog number: T0254;
trichloroacetic acid (6.1N) : Sigma-Aldrich, Catalog number: T0699;
p-dimethylaminobenzaldehyde: Sigma-Aldrich, Catalog number: 156477;
L-Kynurenine: Sigma-Aldrich, Catalog number: K8625;
Microplate reader: SpectraMax M2, Molecular Devices;
96-well plate: Beckman Dickinson, Catalog number: 353072.
2. Solution preparation
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 μM, respectively.
3. Method
When the inhibitor activity of compounds were determined, 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 μL per well, and incubated in a cell culture incubator at 5%CO 2 and 37℃. After the cell adherence, the test compound was diluted 3 times in serum-free DMEM medium to the corresponding concentration on the same day, and then 10 μL/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 μM, DMSO final concentration: 0.5%) or 10 μL/well control solution (0.5%DMSO) were added to the 180 μL/well cell culture system, then 10 μL/well of mixture of human IFNγ (final concentration of 50 ng/mL) and L-Trp (final concentration of 50 μmol/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℃ for 48 hours.
140 μL of the supernatant per well of the 96 well plate was transferred to a new 96 well plate. Then 10 μL of trichloroacetic acid was mixed into each well and incubated at 65℃ for 20 min in  water bath. The reaction mixture was then centrifuged at 1200 g for 10min, 100 μL of the supernatant per well was transferred to another new 96 well plate and mixed with 100 μL of 20 g/L of p-dimethylaminobenzaldehyde in glacial acetic acid per well.
4. Detection
After mixing for 1 minute, 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-γ 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:
Figure PCTCN2020090598-appb-000187
wherein:
· [kynurenine]  Compound: represents the concentration of kynurenine in the cell well containing human IFN-γ and the test compound.
· [kynurenine]  IFN-γ: represents the concentration of kynurenine in the cell well containing only human IFN-γ.
5. Results
Figure PCTCN2020090598-appb-000188
Figure PCTCN2020090598-appb-000189
Figure PCTCN2020090598-appb-000190
Figure PCTCN2020090598-appb-000191
Example 7
Determination of IDO1 activity in human whole blood
1. Reagents and materials
Human peripheral blood: routinely incubated at 37℃ in cell incubator supplied with 5%CO 2
RPMI -1640: GIBCO, catalog number 11875-093
Human IFNγ: R&D Systems, catalog number 285-IF-100
Salmonella typhimurium (LPS) : Calbiochem, catalog number 437650
Tryptophan (L-Trp) : Sigma-Aldrich, catalog number T0254
Kynurenine (L-Kynurenine) : Sigma-Aldrich, catalog number K8625
96-well plate: Beckman Dickinson, Catalog number: 353072
Dimethyl sulfoxide (DMSO) : Sigma-Aldrich, catalog number 34869-4L.
2. Solution preparation
Preparation of Standard Curve Solution: 5 μL of the standard curve working solution was added to 45 μL 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 μM.
3. Method
When the activity of compounds were determined, the whole blood was seeded in a 96 well plates at 180 μL/well, and incubated in a cell incubator at 5%CO 2 and 37 ℃. Half an hour later, the test compound was diluted 3 times in serum-free RPMI-1640 medium to the corresponding concentration, and then 10 μL/well of different concentrations of the diluted compound (the final concentration: 0.30, 0.10, 0.033, 0.011, 0.0037 and 0.0012 μM, and the final concentration of DMSO was 0.25%) or 10 μL/well control solution (0.25%DMSO) were added to the 180 μL/well human whole blood culture system, then 10 μL/well of mixture of human IFNγ (final concentration of 150 ng/mL) , LPS (final concentration of 150 μmol/L) and L-Trp (final concentration of 50 μmol/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℃ for 24 hours.
After the 96 well plate was centrifuged for 10min, 70 μL of the plasma supernatant per well was transferred to a new 1.5mL of tube, and then was detected.
4. Detection
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-γ control well –control solution well) } ×100%, wherein:
Test compound well : represents the concertration of Kynurenine in human whole blood containing human IFN-γ and the test compound.
Human IFN-γ control well: represents the concertration of Kynurenine in human whole blood containing only human IFN-γ.
Control solution well: represents the concertration of Kynurenine in uncultured human whole blood plasma.
5. Results
Figure PCTCN2020090598-appb-000192
Example 8
Determination of CYP enzyme inhibitory activity of compounds
1. Materials and methods
1.1 Materials
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. ) . Internal standard: 7-hydroxycoumarin (for CYP2C9) and phenacetin (for CYP2D6) were the products of Sigma-Aldrich (U.S.A. ) . Acetonitrile and methanol (HPLC grade) were purchased from Fisher Scientific Inc. (U.S.A. ) , and formic acid (HPLC grade) was purchased from Sigma-Aldrich (U.S.A. ) . DMSO, EDTA and MgCl 2 were purchased from Sinopharm Chemical Reagent Co., Ltd. Pure water for analysis was prepared by Millipore ultrapure water system.
1.2 Incubation Condition
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℃ 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 μL. 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 ℃ in water bath to start the reaction. After incubation at 37 ℃ for 20 minutes, 125 μL 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 ℃ for 10 min, and the supernatant was transferred and injected for LC-MS/MS analysis.
1.3 Data analysis
Analyst 1.4.2 (Applied Biosystem, USA) software was used to integrate substrate metabolites and internal standards. The ratio of the peak areas of the substrate metabolite to the internal standard was used for calculation. The formula for calculating the percentage of remaining enzyme activity was as following: 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%
Table 1. Incubation conditions
Figure PCTCN2020090598-appb-000193
Table 2. The constitution of incubation system
Figure PCTCN2020090598-appb-000194
By the approach described as above, the inhibitory effects of some of the compounds disclosed in the present invention were shown as below.
Table 3
Compound No. 2D6 2C9
1 53.4% 52.1%
98 62.9% 78.2%
138 56.6% 54.9%
172 21.8% 21.7%
Example 9
Using Caco-2 cell monolayer model to evaluate the membrane permeability of tested compounds
1. Materials
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
Figure PCTCN2020090598-appb-000195
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) was purchased from Sinopharm Chemical Reagent Co., China. Deionized water (resistivity ≥18 MΩ·cm) was produced by
Figure PCTCN2020090598-appb-000196
purification system in house. HTS
Figure PCTCN2020090598-appb-000197
24-well cell culture system containing an array of 24 inserts with permeable supports (called A side below, polycarbonate membrane, pore size: 0.4 μm, 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.
2. Solution preparation
Preparation of 10 mM stock solution of test compound: a certain amount of the test compound was weighed and dissolved with DMSO to get 10 mM stock solution.
Preparation of propranolol stock solution (internal standard for positive control) : a certain amount of propranolol hydrochloride was weighed and dissolved with DMSO to get 10 mM stock solution.
Preparation of fluorescein sodium stock solution: a certain amount of fluorescein sodium salt was weighed and dissolved with DMSO to get 10 mM stock solution.
Preparation of 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.
Solution 1: 495 mL HBSS+ 5 mL HEPES + 5 μL 10 mM propranolol stock solution.
Dilution 1: 400 mL deionized water + 400 mL ACN+ 8 μL 10 mM propranolol stock solution + 16 μL 50 mM cortisone stock solution.
Preparation of test solution: 4.99 mL Solution 1+ 5 μL 10 mM stock solution of test compound + 5 μL 10 mM fluorescein sodium stock solution.
3. Experimental method
Firstly, after the
Figure PCTCN2020090598-appb-000198
culture system was incubated for 21 days in a cell culture incubator, culture mediums from both A and B sides of the plate were removed, and then the plate was rinsed once with Solution 1 at 37℃. After that, Solution 1 was transferred to both A and B sides of the plate (0.3 mL to the A side, 1.0 mL to the B side) , which was then put into the shaker for the pre-incubation of 30 min at 37℃. After this pre-incubation, TEER (transepithelial electrical resistance) values were measured, and the monolayers were considered as qualified and used for the subsequent transport test only if the TEER reached 150 Ω·cm 2. For the incubation, to determine the A→B transport, 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 μL 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.
0 h samples and samples from donor side were diluted to 1/20 with Solution 1, and 200 μL of the diluted samples and 150 μL undiluted samples from receiver side were further diluted to 1/2 with Dilution 1. Finally, 150 μL of the samples were transferred for concentration determination and detection of fluorescence intensity.
4. Analytical method and data process
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 μL 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.
The equations for calculating parameters were shown as below:
Figure PCTCN2020090598-appb-000199
Figure PCTCN2020090598-appb-000200
Efflux Ratio = P app, B→A/ Papp, A→B
Figure PCTCN2020090598-appb-000201
P app: apparent permeability coefficient;
P app, B→A: apparent permeability coefficient of B→A;
P app, A→B: apparent permeability coefficient of A→B;
P app, LY: apparent permeability coefficient of fluorescence;
C r, t: compound concentration of receiver side at time t;
C d, t: compound concentration of donor side at time t;
C d, 0: compound concentration of donor side at time zero;
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) ;
S: surface area of the cell monolayer, 0.33 cm 2;
t: incubation time (sec. ) ;
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.
By the approach described as above, the membrane permeability of some of the compounds disclosed in the invention were shown as below.
Table 4
Compound No. P app, A→B (10 -6cm/sec) P app, B→A (10 -6cm/sec)
1 6.43 4.51
98 11.4 8.76
138 36.6 26.9
172 38.1 41.6

Claims (49)

  1. A compound of formula (I) :
    Figure PCTCN2020090598-appb-100001
    or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein
    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 6R 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) ;
    Figure PCTCN2020090598-appb-100002
    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) ;
    Figure PCTCN2020090598-appb-100003
    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’ , - (C 1-6 alkyl)  n-NR 1’ R 2’ C (O) R 3’ , - (C 1-6 alkyl)  n-C (O) R 3’ , - (C 1-6 alkyl)  n-C (O) OR 4’ , - (C 1-6 alkyl)  n-OR 5’ , - (C 1-6 alkyl)  n-S (O)  mNR 1’ R 2’ , - (C 1-6 alkyl)  n-NR 1’ R 2’S (O)  mR 6’ , - (C 1-6 alkyl)  n-S (O)  mR 6’ , and - (C 1-6 alkyl)  n-SR 7’ ; in which each of said phenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl is optionally substituted with one or more groups chosen from halo, -CN, -OH, -NH 2, C 1-6 haloalkyl, -O (C 1-6 haloalkyl) , C 1-6 alkyl, -O (C 1-6 alkyl) , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl)  2, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl;
    n is 0 or 1;
    m is 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.
  2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, X is CR 3; Y is CR 4.
  3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, R 1, R 2, R 3, and R 4 are independently chosen from H or halo.
  4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, R 1, R 2, R 3, and R 4 are all H.
  5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, X is CH; Y is N.
  6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, X is N; Y is N.
  7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, p is 0, Z is CR 6R 7.
  8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, Z is CH 2.
  9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, p is 1, Z is CHR 6.
  10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, R 6 is H, -OH, C 1-6 alkyl, or -O (C 1-6 alkyl) .
  11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, p is 1, Z is NR 5.
  12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, R 5 is H or C 1-6 alkyl.
  13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, p is 1, Z is O.
  14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100004
    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) .
  15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100005
    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) .
  16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100006
    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) .
  17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100007
    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.
  18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100008
    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.
  19. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100009
    is phenyl, which is substituted with ethynyl.
  20. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100010
    is phenyl, which is substituted with halo.
  21. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100011
    is phenyl, which is substituted with -OCF 3 or -OCHF 2.
  22. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100012
    is phenyl, which is substituted with -CN.
  23. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, the compound is formula (I-1) ,
    Figure PCTCN2020090598-appb-100013
    in which 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) ; X, Y, Z, and
    Figure PCTCN2020090598-appb-100014
    are defined as of any one of claims 1-6.
  24. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, the compound is formula (I-2) ,
    Figure PCTCN2020090598-appb-100015
    in which 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) ; X, Y, Z, and
    Figure PCTCN2020090598-appb-100016
    are defined as of any one of claims 1-6.
  25. The compound according to claims 23 or 24, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, R a is chosen from F, Cl, Br, -CN, methyl, ethyl, ethynyl, -CF 3, -OCF 3, -OCHF 2, or -OCH 3.
  26. The compound according to claims 23 or 24, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, R a is ethynyl.
  27. The compound according to claims 23 or 24, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, R a is halo.
  28. The compound according to claims 23 or 24, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, R a is -CN.
  29. The compound according to any one of claims 1-28, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100017
    is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with one or more groups chosen from:
    1) halo;
    2) -NO 2;
    3) oxo;
    4) - (C 1-6 alkyl)  n-CN;
    5) C 1-6 alkyl;
    6) C 1-6 haloalkyl;
    7) C 3-6 cycloalkyl;
    8) - (C 1-6 alkyl)  n-4-6 membered heterocyclyl;
    9) 5-6 membered heteroaryl;
    10) - (C 1-6 alkyl)  n-NR 1’ R 2’ ;
    11) -CONR 1’ R 2’ ;
    12) -NR 1’ R 2’ C (O) R 3’ ;
    13) -C (O) OR 4’ ;
    14) - (C 1-6 alkyl)  n-OR 5’ ;
    15) -S (O)  2NR 1’ R 2’ ; or
    16) -NR 1’ R 2’S (O)  2R 6’ ;
    in which 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 is 0 or 1;
    R 1’ , R 2’ , R 3’ , R 4’ , R 5’ , and R 6’a re 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’a nd R 2’ together with the N atom they are attached to form a 4-6 membered heterocyclic ring.
  30. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100018
    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) .
  31. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100019
    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) .
  32. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100020
    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) .
  33. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100021
    is
    Figure PCTCN2020090598-appb-100022
    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) .
  34. The compound according to claim 33, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100023
    is
    Figure PCTCN2020090598-appb-100024
    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) .
  35. The compound according to claim 33, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100025
    is
    Figure PCTCN2020090598-appb-100026
    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) .
  36. The compound according to claim 35, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100027
    is
    Figure PCTCN2020090598-appb-100028
    each of which is substituted with - (C 1-6 alkyl) -OH and C 1-6 haloalkyl.
  37. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100029
    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’a re independently chosen from H, C 1-6 alkyl, or C 1-6 haloalkyl.
  38. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100030
    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) .
  39. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100031
    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) .
  40. The compound according to claim 38, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100032
    is
    Figure PCTCN2020090598-appb-100033
    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) .
  41. The compound according to claim 39, or a pharmaceutically acceptable salt thereof, and/or deuterates, solvates, racemic mixtures, enantiomers, diasteromers, and tautomers thereof, wherein, 
    Figure PCTCN2020090598-appb-100034
    is
    Figure PCTCN2020090598-appb-100035
    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) .
  42. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is chosen from Compounds 1-331.
  43. A pharmaceutical composition comprising the compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.
  44. A use of a compound of any one of claims 1-42 or 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 in a subject.
  45. The use of claim 44, wherein, the disease mediated by IDO or at least in part by IDO is cancer, an autoimmune disease, obesity, or an obesity-related disease.
  46. The use of claim 45, wherein, the cancer is chosen from solid tumor or hematologic malignancy; the autoimmune disease is chosen from arthritis (such as rheumatoid arthritis, collagen induced arthritis) .
  47. The use of claim 46, wherein, the cancer is chosen from skin cancer (including melanoma and basal carcinoma) , lung cancer (including 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 (including Kaposi's sarcoma) , leukemia, lymphoma, or myeloma.
  48. A combination comprising the compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.
  49. The combination of claim 48, wherein, said additional therapeutic agent is an immune checkpoint inhibitor, a targeted therapeutic agent, or a chemotherapeutic agent.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022037585A1 (en) * 2020-08-18 2022-02-24 Hutchison Medipharma Limited Pyrimidinone compounds and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009073620A2 (en) * 2007-11-30 2009-06-11 Newlink Genetics Ido inhibitors
WO2015150097A1 (en) * 2014-04-04 2015-10-08 Iomet Pharma Ltd Indole derivatives for use in medicine
WO2016054804A1 (en) * 2014-10-10 2016-04-14 Merck Sharp & Dohme Corp. Substituted pyrimidines as inhibitors of hif prolyl hydroxylase
WO2019099294A1 (en) * 2017-11-14 2019-05-23 Merck Sharp & Dohme Corp. Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009073620A2 (en) * 2007-11-30 2009-06-11 Newlink Genetics Ido inhibitors
WO2015150097A1 (en) * 2014-04-04 2015-10-08 Iomet Pharma Ltd Indole derivatives for use in medicine
WO2016054804A1 (en) * 2014-10-10 2016-04-14 Merck Sharp & Dohme Corp. Substituted pyrimidines as inhibitors of hif prolyl hydroxylase
WO2019099294A1 (en) * 2017-11-14 2019-05-23 Merck Sharp & Dohme Corp. Novel substituted biaryl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022037585A1 (en) * 2020-08-18 2022-02-24 Hutchison Medipharma Limited Pyrimidinone compounds and uses thereof

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