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WO2021191376A1 - Composés de triazolone - Google Patents

Composés de triazolone Download PDF

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Publication number
WO2021191376A1
WO2021191376A1 PCT/EP2021/057800 EP2021057800W WO2021191376A1 WO 2021191376 A1 WO2021191376 A1 WO 2021191376A1 EP 2021057800 W EP2021057800 W EP 2021057800W WO 2021191376 A1 WO2021191376 A1 WO 2021191376A1
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WO
WIPO (PCT)
Prior art keywords
methyl
triazolo
amino
pyrimidin
phenyl
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PCT/EP2021/057800
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English (en)
Inventor
Michelle Laurae LAMB
Yun Zhang
Bo Peng
Jason Shields
Ariamala Gopalsamy
Andrew Pike
Kurt Pike
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2021191376A1 publication Critical patent/WO2021191376A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Adenosine modulates of a number of physiological functions. Intracellularly, adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle; extracellular adenosine engages in intercellular signaling. For example, extracellular adenosine is a potent immunosuppressor, preventing an overzealous immune response during inflammation and infection. Adenosine also acts on other systems, including the cardiovascular system, and the central nervous system.
  • adenosine The action of adenosine is mediated by a family of G-protein coupled receptors. At least four subtypes of adenosine receptors have been identified: AIR, A2aR, A2bR, and A3R.
  • the AIR and A3 subtypes inhibit the activity of the enzyme adenylate cyclase, whereas the A2a and A2b subtypes stimulate the activity of the same enzyme, thereby modulating the level of cyclic AMP in cells.
  • A2a and A2b adenosine receptors are critical regulatory mechanisms that protects tissues against excessive immune reactions. In tumors, this pathway is hijacked and hinders antitumor immunity, promoting cancer progression.
  • the tumor microenvironment contains high levels of extracellular adenosine.
  • the adenosine receptor notably A2aR and A2bR, have been identified as targets for cancer therapies.
  • adenosine receptor antagonists Numerous adenosine receptor antagonists have been reported.
  • international patent application WO 2006/138734 discloses triazolopyrimidine cannabinoid receptor 1 (CB-1) antagonists.
  • WO 2008/002596 and WO 2009/111449 disclose adenosine A2a receptor antagonists which include a triazolone moiety.
  • WO 2012/038980 discloses fused tricyclic compounds as adenosine receptor antagonists.
  • WO 2016/161282 discloses heterocyclic compounds as LSD1 inhibitors.
  • WO 2018/166493 discloses heteroaryl[4,3-c]pyrimidine-5-amine derivatives for use as A2a receptor antagonists.
  • a compound of Formula (I): or a pharmaceutically acceptable salt thereof, is provided, wherein: ring A is:
  • R 1 is H, Ci-6alkyl, or C3-6cyclolkyl, wherein alkyl and cycloalkyl are each optionally substituted with one or more substituents independently selected from -OR a , halo and cyano; each R 2 , independently, is halo, cyano, Ci-3alkyl, -0-Ci-3alkyl, -CCkR 3 , or -NR 7 R 8 ; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR a , halo, and cyano;
  • R 3 is aryl optionally substituted with from one to three substituents selected from halo, cyano, -R a , and -OR a ;
  • R 4 is -CH2-R 5 ;
  • a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, is provided.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the treatment of a disease or condition mediated by the adenosine receptor, such as cancer, is provided.
  • the disease or condition mediated by the adenosine receptor is lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor.
  • R 1 is H, Ci-6alkyl, or C3-6cyclolkyl, wherein alkyl and cycloalkyl are each optionally substituted with one or more substituents independently selected from -OR a , halo and cyano; each R 2 , independently, is halo, cyano, Ci-3alkyl, -0-Ci-3alkyl, -CCkR 3 , or -NR 7 R 8 ; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR a , halo, and cyano;
  • R 3 is aryl optionally substituted with from one to three substituents selected from halo, cyano, -R a , and -OR a ;
  • R 4 is -CH2-R 5 ;
  • R 1 can be H, -CH3, or -CH2CN.
  • Each R 2 independently, can be H or -CH3.
  • R 5 can be Ci-3alkyl.
  • R 5 can be heterocyclyl.
  • R 5 can be tetrahydrofuranyl.
  • R 5 can be heteroaryl.
  • R 5 can be pyridyl or oxazolyl.
  • R 5 can be substituted by one or to four groups R 6 , wherein each R 6 , independently, can be halo, -OR a , or Ci- 6 alkyl; wherein alkyl can be optionally substituted with one or more substituents independently selected from halo.
  • Each R 6 independently, can be halo, methyl, difluoromethyl, trifluoromethyl, or methoxy.
  • a pharmaceutical composition can include the compound of Formula (I), and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be for use of the compound of any one of claims 1 to 12 in the treatment of a disease or condition mediated by the adenosine receptor, for example, cancer.
  • the disease or condition mediated by the adenosine receptor can be lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor.
  • halo refers to fluoro, chloro, bromo and iodo.
  • alkyl refers to a fully saturated straight-chain or branched aliphatic group, having the number of carbon atoms specified, if designated (e.g., Ci-ioalkyl refers to an alkyl group having one to ten carbons). Examples include as methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. If no size is designated, “alkyl” refers to a group having from 1 to 10 carbon atoms.
  • alkenyl refers to an unsaturated straight-chain or branched aliphatic group, which contain at least one carbon-carbon double bond, and having the number of carbon atoms specified, if designated.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methylbut-l-enyl, 1-pentenyl and 4-hexenyl. If no size is designated, “alkenyl” refers to a group having from 2 to 10 carbon atoms.
  • alkynyl refers to an unsaturated straight-chain or branched aliphatic group, which contain at least one carbon-carbon triple bond, and having the number of carbon atoms specified, if designated.
  • alkynyl groups include, but are not limited to, ethynyl, propargyl, and but-2-ynyl. If no size is designated, “alkynyl” refers to a group having from 2 to 10 carbon atoms.
  • Alkenyl and alkynyl groups can contain more than one unsaturated bond, or a mixture of double and triple bonds.
  • a cycloalkyl group can contain fused and/or bridged rings, including where the fused or bridged ring(s) are cycloalkyl.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, cyclohexynyl, cycloheptyl, norbornyl, 4-oxocyclohex-l-yl and 3-oxocyclohept-5-en-l-yl.
  • a ring nitrogen or a ring sulfur atom independently, can optionally be oxidized, including for example -N(O)-, -S(O)-, or - S(0) 2 -.
  • a ring nitrogen atom in a heterocyclyl group can optionally be quaternized, for example, -N + (CH3)2-.
  • a heterocyclyl group can contain fused and/or bridged rings, including where the fused or bridged ring(s) are cycloalkyl or heterocyclyl groups.
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorphonlinyl, dihydropyranyl, dihydropyridinyl, tetrahydropyranyl, octahydroquinolinyl, octahydroindolizinyl, and decahydroquinolinyl.
  • aryl refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group containing from 6 to 14 ring atoms.
  • Aryl may contain fused rings, including aryl rings fused to cycloalkyl, heterocyclyl, or aryl rings. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, and dihydro- lH-indenyl.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 ring atoms, where from 1 to 4 ring atoms are independently N, O, or S.
  • a ring nitrogen or a ring sulfur atom can optionally be oxidized, including for example -N(O)-, -S(O)-, or -S(0)2-.
  • a heteroaryl group can contain fused and/or bridged rings, including where the fused or bridged ring(s) are cycloalkyl, heterocyclyl, aryl, or heteroaryl groups.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, pyridyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl, 5,6,7,8-tetrahydroquinolinyl, benzofuranyl, pyrrolopyridinyl, pyrrolopyrimidinyl, triazinyl, and tetrazolyl.
  • multicyclic ring system refers to a cycloalkyl, heterocyclyl, aryl, or heteroaryl group which includes two or more fused and/or bridged rings.
  • pharmaceutically acceptable salts refers those salts of the compounds of Formula (I) which retain the biological activity of the free compounds and which can be administered as a pharmaceutical to humans and/or animals.
  • the desired salt of a basic functional group of a compound may be prepared by treating the compound with an acid.
  • suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • suitable organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid.
  • the desired salt of an acidic functional group of a compound can be prepared by treating the compound with a base.
  • suitable inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts.
  • organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, and triethylamine salts.
  • Compounds of Formula (I) may contain the stated atoms in any of their isotopic forms.
  • embodiments of the invention that may be mentioned include those in which: (a) the compound of Formula (I) is not isotopically enriched or labelled with respect to any atoms of the compound; and (b) the compound of Formula (I) is isotopically enriched or labelled with respect to one or more atoms of the compound.
  • Illustrative compounds of Formula (I), or a pharmaceutically acceptable salt thereof include:
  • Compounds of Formula (I) can be adenosine receptor antagonists, i.e. antagonists of one or more of AIR, A2aR, A2bR, and A3R.
  • adenosine receptor antagonist refers to a compound, e.g., a compound of Formula (I) that binds to the adenosine receptor and antagonizes its activity.
  • the compound of Formula (I) is a selective adenosine receptor antagonist.
  • selective refers the property of a compound of Formula (I) that is an adenosine receptor antagonist but is substantially inactive at other biological targets.
  • substantially inactive describes a compound that (i) has significantly weaker affinity for a given receptor as compared to its affinity for the adenosine receptor; (ii) does not show substantial agonist or antagonist activity at a given receptor; or both (i) and (ii).
  • selective adenosine receptor antagonist refers to a compound that shows binding affinity for one or more adenosine receptor subtypes that is at least 100 times greater, at least 1,000 times greater, or at least 10,000 times greater than its affinity for a given receptor.
  • the ratio of binding Ki values can be at least 100, at least 1,000, or at least 10,000.
  • a selective adenosine receptor antagonist can be substantially inactive toward other G-protein coupled receptors, such as the cannabinoid receptors, referred to as CB-1 and CB-2.
  • a compound of Formula (I) can have a binding affinity Ki for A2aR of, e.g., 100 nM or less, 10 nM or less, or 1 nM or less.
  • a compound of Formula (I) can have a binding affinity Ki for A2bR of, e.g., 100 nM or less, 10 nM or less, or 1 nM or less.
  • a compound of Formula (I) can have a binding affinity Ki for CB-1 of, e.g., 1,000 nM or greater, 10,000 nM or greater, 13,000 nM or greater.
  • a compound of Formula (I) can be a selective adenosine receptor antagonist with respect to CB-1.
  • a compound of Formula (I) can be active as an adenosine receptor antagonist but substantially inactive at CB-1.
  • the compounds of Formula (I) can also be selective between the different subtypes of adenosine receptor.
  • the compounds of Formula (I) are A2aR-selective; A2bR-selective; or dual A2aR/A2bR-selective.
  • the selectivity is determined in a binding affinity assay. In other embodiments, the selectivity is determined as an ICso value in a cell-based assay, e.g., a cell- based cAMP accumulation assay.
  • a cell-based assay e.g., a cell- based cAMP accumulation assay.
  • concentrations of adenosine 1 micromolar and above, 2 micromolar and above, 5 micromolar and above, 10 micromolar and above, or 100 micromolar and above.
  • a dual A2aR/A2bR antagonist shows an ICso in a cell based assay for A2aR that is less than 20 nM and an ICso in a cell based assay for A2bR that is less than 20 nM.
  • the ratio of an ICso in a cell based assay for A2aR to ICso for A2bR is less than 100, or less than 25.
  • a pharmaceutical composition which includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl / hydroxybenzoate; and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Compounds of Formula (I) are useful in the treatment of diseases or conditions mediated by the adenosine receptor.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of diseases or conditions mediated by the adenosine receptor.
  • the disease or condition is mediated by A2aR; in other embodiments, by A2bR; in still other embodiments, by both A2aR and A2bR.
  • disease or conditions mediated by the adenosine receptor include cancer, including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor; movement disorders, including Parkinson’s disease and Huntington’s disease; and attention disorders, including attention deficit disorder and attention deficit-hyperactivity disorder.
  • Other diseases and conditions mediated by the adenosine receptor are known.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition mediated by the adenosine receptor.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor).
  • cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition mediated by the adenosine receptor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.
  • cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor
  • cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, mela
  • a method of treating a disease or condition mediated by the adenosine receptor which includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment.
  • a method of treating cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor
  • cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor
  • a method of treating a disease or condition mediated by the adenosine receptor which includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.
  • a method of treating cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor
  • cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of a disease or condition mediated by the adenosine receptor.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor).
  • cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of a disease or condition mediated by the adenosine receptor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.
  • cancer including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, renal cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma, or other solid tumor, wherein the compound is a selective adenosine receptor antagonist with respect to CB-1.
  • Scheme 2 illustrates the conversion of compounds of Formula (IV) into the intermediate 7-substituted-5-amino-8-bromo-[l,2,4]triazolo[4,3-c]pyrimidin-3-one compounds of Formula (V). Briefly, the compound of Formula (IV) is treated with triphosgene to effect closure of the triazolone ring, followed by bromination with (CFb ⁇ PhlSCBn . Scheme 2
  • Scheme 3 a illustrates the conversion of compounds of Formula (V) into compound of Formula (I).
  • the alkylation of the compound of Formula (V) with R 4 can be carried out using a variety of methods, for example, Mitsonobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; or alcohol chlorination followed by an alkylation reaction.
  • a compound such as R 4 -Br may be used in a direct alkylation of the compound of Formula (V).
  • R 4 can be further modified after alkylation of the compound of Formula (V).
  • Scheme 3b illustrates an alternate route for the conversion of compounds of Formula (V) into compounds of Formula (I).
  • [Pg] represents a suitable reagent for installing the protecting group denoted Pg.
  • the alkylation of the compound of Formula (Va) with R 4 can be carried out using a variety of methods, for example, Mitsonobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; alcohol chlorination followed by an alkylation reaction.
  • a compound such as R 4 -Br may be used in a direct alkylation of the compound of Formula (Va).
  • R 4 can be further modified after alkylation of the compound of Formula (V).
  • a compound of Formula (I) can be further modified, for example, to form a different compound of Formula (I).
  • LC-MS was carried out using a Waters UPLC fitted with a Waters SQD mass spectrometer or Shimadzu LC- 20AD LC-20XR LC-30AD with a Shimadzu 2020 mass spectrometer.
  • Reported molecular ions correspond to [M+H]+ unless otherwise noted; for molecules with multiple isotopic patterns (Br, Cl, etc.) the reported value is the one obtained for the lowest isotope mass unless otherwise specified.
  • Flash chromatography was performed using straight phase flash chromatography on a SPlTM Purification system from BiotageTM, CombiFlash ® Rf from ISCO or on Gilson system from Thermo Fisher using normal phase silica FLASH+TM (40M, 25M or 12 M) or SNAPTM KP- Sil Cartridges (340, 100, 50 or 10), Flash Column silica-CS columns from Agela, with C18-flash columns or standard flash chromatography. In general, all solvents used were commercially available and of analytical grade. Anhydrous solvents were routinely used for reactions. Phase Separators used in the examples are ISOLUTE® Phase Separator columns. The intermediates and examples named below were named using ACD/Name 12.01 from Advanced Chemistry Development, Inc. (ACD/Labs). The starting materials were obtained from commercial sources or made via literature routes.
  • UV inactive compounds an ELSD detector (Polymer Laboratories PL-ELS 2100 ICE) is connected with the above instrument.
  • Step 1 This reaction was performed as 2x 250 g batches. To a degassed suspension of phenyl boronic acid (250 g, 2.05 mol), 4,6-dichloro-2-aminopyrimidine (672 g, 4.10 mol) and K2CO3 (848 g, 6.15 mol) in CTbCN (15 L) and H2O (2 L) at room temperature was added Pd(PPh3)4 (118 g, 0.10 mol) and the resultant reaction mixture was heated to 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The residue obtained was vigorously stirred with H2O (4 L) and DCM (10 L), undissolved solids were filtered-off through a Buchner funnel and rinsed with DCM (3 L).
  • Step 2 To a stirred suspension of 4-chloro-6-phenylpyrimidin-2-amine (350 g, 1.70 mol) in EtOH (4.0 L), hydrazine hydrate (255 g, 5.1 mol) was added and the mixture was heated to 90 °C for 15 h. The reaction was concentrated under reduced pressure. The residue obtained was triturated with diethyl ether (1 L) and 10 % sodium bicarbonate solution (1 L). The solid obtained was collected by filtration through a Buchner funnel, rinsed with Diethyl ether (200 mL) and dried under vacuum to afford 4-hydrazinyl-6-phenylpyrimidin-2-amine (250 g, 73%) as an off-white solid.
  • Step 3 To a solution of 4-hydrazinyl-6-phenylpyrimidin-2-amine (250 g, 1.24 mol) in dry THF (3.0 L) under N2, cooled to -30 °C was added triphosgene (735 g, 2.48 mol) portion wise and the mixture was stirred at same temperature for 45 min. The reaction was quenched cautiously into ice cold water (10 L) with vigorous stirring. After the effervescence stopped, the reaction mass was concentrated under reduced pressure.
  • Step 4 To a suspension of 5-amino-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 0.88 mol) in DCM/MeOH 1:1 (2 L) under N2 atmosphere, CaCCh (88 g, 0.88 mol) followed by (CH3)3PhN + Bn (331 g, 0.88 mol) were added and the mixture was stirred at room temperature for 1 h.
  • Table 1 contains additional intermediates that were made following Route A from the appropriate reagents. Table 1. Characterization data for intermediate lb
  • Step 1 Diiodine (887 mg, 3.49 mmol) was added to 3-methylpent-4-en-l-ol (350 mg, 3.49 mmol) in acetonitrile (11 mL) under nitrogen. The resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with saturated aqueous Na2S2Cb solution (20 mL). The aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated to afford 2-(iodomethyl)-3-methyl- tetrahydrofuran as a yellow oil. This oil was used directly for Step 2 without further purification.
  • Step 2 5-amino-8-bromo-7-phenyl-2H-[l,2,4]triazolo[4,3-c]pyrimidin-3-one (1.070 g, 3.49 mmol) and above yellow oil was mixed with K2CO3 (483 mg, 3.49 mmol) in DMF (11.00 mL). The mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with saturated brine (50 mL), extracted with EtOAc (3 x 75 mL), the organic layer was dried over anhydrous Na2S04, filtered and evaporated to afford yellow oil. The crude product was purified by flash chromatography on silica using 0 to 20% MeOH in DCM to afford the title compound (0.162 g,
  • Step 1 A solution of diethylaminosulfur trifluoride (147 pL, 1.11 mmol) in DCM (1 mL) was added dropwise to methyl 4-oxotetrahydrofuran-2-carboxylate (100 mg, 0.69 mmol) in DCM (1 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at rt for 3 h. The reaction mixture was quenched with saturated aqueous NaHCCh (5 mL), the aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (50 mL).
  • Step 2 Lithium aluminum hydride (1.0 M in THF, 1.8 mL, 1.81 mmol) was added dropwise to a solution of methyl 4,4-difluorotetrahydrofuran-2-carboxylate (100 mg, 0.60 mmol) in THF (2 mL) at -60 °C over a period of 2 minutes under nitrogen. The resulting mixture was then stirred at rt for 3 h. The reaction mixture was quenched sequentially with water (0.09 mL), 1M NaOH (0.112 mL) and water (0.09 mL).The mixture was filtered through a pad of celite. The filtrate was partitioned between EtOAc and water.
  • Step 3 MsCl (260 pL, 3.33 mmol) was added dropwise to a solution of (4,4- difluorotetrahydrofuran-2-yl)methanol (307 mg, 2.22 mmol) and Et3N (929 pL, 6.66 mmol) in DCM (10 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at it for 2 h. The reaction mixture was diluted with EtOAc (5 mL) and washed sequentially with water (2 mL x 2). The organic layer was separated, dried over Na2SC>4, filtered and evaporated to afford crude mesylate intermediate.
  • Table 3 contains additional intermediates that were made following Route C or Route D from the appropriate reagents.
  • Example 1-1 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[5- (trifluoromethyl)oxazol-4-yl] methyl]- [1,2, 4]triazolo [4,3-c] pyrimidin-3-one l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (0.403 g,
  • Example 1-2 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl-2-((5- (trifluoromethyl)thiazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-3 5-amino-2-((3-(difluoromethyl)pyridin-2-yl)methyl)-8-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-5 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5-methyloxazol-4- yl)methyl)-7-phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one
  • Example 1-6 5-amino-2-((5-(difluoromethyl)oxazol-4-yl)methyl)-8-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-7 5-[5-amino-2-[[3-(difluoromethyl)-2-pyridyl]methyl]-7-phenyl- [l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-lH-pyridin-2-one
  • Example 1-8 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl-2-((4- (trifluoromethyl)oxazol-5-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-12 5-amino-2-((5-fluoropyridin-2-yl)methyl)-8-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-13 5-amino-8-(l-ethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5-methyloxazol-4- yl)methyl)-7-phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one
  • Example 1-14 5-[5-amino-7-(4-fluorophenyl)-2-[(5-methoxy-2-pyridyl)methyl]- [l,2,4]triazolo[l,5-c]pyrimidin-8-yl]-l-methyl-pyridin-2-one
  • Example 1-15 5-amino-7-phenyl-8-(pyridazin-4-yl)-2-((5-(trifluoromethyl)oxazol-4- yl)methyl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one
  • Example 1-16 5-amino-2-((5-cyclopropyloxazol-4-yl)methyl)-8-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-18 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5-methylisoxazol-3- yl)methyl)-7-phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one
  • Example 1-20 5-amino-2-((5-(difluoromethyl)pyridin-2-yl)methyl)-7-phenyl-8-(pyridazin- 4-yl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one
  • Example 1-21 5-amino-8-(l-cyclopropyl-6-oxo-l,6-dihydropyridin-3-yl)-2-((5- methyloxazol-4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-23 5-amino-8-(l-(difluoromethyl)-6-oxo-l,6-dihydropyridin-3-yl)-2-((5- methyloxazol-4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-28 5-amino-2-[(4-methyloxazol-5-yl)methyl]-8-(l-methyl-6-oxo-3-pyridyl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one
  • Example 1-31 2-(5-(5-amino-2-((5-methyloxazol-4-yl)methyl)-3-oxo-7-phenyl-2, 3-dihydro- [l,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-oxopyridin-l(2H)-yl)acetonitrile
  • Example 1-33 5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(l-(oxazol-4- yl)ethyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-34 2-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-amino-7-phenyl-8-(pyridazin-4- yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-35 2-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-5-amino-8-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-39 5-amino-2-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-8-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-44 5-amino-2-((5-methyloxazol-4-yl)methyl)-8-(6-oxo-l-(2,2,2-trifluoroethyl)- l,6-dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-45 5-amino-2-((l-methyl-5-(trifluoromethyl)-lH-imidazol-4-yl)methyl)-8-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-46 5-amino-8-(6-oxo-l-(2,2,2-trifluoroethyl)-l,6-dihydropyridin-3-yl)-7-phenyl- 2-((5-(trifluoromethyl)oxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-51 5-amino-7-(4-fluorophenyl)-2-((5-fluoropyridin-2-yl)methyl)-8-(pyridazin-4- yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • the title compound was prepared in a similar fashion to Example 1-1 (0.047 g, 29.4 %) as a yellow solid.
  • Example 1-55 5-amino-7-(4-fluorophenyl)-2-((5-fluoropyridin-2-yl)methyl)-8-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-56 5-amino-7-(4-fluorophenyl)-8-(5-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2- (3,3,3-trifluoropropyl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one
  • Example 1-58 5-amino-7-(4-fluorophenyl)-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2- ((5-methylisoxazol-3-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • the title compound was prepared in a similar fashion to Example 1-1 (87 mg, 40.8 %) as a yellow solid.
  • Example 1-60 (R)-5-amino-7-(4-fluorophenyl)-8-(pyridazin-4-yl)-2-((tetrahydrofuran-2- yl)methyl)- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one
  • Example 1-61 5-amino-8-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-7-(4-fluorophenyl)- 2-((5-methyloxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 1-62 5-amino-7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl]-8-(l-methyl-6- oxo-3-pyridyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one
  • Example 1-69 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2R,3R)-3- methyltetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one
  • Example 1-70 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2R,3R)-3- (trifluoromethyl)tetrahydrofuran-2-yl] methyl]- [1,2, 4]triazolo [4,3-c] pyrimidin-3-one
  • Example 1-72 5-amino-2-[(4,4-difluorotetrahydrofuran-2-yl)methyl]-8-(l-methyl-6-oxo-3- pyridyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one
  • Example 1-72 The title compound was prepared from Example 1-72 after chiral HPLC separation (Column: CHIRALPAK IA, 2*25cm, 5um; Mobile Phase A: MTBE (0.5% 2M ME-MeOH), Mobile Phase B: MeOH; Flow rate:20 mL/min; Gradient: 10 B to 10 B in 20 min; 220/254 nm; RT:11.531) (33.2 mg, 15.6%) as a solid.
  • Example 1-74 5-amino-8-(l-methyl-6-oxo-3-pyridyl)-7-phenyl-2-[[rel-(2S)-4,4- difluorotetrahydrofuran-2-yl]methyl]-[l,2,4]triazolo[4,3-c]pyrimidin-3-one
  • Example 1-72 The title compound was prepared from Example 1-72 after chiral HPLC separation (Column: CHIRALPAK IA, 2*25cm, 5um; Mobile Phase A: MTBE (0.5% 2M ME-MeOH), Mobile Phase B: MeOH; Flow rate:20 mL/min; Gradient: 10 B to 10 B in 20 min; 220/254 nm; RT:15.121) (34.4 mg, 16.1%) as a solid.
  • Example 2-1 5-amino-2-((5-methylisoxazol-3-yl)methyl)-8-(6-oxo-l,6-dihydropyridin-3-yl)- 7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Stepl 5-amino-8-bromo-2-((5-methylisoxazol-3-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3- c]pyrimidin-3(2H)-one (213 mg, 0.53 mmol) , 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (212 mg, 0.90 mmol), PdCl2(dtbpf) (27.7 mg, 0.04 mmol), triethylamine (0.259 mL, 1.86 mmol), dioxane (1.0 mL) and H2O (0.5 ml) were added and the resulting mixture was purged with nitrogen gas and then was stirred at 88 °C for 5 hrs.
  • Step2 5-amino-2-((5-methylisoxazol-3-yl)methyl)-8-(6-oxo-l,6-dihydropyridin-3-yl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 2-2 5-amino-8-(5-(difluoromethyl)-6-oxo-l,6-dihydropyridin-3-yl)-2-(3- fluoropropyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 3-1 tert-butyl (S)-2-((5-amino-8-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-3-oxo- 7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)methyl)morpholine-4-carboxylate
  • Stepl l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (106 mg, 0.16 mmol) was combined with TEA (1.1 mL, 8.17 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2(lH)-one (768 mg, 3.27 mmol) and l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (768 mg, 3.27 mmol), dioxane (5 mL) and water (0.500 mL).
  • Step2 Mesyl Chloride (35.0 m ⁇ , 0.45 mmol) was added dropwise to a solution of tert- butyl (ri)-2-(hydroxymethyl)morpholine-4-carboxylate (78 mg, 0.36 mmol) and Et3N (125 m ⁇ , 0.90 mmol) in DCM (1 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at rt for 2 hrs. The reaction mixture was then diluted with EtOAc (5 mL), and washed with water (2 mL x 2). The organic layer was separated and was dried over anhydrous Na2SC>4, concentrated to afford crude mesylate intermediate.
  • Example 4-1 5-amino-8-(6-(hydroxymethyl)pyridazin-4-yl)-2-((5-methyloxazol-4- yl)methyl)-7-phenyl- [l,2,4]triazolo [4,3-c] pyrimidin-3(2H)-one
  • Stepl Et3N (0.115 mL, 0.82 mmol) was added to 5-amino-8-bromo-2-((5-methyloxazol- 4-yl)methyl)-7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (110 mg, 0.27 mmol), 3-(((tert- butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazine (1.1 g, 3.14 mmol)(crude) and l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (17.87 mg, 0.03 mmol) in 1,4-dioxane (6 mL) and water (2 mL) at rt under nitrogen.
  • Step2 Potassium fluoride (32.0 mg, 0.55 mmol) was added to 5-amino-8-(6-(((tert- butyldimethylsilyl)oxy)methyl)pyridazin-4-yl)-2-((5-methyloxazol-4-yl)methyl)-7-phenyl- [l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (60 mg, 0.11 mmol) in MeOH (2 mL) at rt under nitrogen. The resulting mixture was stirred at 60 °C for 3 hrs. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (31.1 mg, 65.5 %) as a yellow solid.
  • Example 4-2 5-amino-8-(6-(hydroxymethyl)pyridazin-4-yl)-7-phenyl-2-((5- (trifluoromethyl)oxazol-4-yl)methyl)-[l,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one
  • Example 5-1 5-amino-8-[6-(difluoromethyl)pyridazin-4-yl]-2-[(5-fluoro-2-pyridyl)methyl]- 7-phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one
  • Stepl Manganese(IV) oxide (23.47 mg, 0.27 mmol) was added to 5-amino-2-((5- fluoropyridin-2-yl)methyl)-8-(6-(hydroxymethyl)pyridazin-4-yl)-7-phenyl-[l,2,4]triazolo[4,3- c]pyrimidin-3(2H)-one (30 mg, 0.07 mmol) in DCM (10 mL) at 0°C under nitrogen. The resulting mixture was stirred at 80 °C for 2 hrs. The mixture was filtered through Celite.
  • Step2 DAST (0.031 mL, 0.24 mmol) was added dropwise to 5-(5-amino-2-((5- fluoropyridin-2-yl)methyl)-3-oxo-7-phenyl-2,3-dihydro-[l,2,4]triazolo[4,3-c]pyrimidin-8- yl)pyridazine-3-carbaldehyde (30 mg, 0.07 mmol) in DCM (1 mL) at 0°C over a period of 1 minute under nitrogen. The resulting mixture was stirred at rt for 1 hr. The reaction mixture was quenched with water. The solvent was removed under reduced pressure.
  • Example 5-2 5-amino-2-[(3-fluoro-2-pyridyl)methyl]-8-(l-methyl-6-oxo-pyridazin-3-yl)-7- phenyl-[l,2,4]triazolo[4,3-c]pyrimidin-3-one
  • Example 5-3 5-amino-7-(4-fluorophenyl)-2-[(3-fluoro-2-pyridyl)methyl]-8-(l-methyl-6- oxo-pyridazin-3-yl)-[l,2,4]triazolo[4,3-c]pyrimidin-3-one
  • Example 6 cAMP Accumulation Inhibition Assay
  • pIRES_neo3 expression vectors were generated for human A2AR (UniProt P29274) or human A2BR (UniProt P29275) modified with an N-terminal preprolactin signal peptide to aid functional expression.
  • 6 pg of plasmid was transfected into CHO-K1 cells using PEI transfection agent, and single cell clones were selected over 22-45 days in the presence of 0.5 mg/mL G418 (Sigma, G8168). Selected single cell clones were cultured in Ham’s F12 medium supplemented with 0.5 mg/mL G418.
  • Cells were harvested to a seeding density of 1.5 x 10 5 cells/mL in Ham’s F12 media in the absence of G418, supplemented with 0.2 U/mL adenosine deaminase (Sigma, 52544) and 40 pL/well seeded into 384 well plates. Following overnight incubation (18 h), the monolayer was washed 3X with PBS to remove adenosine deaminase. Cells were incubated in 40 pM Rolipram (Sigma) prepared in Stimulation Buffer (CisBio) for 10 minutes at room temperature before addition of a concentration response of test antagonist using an Echo acoustic dispenser.
  • Cell membrane homogenates (5 pg protein) are incubated for 30 min at 22°C with 2 nM [3H]CP 55940 in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgC12, 2.5 mM EDTA and 0.3% BSA. Nonspecific binding is determined in the presence of 10 mM WIN 55212-2.
  • the samples are filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) presoaked with 0.3% PEI and rinsed several times with an ice-cold buffer containing 50 mM Tris-HCl (pH 7.4) and 0.5% BSA using a 96-sample cell harvester (Unifilter, Packard).
  • the filters are dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).
  • the results are expressed as a percent inhibition of the control radioligand specific binding.
  • the standard reference compound is CP 55940 which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated.
  • Example 8 CB1 functional antagonism assay (cAMP in CHO cells)
  • HBSS buffer Invitrogen
  • 20 mM HEPES pH 7.4
  • ICso determination concentrations
  • the reference agonist CP 55940 and the adenylyl cyclase activator NKH 477 are added at respective final concentrations of 3 nM and 3 pM.
  • CP 55940 is omitted from the wells containing 3 pM AM 281.
  • the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti -cAMP antibody labeled with europium cryptate) are added.
  • the cAMP concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio).
  • the standard reference antagonist is AM 281, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its ICso value is calculated.

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Abstract

L'invention concerne des composés de triazolone de formule (I) : et des sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne également des procédés de fabrication et d'utilisation des composés de formule (I). Les composés de Formule (I) et des sels pharmaceutiquement acceptables de ceux-ci peuvent être utiles en tant qu'antagonistes du récepteur de l'adénosine, par exemple dans le traitement de maladies ou d'états médiés par le récepteur de l'adénosine, tels que le cancer, les troubles du mouvement ou les troubles de l'attention.
PCT/EP2021/057800 2020-03-26 2021-03-25 Composés de triazolone WO2021191376A1 (fr)

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WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2

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