WO2024092185A1 - Composés d'acyl sulfonamide en tant qu'inhibiteurs du polyomavirus - Google Patents

Composés d'acyl sulfonamide en tant qu'inhibiteurs du polyomavirus Download PDF

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WO2024092185A1
WO2024092185A1 PCT/US2023/078000 US2023078000W WO2024092185A1 WO 2024092185 A1 WO2024092185 A1 WO 2024092185A1 US 2023078000 W US2023078000 W US 2023078000W WO 2024092185 A1 WO2024092185 A1 WO 2024092185A1
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compound
group
fluorophenyl
sulfonyl
carboxamide
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PCT/US2023/078000
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English (en)
Inventor
Benjamin R. TAFT
James C. SUTTON JR.
David C. Tully
Patrick Sang-Tae LEE
Matthew James HESSE
Subramanian Karur
Keith Bruce PFISTER
Lifeng Wan
Nikolas A. SAVAGE
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Via Nova Therapeutics, Inc.
Novartis Ag
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Publication of WO2024092185A1 publication Critical patent/WO2024092185A1/fr

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    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • BK polyomavirus BKV or BKPyV was first isolated from an immunosuppressed kidney transplant recipient in 1971 (Gardner et al., Lancet 19711:1253) and was one of the first two human polyomaviruses identified (alongside JC polyomavirus [JCV or JCPyV]).
  • BKV human polyomavirus
  • JCV Merkel Cell polyomavirus
  • MCPyV Merkel Cell polyomavirus
  • TsPyV Trichodysplasia Spinulosa-associated polyomavirus
  • HPyV7 human polyomavirus 7
  • BKV like the other members of the polyomavirus family, is a small (40-45 nm in diameter), non-enveloped, icosahedral virion with a closed circular double-stranded DNA genome approximately 5 kb in length.
  • BKV encodes only seven proteins and notably lacks traditional enzymatic targets for antiviral drugs (i.e., kinases, polymerases, and proteases).
  • the genome can be divided into three regions: the early coding region, the late coding region, and a non-coding control region (NCCR).
  • the early coding region encodes for the three regulatory proteins (large, small, and truncated tumor antigens [TAg, tAg, and truncTAg, respectively]), which are the first viral proteins expressed in a newly infected cell and are responsible for facilitating viral DNA replication and establishing a favorable cellular environment.
  • the late coding region encodes the three structural proteins (VPl, VP2, and VP3) that comprise the viral capsid, as well as the agnoprotein, which plays a regulatory role during viral replication.
  • viral microRNAs are encoded in the direction of the late coding region and may have a role in downregulating early gene expression.
  • the NCCR contains the origin of replication and bidirectional promoter/enhancer elements that drive expression of both the early and late viral gene products.
  • the virus subsequently undergoes endocytosis via a caveolin-dependent pathway (Eash et al., J. Virol.200478:11583) and is trafficked in endosomes to the endoplasmic reticulum (Jiang et al., J. Virol. 200983:1350; Moriyama and Sorokin, Virology 2008371:336), where host cell enzymes orchestrate capsid disassembly. The partially disassembled particle is ultimately trafficked to the nucleus, where host cell transcription machinery initiates viral gene expression (Helle et al., Viruses 20179:327).
  • BKVN BKV nephropathy
  • KTRs kidney transplant recipients
  • HCT hemorrhagic cystitis in hematopoietic cell transplant
  • BKV reactivation in KTRs is first detected as viruria (30 to 50% of patients), with approximately one-third of these patients progressing to viremia (virus in the blood), and subsequently one-third of viremic patients progressing to biopsy-confirmed BKVN (3 to 4% of all KTRs, published rates ranging from 1 to 10%) (Ambalathingal et al., Clin. Micorbiol. Rev. 201730:503; Nickeleit, et al., J. Am. Soc. Nephrol.201829:680).
  • 15% to 50% of patients diagnosed with BKVN will suffer graft loss (Nickeleit, et al., J. Am. Soc.
  • BKV is the leading viral cause of late hemorrhagic cystitis, a painful infection of the bladder associated with hematuria and affecting approximately 10% of HCT recipients (published rates ranging from 6% to 16%) (Giraud et al., Haematologica 200691:401; El- Zimaity et al., Blood 2004103:4674).
  • the current standard of care is generally supportive, primarily involving forced hydration, bladder irrigation, and pain management measures.
  • BKV-associated hemorrhagic cystitis prolongs hospitalizations, often requires administration of blood products and urologic intervention, and can lead to death in severe cases (Gilis et al., Bone Marrow Transplant.201449:664-670; Lunde et al., Bone Marrow Transplant.201550:1432- 1437). [0008] There are currently no specific or effective antiviral therapies approved for BKV.
  • each R of Formula (I) can independently be C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, oxo, -NH 2 , nitro, cyano, -SO 2 R 11 , or -P(R 11 ) 3 .
  • R 2 of Formula (I) can be absent, hydrogen, or C 1-20 alkyl.
  • R 2 can be combined with an R 9 and X 1 to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R 11 groups.
  • R 3 of Formula (I) can be hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 2-9 carboxyalkyl, or 2- to 20-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R 11 groups.
  • R 3 can be combined with R 4 and the nitrogen to which R 3 and R 4 are attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • R 3 can be combined with an R 10 and the nitrogen to which R 3 is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • R 4 of Formula (I) can be hydrogen, C 1-20 alkyl, C 2-20 alkynyl, C 2- 9 carboxyalkyl, or 2- to 20-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R 11 groups.
  • R 4 can be combined with R 3 and the nitrogen to which R 3 and R 4 are attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • R 5 of Formula (I) can be hydrogen, C 1-20 alkyl, C 1-20 alkoxy, C 1-20 alkylhydroxy, halogen, C 1-20 haloalkyl, or C 3-12 cycloalkyl.
  • R 6 and R 7 of Formula (I) can each independently be C 1-20 alkyl. Alternatively, R 6 and R 7 can be combined with the carbon to which they are attached to form a C 3-12 cycloalkyl or a 3- to 15-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 R 11 groups.
  • R 8 of Formula (I) can be C 3-12 cycloalkyl, C 6-14 aryl, or 5- to 16-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1-4 R 11 groups.
  • Each R 9 of Formula (I) can independently be hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, oxo, -NH 2 , nitro, cyano, or C 1-6 cyanoalkyl.
  • an R 9 can be combined with R 2 and X 1 to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R 11 groups.
  • Each R 10 of Formula (I) can independently be hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, oxo, - NH 2 , nitro, cyano, or C 1-6 cyanoalkyl.
  • an R 10 can be combined with R 3 and the nitrogen to which R 3 is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • Each R 11 can independently be C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, 2- to 12-membered heteroalkyl, C 3-12 cycloalkyl, 5- to 16-membered heteroaryl, C 3-12 cycloalkoxy, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, oxo, -NH 2 , nitro, cyano, or diazirine, wherein the cycloalkyl, heteroaryl, and cycloalkoxy are optionally substituted with one or more hydroxy or halogen groups or a combination thereof.
  • X 1 , X 2 , A 1 , and A 2 of Formula (I) can each independently be C, N, O, or S.
  • Subscripts m, n, and p of Formula (I) can each independently be an integer from 0 to 4.
  • the provided compounds can alternatively have the formula of a pharmaceutically acceptable salt, solvate, or isomer of Formula (I).
  • pharmaceutical compositions including a disclosed compound (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof) and a pharmaceutically acceptable carrier.
  • methods of treating a disorder are provided.
  • the methods include administering a therapeutically effective amount of a disclosed compound (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof), or a therapeutically effective amount of a disclosed pharmaceutical composition including a provided compound and a pharmaceutically acceptable carrier, to a subject in need thereof.
  • a disclosed compound e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof
  • a therapeutically effective amount of a disclosed pharmaceutical composition including a provided compound and a pharmaceutically acceptable carrier e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof
  • a disclosed pharmaceutical composition including a provided compound and a pharmaceutically acceptable carrier
  • the various aspects of the disclosure generally include a small molecule having inhibitory activity against polyomaviruses including BK virus genotypes I, II, III, and IV; JC virus, Merkel Cell polyomavirus, Simian virus 40, and Murine polyomavirus.
  • the provided inhibitory compounds advantageously act on an intracellular target.
  • the provided compounds are beneficially characterized by high potency, good solubility, low lipophilicity, and low interaction with the hERG potassium channel.
  • the compounds may avoid toxicity liabilities, such as thrombocytopenia and neutropenia, unfavorable for BK virus and JC virus indications.
  • Treatment methods applying the provided compounds can be used to intervene after kidney transplant to block BK virus replication and prevent BK virus-associated nephropathy. Additional disclosed methods can be effective in treating JC virus-induced progressive multifocal leukoencephalopathy.
  • B. DEFINITIONS [0015] The abbreviations used herein have their conventional meaning within the chemical and biological arts. Description of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art.
  • substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, or physiological conditions.
  • substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
  • a polymer optionally includes a combination of two or more polymers, and the like.
  • the term “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).
  • the term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field, for example ⁇ 20%, ⁇ 10%, or ⁇ 5%, are within the intended meaning of the recited value.
  • the terms “including,” “comprising,” “having,” “containing,” and variations thereof, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps beyond those explicitly recited.
  • the phrase “consisting of” is closed and excludes any element, step, or ingredient not explicitly specified.
  • the phrase “consisting essentially of” limits the scope of the described feature to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the disclosed feature.
  • the term “alkyl,” by itself or as part of another substituent refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated.
  • a branched alkyl may include one or branches having a geminal, vicinal, and/or isolated pattern.
  • an alkyl may include gem-methyl groups.
  • Alkyl may include any number of carbons, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 .
  • C 1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc.
  • Alkyl may also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc.
  • alkyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy.
  • alkenyl refers to an alkyl group having at least one carbon-carbon double bond.
  • Alkenyl may include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6 .
  • Alkenyl groups may have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more.
  • alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, and 1,3,5-hexatrienyl.
  • alkenyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy.
  • alkynyl by itself or as part of another substituent, refers to an alkyl group having at least one carbon-carbon triple bond.
  • Alkynyl may include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6 .
  • alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.
  • alkynyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy.
  • alkoxy refers to a substituted alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-.
  • alkoxy groups may have any suitable number of carbon atoms, such as C 16 .
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, etc.
  • hydroxyalkyl or “alkylhydroxy” refer to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a hydroxy group.
  • alkylhydroxy groups can have any suitable number of carbon atoms, such as C 1-6 .
  • Exemplary alkylhydroxy groups include, but are not limited to, hydroxy-methyl, hydroxyethyl (where the hydroxy is in the 1- or 2-position), hydroxypropyl (where the hydroxy is in the 1-, 2- or 3-position), hydroxybutyl (where the hydroxy is in the 1-, 2-, 3- or 4-position), hydroxypentyl (where the hydroxy is in the 1-, 2-, 3-, 4- or 5-position), hydroxyhexyl (where the hydroxy is in the 1-, 2-, 3-, 4-, 5- or 6-position), 1,2-dihydroxyethyl, and the like.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • haloalkyl refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms.
  • alkyl group haloalkyl groups can have any suitable number of carbon atoms, such as C 1-6 .
  • haloalkyl includes trifluoromethyl, fluoromethyl, etc.
  • perfluoro can be used to define a compound or radical where all the hydrogens are replaced with fluorine.
  • perfluoromethyl refers to 1,1,1-trifluoromethyl.
  • the term “carboxy” refers to a carboxylic acid group of the formula -C(O)OH or -CO 2 H.
  • the term “carboxyalkyl” refers to a carboxy group linked to an alkyl, as described above, and generally having the formula -C 1-20 alkyl-C(O)OH.
  • the term “cyano,” by itself or as part of another substituent refers to a carbon atom triple-bonded to a nitrogen atom (i.e., the moiety –C ⁇ N).
  • cyanoalkyl refers to a cyano group linked to an alkyl, as described above, and generally having the formula -C 1-20 alkyl-C ⁇ N.
  • heteroalkyl by itself or as part of another substituent, refers to an alkyl group of any suitable length and having from 1 to 3 heteroatoms such as N, O and S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O) 2 -.
  • heteroalkyl may include ethers, thioethers and alkyl-amines.
  • the heteroatom portion of the heteroalkyl may replace a hydrogen of the alkyl group to form a hydroxy, thio, or amino group.
  • the heteroatom portion may be the connecting atom, or be inserted between two carbon atoms.
  • cycloalkyl by itself or as part of another substituent, refers to a saturated or partially unsaturated, monocyclic, fused polycyclic, spiro polycyclic, or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated.
  • Cycloalkyl may include any number of carbons, such as C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 .
  • Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • Saturated bicyclic and polycyclic cycloalkyl rings include, for example, bicyclo[1.1.1]pentane, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds in the ring.
  • Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy.
  • heterocyclyl by itself or as part of another substituent, refers to a saturated heterocyclyl ring system having from 3 to 15 ring members, a partially unsaturated non-aromatic ring, or a partially unsaturated, non-aromatic fused, spiro, or bridged multiple-ring system in which one or more of the carbon atoms are each independently replaced with the same or different heteroatom such as N, O and S.
  • heteroatoms may also be useful, including, but not limited to, B, Al, Si and P.
  • the heteroatoms may be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-.
  • Heterocyclyl groups may include any number of ring atoms, such as, C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , C 3-12 , or C 3-15 , wherein at least one of the carbon atoms is replaced by a heteroatom.
  • heterocyclyl groups such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4.
  • the heterocyclyl group may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane,
  • heterocycloalkyl rings of heterocyclyl groups may also be fused to aromatic or non-aromatic rings to form members including, but not limited to, indoline.
  • Heterocyclyl groups thus include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems.
  • Examples include dihydroquinolines, e.g., 3,4- dihydroquinoline, dihydroisoquinolines, e.g., 1,2- dihydroisoquinoline, tetrahydroquinolines, e.g., 1,2,3,4-tetrahydroquinoline, tetrahydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., isoindoline, isoindolones (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'- isoindolin]-3'-one, and the like.
  • dihydroquinolines e.g., 3,4- dihydroquinoline
  • dihydroisoquinolines e.g., 1,2- dihydroisoquinoline
  • tetrahydroquinolines e.g., 1,2,3,4-tetra
  • Heterocyclyl groups may have 3-15 members, or 3-12 members, or 3-10 members, or 3-7 members, or 5-6 members.
  • heterocyclyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy.
  • the heterocyclyl groups may be linked via any position on the ring.
  • aziridine may be 1- or 2-aziridine
  • azetidine may be 1- or 2- azetidine
  • pyrrolidine may be 1-, 2- or 3-pyrrolidine
  • piperidine may be 1-, 2-, 3- or 4-piperidine
  • pyrazolidine may be 1-, 2-, 3-, or 4- pyrazolidine
  • imidazolidine may be 1-, 2-, 3- or 4-imidazolidine
  • piperazine may be 1-, 2-, 3- or 4-piperazine
  • tetrahydrofuran may be 1- or 2-tetrahydrofuran
  • oxazolidine may be 2-, 3-, 4- or 5- oxazolidine
  • isoxazolidine may be 2-, 3-, 4- or 5-isoxazolidine
  • thiazolidine may be 2-, 3-, 4- or 5-thiazolidine
  • isothiazolidine may be 2-, 3-, 4- or 5- isothiazolidine
  • morpholine may be 2-, 3- or 4-morpholine.
  • heterocyclylene refers to a heterocyclyl group, as defined above, linking at least two other groups. The two moieties linked to the heterocyclyl are linked to different atoms of the heterocyclyl.
  • aryl refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups may include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members.
  • Aryl groups may be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group.
  • Representative aryl groups include phenyl, naphthyl and biphenyl.
  • Other aryl groups include benzyl, having a methylene linking group.
  • Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl.
  • Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl.
  • Some other aryl groups have 6 ring members, such as phenyl.
  • aryl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy.
  • heteroaryl refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms may also be useful, including, but not limited to, -S(O)- and -S(O) 2 -.
  • Heteroaryl groups may include any number of ring atoms, such as C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , or C 3-12 , wherein at least one of the carbon atoms is replaced by a heteroatom. Any suitable number of heteroatoms may be included in the heteroaryl groups, such as 1, 2, 3, 4; or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5.
  • Heteroaryl groups may have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.
  • the heteroaryl group may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups may also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran.
  • Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine.
  • heteroaryl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy. [0038] The heteroaryl groups may be linked via any position on the ring.
  • pyrrole includes 1-, 2-, and 3-pyrrole
  • pyridine includes 2-, 3-, and 4-pyridine
  • imidazole includes 1-, 2-, 4-, and 5-imidazole
  • pyrazole includes 1-, 3-, 4-, and 5-pyrazole
  • triazole includes 1-, 4-, and 5- triazole
  • tetrazole includes 1- and 5-tetrazole
  • pyrimidine includes 2-, 4-, 5-, and 6- pyrimidine
  • pyridazine includes 3- and 4-pyridazine
  • 1,2,3-triazine includes 4- and 5-triazine
  • 1,2,4-triazine includes 3-, 5-, and 6-triazine
  • 1,3,5-triazine includes 2-triazine
  • thiophene includes 2- and 3- thiophene
  • furan includes 2- and 3-furan
  • thiazole includes 2-, 4-, and 5-thiazole
  • isothiazole includes 3-, 4-, and 5-isothiazole
  • heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran.
  • N, O or S such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-,
  • heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroatoms such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine.
  • heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.
  • heteroaryl groups include from 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline.
  • Other heteroaryl groups include from 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran.
  • heteroaryl groups include from 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups include from 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.
  • the term “nitro,” by itself or as part of another substituent refers to the moiety –NO 2 .
  • the term “fused” refers to a ring substituent which is joined by two bonds at adjacent atoms. Decahydronaphthalene is an example of a fused ring system.
  • the term “spiro” refers to a ring substituent which is joined by two bonds at the same atom.
  • spiro groups include 1,1-diethylcyclopentane, dimethyl- dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.
  • bridged refers to a ring substituent which is joined by two bonds at non-adjacent atoms.
  • Quinuclidinyl and adamantyl are examples of bridged ring systems
  • salt refers to acid or base salts of the compounds of the present disclosure.
  • an “agriculturally acceptable salt” is one that is compatible with other ingredients of a formulation composition containing the compound, and that is not deleterious to a recipient thereof. It is thus understood that the agriculturally acceptable salts are non-toxic.
  • Illustrative examples of salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • Salts of the acidic compounds of the present disclosure are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
  • bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.
  • acid addition salts such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid
  • a basic group such as pyridyl
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • the term “solvate” refers to a compound that is complexed to at least one solvent molecule.
  • the compounds of the present disclosure may be complexed with from 1 to 10 solvent molecules.
  • the solvent is water and the solvate is a hydrate.
  • the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. Isomers thus include compounds having different arrangements of the same formula of atoms in a molecule possessing one or more asymmetric carbon atoms or double bonds. Isomers may include racemates, enantiomers, diastereomers, geometric isomers, and individual isomers. [0049] As used herein, the term “subject” refers to a vertebrate, and preferably to a mammal.
  • Mammalian subjects for which the provided composition is suitable include, but are not limited to, mice, rats, simians, humans, farm animals, sport animals, and pets.
  • the subject is human.
  • the subject is male.
  • the subject is female.
  • the subject is an adult.
  • the subject is an adolescent.
  • the subject is a child.
  • the subject is above 10 years of age, e.g., above 20 years of age, above 30 years of age, above 40 years of age, above 50 years of age, above 60 years of age, above 70 years of age, or above 80 years of age.
  • the subject is less than 80 years of age, e.g., less than 70 years of age, less than 60 years of age, less than 50 years of age, less than 40 years of age, less than 30 years of age, less than 20 years of age, or less than 10 years of age.
  • pharmaceutically acceptable excipient and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and may be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject.
  • Non-limiting examples of pharmaceutically acceptable excipients and carriers include water, NaCl, normal saline solutions, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, and the like.
  • administering refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
  • the term “therapeutically effective amount” refers to an amount or dose of a compound, composition, or formulation that produces therapeutic effects for which it is administered.
  • the exact amount or dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • the terms “treat”, “treating” and “treatment” refers to a procedure resulting in any indicia of success in the elimination or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of one or more symptoms.
  • the treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination or laboratory test.
  • the polyomavirus inhibitor is an acyl sulfonamide compound having the structure 1 wherein each R of Formula (I) can independently be C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, oxo, -NH 2 , nitro, cyano, -SO 2 R 11 , or -P(R 11 ) 3 .
  • R 2 of Formula (I) can be absent, hydrogen, or C 1-20 alkyl.
  • R 2 can be combined with an R 9 and X 1 to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R 11 groups.
  • R 3 of Formula (I) can be hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 2-9 carboxyalkyl, or 2- to 20-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R 11 groups.
  • R 3 can be combined with R 4 and the nitrogen to which R 3 and R 4 are attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • R 3 can be combined with an R 10 and the nitrogen to which R 3 is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • R 4 of Formula (I) can be hydrogen, C 1-20 alkyl, C 2-20 alkynyl, C 2- 9 carboxyalkyl, or 2- to 20-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R 11 groups.
  • R 4 can be combined with R 3 and the nitrogen to which R 3 and R 4 are attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • R 5 of Formula (I) can be hydrogen, C 1-20 alkyl, C 1-20 alkoxy, C 1-20 alkylhydroxy, halogen, C 1-20 haloalkyl, or C 3-12 cycloalkyl.
  • R 6 and R 7 of Formula (I) can each independently be C 1-20 alkyl. Alternatively, R 6 and R 7 can be combined with the carbon to which they are attached to form a C 3-12 cycloalkyl or a 3- to 15-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 R 11 groups.
  • R 8 of Formula (I) can be C 3-12 cycloalkyl, C 6-14 aryl, or 5- to 16-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1-4 R 11 groups.
  • Each R 9 of Formula (I) can independently be hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, oxo, -NH 2 , nitro, cyano, or C 1-6 cyanoalkyl.
  • an R 9 can be combined with R 2 and X 1 to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R 11 groups.
  • Each R 10 of Formula (I) can independently be hydrogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, oxo, - NH 2 , nitro, cyano, or C 1-6 cyanoalkyl.
  • an R 10 can be combined with R 3 and the nitrogen to which R 3 is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • Each R 11 can independently be C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, 2- to 12-membered heteroalkyl, C 3-12 cycloalkyl, 5- to 16-membered heteroaryl, C 3-12 cycloalkoxy, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, oxo, -NH 2 , nitro, cyano, or diazirine, wherein the cycloalkyl, heteroaryl, and cycloalkoxy are optionally substituted with one or more hydroxy or halogen groups or a combination thereof.
  • X 1 , X 2 , A 1 , and A 2 of Formula (I) can each independently be C, N, O, or S.
  • Subscripts m, n, and p of Formula (I) can each independently be an integer from 0 to 4.
  • the provided compounds can alternatively have the formula of a pharmaceutically acceptable salt, solvate, or isomer of Formula (I).
  • at least one R 1 of Formula (I) is halogen, nitro, or cyano.
  • each R 1 is independently halogen, nitro, or cyano.
  • at least one R 1 is fluorine, chlorine, nitro, or cyano.
  • each R 1 is independently fluorine, chlorine, nitro, or cyano. In some embodiments, at least one R 1 is fluorine, nitro, or cyano. In some embodiments, each R 1 is independently fluorine, nitro, or cyano. In some embodiments, at least one R 1 is fluorine or cyano. In some embodiments, each R 1 is independently fluorine or cyano. In some embodiments, at least one R 1 is nitro. In some embodiments, each R 1 is nitro. In some embodiments, at least one R 1 is halogen. In some embodiments, each R 1 is independently halogen. In some embodiments, at least one R 1 is chlorine or fluorine.
  • each R 1 is independently chlorine or fluorine. In some embodiments, at least one R 1 is fluorine. In some embodiments, each R 1 is fluorine. In some embodiments, at least one R 1 is chlorine. In some embodiments, each R 1 is chlorine. In some embodiments, at least one R 1 is cyano. In some embodiments, each R 1 is cyano. [0056] In some embodiments, e.g., when X 1 is C, R 2 of Formula (I) is hydrogen. In some embodiments, e.g., when X 1 is O, R 2 is absent. In some embodiments, R 2 is C 1-6 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl.
  • R 2 is propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is sec-butyl. In some embodiments, R 2 is tert-butyl. In some embodiments, R 2 is pentyl. In some embodiments, R 2 is isopentyl. In some embodiments, R 2 is 2-methylbutyl. In some embodiments, R 2 is pentan-2-yl. In some embodiments, R 2 is 3-methylbutan-2-yl. In some embodiments, R 2 is pentan-3-yl. In some embodiments, R 2 is neopentyl.
  • R 2 is tert-pentyl. In some embodiments, R 2 is hexyl. In some embodiments, R 2 is 4-methylpentyl. In some embodiments, R 2 is 3- methylpentyl. In some embodiments, R 2 is 2-methylpentyl. In some embodiments, R 2 is hexan-2- yl. In some embodiments, R 2 is 2,3-dimethylbutyl. In some embodiments, R 2 is 4-methylpentan- 2-yl. In some embodiments, R 2 is 3-methylpentan-2-yl. In some embodiments, R 2 is 2-ethylbutyl. In some embodiments, R 2 is hexan-3-yl.
  • R 2 is 3,3-dimethylbutyl. In some embodiments, R 2 is 2,2-dimethylbutyl. In some embodiments, R 2 is 2-methylpentan-2-yl.
  • R 3 and R 4 of Formula (I) are each independently hydrogen, C 1-6 alkyl, C 2-12 alkynyl, C 2-9 carboxyalkyl, or 2- to 12-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R 11 groups. In some embodiments, R 3 and R 4 are each independently C 1-6 alkyl or C 2-12 alkynyl.
  • R 3 and R 4 are each independently C 1-6 alkyl or C 2-9 carboxyalkyl. In some embodiments, R 3 and R 4 are each independently C 1-6 alkyl or 2- to 12-membered heteroalkyl. In some embodiments, R 3 and R 4 are each independently methyl or C 2-12 alkynyl. In some embodiments, R 3 and R 4 are each independently methyl or C 2-9 carboxyalkyl. In some embodiments, R 3 and R 4 are each independently methyl or 2- to 12-membered heteroalkyl. In some embodiments, R 3 and R 4 are each independently methyl or hexynyl. In some embodiments, R 3 and R 4 are each independently methyl or methyl-d 3 .
  • R 3 and R 4 are each independently methyl or propyl. In some embodiments, R 3 and R 4 are each independently methyl or diazirinylheptynyl. In some embodiments, R 3 and R 4 are each independently methyl or mehoxyethyl. In some embodiments, R 3 and R 4 are each independently methyl or methoxyoxobutyl. In some embodiments, R 3 and R 4 are each methyl. [0058] In some embodiments, R 3 and R 4 of Formula (I) are combined with the nitrogen to which they are attached to form a 3- to 15-membered heterocyclyl optionally substituted with 1-4 R 11 groups.
  • R 3 and R 4 are combined with the nitrogen to which they are attached to form an azetidinyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a fluoroazetidinyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a methylazetidinyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a methoxyazetidinyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a difluoroazetidinyl.
  • R 3 and R 4 are combined with the nitrogen to which they are attached to form a methylfluoroazetidinyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a methoxyfluoroazetidinyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a difluoromethylazetidinyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a triifluoromethylazetidinyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a difluoromethoxyazetidinyl.
  • R 3 and R 4 are combined with the nitrogen to which they are attached to form a cyclopropoxyazetidinyl. [0059] In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form an azabicyclo[3.1.0]hexyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a difluoroazabicyclo[3.1.0]hexyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form an azaspiro[2.3]hexyl optionally substituted with 1-4 R 11 groups.
  • R 3 and R 4 are combined with the nitrogen to which they are attached to form a difluoroazaspiro[2.3]hexyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form an azaspiro[3.3]heptyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a difluoroazaspiro[3.3]heptyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form an oxaazaspiro[3.3]heptyl .
  • R 3 and R 4 are combined with the nitrogen to which they are attached to form a pyrrolidyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a fluoropyrrolidyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a difluoropyrrolidyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a methoxypyrrolidyl. In some embodiments, R 3 and R 4 are combined with the nitrogen to which they are attached to form a morpholyl optionally substituted with 1-4 R 11 groups.
  • R 5 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 haloalkyl, or C 3-6 cycloalkyl.
  • R 5 is hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, or cyclopropyl.
  • R 5 is hydrogen.
  • R 5 is C 1-6 alkyl.
  • R 5 is methyl.
  • R 5 is ethyl.
  • R 5 is C 1-6 alkoxy.
  • R 5 is methoxy.
  • R 5 is halogen.
  • R 5 is fluorine. In some embodiments, R 5 is chlorine. In some embodiments, R 5 is C1-6 haloalkyl. In some embodiments, R 5 is difluoromethyl. In some embodiments, R 5 is trifluoromethyl. In some embodiments, R 5 is C 3-6 cycloalkyl. In some embodiments, R 5 is cyclopropyl. [0062] In some embodiments, R 6 and R 7 are each independently C 1-6 alkyl. In some embodiments, at least one of R 6 and R 7 is methyl. In some embodiments, R 6 and R 7 are each methyl. In some embodiments, at least one of R 6 and R 7 is ethyl.
  • At least one of R 6 and R 7 is propyl. In some embodiments, at least one of R 6 and R 7 is isopropyl. In some embodiments, at least one of R 6 and R 7 is butyl. In some embodiments, at least one of R 6 and R 7 is isobutyl. In some embodiments, at least one of R 6 and R 7 is sec-butyl. In some embodiments, at least one of R 6 and R 7 is tert-butyl. In some embodiments, at least one of R 6 and R 7 is pentyl. In some embodiments, at least one of R 6 and R 7 is isopentyl. In some embodiments, at least one of R 6 and R 7 is 2-methylbutyl.
  • At least one of R 6 and R 7 is pentan-2-yl. In some embodiments, at least one of R 6 and R 7 is 3-methylbutan-2-yl. In some embodiments, at least one of R 6 and R 7 is pentan-3-yl. In some embodiments, at least one of R 6 and R 7 is neopentyl. In some embodiments, at least one of R 6 and R 7 is tert-pentyl. In some embodiments, at least one of R 6 and R 7 is hexyl. In some embodiments, at least one of R 6 and R 7 is 4- methylpentyl. In some embodiments, at least one of R 6 and R 7 is 3-methylpentyl.
  • At least one of R 6 and R 7 is 2-methylpentyl. In some embodiments, at least one of R 6 and R 7 is hexan-2-yl. In some embodiments, at least one of R 6 and R 7 is 2,3-dimethylbutyl. In some embodiments, at least one of R 6 and R 7 is 4-methylpentan-2-yl. In some embodiments, at least one of R 6 and R 7 is 3-methylpentan-2-yl. In some embodiments, at least one of R 6 and R 7 is 2-ethylbutyl. In some embodiments, at least one of R 6 and R 7 is hexan-3-yl.
  • R 6 and R 7 is 3,3-dimethylbutyl. In some embodiments, at least one of R 6 and R 7 is 2,2-dimethylbutyl. In some embodiments, at least one of R 6 and R 7 is 2- methylpentan-2-yl. [0063] In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a C 3-8 cycloalkyl or a 3- to 15-membered heterocyclyl wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 R 11 groups.
  • R 6 and R 7 are combined with the carbon to which they are attached to form a C 3-8 cycloalkyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a cyclobutyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a cyclopentyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a cyclohexyl optionally substituted with 1-4 R 11 groups.
  • R 6 and R 7 are combined with the carbon to which they are attached to form a methylcyclohexyl. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a difluorocyclohexyl. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a trifluoromethylcyclohexyl. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a cycloheptyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a spiro[3.3]heptyl optionally substituted with 1-4 R 11 groups.
  • R 6 and R 7 are combined with the carbon to which they are attached to form a bicyclo[2.2.2]octyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a methylbicyclo[2.2.2]octyl. [0064] In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a 3- to 15-membered heterocyclyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a tetrahydropyryl optionally substituted with 1-4 R 11 groups.
  • R 6 and R 7 are combined with the carbon to which they are attached to form a difluorotetrahydropyryl. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a tetrohydrofuryl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form an oxepanyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a hydroxyfluorooxepanyl. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a hydroxyfluorooxepanyl.
  • R 6 and R 7 are combined with the carbon to which they are attached to form a methyldioxepanyl. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form an oxabicyclo[4.1.0]heptyl optionally substituted with 1-4 R 11 groups. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form a difluorooxabicyclo[4.1.0]heptyl. In some embodiments, R 6 and R 7 are combined with the carbon to which they are attached to form an oxabicyclo[2.2.1]heptyl optionally substituted with 1-4 R 11 groups.
  • R 6 and R 7 are combined with the carbon to which they are attached to form an oxaspiro[2.4]heptyl optionally substituted with 1-4 R 11 groups.
  • R 8 of Formula (I) is C 3-8 cycloalkyl optionally substituted with 1-4 R 11 groups.
  • R 8 is cyclohexyl.
  • R 8 is cycloheptyl.
  • R 8 is C 6-12 aryl optionally substituted with 1-4 R 11 groups.
  • R 8 is phenyl optionally substituted with 1-4 R 11 groups.
  • R 8 is fluorophenyl.
  • R 8 is difluorophenyl. In some embodiments, R 8 is chlorophenyl. In some embodiments, R 8 is fluorochlorophenyl. In some embodiments, R 8 is trifluoromethylphenyl. In some embodiments, R 8 is aminoethylphenyl. In some embodiments, R 8 is 5- to 16-membered heteroaryl optionally substituted with 1-4 R 11 groups. In some embodiments, R 8 is a saturated cyclic amine. In some embodiments, R 8 is pyridyl. In some embodiments, R 8 is pyrazyl. [0066] In some embodiments, each R 9 and R 10 of Formula (I) is independently hydrogen, C 1-6 alkoxy, or halogen.
  • At least one R 9 and/or at least one R 10 is hydrogen. In some embodiments, each R 9 and R 10 is hydrogen. In some embodiments, at least one R 9 and/or at least one R 10 is C 1-6 alkoxy. In some embodiments, at least one R 9 and/or at least one R 10 is methoxy. In some embodiments, each R 9 and R 10 is C 1-6 alkoxy. In some embodiments, at least one R 9 and/or at least one R 10 is C 1-6 halogen. In some embodiments, each R 9 and R 10 is C 1-6 halogen. In some embodiments, at least one R 9 and/or at least one R 10 is C 1-6 fluorine.
  • one R 9 is combined with R 2 and X 1 to form a 3- to 15- membered heterocyclylene optionally substituted with 1-4 R 11 groups. In some embodiments, one R 9 is combined with R 2 and X 1 to form a piperidinylene optionally substituted with 1-4 R 11 groups. In some embodiments, one R 9 is combined with R 2 and X 1 to form a pyrrolidinylene optionally substituted with 1-4 R 11 groups. [0068] In some embodiments, one R 10 is combined with R 3 and the nitrogen to which R 3 is attached to form a 3- to 15-membered heterocyclyl optionally substituted with 1-4 R 11 groups.
  • each R 10 is combined with R 3 and the nitrogen to which R 3 is attached to form a morpholyl optionally substituted with 1-4 R 11 groups. In some embodiments, one R 10 is combined with R 3 and the nitrogen to which R 3 is attached to form a oxazepanyl optionally substituted with 1-4 R 11 groups.
  • each R 11 is independently C 1-6 alkyl, C 1-6 alkoxy, hydroxy, 2- to 8-membered heteroalkyl, C 3-12 cycloalkoxy, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, or diazirine.
  • each R 11 is independently methyl, methoxy, 2-methoxyethyl, 2- aminoethyl, fluorine, chlorine, cyclopropoxy, trifluoromethyl, difluoromethoxy, or diazirine.
  • at least one R 11 is C 1-6 alkyl. In some embodiments, at least one R 11 is methyl. In some embodiments, at least one R 11 is C 1-6 alkoxy. In some embodiments, at least one R 11 is methoxy. In some embodiments, at least one R 11 is hydroxy. In some embodiments, at least one R 11 is 2- to 8-membered heteroalkyl. In some embodiments, at least one R 11 is 2- methoxyethyl.
  • At least one R 11 is 2-aminoethyl. In some embodiments, at least one R 11 is halogen. In some embodiments, at least one R 11 is fluorine. In some embodiments, at least one R 11 is chlorine. In some embodiments, at least one R 11 is C 1-6 haloalkyl. In some embodiments, at least one R 11 is difluoromethyl. In some embodiments, at least one R 11 is trifluoromethyl. In some embodiments, at least one R 11 is diazirine. In some embodiments, at least one R 11 is C 3-12 cycloalkoxy. In some embodiments, at least one R 11 is cyclopropoxy.
  • At least one R 11 is C 1-6 haloalkoxy. In some embodiments, at least one R 11 is difluoromethoxy. [0070] In some embodiments, at least one of X 1 , X 2 , A 1 , and A 2 of Formula (I) is C. In some embodiments, A 1 , and A 2 are each C. In some embodiments, X 2 is C. In some embodiments, at least one of X 1 , X 2 , A 1 , and A 2 is N. In some embodiments, X 1 is N. In some embodiments, at least one of X 1 , X 2 , A 1 , and A 2 is O. In some embodiments, X 1 is O and R 2 is absent.
  • At least one of X 1 , X 2 , A 1 , and A 2 is S. In some embodiments, X 2 is S. [0071] In some embodiments, at least one of the subscripts m, n, and p is an integer from 0 to 3. In some embodiments, the subscripts m, n, and p are each independently an integer from 0 to 3. In some embodiments, at least one of the subscripts m, n, and p is an integer from 1 to 4. In some embodiments, the subscripts m, n, and p are each independently an integer from 1 to 4. In some embodiments, at least one of the subscripts m, n, and p is an integer from 0 to 2.
  • the subscripts m, n, and p are each independently an integer from 0 to 2. In some embodiments, at least one of the subscripts m, n, and p is an integer from 1 to 3. In some embodiments, the subscripts m, n, and p are each independently an integer from 1 to 3. In some embodiments, at least one of the subscripts m, n, and p is an integer from 2 to 4. In some embodiments, the subscripts m, n, and p are each independently an integer from 2 to 4. In some embodiments, at least one of the subscripts m, n, and p is 1 or 2. In some embodiments, the subscripts m, n, and p are each independently 1 or 2.
  • m is 1. In some embodiments, m is 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, p is 1. In some embodiments, p is 2. [0072] In some embodiments, the compound of Formula (I) has the following structure:
  • the compound of Formula (I) has the following structure: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X 1 , X 2 , A 1 , A 2 , and n are as defined above.
  • the compound of Formula (I) has the following structure: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and n are as defined above.
  • the compound of Formula (I) has the following structure: wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined above, and R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, nitro, or cyano. In some embodiments, at least one of R 1a , R 1b , and R 1c is hydrogen, halogen, nitro, or cyano.
  • R 1a , R 1b , and R 1c are each independently hydrogen, halogen, nitro, or cyano. In some embodiments, at least one of R 1a , R 1b , and R 1c is hydrogen, fluorine, chlorine, nitro, or cyano. In some embodiments, R 1a , R 1b , and R 1c are each independently hydrogen, fluorine, chlorine, nitro, or cyano. In some embodiments, at least one of R 1a , R 1b , and R 1c is hydrogen, fluorine, nitro, or cyano. In some embodiments, R 1a , R 1b , and R 1c are each independently hydrogen, fluorine, nitro, or cyano.
  • At least one of R 1a , R 1b , and R 1c is fluorine or cyano. In some embodiments, R 1a , R 1b , and R 1c are each independently fluorine or cyano. In some embodiments, at least one of R 1a , R 1b , and R 1c is nitro. In some embodiments, R 1a , R 1b , and R 1c are each nitro. In some embodiments, at least one of R 1a , R 1b , and R 1c is halogen. In some embodiments, R 1a , R 1b , and R 1c are each independently halogen.
  • At least one of R 1a , R 1b , and R 1c is chlorine or fluorine. In some embodiments, R 1a , R 1b , and R 1c are each independently chlorine or fluorine. In some embodiments, at least one of R 1a , R 1b , and R 1c is fluorine. In some embodiments, R 1a , R 1b , and R 1c are each fluorine. In some embodiments, at least one of R 1a , R 1b , and R 1c is chlorine. In some embodiments, R 1a , R 1b , and R 1c are each chlorine. In some embodiments, at least one of R 1a , R 1b , and R 1c is cyano.
  • R 1a , R 1b , and R 1c are each cyano.
  • the compound of Formula (I) has the following structure: wherein R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 11 are as defined above.
  • the compound of Formula (I) has the following structure: wherein R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above.
  • the compound of Formula (I) has the structure:
  • R 11a , R 11b , R 11c , and R 11d are each independently C 1-6 alkyl, C 1-6 alkoxy, hydroxy, 2- to 8-membered heteroalkyl, halogen, C 3-12 cycloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or diazirine, wherein the cycloalkoxy is optionally substituted with one or more hydroxy or halogen groups or a combination thereof.
  • the compound of Formula (I) is:
  • the compound of Formula I is:
  • the compound of Formula I is: [0081] In some embodiments, the compound of Formula I is: [0082] In some embodiments, the compound of Formula I is: [0083] In some embodiments, the compound of Formula (I) is:
  • the compounds provided herein may also be the salts, solvates, and isomers of any on the structures disclosed above.
  • Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in art.
  • acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like
  • salts of organic acids such as glucuronic or galactunoric acids and the like
  • Certain specific compounds of the present disclosure contain basic acidic functionalities that allow the compounds to be converted into base addition salts. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • he parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds of the present disclosure may be radiolabeled with radioactive isotopes, such as for example deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon- 13 ( 13 C), or carbon-14 ( 14 C).
  • the present invention further includes compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide any of the compounds disclosed above.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. D.
  • compositions including one or more pharmaceutically acceptable carriers, diluents, excipients, or buffers and one or more of the compounds provided herein.
  • the pharmaceutically acceptable carrier, diluent, excipient, or buffer is suitable for use in a subject, for example, a human.
  • Pharmaceutically acceptable excipients include, but are not limited to, liquids such as water, saline, glycerol, sugars and ethanol.
  • the preparation of pharmaceutically acceptable carriers and excipients is described in, e.g., Remington: The Science and Practice of Pharmacy, 22nd edition, Loyd V. Allen et al, editors, Pharmaceutical Press (2012).
  • the composition also includes an additional active compound or other chemotherapeutic agent.
  • the pharmaceutical composition further includes one or more stabilizing compounds, which may be administered in any sterile, biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and water.
  • the pharmaceutical compositions also contain a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts can include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • compositions provided herein can be prepared in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by a subject, e.g., a human patient.
  • compositions of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compositions described herein can be administered by inhalation, for example, intranasally.
  • the compositions of the present invention can be administered transdermally.
  • the compositions of this invention can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35, (1995):1187-1193; Tjwa, Ann. Allergy Asthma Immunol.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
  • Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage).
  • compositions of the invention may also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
  • Push-fit capsules may contain the compounds of the present invention mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the compounds of the present invention may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the compounds of the present disclosure are dispersed homogeneously therein, as by stirring.
  • the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations may be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations may be adjusted for osmolarity.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Oil suspensions may be formulated by suspending the compounds of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil; or in a mineral oil such as liquid paraffin; or a mixture of these.
  • the oil suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol.
  • Sweetening agents such as glycerol, sorbitol or sucrose, may be added to provide a palatable oral preparation.
  • These formulations may be preserved by the addition of an antioxidant such as ascorbic acid.
  • an injectable oil vehicle see Minto, J. Pharmacol. Exp. Ther.281, (1997):93.
  • the pharmaceutical formulations of the disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil or a mineral oil, described above, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan mono- oleate.
  • the emulsion may also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs.
  • compositions of the present invention may also be delivered as microspheres for slow release in the body.
  • microspheres may be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7, (1995):623); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12, (1995):857); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49, (1997):669).
  • compositions of the present disclosure are formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ.
  • parenteral administration such as intravenous (IV) administration or administration into a body cavity or lumen of an organ.
  • Such formulations for administration will commonly comprise a solution of the compositions of the present disclosure dissolved in a pharmaceutically acceptable carrier.
  • acceptable vehicles and solvents that may be employed are water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter.
  • These formulations may be sterilized by conventional, well known sterilization techniques.
  • the formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH-adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • concentration of the compositions of the present disclosure in these formulations may vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs.
  • the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.
  • formulations of the compositions of the present disclosure are delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis.
  • liposomes particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, delivery may be focused into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13, (1996):293; Chonn, Curr. Opin.
  • Lipid-based formulations include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS).
  • SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can disperse spontaneously in aqueous media and form fine emulsions (SEDDS) or microemulsions (SMEDDS).
  • Lipids useful in the formulations of the present disclosure include any natural or synthetic lipids including, but not limited to, sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, LABRAFIL®, LABRASOL®, CREMOPHOR®, SOLUTOL®, TWEEN®, CAPRYOL®, CAPMUL®, CAPTEX®, and PECEOL®.
  • F. METHODS OF TREATING A DISORDER [0107]
  • the present disclosure provides a method of treating a disorder. The method includes administering to a subject in need of such a treatment a therapeutically effective amount of a compound disclosed herein or a formulation thereof as disclosed herein, thereby treating the disorder.
  • the treatment is given with a curative intent. In some embodiments, the treatment is given with an aim to prolong the life of the subject. In some embodiments, the treatment is given for the purpose of reducing symptoms associated with the disorder. In some embodiments, symptoms reduced by the treatment include viruria. In some embodiments, the reduced symptoms include viremia. In some embodiments, the treatment is given prophylactically to a subject, e.g., a kidney transplant recipient, considered to be at an elevated risk of developing a disorder or symptoms typically associated with a disorder. [0108] In some embodiments, the disorder is an infection with a polyomavirus. In some embodiments, the disorder is an infection with a genotype I BK virus.
  • the disorder is an infection with a genotype II BK virus. In some embodiments, the disorder is an infection with a genotype III BK virus. In some embodiments, the disorder is an infection with a genotype IV BK virus. In some embodiments, the disorder is an infection with JC virus. In some embodiments, the disorder is an infection with a Merkel virus. [0109] Thus, as a further embodiment, the present disclosure provides the use of any of the compounds disclosed herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof) for the manufacture of a medicament.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof for the manufacture of a medicament.
  • the medicament is for treatment of an infection with a polyomavirus such as a genotype I BK virus, a genotype II BK virus, a genotype III BK virus, a genotype IV BK virus, a JC virus, and/or a Merkel virus.
  • a polyomavirus such as a genotype I BK virus, a genotype II BK virus, a genotype III BK virus, a genotype IV BK virus, a JC virus, and/or a Merkel virus.
  • a polyomavirus such as a genotype I BK virus, a genotype II BK virus, a genotype III BK virus, a genotype IV BK virus, a JC virus, and/or a Merkel virus.
  • the present disclosure provides the use of a compound of Formula (I) or a salt, solvate, or isomer thereof for the manufacture of a medicament for the treatment of an infection with a genotype I BK virus, a genotype II BK virus, a genotype III BK virus, a genotype IV BK virus, a JC virus, and/or a Merkel virus.
  • the subject is an organ transplant patient.
  • the subject can be, for example, the recipient of renal or hematopoietic stem cell transplantation.
  • the subject is an immunocompromised patient.
  • the subject can be, for example, a transplant recipient who is immunocompromised from immunosuppressive therapy used to prevent transplant rejection.
  • the subject can be, for example, an HIV-positive patient.
  • disorders or conditions suitable for treatment with the provide methods include, but are not limited to, nephropathy, hemorrhagic cystitis, pneumonitis, retinitis, meningoencephalitis, and/or progressive multifocal leukoencephalopathy.
  • G. EXEMPLARY EMBODIMENTS [0111] The following embodiments are contemplated. All combinations of features and embodiments are contemplated.
  • Embodiment 1 A compound having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein each R 1 is independently C 1-6 alkyl, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, oxo, -NH 2 , nitro, cyano, -SO 2 R 11 , or -P(R 11 ) 3 ; R 2 is absent, hydrogen, or C 1-20 alkyl; or is combined with R 9 and X 1 to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R 11 groups; R 3 is hydrogen, C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 2-9 carboxyalkyl, or 2- to 20-membered heteroalkyl; is combined with R 4 and the nitrogen to which R 3 and R 4 are attached to form a 3- to 15-membered heterocycl
  • Embodiment 2 An embodiment of embodiment 1, wherein each R 1 is halogen, nitro, or cyano.
  • Embodiment 3 An embodiment of embodiment 2, wherein each R 1 is fluorine, chlorine, nitro, or cyano.
  • Embodiment 4 An embodiment of any one of embodiments 1-3, wherein R 2 is absent, hydrogen, or C 1-20 alkyl.
  • Embodiment 5 An embodiment of embodiment 4, wherein R 2 is absent, hydrogen, or methyl.
  • Embodiment 6 An embodiment of any one of embodiments 1-5, wherein R 3 and R 4 are each independently hydrogen, C 1-6 alkyl, C 2-12 alkynyl, C 2-9 carboxyalkyl, or 2- to 12-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R 11 groups.
  • Embodiment 7 An embodiment of embodiment 6, wherein R 3 and R 4 are each independently methyl, methyl-d 3 , propyl, hexynyl, diazirinylheptynyl, methoxyoxobutyl, and mehoxyethyl.
  • Embodiment 8 An embodiment of embodiment 7, wherein R 3 and R 4 are each methyl.
  • Embodiment 9 An embodiment of any one of embodiments 1-5, wherein R 3 and R 4 are each combined with the nitrogen to which they are attached to form a 3- to 15-membered heterocyclyl optionally substituted with 1-4 R 11 groups.
  • Embodiment 10 An embodiment of embodiment 9, wherein R 3 and R 4 are each combined with the nitrogen to which they are attached to form an azetidinyl group, a methylazetidinyl group, a methylfluoroazetidinyl group, a methoxyfluoroazetidinyl group, a difluoromethylazetidinyl group, a triifluoromethylazetidinyl group, a fluoroazetidinyl group, a difluoroazetidinyl group, a methoxyazetidinyl group, a difluoromethoxyazetidinyl group, a cyclopropoxyazetidinyl group, a fluoropyrrolidyl group, a difluoropyrrolidyl group, a methoxypyrrolidyl group, an azabicyclo[3.1.0]hexyl
  • Embodiment 11 An embodiment of any one of embodiments 1-10, wherein R 5 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 haloalkyl, or C 3-6 cycloalkyl.
  • Embodiment 12 An embodiment of embodiment 11, wherein R 5 is hydrogen, methyl, ethyl, methylethyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, or cyclopropyl.
  • Embodiment 13 An embodiment of any one of embodiments 1-12, wherein R 6 and R 7 are combined with the carbon to which they are attached to form a C 3-8 cycloalkyl or a 3- to 15- membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with 1-4 R 11 groups.
  • Embodiment 14 An embodiment of embodiment 13, wherein R 6 and R 7 are combined with the carbon to which they are attached to form a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methylcyclohexyl group, a difluorocyclohexyl group, a trifluoromethylcyclohexyl group, a cycloheptyl group, a spiro[3.3]heptyl group, a tetrahydropyryl group, a difluorotetrahydropyryl group, a tetrohydrofuryl group, an oxepanyl group, a hydroxyfluorooxepanyl group, a methyldioxepanyl group, an oxabicyclo[4.1.0]heptyl group, a difluorooxabicyclo[4.1.0]heptyl group, an oxabicyclo[[4.1.0]
  • Embodiment 15 An embodiment of any one of embodiments 1-12, wherein R 6 and R 7 are each independently C 1-6 alkyl.
  • Embodiment 16 An embodiment of embodiment 15, wherein R 6 and R 7 are each methyl.
  • Embodiment 17 An embodiment of any one of embodiments 1-16, wherein R 8 is C 6-12 aryl or C 3-8 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1-4 R 11 groups.
  • Embodiment 18 An embodiment of any one of embodiments 17, wherein R 8 is phenyl, fluorophenyl, difluorophenyl, chlorophenyl, fluorochlorophenyl, trifluoromethylphenyl, or cycloheptyl.
  • Embodiment 19 An embodiment of any one of embodiments 1-18, wherein each R 9 and R 10 is independently hydrogen, C 1-6 alkoxy, or halogen.
  • Embodiment 20 An embodiment of embodiment 19, wherein each R 9 and R 10 is independently hydrogen, methoxy, or fluorine.
  • Embodiment 21 An embodiment of any one of embodiments 1-18, wherein one R 9 is combined with R 2 and X 1 to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R 11 groups.
  • Embodiment 22 An embodiment of embodiment 21, wherein one R 9 is combined with R 2 and X 1 to form a piperidinylene group or a pyrrolidinylene group.
  • Embodiment 23 An embodiment of any one of embodiments 1-18, wherein one R 10 is combined with R 3 and the nitrogen to which R 3 is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R 11 groups.
  • Embodiment 24 An embodiment of embodiment 23, wherein one R 10 is combined with R 3 and the nitrogen to which R 3 is attached to form a morpholyl group or an oxazepanyl group.
  • Embodiment 25 An embodiment of any one of embodiments 1-24, wherein each R 11 is independently C 1-6 alkyl, C 1-6 alkoxy, hydroxy, 2- to 8-membered heteroalkyl, halogen, C 3-12 cycloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or diazirine, wherein the cycloalkoxy is optionally substituted with one or more hydroxy or halogen groups or a combination thereof.
  • Embodiment 26 An embodiment of embodiment 25, wherein each R 11 is independently methyl, methoxy, hydroxy, 2-methoxyethyl, 2-aminoethyl, fluorine, chlorine, cyclopropoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or diazirine.
  • Embodiment 27 An embodiment of any one of embodiments 1-26, wherein X 1 is N.
  • Embodiment 28 An embodiment of any one of embodiments 1-26, wherein R 2 is absent and X 1 is O.
  • Embodiment 29 An embodiment of any one of embodiments 1-28, wherein X 2 is S.
  • Embodiment 30 An embodiment of any one of embodiments 1-28, wherein X 2 is C.
  • Embodiment 31 An embodiment of any one of embodiments 1-30, wherein A 1 and A 2 are each C.
  • Embodiment 32 An embodiment of any one of embodiments 1-31, wherein n is 2.
  • Embodiment 33 An embodiment of any one of embodiments 1-32, wherein m is 2.
  • Embodiment 34 An embodiment of any one of embodiments 1-33, wherein p is 1.
  • Embodiment 35 An embodiment of embodiment 1, having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof.
  • Embodiment 36 An embodiment of embodiment 35, having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof.
  • Embodiment 37 An embodiment of embodiment 36, having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, halogen, C 1-6 haloalkyl, nitro, or cyano.
  • Embodiment 38 An embodiment of embodiment 36, having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof.
  • Embodiment 39 An embodiment of embodiment 38, having the formula:
  • Embodiment 40 An embodiment of embodiment 1, having the formula:
  • Embodiment 41 An embodiment of embodiment 1, wherein the compound is:
  • Embodiment 42 An embodiment of embodiment 1, wherein the compound is:
  • Embodiment 43 An embodiment of embodiment 1, wherein the compound is:
  • Embodiment 44 An embodiment of embodiment 1, wherein the compound is:
  • Embodiment 45 An embodiment of embodiment 1, wherein the compound is:
  • Embodiment 46 An embodiment of embodiment 1, wherein the compound is:
  • Embodiment 47 A pharmaceutical composition comprising the compound of any one of embodiments 1-46 and a pharmaceutically acceptable carrier.
  • Embodiment 48 A method of treating a disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments 1-46 or the composition of embodiment 47.
  • Embodiment 49 An embodiment of embodiment 48, wherein the disorder is an infection with a polyomavirus.
  • Embodiment 50 An embodiment of embodiment 49, wherein the polyomavirus is selected from the group consisting of BK virus, JC virus, and Merkel cell virus.
  • Embodiment 51 An embodiment of any one of embodiments 48-50, wherein the subject is an organ transplant patient.
  • Embodiment 52 An embodiment of any one of embodiments 48-51, wherein the subject is an immunocompromised patient EXAMPLES [0164]
  • the present disclosure will be better understood in view of the following non-limiting examples. The following examples are intended for illustrative purposes only and do not limit in any way the scope of the present invention.
  • the provided compounds can be synthesized by a variety of methods known to one of skill in the art (see Comprehensive Organic Transformations Richard C. Larock, 1989) or by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the disclosed compounds are both readily apparent and accessible to those of skill in the relevant art.
  • BK VIRUS ENTRY ASSAY Primary renal proximal tubule epithelial (RPTE) cells (ATCC, cat# PCS-400-010) or RPTE cells immortalized with human telomerase reverse transcriptase (RPTE-hTERT; Zhao and Imperiale, Microbiol. Resour. Announc.20098:e01129-19) were pre-incubated with compound for 2 hours, then infected with BK virus serotype I (MOI 0.1-0.5 infectious units/cell [IU/cell]) and incubated for 48 hours to allow for viral entry and gene expression.
  • RPTE Primary renal proximal tubule epithelial cells
  • RPTE-hTERT immortalized with human telomerase reverse transcriptase
  • Zhao and Imperiale Microbiol. Resour. Announc.20098:e01129-19
  • BK VIRUS SPREAD ASSAY Primary renal proximal tubule epithelial (RPTE) cells (ATCC, cat# PCS-400-010) were pre-incubated with compound for 2 hours, then infected with BK virus serotype I (MOI 0.1 IU/cell) and incubated for 120 hours (5 days) to allow for viral entry, propagation, and progeny virion release from the first round of infection, as well as viral entry and gene expression resulting from the second round of infection.
  • RPTE Primary renal proximal tubule epithelial
  • HEK293 CYTOTOXICITY ASSAY Human embryonic kidney (HEK293) epithelial cells (ATCC, cat# CRL-1573) were incubated with compound (top concentration of 100 ⁇ M) for 72 hours (3 days) and analyzed by Cell Titer-Glo Luminescent Cell Viability Assay (Promega) to generate CC50 values relative to DMSO-treated control wells. As shown in Table 1, the compounds disclosed herein did not generally show cytotoxicity in this cell line after incubation with the compounds.
  • RPTE CYTOTOXICITY ASSAY Primary renal proximal tubule epithelial (RPTE) cells (ATCC, cat# PCS-400-010) were incubated with compound (top concentration of 71 ⁇ M) for 120 hours (5 days) and analyzed by Cell Titer-Glo Luminescent Cell Viability Assay (Promega) to generate CC50 values relative to DMSO-treated control wells.
  • RPTE cells immortalized with human telomerase reverse transcriptase were incubated with compound (top concentration of 10 ⁇ M) for 48 hours and nuclei count (relative to DMSO-treated control wells) was reported as a measure of viability to generate CC50 values.
  • Bcl-2 (UniProt ID P10415) and Bcl-2-like protein 1 (Bcl-xL, UniProt ID Q07817) were cloned with C-terminal Avi-tags, expressed in E. coli, and purified (> 95% purity) in a final buffer of 25 mM Tris-HCl pH 8.0, 150 mM NaCl, 1 mM TCEP, and 5% Glycerol. Biotinylated Bcl-2 and Bcl-xL were immobilized on a Series S streptavidin sensor chip to approximately 20 response units (RUs) and remaining free streptavidin sites were blocked with biotin-PEG2.
  • RUs response units
  • test compounds Concentrations of 0.412 ⁇ M, 1.23 ⁇ M, 3.70 ⁇ M, 11.1 ⁇ M, 33.3 ⁇ M, and 100 ⁇ M were then flowed over the surface (flow rate 100 ⁇ I/minute) and allowed to bind Bcl-2 and Bcl- xL during the association phase (60 seconds), followed by a buffer wash during the dissociation phase (120 seconds).
  • Bcl-2 and/or Bcl-xL inhibitor control compounds including ABT-737 (IUPAC: 4- ⁇ 4-[(4′- Chloro[1,1′-biphenyl]-2-yl)methyl]piperazin-1-yl ⁇ -N-(4- ⁇ [(2R)-4-(dimethylamino)-1- (phenylsulfanyl)butan-2-yl]amino ⁇ -3-nitrobenzene-1-sulfonyl)benzamide) and four proprietary compounds, were also tested.
  • ABT-737 IUPAC: 4- ⁇ 4-[(4′- Chloro[1,1′-biphenyl]-2-yl)methyl]piperazin-1-yl ⁇ -N-(4- ⁇ [(2R)-4-(dimethylamino)-1- (phenylsulfanyl)butan-2-yl]amino ⁇ -3-nitrobenzene-1-sulfonyl)benzamide
  • the proprietary control compounds had Kd values for Bcl-2 and Bcl-xL, respectively, of 3.6 nM and 7.1 nM, 34 nM and 49 nM, 513 nM and 311 nM, and 4.8 ⁇ M and 4.4 ⁇ M.
  • ABT- 737 bound tightly to both proteins with no observable dissociation, and thus an accurate Kd value could not be determined.
  • the results from these control compounds were comparable to historical data. In contrast, as shown in Table 2, none of the tested compounds exhibited any significant binding to Bcl-2, as would be indicated by a Kd value below 100 ⁇ M with respect to Bcl-2.
  • BCL-2/BCL-XL CELL-BASED ASSAYS [0174]
  • Toledo cell line (ATCC CRL-2631, human diffuse large cell lymphoma [DLCL] cell line) expresses high levels of Bcl-2 and Bcl-xL and has previously been shown to be dependent on Bcl-2 signaling for survival (Stang et al., Exp Hematol 2009; 37(1):122-134).
  • NCI-H146 cell line (ATCC HTB-173, human small cell lung cancer [SCLC] cell line) expresses high levels of Bcl-2 and Bcl-xL and has previously been shown to be sensitive to Bcl-2/-xL inhibitors (Hann et al., Cancer Res 2008; 68(7):2321-2328).
  • test compounds or control compounds known Bcl-2 and/or Bcl-xL inhibitors including ABT-737, ABT-199, and ABT-263
  • test compounds or control compounds known Bcl-2 and/or Bcl-xL inhibitors including ABT-737, ABT-199, and ABT-263
  • test compounds or control compounds known Bcl-2 and/or Bcl-xL inhibitors including ABT-737, ABT-199, and ABT-263
  • Cell Titer-Glo Luminescent Cell Viability Assay Promega
  • Alcohol 1 (6.00 g, 63.5% yield) as a colorless oil, which was used for the next step directly, without further purification.
  • a racemic mixture (150 mg, 280 ⁇ mol, 100% purity) comprising (S)-N-((4-((1- (dimethylamino)-5-phenylpentan-3-yl)oxy)-3-nitrophenyl)sulfonyl)-1-fluorocyclohexane-1- carboxamide and (R)-N-((4-((1-(dimethylamino)-5-phenylpentan-3-yl)oxy)-3- nitrophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide was obtained as a white solid in 39.4% yield according to the general procedure of Example 10.
  • reaction mixture was heated to 10°C and stirred for 12 hrs under N 2 .
  • the reaction solution was slowly poured into ice water (15.0 mL), then extracted with EtOAc (10.0 mL x 3).
  • the combined organic phases were washed with saturated brine (20.0 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum.
  • the mixture was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:20%-55% B over 8.0 min) to give (R)-N-((3-chloro-4-((4-(dimethylamino)-1-((4-fluorophenyl)thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (17.7 mg, 29.7 ⁇ mol, 26.7% yield, 99.1% purity) as a white solid.
  • N-((3-cyano-4-((2S,4S)-2-(2-(dimethylamino)ethyl)-4-phenylpyrrolidin-1-yl)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (13.8 mg, 99.3% purity) was obtained as a white solid in 35.0% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide.
  • reaction mixture was quenched by addition saturated NaHCO 3 solution (300 mL) at 0 °C, and extracted with 2-MeTHF (100 mL x 3). The combined organic layers were washed with sat. brine (200 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give compound 3 (39.0 g, crude) as a yellow solid.
  • reaction mixture was quenched by addition H 2 O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 5). The combined organic layers were washed with brine (10.0 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • the crude product was purified by prep-HPLC (column: Waters X bridge BEH C18100*30mm*10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35%-65%, 8min) to give N-((3-cyano-4-((1-(dimethylamino)-5-phenylpentan-3-yl)oxy)-5-fluorophenyl)sulfonyl)-1- fluorocyclohexane-1-carboxamide (92.9% purity) (27.1 mg, theory amount: 72.3 mg, 34.8% yield) as a white solid and the product was purified by prep-HPLC(column: Phenomenex Luna C1875*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 30%-50%,8min) as a white solid.
  • prep-HPLC columnumn: Phenomenex Luna C1875*30mm*3um;mobile phase: [water(
  • Step 2 Compound (R)-N-((3,5-dichloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)butan- 2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide (15.0 mg, 99.6% purity) was obtained as white solid in 97.3% yield according to the general procedure of (R)-N- ((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide .
  • Step 1 Compound 13 (160 mg, 79.5% purity) was obtained as yellow oil in 48.1% yield according to the general procedure of compound 9.
  • 1 H NMR: (400 MHz, CDCl 3 ) ⁇ 7.05 - 6.92 (m, 2H), 6.90 - 6.78 (m, 2H), 5.28 - 4.96 (m, 2H), 4.09 - 3.85 (m, 3H), 3.81 - 3.61 (m, 3H), 3.24 - 3.07 (m, 2H), 2.63 (br dd, J 6.4, 12.8 Hz, 2H), 1.83 - 1.63 (m, 3H), 1.50 - 1.44 (m, 9H)
  • Step 2 Compound Amine 12 (180 mg) was obtained as light yellow solid according to the general procedure of compound 6.
  • Step 4 Compound (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide (21.0 mg, 98.5% purity) was obtained as white solid in 57.7% yield according to the general procedure of (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide .
  • Step 2 Compound (R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide (25.0 mg, 97.9% purity) was obtained as white solid in 64.4% yield according to the general procedure of (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide .
  • Step 2 Compound (R)-N-((3,5-dichloro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2- carboxamide(15.0 mg, 97.4% purity) was obtained as white solid in 57.8% yield according to the general procedure of (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide .
  • Step 2 [0436] Charge compound 1-2 (3.40 g, 8.78 mmol, 1.00 eq) to a 100 mL three-neck bottle(R1). Charge DMF ( 24.0 mL) to R1. Charge compound 2A (1.35 g, 10.5 mmol, 1.20 eq) to R1. Charge K 2 CO 3 (2.43 g, 17.6 mmol, 2.00 eq) to R1.
  • Step 4 [0438] Charge compound 1-4 ( 1.20 g, 3.80 mmol, 1.00 eq) to a 40 mL seale dtube. Charge THF ( 15.0 mL) to R1 at 25 °C. Charge Py ( 602 mg, 7.61 mmol, 614 ⁇ L, 2.00 eq) to R1 at 0 °C. Charge methylsulfonyl methanesulfonate ( 994 mg, 5.71 mmol, 1.50 eq) to R1 at 0 °C. Stir R1 at 25 °C for 72 hrs.
  • Step 5 Charge compound 1-5 ( 1.4 g, 3.56 mmol, 1.00 eq) to a 40 mL sealed tube(R1) equipped with N 2 . Charge THF ( 10.0 mL) to R1 at 25 °C.
  • the crude product (500 mg) was purified by pre-HPLC( column: Xtimate C18150*40mm*10um; mobile phase: [water( NH 4 HCO 3 )-ACN]; gradient: 30% - 70% B over 32 min) to give compound 1-6 (100 mg, 259.55 ⁇ mol, 19.96% yield, 99.8% purity) as a yellow oil.
  • Step 8 Charge Acid 9 (11.7 mg, 81.3 ⁇ mol, 2.00 eq) to a 8 mL seal tube (R1) at 25 °C. Charge ACN (1.00 mL) to R1 at 25 °C. Charge EDCI (15.6 mg, 81.3 ⁇ mol, 2.00 eq) to R1 at 25 °C. Charge DMAP (9.93 mg, 81.3 ⁇ mol, 2.00 eq) to R1 at 25 °C. Charge compound 1-8 (20.0 mg, 40.7 ⁇ mol, 1.00 eq)to R1 at 25 °C. Stir R1 at 25 °C for 12 hrs.
  • Step 1 Compound 1-9 (20.0 mg, 39.3 ⁇ mol) was obtained as yellow oil in 31.6% yield according to the general procedure of compound 1-8 HPLC: column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water( HCl) - ACN]; gradient: 10% -50% B over 20 min. B.
  • Step 1 Compound 1-10 (50.0 mg, 104 ⁇ mol) was obtained as yellow oil in 79.2% yield according to the general procedure of compound 1-8 .
  • HPLC column: Xtimate C18 150*40mm*10um; mobile phase: [ water( HCl) - ACN]; gradient: 0% - 40% B over 36 min.
  • Step 2 [0446] (R)-N-((3-cyano-5-fluoro-4-(((R)-1-((4-fluorophenyl)thio)-4-(3-methoxyazetidin-1- yl)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide (8.00 mg, 13.1 ⁇ mol, 100% purity) was obtained as white solid in 25.4% yield according to the general procedure of (R)-N-((3-chloro-5-fluoro-4-(((R)-1-((4-fluorophenyl)thio)-4-(3-methoxyazetidin- 1-yl)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide.
  • Step 1 [0449] Charge compound J-1 (2.50 g, 15.0 mmol, 1.00 eq) to a 100 mL three-neck bottle (R1). Charge DCM (50.0 mL) to R1. Charge (4-methoxyphenyl)methyl 2,2,2-trichloroethanimidate (4.24 g, 15.0 mmol, 1.00 eq) to R1. Charge [(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1- yl]methanesulfonic acid;hydrate (375 mg, 1.50 mmol, 0.1 eq) to R1. R1 was stirred at 25 °C for 12 hrs.
  • Step 6 [0454] Charge NaH (59.0 mg, 1.48 mmol, 60% purity, 3.00 eq) in THF (2.00 mL) to a 10 mL round bottom flask (R1) equipped with N 2 balloon. Charge compound J-6 (140 mg, 492 ⁇ mol, 1.00 eq) to R1 at 0°C. Stirred R1 at 25°C for 0.5 hrs.
  • Step 9 [0457] Charge compound 9-1 (155 mg, 295 ⁇ mol, 1.00 eq) in THF (1.00 mL) to 8 mL flask (R1) at 25°C. Charge Pyridine (46.7 mg, 591 ⁇ mol, 47.7 ⁇ L, 2.00 eq) and methyl sulfonyl methane sulfonate (77.2 mg, 443 ⁇ mol, 1.50 eq) to R1 at 0°C. Stir R1 at 25°C for 4 hrs.
  • Step 3 Compound K-6 (325 mg, 601 ⁇ mol, 96.3% yield) was obtained as light yellow oil according to the general procedure of compound 7-3.
  • Step 4 Compound K-6 (140 mg, 226 ⁇ mol, 97.8% yield) was obtained as light yellow oil according to the general procedure of compound 7-4.
  • Step 1 [0484] Compound L-4 (390 mg, 96.9% purity) was obtained as colorless oil in 74.4% yield according to the general procedure of compound K-4.
  • Step 2 [0485] Compound L-5 (410 mg, 94.9% purity) was obtained as yellow oil in 84.7% yield according to the general procedure of compound K-5.
  • Step 3 [0486] Compound L-6 (256 mg, 90.0% purity) was obtained as yellow oil in 71.7% yield according to the general procedure of compound K-6.
  • Step 1 Compound 8 (1.00 g, 2.08 mmol) was obtained as yellow oil in 56.7% yield according to the general procedure of compound 2.HPLC: column: Welch Xtimate C18250*50mm*10um; mobile phase: [ water( NH 4 HCO 3 ) - ACN]; gradient:15% - 55% B over 25 min.
  • HPLC column: Welch Xtimate C18250*50mm*10um; mobile phase: [ water ( NH 4 HCO 3 ) - ACN]; gradient: 10% - 45% B over 20 min.
  • SFC column: DAICEL CHIRALPAK IC (250mm*50mm, 10um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%:40%, isocratic elution mode.
  • EXAMPLE 140 2-METHYL-1,3-DIOXANE-2-CARBOXYLIC ACID (ACID 18) [0506] Compound 1 (10.0 g, 114 mmol, 8.00 mL, 1.00 eq), compound 2 (13.0 g, 170 mmol, 12.3 mL, 1.50 eq) and Amberlite IR-120 (plus) resin (1.00 g, 11.4 mmol) was added to toluene (100 mL), the mixture were heated at reflux in a Dean-Stark apparatus for 16 hrs. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated and the resulting residue dissolved in 2 M aqueous NaOH (20.0 mL).
  • Step 2 [0508] Charge CH 2 Cl 2 (3.00 mL) and THF (1.00 mL) to a 100 mL round bottom flask (R1) equipped with a N 2 balloon. Charge compound 2 (104 mg, 252 ⁇ mol, 1.00 eq) to R1 at 25 °C. Charge imidazole (25.7 mg, 377 ⁇ mol, 1.50 eq) to R1 at 25 °C. Charge TBSCl (56.9 mg, 377 ⁇ mol, 46.4 ⁇ L, 1.50 eq) to R1 at 25 °C. Stir R1 at 25 °C for 16 hr.
  • the mixture was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; gradient: 6%-46% B over 32 min) to give (R)-N-((4- (((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)thio)butan-2-yl)amino)-3-cyano-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxamide (5.00 mg, 8.61 ⁇ mol, 15.6% yield, 98.6% purity) as a white solid.
  • Step 1 [0515] Compound 3 (99.0 mg) was obtained as light yellow solid in 57.9% yield according to the general procedure of compound 2.
  • Step 5 [0519] Compound 3-4 (18.0 mg, crude) was obtained as light yellow oil according to the general procedure of compound 2-4.
  • F. Step 6 [0520] (R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-cyclopropoxyazetidin-1-yl)-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2- carboxamide (10.0 mg, 98.3% purity) was obtained as white solid in 53.2% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3-cyano-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-
  • Step 2 Compound 4-1 (50.0 mg, 90.3% purity) was obtained as colorless oil in 51.2% yield according to the general procedure of compound 2-1.
  • 1 H NMR: (400 MHz, CD 3 OD) ⁇ 7.70 (s, 2H), 7.39 - 7.26 (m, 2H), 7.06 - 6.96 (m, 2H), 4.43 - 4.31 (m, 1H), 3.78 - 3.70 (m, 2H), 3.22 - 3.04 (m, 2H), 2.12 (dt, J 5.2, 7.2 Hz, 1H), 1.84 - 1.73 (m, 1H), 0.85 (s, 9H), 0.05 - -0.10 (m, 6H) C.
  • Step 3 Compound 4-2 (46.0 mg) was obtained as colorless oil in 74.9% yield according to the general procedure of compound 2-2.
  • 1 H NMR: (400 MHz, CD 3 OD) ⁇ 7.82 (s, 2H), 7.31 - 7.24 (m, 2H), 7.04 - 6.97 (m, 2H), 3.85 - 3.75 (m, 2H), 3.14 (d, J 6.4 Hz, 2H), 2.16 - 1.99 (m, 2H), 1.84 - 1.75 (m, 1H), 1.67 - 1.43 (m, 4H), 1.38 - 1.26 (m, 4H), 1.19 (s, 3H), 0.84 (s, 9H), 0.04 - - 0.10 (m, 6H) D.
  • Step 5 Compound 4-4 (13.0 mg, crude) was obtained as light yellow oil according to the general procedure of compound 2-4.
  • F. Step 6 [0526] (R)-N-((3,5-dichloro-4-(((R)-4-(3-cyclopropoxyazetidin-1-yl)-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2- carboxamide (65.0 mg, 98.3% purity) was obtained as white solid in 47.9% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3-cyano-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H- pyran-2
  • Step 5 [0531] Compound 5-4 (10.0 mg, crude) was obtained as light yellow oil according to the general procedure of compound 2-4. F.
  • Step 6 [0532] (R)-N-((3-chloro-4-(((R)-4-(3-cyclopropoxyazetidin-1-yl)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2- carboxamide (5.80 mg, 98.2% purity) was obtained as white solid in 55.4% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3-cyano-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H
  • Step 1 [0535] Charge compound 5C (500 mg, 2.32 mmol, 1.00 eq) to a 40 ml microwave tube (R1). Charge NMP (10 mL) to R1 at 25°C.
  • Step 1 Compound D1-5 (380 mg, crude) was obtained as yellow oil according to the general procedure of compound D6-3.
  • Step 2 [0561] (R)-N-((3-chloro-5-cyano-4-((4-(dimethylamino)-1-((4-fluorophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (23.0 mg, 94.6% purity) was obtained as a white solid in 44.0% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide .
  • Step 2 [0565] Charge compound 2 (21.4 g, 76.3 mmol, 1.00 eq) to a 500 mL Hydrogenation bottle (R1) equipped with H 2 (15.0 psi) balloon. Charge MeOH (150 mL) to R1 at 25 °C.
  • Step 3 Charge compound 3 (11.0 g, 75.3 mmol, 1.00 eq) to a 100 mL three-neck bottle (R1) equipped with a N 2 balloon. Charge MeOH (10.0 mL) to R1 at 25 °C.
  • Step 1 [0568] Charge compound 5 (500 mg, 2.15 mmol, 1.00 eq) to a 40 ml sealed tube (R1). Charge toluene (5.00 mL) to R1 at 25 °C.
  • the mixture was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH 3 H 2 O)-ACN]; gradient: 40%-80% B over 20 min) to give compound 1-3 (8.00 mg, 19.8 ⁇ mol, 45.5% yield, 97.4% purity) as a yellow solid.
  • Step 1 [0572] Charge compound 5 (500 mg, 2.15 mmol, 1.00 eq) to a 40 ml sealed tube (R1). Charge toluene (5.00 mL) to R1 at 25 °C. Charge cyclohexanethiol (250 mg, 2.15 mmol, 263 ⁇ L, 1.00 eq) to R1 at 25 °C.
  • CMBP 935 mg, 3.87 mmol, 1.80 eq
  • R1 stir R1 at 90 °C for 12 hrs.
  • the mixture was concentrated to give crude product. Sat. citric acid solution (100 mL) was added to R1.
  • the mixture was back-extracted with EtOAc (30.0 mL), the organic layer was discarded.
  • Step 2 [0577] Compound 3-2 (60.0 mg, crude) was obtained as yellow oil according to the general procedure of compound 1-2.
  • C Step 3 [0578] Charge compound 4 (10.0 mg, 27.9 ⁇ mol, 1.00 eq) to a 2.00 mL sealed bottle (R1). Charge DMSO (0.30 mL) to R1 at 25 °C. Charge DIEA (18.0 mg, 140 ⁇ mol, 24.3 ⁇ L, 5.00 eq) to R1 at 25 °C. Charge compound 3-2 (7.45 mg, 27.9 ⁇ mol, 1.00 eq, HCl) to R1 at 25 °C. Stir R1 at 90 °C for 12 hrs.
  • Step 1 Compound 6-1 (10.0 mg, crude) was obtained by pre-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water NH 4 HCO 3 )-ACN]; radient: 18%-58% B over 32 min) as yellow oil according to the general procedure of compound 1-1.
  • Step 1 [0590] Charge compound 5 (90.0 mg, 387 ⁇ mol, 1.00 eq) to a 4.00 mL sealed tube (R1). Charge THF (2.00 mL) to R1 at 25 °C. Charge PBu 3 (118 mg, 581 ⁇ mol, 143 ⁇ L, 1.50 eq) to R1 at 25 °C.
  • Step 3 Compound 7-3 (10.0 mg, 21.9 ⁇ mol) was obtained by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (HCl) - ACN]; gradient: 2%-42% B over 36 min) as yellow solid in 28.3 % yield according to the general procedure of compound 2-3. D. Step 4
  • Step 4 [0601] (R)-N-((4-((1-((2-chloro-4-fluorophenyl)thio)-4-(dimethylamino)butan-2-yl)amino)-3- cyano-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (10.0 mg, 97.6% purity) was obtained as white solid in 29.0 % yield according to the general procedure of compound (R)- N-((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide.
  • Step 1 Compound 10-1 (3.00 mg, 85.0% purity) was obtained as white solid in 1.57% yield according to the general procedure of compound 7-1.
  • Step 2 Compound 10-2 (4.00 mg, crude) was obtained as light yellow solid according to the general procedure of compound 7-2.
  • Step 4 (R)-N-((4-((1-((4-chloro-2-fluorophenyl)thio)-4-(dimethylamino)butan-2-yl)amino)-3- cyano-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (6.00 mg, 97.8% purity) was obtained as white solid in 70.3 % yield according to the general procedure of compound (R)- N-((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide.

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Abstract

L'invention concerne des composés utiles pour traiter une infection virale provoquée par un polyomavirus, par exemple, par inhibition de la réplication du polyomavirus. L'invention concerne également des compositions et des procédés comprenant les composés selon l'invention.
PCT/US2023/078000 2022-10-27 2023-10-27 Composés d'acyl sulfonamide en tant qu'inhibiteurs du polyomavirus WO2024092185A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080586A1 (fr) * 2002-03-21 2003-10-02 Abbott Laboratories Promoteurs de l'apoptose de la n-sulfonyluree

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080586A1 (fr) * 2002-03-21 2003-10-02 Abbott Laboratories Promoteurs de l'apoptose de la n-sulfonyluree

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