WO2023076866A1 - Inhibiteurs sulfoximines tricycliques d'enpp1 - Google Patents

Inhibiteurs sulfoximines tricycliques d'enpp1 Download PDF

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WO2023076866A1
WO2023076866A1 PCT/US2022/078603 US2022078603W WO2023076866A1 WO 2023076866 A1 WO2023076866 A1 WO 2023076866A1 US 2022078603 W US2022078603 W US 2022078603W WO 2023076866 A1 WO2023076866 A1 WO 2023076866A1
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compound
pharmaceutically acceptable
tautomer
acceptable salt
foregoing
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PCT/US2022/078603
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Derek A. Cogan
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Volastra Therapeutics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates generally to inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to tricyclic compounds bearing a sulfoximine moiety that are inhibitors of ENPP1 and methods of their use for treating disease mediated by ENPP1.
  • ENPP1 ectonucleotide pyrophosphatase/phosphodiesterase 1
  • Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 is an enzyme that hydrolyzes phosphorylated nucleotides, including adenosine triphosphate (ATP) and 2 ’,3 ’-cyclic adenosine monophosphate-guanidine monophosphate (cGAMP).
  • ENPP1 consumes substrates preventing their role in resolving disease.
  • the concomitant increase in hydrolysis products can also have detrimental effects. Therefore, inhibitors of ENNPl’s enzyme activity will have a beneficial effect in certain human diseases.
  • cGAMP is an activator of the immune response via the STING pathway.
  • ATP activates immune cells via purinergic receptor signaling.
  • ENPP1 can be expressed as a mechanism to degrade cGAMP and ATP and evade the immune response.
  • Such expression of ENPP1 has been identified in cancers with especially poor prognosis. Therefore, ENPP1 inhibition can be an effective treatment in cancers, especially in cases where ENPP1 expression is high or cytosolic DNA levels are elevated.
  • Adenosine monophosphate (AMP) is also a product of both ATP and cGAMP hydrolysis. Adenosine is generated from AMP by enzymes such as CD73, and further suppresses the immune response and supports tumor survival by adenosine receptor pathways.
  • ENPP1 has also been implicated in bacterial or viral infections, insulin resistance and type II diabetes, chondrocalcinosis, calcium pyrophosphate deposition disorder (CPPD), or hypophosphatasia. Therefore, ENPP1 inhibition can be used to treat any of these disorders.
  • the present disclosure provides compounds of Formula (I), compositions thereof, and methods of using said compounds and compositions thereof for the treatment of diseases or conditions associated with ENPP1.
  • a compound of Formula (I) or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing wherein: R 1 and R 2 are each independently H, halo, -OH, -O(Ci-3 alkyl), or -CN; R 3 is Ci-6 alkyl, C3-6 cycloalkyl, or -CH2(C3-6 cycloalkyl), each of which is optionally substituted; Y 1 is CH or N; Y 2 , Y 5 , and Y 6 are each independently N or C, wherein no more than one of Y 2 , Y 5 , and Y 6 is N; Y 3 and Y 4 are each independently N, NR Y1 , O, or CR Y2 wherein when one of Y 3 or Y 4 is O, then the other
  • composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a method of inhibiting ENPP1 comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • CPPD calcium pyrophosphate deposition disorder
  • references to a compound of Formula (I) includes all subgroups of Formula (I) defined herein, such as Formula (la) or (lb), including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) or (lb), include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) or (lb) include polymorphs, solvates, cocrystals, isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) or (lb), include polymorphs, solvates, and/or co-crystals thereof.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) or (lb) include isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula (I) and subgroups thereof, such as Formula (la) or (lb) include solvates thereof.
  • Alkyl encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms.
  • Ci-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “propyl” includes n-propyl and isopropyl; and “butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec -butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl.
  • Ci-6 alkyl When a range of values is given (e.g., Ci-6 alkyl), each value within the range as well as all intervening ranges are included.
  • Ci-6 alkyl includes Ci, C2, C3, C4, C 5 , C 6 , C1-6, C2-6, C3-6, C4-6, C5-6, Ci-5, C2-5, C3-5, C4-5, C14, C2 , C3-4, Ci-3, C2-3, and C1-2 alkyl.
  • Alkenyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond.
  • the group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s).
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2- yl), and butenyl (e.g., but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl).
  • propenyl e.g., prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2- yl
  • butenyl e.g., but-l-en-l-y
  • Alkynyl refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond.
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-l-yn-l-yl, prop-2-yn-l-yl) and butynyl (e.g., but-l-yn-l-yl, but-l-yn-3-yl, but-3- yn-l-yl).
  • Cycloalkyl indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms.
  • Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and caged ring groups (e.g., norbomane, bicyclo[2.2.2]octane).
  • one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon.
  • a 1,2,3,4-tetrahydronaphthalen-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while l,2,3,4-tetrahydronaphthalen-5- yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.
  • polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.
  • Cycloalkenyl indicates a non-aromatic carbocyclic ring, containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond.
  • Cycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo[2.2.2]octene).
  • one ring of a polycyclic cycloalkenyl group may be aromatic, provided the polycyclic alkenyl group is bound to the parent structure via a non-aromatic carbon atom.
  • inden- 1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group
  • inden-4-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group.
  • polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are described below.
  • Aryl indicates an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms.
  • Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring.
  • a l,2,3,4-tetrahydronaphthalen-5- yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group
  • 1,2,3,4-tetrahydronaphthalen-l-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group.
  • aryl does not encompass or overlap with “heteroaryl,” as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups).
  • aryl is phenyl or naphthyl.
  • aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.
  • Hetero aryl indicates an aromatic ring containing the indicated number of atoms
  • heteroaryl made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon.
  • Heteroaryl groups do not contain adjacent S and O atoms.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the heteroaryl group is not more than 1.
  • heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits.
  • pyridyl includes 2-pyridyl, 3- pyridyl and 4-pyridyl groups
  • pyrrolyl includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.
  • a heteroaryl group is monocyclic.
  • examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4- oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2, 3 -thiadiazole, 1,2,4- thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.
  • pyrrole pyrazole
  • both rings of a polycyclic heteroaryl group are aromatic.
  • examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, lH-pyrrolo[2,3-b]pyridine, lH-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[l,2,3]triazolo[4,5-b]pyridine, lH-pyrrolo[3,2-b]pyridine, lH-pyrazolo[4,3-b]pyridine, lH-imidazo[4,5-b]pyridine, lH-[l,2,3]triazolo[4,5-b]pyridine, lH-pyrrolo[2,3]pyridine,
  • polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring.
  • a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl
  • a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group
  • 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group.
  • polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non- aromatic ring are described below.
  • Heterocycloalkyl indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon.
  • Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide.
  • one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
  • a 1, 2,3,4- tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non- aromatic nitrogen atom) is considered a heterocycloalkyl group
  • 1, 2,3,4- tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group.
  • Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.
  • Heterocycloalkenyl indicates a non-aromatic ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl.
  • Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic).
  • heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3 -dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2, 5 -dihydro thiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-lH-pyrrolyl, 2,5-dihydro-lH-pyrrolyl), dihydroimidazolyl (e.g., 2,3- dihydro-lH-imidazolyl, 4,5-dihydro-lH-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4- dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1, 2,3,4- tetrahydropyridiny
  • one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom.
  • a 1,2-dihydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group
  • l,2-dihydroquinolin-8-yl group is not considered a heterocycloalkenyl group.
  • polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.
  • polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl)
  • a non-aromatic ring e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl
  • indenyl 2,3-dihydro-lH-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[l,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[l,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-lH-indazolyl, 2,3-dihydro-lH-benzo[d]imid
  • each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atom through which the moiety is bound to the parent structure.
  • Halogen or “halo” refers to fluoro, chloro, bromo or iodo.
  • compounds disclosed and/or described herein include all possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers. When the compounds described herein contain moieties capable of tautomerization, and unless specified otherwise, it is intended that the compounds include all possible tautomers.
  • Protecting group has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete.
  • a variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).
  • a “hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group.
  • amines and other reactive groups may similarly be protected.
  • pharmaceutically acceptable salt refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p- toluenesulfonic acid, stearic acid and salicylic acid.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19).
  • bases compounds see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19.
  • a “solvate” is formed by the interaction of a solvent and a compound.
  • suitable solvents include, for example, water and alcohols (e.g., ethanol).
  • Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates and hemi-hydrates.
  • substituted means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo and the like.
  • substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino
  • unsubstituted means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.
  • a substituted group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another.
  • a substituted group or moiety bears from one to five substituents.
  • a substituted group or moiety bears one substituent.
  • a substituted group or moiety bears two substituents.
  • a substituted group or moiety bears three substituents.
  • a substituted group or moiety bears four substituents.
  • a substituted group or moiety bears five substituents.
  • optionally substituted alkyl encompasses both “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, synthetically non-feasible, and/or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.
  • the compounds disclosed and/or described herein can be enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
  • the compound contains at least one deuterium atom.
  • deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997.
  • deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and/or described herein.
  • Deuterium substituted compounds can be synthesized using various methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • the terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal, bird, or fish.
  • the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans.
  • the patient, individual, or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment.
  • the compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
  • therapeutically effective amount refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment.
  • a therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation (e.g., inhibition) of ENPP1.
  • the therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art.
  • the therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
  • Treatment includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms).
  • the term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder.
  • compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
  • R 1 and R 2 are each independently H, halo, -OH, -O(Ci-3 alkyl), or -CN;
  • R 3 is Ci-6 alkyl, C3-6 cycloalkyl, or -CH2(C3-6 cycloalkyl), each of which is optionally substituted;
  • Y 1 is CH or N
  • Y 2 , Y 5 , and Y 6 are each independently N or C, wherein no more than one of Y 2 , Y 5 , and Y 6 is N;
  • Y 3 and Y 4 are each independently N, NR Y1 , O, or CR Y2 wherein when one of Y 3 or Y 4 is O, then the other of Y 3 and Y 4 is not O, and Y 2 , Y 5 , and Y 6 are each C;
  • R Y1 is H or C1-6 alkyl
  • R Y2 is H, halo, -CN, C1-3 alkyl, -OH, or -O(Ci- 3 alkyl);
  • A is Ce-14 aryl, C3-10 cycloalkyl, 4- to 14-membered heteroaryl, or 3- to 14-membered heterocycloalkyl, each of which is optionally substituted;
  • L is -C(R L1 )(R L2 )-;
  • R L1 and R L2 are each independently H or C1-3 alkyl.
  • R 1 and R 2 are each independently H, halo, -OH, -O(Ci-3 alkyl), or -CN.
  • R 1 is -O(Ci-3 alkyl) and R 2 is H, halo, or -O(Ci-3 alkyl).
  • R 1 is -OCH3 and R 2 is H, fluoro, or -OCH3.
  • R 1 is -O(Ci-3 alkyl).
  • R 1 is -OCH3.
  • R 2 is H.
  • R 2 is halo.
  • R 2 is fluoro.
  • R 3 is Ci-6 alkyl, C3-6 cycloalkyl, or -CH2(C3-6 cycloalkyl), each of which is optionally substituted. In some variations, R 3 is C1-6 alkyl. In some variations, R 3 is methyl.
  • R 3 is optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo, -CN, C1-6 alkyl, -OH, and -O(Ci-6 alkyl). In some variations, R 3 is optionally substituted with one, two, three, four, five, or more halo.
  • Y 1 is CH or N. In some variations, Y 1 is CH. In some variations, Y 1 is N.
  • Y 2 , Y 5 , and Y 6 are each independently N or C. In some variations, no more than one of Y 2 , Y 5 , and Y 6 is N. In some variations, Y 2 is N, Y 5 is C, and Y 6 is C. In some variations, Y 2 is N. In some variations, Y 5 is C. In some variations, Y 6 is C.
  • R Y1 is H or C1-6 alkyl. In some variations, R Y1 is H. In some variations, R Y1 is methyl, ethyl, or propyl.
  • R Y2 is H, halo, -CN, C1-3 alkyl, -OH, or -O(Ci-3 alkyl). In some variations, R Y2 is H. In some variations, R Y2 is methyl, ethyl, or propyl.
  • A is Ce-14 aryl, C3-10 cycloalkyl, 4- to 14-membered heteroaryl, or 3- to 14-membered heterocycloalkyl, each of which is optionally substituted.
  • A is Ce-14 aryl, C3-8 cycloalkyl, 6- to 14-membered heteroaryl, or 3- to 8- membered heterocycloalkyl, each of which is optionally substituted.
  • A is optionally substituted Ce-14 aryl.
  • A is optionally substituted phenyl. In some variations, wherein denotes the point of attachment to L.
  • A is optionally substituted with one, two, three, four, five, or more substituents independently selected from the group consisting of halo, -CN, Ci-6 alkyl, -OH, and -O(Ci-6 alkyl). In some variations, A is optionally substituted with one, two, three, four, five, or more halo. In some variations, A is optionally substituted with one, two, three, four, five, or more fluoro.
  • L is -C(R L1 )(R L2 )-. In some variations, L is -CH2-. In some embodiments, R L1 and R L2 are each independently H or C1-3 alkyl.
  • heteroaryl or heterocycloalkyl contains one, two, three, four, five, or six heteroatoms.
  • each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • Tautomeric forms of the compounds are contemplated and included herein.
  • compounds of Formula (lb) may exist in either of the both of these forms are contemplated and included herein.
  • any of the compounds described herein, such as a compound of Formula (I), (la), or (lb), or any variation thereof, or a compound of Table 1 may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom).
  • the compound is deuterated at a single site.
  • the compound is deuterated at multiple sites.
  • Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. Hydrogen atoms may also be replaced with deuterium atoms using other method known in the art.
  • any formula given herein such as Formula (I), (la), or (lb), is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio.
  • any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
  • the solvent is water and the solvates are hydrates.
  • the compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
  • the salts of the compounds provided herein are pharmaceutically acceptable salts.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • provided are pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , R Y1 , R Y2 , A, L, R L1 , or R L2 provided herein can be combined with every other variation or embodiment of R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , R Y1 , R Y2 , A, L, R L1 , or R L2 as if each combination had been individually and specifically described.
  • Formula (I) includes all subformulae thereof.
  • Formula (I) includes compounds of Formula (la) or (lb).
  • compositions such as pharmaceutical compositions, that include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein.
  • the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate.
  • compositions such as pharmaceutical compositions that contain one or more compounds described herein, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a pharmaceutically acceptable composition comprising a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a composition may contain a synthetic intermediate that may be used in the preparation of a compound described herein.
  • the compositions described herein may contain any other suitable active or inactive agents.
  • compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds that are substantially pure.
  • packaged pharmaceutical compositions comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.
  • the compounds of the present disclosure are inhibitors of ENPP1 enzymatic activity.
  • the compounds and pharmaceutical compositions herein may be used to inhibit ENPP1.
  • the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual.
  • the inhibitory activity of the compounds described herein against ENPP1 may be determined and measured by methods known in the art including, but not limited to, inhibition of ENPP1 hydrolysis of 2’,3’-cGAMP (Cyclic guanosine monophosphateadenosine monophosphate) (Mardjuki, R. et al. (2020), Journal of Biological Chemistry, 295(15), 4881-4892), inhibition of ENPP1 hydrolysis of pNP-TMP (p-nitrophenyl thymidine 5’-monophosphate), or inhibition of ENPP1 hydrolysis of pNP-AMP (p-nitrophenyl adenosine 5'-monophosphate) (Lee, S. et al. (2017), Frontiers in Pharmacology 8, 54).
  • provided herein is a method of inhibiting ENPP1 comprising contacting a cell with an effective amount of a compound or a pharmaceutical composition as described herein.
  • methods of inhibiting ENPP1 comprising contacting a cell with an effective amount of a compound Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • provided herein are methods of inhibiting ENPP1 comprising contacting a cell with an effective amount of a pharmaceutical composition comprising a compound a compound Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a pharmaceutical composition comprising a compound a compound Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the cell is contacted in vitro.
  • the cell is contacted in vivo.
  • the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual, comprising administering an effective amount of a compound or a pharmaceutical composition as described herein.
  • the compounds disclosed and/or described herein may prevent a disease or disorder from developing in an individual at risk of developing the disease or disorder, or lessen the extent of a disease or disorder that may develop.
  • provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as described herein. In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • the disease or condition is mediated by ENPP1.
  • the disease or condition is cancer.
  • the disease or condition is a bacterial or viral infection.
  • the disease or condition is a bacterial infection.
  • the disease or condition is a viral infection.
  • the disease or condition is insulin resistance.
  • the disease or condition is type II diabetes. In some embodiments, the disease or condition is chondrocalcinosis. In some embodiments, the disease or condition is calcium pyrophosphate deposition disorder (CPPD). In some embodiments, the disease or condition is hypophosphatasia.
  • CPPD calcium pyrophosphate deposition disorder
  • methods of treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein.
  • Also provided herein is the use of a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing in the manufacture of a medicament for treatment of a disease in a subject.
  • provided herein are methods of treating cancer, comprising administering to an individual in need thereof a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is the use of a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for treatment of a cancer.
  • the provided are methods of treating a bacterial and/or viral infetion in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is the use of a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for treatment of a bacterial and/or viral infection.
  • the provided are methods of treating type II diabetes, comprising administering to the individual in need thereof a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided herein is the use of a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the manufacture of a medicament for treatment of type II diabetes.
  • CPPD calcium pyrophosphate deposition disorder
  • methods of treating calcium pyrophosphate deposition disorder (CPPD) in an individual comprising administering to the individual in need thereof a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), (la), or (lb), or a compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing in the manufacture of a medicament for treatment of calcium pyrophosphate deposition disorder (CPPD).
  • a daily dose ranges from about 0.01 to 100 mg/kg of body weight; in some embodiments, from about 0.05 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg/kg of body weight.
  • the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day.
  • the amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day
  • an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetic s .
  • Administration of the compounds and compositions disclosed and/or described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
  • the compound or composition is administered orally or intravenously.
  • the compound or composition disclosed and/or described herein is administered orally.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms.
  • the compounds disclosed and/or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate.
  • sustained or controlled release dosage forms e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms
  • the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
  • the compounds disclosed and/or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate).
  • the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate).
  • the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and/or described herein.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and/or described herein, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and/or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives).
  • a diluent e.g., lactose, sucrose, dicalcium phosphate
  • a lubricant e.g., magnesium stearate
  • a binder e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives.
  • Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides)
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and/or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension.
  • a carrier e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject.
  • composition will comprise from about 0.2 to 2% of a compound disclosed and/or described herein in solution.
  • compositions of the compounds disclosed and/or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.
  • compositions can include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like.
  • additional medicinal agents include those described herein.
  • the article of manufacture may comprise a container with a label.
  • Suitable containers include, for example, bottles, vials, and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container may hold a pharmaceutical composition provided herein.
  • the label on the container may indicate that the pharmaceutical composition is used for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
  • kits containing a compound or composition described herein and instructions for use.
  • the kits may contain instructions for use in the treatment of any disease or condition described herein in an individual in need thereof.
  • a kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags.
  • a kit may also contain sterile packaging.
  • compositions described and/or disclosed herein may be administered alone or in combination with other therapies and/or therapeutic agents useful in the treatment of the aforementioned disorders.
  • the compounds and compositions described and/or disclosed herein may be combined with one or more other therapies to treat the diseases or conditions described herein, including but not limited to cancer, bacterial and/or viral infections, insulin resistance, type II diabetes, chondrocalcinosis, calcium pyrophosphate deposition disorder (CPPD), and hypophosphatasia.
  • R 1 and R 2 are each independently H, halo, -OH, -O(Ci-3 alkyl), or -CN;
  • R 3 is Ci-6 alkyl, C3-6 cycloalkyl, or -CH2(C3-6 cycloalkyl), each of which is optionally substituted;
  • Y 1 is CH or N
  • Y 2 , Y 5 , and Y 6 are each independently N or C, wherein no more than one of Y 2 , Y 5 , and Y 6 is N; Y 3 and Y 4 are each independently N, NR Y1 , O, or CR Y2 wherein when one of Y 3 or Y 4 is O, then the other of Y 3 and Y 4 is not O, and Y 2 , Y 5 , and Y 6 are each C;
  • R Y1 is H or Ci-6 alkyl
  • R Y2 is H, halo, -CN, C1-3 alkyl, -OH, or -O(Ci- 3 alkyl);
  • A is Ce-14 aryl, C3-10 cycloalkyl, 4- to 14-membered heteroaryl, or 3- to 14-membered heterocycloalkyl, each of which is optionally substituted;
  • L is -C(R L1 )(R L2 )-;
  • R L1 and R L2 are each independently H or C1-3 alkyl.
  • a pharmaceutical composition comprising a compound of any one of embodiments 1- 15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a method of inhibiting ENPP1 comprising contacting a cell with an effective amount of a compound of any one of embodiments 1-15, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 16.
  • CPPD calcium pyrophosphate deposition disorder
  • a particular enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Intermediates E and G may be prepared from compounds of the structure A.
  • Compound A may undergo nitration with, for example, concentrated nitric acid in an acidic solvent, such as propionic acid, to provide B.
  • Reaction of B with POCI3 provides chlorides C that can be reacted with amines D or F to provide E or G respectively.
  • G may alternatively be prepared by the reaction of E with PhI(OAc)2 and an ammonia salt, such as ammonium acetate or ammonium carbamate.
  • Compounds E and G may be reduced to H and K respectively, with, for example, hydrogen gas and a metal catalyst such as Pd/C. Condensation of H and K with methyl orthoformate provides J and la respectively.
  • J and la may alternatively be prepared by the reaction of E or G with iron metal in methanol with ammonium chloride.
  • Compounds of the structure la may be also be prepared by the reaction of J with PhI(OAc)2 and an ammonia salt, such as ammonium acetate or ammonium carbamate.
  • Ib may be prepared by reacting K with triphosgene and a base such as triethylamine. Alternatively, Ib may be prepared in two steps from H. First H is reacted with triphosgene to provide L which may then react withPhI(OAc)2 and an ammonia salt, such as ammonium acetate or ammonium carbamate.
  • Step 2 To a suspension of A-02 (1.0 g, 4.5 mmol) in SOCh(10 mL, 138 mmol) was added DMF (60 pL, 0.78 mmol) and the mixture was stirred at 100 °C for 16 h and concentrated to provide 4-chloro-7-methoxy-3 -nitro-quinoline hydrochloride (A-03, 1.3 g).
  • Step 3 A mixture of [4-(methylsulfonimidoyl) phenyl] methanamine hydrochloride (A-04, 0.20 g, 0.91 mmol) and iPnNEt (1.0 mL, 5.7 mmol), iPrOH (5.0 mL), and DMF (2.5 mL) was stirred at 20 °C for 15 min. A-02 (0.20 mg, 0.73 mmol) was added and the mixture was stirred at 20 °C for 12 h and at 50 °C for 2 h, and was added water (20 mL).
  • Step 4 To a mixture of A-05 (0.10 g, 0.26 mmol), MeOH (7.0 mL), H2O (1.8 mL), Fe powder (0.15 g, 2.7 mmol), and NH4CI (0.17 g, 3.2 mmol) was stirred at 70 °C for 12 h. The mixture was filtered through celite, the filter cake was washed with MeOH (6.0 mL x 3), and the filtrate was concentrated and purified twic e by preparative HPLC: first by Cl 8, 1-30% MeCN in H2O [10 mM NH4HCO3]; second by C18 5-40% MeCN in H2O [0.1 % formic acid].
  • Step 1 A degassed mixture of (3 -methylsulfanylphenyl) methanamine (A-06, 0.4 g, 2.6 mmol), A-03 (0.50 g, 1.8 mmol), iPnNEt (1.8 mL, 10 mmol), iPrOH (3.0 mL) and DMF (3.0 mL) was stirred at 20 °C for 1 h under N2.
  • Step 2 A degasses mixture of A-07 (0.50 g, 1.4 mmol), MeOH (20 mL), THF (20 mL), and 10% Pd/C (0.40 g) under N2 was charged with H2 (15 psi) and stirred at 20 °C for 4 h. The mixture was filtered and the filtrate was concentrated provide 7-methoxy-N4-[(3- methylsulfanylphenyl)methyl]quinoline-3,4-diamine (A-08, 0.50 g).
  • Step 3 A degassed mixture of A-08 (0.50 g, 1.5 mmol), HC(OMe)3 (0.84 mL, 7.7 mmol), dioxane (5.0 mL) was stirred at 100 °C for 12 h under N2, then was poured into water (20 mL). The resulting mixture was extracted with EtOAc (2 x 20 mL) and the extract was washed with brine (10 mL), dried over Na2SO4, and concentrated to provide 7-methoxy-l- [(3 -methylsulfanylphenyl) methyl] imidazo [4, 5-c]quinoline (A-09, 0.30 g).
  • Step 4 A mixture of A-09 (0.30 mg, 0.89 mmol), EtOH (10 mL), PhI(OAc)2
  • Step 2 4-Chloro-6-fluoro-7-methoxy-3-nitro-quinoline hydrochloride (A-12) was prepared from A-10 in the manner described in the synthesis of A-03 (Synthetic Example S- 01, Step 2).
  • Step 3 6-fluoro-7-methoxy-N-[[4-(methylsulfonimidoyl)phenyl]methyl]-3-nitro- quinolin-4-amine (A-13) was prepared from A-12 and A-04 in the manner described in the synthesis of A-05 (Synthetic Example S-01, Step 3).
  • Step 4. (4-((8-fluoro-7-methoxy-lH-imidazo[4,5-c]quinolin-l- l)methyl)phenyl)(imino)(methyl)-l 6 -sulfanone (Compound 3) was prepared from A-13 in the manner described in the synthesis of Compound 1 (Synthetic Example S-01, Step 4).
  • Step 1 7-methoxy-3-nitro-l,8-naphthyridin-4-ol (A-15) was prepared from 7- methoxy-l,8-naphthyridin-4-ol (A-14) in the manner described in the synthesis of A-02 (Synthetic Example S-01, Step 1).
  • Step 3 7-methoxy-N-[[4-(methylsulfonimidoyl)phenyl]methyl]-3-nitro-l,8- naphthyridin-4-amine (A-17) was prepared from A-16 and A-04 in the manner described in the synthesis of A-05 (Synthetic Example S-01, Step 3). [0127] Step 4.
  • Step 1 6-fluoro-7-methoxy-N-[(4-methylsulfanylphenyl)methyl]-3-nitro- quinolin-4-amine (A-19) was prepared from A-12 and A-18 in the manner described in the synthesis of A-07 (Synthetic Example S-02, Step 1).
  • Step 2 6 -fluoro-7-methoxy-N4-[(4-methylsulfanylphenyl)methyl]quinoline-3,4- diamine (A-20) was prepared from A-19 in the manner described in the synthesis of A-08 (Synthetic Example S-02, Step 2).
  • Step 3 To a mixture of A-19 (0.18 g, 0.52 mmol), CH2CI2 (9.0 mL) was added EtsN (0.10 mL, 0.72 mmol) was added a solution of triphosgene (0.17 mg, 0.57 mmol) in CH2CI2 (1.0 mL) at 0 °C. The mixture was stirred for 5 h, allowed its temperature warm to 25 °C, and saturated aqueous of NaHCOs (5.0 mL) was added into the mixture to quenched the reaction.
  • Step 4 A mixture of A-21 (90 mg, 0.24 mmol), EtOH (3.0 mL), THF (3.5 mL), PhI(OAc)2 (0.27 g, 0.84 mmol), and NH4OAC (90 mg, 1.2 mmol) was stirred at 25 °C for 12 h.
  • Step 1 7-methoxy-N4-[[4-(methylsulfonimidoyl) phenyl] methyl] quinoline-3,4- diamine (A-22) was prepared from A-05 in the manner described in the synthesis of A-20 (Synthetic Example S-05, Step 2).
  • Step 2 7-methoxy-l-(4-(S-methylsulfonimidoyl)benzyl)-l,3-dihydro-2H- imidazo[4,5-c]quinolin-2-one (Compound 6) was prepared from A-22 in the manner described in the synthesis of A-21 (Synthetic Example S-05, Step 3). ESI MS, m/z 383.1 (M++H) + .
  • Step 1 7-methoxy-N-[(3-methylsulfanylphenyl)methyl]-3-nitro-l,8-naphthyridin- 4-amine (A-23) was prepared from A-16 and A-06 in the manner described in the synthesis of A-07 (Synthetic Example S-02, Step 1).
  • Step 2 7-methoxy-N4-[(3-methylsulfanylphenyl) methyl]-l, 8-naphthyridine-3, 4-diamine (A-24) was prepared from A-023 in the manner described in the synthesis of A-08 (Synthetic Example S-02, Step 2).
  • Step 4 7-methoxy-l-(3-(S-methylsulfonimidoyl)benzyl)-l,3-dihydro-2H- imidazo[4,5-c][l,8]naphthyridin-2-one (Compound 8) was prepared from A-25 in the manner described in the synthesis of Compound 5 (Synthetic Example S-05, Step 4). ESI MS, m/z 384.0 (M+H) + .
  • Step 1 6, 7-dimethoxy-3-nitro-quinolin-4-ol (A-27) was prepared from 6,7- dimethoxyquinolin-4-ol (A-26) in the manner described in the synthesis of A-02 (Synthetic Example S-01, Step 1).
  • Step 2 4-chloro-6,7-dimethoxy-3-nitro-quinoline hydrochloride (A-28) was prepared from A-27 in the manner described in the synthesis of A-03 (Synthetic Example S- 01, Step 2).
  • Step 3 6,7-dimethoxy-N-[[4-(methylsulfonimidoyl)phenyl]methyl]-3-nitro- quinolin-4-amine (A-29) was prepared from A-28 and A-04 in the manner described in the synthesis of A-05 (Synthetic Example S-01, Step 3).
  • Step 4. 6 7-dimethoxy-N4-[[4-(methylsulfonimidoyl) phenyl] methyl] quinoline- 3, 4-diamine (A-30) was prepared from A-029 in the manner described in the synthesis of A- 08 (Synthetic Example S-02, Step 2).
  • Step 5 7,8-dimethoxy-l-(4-(S-methylsulfonimidoyl)benzyl)-lH-imidazo [4,5- c] quinolone (Compound 9) was prepared from A-30 in the manner described in the synthesis of A-21 (Synthetic Example S-05, Step 3). ESI MS, m/z 397.0 (M+H) + .
  • Stepl A mixture of 2, 6-difluoro-4-methylsulfanyl-benzoic acid (A-31, 0.80 g, 3.9 mmol), SOCI2 (10 mL), and DMF (6
  • Step 2 To a mixture of A-32 (0.32 mg, 1.6 mmol), and THF (15 mL) was added dropwise BH3-Me2S (10 M, 0.79 mL) at -70 °C. The mixture was stirred at -70 °C for 12 h and MeOH (2.0 mL) was added at 25 °C, and the mixture was concentrated. The mixture was stirred in MeOH and HC1 in dioxane (4M, 1.5 mL) and heated to reflux for 30 min, cooled, concentrated, and treated with saturated Na2CO3 until the pH was 7.
  • a mixture of A-33 (80 mg, 0.42 mmol), DMF (3.0 mL), iPrOH (3.0 mL), iPnNEt (0.37 mL, 2.1 mmol), and A-16 (0.11 g, 0.38 mmol) was stirred at 20 °C for 12 h, poured into water, (10 mL), and extracted with EtOAc (2 x 10 mL).
  • Step 4 A degassed mixture of A-34 (60 mg, 0.15 mmol), Pd/C (10%, 30 mg), THF (5.0 mL), was stirred at 20 °C for 12 h under 15 psi of H2. The reaction was concentrated to provide N4-[(2, 6-difluoro-4-methylsulfanyl -phenyl) methyl] -7-methoxy- l,8-naphthyridine-3, 4-diamine (A-35, 90 mg).
  • Step 5 A mixture of A-34 (70 mg, 0.19 mmol), CH2CI2 (5.0 mL), bis(trichloromethyl)carbonate, (57 mg, 0.19 mmol), and EtsN (0.27 mg, 1.9 mmol) was stirred at 0 °C for 1 h. Saturated aqueous NaHCOs (2.0 mL) was added and the mixture was poured into water (10 mL).
  • Step 6 A mixture of A-35 (80 mg, 0.21 mmol), EtOH (2.0 mL), PhI(OAc)2 (200 mg, 0.62 mmol), and NH4OAC (79 mg, 1.0 mmol) was stirred at 20 °C for 1 h. The micture was concentrated and purified by preparative HPLC (Cl 8, 1 %-80% MeCN in water [0.1% formic acid]) to provide l-(2, 6-difluoro-4-(S-methylsulfonimidoyl) benzyl) -7-methoxy-lH- imidazo [4, 5-c] [1, 8] naphthyridin-2(3H)-one (2.7 mg).
  • Test compounds were plated in a 3x dilution scheme in a 384 well plate. To 50 nL of test compound in DMSO was added 2.5 pL ENPP-1 ECD in Assay Buffer (Tris-HCl pH 8.0 or pH 7.4 (50 mM), NaCl (150 mM), and 0.01% Triton X-100 in water (2.5 nM final concentration). Enzyme was omitted in control wells reserved to define maximum inhibition (max). Control wells were reserved to define no inhibition (min), and DMSO was used in place of compound solution.
  • Assay Buffer Tris-HCl pH 8.0 or pH 7.4 (50 mM), NaCl (150 mM), and 0.01% Triton X-100 in water (2.5 nM final concentration.
  • Enzyme was omitted in control wells reserved to define maximum inhibition (max). Control wells were reserved to define no inhibition (min), and DMSO was used in place of compound solution.
  • the plate was centrifuged for 30 s, and the mixture was incubated for 30 min at room temperature ( ⁇ 25 °C) or at 37 °C.
  • AMP-GloTM Reagent I Promega Corp.; 5 pL
  • AMP Detection solution 100 pL was added to each well, the plate centrifuged and incubated for 60 min.
  • Luminescence was measured with an Envision plate reader, and % Inhibition was calculated for each well as: (([max - min] - [test - min])/[max - min].

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Abstract

La présente divulgation concerne de manière générale des inhibiteurs d'ectonucléotide pyrophosphatase/phosphodiestérase 1 (ENPP1), des compositions associées et des procédés d'utilisation desdits composés et des compositions associées. Plus spécifiquement, la présente divulgation concerne des composés tricycliques portant une fraction sulfoximine qui sont des inhibiteurs d'ENPP1 et des procédés d'utilisation de ceux-ci pour traiter une maladie médiée par ENPP1.
PCT/US2022/078603 2021-10-25 2022-10-24 Inhibiteurs sulfoximines tricycliques d'enpp1 WO2023076866A1 (fr)

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WO2024074128A1 (fr) * 2022-10-08 2024-04-11 Insilico Medicine Ip Limited Inhibiteurs de l'ectonucléotide pyrophosphatase-phosphodiestérase 1 (enpp1) et leurs utilisations

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WO2019177971A1 (fr) * 2018-03-12 2019-09-19 Mavupharma, Inc. Inhibiteurs d'ectonucléotide pyrophosphatase-phosphodiestérase 1 (enpp -1) et leurs utilisations
WO2021061803A1 (fr) * 2019-09-23 2021-04-01 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Inhibiteurs de phosphodiestérase et leur utilisation

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US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024074128A1 (fr) * 2022-10-08 2024-04-11 Insilico Medicine Ip Limited Inhibiteurs de l'ectonucléotide pyrophosphatase-phosphodiestérase 1 (enpp1) et leurs utilisations

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