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WO2025080653A1 - Composés pyrrolo[2,1-f][1,2,4]triazine agissant contre des cancers, des maladies inflammatoires et une maladie fibrotique par interaction avec des protéines de la superfamille ras - Google Patents

Composés pyrrolo[2,1-f][1,2,4]triazine agissant contre des cancers, des maladies inflammatoires et une maladie fibrotique par interaction avec des protéines de la superfamille ras Download PDF

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Publication number
WO2025080653A1
WO2025080653A1 PCT/US2024/050482 US2024050482W WO2025080653A1 WO 2025080653 A1 WO2025080653 A1 WO 2025080653A1 US 2024050482 W US2024050482 W US 2024050482W WO 2025080653 A1 WO2025080653 A1 WO 2025080653A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable form
cancer
protein
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/US2024/050482
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English (en)
Inventor
Yaron R. HADARI
Michael Schmertzler
Theresa M. Williams
Carolina BIGARELLA
Luca CARTA
Rebecca HUTCHESON
Sufang ZHANG
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Shy Therapeutics LLC
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Shy Therapeutics LLC
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Publication of WO2025080653A1 publication Critical patent/WO2025080653A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • methods of modulating the activity of cellular targets by administering to a subject a compound of Formula I, or a pharmaceutically acceptable form thereof.
  • methods of treating cancer, fibrotic diseases, and inflammatory diseases by administering to a subject a compound of Formula I, or a pharmaceutically acceptable form thereof.
  • R 1 R 2 or a pharmaceutically acceptable form thereof, wherein: Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R 5 substituent and optionally substituted with 1-2 R 6 substituents; H 3 CO H 3 CO R 1 , , NAI-1541502036v1 OCH 3 OCH 3 OCH 3 OCH 3 N H 3 CO , , , R 2 2 NAI-1541502036v1 N N N N N N N or R 5 and R 6 are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, halo, –NR 9 R 10 , C 1-6 alkoxy, C 1-6 haloalkoxy, –C(O)NR 9 R 10 , –(CO)R 8 , –
  • a compound of Formula IA 3 NAI-1541502036v1 R1 R 2 N or a pharmaceutically acceptable R 1 , R 2 , R 3 , R 4 , R 5 wherein , R 6 , m, are as [0005] Also provided herein is a compound of Formula IA(1): R 1 R 2 wherein R 1 , R 2 , R 3 , R 4 , and R 5 , are as defined herein; or a pharmaceutically acceptable form thereof.
  • a compound of Formula IB(1) R 1 R 2 wherein R 1 , R 2 , R 3 , R 4 , and R 5 , are as defined herein; or a pharmaceutically acceptable form thereof.
  • 5 NAI-1541502036v1 also provided herein is a compound of Formula IB(2): R 1 R 2 N wherein R 1 , R 2 , R 3 , R 4 , R 5 , and or a pharmaceutically
  • a compound of Formula II R 11 R 12 or a pharmaceutically acceptable form thereof, wherein: Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R 15 substituent and optionally substituted with 1-2 R 16 substituents; OCH 3 OCH 3 OCH 3 R 11 , , N R 12 , 6 NAI-1541502036v1 OCH 3 OCH 3 O ; and are each independently C1-6 alkyl, C3-6 cycloalkyl, C
  • R 11 R 12 N wherein R 11 , R 12 , R 13 , R 14 , R 15 , and are as defined herein; and wherein m is 0, 1 or 2; or a pharmaceutically acceptable form thereof.
  • a compound of Formula IIA(1) R 11 R 12 wherein R 11 , R 12 , R 13 , R 14 , and R 15 , are as defined herein; and or a pharmaceutically acceptable form thereof.
  • R 11 R 12 wherein R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , are as defined herein; and wherein m is 0, 1 or 2; 8 NAI-1541502036v1 or a pharmaceutically acceptable form thereof.
  • R 11 R 12 N wherein R 11 , R 12 , R 13 , R 14 , and R 15 , are as defined herein; and or a pharmaceutically acceptable form thereof.
  • R 11 R 12 wherein R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , are as defined herein; and or a pharmaceutically acceptable form thereof.
  • a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a
  • a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof wherein the compound is a modulator of Ras superfamily activity according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • 9 NAI-1541502036v1 the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M 10 NAI-1541502036v1 according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to Akt Phosphorylation Assay.
  • a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof wherein the compound activates phosphorylation of Akt according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • Akt Phosphorylation Assay a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits phosphorylation of Smad2/3 according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater 11 NAI-1541502036v1 than 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 ⁇ M according to Phospho- Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to JNK Activation Assay.
  • a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof wherein the compound inhibits MAPK p38 according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof 12 NAI-1541502036v1 inhibits MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or 100% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, wherein the compound inhibits proliferation in MiaPaca2 according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1 ⁇ M or less, 0.9 ⁇ M or less, 0.8 ⁇ M or less, 0.75 ⁇ M or less, 0.7 ⁇ M or less, 0.6 ⁇ M or less, 0.5 ⁇ M or less, 0.4 ⁇ M or less, 0.3 ⁇ M or less, 0.25 ⁇ M or less, 0.2 ⁇ M or less, 0.15 ⁇ M or less, 0.1 ⁇ M or less, 0.09 ⁇ M or less, 0.05 ⁇ M or less, or 0.03 ⁇ M or less, according to Proliferation Assay.
  • a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof wherein the compound inhibits IL-6 according to IL-6 Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to IL-6 Quantification Assay.
  • a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, 13 NAI-1541502036v1 IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits TNF-alpha according to TNF-alpha Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to TNF-alpha Quantification Assay.
  • Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof that has a half-life of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay.
  • a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof that has a kinetic solubility of 10 ⁇ M or more, 20 ⁇ M or more, 30 ⁇ M or more, 40 ⁇ M or more, 50 ⁇ M or more, 60 ⁇ M or more, 70 ⁇ M or more, 80 ⁇ M or more, 90 ⁇ M or more, 100 ⁇ M or more, 150 ⁇ M or more, or 200 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay.
  • Also provided herein is a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof that inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI- H727, MiaPaca-2, or Panc1, according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in Kasumi-1, BT- 549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC50 value of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MM.R1 with an IC50 value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay.
  • methods of modulating a Ras superfamily protein, 14 NAI-1541502036v1 comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating a Ras superfamily protein comprising contacting the Ras superfamily protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating caspase activity comprising contacting the caspase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating caspase activity comprising contacting the caspase with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating Erk1/2 activity comprising contacting an Erk1/2 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating Erk1/2 activity comprising contacting an Erk1/2 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating Akt activity comprising contacting an Akt protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating Akt activity comprising contacting an AKT protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating Smad2/3 activity comprising contacting a Smad2/3 protein with an effective amount of a compound of Formula I, IA, IA(1), 15 NAI-1541502036v1 IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating Smad2/3 activity comprising contacting a Smad2/3 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating JNK activity comprising contacting a JNK protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating MAPK p38 activity comprising contacting a MAPK p38 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating IL-6 activity comprising contacting a IL-6 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating IL-6 activity comprising contacting a IL-6 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating TNF-alpha activity comprising contacting a TNF-alpha protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form 16 NAI-1541502036v1 thereof.
  • Also provided herein are methods of modulating TNF-alpha activity comprising contacting a TNF-alpha protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of treating cancer in a subject comprising administering a therapeutically effective amount of the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject having cancer.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • methods of treating a fibrotic disease in a subject comprising administering a therapeutically effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.
  • methods treating an inflammatory disease in a subject comprising administering a therapeutically effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.
  • a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.
  • pharmaceutical compositions provided herein comprising therapeutically effective amounts of one or more of compounds provided herein (e.g.
  • biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmacokinetic behavior of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test for such activities.
  • pharmaceutically acceptable derivatives of a compound include, but are not limited to, salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates or hydrates thereof.
  • Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
  • the compounds produced may be administered to animals or humans without substantial toxic effects 18 NAI-1541502036v1 and either are pharmaceutically active or are prodrugs.
  • salts include, but are not limited to, amine salts, such as but not limited to N,N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides, such
  • esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids.
  • the terms “fibrosis” or “fibrotic disease” may be used interchangeably and refer to any pathological wound healing process in which connective tissue replaces normal parenchymal tissue, leading to considerable tissue re-modeling and the formation of permanent scar tissue.
  • the fibrotic disease may be fibrosis of the kidney, such as progressive kidney disease.
  • the fibrotic disease may be fibrosis of the cardiovascular system, such as atherosclerosis or restenosis.
  • the fibrotic disease may be pulmonary fibrosis.
  • the fibrotic disease may be cystic fibrosis.
  • the fibrotic disease may be idiopathic fibrosis, such as idiopathic pulmonary fibrosis.
  • the fibrotic disease may be fibrosis of the lung, such as progressive massive fibrosis or radiation-induced lung injury.
  • the fibrotic disease may be bridging fibrosis.
  • the fibrotic disease may be fibrosis of the liver, such as cirrhosis.
  • the fibrotic disease may be fibrosis of the intestine, such as Crohn’s disease.
  • the fibrotic disease may be fibrosis of the muscular system, such as Duchenne muscular dystrophy (DMD).
  • DMD Duchenne muscular dystrophy
  • the fibrotic disease may be fibrosis of the brain, such as glial scar.
  • the fibrotic disease may be fibrosis of the joints, such as arterial stiffness, fibrosis of the knee or fibrosis of the shoulder.
  • the fibrotic disease may be fibrosis of the skin, such as Keloid.
  • the fibrotic disease may be fibrosis of the bone marrow, such as myelofibrosis.
  • the fibrotic disease may be fibrosis of the heart, such as myocardial fibrosis.
  • the fibrotic disease may be fibrosis of the soft tissue.
  • the fibrotic disease may be fibrosis of the tendons. In some embodiments, the fibrotic disease may be fibrosis of the lymph nodes. In some embodiments, the fibrotic disease may be fibrosis of the eyes. In some embodiments, the fibrotic disease may be retroperitoneum. In some embodiments, the fibrotic disease may be scleroderma. In some embodiments, the fibrotic disease may be surgical scarring.
  • DMD Duchenne muscular dystrophy
  • the DMD may be Becker Muscular Dystrophy (BMD), an intermediate clinical presentation between DMD and BMD, or DMD-associated dilated cardiomyopathy (heart- disease) with little or no clinical skeletal, or voluntary, muscle disease.
  • BMD Becker Muscular Dystrophy
  • the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.
  • the K d refers to the measured equilibrium dissociation constant between a compound (or ligand) and a protein (or binding domain of a protein).
  • Smad 2/3 means the members of the receptor-regulated Smad (R- Smads) family of transcription factors, Smad2 and Smad3, collectively.
  • MAPK mitogen-activated protein kinase, which includes the stress-activated MAPK protein, MAPK p38, or simply p38.
  • JNK means the stress-activated MAPK protein c-Jun NH 2 -terminal kinase.
  • Ras superfamily means the protein superfamily of small guanosine triphosphatases (GTPases) which consists of the five main families Ras, Rho, Rab, Ran and Arf, or mutants thereof. Subfamilies of the five main families are also included, e.g., the Rac subfamily of the Rho main family.
  • Ras superfamily of proteins are small GTPases with substantial amino acid sequence homology that act as signal transducers between cell surface receptors and several intracellular signaling cascades. These proteins are involved in the regulation of essential cellular functions such as cell survival, proliferation, motility and cytoskeletal organization (see Karnoub et al., Nat. Rev. Mol.
  • Ras Ras superfamily
  • lipid vesicle trafficking fibrosis
  • inflammation inflammation and apoptosis.
  • Ras family The GTP binding domains of one subfamily of the Ras superfamily having substantial 21 NAI-1541502036v1 sequence homology is commonly referred to as the Ras family or Ras.
  • Ras proteins There are four isoforms of Ras proteins, expressed from three different genes: H-Ras (Harvey sarcoma viral oncogene), N-Ras (neuroblastoma oncogene), and the splice variants K- Ras4A and K-Ras4B (Kirsten sarcoma viral oncogene) (see Karnoub et al., supra).
  • H-Ras Hardvey sarcoma viral oncogene
  • N-Ras neutral sarcoma viral oncogene
  • K- Ras4A and K-Ras4B Kerrsten sarcoma viral oncogene
  • Rho family The GTP binding domains of another subfamily of the Ras superfamily having substantial sequence homology is commonly referred to as the Rho family and includes proteins and groups of proteins referred to as Rho, Rac and Cdc42.
  • Ras isoforms share sequence identity in all of the regions that are responsible for GDP/GTP binding, GTPase activity, and effector interactions, suggesting a functional redundancy.
  • Ras Receptor Tyrosine Kinases
  • growth factor receptors growth factor receptors
  • cytokine receptors integrins.
  • Ras proteins cycle between 'on' and 'off' conformations that are conferred by the binding of GTP and GDP, respectively.
  • GEFs guanine nucleotide exchange factors
  • Sos Son of sevenless
  • GAPs GTPase-activating proteins
  • the region of Sos functional for nucleotide exchange on Ras spans about 500 residues, and contains blocks of sequence that are conserved in Sos and other Ras-specific GEF’s such as Cdc25, Sdc25 and Ras guanine-nucleotide-release factor (GRF) (Boguske et al, Nature 366, 643-654 (1993)).
  • Ras once activated, Ras initiates signaling of the “MAPK pathway” (also referred to as the Ras-RAF-MEK-MAPK/ERK1/2 pathway) that affects cell growth, differentiation, proliferation, apoptosis and migration.
  • the MAPK pathway operates through a sequence of interactions among kinases.
  • Akt also known as protein kinase B or PKB
  • PDK1 protein kinase B
  • Akt is phosphorylated and activated by PDK1, PDK2 and mTORC2.
  • the Akt pathway can also be activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors and G-protein-coupled receptors that directly interact and activate PI3K.
  • Ras activation is also associated with signaling through other molecular pathways other than phosphoinositide 3-kinases (PI3Ks), such as Rac1 GEF and the Ral-guanine nucleotide dissociation stimulator (GDS).
  • PI3Ks phosphoinositide 3-kinases
  • PI3K that is part of the PI3K/AKT/mTOR pathway regulating intracellular signaling important for several cellular functions such as survival, anti-apoptotic and cell cycle regulation.
  • Ras and its downstream pathways including ERK1/2 and Akt, have been studied extensively. They are causally associated with a range of diseases, including certain cancers, inflammatory disorders, Ras-associated autoimmune leukoproliferative disorder, type II diabetes, and certain Rasopathies.
  • activation of MAPKs, in particular ERK1/2 is a component of the inflammatory response.
  • the compounds provided herein which are ERK1/2 inhibitors via inhibition of Ras and/or a Ras superfamily member, are useful in the treatment of inflammatory diseases.
  • activation of Akt is a component of the inflammatory response.
  • the compounds provided herein, which are Akt inhibitors via inhibition of Ras and/or a Ras superfamily member are useful in the treatment of inflammatory diseases.
  • there is more than one distinct route to aberrant Ras activation including mutational activation of Ras itself, excessive activation of the wild-type protein through upstream signaling, and loss of a GAP function that is required to terminate 23 NAI-1541502036v1 activity of the protein.
  • Ras is causally associated with inflammatory diseases including the following: rheumatoid arthritis (Abreu JR, de Launay D, Sanders ME, Grabiec AM, Sande van de MG, Tak PP, Reedquist KA: The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue (Arthritis Res Ther.2009, 11: R121-10.1186/ar2785), which is the most common cause of disability (Hootman JM, Brault MW, Helmick CG, Theis KA, Armour BS.
  • Ras has been causally associated with Ras-associated autoimmune leukoproliferative disorder, a nonmalignant clinical syndrome initially identified in a subset of putative autoimmune lymphoproliferative syndrome (ALPS) patients.
  • APS putative autoimmune lymphoproliferative syndrome
  • Ras or “Ras family” or “Ras subfamily” or “Ras group” means DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; RRAS2, or mutants thereof.
  • Rho or “Rho family” or “Rho subfamily” or “Rho group” means 24 NAI-1541502036v1 RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42, or mutants thereof.
  • Rho subfamily of the Ras superfamily currently includes approximately 22 proteins most of which scientists commonly divide into subgroups including those referred to as Cdc42, Rac, and Rho. (Boureux A, Vignal E, Faure S, Fort P (2007).”Evolution of the Rho family of ras-like GTPases in eukaryotes". Mol Biol Evol 24 (1): 203–16).
  • the three most commonly studied members of the Rho subfamily have been Cdc42, Rac1, and RhoA.
  • the Cdc42 group includes Cdc42, TC10, TCL, Chip, and Wrch-1.
  • the Rac group includes Rac1, Rac2, Rac3, and RhoG.
  • the RhoA group includes RhoA, RhoB, and RhoC.
  • Rho subfamily GTPases not included in the Cdc42, Rac, or Rho groups include RhoE/Rnd3, RhoH/TTF, Rif, RhoBTB1, RhoBTB2, Miro-1, Miro-2, RhoD, Rnd1, and Rnd2.
  • Rho subfamily GTPases cycle between 'on' and 'off' conformations that are conferred by the binding of GTP and GDP, respectively.
  • GEFs guanine nucleotide exchange factors
  • GAPs GTPase-activating proteins
  • Rho subfamily associated kinases (ROCK1 and ROCK2) are implicated as mediators of multiple profibrotic processes including those associated with idiopathic pulmonary fibrosis. (Knipe RS, Tager EM, and Liao JK.
  • Rho kinases critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.” Pharmacol Rev.201567(1):103-17.
  • Rho subfamily members have been identified as potential Therapeutic Molecular Targets.
  • Rho subfamily members have been identified as potential Therapeutic Molecular Targets in cancer.
  • Rho subfamily members have been identified as potential Therapeutic Molecular Targets in fibrotic disease.
  • GTP binding site or “GTP binding domain” both mean the region of a protein which binds GTP, and the surrounding region of said protein in which another compound may bind, wherein such binding blocks the ability of GTP to bind to said protein.
  • GDP binding site or “GDP binding domain” both mean the region of a protein which binds GDP, and the surrounding region of said protein in which another compound may bind, wherein such binding blocks the ability of GDP to bind to said protein.
  • guanosine binding region means a region of a protein which is part of the GDP binding domain or GTP binding domain, that mediates interaction with the guanosine portion of GDP or GTP.
  • metal region means a region of a protein which is part of the GDP binding domain or GTP binding domain, that is proximal to a magnesium (Mg202) binding site.
  • alternative Tyr32 conformation means the conformation of the GTP or GDP binding domain in the region of Tyr 32 in KRas crystal structure PDB code:3gft in comparsion to the KRas crystal structure PDB code:4epr.
  • apoptosis refers to a process of programmed cell death which plays important roles in physiology and pathology. It is activated during embryonic development and beyond to eliminate unwanted or damaged cells. Apoptosis also plays important roles in preventing cancer. Loss of apoptotic control allows tumor cells to survive longer and provides them time to accumulate mutations which can increase invasiveness during cancer progression, stimulate angiogenesis, deregulate cell proliferation, and interfere with differentiation. [00116] Without being bound by theory, in regard to apoptosis, it has been demonstrated that several members of the Ras superfamily of small GTPases have pro- and anti-apoptosis functions.
  • Rho family of GTPases such as Rho, Rac and cdc42 can activate apoptosis via the JNK or p38 pathways.
  • members of the Ras and Rab families of GTPases have anti-apoptotic activity mediated by activating the PI3K/Akt/mTOR survival pathway which prevent apoptosis and leads to increased cellular proliferation.
  • GAPs GTPase Activating Proteins
  • JNK c-Jun N-terminal kinase pathway
  • MAPK mitogen-activated protein kinase
  • the JNK pathway is activated by environmental stresses (ionizing radiation, heat, oxidative stress such as reactive oxygen species (ROS) and DNA damage), inflammatory cytokines, as well as growth factors. JNK activation often involves the Rho family of GTPases such as Rho, Cdc42 and Rac.
  • JNK activates apoptotic signaling by the upregulation of pro-apoptotic genes through transactivation of c-Jun/AP1-dependent or p53/73 protein-dependent mechanisms. In these pathways directed at mitochondrial apoptotic proteins, activated JNK directly modulates the activities of mitochondrial pro-apoptotic proteins through distinct phosphorylation events.
  • MAPK MAPK
  • MAPK p38 MAPK
  • apoptosis can be activated by both extrinsic (death ligand) and intrinsic (mitochondrial) pathways.
  • extrinsic death ligand
  • intrinsic mitochondrial
  • these proteins Upon apoptotic stimuli, these proteins are activated and oligomerize at the mitochondrial outer membrane to mediate its permeabilization.
  • Permeabilization enables the release of cytochrome c from mitochondria which, in turn, induces a series of biochemical reactions resulting in caspase activation and subsequent cell death.
  • induction of apoptosis can be mediated by several mechanisms, including inhibition of the ubiquitin proteasome system (UPS).
  • UPS ubiquitin proteasome system
  • the UPS system is a major proteolytic pathway for the removal of cytosolic, nuclear, and membrane associated proteins and has essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins.
  • the proteins targeted for degradation are selected by tagging them covalently with ubiquitin, typically with lysine48- linked tetraubiquitin chains, followed by proteolysis within the 26S proteasome.
  • the 26S proteasome holoenzyme consists of a 19S regulatory particle (RP) which is responsible for recognizing the ubiquitin signal and unfolding the target protein, and a 20S core particle (CP), which hydrolyzes the unfolded polypeptide into short peptides of varying lengths. Accordingly, impairment of the UPS has been associated with several pathological conditions including cancers.
  • Tumor cells can be characterized by the loss of cell cycle checkpoint control and can often be subjected to elevated levels of stress because of hyperactivation of oncogenic signaling and/or adverse microenvironmental conditions. Therefore, transformed cells can rely to a great extent on the correct function of UPS for survival and proliferation. Inhibition of the UPS, such as with proteasome inhibitors, can induce cell death and apoptosis.
  • proteasome inhibitors have gained FDA approval to treat multiple myeloma cancer patients. The three proteasome inhibitors, Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib), are reported as targeting the proteolytic sites within the 20S CP.
  • caspase(s) refers to one or more of a family of cysteine proteases that cleave proteins following aspartic acid residues. All caspases are synthesized in cells as catalytically inactive zymogens and must undergo a cleavage 28 NAI-1541502036v1 activation process to yield large and small subunits which dimerize to create active enzymes. Caspases exist in a hierarchy including so-called upstream caspases 2, 8, 9, and 10 and downstream caspases 3, 6, and 7.
  • Active caspase-9 initiates caspase cleavage which activate downstream executioner caspases 3, 6 and 7 which cleave other cellular targets and initiate apoptosis.
  • the anti-proliferative inhibitory activity of the compounds disclosed herein is mediated by the induction of apoptosis, as determined by an Anexin V apoptosis assay kit.
  • the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures.
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter enzymatic and biological activities of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • MS mass spectrometry
  • a substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.
  • the instant disclosure is meant to include all such possible isomers, as well as, their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chiral reverse phase HPLC.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • Formula A includes, but is not limited to, the three tautomeric structures below. 29 NAI-1541502036v1 N R N R H N R N NH [00125]
  • acids and other compounds are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, the IUPAC-IUB Commission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944), or the IUPAC Nomenclature of Organic Chemistry (see, Favre HA and Powell WH, Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013, Cambridge, UK: The Royal Society of Chemistry, 2013: Print ISBN 978-0-85404- 182-4, PDF eISBN 978-1-84973-306-9, DOI 10.1039/9781849733069; Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979.
  • alkyl, alkenyl and alkynyl carbon chains if not specified, contain from 1 to 20 carbons, or 1 to 16 carbons, and are straight or branched.
  • Exemplary alkyl, alkenyl and alkynyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, ethenyl, propenyl, butenyl, pentenyl, acetylenyl and hexynyl.
  • lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having from about 1 or about 2 carbons up to about 6 carbons.
  • alk(en)(yn)yl refers to an alkyl group containing at least one double bond and at least one triple bond.
  • cycloalkyl refers to a saturated mono- or multicyclic ring system, in certain embodiments of 3 to 10 carbon atoms, in other embodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl refer to mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond. Cycloalkenyl and cycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbon atoms, with cycloalkenyl groups, in further embodiments, containing 4 to 7 carbon atoms and cycloalkynyl groups, in further embodiments, containing 8 to 10 carbon atoms.
  • ring systems of the cycloalkyl, cycloalkenyl and cycloalkynyl groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion.
  • Cycloalk(en)(yn)yl refers to a cycloalkyl group containing at least one double bond and at least one triple bond. In some embodiments, the cycloalkyl ring is unsaturated or partially saturated.
  • “carbocyclic” refers to a mono- or multicyclic ring system, in which all of the atoms composing the ring are carbon atoms, such as benzene or cyclopropane.
  • the carbocyclic ring is unsaturated or partially saturated.
  • substituted alkyl refers to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein.
  • aryl refers to aromatic monocyclic or multicyclic groups containing from 6 to 19 carbon atoms.
  • Aryl groups include, but are not limited to groups such as fluorenyl, substituted fluorenyl, phenyl, substituted phenyl, naphthyl and substituted naphthyl.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system, in certain embodiments, of about 5 to about 15 members where one or more, in some embodiments 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
  • the heteroaryl group may be optionally fused to a benzene ring.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and 31 NAI-1541502036v1 isoquinolinyl.
  • the heteroaryl may be optionally fused to a heterocycloalkyl ring.
  • the heteroaryl may be a partially saturated heteroaryl, such as a phenyl ring fused to a heterocycloalkyl ring, for example a phenyl ring fused to a tetrahydrofuryl ring.
  • heterocycloalkyl refers to a monocyclic or multicyclic non-aromatic ring system, in some embodiments of 3 to 10 members, in another embodiment of 4 to 7 members, in a further embodiment of 5 to 6 members, where one or more, in certain embodiments, 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
  • the nitrogen is optionally substituted with hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, amidino, sulfonyl or the nitrogen may be quaternized to form an ammonium group where the substituents are selected as above.
  • the heterocyclyl ring is saturated. In some embodiments, the heterocyclyl ring is unsaturated or partially saturated.
  • substituted aryl refers to aryl, heteroaryl and heterocyclyl groups, respectively, that are substituted with one or more substituents, in certain embodiments one to three or four substituents, where the substituents are as defined herein.
  • aralkyl refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by an aryl group.
  • heteroarylkyl refers to an alkyl group in which one of the hydrogen atoms of the alkyl is replaced by a heteroaryl group.
  • halo refers to F, Cl, Br or I.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.
  • haloalkoxy refers to RO in which R is a haloalkyl group.
  • hydroxalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxyl group (-OH).
  • cycloalkoxy refers to an -OR group, in which R is a cycloalkyl 32 NAI-1541502036v1 group.
  • carboxy refers to a divalent radical, -C(O)O-.
  • aminocarbonyl refers to -C(O)NH 2 .
  • arylalkylaminocarbonyl refers to -C(O)NRR' in which one of R and R' is aryl, including lower aryl, such as phenyl, and the other of R and R' is alkyl, including lower alkyl.
  • arylaminocarbonyl refers to -C(O)NHR in which R is aryl, including lower aryl, such as phenyl.
  • hydroxycarbonyl refers to -COOH.
  • alkoxycarbonyl refers to -C(O)OR in which R is alkyl, including lower alkyl.
  • aryloxycarbonyl refers to -C(O)OR in which R is aryl, including lower aryl, such as phenyl.
  • alkoxy and arylthio refer to RO- and RS- , in which R is alkyl, including lower alkyl.
  • aryloxy and arylthio refer to RO- and RS-, in which R is aryl, including lower aryl, such as phenyl.
  • haloalkyl may include one or more of the same or different halogens.
  • cyclic structure may be a cycloalkyl, carbocyclic, heterocyclic, aryl or heteroaryl group.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, pig, sheep, goat horse
  • dog dog
  • cat rabbit
  • rat or mouse
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in some embodiments, a human.
  • the terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
  • therapeutically effective amount are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a therapeutically effective amount of a compound provided herein can be administered in one dose (i.e., a single dose administration) or divided and administered over time (i.e., continuous administration or multiple sub-dose administration).
  • Single dose administration, continuous administration, or multiple sub-dose administration can be repeated, for example, to maintain the level of the compound in a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human.
  • a biological molecule e.g., a protein, enzyme, RNA, or DNA
  • pharmaceutically acceptable carrier e.g., pharmaceutically acceptable excipient
  • physiologically acceptable carrier e.g., physiologically acceptable carrier
  • physiologically acceptable excipient refers 34 NAI-1541502036v1 to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable form” of compounds disclosed herein includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of compounds disclosed herein.
  • a “pharmaceutically acceptable form” includes, but is not limited to, a pharmaceutically acceptable salt, solvate, isomer, and isotopologue (i.e., isotopically labeled derivative) of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), as disclosed herein.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • the term “percent by weight” or “% by weight” refers to the weight of a specified component (e.g., an active compound or excipient) in a composition (e.g., a pharmaceutical composition) as a percentage of the total weight of the composition. Thus, the sum of the weight percentages of all the components in a composition is 100%.
  • active ingredient and “active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, 35 NAI-1541502036v1 disorder, or disease.
  • active ingredient and “active substance” may be an optically active isomer or an isotopic variant of a compound described herein.
  • drug refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • chemotherapeutic agent refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • “optically active” and “enantiomerically active” and “diastereomerically active” refer to a collection of molecules which has an enantiomeric excess or a diasteromeric excess.
  • the collection of enantiomerically active molecules may have an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • the compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the racemate in question.
  • the collection of diastereomerically active molecules may have a diastereomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • the compound comprises about 95% or more of one diastereomer and about 5% or less of the other diastereomers based on the total weight of the diastereomeric mixture in question.
  • R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • racemate is understood to refer to an equimolar mixture of a pair of 36 NAI-1541502036v1 enantiomers. It does not exhibit optical activity.
  • the chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix ( ⁇ )-, or rac- (or rac. or racem-) or by the symbols RS and SR. See IUPAC Recommendations 1996, Basic Terminology of Stereochemistry, Pure & Appl. Chem.,Vol.68, No.12, pp.2193-2222, 1996.
  • Racemic compounds disclosed herein that contain two asymmetric centers with known relative configuration are named using the configurational descriptors R,S or R,R, preceded by the prefix rac-.
  • Racemic Compound A is named rac-(1R,3S)-1- bromo-3-chlorocyclohexane and is a 1:1 mixture of enantiomers (1R,3S)-1-bromo-3- chlorocyclohexane and (1S,3R)-1-bromo-3-chlorocyclohexane.
  • centers according to Cahn-Ingold-Prelog Rules (see R.S. Cahn, C.K. Ingold and V. Prelog, Angew. Chem.
  • an “isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon- 37 NAI-1541502036v1 11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), and chlorine-37 ( 37 Cl).
  • an “isotopic variant” of a compound is in a stable form, that is, non-radioactive. It will be understood that, in a compound as provided herein, any hydrogen can be 2 H, for example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, and any oxygen can be 18 O, where feasible according to the judgment of one of skill. In certain embodiments, an “isotopic variant” of a compound contains unnatural proportions of deuterium. In some embodiments, a pharmaceutically acceptable deriviative of a compound is an isotopic variant.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which present in stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable.
  • the complex or aggregate is in a crystalline form.
  • the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate.
  • hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
  • the phrase “an isotopic variant thereof; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof” has the same meaning as the phrase “an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable salt of an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable solvate of the compound referenced therein; or a pharmaceutically acceptable solvate of an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of an isotopic variant of the compound referenced therein or its variant or its variant.”
  • R 1 R 2 N or a pharmaceutically acceptable Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R 5 substituent and optionally substituted with 1-2 R 6 substituents; H 3 CO H 3 CO , , , O O O , R 2 R 3 or ; R 4 C 1-6 alkyl; R 5 and R 6 are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, halo, –NR 9 R 10 , C 1-6 alkoxy, C 1-6 haloalkoxy, –C(O)NR 9 R 10 , –(CO)R 8 , –(CO)OH, –(CO)OR 8 , or CN, wherein the C
  • the compound of Formula I is such that Y is an imidazolyl optionally substituted with 1 R 5 substituent and optionally substituted with 1-2 R 6 substituents. In some embodiments, the compound of Formula I is such that Y is a C-linked imidazolyl that is substituted with 1 R 5 substituent at a nitrogen of the imidazolyl ring and optionally substituted with 1-2 R 6 substituents at carbons of the imidazolyl ring. In some embodiments, the compound of Formula I is a compound of Formula IA: R 1 R 2 or a pharmaceutically acceptable form thereof; wherein m is 0, 1 or 2.
  • the compound is a compound of Formula I, wherein m is 0, and the compound is a compound of Formula IA(1): 41 NAI-1541502036v1 R1 R 2 N or a pharmaceutically acceptable some the compound is a compound of Formula I, wherein m is 1. In some embodiments, the compound is a compound of Formula I, wherein m is 2. [00176] In some embodiments, the compound of Formula I, Formula IA, or Formula IA(1), is H 3 CO H 3 CO . , is F OCH 3 OCH 3 OCH 3 OCH 3 O , , O OCH 3 O N .
  • the compound of Formula I, Formula IA, or Formula O O O , (1) is O N or , is 43 NAI-1541502036v1 3 N N such that R is .
  • the compound of Formula I, Formula IA, or Formula IA(1) is 3 N N such that R is .
  • the compound of Formula I, Formula IA, or Formula IA(1) is N N the compound of Formula I, Formula IA, or Formula IA(1), is N N such .
  • the compound of Formula I, Formula IA, or Formula IA(1), is N N such .
  • the compound of Formula I, Formula IA, or Formula IA(1) is such [00186] a compound of Formula IB: R 1 R 2 or a pharmaceutically acceptable form thereof, wherein: OCH 3 H 3CO H CO O 3 ; R 4 is hydrogen or C 1-6 alkyl; R 5 and R 6 are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, halo, –NR 9 R 10 , C 1-6 alkoxy, C 1-6 haloalkoxy, –C(O)NR 9 R 10 , –(CO)R 8 , –(CO)OH, –(CO)OR 8 , or CN, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocyclo
  • the compound is a compound of Formula IB, wherein m is 0, and the compound is a compound of Formula IB(1): 45 NAI-1541502036v1 R1 R 2 N or a pharmaceutically acceptable
  • the compound is a compound of Formula IB, wherein m is 1, and, for example, the compound is a compound of Formula IB(2): R 1 R 2 or a pharmaceutically
  • the compound is a compound of Formula IB, wherein m is 2, or a pharmaceutically acceptable form thereof.
  • the compound of Formula IB, Formula IB(1), or Formula OCH 3 IB(2) is such .
  • R 2 is methyl.
  • the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2), is such that R 4 is hydrogen or C 1-6 alkyl. In some embodiments, R 4 is hydrogen, methyl, ethyl, or isopropyl. In some embodiments, R 4 is hydrogen.
  • the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2) is such that R 5 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, –C(O)NR 9 R 10 , –(CO)R 8 , or –C(O)OR 8 , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, and C 1-6 heteroalkyl are each independently optionally substituted with 1-3 R 7 substituents.
  • R 5 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, and C 1-6 heteroalkyl, are each independently optionally substituted with 1-3 R 7 substituents.
  • R 5 is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R 7 , wherein R 7 is -OH, C 1-3 alkoxy, or C 1-3 haloalkoxy.
  • R 5 is methyl, ethyl, or isopropyl. In some embodiments, R 5 is methyl.
  • the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2) is such that R 6 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, and C 1-6 heteroalkyl, are each independently optionally substituted with 1-3 R 7 substituents.
  • R 6 is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R 7 , wherein R 7 is -OH, C 1-3 alkoxy, or C 1-3 haloalkoxy. In some embodiments, R 6 is methyl, ethyl, or isopropyl. In some embodiments, R 6 is methyl.
  • the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2) is such that R 7 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, 3-6 membered heterocycloalkyl, –NR 9 R 10 , –(CO)R 8 , oxo, C 1-6 alkoxy, or C 3-6 cycloalkoxy.
  • R 7 is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, 3-5 membered heterocycloalkyl, –NR 9 R 10 , –(CO)R 8 , oxo, C 1-4 alkoxy, or C 3-5 cycloalkoxy.
  • R 7 is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C 2-3 hydroxyalkyl, C 2-4 heteroalkyl, –NR 9 R 10 , –(CO)R 8 , oxo, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.
  • the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2) is such that R 8 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or C 2-4 heteroalkyl.
  • the compound of Formula I, Formula IA, Formula IA(1), Formula IB, Formula IB(1), or Formula IB(2) is such that R 9 and R 10 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, –OH, or C 1-4 alkoxy.
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy. In some embodiments, R 9 and R 10 are each independently selected from the group consisting of hydrogen or methyl. In some embodiments, R 9 and R 10 are each hydrogen.
  • R 11 R 12 or a pharmaceutically acceptable form thereof, wherein: Y is an imidazolyl; wherein the imidazolyl is optionally substituted with 1 R 15 substituent and optionally substituted with 1-2 R 16 substituents; 48 NAI-1541502036v1 OCH 3 OCH 3 OCH 3 N N N H 3CO ; R 15 and R 16 are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, aryl, C 5-10 heteroaryl, C3-7 heterocycloalkyl, C1-6 heteroalkyl, halo, –NR 19 R 20 , C1-6 alkoxy, C 1-6 haloalkoxy, –C(O)NR 19 R 20 , –(CO)R 18 , –(CO)OH, –(CO)OR 18 , or CN, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C
  • the compound of Formula II is such that Y is an imidazolyl optionally substituted with 1 R 15 substituent and optionally substituted with 1-2 R 16 substituents.
  • the compound of Formula I is such that Y is a C-linked imidazolyl that is substituted with 1 R 15 substituent at a nitrogen of the imidazolyl ring and optionally substituted with 1-2 R 16 substituents at carbons of the imidazolyl ring.
  • the compound of Formula II is a compound of Formula IIA: R 11 R 12 or a pharmaceutically acceptable 0, 1 or 2.
  • the 50 NAI-1541502036v1 compound is a compound of Formula II, wherein m is 0, and the compound is a compound of Formula IIA(1): R 11 R 12 N or a pharmaceutically acceptable form thereof.
  • the compound is a compound of Formula I, wherein m is 1.
  • the compound is a compound of Formula I, wherein m is 2.
  • the compound of Formula II is a compound of Formula IIB: R 11 R 12 or a pharmaceutically acceptable form thereof; wherein m is 0, 1 or 2.
  • the compound is a compound of Formula IIB, wherein m is 0, and the compound is a compound of Formula IIB(1): R 11 R 12 or a pharmaceutically acceptable form thereof.
  • the compound is a compound of Formula IIB, wherein m is 1, and, for example, the compound is a compound of Formula IIB(2): 51 NAI-1541502036v1 R11 R 12 N or a pharmaceutically acceptable
  • the compound is a compound of Formula IIB, wherein m is 2, or a pharmaceutically acceptable form thereof.
  • the compound of Formula II, Formula IIA, Formula IIA(1), OCH 3 OCH 3 Formula IIB, Formula IIB(1), or Formula IIB(2) is such or OCH 3 is , , .
  • IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2) is such that R 12 52 NAI-1541502036v1 N or , , N Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R 13 or N .
  • R 13 is .
  • R 13 is Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2), is such that R 14 is hydrogen or C 1-6 alkyl.
  • R 14 is hydrogen, methyl, ethyl, or isopropyl. In some embodiments, R 14 is hydrogen. 53 NAI-1541502036v1 [00211]
  • the compound of Formula II, Formula IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2) is such that R 15 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1- 6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, –C(O)NR 19 R 20 , –(CO)R 18 , or –C(O)OR 18 , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1- 6 haloalkyl, aryl, C 5-10 heteroaryl, C 3-7 heterocycloalkyl, and C 1-6 heteroalkyl
  • R 15 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, and C 1-6 heteroalkyl, are each independently optionally substituted with 1-3 R 17 substituents.
  • R 15 is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R 17 , wherein R 17 is -OH, C 1-3 alkoxy, or C 1-3 haloalkoxy.
  • R 15 is methyl, ethyl, or isopropyl. In some embodiments, R 15 is methyl.
  • the compound of Formula II, Formula IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2) is such that R 16 is C 1-6 alkyl, C 3-6 cycloalkyl, C 1- 6 haloalkyl, or C 1-6 heteroalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, and C 1-6 heteroalkyl, are each independently optionally substituted with 1-3 R 17 substituents.
  • R 16 is methyl, ethyl, or isopropyl, wherein the methyl, ethyl, and isopropyl are each independently optionally substituted with 1-3 R 17 , wherein R 17 is -OH, C 1-3 alkoxy, or C 1-3 haloalkoxy. In some embodiments, R 16 is methyl, ethyl, or isopropyl. In some embodiments, R 16 is methyl.
  • the compound of Formula II, Formula IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2) is such that R 17 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, C 1-6 heteroalkyl, 3-6 membered heterocycloalkyl, –NR 19 R 20 , –(CO)R 18 , oxo, C 1-6 alkoxy, or C 3-6 cycloalkoxy.
  • R 17 is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-5 cycloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, 3-5 membered heterocycloalkyl, –NR 19 R 20 , –(CO)R 18 , oxo, C 1-4 alkoxy, or C 3-5 cycloalkoxy.
  • R 17 is independently selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, C 2-3 hydroxyalkyl, C 2-4 heteroalkyl, –NR 19 R 20 , –(CO)R 18 , oxo, methoxy, ethoxy, isopropoxy, cyclopropoxy, or cyclobutoxy.
  • the compound of Formula II, Formula IIA, Formula IIA(1), 54 NAI-1541502036v1 Formula IIB, Formula IIB(1), or Formula IIB(2) is such that R 18 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or C 2-4 heteroalkyl.
  • the compound of Formula II, Formula IIA, Formula IIA(1), Formula IIB, Formula IIB(1), or Formula IIB(2) is such that R 19 and R 20 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, –OH, or C 1-4 alkoxy.
  • R 19 and R 20 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, or ethoxy.
  • R 19 and R 20 are each independently selected from the group consisting of hydrogen or methyl.
  • R 19 and R 20 are each hydrogen.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) has a molecular weight (MW) of no more than 1000 g/mol. In some embodiments, the compound has a MW of no more than 900 g/mol, no more than 800 g/mol, no more than 700 g/mol, no more than 600 g/mol, or no more than 500 g/mol. In some embodiments, the compound has a MW of no more than 900 g/mol.
  • the compound has a MW of no more than 800 g/mol. In some embodiments, the compound has a MW of no more than 700 g/mol. In some embodiments, the compound has a MW of no more than 600 g/mol. In some embodiments, the compound has a MW of no more than 500 g/mol. In some embodiments, the compound has a MW of no more than 450 g/mol.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or
  • the compound is selected from the group consisting of Compounds 9, 10, 11, 13, 14, 15, 16, 18, 19, 22, and 23, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9, 11, 19, 22, and 23, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9 and 11, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of 55 NAI-1541502036v1 Compounds 36, 37, 38, 39, 40, and 62, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 69, 70, 71, 72, 73, 74, 75, 76, 84, 85, 86, 87, 88, 89, 90, and 91, or a pharmaceutically acceptable form thereof.
  • the compound of Formula IA or IA(1) is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 25, 26, 27, 28, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 70, 71, 72, 73, 74, 75, 76, 84, 85, 86, 87, 88, 89, 90, and 91, or a pharmaceutically acceptable form thereof.
  • the compound of Formula IB(1) is selected from the group consisting of Compounds 22, 23, 24, and 30, or a pharmaceutically acceptable form thereof.
  • the compound of Formula IB(2) is selected from the group consisting of Compounds 31, 32, 33, and 69, or a pharmaceutically acceptable form thereof.
  • the compound of Formula II is selected from the group consisting of Compounds 16, 17, 18, 19, 20, 21, 29, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 77, 78, 79, 80, 81, 82, 83, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the compound of Formula IIA or IIA(1) is selected from the group consisting of Compounds 16, 17, 18, 19, 20, 21, 29, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 77, 78, 79, 80, 81, 82, 83, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the compound of Formula IIB(1) is selected from the group consisting of Compounds 63, 64, and 65, or a pharmaceutically acceptable form thereof.
  • the compound of Formula IIB(2) is selected from the group consisting of Compounds 66, 67, and 68, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof is a modulator of Ras superfamily activity according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 ⁇ M 56 NAI-1541502036v1 according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more at 20 ⁇ M according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 75% or more at 20 ⁇ M according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 90% or more at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 95% or more at 20 ⁇ M according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 50% to about 60% at 20 ⁇ M according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 60% to about 70% at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 70% to about 80% at 20 ⁇ M according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 80% to about 90% at 20 ⁇ M according to a Ras Superfamily Activity Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by about 90% to about 100% at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits 57 NAI-1541502036v1 phosphorylation of Erk1/2 according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 75% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 80% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 85% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 90% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 95% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by about 50% to about 60% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by about 60% to about 70% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by about 70% to about 80% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by about 80% to about 90% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by about 90% to about 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound is 58 NAI-1541502036v1 selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 75% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 85% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 90% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 95% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by equal or greater than 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 50% to about 60% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 60% to about 70% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 70% to about 80% at 10 ⁇ M according to Erk1/2 59 NAI-1541502036v1 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 80% to about 90% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 90% to about 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by about 100% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 75% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 85% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 90% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 95% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 50% to about 60% at 10 ⁇ M according to 60 NAI-1541502036v1 Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 60% to about 70% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 70% to about 80% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 80% to about 90% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by about 90% to about 100% at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof.
  • the compound [00230]
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates phosphorylation of Akt according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 75% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 85% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 90% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 95% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by equal or greater than 100% at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 50% to about 60% at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 60% to about 70% at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 70% to about 80% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 80% to about 90% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 90% to about 100% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by about 100% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more at 10 ⁇ M according to Phospho-Smad2/3 62 NAI-1541502036v1 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 75% or more at 10 ⁇ M according to Phospho- Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 80% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 85% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 90% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 95% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by about 50% to about 60% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by about 60% to about 70% at 10 ⁇ M according to Phospho- Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by about 70% to about 80% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by about 80% to about 90% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by about 90% to about 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater 63 NAI-1541502036v1 than 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 75% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 85% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 90% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 95% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by equal or greater than 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 50% to about 60% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 60% to about 70% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 70% to about 80% at 10 ⁇ M according to Phospho- Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 80% to about 90% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 90% to about 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by about 100% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, 90 or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits JNK according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits JNK by 75% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 85% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 90% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by 95% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 50% to about 60% at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits JNK by about 60% to about 70% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 70% to about 80% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 80% to about 90% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits JNK by about 90% to about 100% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 29, 30, 32, 33, and 34, or a pharmaceutically acceptable form thereof.
  • the compound is Compound 8, or a pharmaceutically acceptable form thereof. In some 65 NAI-1541502036v1 embodiments, the compound is selected from the group consisting of Compounds 29, 32, and 34, or a pharmaceutically acceptable form thereof. [00234] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates JNK according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates JNK by 75% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 85% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 90% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by 95% or more at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by equal or greater than 100% at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates JNK by about 50% to about 60% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 60% to about 70% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 70% to about 80% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 80% to about 90% at 10 ⁇ M according to JNK Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates JNK by about 90% to about 100% at 10 ⁇ M according to JNK Activation Assay.
  • 66 NAI-1541502036v1 the compound or pharmaceutically acceptable form thereof activates JNK by about 100% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits MAPK p38 according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 75% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 85% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 90% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 50% to about 60% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 60% to about 70% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 70% to about 80% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 80% to about 90% at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by about 90% to about 100% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or 67 NAI-1541502036v1 pharmaceutically acceptable form thereof inhibits MAPK p38 by 95% or more at 10 ⁇ M according to MAPK p38 Activation Assay. [00236] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof activates MAPK p38 according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, or about 100% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 75% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 85% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 90% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 ⁇ M or less, 1.1 ⁇ M or less, 1 ⁇ M or less, 0.9 ⁇ M or less, 0.8 ⁇ M or less, 0.75 ⁇ M or less, 0.7 ⁇ M or less, 0.6 ⁇ M or less, 0.5 ⁇ M or less, 0.4 ⁇ M or less, 0.3 ⁇ M or less, 0.25 ⁇ M or less, 0.2 ⁇ M or less, 0.15 ⁇ M or less, 0.1 ⁇ M or less, 0.09 ⁇ M or less, 0.05 ⁇ M or less, or 0.03 ⁇ M or less, according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.25 ⁇ M to about 1.1 ⁇ M, about 1.1 ⁇ M to about 1 ⁇ M, about 1.0 ⁇ M to about 0.9 ⁇ M, about 0.9 ⁇ M to about 0.8 ⁇ M, about 0.8 ⁇ M to about 0.75 ⁇ M, about 0.75 ⁇ M to about 0.7 ⁇ M, about 0.7 ⁇ M to about 0.6 ⁇ M, about 0.6 ⁇ M to about 0.5 ⁇ M, about 0.5 ⁇ M to about 0.4 ⁇ M, about 0.4 ⁇ M to about 0.3 ⁇ M, about 0.3 ⁇ M to about 0.25 ⁇ M, about 0.25 ⁇ M to about 0.2 ⁇ M, about 0.2 ⁇ M to about 0.15 ⁇ M, about 0.15 ⁇ M to about 0.1 ⁇ M, about 0.1 ⁇ M to about 0.01 ⁇ M, about 0.01 ⁇ M to about 0.001 ⁇ M, about
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.6 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.5 ⁇ M or less according to Proliferation Assay.
  • the compound or 69 NAI-1541502036v1 pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.4 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.3 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.25 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.20 ⁇ M or less according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.15 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.10 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.09 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.05 ⁇ M or less according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.03 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.25 ⁇ M to about 1.1 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.1 ⁇ M to about 1 ⁇ M according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 1.0 ⁇ M to about 0.9 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.9 ⁇ M to about 0.8 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.8 ⁇ M to about 0.75 ⁇ M according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.5 ⁇ M to about 0.4 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.4 ⁇ M to about 0.3 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.3 ⁇ M to about 0.25 ⁇ M according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.25 ⁇ M to about 0.2 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.2 ⁇ M to about 0.15 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.15 ⁇ M to about 0.1 ⁇ M according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value about 0.1 ⁇ M to about 0.01 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.01 ⁇ M to about 0.001 ⁇ M according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of about 0.001 ⁇ M to about 0.0001 ⁇ M according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of less than about 0.0001 ⁇ M according to Proliferation Assay.
  • the compound is selected from the group consisting of Compounds 1, 3, 4, 9, 10, 11, 12, 13, 16, 18, 19, 22, 23, 28, 31, 32, 36, 37, 38, 39, 40, 47, 48, 49, 52, 57, 62, 65, 68, 75, 80, 81, 82, 83, 85, 87, and 94, or a pharmaceutically acceptable form thereof.
  • the compound is selected from the group consisting of Compounds 9, 10, 11, 16, 18, 19, 28, 36, 37, 38, 39, 40, 48, 57, 62, and 65, or a pharmaceutically 71 NAI-1541502036v1 acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9, 10, 11, 36, 37, 38, 39, 40, 62, and 65, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 9 and 11, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is selected from the group consisting of Compounds 36, 37, 38, 39, 40, and 62, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits IL-6 according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more at 10 ⁇ M according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 75% or more at 10 ⁇ M according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 85% or more at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 90% or more at 10 ⁇ M according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 95% or more at 10 ⁇ M according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 50% to about 60% at 10 ⁇ M according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 60% to about 70% at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 70% to about 80% at 10 ⁇ M according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 80% to about 90% at 10 ⁇ M 72 NAI-1541502036v1 according to IL-6 Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits IL-6 by about 90% to about 100% at 10 ⁇ M according to IL-6 Quantification Assay. In some embodiments, the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits TNF- alpha according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to TNF-alpha Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 100% at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF- alpha by 50% or more at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 75% or more at 10 ⁇ M according to TNF-alpha Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 85% or more at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 90% or more at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 95% or more at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 50% to about 60% at 10 ⁇ M according to TNF-alpha Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 60% to about 70% at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 70% to about 80% at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 80% to about 90% at 10 73 NAI-1541502036v1 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by about 90% to about 100% at 10 ⁇ M according to TNF-alpha Quantification Assay.
  • the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof has a kinetic solubility of 10 ⁇ M or more, 20 ⁇ M or more, 30 ⁇ M or more, 40 ⁇ M or more, 50 ⁇ M or more, 60 ⁇ M or more, 70 ⁇ M or more, 80 ⁇ M or more, 90 ⁇ M or more, 100 ⁇ M or more, 150 ⁇ M or more, or 200 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay.
  • the compound has a kinetic solubility of 10 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 20 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 30 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 40 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay.
  • the compound has a kinetic solubility of 50 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 60 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 70 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 80 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay.
  • the compound has a kinetic solubility of 90 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 100 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 150 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay. In some embodiments, the compound has a kinetic solubility of 200 ⁇ M or more in pH 7.4 buffer comprising 2% DMSO according to Kinetic Solubility Assay.
  • the compound is selected from the group consisting of 74 NAI-1541502036v1 Compounds 9 and 11, or a pharmaceutically acceptable form thereof. In some embodiments, the compound is Compound 9, or a pharmaceutically acceptable form thereof. [00241] In some embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof has a half-life of 10 minutes or more, 20 minutes or more, 30 minutes or more, 40 minutes or more, or 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay.
  • the compound has a half-life of 10 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound has a half-life of 20 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound has a half-life of 30 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay. In some embodiments, the compound has a half- life of 40 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay.
  • the compound has a half-life of 50 minutes or more in mouse liver microsomes according to Mouse Liver Microsome Metabolic Stability Assay.
  • the compound is Compound 11, or a pharmaceutically acceptable form thereof.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI- H727, MiaPaca-2, or Panc1, according to Proliferation Assay.
  • the compound inhibits proliferation in Kasumi-1 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in BT-549 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in GP2d according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in A375 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in MM.1R according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in IM.9 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in RPMI8226 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in NCI-H358 according to Proliferation Assay.
  • the compound inhibits proliferation in NCI-H727 according to Proliferation 75 NAI-1541502036v1 Assay. In some embodiments, the compound inhibits proliferation in MiaPaca-2 according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Panc1 according to Proliferation Assay.
  • the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC 50 value of 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay.
  • the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC 50 value of 50 nM or less according to Proliferation Assay.
  • the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI- H727, MiaPaca-2, or Panc1, with an IC 50 value of 40 nM or less according to Proliferation Assay.
  • the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC 50 value of 30 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC 50 value of 20 nM or less according to Proliferation Assay.
  • the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC 50 value of 10 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC 50 value of 1 nM or less according to Proliferation Assay.
  • the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC 50 value of 0.1 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in Kasumi-1, BT-549, GP2d, A375, MM.1R, IM.9, RPMI8226, NCI-H358, NCI-H727, MiaPaca-2, or Panc1, with an IC 50 value of 0.01 nM or less according to Proliferation Assay.
  • the compound inhibits proliferation in MM.R1 with an IC 50 value of 1 nM or less, 0.1 nM or less, or 0.01 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in MM.R1 with an IC 50 value of 1 nM or less according to Proliferation Assay. In some embodiments, the compound inhibits proliferation in MM.R1 with an IC 50 value of 0.1 nM or less according to Proliferation Assay. In 76 NAI-1541502036v1 some embodiments, the compound inhibits proliferation in MM.R1 with an IC 50 value of 0.01 nM or less according to Proliferation Assay.
  • the compound is selected from the group consisting of Compounds 9 and 11, or a pharmaceutically acceptable form thereof.
  • the pharmaceutically acceptable form of the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is an isomer, isotopic variant, pharmaceutically acceptable salt, polymorph, or solvate of said compound.
  • the pharmaceutically acceptable form of the compound is exclusive of a salt form.
  • the isomer of the compound is a diastereomer or enantiomer of the compound.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a tautomer of the compound.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a racemate or a mixture of diasteromers.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a single enantiomer or a single diasteromer.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a single enantiomer, such as an (R) enantiomer.
  • the compound has an enantiomeric excess of greater than 10% of the (R) enantiomer.
  • the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (R) enantiomer.
  • the compound has an enantiomeric excess of 15% or more of the (R) enantiomer.
  • the compound has an enantiomeric excess of 25% or more of the (R) enantiomer.
  • the compound has an enantiomeric excess of 50% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 75% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 90% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 95% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of 98% or more of the (R) enantiomer.
  • the compound has an enantiomeric excess of 99% or more of the (R) enantiomer. In some embodiments, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R) enantiomer. [00248] In one embodirment, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a single enantiomer, such as an (S) enantiomer.
  • the compound has an enantiomeric excess of greater than 10% of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 15% or more of the (S) enantiomer.
  • the compound has an enantiomeric excess of 25% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 50% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 75% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 90% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 95% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of 98% or more of the (S) enantiomer.
  • the compound has an enantiomeric excess of 99% or more of the (S) enantiomer. In some embodiments, the compound has an enantiomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (S) enantiomer.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) is a single diastereomer, such as a (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-single diastereomer.
  • the compound is an (R)/(R)-single diastereomer.
  • the compound is an (R)/(S)-single diastereomer.
  • the compound is an (S)/(R)-single diastereomer.
  • the compound is an (S)/(S)-single diastereomer.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2) has a diastereomeric excess of greater than 10% of the 78 NAI-1541502036v1 (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer.
  • the compound has a diastereomeric excess of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 15% or more of the (R) enantiomer.
  • the compound has a diastereomeric excess of 25% or more of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 50% or more of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer.
  • the compound has a diastereomeric excess of 75% or more of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 90% or more of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer.
  • the compound has a diastereomeric excess of 95% or more of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of 98% or more of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer.
  • the compound has a diastereomeric excess of 99% or more of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer.
  • the compound has a diastereomeric excess of about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, of the (R)/(R)-, (R)/(S)-, (S)/(R)-, or (S)/(S)-diastereomer. In some embodiments, the compound has a diastereomeric excess of the (R)/(R)-diastereomer. In some embodiments, the compound has a diastereomeric excess of the (R)/(S)-diastereomer.
  • the compound has a diastereomeric excess of the (S)/(R)-diastereomer. In some embodiments, the compound has a diastereomeric excess of the (S)/(S)-diastereomer. [00251] In certain embodiments, the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, is suitable for conjugation to an antibody or a fragment of an antibody.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof is suitable for delivery to a subject in the form of an 79 NAI-1541502036v1 antibody-drug conjugate. 3.3.
  • RESULATING ACTIVITY OF CELLULAR TARGETS [00252]
  • methods of modulating a Ras superfamily protein comprising contacting the Ras superfamily protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating a Ras superfamily protein comprising contacting the Ras superfamily protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below.
  • the Ras superfamily protein is a Ras protein, or a mutant thereof.
  • the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRASI; NKIRAS2; NRAS; RALA; RALB; RAPIA; RAPIB; RAP2A; RAP2B; RAP2C; RASDI; RASD2; RASLIOA; RASLIOB; RASLI IA; RASLIIB; RASL12; REMI; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2.
  • the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof. In some embodiments, the Ras protein is a KRAS mutant. In some embodiments, the KRAS mutant is a 80 NAI-1541502036v1 KRas G12D mutant, KRas G12C mutant, or KRas Q61H mutant. In some embodiments, the Ras protein is HRAS or a mutant thereof. In some embodiments, the Ras protein is NRAS or a mutant thereof. [00257] In some embodiments of the methods provided herein, the Ras superfamily protein is a Rac protein, or a mutant thereof.
  • the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof. In some embodiments, the Rac protein is wild-type RAC1.
  • the Ras superfamily protein is a Rho protein, or a mutant thereof.
  • the Rho protein is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; CDC42, or a mutant thereof.
  • the Rho protein is wild-type RHOA.
  • the Ras superfamily protein is a Cdc42 protein, or a mutant thereof.
  • the Ras superfamily protein is a Rheb protein, or a mutant thereof.
  • the contacting of the Ras superfamily protein takes place in a cell.
  • the cell is in a subject.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • the subject suffers from a cancer.
  • the subject is a human.
  • the cancer is lung cancer.
  • the lung cancer is non- small cell lung cancer (NSCLC).
  • the lung cancer is small cell lung cancer (SCLC).
  • the lung cancer is mesothelioma.
  • the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC).
  • the subject is a human.
  • kits for inhibiting a proteasome ATPase comprising contacting a proteasome ATPase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of inhibiting an AAA-ATPase of a 19S regulatory particle comprising contacting an AAA-ATPase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of inhibiting one or more proteasome ATPases comprising contacting a proteasome ATPase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of inhibiting one or more AAA-ATPases of a 19S regulatory particle comprising contacting an AAA-ATPase with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method inhibits ATPase activity.
  • the method comprises contacting the proteasome ATPase and/or the AAA-ATPase of a 19S regulatory particle with a compound or pharmaceutically acceptable form thereof that inhibits ATPase activity by 33% or more at 100 ⁇ M according to ATPase Activity Inhibition Assay.
  • the compound is selected from the group consisting of Compounds A, B, 9, and 38, or a pharmaceutically acceptable form thereof.
  • the compound is a compound specifically disclosed in International Patent 83 NAI-1541502036v1 Application PCT/US2023/065530, filed April 7, 2023, now published as WO 2023/196975.
  • methods of modulating Erk1/2 activity comprising contacting an Erk1/2 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating Erk1/2 activity comprising contacting an Erk1/2 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below.
  • the method inhibits phosphorylation of the Erk1/2 protein.
  • the method comprises contacting the Erk1/2 protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the Erk1/2 protein by 50% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof.
  • the method activates phosphorylation of the Erk1/2 protein.
  • the method comprises contacting the Erk1/2 protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Erk1/2 protein by 50% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.
  • the contacting of the Erk1/2 protein takes place in a cell.
  • the cell is in a subject.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • Provided herein are methods of modulating Akt activity, comprising contacting an 84 NAI-1541502036v1 Akt protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating Akt activity comprising contacting an AKT protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method inhibits phosphorylation of the Akt protein.
  • the method comprises contacting the Akt protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the Akt protein by 50% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof.
  • the method activates phosphorylation of the Akt protein.
  • the method comprises contacting the Akt protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Akt protein by 50% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.
  • the contacting of the Akt protein takes place in a cell.
  • the cell is in a subject.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • Provided herein are methods of modulating Smad2/3 activity, comprising contacting a Smad2/3 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), 85 NAI-1541502036v1 IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating Smad2/3 activity comprising contacting a Smad2/3 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method inhibits phosphorylation of the Smad2/3 protein.
  • the method comprises contacting the Smad2/3 protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the Smad2/3 protein by 50% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the method comprises contacting the Smad2/3 protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the Smad2/3 protein by 85% or more.
  • the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof.
  • the method activates phosphorylation of the Smad2/3 protein.
  • the method comprises contacting the Smad2/3 protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the Smad2/3 protein by 50% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, and 90, or a pharmaceutically acceptable form thereof.
  • the contacting of the Smad2/3 protein takes place in a cell.
  • the cell is in a subject.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • methods of modulating JNK activity comprising contacting a 86 NAI-1541502036v1 JNK protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating JNK activity comprising contacting a JNK protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method inhibits phosphorylation of the JNK protein.
  • the method comprises contacting the JNK protein with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the JNK protein by 50% or more according to JNK Activation Assay.
  • the compound is Compound 8, or a pharmaceutically acceptable form thereof.
  • the method activates phosphorylation of the JNK protein.
  • the method comprises contacting the JNK protein with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the JNK protein by 50% or more according to JNK Activation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the contacting of the JNK protein takes place in a cell.
  • the cell is in a subject.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • kits for modulating MAPK p38 activity comprising contacting a MAPK p38 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating MAPK p38 activity comprising contacting a MAPK p38 protein with an effective amount of a pharmaceutical composition 87 NAI-1541502036v1 comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method inhibits phosphorylation of the MAPK p38 protein.
  • the method comprises contacting the MAPK p38 with a compound or pharmaceutically acceptable form thereof that inhibits phosphorylation of the MAPK p38 by 50% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the method activates phosphorylation of the MAPK p38 protein.
  • the method comprises contacting the MAPK p38 with a compound or pharmaceutically acceptable form thereof that activates phosphorylation of the MAPK p38 by 50% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the contacting of the MAPK p38 protein takes place in a cell.
  • the cell is in a subject.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • IL-6 activity comprising contacting a IL- 6 protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • methods of modulating IL-6 activity comprising contacting a IL-6 protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 88 NAI-1541502036v1 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method inhibits IL-6 activity.
  • the method comprises contacting the IL-6 protein with a compound or pharmaceutically acceptable form thereof that inhibits IL-6 activity by 50% or more at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94, or a pharmaceutically acceptable form thereof.
  • the contacting of the IL-6 protein takes place in a cell.
  • the cell is in a subject.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • methods of modulating TNF-alpha activity comprising contacting a TNF-alpha protein with an effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof.
  • Also provided herein are methods of modulating TNF-alpha activity comprising contacting a TNF-alpha protein with an effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, as disclosed herein below.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method inhibits TNF-alpha activity.
  • the method comprises contacting the TNF-alpha protein with a compound or pharmaceutically acceptable form thereof that inhibits TNF-alpha activity by 50% or more at 10 ⁇ M according to TNF-alpha Quantification Assay.
  • the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof.
  • the contacting of the TNF- 89 NAI-1541502036v1 alpha protein takes place in a cell.
  • the cell is in a subject.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • METHODS OF TREATING CANCER [00295]
  • cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites.
  • Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia.
  • the neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host’s immune surveillance.
  • a) Tumor evolution commences when a cell within a normal population sustains a genetic mutation that expands its tendency to proliferate.
  • one or more additional mutations may further alter cell behavior and the effect of the cells on their environment.
  • d) The influenced and genetically altered cells turn still more abnormal in growth and 90 NAI-1541502036v1 appearance. If the tumor mass does not invade through any boundaries between tissues, it is termed an in situ tumor. This tumor may stay contained indefinitely, however, some cells may acquire still more mutations.
  • metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of non-neoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. (Volastyan, S., et al., Cell, 2011, vol.147, 275-292) [00303] Without being bound by theory, an enormous variety of cancers affect different tissues throughout the body, which are described in detail in the medical literature.
  • solid tumors including carcinomas, sarcomas and lymphomas.
  • Different types of solid tumors are named for the type of cells that form them. Examples include cancer of the lung, colon, rectum, pancreatic, prostate, breast, brain, and intestine.
  • Other human tumors derive from cells involved in the formation of immune cells and other blood cells, including leukemias and myelomas.
  • current cancer therapy may involve surgery, chemotherapy, hormonal therapy, biological therapy, targeted therapy, immunotherapy and/or radiation treatment to eradicate neoplastic cells in a patient (see, e.g., Stockdale, 1998, Medicine, vol.3, Rubenstein and Federman, eds., Chapter 12, Section IV; and Baudino TA “Targeted Cancer Therapy: The Next Generation of Cancer Treatment”, Curr Drug Discov Technol.2015; 12(1):3-20).
  • such therapies may be used independently or in combinations.
  • Choices of therapy will depend on the history and nature of the cancer, the 91 NAI-1541502036v1 condition of the patient, and, under the circumstances, the anticipated efficacy and adverse effects of the therapeutic agents and methods considered.
  • chemotherapy there are a variety of chemotherapeutic agents and methods of delivery of such agents available for the treatment of different cancers. Most first generation chemotherapeutic agents were not tumor specific, have broad systemic effects, are toxic, and may cause significant and often dangerous side effects, including severe nausea, bone marrow depression, and immunosuppression.
  • Even with administration of combinations of chemotherapeutic agents many tumor cells are or become resistant to chemotherapeutic agents.
  • kits for treating cancer in a subject comprising administering a therapeutically effective amount of the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject having cancer.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 92 NAI-1541502036v1 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein.
  • the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits the activity one or more Ras superfamily protein.
  • the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 45% or more at 20 ⁇ M according to a Ras Superfamily Activity. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 ⁇ M according to a Ras Superfamily Activity. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates Erk1/2 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 80% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 85% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a 93 NAI-1541502036v1 pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 45% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 50% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 ⁇ M according to 94 NAI-1541502036v1 Akt Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates Smad2/3 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 80% or more at 10 ⁇ M according to Phospho- Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein by 50% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, and 90, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form that modulates JNK activity.
  • the compound or pharmaceutically acceptable form thereof inhibits JNK by 95 NAI-1541502036v1 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by 50% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound is Compound 8, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein.
  • the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by about 50% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof. [00317]
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein.
  • the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by about 50% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 protein.
  • the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof 96 NAI-1541502036v1 activates phosphorylation of the MAPK p38 by 50% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the compounds disclosed herein inhibit cell proliferation, such as inhibit cell proliferation in a cell viability assay.
  • the anti-proliferative activity of the compounds disclosed herein are administered according to the methods of treating disclosed herein to treat cancer, including solid, soft and blood-born tumors.
  • the method administering a compound or pharmaceutically acceptable form thereof that inhibits proliferation in MiaPaca2.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.25 ⁇ M or less, 1.1 ⁇ M or less, 1 ⁇ M or less, 0.9 ⁇ M or less, 0.8 ⁇ M or less, 0.75 ⁇ M or less, 0.7 ⁇ M or less, 0.6 ⁇ M or less, 0.5 ⁇ M or less, 0.4 ⁇ M or less, 0.3 ⁇ M or less, 0.25 ⁇ M or less, 0.2 ⁇ M or less, 0.15 ⁇ M or less, 0.1 ⁇ M or less, 0.09 ⁇ M or less, 0.05 ⁇ M or less, or 0.03 ⁇ M or less, according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.1 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 1.0 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.60 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.15 ⁇ M or less according to Proliferation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.1 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.09 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.05 ⁇ M or less according to Proliferation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits proliferation in MiaPaca2 with an IC50 value of 0.03 ⁇ M or less according to Proliferation Assay.
  • the compound is selected from the group consisting of Compounds 1, 3, 4, 9, 10, 97 NAI-1541502036v1 11, 12, 13, 16, 18, 19, 22, 23, 28, 31, 32, 36, 37, 38, 39, 40, 47, 48, 49, 52, 57, 62, 65, 68, 75, 80, 81, 82, 83, 85, 87, and 94, or a pharmaceutically acceptable form thereof.
  • the compound is selected from the group consisting of Compounds 9, 10, 11, 16, 18, 19, 36, 37, 38, 39, 40, 62, and 65, or a pharmaceutically acceptable form thereof.
  • the compound is selected from the group consisting of Compounds 9, 10, and 11, or a pharmaceutically acceptable form thereof.
  • the compound is selected from the group consisting of Compounds 36, 37, 38, 39, 40, and 62, or a pharmaceutically acceptable form thereof.
  • the cancer is a solid tumor. In some embodiments, the cancer is a blood borne tumor (or a hematological cancer).
  • the cancer is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma.
  • the cancer is pancreatic cancer.
  • the cancer is colon cancer.
  • the cancer is triple negative breast cancer.
  • the cancer is multiple myeloma.
  • the cancer is lung cancer.
  • the lung cancer is non- small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is mesothelioma. In some embodiments, the cancer is hepatocellular carcinoma, pancreatic cancer, glioblastoma, esophageal carcinoma, mesothelioma, or small cell lung cancer (SCLC). [00320] In some embodiments of the methods provided herein, the cancer is a cancer dependent on a Ras superfamily protein. In some embodiments, the Ras superfamily protein is a Ras protein, or a mutant thereof.
  • the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRASI; NKIRAS2; NRAS; RALA; RALB; RAPIA; RAPIB; RAP2A; RAP2B; RAP2C; RASDI; RASD2; RASLIOA; RASLIOB; RASLI IA; RASLIIB; RASL12; REMI; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2.
  • the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof.
  • the Ras protein is a KRAS mutant. In some embodiments, the KRAS mutant is a KRas G12D mutant, KRas G12C mutant, or KRas Q61H mutant. In some embodiments, the Ras protein is HRAS or a mutant thereof. In some embodiments, the Ras protein is NRAS or a 98 NAI-1541502036v1 mutant thereof. In some embodiments, the Ras superfamily protein is a Rac protein, or a mutant thereof. In some embodiments, the Rac protein is RAC1; RAC2; RAC3; RHOG, or a mutant thereof. In some embodiments, the the Rac protein is wild-type RAC1.
  • the Ras superfamily protein is a Rho protein, or a mutant thereof.
  • the Rho protein is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; CDC42, or a mutant thereof.
  • the Rho protein is wild-type RHOA.
  • the Ras superfamily protein is a Cdc42 protein, or a mutant thereof.
  • the Ras superfamily protein is a Rheb protein, or a mutant thereof.
  • the administration activates caspase activity in a cancerous cell of the subject.
  • the activation induces apoptosis of the cancerous cell.
  • the subject is a human.
  • Also provided herein are methods of treating subjects who have been previously treated for cancer but are non-responsive to standard therapies, as well as those who have not previously been treated. Also provided are methods of treating subjects regardless of subject’s age, although some diseases or disorders are more common in certain age groups. Also provided are methods of treating subjects who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not.
  • cancer includes, but is not limited to, solid tumors and blood borne tumors.
  • cancer refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus.
  • Specific cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant 99 NAI-1541502036v1 giolma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell
  • the cancer is a solid tumor.
  • the solid tumor is metastatic.
  • the solid tumor is drug-resistant.
  • the solid tumor is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrium cancer, skin cancer (melanoma), cervix cancer, urinary tract cancer, glioblastoma, esophageal carcinoma, mesothelioma, or multiple myeloma.
  • the solid tumor is lung cancer.
  • the lung cancer is non- small cell lung cancer (NSCLC).
  • methods provided herein encompass treating, preventing or managing various types of leukemias such as chronic lymphocytic leukemia (CLL), chronic 100 NAI-1541502036v1 myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute myeloblastic leukemia (AML) by administering a therapeutically effective amount of a compound provided herein or a derivative thereof.
  • the methods provided herein encompass treating, preventing or managing acute leukemia in a subject.
  • the acute myeloid leukemia is myeloblastic leukemia (M1). In some embodiments, the acute myeloid leukemia is myeloblastic leukemia (M2). In some embodiments, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant (M3V)). In some embodiments, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia (M4E)). In some embodiments, the acute myeloid leukemia is monocytic leukemia (M5). In some embodiments, the acute myeloid leukemia is erythroleukemia (M6).
  • the acute myeloid leukemia is megakaryoblastic leukemia (M7).
  • the methods of treating, preventing or managing acute myeloid leukemia in a subject comprise the step of administering to the subject an amount of a compound provided herein or a derivative thereof effective to treat, prevent or manage acute myeloid leukemia alone or in combination.
  • the methods comprise the step of administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in amounts effective to treat, prevent or manage acute myeloid leukemia.
  • the methods provided herein encompass treating, preventing or managing acute lymphocytic leukemia (ALL) in a subject.
  • ALL acute lymphocytic leukemia
  • acute lymphocytic leukemia includes leukemia that originates in the blast cells of the bone marrow (B- cells), thymus (T-cells), and lymph nodes.
  • the acute lymphocytic leukemia can be categorized according to the French-American-British (FAB) Morphological Classification Scheme as L1 - Mature-appearing lymphoblasts (T cells or pre-B-cells), L2 - Immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells), and L3 - Lymphoblasts (B-cells; Burkitt's cells).
  • FAB French-American-British
  • the acute lymphocytic leukemia originates in the blast 101 NAI-1541502036v1 cells of the bone marrow (B-cells). In some embodiments, the acute lymphocytic leukemia originates in the thymus (T-cells). In some embodiments, the acute lymphocytic leukemia originates in the lymph nodes. In some embodiments, the acute lymphocytic leukemia is L1 type characterized by mature-appearing lymphoblasts (T-cells or pre-B-cells).
  • the acute lymphocytic leukemia is L2 type characterized by immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells). In some embodiments, the acute lymphocytic leukemia is L3 type characterized by lymphoblasts (B-cells; Burkitt's cells). In certain embodiments, the acute lymphocytic leukemia is T cell leukemia. In some embodiments, the T-cell leukemia is peripheral T-cell leukemia. In another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In another embodiment, the T-cell leukemia is cutaneous T-cell leukemia.
  • the T-cell leukemia is adult T-cell leukemia.
  • the methods of treating, preventing or managing acute lymphocytic leukemia in a subject comprise the step of administering to the subject an amount of a compound provided herein or a derivative thereof effective to treat, prevent or manage acute lymphocytic leukemia alone or in combination with a second active agent.
  • the methods comprise the step of administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in amounts effective to treat, prevent or manage acute lymphocytic leukemia.
  • the methods provided herein encompass treating, preventing or managing chronic myelogenous leukemia (CML) in a subject.
  • CML chronic myelogenous leukemia
  • the methods comprise the step of administering to the subject an amount of a compound provided herein or a derivative thereof effective to treat, prevent or manage chronic myelogenous leukemia.
  • the methods comprise the step of administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in amounts effective to treat, prevent or manage chronic myelogenous leukemia.
  • the methods provided herein encompass treating, preventing or managing chronic lymphocytic leukemia (CLL) in a subject.
  • the methods comprise the step of administering to the subject an amount of a compound provided herein or a derivative thereof effective to treat, prevent or manage chronic lymphocytic leukemia.
  • the methods comprise the step of administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in amounts effective to treat, 102 NAI-1541502036v1 prevent or manage chronic lymphocytic leukemia.
  • provided herein are methods of treating, preventing, and/or managing disease in subjects with impaired renal function.
  • provided herein are method of treating, preventing, and/or managing cancer in subjects with impaired renal function.
  • provided herein are methods of providing appropriate dose adjustments for subjects with impaired renal function due to, but not limited to, disease, aging, or other subject factors.
  • provided herein are methods of treating, preventing, and/or managing lymphoma, including non-Hodgkin’s lymphoma.
  • methods for the treatment or management of non-Hodgkin's lymphoma including but not limited to, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.
  • provided herein are methods of treating, preventing, and/or managing multiple myeloma, including relapsed/refractory multiple myeloma in subjects with impaired renal function or a symptom thereof, comprising administering a therapeutically effective amount of a compound provided herein, or a derivative thereof to a subject having relapsed/refractory multiple myeloma with impaired renal function.
  • the subject to be treated with one of the methods provided herein has not been treated with anticancer therapy prior to the administration of the compound provided herein, or a derivative thereof.
  • the subject to be treated with one of the methods provided herein has been treated with anticancer therapy prior to the administration of the compound provided herein, or a derivative thereof. In certain embodiments, the subject to be treated with one of the methods provided herein has developed drug resistance to the anticancer therapy.
  • the methods provided herein encompass treating a patient regardless of subject’s age, although some diseases or disorders are more common in certain age groups.
  • Ras signaling is causally implicated in rasopathies.
  • the compounds provided herein, which inhibit the function of one or more members of the Ras superfamily are useful in the treatment of rasopathies including neurofibromatosis type 1, Noonan’s syndrome, and Costello syndrome. 3.5.
  • Fibrosis or the accumulation of extracellular matrix molecules that constitute scar 103 NAI-1541502036v1 tissue, is a common result of tissue injury. Fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the common fibrotic diseases which altogether represent a large unmet medical need. (Friedman SL, Sheppard D, Duffield JS, Violette S. Sci Transl Med 2013 Jan9; 5(167): 167sr1).
  • fibrosis also known as fibrotic scarring
  • fibrotic scarring is a pathological wound healing process in which connective tissue replaces normal parenchymal tissue, leading to considerable tissue re-modeling and the formation of permanent scar tissue.
  • ECM extracellular matrix
  • Mechanisms of fibrogenesis include inflammation as well as other pathways and generally involve reorganization of the actin cytoskeleton of affected cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages.
  • actin filament assembly and actomyosin contraction are directed by the Rho-associated coiled-coil forming protein kinase (ROCK) family of serine/threonine kinases (ROCK1 and ROCK2) and thus Rho is associated with fibrogenesis.
  • ROCK Rho-associated coiled-coil forming protein kinase
  • ROCK2 serine/threonine kinases
  • idiopathic pulmonary fibrosis is characterized by progressive lung scarring, short median survival, and limited therapeutic options, creating great need for new pharmacologic therapies. It is thought to result from repetitive environmental injury to the lung epithelium.
  • fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage.
  • Examples include: fibrosis of kidney, fibrosis of cardiovascular system, pulmonary fibrosis, cystic fibrosis, idiopathic fibrosis, fibrosis of the lung, bridging fibrosis, fibrosis of the liver, fibrosis of the intestine, fibrosis of the muscular system, fibrosis of the brain, fibrosis of the joints, fibrosis of the skin, fibrosis of the bone marrow, fibrosis of the heart, fibrosis of the soft tissue, fibrosis of the tendons, fibrosis of the 104 NAI-1541502036v1 lymph nodes, fibrosis of the eyes, retroperitoneum, scleroderma and surgical scarring.
  • tissue repair is a complex one, with tight regulation of ECM synthesis and degradation ensuring maintenance of normal tissue architecture.
  • the process can lead to a progressive irreversible fibrotic response if tissue injury is severe or repetitive, or if the wound healing response itself becomes deregulated.
  • Fibrosis is initiated when immune cells such as macrophages and damaged tissue between surfaces called interstitium release soluble factors that stimulate fibroblasts.
  • the best characterized pro-fibrotic mediators are the transforming growth factor- ⁇ (TGF- ⁇ ligands such as TGF- ⁇ 1, - ⁇ 2 and - ⁇ 3, bone morphogenetic proteins (BMPs), and Activin.
  • TGF- ⁇ ligands such as TGF- ⁇ 1, - ⁇ 2 and - ⁇ 3, bone morphogenetic proteins (BMPs)
  • BMPs bone morphogenetic proteins
  • Activated Smad2/3 form a trimeric complex with Smad4 that translocates to the nucleus to regulate target gene expression.
  • CTGF connective tissue growth factor
  • PDGF platelet-derived growth factor
  • IL-10 interleukin 10
  • DMD is one of four conditions known as dystrophinopathies. Three diseases that belong to this group are Becker Muscular Dystrophy (BMD, a mild form of DMD); an intermediate clinical presentation between DMD and BMD; and DMD-associated dilated cardiomyopathy (heart-disease) with little or no clinical skeletal, or voluntary, muscle disease.
  • BMD Becker Muscular Dystrophy
  • DMD-associated dilated cardiomyopathy (heart-disease) with little or no clinical skeletal, or voluntary, muscle disease.
  • DMD primarily affects boys, but in rare cases it can affect girls. In Europe and North 105 NAI-1541502036v1 America, the prevalence of DMD is approximately 6 per 100,000 individuals.
  • Muscle weakness is the principal symptom of DMD. Symptom onset is in early childhood, usually between ages 2 and 3.
  • BMD Becker muscular dystrophy
  • DMD has an X-linked recessive inheritance pattern and is passed on by the mother, who is referred to as a carrier.
  • targeted therapies are a cornerstone of what is also referred to as precision medicine, a form of medicine that uses information about a person’s genes and proteins to prevent, diagnose, and treat disease.
  • Such therapeutics are sometimes 106 NAI-1541502036v1 called "molecularly targeted drugs,” “molecularly targeted therapies,” or similar names.
  • the process of discovering them is often referred to as “rational drug design.”
  • This concept can also be referred to as “personalized medicine.”
  • a series of actions among molecules in a cell that leads to a certain end point or cell function is referred to as a molecular pathway.
  • molecularly targeted drugs interact with a particular target molecule, or structurally related set of target molecules, in a pathway; thus modulating the endpoint effect of that pathway, such as a disease-related process; and, thus, yielding a therapeutic benefit.
  • molecularly targeted drugs may be small molecules or biologics, usually antibodies. They may be useful alone or in combinations with other therapeutic agents and methods.
  • targeted therapeutics may have fewer adverse side effects.
  • fibrotic disorders such as idiopathic pulmonary fibrosis, hepatic fibrosis, and systemic sclerosis
  • methods of treating a fibrotic disease in a subject comprising administering a therapeutically effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein.
  • the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 ⁇ M according to a Ras Superfamily Activity.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates Erk1/2 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 80% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 85% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 108 NAI-1541502036v1 protein by 45% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 50% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound or pharmaceutically 109 NAI-1541502036v1 acceptable form thereof inhibits phosphorylation of the Smad2/3 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 80% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein.
  • the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by 50% or more at 10 ⁇ M according to MAPK p38 Activation Assay.
  • the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates IL-6 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6.
  • the compound or pharmaceutically acceptable 111 NAI-1541502036v1 form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 75% or more at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates TNF-alpha activity.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 75% or more at 10 ⁇ M according to TNF-alpha Quantification Assay. In some embodiments, the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof. [00369] In some embodiments, the compound of Formula I administered according to any of the methods disclosed herein treats, prevents, or inhibits fibrosis in the subject.
  • the compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, administered according to any of the methods disclosed herein inhibits fibrosis in the liver, lung, skin, soft tissue, tendons, lymph nodes, lung, kidney, heart, eye, or retroperitoneum of said subject.
  • the compound administered according to any of the methods disclosed herein treats, prevents, or ameliorates one or more symptoms of a fibrotic disease in the subject.
  • the compound administered according to any of the methods disclosed herein treats, prevents, or ameliorates the fibrotic disease in the subject.
  • the fibrotic disease is selected from the group consisting of fibrosis of kidney, fibrosis of cardiovascular system, pulmonary fibrosis, cystic fibrosis, idiopathic fibrosis, fibrosis of the lung, bridging fibrosis, fibrosis of the liver, fibrosis of the intestine, fibrosis of the muscular system, fibrosis of the brain, fibrosis of the joints, fibrosis of the skin, fibrosis of the bone marrow, fibrosis of the heart, 112 NAI-1541502036v1 fibrosis of the soft tissue, fibrosis of the tendons, fibrosis of the lymph nodes, fibrosis of the eyes, retroperitoneum, scleroderma and surgical scarring.
  • the fibrotic disease is fibrosis of the kidney. In some embodiments, the fibrosis of the kidney is progressive kidney disease. In some embodiments, the fibrotic disease is fibrosis of the cardiovascular system. In some embodiments, the fibrosis of the cardiovascular system is atherosclerosis or restenosis. In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is cystic fibrosis. In some embodiments, the fibrotic disease is idiopathic fibrosis. In some embodiments, the idiopathic fibrosis is idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease is fibrosis of the lung.
  • the fibrosis of the lung is progressive massive fibrosis and radiation-induced lung injury. In some embodiments, the fibrotic disease is bridging fibrosis. In some embodiments, the fibrotic disease is fibrosis of the liver. In some embodiments, the fibrosis of the liver is cirrhosis. In some embodiments, the fibrotic disease is fibrosis of the intestine. In some embodiments, the fibrosis of the intestine is Crohn’s disease. In some embodiments, the fibrotic disease is fibrosis of the muscular system. In some embodiments, the fibrosis of the muscular system is Duchenne muscular dystrophy (DMD).
  • DMD Duchenne muscular dystrophy
  • the Duchenne muscular dystrophy is Becker Muscular Dystrophy (BMD), an intermediate clinical presentation between DMD and BMD, or DMD-associated dilated cardiomyopathy.
  • the fibrotic disease is fibrosis of the brain.
  • the fibrosis of the brain is glial scar.
  • the fibrotic disease is fibrosis of the joints.
  • the fibrosis of the joints is arterial stiffness.
  • the fibrosis of the joints is fibrosis of the knee.
  • the fibrosis of the joints is fibrosis of the shoulder.
  • the fibrotic disease is fibrosis of the skin.
  • the fibrosis of the skin is Keloid. In some embodiments, the fibrotic disease is fibrosis of the bone marrow. In some embodiments, the fibrosis of the bone marrow is Myelofibrosis. In some embodiments, the fibrotic disease is fibrosis of the heart. In some embodiments, the fibrosis of the heart is Myocardial fibrosis. In some embodiments, the fibrotic disease is fibrosis of the soft tissue. In some embodiments, the fibrotic disease is fibrosis of the tendons. In some embodiments, the fibrotic disease is fibrosis of the lymph nodes. In some embodiments, the fibrotic disease is fibrosis of the eyes.
  • the fibrotic disease is retroperitoneum. In some embodiments, the fibrotic disease is scleroderma. In some embodiments, the fibrotic disease is surgical scarring. 113 NAI-1541502036v1 3.6. METHODS OF TREATING INFLAMMATION [00370] Inflammation is a complex protective biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair.
  • harmful stimuli such as pathogens, damaged cells, or irritants
  • Inflammation is classified as either acute or chronic.
  • Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues.
  • a series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue.
  • Prolonged inflammation known as chronic inflammation, is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
  • kits for treating an inflammatory disease in a subject comprising administering a therapeutically effective amount of a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.
  • methods of treating an inflammatory disease in a subject comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, IA, IA(1), IB, IB(1), IB(2), II, IIA, IIA(1), IIB, IIB(1), or IIB(2), or pharmaceutically acceptable form thereof, to the subject.
  • the compound is selected from the group consisting of Compounds 1, 2, 114 NAI-1541502036v1 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates the activity of one or more Ras superfamily protein.
  • the compound or pharmaceutically acceptable form thereof modulates Ras superfamily activity of one or more GTPase by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 20 ⁇ M according to a Ras Superfamily Activity Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits the activity one or more Ras superfamily protein.
  • the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 45% or more at 20 ⁇ M according to a Ras Superfamily Activity. In some embodiments, the compound or pharmaceutically acceptable form thereof modulates the activity of one or more Ras superfamily protein by 50% or more at 20 ⁇ M according to a Ras Superfamily Activity. In some embodiments, the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 9, 10, 11, 12, 13, 16, 18, 22, 23, 24, 27, 28, 32, 33, 36, 37, 38, 39, 40, 57, 62, 75, 84, 86, and 92, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 80% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Erk1/2 protein by 85% or more at 10 ⁇ M 115 NAI-1541502036v1 according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 21, 49, 51, 53, 56, 67, 68, 79, 80, 81, 82, 89, and 94, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Erk1/2 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Erk1/2 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 45% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Erk1/2 protein by 50% or more at 10 ⁇ M according to Erk1/2 Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 13, 16, 18, 23, 27, 28, 36, 37, 38, 40, 54, 55, 57, 60, 61, 62, 75, and 83, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates Akt activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Akt protein by 85% or more at 10 ⁇ M according to Akt Phosphorylation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 19, 20, 49, 51, 53, 56, 79, 80, 81, and 94, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of Akt by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Akt 116 NAI-1541502036v1 Phosphorylation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Akt protein by 50% or more at 10 ⁇ M according to Akt Phosphorylation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 22, 27, 28, 32, 36, 37, 38, 39, 40, 47, 54, 55, 57, 59, 60, 61, 62, 66, 67, 74, 75, 76, 83, 84, 86, 87, 88, and 91, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates Smad2/3 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 80% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the Smad2/3 protein by 85% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound is selected from the group consisting of Compounds 19, 20, 21, 29, 49, 51, 56, 58, 61, 63, 64, 65, 68, 77, 79, 80, 81, 87, 88, 89, and 94, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of Smad2/3 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the Smad2/3 protein by 50% or more at 10 ⁇ M according to Phospho-Smad2/3 Inhibition Assay.
  • the compound is Compound 12, 14, 25, 26, 31, 32, 33, 37, 78, and 90, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form that modulates JNK activity.
  • the compound or pharmaceutically acceptable form thereof inhibits JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the JNK protein by about 50% at 10 ⁇ M according to JNK Activation Assay.
  • the compound is Compound 8, or a pharmaceutically acceptable form thereof.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein.
  • the compound or pharmaceutically acceptable form thereof activates JNK by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to JNK Activation Assay.
  • the compound or pharmaceutically acceptable form thereof activates phosphorylation of the JNK protein by about 50% or more at 10 ⁇ M according to JNK Activation Assay.
  • the compound is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates MAPK p38 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 protein.
  • the compound or pharmaceutically acceptable form thereof inhibits MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof inhibits phosphorylation of the MAPK p38 by about 50% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 protein.
  • the compound or pharmaceutically acceptable form thereof activates MAPK p38 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or 118 NAI-1541502036v1 more, 90% or more, 95% or more, or equal or greater than 100% at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound or pharmaceutically acceptable form thereof activates phosphorylation of the MAPK p38 by about 50% or more at 10 ⁇ M according to MAPK p38 Activation Assay. In some embodiments, the compound is selected from the group consisting of Compounds 2, 3, 4, 5, 6, and 7, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates IL-6 activity.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits IL-6 by 75% or more at 10 ⁇ M according to IL-6 Quantification Assay.
  • the compound is selected from the group consisting of Compounds 4, 9, 10, 11, 16, 17, 19, 20, 92, and 94, or a pharmaceutically acceptable form thereof.
  • the method administering a compound or pharmaceutically acceptable form thereof that modulates TNF-alpha activity.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more at 10 ⁇ M according to TNF-alpha Quantification Assay.
  • the compound or pharmaceutically acceptable form thereof inhibits TNF-alpha by 75% or more at 10 ⁇ M according to TNF-alpha Quantification Assay.
  • the compound is Compound 20 and 94, or a pharmaceutically acceptable form thereof.
  • the inflammatory disease is inflammation-associated cancer development.
  • the compounds provided herein are useful in treatment of cancer. It is well recognized that the immune inflammatory state serves as a key mediator of the middle stages of tumor development. It is also well known that chronic inflammation can 119 NAI-1541502036v1 predispose an individual to cancer. Chronic inflammation is caused by a variety of factors, including bacterial, viral, and parasitic infections.
  • Anti-inflammatory cancer therapy prevents premalignant cells from turning fully cancerous or impedes existing tumors from spreading to distant sites in the body.
  • the compounds provided herein are useful in treating inflammatory cancers.
  • Such cancers, and the chronic inflammatory conditions that predispose susceptible cells to neoplastic transformation include gastric adenocarcinoma (gastritis), mucosa-associated lymphoid tissue (MALT) lymphoma (gastritis), bladder, liver and rectal carcinomas (schistosomiasis), cholangiocarcinoma and colon carcinoma (cholangitis), gall bladder cncer (chronic cholecystitis), ovarian and cervical carcinoma (pelvic inflammatory disease, chronic cervicitis), skin carcinoma (osteomyelitis), colorectal carcinoma (inflammatory bowel disease), esophageal carcinoma (reflux esophagitis, Barrett’s esophagus), bladder cancer (bladder inflammation (cystitis)), mesothelioma and lung carcinoma (asbestosis, silicosis), oral squamous cell carcinoma (gingivitis, lichen planus), pancreatic carcinoma (pancre
  • the compounds provided herein are useful in treating inflammatory diseases in the airways, such as nonspecific bronchial hyper-reactivity, chronic bronchitis, cystic fibrosis, and acute respiratory distress syndrome (ARDS).
  • ARDS acute respiratory distress syndrome
  • the compounds provided herein are useful in treating asthma and idiopathic lung fibrosis or idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, and interstitial lung disease.
  • the differentiation of fibroblasts into cell types called myofibroblasts occurs during wound healing, when the cells contribute to the deposition of extracellular matrix (ECM) in the transient process of wound repair.
  • ECM extracellular matrix
  • chronic inflammatory diseases such as asthma
  • pathological tissue remodeling often occurs, and is mediated by the functions of increased numbers of myofibroblasts in the diseased tissue, see Hinz, B. et al. Am J Pathol.2007; 170: 1807–1816.
  • the compounds provided herein prevent or reduce TGF- ⁇ -induced myofibroblast differentiation, as measured by the expression of alpha smooth muscle actin ( ⁇ -SMA), a hallmark of myofibroblast differentiation (Serini, G.
  • ⁇ -SMA alpha smooth muscle actin
  • the compounds provided herein are useful in treating 123 NAI-1541502036v1 psoriasis, chronic plaque psoriasis, psoriatic arthritis, acanthosis, atopic dermatitis, various forms of eczema, contact dermatitis (includes allergic dermatitis), systemic sclerosis (scleroderma), wound healing, and drug eruption.
  • a pharmaceutically acceptable non toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin.
  • excipients such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin.
  • Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art.
  • kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • the compound can be administered in an amount of about 25 mg/day. In a particular embodiment, the compound can be administered in an amount of about 10 mg/day. In a particular embodiment, the compound can be administered in an amount of about 5 mg/day. In a particular embodiment, the compound can be administered in an amount of about 4 mg/day. In a particular embodiment, the compound can be administered in an amount of about 3 mg/day.
  • the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, or from about 5,000 to about 10,000 ng*hr/mL.
  • AUC area under the curve
  • the compound provided herein, or a derivative thereof is administered parenterally. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously.
  • the compound provided herein, or a derivative thereof can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time.
  • the compound can be administered repeatedly if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.
  • stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement.
  • Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the 135 NAI-1541502036v1 tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.
  • the compound provided herein, or a derivative thereof can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID).
  • the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug).
  • the term “daily” is intended to mean that a therapeutic compound, such as the compound provided herein, or a derivative thereof, is administered once or more than once each day, for example, for a period of time.
  • the term “continuous” is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily for an uninterrupted period of at least 10 days to 52 weeks.
  • the term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals.
  • intermittent administration of the compound provided herein or a derivative thereof is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
  • cycling as used herein is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily or continuously but with a rest period.
  • administration is once a day for two to six days, then a rest period with no administration for five to seven days.
  • the frequency of administration is in the range of about a daily dose to about a monthly dose.
  • administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks.
  • the compound provided herein, or a derivative thereof is administered once a day.
  • the compound provided herein, or a derivative thereof is administered twice a day.
  • the compound provided herein, or a derivative thereof is administered three times a day.
  • the compound provided herein, or a derivative thereof is administered four times a day.
  • the compound provided herein, or a derivative thereof is 136 NAI-1541502036v1 administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day for one week, two weeks, three weeks, or four weeks. In some embodiments, the compound provided herein, or a derivative thereof, is administered once per day for 4 days. In some embodiments, the compound provided herein, or a derivative thereof, is administered once per day for 5 days. In some embodiments, the compound provided herein, or a derivative thereof, is administered once per day for 6 days.
  • the compound provided herein, or a derivative thereof is administered once per day for one week. In another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for two weeks. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for three weeks. In still another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for four weeks.
  • Combination Therapy With A Second Active Agent [00450] The compound provided herein, or a derivative thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of cancers, inflammatory diseases, rasopathies, or fibrotic disease.
  • provided herein is a method of treating, preventing, or managing cancers, inflammatory diseases, rasopathies, and fibrotic disease, comprising administering to a subject a compound provided herein, or a derivative thereof; in combination with one or more second active agents.
  • the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound provided herein, a compound provided herein, e.g., the compound provided herein, or a derivative thereof
  • a prophylactic or therapeutic agent such as a compound provided herein, a compound provided herein, e.g., the compound provided herein, or a derivative thereof
  • can be administered prior to e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before
  • concomitantly with, or subsequent to e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 137 NAI-1541502036v1 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks
  • Triple therapy is also contemplated herein.
  • Administration of the compound provided herein, or a derivative thereof and one or more second active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration.
  • the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease or disorder being treated.
  • the route of administration of the compound provided herein, or a derivative thereof is independent of the route of administration of a second therapy.
  • the compound provided herein, or a derivative thereof is administered orally.
  • the compound provided herein, or a derivative thereof is administered intravenously.
  • the compound provided herein, or a derivative thereof is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • the compound provided herein, or a derivative thereof, and a second therapy are administered by the same mode of administration, orally or by IV.
  • the compound provided herein, or a derivative thereof is administered by one mode of administration, e.g., by IV, whereas the second agent is administered by another mode of administration, e.g., orally.
  • the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg.
  • the specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount of the compound provided herein, or a derivative thereof, and any optional additional active agents concurrently administered to the subject.
  • Step B Methyl 4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2-carboxylate Int-1d.
  • Step C Methyl 1-amino-4-(1-isopropyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2- carboxylate Int-1e.
  • Step D 6-(1-Isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-1f.
  • Step E 4-Chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H- imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Intermediate Int-1.
  • N-iodosuccinimde 35.62 g, 158.31 mmol was added portionwise to the solution of ethyl 3-methyl-1H-pyrrole-2-carboxylate (Int-2a) (25.0 g, 163.21 mmol) in DMF (600 mL). The mixture was stirred at ambient temperature for 16h. The mixture was poured into ice water. The formed precipitate was filtered through celite and dried in vacuo. Ethyl 4-iodo-3-methyl-1H- pyrrole-2-carboxylate Int-2b (33.0 g, 118.25 mmol, 72.5% yield) was obtained.
  • Step B Ethyl 3-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate Int- 2d.
  • Ethyl 4-iodo-3-methyl-1H-pyrrole-2-carboxylate Int-2b (21.24 g, 76.1 mmol), 1- methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Int-2c (19.0 g, 91.32 mmol), Pd(dppf)Cl 2 .
  • Step C Ethyl 3-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate Int-2d (7.0 g, 30.01 mmol, 39.4% yield) was obtained. [00477] Step C: Ethyl 1-amino-3-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrole-2- carboxylate Int-2e.
  • Step D 5-Methyl-2-(1-methyl-1H-imidazol-2-yl)-6-(1-methyl-1H-pyrazol-3- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-2f.
  • the formed precipitate was collected by filtration, washed by water (2*10 mL) and dried in vacuo and purified by flash chromatography (SiO 2 , Hexane-EtOAc).5- Methyl-2-(1-methyl-1H-imidazol-2-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin- 4-ol Int-2f (1.85 g, 5.98 mmol, 32.3% yield) was obtained.
  • Step E 4-Chloro-5-methyl-2-(1-methyl-1H-imidazol-2-yl)-6-(1-methyl-1H-pyrazol- 3-yl)pyrrolo[2,1-f][1,2,4]triazine Intermediate Int-2.
  • Int-2f (1.85 g, 5.98 mmol) was dissolved in phosphoroyl trichloride (9.17 g, 59.8 mmol, 5.57 mL).
  • Step B Methyl 1-amino-4-(1,2-dimethyl-1H-imidazol-4-yl)-3-methyl-1H-pyrrole-2- carboxylate Int-3c.
  • Sodium hydride (0.4g, 10 mmol) (60% on mineral oil), was added portion wise to a solution of methyl 4-(1,2-dimethyl-1H-imidazol-4-yl)-3-methyl-1H-pyrrole-2-carboxylate Int- 3b (1.59 g, 6.8 mmol) in DMF (15 mL) at 0°C. The mixture was stirred for 1h at room temperature.
  • Step C 6-(1,2-Dimethyl-1H-imidazol-4-yl)-5-methyl-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-3d.
  • Step D 4-Chloro-6-(1,2-dimethyl-1H-imidazol-4-yl)-5-methyl-2-(1-methyl-1H- imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-3.
  • Step B (Z)-4,4'-(1-(Phenylsulfonyl)ethene-1,2-diyl)dipyridine Int-1c.
  • Step C Ethyl 3,4-di(pyridin-4-yl)-1H-pyrrole-2-carboxylate Int-4d.
  • Potassium t-butoxide (1.29 g, 11.49 mmol) was added portionwise to the solution of (Z)-4,4'-(1-(phenylsulfonyl)ethene-1,2-diyl)dipyridine Int-1c (3.7 g, 11.49 mmol) and ethyl 2- isocyanoacetate (1.3 g, 11.49 mmol) in dry THF (60 mL) at (-10°C), and stirred at room temperature overnight.
  • Step D Ethyl 1-amino-3,4-di(pyridin-4-yl)-1H-pyrrole-2-carboxylate Int-4e.
  • Sodium hydride (245 mg, 6.125 mmol)(60% in mineral oil), was added portionwise to a solution of ethyl 3,4-di(pyridin-4-yl)-1H-pyrrole-2-carboxylate Int-4d (1.2 g, 4.09 mmol) in DMF (30 mL) at 0°C. The mixture was stirred for 1 h at room temperature.
  • Step E 2-(1-Methyl-1H-imidazol-2-yl)-5,6-di(pyridin-4-yl)pyrrolo[2,1- f][1,2,4]triazin-4-ol Int-4f.
  • Step F 4-Chloro-2-(1-methyl-1H-imidazol-2-yl)-5,6-di(pyridin-4-yl)pyrrolo[2,1- 147 NAI-1541502036v1 f][1,2,4]triazine Int-4.
  • Step B Ethyl 1-amino-5-(3-methoxy-2-methylphenyl)-4-phenyl-1H-pyrrole-3- carboxylate Int-5d.
  • [00513] To a solution of ethyl 5-(3-methoxy-2-methylphenyl)-4-phenyl-1H-pyrrole-3- carboxylate Int-5c (670.01 mg, 2.0 mmol) in DMF (15 mL) sodium hydride (103.87 mg, 4.33 mmol) was added at 0°C. After 1 h O-(2,4-dinitrophenyl)hydroxylamine (517.11 mg, 2.6 mmol) was added portion-wise at 0°C.
  • Step C 6-(3-Methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5- phenylpyrrolo[2,1-f][1,2,4]triazin-4-ol Int-5e.
  • Step D 4-Chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5- phenylpyrrolo[2,1-f][1,2,4]triazine Int-5.
  • Step B 1-Cyclobutyl-2-(3-methoxy-2-methylphenyl)-2-(phenylsulfonyl)ethyl methanesulfonate Int-6c.
  • Methanesulfonyl chloride (3.91 g, 34.29 mmol) was added dropwise at 0°C to a stirred solution of 1-cyclobutyl-2-(3-methoxy-2-methylphenyl)-2-(phenylsulfonyl)ethan-1-ol Int-6b (4.12 g, 11.43 mmol) in pyridine (40 mL). The mixture was stirred at room temperature overnight.
  • reaction mixture was concentrated in vacuo, diluted with ice water (50 mL) and extracted 3 times by EtOAc (3*50 mL). The organic phase was washed with 1N HCl (20 mL), water, and brine, dried over Na 2 SO 4 and concentrated in vacuo to give 1-cyclobutyl-2-(3- methoxy-2-methylphenyl)-2-(phenylsulfonyl)ethyl methanesulfonate Int-6c (3.4 g, 80.0% purity, 6.2 mmol, 54.3% yield).
  • Step C (E)-1-(2-Cyclobutyl-1-(phenylsulfonyl)vinyl)-3-methoxy-2-methylbenzene Int-6c.
  • DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (1.2 g, 7.91 mmol) was added dropwise at room temperature to a stirred solution of 1-cyclobutyl-2-(3-methoxy-2-methylphenyl)-2- (phenylsulfonyl)ethyl methanesulfonate Int-6c (2.89 g, 6.59 mmol) in CH 2 Cl 2 (40 mL). The mixture was stirred at 45°C overnight.
  • Step D Ethyl 3-cyclobutyl-4-(3-methoxy-2-methylphenyl)-1H-pyrrole-2-carboxylate Int-6e.
  • Step E Ethyl 1-amino-3-cyclobutyl-4-(3-methoxy-2-methylphenyl)-1H-pyrrole-2- carboxylate Int-6f.
  • Sodium hydride (0.2g, 5 mmol) (60% in mineral oil), was added portion-wise to a solution of ethyl 3-cyclobutyl-4-(3-methoxy-2-methylphenyl)-1H-pyrrole-2-carboxylate Int-6e (1.0 g, 3.19 mmol) in DMF (12 mL) at 0°C. The mixture was stirred for 1 h at room temperature.
  • Step F 5-Cyclobutyl-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-6g.
  • Step G 4-Chloro-5-cyclobutyl-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H- imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-6.
  • Example Int-7 Synthesis of Intermediate Int-7 [00535]
  • Scheme 7 The Synthesis of Intermediate Int-7. Cl 3 [00537] To the solution of 1-(chloromethyl)-3-methoxybenzene Int-7a (5.4 g, 34.61 mmol) in dry IPA (80 mL), sodium benzenesulfinate (5.96 g, 36.34 mmol) was added portion wise at room temperature, and heated 80°C overnight. Afterwards the reaction mixture was evaporated under reduced pressure, diluted with water (100 mL) and extracted 3 times by EtOAc (3*100 mL).
  • Step B 1-Cyclopropyl-2-(3-methoxyphenyl)-2-(phenylsulfonyl)ethan-1-ol Int-7c.
  • Step C 1-Cyclopropyl-2-(3-methoxy-2-methylphenyl)-2-(phenylsulfonyl)ethyl acetate Int-7d.
  • Acetyl acetate (644.56 mg, 6.32 mmol) was added dropwise at room temperature to a stirred solution of 1-cyclopropyl-2-(3-methoxyphenyl)-2-(phenylsulfonyl)ethan-1-ol Int-7c (2.0 g, 6.02 mmol) in pyridine (20 mL). The mixture was stirred at room temperature overnight.
  • Step D (E)-1-(2-Cyclopropyl-1-(phenylsulfonyl)vinyl)-3-methoxybenzene Int-7e.
  • DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (723.5 mg, 4.76 mmol) was added dropwise at room temperature to a stirred solution of 1-cyclopropyl-2-(3-methoxy-2- methylphenyl)-2-(phenylsulfonyl)ethyl acetate Int-7d (2.12 g, 5.66 mmol) in CH 2 Cl 2 (25 mL). The mixture was stirred at 45°C overnight.
  • Step E Ethyl 3-cyclopropyl-4-(3-methoxyphenyl)-1H-pyrrole-2-carboxylate Int-7f.
  • Step F Ethyl 1-amino-3-cyclopropyl-4-(3-methoxyphenyl)-1H-pyrrole-2- carboxylate Int-7g.
  • Sodium hydride 0.1g, 2.5 mmol
  • Int-7f a solution of ethyl 3-cyclopropyl-4-(3-methoxyphenyl)-1H-pyrrole-2-carboxylate Int-7f (500.0 mg, 1.75 mmol) in DMF (5 mL) at 0°C. The mixture was stirred for 1 h at room temperature.
  • Step G 5-Cyclopropyl-6-(3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-7h.
  • Step H 4-Chloro-5-cyclopropyl-6-(3-methoxyphenyl)-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazine Int-7.
  • Step B Ethyl 4-(3-methoxy-2-methylphenyl)-3-(4-methoxypyridin-2-yl)-1H-pyrrole- 2-carboxylate Int-8b.
  • Step C Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-(4-methoxypyridin-2-yl)- 1H-pyrrole-2-carboxylate Int-8c.
  • Sodium hydride (0.4 g, 10 mmol )(60% in mineral oil), was added portion wise to a solution of ethyl 4-(3-methoxy-2-methylphenyl)-3-(4-methoxypyridin-2-yl)-1H-pyrrole-2- carboxylate Int-8b (2.47 g, 6.74 mmol) in DMF (30 mL) at 0°C, and stirred for 1h at this temperature.
  • Step D 6-(3-Methoxy-2-methylphenyl)-5-(4-methoxypyridin-2-yl)-2-(1-methyl-1H- imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-8d.
  • Step E 4-Chloro-6-(3-methoxy-2-methylphenyl)-5-(4-methoxypyridin-2-yl)-2-(1- methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-8.
  • Step E 6-(1-Isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5-(pyridin- 2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-9f.
  • Step F 4-Chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5- (pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-9.
  • Step B (E)-2-(2-(1-Isopropyl-4-methyl-1H-pyrazol-3-yl)-2- (phenylsulfonyl)vinyl)pyridine Int-10c.
  • Step C Ethyl 4-(1-isopropyl-4-methyl-1H-pyrazol-3-yl)-3-(pyridin-2-yl)-1H- pyrrole-2-carboxylate Int-10d.
  • Step E 6-(1-Isopropyl-4-methyl-1H-pyrazol-3-yl)-2-(1-methyl-1H-imidazol-2-yl)-5- (pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-10f.
  • Step B 1-(1-Methyl-1H-pyrazol-3-yl)-1-(phenylsulfonyl)propan-2-ol Int-11c.
  • Step C (E)-1-Methyl-3-(1-(phenylsulfonyl)prop-1-en-1-yl)-1H-pyrazole Int-11d.
  • Methanesulfonyl chloride (16.38 g, 143.77 mmol, 11.07 mL, 3.0 equiv) was added dropwise at 0°C to a stirred solution of 1-(1-methyl-1H-pyrazol-3-yl)-1-(phenylsulfonyl)propan- 2-ol Int-11c (16.79 g, 80.0% purity, 47.92 mmol) in pyridine (40 mL). The mixture was stirred at RT overnight.
  • Step D Ethyl 3-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate Int- 11e.
  • Potassium t-butoxide (7.46 g, 66.56 mmol) was added portionwise to the solution of (E)-1-methyl-3-(1-(phenylsulfonyl)prop-1-en-1-yl)-1H-pyrazole Int-11d (19.4 g, 60.0% purity, 44.37 mmol) and ethyl 2-isocyanoacetate (7.52 g, 66.56 mmol) in dry THF (60 mL) at (-10°C) and stirred at room temperature overnight.
  • reaction mixture was diluted with ice water (40 mL) and extracted 3 times with ethyl acetate (3*40 mL).
  • Step E Ethyl 1-amino-3-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrole-2- carboxylate Int-11f.
  • Sodium hydride (0.95 g, 23.7 mmol) (60% in mineral oil), was added portionwise to a solution of ethyl 3-methyl-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrole-2-carboxylate Int-11e (3.7 g, 15.87 mmol) in DMF (37 mL) at 0°C. The mixture was stirred for 1 h at 0°C.
  • O-(2,4- dinitrophenyl)hydroxylamine (4.74 g, 23.81 mmol) was added in one portion. The mixture was stirred for 16 h at room temperature. Then the mixture was poured into ice water and extracted with ethyl acetate (3*100 mL).
  • Step F 5-Methyl-2-(1-methyl-1H-imidazol-4-yl)-6-(1-methyl-1H-pyrazol-3- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-11g.
  • Step G 4-Chloro-5-methyl-2-(1-methyl-1H-imidazol-4-yl)-6-(1-methyl-1H-pyrazol- 3-yl)pyrrolo[2,1-f][1,2,4]triazine Int-11.
  • [00607] To the solution of 5-methyl-2-(1-methyl-1H-imidazol-4-yl)-6-(1-methyl-1H-pyrazol- 3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-11g (620.0 mg, 2.0 mmol) in toluene (12 mL), phosphoryl trichloride (12.18 g, 80.18 mmol) was added dropwise.
  • Step B 1-Methoxy-2-methyl-3-((phenylsulfonyl)methyl)benzene Int-12c.
  • Step D Ethyl 4-(3-methoxy-2-methylphenyl)-3-(pyridin-2-yl)-1H-pyrrole-2- carboxylate Int-12e.
  • Step F 6-(3-Methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5-(pyridin-2- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-12g.
  • Step G 4-Chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-4-yl)-5- (pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-12.
  • Example Int-13 Synthesis of Intermediate Int-13 [00625]
  • Scheme 13 The Synthesis of Intermediate Int-13 170 NAI-1541502036v1 O OH N N [00626] -5- (pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-13a.
  • Step B 4-Chloro-2-(1,2-dimethyl-1H-imidazol-4-yl)-6-(3-methoxy-2-methylphenyl)- 5-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-13.
  • Step B Ethyl 4-(3-methoxy-2-methylphenyl)-3-(5-methoxypyridin-2-yl)-1H- pyrrole-2-carboxylate Int-14c.
  • Step C Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-(5-methoxypyridin-2-yl)- 1H-pyrrole-2-carboxylate Int-14d.
  • Sodium hydride (0.15g, 60% in mineral oil)
  • the mixture was stirred for 1 h at room temperature.
  • Step D 6-(3-Methoxy-2-methylphenyl)-5-(5-methoxypyridin-2-yl)-2-(1-methyl-1H- imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-14e.
  • Step E 4-Chloro-6-(3-methoxy-2-methylphenyl)-5-(5-methoxypyridin-2-yl)-2-(1- methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-14.
  • Step B 5-(2-Methoxyethoxy)picolinaldehyde Int-15c.
  • Step B To a stirred solution of 5-(2-methoxyethoxy)picolinonitrile Int-15b (6.0 g, 33.69 mmol) in tetrahydrofuran (120 mL) at -78°C, DIBAL (50 mL, 1N in cyclohexane) was added and the reaction mixture was stirred for 1 h at -78°C. The reaction mixture was monitored by TLC and quenched with 2N HCI (42 mL) and extracted with dichloromethane (3x80 mL).
  • Step C (E)-2-(2-(3-Methoxy-2-methylphenyl)-2-(phenylsulfonyl)vinyl)-5-(2- methoxyethoxy)pyridine Int-15d.
  • Step D Ethyl 4-(3-methoxy-2-methylphenyl)-3-(5-(2-methoxyethoxy)pyridin-2-yl)- 1H-pyrrole-2-carboxylate Int-15e.
  • Step E Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-(5-(2- methoxyethoxy)pyridin-2-yl)-1H-pyrrole-2-carboxylate Int-15f.
  • Sodium hydride (0.18g, 60% in mineral oil)
  • Int-15e (1.25 g, 3.05 mmol) in DMF (20 mL) at 0°C.
  • Step F 6-(3-Methoxy-2-methylphenyl)-5-(5-(2-methoxyethoxy)pyridin-2-yl)-2-(1- methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-15g.
  • Step G 4-Chloro-6-(3-methoxy-2-methylphenyl)-5-(5-(2-methoxyethoxy)pyridin-2- yl)-2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-15.
  • Example Int-16 Synthesis of Intermediate Int-16 [00659]
  • Scheme 16 The Synthesis of Intermediate Int-16 178 NAI-1541502036v1 A B O NC F NC O O N N H N [00661]
  • Sodium hydride (9.83g, 0.245 mol) (60% in mineral oil) was added in portionwise to the solution of propan-1-ol (10.0 g, 166.51 mmol) in DMF (200 mL). The mixture was stirred at room temperature for 30 min, then 5-fluoropicolinonitrile Int-15a (20.32 g, 166.51 mmol) was added portionwise, and stirred at RT overnight.
  • Step B 5-Propoxypicolinaldehyde Int-16b.
  • Step B To a stirred solution of 5-propoxypicolinonitrile Int-16a (4.75 g, 29.31 mmol) in tetrahydrofuran (100 mL) at -78°C, DIBAL (44 mL, 1M in cyclohexane) was added, and the reaction mixture was stirred for 1 h at -78°C. The reaction mixture was monitored by TLC and quenched with 2N HCI (36 mL) and extracted with dichloromethane (3x80 mL).
  • Step C (E)-2-(2-(3-Methoxy-2-methylphenyl)-2-(phenylsulfonyl)vinyl)-5- propoxypyridine Int-16c.
  • Step D Ethyl 4-(3-methoxy-2-methylphenyl)-3-(5-propoxypyridin-2-yl)-1H-pyrrole- 2-carboxylate Int-16d.
  • Potassium t-butoxide (1.47 g, 13.14 mmol) was added portionwise to the solution of (E)-2-(2-(3-methoxy-2-methylphenyl)-2-(phenylsulfonyl)vinyl)-5-propoxypyridine Int-16c (5.3 g, 70.0% purity, 8.76 mmol) and ethyl 2-isocyanoacetate (1.49 g, 13.14 mmol) in dry THF (100 mL) at (-10°C), and stirred at room temperature overnight.
  • Step E Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-(5-propoxypyridin-2-yl)- 1H-pyrrole-2-carboxylate Int-16e.
  • Sodium hydride 0.175 g, 60% in mineral oil
  • Step F 6-(3-Methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-(5- propoxypyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-16f.
  • Step G 4-Chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5- (5-propoxypyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-16.
  • Step B Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-methyl-1H-pyrrole-2- carboxylate Int-17c.
  • Step C 6-(3-Methoxy-2-methylphenyl)-5-methyl-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-17d.
  • Step D 4-Chloro-6-(3-methoxy-2-methylphenyl)-5-methyl-2-(1-methyl-1H- imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-17.
  • Step C 2-(1,2-Dimethyl-1H-imidazol-4-yl)-5-methyl-6-(1-methyl-1H-pyrazol-3- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-18d.
  • Step D 4-Chloro-2-(1,2-dimethyl-1H-imidazol-4-yl)-5-methyl-6-(1-methyl-1H- pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine Int-18.
  • Step B Methyl 1-amino-4-(1-ethyl-1H-pyrazol-3-yl)-3-methyl-1H-pyrrole-2- carboxylate 19c.
  • Step C 6-(1-Ethyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-19d.
  • Step D 4-Chloro-6-(1-ethyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazine Int-19.
  • Example Int-20 Synthesis of Intermediate Int-20 [00705]
  • Scheme 20 The Synthesis of Intermediate Int-20 187 NAI-1541502036v1 N N O Br [00707]
  • Step B Ethyl 4-bromo-3-(4-methylpyridin-2-yl)-1H-pyrrole-2-carboxylate Int-20d.
  • Step C 1-(tert-Butyl) 2-ethyl 4-bromo-3-(4-methylpyridin-2-yl)-1H-pyrrole-1,2- dicarboxylate Int-20e.
  • Step D 1-(tert-Butyl) 2-ethyl 4-(3-methoxy-2-methylphenyl)-3-(4-methylpyridin-2- yl)-1H-pyrrole-1,2-dicarboxylate Int-20f.
  • Step E Ethyl 4-(3-methoxy-2-methylphenyl)-3-(4-methylpyridin-2-yl)-1H-pyrrole- 2-carboxylate Int-20g.
  • Step F Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-(4-methylpyridin-2-yl)-1H- pyrrole-2-carboxylate Int-20h.
  • Step G 6-(3-Methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-(4- methylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-20i.
  • Step H 4-chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5- (4-methylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine Into-20.
  • Example Int-21 Synthesis of Intermediate Int-21 [00723]
  • Scheme 21 The Synthesis of Intermediate Int-21 N N [00725]
  • a mixture of 2-ethynyl-6-methylpyridine Int-21a (3.0 g, 25.63 mmol) and silver carbonate (701.66 mg, 2.56 mmol) in dioxane (50 mL) was heated to 90°C and ethyl 2- isocyanoacetate Int-21b (3.48 g, 30.75 mmol) was added dropwise under an argon atmosphere.
  • the reaction mixture was stirred at 100°C for 2 h and then cooled and filtered through SiO 2 .
  • Step B Ethyl 4-bromo-3-(6-methylpyridin-2-yl)-1H-pyrrole-2-carboxylate Int-21c.
  • Step C Ethyl 4-(3-methoxy-2-methylphenyl)-3-(6-methylpyridin-2-yl)-1H-pyrrole- 2-carboxylate Int-21d.
  • Step D Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-(6-methylpyridin-2-yl)-1H- pyrrole-2-carboxylate Int-21e.
  • Step E 6-(3-Methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5-(6- methylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-21f.
  • Step F 4-chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5- (6-methylpyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-21.
  • Step B Ethyl 4-bromo-3-(4,6-dimethylpyridin-2-yl)-1H-pyrrole-2-carboxylate Int- 22c.
  • Step C 1-(tert-Butyl) 2-ethyl 4-bromo-3-(4,6-dimethylpyridin-2-yl)-1H-pyrrole-1,2- dicarboxylate Int-22d.
  • Step D 1-(tert-Butyl) 2-ethyl 3-(4,6-dimethylpyridin-2-yl)-4-(3-methoxy-2- methylphenyl)-1H-pyrrole-1,2-dicarboxylate Int-22e.
  • Step E Ethyl 3-(4,6-dimethylpyridin-2-yl)-4-(3-methoxy-2-methylphenyl)-1H- pyrrole-2-carboxylate Int-22f.
  • Step F Ethyl 1-amino-3-(4,6-dimethylpyridin-2-yl)-4-(3-methoxy-2-methylphenyl)- 1H-pyrrole-2-carboxylate Int-22g.
  • Step G 5-(4,6-Dimethylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-2-(1-methyl- 1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-22h.
  • Step H 4-Chloro-5-(4,6-dimethylpyridin-2-yl)-6-(3-methoxy-2-methylphenyl)-2-(1- methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-22.
  • Example Int-23 Synthesis of Intermediate Int-23 [00755]
  • Scheme 23 The Synthesis of Intermediate Int-23 O OH N Cl N 3 - - 2- yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-23a.
  • Step B 4-Chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5- (pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-23.
  • Example Int-24 Synthesis of Intermediate Int-24 [00761]
  • Scheme 24 The Synthesis of Intermediate Int-24 O A O B B 3 1H- pyrazole Int-24b.
  • [00763] To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Int-24a (30.0 g, 0.155 mol) in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (107.5 g, 0.46 mol) and potassium t-butoxide (34.63 g, 0.31 mol) at 25°C.
  • Step B Ethyl 3-methyl-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1H-pyrrole-2- carboxylate Int-24c.
  • Ethyl 4-iodo-3-methyl-1H-pyrrole-2-carboxylate Int-2b (prepared as described in 198 NAI-1541502036v1 herein) (9.68 g, 34.71 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2- trifluoroethyl)-1H-pyrazole Int-24b (11.5 g, 41.65 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.82 g, 3.47 mmol), cesium (I) carbonate (22.61 g, 69.41 mmol), bis(adamantan-1-yl)(butyl)phosphane (2.8 g, 7.81 mmol) were dissolved in degassed dioxane (180 ml) under Ar.
  • Step C Ethyl 1-amino-3-methyl-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-1H- pyrrole-2-carboxylate Int-24d.
  • Sodium hydride (483.32 mg, 60.0% purity, 12.08 mmol) (60% in mineral oil) was added portion wise to a solution of ethyl 3-methyl-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)- 1H-pyrrole-2-carboxylate Int-24c (2.8 g, 9.29 mmol) in DMF (10 mL) at 0°C.
  • Step D 5-Methyl-2-(1-methyl-1H-imidazol-2-yl)-6-(1-(2,2,2-trifluoroethyl)-1H- pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-24e.
  • Step E 4-Chloro-5-methyl-2-(1-methyl-1H-imidazol-2-yl)-6-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine Int-24.
  • Step B 2-(3-Methoxy-2-methylphenyl)-2-(phenylsulfonyl)-1-(tetrahydrofuran-2- yl)ethan-1-ol Int-26c.
  • Acetic anhydride (475.78 mg, 4.66 mmol) was added dropwise at RT to a stirred solution of 2-(3-methoxy-2-methylphenyl)-2-(phenylsulfonyl)-1-(tetrahydrofuran-2-yl)ethan-1-ol Int-26c (1.95 g, 5.18 mmol) in pyridine (40 mL). The mixture was stirred at RT overnight.
  • Step D (E)-2-(2-(3-Methoxy-2-methylphenyl)-2- (phenylsulfonyl)vinyl)tetrahydrofuran Int-26e.
  • Diazabicyclo[5.4.0]undec-7-ene (DBU) (519.18 mg, 3.41 mmol, 510.0 ⁇ L, 1.2 equiv) was added dropwise at RT to a stirred solution of 2-(3-methoxy-2-methylphenyl)-2- (phenylsulfonyl)-1-(tetrahydrofuran-2-yl)ethyl acetate Int-26d (1.98 g, 4.74 mmol) in methylene chloride (25 mL). The mixture was stirred at 45°C overnight.
  • DBU Diazabicyclo[5.4.0]undec-7-ene
  • Step F rac Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-(tetrahydrofuran-2-yl)- 1H-pyrrole-2-carboxylate Int-26g.
  • Sodium hydride (0.328g, 8.2 mmol) (60% in mineral oil), was added portionwise to a solution of rac ethyl 4-(3-methoxy-2-methylphenyl)-3-(tetrahydrofuran-2-yl)-1H-pyrrole-2- carboxylate Int-26f (1.49 g, 4.52 mmol) in DMF (15 mL) at 0°C.
  • Step H rac (R)-4-Chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol- 2-yl)-5-(tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-26.
  • Example Int-27 Synthesis of Intermediate Int-27 [00791]
  • Scheme 27 The Synthesis of Int-27 204 NAI-1541502036v1 O S O (phenylsulfonyl)ethyl)tetrahydro-2H-thiopyran 1,1-dioxide Int-27b.
  • Step B 1-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-(3-methoxy-2- methylphenyl)-2-(phenylsulfonyl)ethyl acetate Int-27c.
  • Acetic anhydride (1.93 g, 18.88 mmol) was added dropwise at RT to a stirred solution of 4-(1-hydroxy-2-(3-methoxy-2-methylphenyl)-2-(phenylsulfonyl)ethyl)tetrahydro-2H- thiopyran 1,1-dioxide Int-27b (6.0 g, 13.68 mmol) in pyridine (60 mL). The mixture was stirred at RT overnight.
  • Step C (E)-4-(2-(3-Methoxy-2-methylphenyl)-2-(phenylsulfonyl)vinyl)tetrahydro- 2H-thiopyran 1,1-dioxide Int-27d.
  • Diazabicyclo[5.4.0]undec-7-ene (DBU) (2.13 g, 13.98 mmol) was added dropwise at RT to a stirred solution of 1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(3-methoxy-2- methylphenyl)-2-(phenylsulfonyl)ethyl acetate Int-27c (9.33 g, 19.41 mmol) in methylene chloride (60 mL). The mixture was stirred at 45°C overnight.
  • DBU Diazabicyclo[5.4.0]undec-7-ene
  • Step D Ethyl 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(3-methoxy-2- methylphenyl)-1H-pyrrole-2-carboxylate Int-27e.
  • Step E Ethyl 1-amino-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(3-methoxy-2- methylphenyl)-1H-pyrrole-2-carboxylate Int-27f.
  • Step F 4-(4-Hydroxy-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)tetrahydro-2H-thiopyran 1,1-dioxide Int-27g.
  • Step G 4-(4-Chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2- yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)tetrahydro-2H-thiopyran 1,1-dioxide Int-27.
  • Example Int-28 Synthesis of Intermediate Int-28
  • Scheme 28 The Synthesis of Int-28 208 NAI-1541502036v1 O O 4-yl)ethan-1-ol Int-28b.
  • Acetic anhydride (2.19 g, 21.51 mmol was added dropwise at RT to a stirred solution of 2-(3-methoxy-2-methylphenyl)-2-(phenylsulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol Int-28b (4.0 g, 10.24 mmol) in pyridine (40 mL). The mixture was stirred at RT overnight.
  • Step C (E)-4-(2-(3-Methoxy-2-methylphenyl)-2-(phenylsulfonyl)vinyl)tetrahydro- 2H-pyran Int-28d.
  • Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.23 g, 8.12 mmol) was added dropwise at RT to a stirred solution of 2-(3-methoxy-2-methylphenyl)-2-(phenylsulfonyl)-1-(tetrahydro-2H- pyran-4-yl)ethyl acetate Int-28c (4.5 g, 10.4 mmol) in methylene chloride (25 mL).
  • Step D Ethyl 4-(3-methoxy-2-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H- pyrrole-2-carboxylate Int-28e.
  • Step E Ethyl 1-amino-4-(3-methoxy-2-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)- 1H-pyrrole-2-carboxylate Int-28f.
  • Sodium hydride (0.328g, 8.2 mmol) (60% in mineral oil), was added portionwise to a solution of ethyl 4-(3-methoxy-2-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrrole-2- carboxylate Int-28e (1.3 g, 3.79 mmol) in DMF (15 mL) at 0°C.
  • Step F 6-(3-Methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5- (tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol Int-28g.
  • Step G 4-Chloro-6-(3-methoxy-2-methylphenyl)-2-(1-methyl-1H-imidazol-2-yl)-5- (tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine Int-28.
  • Step A 5-(2-Methoxyethoxy)-1H-pyrazol-3-amine A-2.
  • Diisopropyl azodicarboxylate (6.67 g, 33.02 mmol) was added portion wise to a solution of triphenylphosphine (8.65 g, 33.02 mmol) in CH 2 Cl 2 (110 mL) at 0-5 °C and stirred at this temperature over 20 min.
  • Step B 5-(Methoxymethyl)-1-methyl-3-nitro-1H-pyrazole A-3c.
  • Step C 5-(Methoxymethyl)-1-methyl-1H-pyrazol-3-amine A-3.
  • a 150-mL single-neck round-bottomed flask equipped with a magnetic stirrer was 213 NAI-1541502036v1 charged with Pd/C (0.1g) and methanol (50 mL). The mixture was hydrogenated (1 atm) at room temperature for 15 h.
  • Step B 3-(Methoxymethyl)-5-nitro-1H-pyrazole A-4c.
  • Example A5 Synthesis of Amine A-5
  • Scheme 33 The Synthesis of Amine A-5 CH 3 O CH 3 O
  • Step A 1-(5-amino-3-(methoxymethyl)-1H-pyrazol-1-yl)propan-1-one A-5.
  • Example A6 Synthesis of Amine A-6
  • Scheme 34 The Synthesis of Amine A-6 CH 3 O CH 3 O
  • Step A Ethyl 5-amino-3-(methoxymethyl)-1H-pyrazole-1-carboxylate A-6.
  • [00853] To a solution of compound 3-(methoxymethyl)-1H-pyrazol-5-amine A-4 (prepared as described herein) (801.2 mg, 6.3 mmol) in THF (15 mL) was added diisopropyl ethyl amine 215 NAI-1541502036v1 (895.73 mg, 6.94 mmol) at room temperature.
  • Example A7 Synthesis of Amine A-7
  • Scheme 35 The Synthesis of Amine A-7 CH 3 O CH 3 O
  • Step A 1-carboxylate A-7.
  • Method 2 was implemented with 3-(methoxymethyl)-1H-pyrazol-5-amine (150.0 mg, 1.18 mmol), propan-2-yl chloroformate (144.2 mg, 1.18 mmol), ethylbis(propan-2-yl)amine (183.16 mg, 1.42 mmol) in THF (15 mL).
  • Step B rac (1R,6R,8R)-8-methoxy-2-oxa-5-azabicyclo[4.2.0]octane hydrochloride salt A-8.
  • Step A 6-(1-Isopropyl-1H-pyrazol-3-yl)-5-methyl-2-(1-methyl-1H-imidazol-2-yl)-N- (pyridazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 1.
  • Sodium hydride 24.63 mg, 1.03 mmol
  • pyridazin-3-amine 53.23 mg, 560.08 ⁇ mol
  • DMF 2 mL
  • the mixture was 217 NAI-1541502036v1 stirred for 30 min at room temperature, then 4-chloro-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl- 2-(1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazine Int-1 (100.0 mg, 281.59 ⁇ mol) was added in one portion. The mixture was stirred at room temperature for 16 h. The mixture was quenched by concentrated aq.
  • Example 2 – Example 4 Synthesis of Compound 2 – Compound 4 [00871] Compound 2 – Compound 4 in Table A were prepared using the Representative Procedure for Method 1 Amination (as detailed in Example 1). [00872]
  • Example 5 Synthesis of Compound 5 [00873]
  • Scheme 38 The Synthesis of Compound 5.
  • N N [00874] [00875] Step A: N-(2-(1H-Imidazol-1-yl)ethyl)-6-(1-isopropyl-1H-pyrazol-3-yl)-5-methyl-2- (1-methyl-1H-imidazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 5.
  • Example 5 – Example 29 Synthesis of Compound 5 – Compound 29
  • Table A provides the structures, final step conditions, yield, and analytical data, for the preparation of Compound 5 – Compound 29.
  • Example 30 – Example 33 Compound 30 – Compound 33
  • Table B provides the structures of of Compound 30 – Compound 33 which can be prepared according to the procedures described herein.
  • Example 34 Synthesis of Compound 34
  • Scheme 39 The Synthesis of Compound 34.
  • Step A N-(4-Methoxy-6-methylpyridin-2-yl)-5-methyl-2-(1-methyl-1H-imidazol-2- yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 34.
  • Sodium hydride 26.84 mg, 60.0% purity, 671.05 ⁇ mol
  • 4-methoxy-6-methylpyridin-2-amine 84.23 mg, 610.04 ⁇ mol
  • Example 35 – Example 53 Compound 35 – Compound 53 [00887] Table B provides the structures of of Compound 35 – Compound 53 which can be prepared according to the procedures described herein.
  • Example 54 Synthesis of Compound 54 [00889] Scheme 40: The Synthesis of Compound 54. [00890] [00891] -N- - -2-(1- methyl-1H-imidazol-2-yl)-5-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 54.
  • Example 55 – Example 56 Compound 55 – Compound 56 [00894] Table B provides the structures of of Compound 55 – Compound 56 which can be prepared according to the procedures described herein.
  • Example 57 Synthesis of Compound 57 [00896] Scheme 41: The Synthesis of Compound 57. 220 NAI-1541502036v1 [00897] R [00898] Step A: 6-(1-Isopropyl-1H-pyrazol-3-yl)-N,2-bis(1-methyl-1H-imidazol-2-yl)-5- (pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine 57.
  • Example 58 – Example 69 Compound 58 – Compound 69 [00901] Table B provides the structures of of Compound 58 – Compound 69 which can be prepared according to the procedures described herein. [00902]
  • Example 70 Synthesis of Compound 70 [00903]
  • Scheme 42 The Synthesis of Compound 70.
  • Step A 1-(3-(Methoxymethyl)-5-((5-methyl-2-(1-methyl-1H-imidazol-2-yl)-6-(1- methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-1H-pyrazol-1-yl)propan-1-one 70.
  • the product was purified by HPLC (SYSTEM15-30% 0-2-7 min H 2 O/acetonitrile/0.1 NaHCO 3 flow 30 mL/min ((loading pump 4 mL acetonitrile) column: XBridge BEH C18100*19 mm,5 microM).
  • the product was purified by HPLC (SYSTEM 23-30-55% 0-2-8 min H 2 O/acetonitrile/0.1 NH 4 HCO 3 , flow 30 mL/min ((loading pump 4 mL acetonitrile) column: 224 NAI-1541502036v1 XBridge BEH C18100*19 mm,5 micro M))) to give isopropyl 3-(methoxymethyl)-5-((5-methyl- 2-(1-methyl-1H-imidazol-2-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4- yl)amino)-1H-pyrazole-1-carboxylate 73 (135.0 mg, 95.0% purity, 254.19 ⁇ mol, 41% yield).
  • Trifluoroacetic acid (69.78 mg, 612.13 ⁇ mol) was added in one portion to the solution of 7-amino-4-methyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one hydrochloride salt (144.8 mg, 673.34 ⁇ mol) and 4-chloro-5-methyl-2-(1-methyl-1H-imidazol-2-yl)-6-(1-methyl-1H- pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazine Int-2 (prepared as described herein) (100.0 mg, 305.72 ⁇ mol) in butan-1-ol (1 mL).
  • Example 76 – Example 96 Compound 76 – Compound 94
  • Table C provides the structures of of Compound 76 – Compound 94 which can be prepared according to the procedures described herein. 226 NAI-1541502036v1 - 6 y p - 2 m i p ( y ] f - 6 y p - 2 m i m y ] f - 6 m i m y m ] f e r u t c u r t S 1 v 6 3 A e e l 0 2 l p 0 5 b m 1 1 2 3 4 5 a a 1 T x - I E A N RM N H ] [ ] [ d l e i Y t e m a N e r u t c u r t S 1 v 6 3 e l 0 2
  • Cell lines Human tumor-derived pancreatic cancer cell line Panc-1 (expressing KRas G12D mutant) and mouse muscle myoblast C2C12 were purchased from American Type Culture Collection and grown in complete DMEM-High Glucose, supplemented with penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), and 10% heat-inactivated FBS at 37°C in a humidified incubator with 5% CO 2 .
  • Method Cells were plated at 350000 cells/well density in a 12-well plate, allowed 3 hours to adhere to the plate, then starved in the appropriate medium in the presence of 0.5% FBS overnight.
  • the small molecules to be tested were added to the cells in the final concentration of 10 ⁇ M in the presence of 0.3% DMSO for 3 hours incubation at 37°C.
  • serial dilutions of compounds were added to cells under the same conditions.
  • Panc-1 cells were stimulated with 10 ng/ml TGF-b1 for 1 hour, and C2C12 cells were stimulated with 10 ng/ml TGF-b1 for 20 minutes (recombinant human TGF-b1, R&D Systems). After stimulation cells were lysed with lysis buffer containing 1% Triton X-100, EDTA, and HaltTM Protease & Phosphatase Inhibitor Cocktail (Thermo Scientific).
  • Protein concentration was assessed by BCA protein assay (Thermo Scientific). Phosphorylation level of Smad2/ Smad3 was determined by western blot.
  • Western blot protocol Equal amounts of protein (15-50 ⁇ g) were separated by SDS- PAGE and transferred to nitrocellulose membranes (Invitrogen by Thermo Fisher Scientific). The membrane was stained with Ponceau S Stain (Boston BioProducts) to verify uniform protein loading. Membranes were blocked with 10% milk and phosphorylation levels of Smad2/Smad3 were assessed by incubating overnight at 4°C with the following antibodies: Phospho-Smad2 (Ser465/467) and Phosph-Smad3 (Ser423/425), both from Cell Signaling Technology.
  • Cell lines Human tumor-derived pancreatic cancer cell line Panc-1 (expressing KRas G12C mutant) was purchased from American Type Culture Collection and grown in complete DMEM-High Glucose medium, supplemented with penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), and 10% heat-inactivated FBS at 37°C in a humidified incubator with 5% CO 2 .
  • Method 1 Cells were plated at 350000 cells/well density in a 12-well plate, allowed 3 hours to adhere to the plate, then starved in the appropriate medium in the presence of 0.5% FBS overnight.
  • the small molecules to be tested were added to the cells in the final concentration of 10 ⁇ M in the presence of 0.3% DMSO for 6 hours incubation at 37°C.
  • serial dilutions of compounds were added to cells under the same conditions.
  • cells were stimulated with 1.5 ng/ml EGF for 15 minutes then cells were lysed with lysis buffer containing 1% Triton X-100, EDTA, and HaltTM Protease & Phosphatase Inhibitor Cocktail (Thermo Scientific). Protein concentration was assessed by BCA protein assay (Thermo Scientific). Phosphorylation level of JNK was determined by western blot.
  • Method 2 Cells were plated at 350000 cells/well density in a 12-well plate in the presence of 10% FBS. The next day small molecules to be tested were added to the cells in the final concentration of 10 ⁇ M in the presence of 0.3% DMSO for 6 hours incubation at 37°C. For IC 50 value determination, serial dilutions of compounds were added to cells under the same conditions. Next, cells were lysed with lysis buffer containing 1% Triton X-100, EDTA, and HaltTM Protease & Phosphatase Inhibitor Cocktail (Thermo Scientific). Protein concentration was assessed by BCA protein assay (Thermo Scientific). Phosphorylation level of JNK was determined by western blot.
  • Cell lines Human tumor-derived pancreatic cancer cell line Panc-1 (expressing KRas G12D mutant) was purchased from American Type Culture Collection and grown in complete DMEM-High Glucose medium, supplemented with penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), and 10% heat-inactivated FBS at 37°C in a humidified incubator with 5% CO 2 .
  • Method 1 Cells were plated at 350000 cells/well density in a 12-well plate, allowed 3 hours to adhere to the plate, then starved in the appropriate medium in the presence of 0.5% FBS overnight.
  • the small molecules to be tested were added to the cells in the final concentration of 10 ⁇ M in the presence of 0.3% DMSO for 6 hours incubation at 37°C.
  • serial dilutions of compounds were added to cells under the same conditions.
  • cells were stimulated with 1.5 ng/ml EGF for 15 minutes then cells were lysed with lysis buffer containing 1% Triton X-100, EDTA, and HaltTM Protease & Phosphatase Inhibitor Cocktail (Thermo Scientific). Protein concentration was assessed by BCA protein assay (Thermo Scientific). Phosphorylation level of MAPK p38 was determined by western blot.
  • Method 2 Cells were plated at 350000 cells/well density in a 12-well plate in 10% FBS. The next day small molecules to be tested were added to the cells in the final concentration of 10 ⁇ M in the presence of 0.3% DMSO for 6 hours incubation at 37°C. For IC 50 value determination, serial dilutions of compounds were added to cells under the same conditions. Next, cells were lysed with lysis buffer containing 1% Triton X-100, EDTA, and HaltTM Protease & Phosphatase Inhibitor Cocktail (Thermo Scientific). Protein concentration was assessed by BCA protein assay (Thermo Scientific). Phosphorylation level of MAPK p38 was determined by western blot.
  • Cell lines Human tumor-derived pancreatic cancer cell line Panc-1 (expressing KRas G12D mutant) was purchased from American Type Culture Collection and grown in complete DMEM-High Glucose medium, supplemented with penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), and 10% heat-inactivated FBS at 37°C in a humidified incubator with 5% CO2.
  • Method 1 Cells were plated at 350000 cells/well density in a 12-well plate, allowed 3 hours to adhere to the plate, then starved in the appropriate medium in the presence of 0.5% FBS overnight.
  • the small molecules to be tested were added to the cells in the final concentration of 10 ⁇ M in the presence of 0.3% DMSO for 6 hours incubation at 37°C.
  • serial dilutions of compounds were added to cells under the same conditions.
  • cells were stimulated with 1.5 ng/ml EGF for 15 minutes then cells were lysed with lysis buffer containing 1% Triton X-100, EDTA, and HaltTM Protease & Phosphatase Inhibitor Cocktail (Thermo Scientific). Protein concentration was assessed by BCA protein assay (Thermo Scientific). Phosphorylation level of Erk1/2 was determined by western blot.
  • Method 2 Cells were plated at 350000 cells/well density in a 12-well plate in 10% FBS. The next day small molecules to be tested were added to the cells in the final concentration of 10 ⁇ M in the presence of 0.3% DMSO for 6 hours incubation at 37°C. For IC50 value determination, serial dilutions of compounds were added to cells under the same conditions. Next, cells were lysed with lysis buffer containing 1% Triton X-100, EDTA, and HaltTM Protease & Phosphatase Inhibitor Cocktail (Thermo Scientific). Protein concentration was assessed by BCA protein assay (Thermo Scientific). Phosphorylation level of Erk1/2 was determined by western blot.
  • Panc-1 Human tumor-derived pancreatic cancer cell line Panc-1 (expressing KRas G12D mutant) was purchased from American Type Culture Collection and grown in complete DMEM- High Glucose supplemented with penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), and 10% heat-inactivated FBS at 37°C in a humidified incubator with 5% CO2.
  • Method 1 Cells were plated at 350000 cells/well density in a 12-well plate, allowed 3 hours to adhere to the plate, then starved in the appropriate medium in the presence of 0.5% FBS overnight.
  • the small molecules to be tested were added to the cells in the final concentration of 10 ⁇ M in the presence of 0.3% DMSO for 6 hours incubation at 37°C. Next, cells were stimulated with 1.5 ng/ml EGF for 15 minutes then cells were lysed with lysis buffer containing 1% Triton X-100, EDTA, and HaltTM Protease & Phosphatase Inhibitor Cocktail (Thermo Scientific). Protein concentration was assessed by BCA protein assay (Thermo Scientific). Phosphorylation level of Akt was determined by western blot. [00964] Method 2: Cells were plated at 350000 cells/well density in a 12-well plate in 10% FBS.
  • Cell lines Abelson murine leukemia virus transformed macrophage cell line RAW 264.7 was purchased from ATCC and grown in complete DMEM-High Glucose medium supplemented with penicillin (100 U/mL), streptomycin (100 ⁇ g/mL), and 10% heat-inactivated FBS at 37°C in a humidified incubator with 5% CO 2 .
  • Method Cells were plated at 40000 cells/well density in a 96-wells plate. After a 3- hour incubation, macrophages were starved with DMEM plus 0.5% FBS o/n.
  • Sandwich ELISA The ELISA Immunoassays Quantikine Mouse TNF-alpha (catalog number MTA00B) and IL6 (catalog number M6000B) were purchased from R&D Systems Inc., Minneapolis, MN.

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Abstract

L'invention concerne des composés de formule (I), ou une forme pharmaceutiquement acceptable de ceux-ci, et des compositions pharmaceutiques les comprenant. L'invention concerne également des méthodes de modulation de l'activité de cibles cellulaires par administration à un sujet d'un composé de formule (I), ou d'une forme pharmaceutiquement acceptable de celui-ci. L'invention concerne en outre des méthodes de traitement du cancer, de maladies fibrotiques et de maladies inflammatoires par administration à un sujet d'un composé ou d'une forme pharmaceutiquement acceptable de celui-ci.
PCT/US2024/050482 2023-10-10 2024-10-09 Composés pyrrolo[2,1-f][1,2,4]triazine agissant contre des cancers, des maladies inflammatoires et une maladie fibrotique par interaction avec des protéines de la superfamille ras Pending WO2025080653A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009601A1 (fr) * 2002-07-19 2004-01-29 Bristol-Myers Squibb Company Inhibiteurs de l'azaindole kinase
WO2008021924A1 (fr) * 2006-08-09 2008-02-21 Bristol-Myers Squibb Company Inhibiteurs de pyrrolotriazine kinase
WO2023196975A1 (fr) 2022-04-08 2023-10-12 Shy Therapeutics, Llc Composés interagissant avec des protéines de la superfamille ras pour le traitement de cancers, de maladies inflammatoires, de rasopathies et d'une maladie fibrotique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009601A1 (fr) * 2002-07-19 2004-01-29 Bristol-Myers Squibb Company Inhibiteurs de l'azaindole kinase
WO2008021924A1 (fr) * 2006-08-09 2008-02-21 Bristol-Myers Squibb Company Inhibiteurs de pyrrolotriazine kinase
WO2023196975A1 (fr) 2022-04-08 2023-10-12 Shy Therapeutics, Llc Composés interagissant avec des protéines de la superfamille ras pour le traitement de cancers, de maladies inflammatoires, de rasopathies et d'une maladie fibrotique

Non-Patent Citations (34)

* Cited by examiner, † Cited by third party
Title
"Nomenclature of Organic Chemistry", 1979, PERGAMON PRESS
"Pharmaceutical Preformulation and Formulation", 2009, CRC PRESS LLC
"Remington: The Science and Practice of Pharmacy", 2012, THE PHARMACEUTICAL PRESS
ARTHRITIS RES THER., 2009, pages 11
BAR-SAGI D, TRENDS ENDOCRIN. METAB., vol. 5, 1994, pages 165 - 169
BIOCHEM., vol. 11, 1972, pages 942 - 944
BOGUSKE ET AL., NATURE, vol. 366, 1993, pages 643 - 654
BOUREUX AVIGNAL EFAURE SFORT P: "Evolution of the Rho family of ras-like GTPases in eukaryotes", MOL BIOL EVOL, vol. 24, no. 1, 2007, pages 203 - 16
BUSTELO XRSAUZEAU VBERENJENO IM: "GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo", BIOESSAYS, vol. 29, no. 4, 2007, pages 356 - 370
CURR DRUG DISCOV TECHNOL., vol. 12, no. 1, 2015, pages 3 - 20
FAVRE HAPOWELL WH: "Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names", 2013, THE ROYAL SOCIETY OF CHEMISTRY
FERRERO-MILIANI LNIELSEN OHANDERSEN PSGIRARDIN SENIELSENANDERSENGIRARDIN, CLIN. EXP. IMMUNOL., February 2007 (2007-02-01), pages 147
FONAROW G, CLEVE. CLIN. J. MED., vol. 70, 2003, pages 431 - 434
FRANK MCCORMICK.: "K-Ras protein as a drug target", JOURNAL OF MOLECULAR MEDICINE (BERLIN, vol. 94, 2016, pages 253 - 258, XP035801349, DOI: 10.1007/s00109-016-1382-7
FRIEDMAN SLSHEPPARD DDUFFIELD JSVIOLETTE S., SCI TRANSL MED, vol. 5, no. 167, 9 January 2013 (2013-01-09), pages 1671
HINZ, B. ET AL., AM J PATHOL., vol. 170, 2007, pages 1807 - 1816
HOOTMAN JMBRAULT MWHELMICK CGTHEIS KAARMOUR BS, PREVALENCE AND MOST COMMON CAUSES OF DISABILITY AMONG ADULTS-UNITED STATES 2005, MMWR, vol. 58, no. 16, 2009, pages 421 - 6
IGNACIO CSSANDVIK AKBRULAND TANDREU-BALLESTER JC, J. CROHNS COLITIS, 16 March 2017 (2017-03-16)
JENS T.: "Carstensen, Drug Stability: Principles & Practice", 1995, MARCEL DEKKER, pages: 379 - 80
JOURNAL OF THE NATIONAL CANCER INSTITUTE, vol. 92, no. 3, 2000, pages 205 - 216
KARNOUB ET AL., NAT. REV. MOL. CELL BIOL., vol. 9, 2008, pages 517 - 531
KATHERIN CALVO ET AL.: "JMMI, and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities", BLOOD, vol. 125, no. 18, 30 April 2015 (2015-04-30), pages 2753 - 2758, XP086685953, DOI: 10.1182/blood-2014-11-567917
KNIPE RSTAGER EMLIAO JK.: "The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis", PHARMACOL REV., vol. 67, no. 1, 2015, pages 103 - 17
MARTIN SCHWARTZ.: "Rho Signalling at a Glance", JOURNAL OF CELL SCIENCE, vol. 117, 2004, pages 5457 - 5458
NAIR ABJACOB S.: "A simple practice guide for dose conversion between animals and human.", J BASIC CLIN PHARMA, vol. 7, 2016, pages 27 - 31
OLSEN DJORGENSEN JT, FRONT. ONCOL., vol. 4, 16 May 2014 (2014-05-16), pages 105
PURE & APPL. CHEM., vol. 68, no. 12, 1996, pages 2193 - 2222
QUINLAN ET AL., FUTURE ONCOL., vol. 5, 2009, pages 105 - 116
R.S. CAHNC.K. INGOLDV. PRELOG: "Angew. Chem. Internat. Ed. Eng.", vol. 5, 1966, pages: 385 - 415
ROITT, I.BROSTOFF, J.KALE, D.: "Immunology", vol. 17, 1993, MOSBY, ST. LOUIS, MO., pages: 1 - 17
SERINI, G.GABBIANI, G., EXP. CELL RES., vol. 250, 1999, pages 273 - 283
SHACTER ET AL., ONCOLOGY, vol. 16, no. 2, 2002, pages 217 - 26
V. PRELOGG. HELMCHEN, ANGEW. CHEM INTERNAT. ED. ENG., vol. 21, 1982, pages 567 - 583
WYNN TA.: "Fibrotic Disease and the TH1/TH2 Paradigm", NAT REV IMMUNOL, vol. 4, no. 8, August 2004 (2004-08-01), pages 583 - 594, XP009070836, DOI: 10.1038/nri1412

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