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WO2025235733A1 - Macrocycles bis-bicyclohétéroaryle et leur utilisation - Google Patents

Macrocycles bis-bicyclohétéroaryle et leur utilisation

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Publication number
WO2025235733A1
WO2025235733A1 PCT/US2025/028355 US2025028355W WO2025235733A1 WO 2025235733 A1 WO2025235733 A1 WO 2025235733A1 US 2025028355 W US2025028355 W US 2025028355W WO 2025235733 A1 WO2025235733 A1 WO 2025235733A1
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Prior art keywords
alkyl
propan
azenometheno
compound
pharmaceutically acceptable
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PCT/US2025/028355
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English (en)
Inventor
Jingrong Jean Cui
Eugene Yuanjin Rui
Evan W. Rogers
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Blossomhill Therapeutics Inc
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Blossomhill Therapeutics Inc
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Publication of WO2025235733A1 publication Critical patent/WO2025235733A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

  • the human genome encodes approximately 518 protein kinases (Manning G, et al. The protein kinase complement of the human genome. Science. 2002, 298:1912–34). Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res.2003, 36:462– 469).
  • the molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al.
  • kinase inhibitors Pottier C, et al. Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731). Resistance can also arise from subpopulations of tolerant/persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of tolerant persister cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring 83573-422399 mediated by chromatin remodeling and autocrine/paracrine communication among tumor cells and within the tumor microenvironment (Swayden M, et al.
  • kinase inhibitors that can target not only the kinase oncogenic drivers, overcome most frequent resistance mutations, but also tolerant persister cancer cells for overcoming resistance, achieving better efficacy and longer disease control. [0004] Therefore, it is desirable to develop a novel, multitargeted kinase inhibitors that are potent against oncogenic driver and point mutations, other emerging and established resistance mutations, and/or emerging resistance targets for tolerant/persistent cancer cells.
  • the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof, [0006] wherein R 1 , A, Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , m, n, and “ ” are as described herein. [0007] In some embodiments, the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof,
  • R 1 , A, X 6 , X 7 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , 6 7 Y , Y , n, p, and “ are as [0009]
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0010] wherein R 1 , R 10 , X 7 , Y 5 , Y 6 , Y 7 , m, n, and “ ” are as described herein.
  • the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, 83573-422399 [0012] wherein R 1 , R 10 , X 5 , X 6 , X 7 , Y 5 , Y 6 , Y 7 , n, p, and “ ” are as described herein. [0013] In some embodiments, the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, [0014] wherein R 1 , X 6 , X 7 , Y 5 , Y 6 , Y 7 , m, n, and “ ” are as described herein.
  • the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, 83573-422399 [0016] wherein R 1 , X 6 , X 7 , Y 5 , Y 6 , Y 7 , n, p, and “ ” are as described herein [0017]
  • the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(VI) or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.
  • the disclosure relates to a compound of Formula (I)-(VI), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(VI), or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to use of a compound of Formula (I)-(VI), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.
  • the disclosure relates to a method of inhibiting a kinase, comprising contacting a cell comprising one or more of aberrant kinases with an effective amount of at least one compound of Formula (I)-(VI), or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
  • a method of inhibiting a kinase comprising contacting a cell comprising one or more of aberrant kinases with an effective amount of at least one compound of Formula (I)-(VI), or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
  • a compound of the formula I [0024] wherein [0025] A is a 5- to 10-membered heteroarylene or C6-C10 arylene; [0026] B/C is a 9-membered bicyclic heteroarylene, wherein [0027] X 1 is C(R 2 ), N(R 3 ), or N; [0028] X 2 is C(R 4 ), N(R 5 ), or N; [0029] X 3 is C or N; [0030] X 4 is C or N; [0031] X 5 is C(R 6 ) or N; [0032] X 6 is C(R 7 ) or N; and [0033] X 7 is C(R 8 ) or N; provided that at least one of X 1 to X 7 is a nitrogen atom
  • each of Z and Z 1 is independently a bond, -O-, -N(R 18 )C(O)-, -C(O)N(R 18 )-, -N(R 18 )-, -N(R 18 )S(O)-, -S(O)N(R 18 )-, -N(R 18 )S(O)2-, -S(O)2N(R 18 )-, -S-, -S(O)-, or -S(O)2-; [0056] each L 1 is independently -C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, -C(R 16 )(R 17 )- C(R 16 )(R 17 )-C(R 16 )(R 17 )-, or -C(R 16
  • each of Z and Z 1 is independently a bond, -O-, -N(R 18 )C(O)-, -C(O)N(R 18 )-, -N(R 18 )-, -N(R 18 )S(O)-, -S(O)N(R 18 )-, -N(R 18 )S(O)2-, -S(O)2N(R 18 )-, -S-, -S(O)-, or -S(O)2-; [0065] each L 1 is independently -C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, -C(R 16 )(R 17 )(R 17 )(R 17 )(R 17 )-, -C(R 16 )(R 17 )(R 17 )(R 17 )(R 17 )(R 17 )-, -C(
  • each of Z and Z 1 is independently a bond, -O-, -N(R 18 )C(O)-, -C(O)N(R 18 )-, -N(R 18 )-, -N(R 18 )S(O)-, -S(O)N(R 18 )-, -N(R 18 )S(O)2-, -S(O)2N(R 18 )-, -S-, -S(O)-, or -S(O)2-; [0074] each L 1 is independently -C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, -C(R 16 )(R 17 )(R 17 )(R 17 )(R 17 )-, -C(R 16 )(R 17
  • each R 1 when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or methoxymethyl; [0089] or a pharmaceutically acceptable salt thereof.
  • each R 1 when present and bonded to nitrogen, is independently methyl or ethyl; [0091] or a pharmaceutically acceptable salt thereof.
  • ring A in the portion is selected from the group , [0094] or a acceptable salt thereof.
  • each L 1 when present, is independently -C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, or -C(R 16 )(R 17 )-C(R 16 )(R 17 )- C(R 16 )(R 17 )-; [0102] or a pharmaceutically acceptable salt thereof. [0103] 16.
  • each L 1 when present, is independently -C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, or -C(R 16 )(R 17 )-C(R 16 )(R 17 )- C(R 16 )(R 17 )-, wherein one or two of R 16 is a C 1 -C 6 alkyl; [0104] or a pharmaceutically acceptable salt thereof. [0105] 17.
  • each L 1 when present, is independently -C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, or -C(R 16 )(R 17 )-C(R 16 )(R 17 )- C(R 16 )(R 17 )-, wherein one or two of R 16 is a C 1 -C 6 alkyl, and the remaining R 16 and R 17 are H or deuterium; [0106] or a pharmaceutically acceptable salt thereof. [0107] 18.
  • R 9 when present, is H or deuterium; or a pharmaceutically acceptable salt thereof.
  • R 10 when present, is H, deuterium, C1-C6 alkyl, or -S(O)2R c ; wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by R e , R f , -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR
  • R 12 when present, is H, deuterium, C 1 -C 6 alkyl, or -S(O) 2 R c ; wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by R e , R f , -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e C(O)R f , -
  • [0212] 49 The compound of clause 1, selected from the group consisting of [0213] (2S)-2-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; [0214] (2S)-2-[(11S)-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1
  • [0221] 50 The compound of clause 1, selected from the group consisting of [0222] (2S)-2-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-1-ol; [0223] (2S)-1-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-2-ol; [0224] (2S)-2-
  • a pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, and optionally one or more excipients.
  • 52. A method of treating disease in a subject comprising, administering a therapeutically effective amount of a compound of any one of clauses 1 to 50, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of clause 51.
  • 53. A compound according to any one of clauses 1 to 50, or a pharmaceutically acceptable salt thereof, for use in a method of treating disease in a subject.
  • 54 Use of a compound according to any one of clauses 1 to 50, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of disease in a subject.
  • a “macrocycle” is a compound comprising a continuous chain of at least 12 atoms connected to form a ring, in which the continuous chain of atoms includes but is not limited to C, N, O, and S.
  • the continuous chain of at least 12 atoms that forms a macrocycle, as described herein, can be counted along the shortest path in the chain of atoms within the ring.
  • the continuous chain of at least 12 atoms in the macrocycle ring can be counted starting from the atom covalently attached to ring A, where the atoms counted in the macrocycle includes the shortest path through ring A, followed by the shortest path of atoms through ring B/C, followed by the shortest path of atoms through ring D/E, and finally the shortest path of atoms through the linker portion and terminating at the atom along the shortest chain that is attached to the atom in ring A that served as the starting point. 83573-422399 [0241]
  • alkyl refers to a straight- or branched-chain monovalent hydrocarbon group.
  • alkylene refers to a straight- or branched-chain divalent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C 1 -C 20 alkyl or C 1 -C 20 alkylene, C 1 -C 12 alkyl or C 1 -C 12 alkylene, or C1-C6 alkyl or C1-C6 alkylene.
  • alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • alkylene groups examples include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH2-)3), iso- propylene ((-C(H)(CH 3 )CH 2 -)), n-butylene ((-CH 2 -) 4 ), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. [0242]
  • alkenyl refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds.
  • alkenylene refers to a straight- or branched- chain di-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” or “alkenylene” to a specific range of atoms, such as C2-C20 alkenyl or C2-C20 alkenylene, C2-C12 alkenyl or C2-C12 alkenylene, or C2-C6 alkenyl or C2-C6 alkenylene. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl.
  • alkynyl refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds.
  • alkynylene refers to a straight- or branched-chain divalent hydrocarbon group having one or more triple bonds.
  • alkynyl groups include acetylenyl (-C ⁇ CH) and propargyl (-CH2C ⁇ CH), but-3-yn-1,4-diyl (-C ⁇ C-CH2CH2-), and the like. It will be appreciated that an alkynyl or alkynylene group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents. 83573-422399 [0244]
  • the term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle.
  • cycloalkylene refers to a saturated or partially saturated, monocyclic or polycyclic divalent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms.
  • Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems.
  • cycloalkyl groups include monovalent radicals of the following entities, while cycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: ,
  • a cyclopropyl moiety can be depicted by the structural
  • a cyclopropylene moiety can be depicted by the structural It will be appreciated that a cycloalkyl or cycloalkylene group can be as described herein.
  • a cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • halogen or “halo” represents chlorine, fluorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include –CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F.
  • haloalkylene refers to an alkyl group with one or more halo substituents.
  • haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH2C(H)(F)-.
  • aryl refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • arylene refers to a divalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system.
  • aryl or arylene can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused- 83573-422399 ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 aryl), monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C 6- C 10 aryl), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 arylene), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C 6 -C 10 arylene).
  • aryl groups are phenyl, naphthalenyl and anthracenyl.
  • arylene groups are phenylene, naphthalenylene and anthracenylene. It will be appreciated that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • heterocycloalkyl refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms.
  • heterocycloalkylene refers to a divalent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms.
  • heterocycloalkyl or “heterocycloalkylene”
  • Polycyclic ring systems include fused, bridged, and spiro systems.
  • the ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • heterocycloalkyl groups include monovalent radicals of the following entities, while heterocycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: 83573-422399 [0249] A where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • heterocycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: 83573-422399 [0249] A where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane.
  • a four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen.
  • Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane.
  • a five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of five-membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-1H- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro- 1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2- one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, and oxazolidin-2-one.
  • a six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heterocycle groups include mono-valent or divalent radicals of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide.
  • a “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.
  • a heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein.
  • a heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • heteroaryl refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle.
  • heteroarylene refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • a 5- to 10-membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S.
  • the ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members.
  • Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties: [0252] or six- membered heterocycle.
  • a five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of five-membered heteroaryl groups include mono- valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • Non-limiting examples of five- membered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • a six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen.
  • Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • Non-limiting examples of six- 83573-422399 membered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • a “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring.
  • Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8- naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, 1H- benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
  • a pyrazolyl moiety can be depicted by the structural formula .
  • an example of a pyrazolylene moiety can be depicted by the structural .
  • a heteroaryl or heteroarylene group can or substituted as described herein.
  • a heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • substituted means that the specified group or moiety bears one or more substituents.
  • the term “unsubstituted” means that the specified group bears no substituents.
  • substituted means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent. [0256] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. [0257] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures 83573-422399 depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Certain chemical entities of Formula (I)-(VI) may be depicted in two or more tautomeric forms.
  • tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that certain chemical entities described herein can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tautomers, and the like.
  • the to a class of substituents is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized.
  • the term C1-C3 refers independently to embodiments that have one carbon member (C1), 83573-422399 embodiments that have two carbon members (C2), and embodiments that have three carbon members (C 3 ).
  • Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • disubstituent –J-K- where J ⁇ K, refers herein to such disubstituent with J attached to a first substituted member and K attached to a second substituted member, and it also refers to such disubstituent with J attached to the second substituted member and K attached to the first substituted member.
  • J ⁇ K refers herein to such disubstituent with J attached to a first substituted member and K attached to a second substituted member, and it also refers to such disubstituent with J attached to the second substituted member and K attached to the first substituted member.
  • certain of the compounds described herein include one or more position that can exists as stereoisomers.
  • certain of the compounds described herein include one or more carbon atoms that can exist in one or more stereoisomeric arrangements.
  • a carbon atom that can exist in stereoisomeric arrangements that is depicted without showing any stereoisomeric arrangement includes as a disclosure each of eh possible stereoisomeric arrangements.
  • a carbon atom having four groups that can be prioritized according to the Cahn-Ingold Prelog Rules known to one of skill in the art will be understood herein as describing no particular stereochemical definition as in the structure on the left below, and also as describing both possible stereoisomers (S) and (R) as shown below where R a > R b > R c > R d according to the Cahn-Ingold Prelog Rules.
  • the portion of A-B defined by the group or chemical structure A can be represented , , or , where “ ” represents a bond to A and the point of covalent bond embodiments
  • the portion of A-B defined by the group or chemical structure B can be represented 83573-422399 , where each of “-*”, “-**”, and “ ” represents a bond to B and the point of covalent bond attachment to [0263]
  • heteroarylene described by the structure [0264] where X 1 is a carbon, X 2 are all carbons, can be depicted as either [0265]
  • the disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(VI), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically 83573-422399 suitable for administration to the subject. See, generally, S.M.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates,
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyra
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like
  • an organic acid such as ace
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(VI), and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(VI)).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject.
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(VI), and uses of such metabolites in the methods of the disclosure.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(VI) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med.
  • the disclosure provides a compound of the formula I, or a pharmaceutically acceptable salt thereof, 83573-422399 [0273] wherein R 1 , A, B, C, D, E, L, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , m, n, and “ ” are as described herein.
  • the disclosure provides a compound of the formula II, or a pharmaceutically acceptable salt thereof, [0275] wherein R 1 , A, 6 7 1 2 3 4 5 X, X, Y, Y, Y, Y, Y6, Y7, n, p, and “ ” are as described herein.
  • the disclosure provides a compound of the formula III, or a pharmaceutically acceptable salt thereof, [0277] wherein R 1 , R 10 , X 7 , Y 5 , Y 6 , Y 7 , m, n, and “ ” are as described herein.
  • the disclosure provides a compound of the formula IV, or a pharmaceutically acceptable salt thereof, [0279] wherein R 1 , R 10 , A, B, C, D, E, L 1 , L 2 , Z 1 , Z, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y 5 , Y 6 , Y 7 , n, p, and “ ” are as described herein.
  • the disclosure provides a compound of the formula V, or a pharmaceutically acceptable salt thereof, [0281] wherein R 1 , R 12 , A, B, C, D, E, L 1 , L 2 , Z 1 , Z, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , Y 5 , Y 6 , Y 7 , m, n, and “ ” are as described herein.
  • the disclosure provides a compound of the formula VI, or a pharmaceutically acceptable salt thereof, 83573-422399 [0283] wherein R 1 , X 6 , X 7 , Y 5 , Y 6 , Y 7 , n, p, and “ ” are as described herein [0284]
  • ring A is 5- to 10-membered heteroarylene.
  • ring A in the portion [0288] is a 5- or 6-membered and each “ ” represents a point of covalent attachment.
  • ring A is of the formula [0290] wherein “ ” is bond or a carbon-carbon double bond, each “ ” represents a point of covalent attachment, and R1 and n are as described herein.
  • ring A is of the formula 83573-422399 [0292] wherein “ ” is bond or a carbon-carbon double bond, each “ ” represents r ing A is a 5-membered heteroarylene, and R 1 and n are as described herein.
  • ring A in the portion is a 5- or 6-membered consisting of , [0300]
  • n is 0, 1, 2, 3, or 4.
  • n is 0, 1, 2, or 3.
  • n is 0, 1, or 2.
  • n is 0 or 1.
  • n is 0.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • ring A is a 5-membered heteroarylene selected from the group consisting of , 83573-422399 , is independently as described herein.
  • each R 1 when present and bonded to carbon, is independently fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or methoxymethyl.
  • each R 1 when present and bonded to a nitrogen atom, is independently deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is independently optionally substituted by
  • each R 1 when present and bonded to nitrogen, is independently methyl or 83573-422399 ethyl.
  • each R 1 is independently C1-C6 alkyl, for example methyl, wherein one hydrogen atom in each C 1 -C 6 alkyl is optionally substituted with an -OR a .
  • n is 1 and R 1 is C1-C6 alkyl, for example methyl.
  • n is 2, and each R 1 is independently C 1 -C 6 alkyl, for example methyl.
  • n is 2, one R 1 is C1-C6 alkyl, for example methyl, wherein one hydrogen atom in C1-C6 alkyl is optionally substituted by -OR a , for example R a is C 1 -C 6 alkyl such that R 1 is C 1 -C 6 alkyl-O-C 1 -C 6 alkyl (e.g., -CH2OCH3), and one R 1 is methyl.
  • ring A in the portion is selected from the group , [0309] In some ring A is a 5-membered heteroarylene selected from the group consisting of , [0311] In some ring A is a 5-membered heteroarylene selected from the group 83573-422399 consisting of [0313] is a C6-C10 arylene, n is 0, ” represents a point of covalent attachment. [0314] In some embodiments, ring A in the portion [0315] is a phenylene, n is 0, 1, ” represents a point of covalent attachment.
  • ring B/C is a 9-membered bicyclic heteroarylene, wherein X 1 is C(R 2 ), N(R 3 ), or N; X 2 is C(R 4 ), N(R 5 ), or N; X 3 is C or N; X 4 is C or N; X 5 is C(R 6 ) or N; X 6 is C(R 7 ) or N; and X 7 is C(R 8 ) or N; provided that at least one of X 1 to X 7 is a nitrogen atom (e.g., N or NR 3 or NR 5 ).
  • X 1 to X 7 is a nitrogen atom (e.g., N or NR 3 or NR 5 ).
  • ring B/C is a 9-membered bicyclic heteroarylene, wherein X 1 is N(R 3 ) or N; X 2 is N(R 5 ) or N; X 3 is C or N; X 4 is C or N; X 5 is C(R 6 ) or N; X 6 is C(R 7 ) or N; and X 7 is C(R 8 ) or N.
  • ring B/C is a 9-membered bicyclic heteroarylene, wherein X 1 is N; X 2 is N(R 5 ), X 3 is C or N; X 4 is C or N; X 5 is C(R 6 ) or N; X 6 is C(R 7 ) or N; and X 7 is C(R 8 ) or N.
  • ring B/C is a 9-membered bicyclic heteroarylene, wherein X 1 is C(R 2 ), N(R 3 ), or N; X 2 is C(R 4 ), N(R 5 ), or N; X 3 is C or N; X 4 is C or N; X 5 is C(R 6 ) or N; X 6 is C(R 7 ) or N; and X 7 is C(R 8 ) or N; provided that at least one of X 1 to X 7 is a nitrogen atom (e.g., N or NR 3 or NR 5 ) and one of X 1 or X 2 is a carbon atom (e.g., CR 2 or CR 4 ).
  • X 1 is C(R 2 ), N(R 3 ), or N
  • X 2 is C(R 4 ), N(R 5 ), or N
  • X 3 is C or N
  • X 4 is C or N
  • X 5 is C(R 6 ) or
  • X 1 is C(R 2 ). In some embodiments, X 2 is C(R 4 ). In some embodiments, X 1 is N(R 3 ) or N. In some embodiments, X 1 is N. In some embodiments, X 2 is N(R 5 ) or N. In some embodiments, X 2 is N. In some embodiments, one of X 1 or X 2 is N. In some embodiments, X 1 is C(R 2 ), and X 2 is N(R 5 ) or N. In some embodiments, X 1 is C(R 2 ) and X 2 is N.
  • X 1 is N(R 3 ) or N
  • X 2 is C(R 4 ). In some embodiments, X 1 is N and X 2 is C(R 4 ).
  • X 3 is C or N. In some embodiments, X 3 is C. In some embodiments, X 3 is N. In some embodiments, X 4 is C or N. In some embodiments, X 4 is C. In some embodiments, X 4 is N. In some embodiments, X 5 is C(R 6 ) or N. In some embodiments, X 5 is C(R 6 ). In some embodiments, X 5 is N. In some embodiments, X 6 is C(R 7 ) or N.
  • X 6 is C(R 7 ). In some embodiments, X 6 is N. In some embodiments, X 7 is C(R 8 ) or N. In some embodiments, X 7 is C(R 8 ). In some embodiments, X 7 is N. [0319] In some embodiments, X 3 is N, X 4 is C, X 5 is C(R 6 ), X 6 is C(R 7 ), and X 7 is C(R 8 ). In some embodiments, X 3 is N, X 4 is C, X 5 is N, X 6 is C(R 7 ), and X 7 is C(R 8 ).
  • X 3 is N, X 4 is C, X 5 is C(R 6 ), X 6 is C(R 7 ), and X 7 is N. In some embodiments, X 3 is N, X 4 is C, X 5 is C(R 6 ), X 6 is N, and X 7 is C(R 8 ). In some embodiments, X 3 is C, X 4 is N, X 5 is C(R 6 ), X 6 is C(R 7 ), and X 7 is C(R 8 ). In some embodiments, X 3 is C, X 4 is N, X 5 is C(R 6 ), X 6 is N, and X 7 is C(R 8 ).
  • X 3 is C, X 4 is C, X 5 is C(R 6 ), X 6 is C(R 7 ), and X 7 is C(R 8 ).
  • X 3 is C, X 4 is C, X 5 is C(R 6 ), X 6 is C(R 7 ), and X 7 is N.
  • X 3 is C, X 4 is C, X 5 is C(R 6 ), X 6 is N, and X 7 is C(R 8 ).
  • ring B/C is of the formula , , , 83573-422399 , [0322]
  • ring D/E is a 9-membered bicyclic heteroarylene, wherein Y 1 is C(R 9 ), N(R 10 ), or N; Y 2 is C(R 11 ), N(R 12 ), or N; Y 3 is C or N; Y 4 is C or N; Y 5 is C(R 13 ) or N; Y 6 is C(R 14 ) or N; and Y 7 is C(R 15 ) or N; provided that at least one of Y 1 to Y 7 is a nitrogen atom (e.g., N or NR 10 or NR 12 ).
  • ring D/E is a 9-membered bicyclic heteroarylene, wherein Y 1 is C(R 9 ), N(R 10 ), or N; Y 2 is C(R 11 ), N(R 12 ), or N; Y 3 is C or N; Y 4 is C or N; Y 5 is C(R 13 ) or N; Y 6 is C(R 14 ) or N; and Y 7 is C(R 15 ) or N; provided that one of Y 1 or Y 2 is a carbon atom (e.g., CR 9 or CR 11 ).
  • ring D/E is a 9-membered bicyclic heteroarylene, wherein Y 1 is N(R 10 ) or N; Y 2 is N(R 12 ) or N; Y 3 is C or N; Y 4 is C or N; Y 5 is C(R 13 ) or N; Y 6 is C(R 14 ) or N; and Y 7 is C(R 15 ) or N.
  • ring D/E is a 9- membered bicyclic heteroarylene, wherein Y 1 is N; Y 2 is N(R 12 ); Y 3 is C or N; Y 4 is C or N; Y 5 is C(R 13 ) or N; Y 6 is C(R 14 ) or N; and Y 7 is C(R 15 ) or N.
  • ring D/E is a 9- membered bicyclic heteroarylene, wherein Y 1 is C(R 9 ), N(R 10 ), or N; Y 2 is C(R 11 ), N(R 12 ), or N; Y 3 is C or N; Y 4 is C or N; Y 5 is C(R 13 ) or N; Y 6 is C(R 14 ) or N; and Y 7 is C(R 15 ) or N provided that at least one of Y 1 to Y 7 is a nitrogen atom (e.g., N or NR 10 or NR 12 ) and one of Y 1 or Y 2 is a carbon atom (e.g., CR 9 or CR 11 ).
  • Y 1 is C(R 9 ), N(R 10 ), or N
  • Y 2 is C(R 11 ), N(R 12 ), or N
  • Y 3 is C or N
  • Y 4 is C or N
  • Y 5 is C(R 13 ) or N
  • Y 1 is C(R 9 ). In some embodiments, Y 2 is C(R 11 ). In some embodiments, Y 1 is N(R 10 ) or N. In some embodiments, Y 1 is N. In some embodiments, Y 2 is N(R 12 ) or N. In some embodiments, Y 2 is N. In some embodiments, one of Y 1 or Y 2 is N. In some embodiments, Y 1 is C(R 9 ), and Y 2 is N(R 12 ) or N. In some embodiments, Y 1 is C(R 9 ) and Y 2 is N. In some embodiments, Y 1 is N(R 10 ) or N, and Y 2 is C(R 11 ).
  • Y 1 is N and Y 2 is C(R 11 ).
  • Y 3 is C or N. In some embodiments, Y 3 is C. In some embodiments, Y 3 is N. In some embodiments, Y 4 is C or N. In some embodiments, Y 4 is C. In some embodiments, Y 4 is N. In some embodiments, Y 5 is C(R 13 ) or N. In some embodiments, Y 5 is C(R 13 ). In some embodiments, Y 5 is N. In some embodiments, Y 6 is C(R 14 ) or N. In some 83573-422399 embodiments, Y 6 is C(R 14 ). In some embodiments, Y 6 is N.
  • Y 7 is C(R 15 ) or N. In some embodiments, Y 7 is C(R 15 ). In some embodiments, Y 7 is N. [0325] In some embodiments, Y 3 is N, Y 4 is C, Y 5 is C(R 13 ), Y 6 is C(R 14 ), and Y 7 is C(R 15 ). In some embodiments, Y 3 is N, Y 4 is C, Y 5 is N, Y 6 is C(R 14 ), and Y 7 is C(R 15 ). In some embodiments, Y 3 is N, Y 4 is C, Y 5 is C(R 13 ), Y 6 is C(R 14 ), and Y 7 is N.
  • Y 3 is N, Y 4 is C, Y 5 is C(R 13 ), Y 6 is N, and Y 7 is C(R 15 ). In some embodiments, Y 3 is C, Y 4 is N, Y 5 is C(R 13 ), Y 6 is C(R 14 ), and Y 7 is C(R 15 ). In some embodiments, Y 3 is C, Y 4 is N, Y 5 is C(R 13 ), Y 6 is N, and Y 7 is C(R 15 ). In some embodiments, Y 3 is C, Y 4 is C, Y 5 is C(R 13 ), Y 6 is C(R 14 ), and Y 7 is C(R 15 ).
  • Y 3 is C
  • Y 4 is C
  • Y 5 is C(R 13 )
  • Y 6 is C(R 14 )
  • Y 7 is N.
  • Y 3 is C
  • Y 4 is C
  • Y 5 is C(R 13 )
  • Y 6 is N
  • Y 7 is C(R 15 ).
  • R 2 when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R 2 , when present, is H or deuterium. In some embodiments, R 2 , when present, is H. In some embodiments, R 2 , when present, is deuterium.
  • R 3 when present, is H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 3 , when present, is H or C 1 -C 6 alkyl. In some embodiments, R 3 , when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, cyclopropyl, and the like. In some embodiments, R 3 , when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like.
  • R 3 when present, is H or deuterium. In some embodiments, R 3 , when present, is H. In some embodiments, R 3 , when present, is deuterium.
  • R 4 when present, is H, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments, R 4 , when present, is H or deuterium. In some embodiments, R 4 , when present, is H. In some embodiments, R 4 , when present, is deuterium.
  • R 5 when present, is H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 5 , when present, is H or C1-C6 alkyl. In some embodiments, R 5 , when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, cyclopropyl, and the like. In some embodiments, R 5 , when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like.
  • R 5 when present, is H or deuterium. In some embodiments, R 5 , when present, is H. In some embodiments, R 5 , when present, is deuterium.
  • R 6 when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R 6 , when present, is H or deuterium. In some embodiments, R 6 , when present, is H. In some embodiments, R 6 , when present, is deuterium.
  • R 7 when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R 7 , when present, is H or deuterium. In some embodiments, R 7 , when present, is H. In some embodiments, R 7 , when present, is deuterium.
  • R 8 when present, is H, deuterium, halogen, C 1 -C 6 alkyl, -NR a R b . In some embodiments, R 8 , when present, is H or deuterium. In some embodiments, R 8 , when present, is H. In some embodiments, R 8 , when present, is deuterium. In some embodiments, R 8 , when present, is halogen, for example fluoro. In some embodiments, R 8 , when present, is C1-C6 alkyl, for example methyl. In some embodiments, R 8 , when present, is -NR a R b .
  • R 9 when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R 9 , when present, is H or deuterium. In some embodiments, R 9 , when present, is H. In some embodiments, R 9 , when present, is deuterium.
  • R 10 is C 1 -C 6 alkyl, for example ethyl or propyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted by -OR e , wherein R e is H such that R 10 is a C1-C6 alkanol (e.g., ethanol or propanol such as 2-hydroxy-propan-1-yl or 1-hydroxy-propan-2-yl).
  • R 10 when present, is H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl.
  • R 10 when present, is H or C 1 -C 6 alkyl.
  • R 10 when present, 83573-422399 is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, cyclopropyl, and the like. In some embodiments, R 10 , when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like. In some embodiments, R 10 , when present, is H or deuterium. In some embodiments, R 10 , when present, is H.
  • R 10 when present, is H, deuterium, methyl, ethyl, or propyl, wherein each hydrogen atom in methyl, ethyl, and propyl is independently optionally substituted by OH.
  • R 10 when present, is deuterium.
  • R 10 when present, is or , wherein the “ ” denotes a point [0340]
  • R 11 when present, is H, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments, R 11 , when present, is H or deuterium. In some embodiments, R 11 , when present, is 83573-422399 H. In some embodiments, R 11 , when present, is deuterium.
  • R 12 is -S(O)2R c , for example where R c is C1-C6 alkyl, for example methyl.
  • R 12 is C1-C6 alkyl, for example ethyl, wherein each hydrogen atom in C1-C6 alkyl is optionally substituted by -OR e , wherein R e is H such that R 12 is a C1-C6 alkanol (e.g., ethanol or propanol).
  • R 12 is C1-C6 alkyl, for example methyl.
  • R 12 when present, is H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R 12 , when present, is H or C1-C6 alkyl. In some embodiments, R 12 , when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, cyclopropyl, and the like. In some embodiments, R 12 , when present, is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and the like.
  • R 12 when present, is H or deuterium. In some embodiments, R 12 , when present, is H. In some embodiments, R 12 , when present, is deuterium. In some embodiments, R 12 , when present, is methyl or -S(O) 2 R e , for example -S(O) 2 C 1 -C 6 alkyl such as 83573-422399 -S(O)2CH3. In some embodiments, R 12 , when present, is H, deuterium, methyl, ethyl, propyl, or -S(O) 2 R e , wherein each hydrogen atom in methyl, ethyl, and propyl is independently optionally substituted by OH.
  • R 13 when present, is H, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments, R 13 , when present, is H or deuterium. In some embodiments, R 13 , when present, is H. In some embodiments, R 13 , when present, is deuterium.
  • R 14 when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R 14 , when present, is H or deuterium. In some embodiments, R 14 , when present, is H. In some embodiments, R 14 , when present, is deuterium. In some embodiments, R 14 , when present, is halogen, for example fluoro or chloro.
  • R 15 when present, is H, deuterium, halogen, or C1-C6 alkyl. In some embodiments, R 15 , when present, is H or deuterium. In some embodiments, R 15 , when present, is H. In some embodiments, R 15 , when present, is deuterium. In some embodiments, R 15 , when present, is -NR a R b , where each of R a and R b is independently C1-C6 alkyl such as methyl. In some embodiments, R 15 , when present, is C3-C6 cycloalkyl, for example cyclopropyl. In some embodiments, R 15 , when present, is halogen, for example chloro or fluoro.
  • R 15 when present, is C1-C6 alkyl, for example methyl, ethyl, or propyl (e.g., isopropyl), optionally substituted by halogen (e.g., fluoro such as difluoromethyl or trifluoromethyl).
  • R 15 when present is -OR c , wherein R c is C1-C6 alkyl, for example methyl.
  • ring B/C is of the formula , 83573-422399
  • ring D/E is of the formula , , or [0347]
  • (L)m is -L 2 -(Z 1 -L 1 )p-Z-, where p 1 is or 2.
  • each of Z and Z 1 is independently a bond, -O-, -N(R 18 )C(O)-, -C(O)N(R 18 )-, -N(R 18 )-, - N(R 18 )S(O)-, S(O)N(R 18 )-, -N(R 18 )S(O)2-, -S(O)2N(R 18 )-, -S-, -S(O)-, or -S(O)2-.
  • p 1 is or 2. In some embodiments, p is 1. In some embodiments, p is 2.
  • each L 1 is independently C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-C(R 16 )(R 17 )-, or C(R 16 )(R 17 )-C(R 16 )(R 17 )-C(R 16 )(R 17 )-C(R 16 )(R 17 )-.
  • L 2 is a bond, C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, or -C(R 16 )(R 17 )-C(R 16 )(R 17 )-C(R 16 )(R 17 )-.
  • each L 1 is independently 83573-422399 -C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 ), or -C(R 16 )(R 17 )-C(R 16 )(R 17 )-C(R 16 )(R 17 )-.
  • each L 1 is independently C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 ), or -C(R 16 )(R 17 )- C(R 16 )(R 17 )-C(R 16 )(R 17 )-, wherein one or two of R 16 is a C1-C6 alkyl.
  • each L 1 is independently C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 ), or -C(R 16 )(R 17 )-C(R 16 )(R 17 )- C(R 16 )(R 17 )-, wherein one or two of R 16 is a C1-C6 alkyl, and the remaining R 16 and R 17 are H or deuterium.
  • L 1 is -C(R 16 )(R 17 )-C(R 16 )(R 17 ).
  • one instance of L 1 is C(R 16 )(R 17 )- and another instance of L 1 , when present, is C(R 16 )(R 17 )-C(R 16 )(R 17 )-.
  • Z is a bond, -O-, -N(R 18 )C(O)-, -C(O)N(R 18 )-, -N(R 18 )-, -N(R 18 )S(O)-, S(O)N(R 18 )-, -N(R 18 )S(O) 2 -, -S(O) 2 N(R 18 )-, -S-, -S(O)-, or -S(O) 2 -.
  • Z is -O-.
  • Z is -N(R 18 )C(O)-.
  • Z is a bond.
  • each Z 1 is independently a bond, -O-, -N(R 18 )C(O)-, -C(O)N(R 18 )- , -N(R 18 )-, N(R 18 )S(O)-, S(O)N(R 18 )-, -N(R 18 )S(O)2-, -S(O)2N(R 18 )-, -S-, -S(O)-, or -S(O)2-.
  • each Z 1 is independently -O- or -N(R 18 )-.
  • L 2 is a bond, C(R 16 )(R 17 )-, -C(R 16 )(R 17 )-C(R 16 )(R 17 )-, or -C(R 16 )(R 17 )-C(R 16 )(R 17 )-C(R 16 )(R 17 )-. In some embodiments, L 2 is a bond.
  • each R 16 and R 17 when present, is independently H, deuterium, halogen, or C 1 -C 6 alkyl, or two of R 16 and R 17 , taken together with the carbon or carbons to which they are attached, combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1- C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R e R , -OS(O)
  • each R 16 and R 17 when present, is independently H, deuterium, halogen, or C1-C6 alkyl, or two of R 16 and R 17 , taken together with the carbon or carbons to which they are attached, combine to form C3-C6 cycloalkyl or 3- to 7-membered heterocycloalkyl; wherein each hydrogen atom in C1-C6 alkyl, C3-C6 cycloalkyl, and 3- to 7-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, or -OR e ,; or one of R 16 or R 17 and an R 18 , taken together with the atoms to which each is attached, combine to form a 4- to 7-membered heterocycloalkyl; wherein each hydrogen atom in 4- to 7- membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, or -
  • each R 18 is independently H, deuterium, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, each R 18 , when present, is independently H, C 1 -C 6 alkyl, or C3-C6 cycloalkyl. In some embodiments, an R 18 and an R 16 or R 17 , taken together with the atoms to which they are attached, combine to form 4- to 7-membered heterocycloalkyl. In some embodiments, each R 18 is independently H, deuterium, methyl, ethyl, propyl, iso-propyl, or cyclopropyl.
  • each R 18 when present, is independently H, methyl, or ethyl.
  • -(L)p- or -L 2 -(Z 1 -L 1 )p-Z- is of the formula [0364]
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkylene-C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C1-C6 alkylene-5- to 10-membered heteroaryl, and C1-C6 alkylene-3- to 7-membered heterocycloal
  • the compounds of the present disclosure are macrocycles.
  • ring A and ring E are connected by a linker portion as described herein, wherein the linker portion comprises a chain of atoms, including but not limited to C, N, O, and S to provide a macrocycle.
  • the disclosure provides a compound selected from the group consisting of 15-(methanesulfonyl)-8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole; [0367] 8-methyl-2,11,12,15-tetrahydro-8H,10H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,7-c'']tripyrazole; [0368] 2-(8-methyl-2,8,11,12-tetrahydro-10H,15H-3,5:16,18- dietheno[1,5]dioxacyclopentadecino[10,11-c:15,14-c':6,
  • the disclosure provides a compound selected from the group consisting of (2S)-2-[(10S)-20-methoxy-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-15H- 5,3-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-15- yl]propan-1-ol; [0374] 2-[(10S)-6,8,10,12-tetramethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol; [
  • the disclosure provides a compound selected from the group consisting of 2-[(10S)-8,10,12-trimethyl-2,8,10,11,12,13-hexahydro-14H-3,5-(azenometheno)- 16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]ethan-1-ol; [0406] (2S)-1-[(10S)-12-ethyl-8,10-dimethyl-2,8,10,11,12,13-hexahydro-14H-3,5- (azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14- yl]propan-2-ol; [0407] (2S)
  • the disclosure provides a compound selected from the group consisting of (2S)-2-[(11S)-7,9,11,13-tetramethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol; [0413] (2S)-2-[(11S)-13-ethyl-7,9,11-trimethyl-11,12,13,14-tetrahydro-9H,15H-6,3- (azenometheno)-17,19-ethenoimidazo[2,1-j]dipyrazolo[3,4-f:4',3'- n][1,4,11]oxadiazacyclopentadecin-15-yl]propan-1-ol;
  • the disclosure provides a compound selected from the group consisting of (2S)-2-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)- 16,18-ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)- yl]propan-1-ol; [0421] (2S)-1-[(10S)-6,8,10,12-tetramethyl-10,11,12,13-tetrahydro-5,3-(azenometheno)-16,18- ethenoimidazo[4,5-j]dipyrazolo[3,4-f:4',3'-n][1,4]oxazacyclopentadecin-14(8H)-yl]propan-2-ol; [0422] (2S)-2-[(10S)-6,8,
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient.
  • compositions according to the disclosure are sterile compositions.
  • Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art. [0428] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl
  • the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi- dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form 83573-422399 or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 ⁇ g/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • the inventive compositions may be formulated for rectal administration as a suppository.
  • the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration.
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdermal delivery.
  • the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • the term “subject” refers to a mammalian patient in need of such treatment, such as a human.
  • Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation.
  • cancer includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia
  • MDS myelodys
  • an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment, such as those described herein having a disease, such as cancer, including those associated with aberrant oncogenic driver mutations such as those described herein, and resistance mutations, such as those described herein.
  • Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease.
  • compositions and formulations of the disclosure, as well as methods of treatment can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.
  • Examples of commercially available materials that can be used in the syntheses of the disclosure include 5-bromo-1H-pyrazolo[3,4-c]pyridine; 5-bromo-7-methyl-1H-pyrazolo[3,4-c]pyridine; 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine; 5-bromo-7-fluoro-1H-indazole; ethyl (2S)-2- hydroxypropanoate; (2R)-propane-1,2-diol; tert-butyl N-[(2R)-2-hydroxypropyl]carbamate; (R)- 2-methyloxirane; ethyl 7-methoxy-2H-indazole-3-carboxylate; methyl 5-bromo-1H-indazole-3- carboxylate; methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate; methyl 6-fluoro-1H- ind
  • I-1-3 was prepared in a manner similar to those described in step 2 of Intermediate Method I-1A starting from 5-bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine.
  • I-1-4 was prepared in a manner similar to those described in Intermediate Method I-1A starting from 5-bromo-7-fluoro-1H-indazole and using dioxane in step 2 instead of Toluene.
  • Intermediate Table 1 1
  • I-3-3 was prepared in a similar manner to those described in Intermediate Method I-3A starting from methyl 5-bromo-1H-indazole-3-carboxylate and I-2-1.
  • I-3-4 was prepared in a similar manner to those described in Intermediate Method I-3A using methyl 5-bromo-1H-indazole-3-carboxylate and I-2-3.
  • I-3-5 was prepared in a manner similar to those described in Intermediate Method I-3A from methyl 5-bromo-1H-indazole-3-carboxylate and I-2-4.
  • Step 3 To a solution of methyl (S)-5-bromo-2-(2-hydroxypropyl)-2H-indazole-3- carboxylate (3.00 g, 9.58 mmol, 1 eq), TBDPSCl (3.16 g, 11.5 mmol, 1.2 eq) in DCM (10 mL) 83573-422399 was added TEA (2.91 g, 28.7 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • I-3-8 was prepared in a similar manner described in Intermediate Method I-3C starting from methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate and I-2-6.
  • reaction mixture was diluted with H2O (1000 mL) and extracted with EA (2 ⁇ 1000 mL). The combined organic layers were washed with brine (2 ⁇ 1000 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 A mixture of ethyl 5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- c]pyridin-3-yl)-1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazole-3- carboxylate (880 mg, 1.31 mmol, 1 eq) in THF (10 mL) was degassed and purged with N2 for 3 times.
  • Step 3 To a solution of (5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- c]pyridin-3-yl)-1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7-methoxy-1H-indazol-3- yl)methanol (325 mg, 0.515 mmol, 1 eq) in DCM (3 mL) was added DMP (262 mg, 0.618 mmol, 1.2 eq). The mixture was stirred at 25 °C for 0.5 hours.
  • I-4-2, I-4-3, and I-4-4 were prepared in a manner similar to those described in Intermediate Method I-4A using the SMs as listed below in intermediate table 4.
  • I-4-5 was prepared in a manner similar to those described in Intermediate Method I-4A step 1 with the SMs as listed below in intermediate table 4.
  • I-4-6 was prepared in a manner similar to those described in Intermediate Method I-4A using the SMs as listed below in intermediate table 4.
  • I-4-7, I-4-8, I-4-9 and I-4-10 were prepared from the SMs as listed below in intermediate table 4 in a manner similar to those described in step 1 of Intermediate Method I-4A.
  • I-4-12 and I-4-13 were prepared in a manner similar to those described in Intermediate Method I-4A step 1 using the SMs as listed below in intermediate table 4.
  • I-4-14, I-4-15 and I-4-16 were prepared in a manner similar to those described in Intermediate Method I-4B step 1 using the SMs as listed below in intermediate table 4 and substituting Na2CO3 for Cs2CO3.
  • I-4-17 was prepared in a manner similar to those described in Intermediate Method I-4B step 1 using the SMs as listed below in intermediate table 4 and substituting K2CO3 for Cs2CO3.
  • I-4-18 was prepared in a manner similar to those described in Intermediate Method I-4B step 1 using the SMs as listed below in intermediate table 4 and substituting Na2CO3 for Cs2CO3 along with decreasing reaction time to 1 hour.
  • I-4-19 was prepared in a manner similar to those described in Intermediate Method I-4A step 1 using the SMs as listed below in intermediate table 4.
  • reaction mixture was diluted with H 2 O (3 mL) and extracted with EA (1 mL ⁇ 3). The combined organic layers were washed with Brine (3 mL ⁇ 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the mixture was 83573-422399 degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 h. On completion, the mixture was concentrated to give a residue.
  • Step 2 Performed according to Deprotection Method D1.
  • Step 3 To a solution of 5-(5-(1,3-dimethyl-5-(((S)-1-(methylamino)propan-2-yl)oxy)- 1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-1-((S)-1-hydroxypropan-2-yl)-7-methoxy- 1H-indazole-3-carbaldehyde (25.0 mg, 0.044 mmol, 1 eq, HCl salt) in THF (0.5 mL) and DMF (0.1 mL) was added AcOH (2.64 mg, 0.044 mmol, 1 eq) until the solution pH was between 5-6.
  • Step 5 Conducted in a manner described in Deprotection Method D3.
  • Step 6 To a solution of 5-(5-(5-(((S)-1-aminopropan-2-yl)oxy)-1-methyl-1H-pyrazol-4- yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2-((tert- butyldimethylsilyl)oxy)ethyl)-2H-indazole-3-carbaldehyde (20.0 mg, 0.0304 mmol, 1 eq) in MeOH (0.5 mL) was added AcOH (0.030 mmol, 1.74 ⁇ L, 1 eq).
  • Step 2. Conducted in a manner described in Deprotection Method D1.
  • Step 3. Conducted in a manner described in Reduction Method R2.
  • Step 4. Conducted in a manner described in Deprotection Method D6.
  • General Method F [0638] Preparation of (2S)-1-[(10S)-6-(methoxymethyl)-8,10-dimethyl-2,8,10,11,12,13- hexahydro-14H-3,5-(azenometheno)-16,18-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''- n][1,4]oxazacyclopentadecin-14-yl]propan-2-ol (Ex.19) 83573-422399 C steps 1-4 using starting materials I-4-7, I-5-4 and I-2-7.
  • Step 5 Performed according to Deprotection Method D8.
  • Step 6 To a solution of tert-butyl ((2S)-2-((4-(3-(3-formyl-2-((S)-2-hydroxypropyl)-2H- indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3- (methoxymethyl)-1-methyl-1H-pyrazol-5-yl)oxy)propyl)carbamate (90.0 mg, 128 ⁇ mol, 1 eq) in DCM (1 mL) was added TBDPSCl (38.7 mg, 141 ⁇ mol, 1.1 eq) and imidazole (26.0 mg, 384 ⁇ mol, 3 eq) and stirred at 0 °C for 1 h.
  • Step 7 Conducted in a manner described in Deprotection Method D1.
  • Step 8. To a solution of 5-(5-(5-(((S)-1-aminopropan-2-yl)oxy)-3-(methoxymethyl)-1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-((S)-2-((tert- butyldiphenylsilyl)oxy)propyl)-2H-indazole-3-carbaldehyde (140 mg, 185 ⁇ mol, 1 eq) in THF (2 mL) was added sodium triacetoxyboranuide (78.4 mg, 370 ⁇ mol, 2 eq) and CH 3 COOH (185 ⁇ mol, 10.6 ⁇ L, 1 eq) and stirred and stirred at 25 °C for 1 h.
  • Step 4 A mixture of AlCl3 (9.12 mg, 68.4 ⁇ mol, 0.5 eq) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 0 °C for 0.1 hour under N2 atmosphere. Then LAH (2.5 M in THF, 0.1 mL, 2 eq) was added into the mixture, and then the mixture was stirred at 0 °C for 0.1 hour under N2 atmosphere.
  • Step 2 was performed in a similar manner to step 2 of General Method H using I-2-8.
  • Step 3 was performed in a similar manner to step 3 of General Method H with time being decreased to 1 hour.
  • Step 4. To a solution of 2-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-5-(5-(5-(((S)- 1-(ethylamino)propan-2-yl)oxy)-3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl)-7-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-7-fluoro-2H-indazole-3-carboxylic acid (850 mg, 1.07 mmol, 1 eq) in ACN (10 mL) was added NMI (3.22 mmol, 256 ⁇ L, 3 eq)
  • Step 2 A mixture of tert-butyl ((2S)-2-((4-(3-(2-(2-hydroxyethyl)-3-(hydroxymethyl)- 2H-indazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1-methyl-1H- pyrazol-5-yl)oxy)propyl)carbamate (90.0 mg, 139 ⁇ mol, 1 eq) in DCM (1 mL) was added MnO2 (181 mg, 2.09 mmol, 15 eq), and then the mixture was stirred at 40 °C for 16 h.
  • Step 4 was performed in a similar manner to Deprotection Method D1 with time extended to 1 hour.
  • Step 5 To a solution of (S)-5-(5-(5-((1-aminopropan-2-yl)oxy)-1-methyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2H-indazole-3- carbaldehyde (33.0 mg, 44.9 ⁇ mol, 1 eq, HCl) in MeOH (0.5 mL) was added DIEA (11.6 mg, 89.8 ⁇ mol, 2 eq) and AcOH (2.69 mg, 44.9 ⁇ mol, 1 eq) and stirred at 25 °C for 30 mins.
  • Plasmids with ALK mutant cDNAs were made at GenScript by site directed mutagenesis and confirmed by sequencing.
  • Lentivirus carrying EML4-ALK mutations were prepared from the corresponding plasmids with EML4-ALK mutant cDNAs.
  • Ba/F3 cell lines with EML4-ALK gene mutations were generated by infecting Ba/F3 cells with lentivirus containing corresponding ALK mutations. Stable cell lines were selected by puromycin treatment at 2 ⁇ g/mL, followed by interleukin-3 (IL- 3) withdrawal.
  • IL- 3 interleukin-3
  • PC-9 purchased from Aldrich-Sigma, #90071810
  • SK-BR-3 purchased from ATCC HTB-30
  • MV4-11 purchased from ATCC CRL-9591
  • Ba/F3 EML4-ALK cells at 1000 cells in 48 ⁇ L per well were seeded in 384 well plates (Corning, Inc.).2 ⁇ L of compounds were added in a 3 folds titration for 11 doses, starting from 10 ⁇ M. Plates were incubated for 3 days at 37 °C and 5% CO2.
  • Cell proliferation was measured using CellTiter-Glo® 2.0 luciferase-based ATP detection assay (Promega) at 18 ⁇ L per well following the manufacturer’s protocol. Plates were then read on a Tecan Spark® multimode microplate reader. The IC50 values were determined using GraphPad Prism 10 software (GraphPad, Inc.). [0681] Cellular EGFR Phosphorylation Assays [0682] EGFR phosphorylation assays were conducted in NSCLC cells with EGFR activation mutations.
  • PC-9 cells (purchased from Aldrich-Sigma) carry a Glu746-Ala750 deletion (d746- 750) mutation in exon 19 of the EGFR gene and NCI-H1975 cells (purchased from ATCC) carry both L858R activation mutation and T790M gatekeeper mutation in the EGFR gene.
  • A431 cells (purchased from ATCC) with amplification of wildtype EGFR, derived from epidermoid carcinoma, were used to measure the activity against wildtype EGFR. All cells were seeded in 96-well plates. For PC-9 and NCI-H1975 cells, 50 thousand cells were seeded per well. For A431 cells, 30 thousand cells were seeded per well.

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Abstract

La présente invention concerne des composés macrocycliques, des compositions pharmaceutiques contenant des composés macrocycliques, et des procédés d'utilisation de composés macrocycliques pour traiter une maladie, telle que le cancer.
PCT/US2025/028355 2024-05-09 2025-05-08 Macrocycles bis-bicyclohétéroaryle et leur utilisation Pending WO2025235733A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130237518A1 (en) * 2010-10-29 2013-09-12 Merck Sharp & Dohme Corp Novel compounds that are erk inhibitors
US20150290198A1 (en) * 2011-09-30 2015-10-15 Ipsen Pharma S.A.S. Macrocyclic lrrk2 kinase inhibitors
US20150297587A1 (en) * 2012-11-30 2015-10-22 University Of Rochester Mixed lineage kinase inhibitors for hiv/aids therapies
US20190169207A1 (en) * 2014-01-24 2019-06-06 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
WO2023240138A1 (fr) * 2022-06-08 2023-12-14 Blossomhill Therapeutics, Inc. Macrocycles contenant de l'indazole et leur utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130237518A1 (en) * 2010-10-29 2013-09-12 Merck Sharp & Dohme Corp Novel compounds that are erk inhibitors
US20150290198A1 (en) * 2011-09-30 2015-10-15 Ipsen Pharma S.A.S. Macrocyclic lrrk2 kinase inhibitors
US20150297587A1 (en) * 2012-11-30 2015-10-22 University Of Rochester Mixed lineage kinase inhibitors for hiv/aids therapies
US20190169207A1 (en) * 2014-01-24 2019-06-06 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
WO2023240138A1 (fr) * 2022-06-08 2023-12-14 Blossomhill Therapeutics, Inc. Macrocycles contenant de l'indazole et leur utilisation

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