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WO2025014922A1 - Inhibiteurs bicycliques et monocycliques de trpa1 - Google Patents

Inhibiteurs bicycliques et monocycliques de trpa1 Download PDF

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Publication number
WO2025014922A1
WO2025014922A1 PCT/US2024/037153 US2024037153W WO2025014922A1 WO 2025014922 A1 WO2025014922 A1 WO 2025014922A1 US 2024037153 W US2024037153 W US 2024037153W WO 2025014922 A1 WO2025014922 A1 WO 2025014922A1
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alkyl
cycloalkyl
halogenated
halogen
compound
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Fabrizio Giordanetto
Morten Østergaard JENSEN
Vishwannath JOGINI
Roger John Snow
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DE Shaw Research LLC
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DE Shaw Research LLC
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • TRP channels Transient receptor potential channels
  • TRPA1 Transient receptor potential ankyrin 1
  • a member of the TRPA subfamily is a cation-selective, calcium-permeable ion channel (Montell, C., 2005, Sci. STKE, 272:re3).
  • TRPA channels are characterized structurally by the presence of multiple N-terminal ankyrin repeats forming a large intracellular domain (Montell, C., 2005, Sci. STKE, 272:re3).
  • the human TRPA1 has approximately 14 N-terminal ankyrin repeats.
  • the TRPA1 protein is a homotetramer. Each subunit has six transmembrane helices that form a central pore, which is surrounded by voltage-sensor-like domains.
  • TRPA1 protein also contains a C- terminal extension (Terrett, J.A. et al., 2021, J. Med. Chem.64, 7, 3843–3869).
  • ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0007]
  • TRPA1 is highly expressed in the plasma membrane of primary sensory neurons where it functions as a polymodal sensor for exogenous and endogenous stimuli.
  • TRPA1 expression is most prevalent in small diameter sensory neurons and it colocalizes with markers of peptidergic nociceptors, such as TRPV1, calcitonin gene-related peptide (CGRP) and substance P (Kaneko, Y.
  • TRPA1 functions primarily as a sensor for environmental irritants and is thought to give rise to somatosensory modalities, such as pain, cold, and itch.
  • TRPA1 is activated by a range of endogenous and exogenous stimuli for pain and inflammation.
  • TRPA1 can be activated by external irritants, such as allyl isothiocyanate (AITC) and allicin.
  • AITC allyl isothiocyanate
  • TRPA1 can also be activated by cinnamaldehyde, which functions as an agonist to activate the channel through covalent modification of the cysteine residues in the N-terminal ankyrin repeats (Terrett, J.A. et al., 2021, J. Med. Chem.64, 7, 3843–3869).
  • TRPA1 can also be activated by noxious stimuli, including cold temperatures and pungent natural compounds, such as mustard, cinnamon and garlic.
  • TRPA1 knock-out (KO) mouse models have implicated the ion channel in pain signaling. TRPA1 activity plays a role in a number of ailments in patients.
  • TRPA1 familial episodic pain syndrome
  • TRPA1 activation has been implicated in the development of chronic respiratory diseases, including asthma and cough (Caceres, A.I. et al., 2009, Proc. Natl. Acad. Sci.106, 22, 9099-104; Reese, R.M. et al., 2020, Scientific Reports 10, 979, 1-11).
  • Airway hyperresponsiveness, bronchoconstriction, and airway inflammation in asthma appear to be 2 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 triggered by activity of TRPA1 expressed in airway smooth muscle cells, and the sensory nervous system and clinical symptoms can be relieved by TRPA1 antagonists (Balestrini, A.
  • the cough can be associated with asthma, chronic pulmonary obstructive disease (COPD), and idiopathic pulmonary fibrosis (IPF).
  • COPD chronic pulmonary obstructive disease
  • IPF idiopathic pulmonary fibrosis
  • the cough can also be post-viral cough or chronic idiopathic cough as well as cough in sensitive patients (Song, W.-J. and Chang, Y.-S., 2015, Clin. Transl.
  • TRPA1 antagonists can inhibit calcium signaling triggered by cough triggers, such as cigarette smoke extract (CSE) oxidative stress, inflammatory mediator release, and downregulated antioxidant gene expression (Lin, Y.-J. et al., 2015, J. Appl. Physiol.118, 273–281; Wang, Z. et al., 2019, Front. Pharmacol.10, 1253, 1-11).
  • CSE cigarette smoke extract
  • TRPA1 has been implicated in dermatitis and itch.
  • TRPA1 antagonists are effective in atopic dermatitis (Wilson, S.R. et al., 2013, J. Neurosci.33, 22, 9283–9294), contact dermatitis (Liu, B. et al., 2013, FASEB J.27, 9, 3549-3563), psoriasis-associated itch (Wilson, S.R. et al., 2013 J. Neurosci.33, 22, 9283–9294), and IL-31-dependent itch (Cevikbas, F. et al., 2014, J. Allergy Clin. Immunol.133, 2, 448–460).
  • TRPA1 is required for the observed hypersensitivity in inflammatory pain models (Bautista, D.M. et al. 2013, Annu. Rev.
  • TRPA1 plays a role in the inflammatory pain associated with this metabolic disorder.
  • TRPA1 may also have a role in the pathogenesis of cancer and other inflammatory diseases.
  • TRPA1 also plays a role in arthritis and osteoarthritic pain (Horvath, A. et al., 2016, Arthritis Res. Ther.18, 6, 1-14). Activation of TRPA1 has been shown to elicit an inflammatory response in osteoarthritic chondrocytes (Nummenmaa, E. et al., 2016, Arthritis Res. Ther.18, 185). This is supported by observations that TRPA1 inhibition and genetic deletion reduces knee swelling, histopathological destruction, and inflammatory mediators in osteoarthritic mouse chondrocytes and murine cartilage (Nummenmaa, E. et al., 2016, Arthritis Res.
  • TRPA1 also has a role in colitis and visceral hypersensitivity and in mediating gastrointestinal (GI) hypersensitivity to mechanical stimuli. TRPA1 expression is elevated in the inflamed mouse gut (Cseko, K. et al., 2019, Pharmaceuticals 12, 48, 1-19; Izzo, A. et al., 2012, Br. J.
  • TRPA1 is highly expressed in sensory neurons innervating the bladder, suggesting that TRPA1 is a potential drug target for bladder disorders, such as bladder instability, urinary incontinence, and cystitis (Streng, T. et al., 2008, Eur. Urol.53, 391–399). TRPA1 is up-regulated in bladder mucosa in patients with bladder outlet obstruction (Du, S. et al., 2008, Urology 72, 2, 450-455). [0016] Thus, there remains a need for development of novel TRPA1 inhibitors as pharmaceutical agents for the treatment of a number of conditions, disorders, and diseases.
  • a compound useful as a TRPA1 inhibitor having a structure of Formula I 4 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 ( ) or Formula II ( ) is described, where the various substituents are defined herein.
  • the compounds of Formula I or Formula II described herein can block or inhibit TRPA1 and be used in the treatment of a variety of conditions. Methods for synthesizing these compounds are also described herein. Pharmaceutical compositions and methods of using these compositions described herein are useful for treating conditions in vitro and in vivo.
  • Such compounds, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for treating pain, a skin disorder, a respiratory disease, a fibrotic disease, an inner ear disorder, fever or another disorder of thermoregulation, a urinary tract disorder, an autoimmune disease, ischemia, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a cardiovascular disorder, or a combination thereof.
  • pharmaceutically active agents and methods for treating pain a skin disorder, a respiratory disease, a fibrotic disease, an inner ear disorder, fever or another disorder of thermoregulation, a urinary tract disorder, an autoimmune disease, ischemia, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, a cardiovascular disorder, or a combination thereof.
  • CNS central nervous system
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described, wherein X is a direct bond or CR 8 R 8 ’; Y1 is a direct bond, CR3R3’, NR9, O, or S; Y 2 is a direct bond, CR 4 R 4 ’, NR 10 , O, or S; wherein when Y 1 is NR 9 , O, or S, Y 2 is a direct bond or CR 4 R 4 ’; and wherein when Y 2 is NR 10 , O, or S, Y 1 is a direct bond or CR 3 R 3 ’; provided that Y1 and Y2 cannot both be direct bonds; R1 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle,
  • n is 2.
  • each occurrence of R5 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.
  • each occurrence of R5 is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl.
  • each occurrence of R6 is independently H, D, alkyl, halogen, OR a , or halogenated alkyl.
  • each occurrence of R6 independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl.
  • L 1 is selected from the group consisting of –CH 2 –CH 2 –, –CH(CH 3 )–CH 2 –, –CH 2 –C(CH 3 ) 2 –, –CH(OH)–CH 2 –, –CH 2 – 9 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0025]
  • L 1 is selected from the group consisting of –CH2–CH2–, –CH(CH3)–CH2–, –CH2–CH(CH3)–, –CH2–C(CH3)2–, –C(CH3)2– [0026] In any one of the embodiment
  • R7 is H, D, or alkyl.
  • R 7 is H, D, CH 3 , or CH 2 CH 3 .
  • R 7 ’ is H, D, or alkyl.
  • R 7 ’ is H, D, CH 3 , or CH 2 CH 3.
  • any one of the embodiments described herein is selected from the group consisting of –CH 2 –, –CH(CH 3 )–, –C(CH 3 ) 2 –, and –CH(CH 2 CH 3 )–. [0033] In any one of the embodiments described herein, is –CH2–. [0034] In any one of the embodiments described herein, L 1 is is – CH 2 –.
  • any one of the embodiments described herein is selected from the group 11 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0038]
  • the compound has the structure of Formula Ib: , wherein R5a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R5b is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R 6a is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 6b is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 21 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR a , SR a , NR a R b , -C 1-4 alkyl;
  • X is a direct bond.
  • X is CR 8 R 8 ’.
  • the compound has the structure of Formula Ic or Id: , wherein each occurrence of R5a is independently H, D, alkyl, halogen, ORa, or fluorinated alkyl; each occurrence of R5b is independently H, D, alkyl, halogen, ORa, or fluorinated alkyl; each occurrence of R6a is independently H, D, alkyl, halogen, ORa, or fluorinated alkyl; each occurrence of R6b is independently H, D, alkyl, halogen, ORa, or fluorinated alkyl; 13 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 each occurrence of R21 is independently H, D, D, alkyl, halogen, ORa, or fluorinated alkyl; 13 ACTIVEUS 204604250 Attorney Docket No.220
  • R21, R22, R24, and R25 are H; and R23 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1- 4 alkyl-OR a .
  • R 23 is CH 3 , CH 2 CH 3 , OH, F, Cl, Br,
  • R23 is Cl.
  • R 8 is H, D, or alkyl.
  • R 8 is H, D, CH 3 , or CH 2 CH 3 .
  • R8’ is H, D, or alkyl.
  • R8’ is H, D, CH3, or CH2CH3.
  • Y 1 is CR 3 R 3 ’.
  • R 3 is H, D, alkyl, halogen, OR a , or halogenated alkyl.
  • R 3 is H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl.
  • 14 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024
  • R3’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.
  • R3’ H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • Y1 is a direct bond.
  • Y2 is CR4R4’.
  • R4 is H, D, alkyl, halogen, ORa, or halogenated alkyl.
  • R4 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • R4’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.
  • R4’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • Y2 is NR10.
  • R10 is H, alkyl, cycloalkyl, aryl, or alkylaryl.
  • R10 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , and CH(CH 3 ) 2 .
  • Y2 is O or S.
  • R 1 is H, D, alkyl, halogen, OR a , or halogenated alkyl.
  • R1 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • R1 and R4 together with the carbon atoms that they are connected to, form a cyclopropyl group which is optionally substituted with D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl.
  • R 1 ’ is H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl.
  • is —(C O)–.
  • R2 is H, D, alkyl, halogen, or halogenated alkyl.
  • R2 is H, D, CH3, CH2CH3, F, Cl, Br, or fluorinated alkyl.
  • R2’ is H, D, alkyl, halogen, or halogenated alkyl.
  • R2’ is H, D, CH3, CH2CH3, F, Cl, Br, or fluorinated alkyl.
  • the compound has the structure of Formula Ie, wherein R5a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R23 is H, D, halogen, alkyl, ORa, or NRaRb; 17 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024
  • R1 is H, D, halogen, alkyl, or ORa
  • R1’ is H, D, halogen, alkyl, or ORa
  • R2 is H, D, halogen, alkyl, or ORa
  • R 3 is H, D, halogen, alkyl, or OR a
  • R 4 is H, D, halogen, alkyl, or
  • a compound of Formula II or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described, wherein 18 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Z is NR11, O, or S; Q is a direct bond or CR13R13’; R 11 is H, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1- 4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl- saturated heterocycle; R 12 is H, D, halogen, alkyl
  • each occurrence of R15 is independently H, D, alkyl, halogen, OR a , or halogenated alkyl.
  • each occurrence of R15 is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl.
  • each occurrence of R 16 is independently H, D, alkyl, halogen, OR a , or halogenated alkyl.
  • each occurrence of R16 independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • L2 is selected from the group consisting of –CH 2 –CH 2 –, –CH(CH 3 )–CH 2 –, –CH 2 –C(CH 3 ) 2 –, –CH(OH)–CH 2 –, –CH 2 – [0085]
  • L 2 is selected from the group consisting of –CH 2 –CH 2 –, –CH(CH 3 )–CH 2 –, –CH 2 –CH(CH 3 )–, –CH 2 –C(CH 3 ) 2 –, –C(CH 3 ) 2 – [0086]
  • the compound has the structure of Formula IIa: , wherein R 15a is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 15b is H, D, alkyl, halogen, OR a ,
  • R 14 ’ is H, D, CH 3 , or CH 2 CH 3.
  • R 14 ’ is selected from the group consisting of –CH 2 –, –CH(CH 3 )–, –C(CH 3 ) 2 –, and –CH(CH 2 CH 3 )–.
  • –CH2– is -CH2-.
  • phenyl which is optionally substituted with by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, and -C1-4alkyl-ORa.
  • any one of the embodiments described herein is selected from the group 22 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 B
  • a 5- or 6-membered heteroaryl which is optionally substituted with by 1-4 substituents each independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, and -C1-4alkyl-ORa.
  • the compound has the structure of Formula Ib: , 23 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 wherein R 15a is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 15b is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 16a is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R16b is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R31 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb,
  • R31, R32, R34, and R35 are H; and R33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1- 4 alkyl-OR a .
  • R33 is CH3, CH2CH3, OH, F, Cl, Br,
  • R 33 is Cl.
  • Q is CR 13 R 13 ’.
  • R13 is H, D, or alkyl.
  • R13 is H, D, CH3, or CH2CH3.
  • R13’ is H, D, or alkyl.
  • R 13 ’ is H, D, CH 3 , or CH 2 CH 3.
  • Q is a direct bond.
  • Z is NR11.
  • R11 is H, alkyl, cycloalkyl, aryl, or heteroaryl.
  • R11 is selected from the group consisting .
  • Z is O or S.
  • R12 is H, D, alkyl, halogen, ORa, or halogenated alkyl.
  • R12 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • R12’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.
  • R12’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • the compound has the structure of Formula IIc, wherein R15a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R 33 is H, D, halogen, alkyl, OR a , or NR a R b ; selected from the group consisting R11 is H, alkyl, aryl or heteroaryl; R 12 is H, D, halogen, alkyl, or OR a ; and R 13 is H, D, halogen, alkyl, or OR a .
  • At least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.
  • R a or R b is H, Me, phenyl
  • Ra and Rb together with the nitrogen atom that they are connected to, form an optionally substituted heterocycle comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.
  • each occurrence of Rx is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.
  • each occurrence of Rx is independently H or alkyl.
  • each occurrence of Rx is independently H or Me.
  • the compound is selected from the group consisting of compounds 1-5, 7-23, and 27-30 in Table 2.
  • the compound is selected from the group consisting of compounds 6 and 24-26 in Table 2.
  • a pharmaceutical composition comprising at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • a method of treating a condition in a mammalian species in need thereof comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of embodiments described herein or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of pain, a skin disorder, a respiratory disease, a fibrotic disease, an inner ear disorder, fever or another disorder of thermoregulation, a urinary tract or bladder disorder, an autoimmune disease, ischemia, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, and a cardiovascular disorder.
  • the condition is selected from the group consisting of pain, a skin disorder, a respiratory disease, a fibrotic disease, an inner ear disorder, fever or another disorder of thermoregulation, a urinary tract or bladder disorder, an autoimmune disease, ischemia, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, and a cardiovascular disorder.
  • CNS central nervous system
  • the pain is acute pain, chronic pain, complex regional pain syndrome, inflammatory pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritis pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, pos- herpetic neuralgia, fibromyalgia, nerve injury, post stock pain, or tooth and tooth injury- related pain.
  • a urinary tract disorder is pelvic hypersensitivity, urinary incontinence, or cystitis, bladder instability, or bladder outlet obstruction.
  • the skin disorder is burns, psoriasis, eczema, or pruritus. [0135] In any one of the embodiments described herein, the skin disorder is atopic dermatitis or psoriasis-induced itching. [0136] In any one of the embodiments described herein, the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, an idiopathic lung disease, chronic obstructive pulmonary disease, asthma, chronic asthma, tracheobronchial or diaphragmatic dysfunction, cough, or chronic cough.
  • the ischemia is CNS hypoxia or a disorder associated with reduced blood flow to CNS.
  • the autoimmune disease is rheumatoid arthritis or multiple sclerosis.
  • the central nervous system disorder is associated with neurodegeneration.
  • the gastroenterological disorder is an inflammatory bowel disease, esophagitis, gastroesophageal reflux disorder, irritable bowel syndrome, emesis, or stomach duodenal ulcer.
  • the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.
  • the mammalian species is human.
  • a method of inhibiting transient receptor potential A1 (TRPA1) in a mammalian species in need thereof comprising administering to the mammalian species a therapeutically effective amount of at least one compound according to any one of embodiments or a pharmaceutically acceptable salt thereof.
  • the mammalian species is human.
  • Any one of the embodiments disclosed herein may be properly combined with any other embodiment disclosed herein.
  • the combination of any one of the embodiments disclosed herein with any other embodiments disclosed herein is expressly contemplated. Specifically, the selection of one or more embodiments for one substituent group can be properly combined with the selection of one or more particular embodiments for any other substituent group.
  • alkyl and alk refer to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms.
  • exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, 29 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 undecyl, dodecyl, and the like.
  • (C1-Cx)alkyl or “C1-xalkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to x carbon atoms.
  • (C 1 -C 4 )alkyl or “C 1-4 alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl.
  • Substituted alkyl refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl.
  • C 2 -C x alkenyl” or “C 2-x alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon double bond.
  • C2-C6alkenyl or “C 2-6 alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2- propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl
  • Substituted alkenyl refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of 30 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 attachment.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond.
  • exemplary groups include ethynyl.
  • C2-Cxalkynyl or “C2-x alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon triple bond.
  • C 2 -C 6 alkynyl or “C 2-6 alknyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • Substituted alkynyl refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring.
  • C 3 -C 7 cycloalkyl or “C 3-7 cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • Substituted cycloalkyl refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • exemplary substituents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro- attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. “Substituted cycloalkenyl” refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • exemplary substituents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cyclic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl, and the like).
  • fused aromatic ring refers to a molecular structure having two or more aromatic rings wherein two adjacent aromatic rings have two carbon atoms in common.
  • “Substituted aryl” refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available point of attachment.
  • exemplary substituents can themselves be optionally substituted.
  • exemplary substituents also include fused cyclic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted.
  • fused cyclic groups especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted.
  • biasing refers to two aryl groups linked by a single bond.
  • biheteroaryl refers to two heteroaryl groups linked by a single bond.
  • heteroaryl-aryl refers to a heteroaryl group and an aryl group linked by a single bond
  • aryl-heteroaryl refers to an aryl group and a heteroaryl group linked by a single bond.
  • the numbers of the ring atoms in the heteroaryl and/or aryl rings are used to specify the sizes of the aryl or heteroaryl ring in the substituents.
  • 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is linked to a 6-membered aryl group.
  • Other combinations and ring sizes can be similarly specified.
  • carrier or “carbon cycle” refers to a fully saturated or partially saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring, or cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl.
  • the term “carbocycle” encompasses cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined hereinabove.
  • substituted carbocycle refers to carbocycle or carbocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl.
  • substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents can themselves be optionally substituted.
  • heterocycle and “heterocyclic” refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., “heteroaryl”) cyclic groups (for example, 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring 34 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 systems) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group may independently be saturated, or partially or fully unsaturated.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • heteroarylium refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.
  • the heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system.
  • Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyrid
  • bicyclic heterocyclic groups include indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyr
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.
  • “Substituted heterocycle” and “substituted heterocyclic” refer to heterocycle or heterocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • exemplary substituents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • oxo refers to substituent group, which may be attached to a carbon ring atom on a carboncycle or heterocycle.
  • an oxo substituent group is attached to a carbon ring atom on an aromatic group, e.g., aryl or heteroaryl, the bonds on the aromatic ring may be rearranged to satisfy the valence requirement.
  • a pyridine with a 2- oxo substituent group may have the structure which also includes its tautomeric form
  • alkylamino refers to a group having the structure -NHR’, wherein R’ is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein.
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.
  • dialkylamino refers to a group having the structure -NRR’, wherein R and R’ are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, 36 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 cycloalkenyl or substituted cyclolalkenyl, aryl or substituted aryl, and heterocycle or substituted heterocycle, as defined herein. R and R’ may be the same or different in a dialkyamino moiety.
  • dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like.
  • R and R’ are linked to form a cyclic structure.
  • the resulting cyclic structure may be aromatic or non-aromatic.
  • Examples of the resulting cyclic structure include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.
  • halogen or “halo” refer to chlorine, bromine, fluorine, or iodine.
  • substituted refers to the embodiments in which a molecule, molecular moiety, or substituent group (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein) is substituted with one or more substituents, where valence permits, preferably 1 to 6 substituents, at any available point of attachment.
  • substituent group e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group or any other group disclosed herein
  • groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.
  • optionally substituted refers to the embodiments in which a molecule, molecular moiety or substituent group (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl 37 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 group or any other group disclosed herein) may or may not be substituted with aforementioned one or more substituents.
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • the compounds of the present invention may form salts which are also within the scope of this invention. Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated.
  • the term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • zwitterions when a compound of the present invention contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a phenol or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein.
  • Pharmaceutically acceptable (i.e., non- toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation.
  • Salts of the compounds of the present invention may be formed, for example, by reacting a compound described herein with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates, or in an aqueous medium followed by lyophilization.
  • the compounds of the present invention which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid; for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2- hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (
  • the compounds of the present invention which contain an acidic moiety, such as but not limited to a phenol or carboxylic acid, may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine, and the like.
  • organic bases for example, organic amines
  • organic amines such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glycamides, t-butyl amines, and salt
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibutyl, and diamyl s
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term “prodrug” as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and/or solvate thereof.
  • Solvates of the compounds of the present invention include, for example, hydrates.
  • Compounds of the present invention, and salts or solvates thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of the compound includes the tautomeric forms thereof.
  • All stereoisomers of the present compounds are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations.
  • racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • the individual optical isomers can be 39 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% of the compounds (“substantially pure” compounds), which is then used or formulated as described herein. Such “substantially pure” compounds of the present invention are also contemplated herein as part of the present invention. [0170] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, 40 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios (by moles or weights) are all contemplated by the present invention.
  • the present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H (D), 3 H (T), 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds of the present invention or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labeled compounds of the present invention for example, those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H (T), and carbon- 14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically-labeled reagent.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • this invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of proliferative disorders.
  • stable preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • cancer and, equivalently, “tumor” refer to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject.
  • the cancer can be a malignant or non-malignant cancer.
  • Cancers or tumors include, but are not limited to, biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial neoplasms; leukemias; lymphomas; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; as well as other carcinomas and sarcomas. Cancers can be primary or metastatic.
  • Non-cancer diseases may include: neurofibromatosis; Leopard syndrome; Noonan syndrome; Legius syndrome; Costello 42 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 syndrome; cardio-facio-cutaneous syndrome; hereditary gingival fibromatosis type 1; autoimmune lymphoproliferative syndrome; and capillary malformation-arterovenous malformation.
  • “effective amount” refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome.
  • an effective amount is a therapeutically effective amount.
  • a therapeutically effective amount is any amount that is necessary or sufficient for promoting or achieving a desired biological response in a subject.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation.
  • the term “subject” refers to a vertebrate animal. In one embodiment, the subject is a mammal or a mammalian species. In one embodiment, the subject is a human.
  • the subject is a non-human vertebrate animal, including, without limitation, non-human primates, laboratory animals, livestock, racehorses, domesticated animals, and non-domesticated animals.
  • Compounds [0181] Novel compounds as TRPA1 inhibitors are described. It has been surprisingly discovered that the compounds disclosed herein exhibit TRPA1 inhibiting properties. Additionally, it has been surprisingly discovered that the compounds disclosed herein selectively block TRPA1 and do not block the hERG channel, and thus have desirable cardiovascular safety profiles. [0182] In one aspect, a compound having a structure of Formula I or II is described ( the various substituents are defined herein. The compounds of Formula I or II described herein can block or inhibit TRPA1 and be used in the treatment of a variety of conditions.
  • compositions and 43 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 methods of using these compositions described herein are useful for treating conditions in vitro and in vivo.
  • Such compounds, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for treating pain, a skin disorder, a respiratory disease, a fibrotic disease, an inner ear disorder, fever or another disorder of thermoregulation, a urinary tract disorder, an autoimmune disease, ischemia, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, and a cardiovascular disorder, or a combination thereof.
  • CNS central nervous system
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described, wherein X is a direct bond or CR8R8’; Y1 is a direct bond, CR3R3’, NR9, O, or S; Y 2 is a direct bond, CR 4 R 4 ’, NR 10 , O, or S; wherein when Y 1 is NR 9 , O, or S, Y 2 is a direct bond or CR4R4’; and when Y2 is NR10, O, or S, Y1 is a direct bond or CR3R3’; provided that Y1 and Y2 cannot both be direct bonds; R 1 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroary
  • n is 2. In other embodiments, n is 3. [0185] in some embodiments, each occurrence of R 5 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen. In some embodiments, each occurrence of R5 is independently cycloalkyl, halogenated cycloalkyl, -C 1-4 alkyl-OR a , or CN. In other embodiments, each occurrence of R 5 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.
  • R5 is independently H, D, ORa (e.g., OH, OMe, or OEt), or halogen (e.g., F, Cl, or Br). [0186] In some embodiments, at least one occurrence of R 5 is H or D. In some embodiments, at least one occurrence of R5 is ORa, e.g., OH, OMe, or OEt. In some embodiments, at least one occurrence of R5 is -C1-4alkyl-ORa, e.g., CH2OH, CH2CH2OH, or CH2OCH3. In some embodiments, at least one occurrence of R 5 is alkyl.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • at least one occurrence of R5 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • at least one occurrence of R 5 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • At least one occurrence of R5 is halogenated alkyl.
  • halogenated alkyl include CF3, CH2F, CHF2, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH2CH2CF3, and CHClCHClCH3.
  • at least one occurrence of R5 is halogenated cycloalkyl.
  • halogenated cycloalkyl include [0187]
  • each occurrence of R5 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or halogenated alkyl (e.g., fluorinated alkyl).
  • each 48 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 occurrence of R5 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • R5 is independently H, D, OH, F, Cl, or Br.
  • R5 is independently H, D, OH, or F.
  • R 5 is independently H, D, or OH.
  • each occurrence of R6 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen.
  • each occurrence of R 6 is independently cycloalkyl, halogenated cycloalkyl, -C 1-4 alkyl-OR a , or CN.
  • each occurrence of R 6 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.
  • R6 is independently H, D, OR a (e.g., OH, OMe, or OEt), halogen (e.g., F, Cl, or Br).
  • at least one occurrence of R 6 is H or D.
  • at least one occurrence of R6 is ORa, e.g., OH, OMe, or OEt.
  • at least one occurrence of R6 is -C1-4alkyl-ORa, e.g., CH2OH, CH2CH2OH, or CH2OCH3.
  • at least one occurrence of R 6 is alkyl.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • at least one occurrence of R6 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • at least one occurrence of R 6 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • At least one occurrence of R6 is halogenated alkyl.
  • halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH2CH2CF3, and CHClCHClCH3.
  • at least one occurrence of R6 is halogenated cycloalkyl.
  • halogenated cycloalkyl include [0189]
  • each occurrence of R6 is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or halogenated alkyl (e.g., fluorinated alkyl).
  • each occurrence of R6 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • R6 is independently H, D, OH, F, 49 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Cl, or Br.
  • each occurrence of R6 independently is H, D, OH, or F. In further embodiments, each occurrence of R6 independently is H, D, or OH. [0190] In some embodiments, L1 is selected from the group consisting of –CH2–CH2–, , .
  • L1 is selected from the group consisting of –CH2–CH2–, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH(OH)– [0191] In some embodiments, L1 is selected from the group consisting of –CH2–CH2–, 50 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 embodiments, L 1 is In some embodiments, L 1 is halogenated alkylene, such as fluorinated alkylene, e.g., , , or .
  • L1 is selected from the group consisting of –CH2–CH2–CH2–, –CH(CH3)–CH2–CH2–, –CH2–CH(CH3)–CH2–, –CH2–CH2–CH(CH3)–, –CH2–C(CH3)2– CH 2 –, –C(CH 3 ) 2 –CH 2 –CH 2 –, –CH(OH)–CH 2 –CH 2 –, –CH 2 –CH(OH)–CH 2 –, and –CH 2 –CH 2 – CH(OH)–.
  • R7 is H, D, alkyl, or -C1-4alkyl-ORa.
  • R 7 is H, D, or alkyl. In some embodiments, R 7 is H or D. In some embodiments, R 7 is H. In other embodiments, R 7 is D. In some embodiments, R 7 is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R7 is H, D, CH3, or CH 2 CH 3 . In some embodiments, R 7 is H, CH 3 , or CH 2 CH 3 .
  • R 7 is – CH2–OH, –CH2–OCH3, –CH2–CH2–OH, –CH2–CH2–OMe, –CH2–CH2–CH2–OH, or –CH2– CH2–CH2–OMe.
  • R7 is H, D, CH3, CH2CH3, or CH2OCH3.
  • R 7 is H, D, CH 3 , or CH 2 OCH 3 .
  • R 7 is H, CH 3 , or CH 2 CH 3 .
  • R7’ is H, D, alkyl, or -C1-4alkyl-ORa.
  • R 7 ’ is H, D, or alkyl. In some embodiments, R 7 ’ is independently H or D. In some embodiments, R 7 ’ is H. In other embodiments, R 7 ’ is D. In some embodiments, R 7 ’ is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R7’ is H, D, CH3, or CH 2 CH 3 . In some embodiments, R 7 ’ is H, CH 3 , or CH 2 CH 3 .
  • R 7 ’ is – CH2–OH, –CH2–OCH3, –CH2–CH2–OH, –CH2–CH2–OMe, –CH2–CH2–CH2–OH, or –CH2– CH2–CH2–OMe.
  • R7’ is H, D, CH3, CH2CH3, or CH2OCH3.
  • R 7 ’ is H, D, CH 3 , or CH 2 OCH 3 .
  • R 7 ’ is H, CH 3 , or CH 2 CH 3 .
  • ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024
  • L1 is selected from the group consisting of –CH2–CH2–, – is –CH 2 –.
  • L 1 is selected from the group consisting of –CH 2 – some embodiments, L1 is –CH2–CH2– and is –CH2–.
  • L1 is selected from the group consisting some embodiments, In some embodiments, [0197] In some embodiments, is an optionally substituted aryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • a in some embodiments is phenyl which is optionally substituted with by 1-3 substituents each independently selected from the group consisting of alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, or heteroaryl.
  • phenyl which is optionally substituted with by 1-3 substituents each independently selected from the group consisting of H, D, halogen, alkyl, CN, OR a , SR a , A or NR a R b .
  • alkyl e.g., CH3, CH2CH3
  • ORa e.g., OH, OCH3,
  • halogen e.g., F, Cl, Br, I
  • -C1-4alkyl-ORa e.g., CH2OCH3
  • halogenated alkyl e.g
  • phenyl which is substituted with at least one alkyl or alkoxy.
  • 53 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0199]
  • phenyl substituted with 1-5 halogens e.g., embodiments, .
  • [0200] In some embodiments, is a heteroaryl.
  • 6-membered heteroaryl which is optionally substituted with by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, ORa, SRa, A NR a R b , -C 1-4 alkyl-SR a , and -C 1-4 alkyl-OR a .
  • Non-limiting examples of 5-membered 55 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 is selected from the group is selected from the group [0202]
  • Non-limiting examples of bicyclic or tricyclic rings include biphenyl, naphthyl, phenanthrenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), carbazolyl, phenanthrolinyl, acridinyl, and phenanthridinyl.
  • X is a direct bond.
  • X is CR 8 R 8 ’.
  • R 8 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R8 is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, aryl, heteroaryl, or halogenated alkyl.
  • R8 is alkynyl, halogenated alkynyl, saturated heterocycle, partially saturated heterocycle, alkylaryl, or alkylheteroaryl.
  • R8 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 8 is alkyl or halogenated alkyl.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R8 is D.
  • R8 is cycloalkyl or halogenated cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non-limiting examples of halogenated cycloalkyl substituted aryl or alkylaryl include phenyl, biphenyl, 57 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 naphthyl, anthracenyl, and the like.
  • Non-limiting examples of alkylaryl include , the like.
  • R 8 is H.
  • R8 is aryl.
  • R8 is phenyl.
  • R8 is heteroaryl.
  • R8 is selected from the group consisting of , [0206]
  • R 8 ’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R 8 ’ is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, aryl, heteroaryl, or halogenated alkyl.
  • R8’ is alkynyl, halogenated alkynyl, saturated heterocycle, partially saturated heterocycle, alkylaryl, or alkylheteroaryl. In some embodiments, R8’ is halogen. 58 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R8’ is alkyl or halogenated alkyl.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R 8 ’ is D.
  • R 8 ’ is cycloalkyl or halogenated cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non-limiting examples of halogenated cycloalkyl some embodiments, R8’ is optionally substituted aryl or alkylaryl.
  • Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • Non-limiting examples of alkylaryl include , the like.
  • R8’ is H.
  • R 8 ’ is aryl.
  • R 8 ’ is phenyl.
  • R 8 ’ is heteroaryl.
  • R 8 ’ is selected from the group consisting of , 59 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0207]
  • Y 1 is a direct bond, CR 3 R 3 ’, NR 9 , O, or S. In some embodiments, Y 1 is a direct bond or CR 3 R 3 ’. In some embodiments, Y 1 is NR 9 , O, or S. In some embodiments, Y1 is NR9 or O. In some embodiments, Y1 is NR9. In some embodiments, Y 1 is O.
  • Y2 is a direct bond, CR4R4’, NR10, O, or S. In some embodiments, Y 2 is a direct bond or CR 4 R 4 ’. In some embodiments, Y 2 is NR 10 , O, or S. In some embodiments, Y 2 is NR 10 or O. In some embodiments, Y 2 is NR 10 . In some embodiments, Y2 is O. [0209] In some embodiments, Y1 is a direct bond; and Y2 is CR4R4’, NR10, O, or S. In some embodiments, Y1 is a direct bond; and Y2 is CR4R4’.
  • Y1 is CR3R3’; and Y 2 is CR 4 R 4 ’, NR 10 , O, or S.
  • Y 1 is CR 3 R 3 ’; and Y 2 is CR 4 R 4 ’.
  • Y 1 is CR 3 R 3 ’; and Y 2 is NR 10 .
  • Y 1 is CR 3 R 3 ’; and Y2 is O, or S.
  • Y1 is NR9, O, or S; and Y2 is CR4R4’.
  • Y2 is a direct bond; and Y1 is CR3R3’, NR9, O, or S.
  • Y2 is a direct bond; and Y1 is CR3R3’. In some embodiments, Y2 is CR4R4’; and Y 1 is CR 3 R 3 ’, NR 9 , O, or S. In some embodiments, Y 2 is CR 4 R 4 ’; and Y 1 is CR 3 R 3 ’. In some embodiments, Y 2 is CR 4 R 4 ’; and Y 1 is NR 9 . In some embodiments, Y 2 is CR 4 R 4 ’; and Y1 is O, or S. In some embodiments, Y2 is NR10, O, or S; and Y1 is CR3R3’.
  • R1 is H, D, or alkyl.
  • R1 is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2.
  • alkyl examples include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 1 is D.
  • R 1 is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R 1 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 1 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 1 is halogenated alkyl.
  • Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R 1 is halogenated cycloalkyl.
  • R 1 is OR a , SR a , or NR a R b .
  • R1 is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1- 4 alkyl-CONR a R b , or -C 1-4 alkyl-NR a COR b .
  • R 1 is NH 2 , CH 2 NH 2 , or CH 2 CH 2 NH 2 . In other specific embodiments, R1 is OH, CH2OH, or CH2CH2OH. [0215] In still other embodiments, R 1 is an optionally substituted 4-, 5-, 6- or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S. In further embodiments, R1 is optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • R1 is an N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • N-containing heterocycle, partially saturated heterocycle 62 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0216]
  • R 1 is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R 1 is selected from the group consisting of H, D, CH 3 , CH2CH3, OH, F, Cl, Br, I, OCH3, CF3, CH2F, CHF2, CN, NH2, NHCH3, N(CH3)2, , 63 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0218] In some embodiments, R 1 is selected from the group consisting of H, D, Cl, Br, F, I, CN, CH3, CH2CH3, CF3, CH2CH2CH3, CH(CH3)2, , , , and .
  • R1’ is H, D, or alkyl.
  • R1’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R1’ is D.
  • R1’ is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R 1 ’ is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 1 ’ is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 1 ’ is halogenated alkyl.
  • Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 1 ’ is halogenated cycloalkyl.
  • R1’ is ORa, SRa, or NR a R b .
  • R1’ is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.
  • R 1 ’ is NH 2 , CH 2 NH 2 , or CH 2 CH 2 NH 2 .
  • R1’ is OH, CH2OH, or CH2CH2OH.
  • R1’ is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R 1 ’ is optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • R 1 ’ is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R1’ is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • R1’ is selected from the group consisting of H, D, CH3, 67 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 is selected from the group consisting of H, D, CH 3 , CH 2 CH 3 , CF 2 H, CH 2 F, CF 3 , CN, Cl, Br, [0226]
  • R 1 ’ is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R 1 ’ is H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl.
  • R1 and R1’ together with the carbon atom that they are connected to, form a 3- to 7-membered cycloalkyl ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl).
  • cycloalkyl ring e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • 68 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 .
  • R 1 and R 1 ’ together with the carbon atom that they are connected to, form a 3- to 7-membered saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S (e.g., azetidinyl, pyrrodidinyl, piperidinyl, oxetanyl, oxolanyl, or thianyl ring).
  • the 3- to 7-membered cycloalkyl ring or saturated heterocycle formed by R1 and R1’ together with the carbon atom they are connected to is substituted by one or more substituents each independently selected from the group consisting of alkyl (e.g., methyl, ethyl, propyl, or butyl), halogenated alkyl (e.g., CF3), halogen (e.g., F, Cl, Br, or I), CN, ORx (e.g., OH, OCH3), -(CH2)1-2ORx (e.g., CH2OH), or N(Rx)2 (e.g., NH2, NHCH3, N(CH3)2).
  • alkyl e.g., methyl, ethyl, propyl, or butyl
  • halogenated alkyl e.g., CF3
  • halogen e.g., F, Cl, Br, or I
  • CN e.g.
  • R 2 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R2 is H, D, or halogen.
  • R 2 is H, D, or alkyl.
  • R 2 is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2.
  • alkyl examples include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 2 is D.
  • R 2 is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2.
  • alkynyl examples include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R 2 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R2 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 2 is halogenated alkyl.
  • Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R 2 is halogenated cycloalkyl.
  • R 2 is an optionally substituted 4-, 5-, 6- or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R2 is selected from the group consisting of , optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • R2 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • Non-limiting examples of N-containing heterocycle, partially saturated heterocycle, and heteroaryl include 70 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0233]
  • R2 is optionally substituted aryl or alkylaryl.
  • Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • Non-limiting examples of alkylaryl include the like.
  • R2 is selected from the group consisting of H, D, Cl, Br, F, I, CH 3 , CH 2 CH 3 , CF 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 .
  • R 2 is H, D, Cl, Br, or F.
  • R2’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R 2 ’ is H, D, or halogen.
  • R 2 ’ is H, D, or alkyl.
  • R 2 ’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 2 ’ is D.
  • R 2 ’ is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R 2 ’ is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R2’ is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 2 is halogenated alkyl.
  • Non- limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R 2 ’ is halogenated cycloalkyl.
  • R2’ is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R2’ is selected from the group consisting of , 72 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R 2 ’ is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • N-containing heterocycle, partially saturated heterocycle 73 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0238]
  • R2’ is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R2’ is selected from the group consisting of H, D, Cl, Br, F, I, CH 3 , CH 2 CH 3 , CF 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 .
  • R 2 ’ is H, D, Cl, Br, or F.
  • R 3 is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH 2 .
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 3 is D.
  • R 3 is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH 2 .
  • Non-limiting examples of 74 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R3 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R3 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R3 is halogenated alkyl.
  • Non- limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R3 is halogenated cycloalkyl.
  • R 3 is OR a , SR a , or NR a R b .
  • R3 is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1- 4 alkyl-CONR a R b , or -C 1-4 alkyl-NR a COR b .
  • R 3 is NH 2 , CH 2 NH 2 , or CH 2 CH 2 NH 2 .
  • R3 is OH, CH2OH, or CH2CH2OH.
  • R 3 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R3 is selected from the group consisting of , 75 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R3 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • N-containing heterocycle, partially saturated heterocycle and [0245]
  • R3 is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R3 is selected from the group consisting of H, D, CH3, 77 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0247] In some embodiments, R3 is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R3 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R3 is H, D, Cl, Br, or F. In some embodiments, R3 is OH.
  • R3’ is H, D, or alkyl.
  • R3’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 3 ’ is D.
  • R 3 ’ is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R 3 ’ is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 3 ’ is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 3 is halogenated alkyl.
  • Non- 78 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R 3 ’ is halogenated cycloalkyl.
  • R3’ is ORa, SRa, or NR a R b .
  • R 3 ’ is -C 1-4 alkyl-OR a , -C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1-4 alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.
  • R3’ is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R 3 ’ is OH, CH 2 OH, or CH 2 CH 2 OH. [0252] In still other embodiments, R3’ is an optionally substituted 4-, 5-, 6- or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S. In further embodiments, R 3 ’ is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R 3 ’ is a N-containing heterocycle, partially saturated heterocycle, or 79 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • N-containing heterocycle, partially saturated heterocycle [0253]
  • R 3 ’ is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R 3 ’ is selected from the group consisting of H, D, CH 3 , CH2CH3, OH, F, Cl, Br, I, OCH3, CF3, CH2F, CHF2, CN, NH2, NHCH3, N(CH3)2, , 80 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, [0255] In some embodiments, R3’ is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R3’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • R3’ is H, D, Cl, Br, or F. In some embodiments, R3’ is OH. 81 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0256]
  • Non- limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3.
  • R 2 and R 3 together with the carbon atoms they are connected to, form a 3- to 7-membered cycloalkyl ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl).
  • the 3- to 7-membered cycloalkyl ring or saturated heterocycle formed by R 2 and R 3 together with the carbon atoms they are connected to is substituted by one or more substituents each independently selected from the group consisting of alkyl (e.g., methyl, ethyl, propyl, or butyl), halogenated alkyl (e.g., CF3), halogen (e.g., F, Cl, Br, or I), CN, OR x (e.g., OH, OCH 3 ), -(CH 2 ) 1-2 OR x (e.g., CH 2 OH), or N(R x ) 2 (e.g., NH 2 , NHCH 3 , N(CH 3 ) 2 ) .
  • substituents each independently selected from the group consisting of alkyl (e.g., methyl, ethyl, propyl, or butyl), halogenated alkyl (e.g.,
  • R4 is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH 2 .
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R4 is D.
  • R4 is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH 2 .
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R4 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 4 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R4 is halogenated alkyl.
  • Non- limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R4 is halogenated cycloalkyl.
  • R 4 is OR a , SR a , or NR a R b .
  • R4 is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1- 4 alkyl-CONR a R b , or -C 1-4 alkyl-NR a COR b .
  • R4 is NH2, CH2NH2, or CH2CH2NH2.
  • R4 is OH, CH2OH, or CH2CH2OH.
  • R 4 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R4 is selected from the group consisting of , optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • R4 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R 4 is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • R 4 is selected from the group consisting of H, D, CH 3 , 85 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, [0265] In some embodiments, R4 is selected from the group consisting of H, D, Cl, Br, F, I, CN, CH 3 , CH 2 CH 3 , CF 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , , , , and .
  • R4 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R4 is H, D, Cl, Br, or F. In some embodiments, R4 is OH.
  • R4’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH 2 .
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R4’ is D.
  • R4’ is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R4’ is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 4 ’ is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 4 ’ is halogenated alkyl.
  • Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 4 ’ is halogenated cycloalkyl.
  • R4’ is ORa, SRa, or NR a R b .
  • R 4 ’ is -C 1-4 alkyl-OR a , -C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1-4 alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.
  • R4’ is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R4’ is OH, CH2OH, or CH2CH2OH. [0270] In still other embodiments, R 4 ’ is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S. In further embodiments, R4’ is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R4’ is an N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • N-containing heterocycle, partially saturated heterocycle 88 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0271]
  • R 4 ’ is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R 4 ’ is selected from the group consisting of H, D, CH 3 , 89 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, [0273]
  • R 4 ’ is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R 4 ’ is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R 4 ’ is H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R 4 ’ is H, D, Cl, Br, or F. In some embodiments, R 4 ’ is OH.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non-limiting examples of 90 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 halogen include F, Cl, Br, and I.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3.
  • R 1 and R 4 together with the carbon atoms they are connected to, form a 3- to 7-membered cycloalkyl ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl).
  • R1 and R4 together with the carbon atoms they are connected to, form a 3- to 7-membered saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, R1 and R4, together with the carbon atoms that they are connected to, form a cyclopropyl group.
  • the 3- to 7-membered cycloalkyl ring or saturated heterocycle formed by R 1 and R 4 together with the carbon atoms they are connected to is substituted by one or more substituents each independently selected from the group consisting of alkyl (e.g., methyl, ethyl, propyl, or butyl), halogenated alkyl (e.g., CF3), halogen (e.g., F, Cl, Br, or I), CN, OR x (e.g., OH, OCH 3 ), -(CH 2 ) 1-2 OR x (e.g., CH 2 OH), or N(R x ) 2 (e.g., NH 2 , NHCH 3 , N(CH 3 ) 2 ) .
  • substituents each independently selected from the group consisting of alkyl (e.g., methyl, ethyl, propyl, or butyl), halogenated alkyl (e.g.,
  • Non- limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec- butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • Non-limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R3 and R4 together with the carbon atoms they are connected to, form a 3- to 7-membered cycloalkyl ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl).
  • R 3 and R 4 together with the carbon atoms they are connected to, form a 3- to 7-membered saturated heterocycle comprising 0-3 91 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 heteroatoms each selected from the group consisting of N, O, and S.
  • R3 and R4 together with the carbon atoms that they are connected to, form a cyclopropyl group.
  • the 3- to 7-membered cycloalkyl ring or saturated heterocycle formed by R3 and R4 together with the carbon atoms they are connected to is substituted by one or more substituents each independently selected from the group consisting of alkyl (e.g., methyl, ethyl, propyl, or butyl), halogenated alkyl (e.g., CF 3 ), halogen (e.g., F, Cl, Br, or I), CN, OR x (e.g., OH, OCH 3 ), -(CH 2 ) 1-2 OR x (e.g., CH 2 OH), or N(R x ) 2 (e.g., NH 2 , NHCH 3 , N(CH3)2).
  • substituents each independently selected from the group consisting of alkyl (e.g., methyl, ethyl, propyl, or butyl), halogenated alkyl (e.g., CF 3 ),
  • R 9 is H, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, C 1-4 alkyl-OR a , - C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, -C1-4alkyl- NRaCORb, or -C1-4alkyl-saturated heterocycle.
  • R9 is H, CF3, CH2F, CHF 2 , -C 1-4 alkyl-OR a , -C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-COOR a , -C 1-4 alkyl- CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle.
  • R9 is H or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH 2 .
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R9 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 9 is halogenated alkyl.
  • halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 9 is 92 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 halogenated cycloalkyl.
  • Non-limiting examples of halogenated cycloalkyl include [0281]
  • R9 is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1- 4alkyl-COORa, -C1-4alkyl-CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle.
  • R9 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R 9 is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R 9 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • R9 is optionally substituted aryl or alkylaryl.
  • R9 is selected from the group consisting of H, CH3, CH2CH3, 94 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 .
  • R 9 is selected from the group consisting of H, CH 3 , [0285] In some embodiments, R 9 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , [0286]
  • R10 is H, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, C1-4alkyl-ORa, - C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-COOR a , -C 1-4 alkyl-CONR a R b , -C 1-4 alkyl- NR a COR b , or -C 1-4 alkyl-saturated heterocycle.
  • R 10 is H, CF 3 , CH 2 F, CHF2, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl- CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, 95 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 heptyl, and octyl.
  • R10 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 10 is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R10 is halogenated cycloalkyl.
  • Non-limiting examples of halogenated cycloalkyl include [0288]
  • R 10 is -C 1-4 alkyl-OR a , -C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1- 4 alkyl-COOR a , -C 1-4 alkyl-CONR a R b , -C 1-4 alkyl-NR a COR b , or -C 1-4 alkyl-saturated heterocycle.
  • R 10 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R10 is optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • R10 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence 96 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 permits.
  • R10 is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R 10 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , 97 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 .
  • R10 is selected from the group consisting of H, CH3, [0292] In some embodiments, R10 is selected from the group consisting of H, CH3, CH2CH3, [0293] In some embodiments, selected from the group consisting of 98 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0294] In some embodiments, selected from the group consisting of [0295] In some embodiments, selected from the group consisting of 99 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0296] In some embodiments, the compound of Formula I has the structure of Formula Ia: , wherein R5a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R 5b is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 6a is H, D, alkyl, hal
  • R5a is H or D.
  • R5a is ORa, e.g., OH or OCH3.
  • R5a is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl.
  • R 5a is halogen, e.g., F, 100 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Cl, Br, or I.
  • R5a is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, or CF2CH3, or CH2CHF2.
  • R 5b is H or D.
  • R 5b is OR a , e.g., OH or OCH3.
  • R5b is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl.
  • R5b is halogen, e.g., F, Cl, Br, or I.
  • R 5b is fluorinated alkyl, e.g., CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CHFCH 3 , CF 2 CH 3 , or CH 2 CHF 2 .
  • R6a is H or D.
  • R6a is ORa, e.g., OH or OCH 3 .
  • R 6a is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl.
  • R 6a is halogen, e.g., F, Cl, Br, or I.
  • R6a is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.
  • R 6b is H or D.
  • R 6b is OR a , e.g., OH or OCH3.
  • R6b is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl.
  • R6b is halogen, e.g., F, Cl, Br, or I.
  • R 6b is fluorinated alkyl, e.g., CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CHFCH 3 , CF 2 CH 3 , or CH 2 CHF 2 .
  • 101 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 CH(CH 2 )–, or -C(CH 3 ) 2 –CH 2 –.
  • the compound of Formula I has the structure of Formula Ib: , wherein R 5a is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 5b is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R6a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R6b is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R21 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R22 is H,
  • X, Y1, Y2, R1, R1’, R2, R2’, R7, and R7’ in Formula Ib are as defined above for the compound of Formula I.
  • R 5a , R 5b , R 6a , and R 6b in Formula Ib are as defined above for the compound of Formula Ia.
  • Other substituents are defined herein.
  • at least one of R 21 , R 22 , R 24 , and R 25 is not H. In some embodiments, at least two of R21, R22, R24, and R25 are not H.
  • At least one of R 21 , R 22 , R 24 , and R 25 is H, D, alkyl, halogenated alkyl, or halogen. In some embodiments, at least one of R 21 , R 22 , R 24 , and R 25 is CN, OR a , SR a , NR a R b , -C 1-4 alkyl-SR a , or -C1-4alkyl-ORa. In some embodiments, at least one of R21, R22, R24, and R25 is ORa, SRa, or NRaRb.
  • At least one of R21, R22, R24, and R25 is H, D, halogen, fluorinated alkyl, alkyl, alkenyl, or alkynyl.
  • at least one of R 21 , R 22 , In some embodiments, at least one of R 21 , R 22 , R 24 , and R 25 is H, Me, Et, i-Pr, n-Bu, CF 2 H, CF2Cl, or CF3.
  • at least one of R21, R22, R24, and R25 is OH, OCH3, CH2OCH3.
  • at least one of R21, R22, R24, and R25 is Cl, F, Br, or I.
  • At least one of R 21 , R 22 , R 24 , and R 25 is Cl. In some embodiments, at least one of R 21 , R 22 , R 24 , and R 25 is CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, or CHClCHClCH3.
  • At embodiments, at least one of R21, R22, R24, and R25 is ethylenyl, propenyl, 2-propenyl, (E)- but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but- 2-enyl, (Z)-pent-2-enyl, or (E)-pent-1-enyl.
  • At least one of R 21 , R 22 , R24, and R25 is ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2- ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • at least one of R21, R22, R 24 , and R 25 is CN.
  • R 21 , R 22 , R 24 , and R 25 are 103 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 independently selected from the group consisting of CH3, CH2CH3, OH, F, Cl, Br, OCH3, [0306]
  • R 21 , R 22 , R 24 , and R 25 are H; and R 23 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa.
  • R21, R22, R24, and R25 are H; and R23 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SR a , NR a R b , or -C 1-4 alkyl-OR a .
  • R 21 , R 22 , R 24 , and R 25 are H; and R 23 is H or D.
  • R21, R22, R24, and R25 are H; and R23 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, or -C1-4alkyl-ORa.
  • R21, R 22 , R 24 , and R 25 are H; and R 23 is H, D, halogen, or alkyl.
  • R 21 , R 22 , R 24 , and R 25 are H; and R 23 is OR a , SR a , or NR a R b .
  • R 21 , R 22 , R 24 , and R25 are H; and R23 is halogen.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • alkenyl include ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1- enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent- 1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non- limiting examples of halogen include F, Cl, Br, and I.
  • R 23 is alkyl (e.g., CH 3 , or CH 2 CH 3 ,), OR a , (e.g., OH or OCH 3 ), halogen (e.g., F, Cl, or Br), -C1-4alkyl-ORa (e.g., CH2OCH3), halogenated alkyl (e.g., CF3), CN, alkynyl (e.g., C ⁇ CH), or cycloalkyl (e.g., In some embodiments, R 23 is CH 3 , certain embodiments, R 23 is halogen (e.g., F, Cl, or Br). In some embodiments, R 23 is Cl.
  • OR a e.g., OH or OCH 3
  • halogen e.g., F, Cl, or Br
  • -C1-4alkyl-ORa e.g., CH2OCH3
  • halogenated alkyl e.g., CF3
  • CN al
  • R 23 is Br.
  • R 21 , R 22 , R 24 , and R 25 are H; and R 23 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa.
  • R21, R22, R24, and R25 are H; R23 is CH3, CH2CH3, OH, F, Cl, Br, OCH3, 104 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 some embodiments, R21, R22, R24, and R25 are H; R 23 is halogen. In some embodiments, R 21 , R 22 , R 24 , and R 25 are H; R 23 is Cl. In some embodiments, R21, R22, R24, and R25 are H; R23 is F. In some embodiments, R21, R22, R24, and R25 are H; R23 is Br.
  • the compound of Formula I has the structure of Formula Ic or Id: , wherein each occurrence of R 5a is independently H, D, alkyl, halogen, OR a , or fluorinated alkyl; each occurrence of R 5b is independently H, D, alkyl, halogen, OR a , or fluorinated alkyl; each occurrence of R6a is independently H, D, alkyl, halogen, ORa, or fluorinated alkyl; each occurrence of R6b is independently H, D, alkyl, halogen, ORa, or fluorinated alkyl; each occurrence of R21 is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR a , SR a , NR a R b , -
  • Y1, Y2, R1, R1’, R2, R2’, R7, R7’ R8, and R8’ in Formula Ic or Id are as defined above for the compound of Formula I.
  • R 5a , R 5b , R 6a , and R 6b in Formula Ic or Id are as defined above for the compound of Formula Ia.
  • R21, R22, R23, R24, and R25 in Formula Ic or Id are as defined above for the compound of Formula Ib.
  • the compound of Formula I has the structure of Formula Ie: wherein R 5a is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 23 is H, D, halogen, alkyl, OR a , or NR a R b ; 106 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024
  • R 1 is H, D, halogen, alkyl, or OR a ;
  • R1’ is H, D, halogen, alkyl, or ORa;
  • R2 is H, D, halogen, alkyl, or ORa;
  • R3 is H, D, halogen, alkyl, or ORa;
  • R 4 is H, D, halogen, alkyl, or OR a ;
  • R 4 ’ is H, D, halogen, alkyl, or OR a ;
  • R8 is H, D, or alky
  • R1, R1’, R2, R3, R4, R4’ R8, and R10 in Formula Ie are as defined above for the compound of Formula I.
  • R5a in Formula Ie is as defined above for the compound of Formula Ia.
  • R 23 in Formula Ie is as defined above for the compound of Formula Ib.
  • a compound of Formula II or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described, wherein Z is NR 11 , O, or S; Q is a direct bond or CR 13 R 13 ’; 107 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024
  • R11 is H, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1- 4 alkyl-NR a R b , -C 1-4 alkyl-COOR a , -C 1-4 alkyl-CONR a R b , -C 1-4 alkyl-NR a COR b , or -C 1-4 alkyl-
  • each occurrence of R15 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, OR a , -C 1-4 alkyl-OR a , or halogen. In some embodiments, each occurrence of R 15 is independently cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or CN. In other embodiments, each occurrence of R15 is independently H, D, alkyl, halogen, OR a , or halogenated alkyl.
  • R 15 is independently H, D, OR a (e.g., OH, OMe, or OEt), or halogen (e.g., F, Cl, or Br).
  • at least one occurrence of R15 is H or D.
  • at least one occurrence of R15 is ORa, e.g., OH, OMe, or OEt.
  • at least one occurrence of R 15 is -C 1-4 alkyl-OR a , e.g., CH 2 OH, CH 2 CH 2 OH, or 109 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 CH2OCH3.
  • At least one occurrence of R15 is alkyl.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • at least one occurrence of R 15 is a cycloalkyl.
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • at least one occurrence of R 15 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • at least one occurrence of R 15 is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • at least one occurrence of R 15 is halogenated cycloalkyl.
  • each occurrence of R 15 is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or halogenated alkyl (e.g., fluorinated alkyl).
  • each occurrence of R15 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.
  • R 15 is independently H, D, OH, F, Cl, or Br.
  • R15 is independently H, D, OH, or F.
  • R15 is independently H, D, or OH.
  • each occurrence of R 16 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, OR a , -C 1-4 alkyl-OR a , or halogen.
  • each occurrence of R16 is independently cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or CN.
  • each occurrence of R16 is independently H, D, alkyl, halogen, OR a , or halogenated alkyl.
  • R 16 is independently H, D, ORa (e.g., OH, OMe, or OEt), or halogen (e.g., F, Cl, or Br). [0319] In some embodiments, at least one occurrence of R16 is H or D. In some embodiments, at least one occurrence of R 16 is OR a , e.g., OH, OMe, or OEt. In some embodiments, at least one occurrence of R16 is -C1-4alkyl-ORa, e.g., CH2OH, CH2CH2OH, or CH2OCH3. In some embodiments, at least one occurrence of R16 is alkyl.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, 110 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 pentyl, hexyl, heptyl, and octyl.
  • at least one occurrence of R16 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • At least one occurrence of R16 is halogen.
  • halogen include F, Cl, Br, and I.
  • at least one occurrence of R16 is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • at least one occurrence of R16 is halogenated cycloalkyl.
  • halogenated cycloalkyl include , [0320]
  • each occurrence of R16 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or halogenated alkyl (e.g., fluorinated alkyl).
  • each occurrence of R 15 is independently H, D, CH 3 , CH 2 CH 3 , OH, F, Cl, Br, or fluorinated alkyl.
  • R16 is independently H, D, OH, F, Cl, or Br.
  • R16 is independently H, D, OH, or F.
  • R16 is independently H, D, or OH.
  • L2 is selected from the group consisting of –CH2–CH2–, – .
  • L 2 is selected from the group consisting of –CH2–CH2–, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH(OH)– 111 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024
  • L2 is –CH2–CH2–.
  • L 2 is In some embodiments, L 2 is halogenated alkylene, such as fluorinated alkylene, e.g., .
  • L2 is selected from the group consisting of –CH2–CH2– CH2–, –CH(CH 3 )–CH 2 – CH 2 –, –CH 2 –CH(CH 3 )–CH 2 –, –CH 2 –CH 2 –CH(CH 3 )–, –CH 2 –C(CH 3 ) 2 – CH2–, –C(CH3)2–CH2–CH2–, –CH(OH)–CH2– CH2–, –CH2–CH(OH)–CH2–, and –CH2– CH2–CH(OH)–.
  • R14 is H, D, alkyl, or -C1-4alkyl-ORa. In some embodiments, R14 is H, D, or alkyl. In some embodiments, R14 is H or D. In some embodiments, R14 is H. In other embodiments, R 14 is D. In some embodiments, R 14 is alkyl.
  • Non-limiting examples 112 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R14 is H, D, CH3, or CH2CH3. In some embodiments, R 14 is H, CH 3 , or CH 2 CH 3 .
  • R 14 is –CH 2 –OH, –CH 2 – OCH3, –CH2–CH2–OH, –CH2–CH2–OMe, –CH2–CH2–CH2–OH, or –CH2–CH2–CH2–OMe.
  • R14 is H, D, CH3, CH2CH3, or CH2OCH3.
  • R14 is H, D, CH 3 , or CH 2 OCH 3 .
  • R 14 is H, CH 3 , or CH 2 CH 3 .
  • R 14 ’ is H, D, alkyl, or -C 1-4 alkyl-OR a .
  • R14’ is H, D, or alkyl. In some embodiments, R14’ is independently H or D. In some embodiments, R 14 ’ is H. In other embodiments, R 14 ’ is D. In some embodiments, R 14 ’ is alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R14’ is H, D, CH3, or CH2CH3. In some embodiments, R14’ is H, CH3, or CH2CH3.
  • R14’ is –CH 2 –OH, –CH 2 –OCH 3 , –CH 2 –CH 2 –OH, –CH 2 –CH 2 –OMe, –CH 2 –CH 2 –CH 2 –OH, or – CH2–CH2–CH2–OMe.
  • R14’ is H, D, CH3, CH2CH3, or CH2OCH3.
  • R14’ is H, D, CH3, or CH2OCH3.
  • R14’ is H, CH3, or CH 2 CH 3 .
  • L2 is selected from the group consisting of –CH2 –, – CH(CH3)–, –C(CH3)2–, and –CH(CH2CH3)–.
  • L2 is selected from the group consisting of –CH2–CH2–, – is –CH 2 –.
  • L 2 is selected from the group consisting of – 113 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 some embodiments, L2 is –CH2–CH2– and is –CH2–.
  • L2 is selected from the group consisting of ; and [0328] In some embodiments, is an optionally substituted aryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • phenyl which is optionally substituted with by 1-3 substituents each independently selected from the group consisting of H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa.
  • 6-membered heteroaryl which is optionally substituted with by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, and -C1-4alkyl-ORa.
  • Non-limiting examples of 5- membered heteroaryl include . 116 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 117 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0333]
  • Non-limiting examples of bicyclic or tricyclic rings include biphenyl, naphthyl, phenanthrenyl, indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), carbazolyl, phenanthrolinyl, acridinyl, and phenanthridinyl.
  • substituents each independently selected from the group consisting of H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, and -C1-4alkyl-ORa.
  • 118 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0335]
  • Z is NR11.
  • Z is O.
  • Z is S.
  • Q is a direct bond. In some embodiments, Q is CR13R13’.
  • Z is NR11; and Q is a direct bond. In some embodiments, Z is NR11; and Q is CR13R13’. In some embodiments, Z is O or S; and Q is a direct bond. In some embodiments, Z is O or S; and Q is CR 13 R 13 ’.
  • R 11 is H, alkyl, cycloalkyl, halogenated alkyl, halogenated cycloalkyl, saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, C1-4alkyl-ORa, - C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1-4 alkyl-COOR a , -C 1-4 alkyl-CONR a R b , -C 1-4 alkyl- NR a COR b , or -C 1-4 alkyl-saturated heterocycle.
  • R 11 is H, CF 3 , CH 2 F, CHF2, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl- CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R 11 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R11 is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 11 is halogenated cycloalkyl.
  • Non-limiting examples of halogenated cycloalkyl include 119 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0340]
  • R11 is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1- 4alkyl-COORa, -C1-4alkyl-CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle.
  • R 11 is an optionally substituted 4-, 5-, 6- or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R11 is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R11 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH 2 , or oxo where valence permits.
  • R 11 is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R 11 is optionally substituted heteroaryl.
  • Non-limiting examples of heteroaryl include the like.
  • 122 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0346]
  • R12 is H, D, or alkyl.
  • R12 is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R12 is D.
  • R12 is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent- 2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R 12 is a cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 12 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 12 is halogenated alkyl.
  • Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R 12 is halogenated cycloalkyl.
  • R12 is ORa, SRa, or NR a R b .
  • R 12 is -C 1-4 alkyl-OR a , -C 1-4 alkyl-SR a , -C 1-4 alkyl-NR a R b , -C 1-4 alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.
  • R12 is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R 12 is OH, CH 2 OH, or CH 2 CH 2 OH. [0349] In still other embodiments, R12 is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R 12 is selected from the group consisting of , 123 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R 12 is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R12 is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R12 is selected from the group consisting of H, D, CH3, 125 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 some embodiments, R 12 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, [0352] In some embodiments, R12 is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R12 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R12 is H, D, Cl, Br, or F.
  • R12’ is H, D, or alkyl.
  • R12’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH 2 .
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • R12’ is D.
  • 126 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R12’ is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2.
  • alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2- ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • R12’ is a cycloalkyl.
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R12’ is halogen.
  • halogen include F, Cl, Br, and I.
  • R 12 ’ is halogenated alkyl.
  • Non-limiting examples of halogenated alkyl include CF 3 , CH 2 F, CHF 2 , CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R 12 ’ is halogenated cycloalkyl.
  • R12’ is ORa, SRa, or NR a R b .
  • R12’ is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.
  • R 12 ’ is NH 2 , CH 2 NH 2 , or CH 2 CH 2 NH 2 . In other specific embodiments, R 12 ’ is OH, CH 2 OH, or CH 2 CH 2 OH. [0357] In still other embodiments, R12’ is an optionally substituted 4-, 5-, 6-, or 7-membered heterocycle, partially saturated heterocycle, or heteroaryl, each containing 1-3 heteroatoms each selected from the group consisting of N, O, and S.
  • R 12 ’ is selected from the group consisting of , 127 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R 12 ’ is a N-containing heterocycle, partially saturated heterocycle, or heteroaryl, wherein each is optionally substituted by alkyl, OH, NH2, or oxo where valence permits.
  • R12’ is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • alkylaryl include the like.
  • R12’ is selected from the group consisting of H, D, CH3, 129 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br, [0360]
  • R12’ is selected from the group consisting of H, D, Cl, Br, F, I, some embodiments, R12’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R12’ is H, D, Cl, Br, or F.
  • R 13 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R13 is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, aryl, heteroaryl, or halogenated alkyl.
  • R13 is alkynyl, halogenated alkynyl, saturated heterocycle, partially saturated heterocycle, alkylaryl, or alkylheteroaryl.
  • R13 is halogen.
  • Non-limiting examples of halogen include F, Cl, Br, and I.
  • R 13 is alkyl or halogenated alkyl.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH 2 F, CF 2 CH 3 , CHClCH 3 , CCl 2 CH 3 , CHBrCH 3 , CH 2 CH 2 CF 3 , and CHClCHClCH 3 .
  • R13 is D.
  • R13 is cycloalkyl or halogenated cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R 13 is optionally substituted aryl or alkylaryl.
  • aryl include phenyl, biphenyl, 130 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 naphthyl, anthracenyl, and the like.
  • alkylaryl include , the like.
  • R 13 is H.
  • R 13 ’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl.
  • R 13 ’ is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, aryl, heteroaryl, or halogenated alkyl.
  • R13’ is alkynyl, halogenated alkynyl, saturated heterocycle, partially saturated heterocycle, alkylaryl, or alkylheteroaryl. In some embodiments, R13’ is halogen. 131 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R13’ is alkyl or halogenated alkyl.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.
  • R 13 ’ is D.
  • R 13 ’ is cycloalkyl or halogenated cycloalkyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non-limiting examples of halogenated cycloalkyl some embodiments, R13’ is optionally substituted aryl or alkylaryl.
  • Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like.
  • Non-limiting examples of alkylaryl include , the like.
  • R13’ is H.
  • R 13 ’ is aryl.
  • R 13 ’ is phenyl.
  • R 13 ’ is heteroaryl.
  • R 13 ’ is selected from the group consisting of 132 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 .
  • R13’ is selected from the group consisting of H, R13’ is of H, selected from the group consisting of 133 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0365]
  • the compound of Formula II has the structure of Formula IIa: , wherein R 15a is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 15b is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R16a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; and R16b is H, D, D, alkyl, halogen, ORa,
  • R 15a is H or D.
  • R 15a is OR a , e.g., OH or OCH 3 .
  • R 15a is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl.
  • R15a is halogen, e.g., F, Cl, Br, or I. In some embodiments, R15a is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH 2 CF 3 , CHFCH 3 , or CF 2 CH 3 , or CH 2 CHF 2 . [0369] In some embodiments, R15b is H or D. In some embodiments, R15b is ORa, e.g., OH or OCH3.
  • R15b is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl.
  • R 15b is halogen, 134 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 e.g., F, Cl, Br, or I.
  • R15b is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.
  • R 16a is H or D.
  • R 16a is OR a , e.g., OH or OCH3.
  • R16a is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl.
  • R16a is halogen, e.g., F, Cl, Br, or I.
  • R 16a is fluorinated alkyl, e.g., CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CHFCH 3 , CF 2 CH 3 , or CH 2 CHF 2 .
  • R16b is H or D.
  • R16b is ORa, e.g., OH or OCH 3 .
  • R 16b is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl.
  • R 16b is halogen, e.g., F, Cl, Br, or I.
  • R16b is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.
  • the compound of Formula II has the structure of Formula IIb: , wherein R15a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R15b is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R16a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R 16b is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R 31 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, OR a , SR a , NR a R b
  • Z, Q, R12, R12’, R14, and R14’ in Formula IIb are as defined above for the compound of Formula II.
  • R 15a , R 15b , R 16a , and R 16b in Formula IIb are as defined above for the compound of Formula IIa.
  • Other substituents are defined herein.
  • at least one of R 31 , R 32 , R 34 , and R 35 is not H. In some embodiments, at least two of R31, R32, R34, and R35 are not H.
  • At least one of R 31 , R 32 , R 34 , and R 35 is H, D, alkyl, halogenated alkyl, or halogen. In some embodiments, at least one of R 31 , R 32 , R 34 , and R 35 is CN, OR a , SR a , NR a R b , -C 1-4 alkyl-SR a , or -C1-4alkyl-ORa. In some embodiments, at least one of R31, R32, R34, and R35 is ORa, SRa, or NRaRb.
  • At least one of R31, R32, R34, and R35 is H, D, halogen, fluorinated alkyl, alkyl, alkenyl, or alkynyl.
  • at least one R 31 , R 32 , R 34 some embodiments, at least one of R 31 , R 32 , R 34 , and R 35 is H, Me, Et, i-Pr, n-Bu, CF 2 H, CF2Cl, or CF3.
  • at least one of R31, R32, R34, and R35 is OH, OCH3, CH2OCH3.
  • At least one of R31, R32, R34, and R35 is Cl, F, Br, or I. In some embodiments, at least one of R 31 , R 32 , R 34 , and R 35 is Cl. In some embodiments, at least one of R 31 , R 32 , R 34 , and R 35 is CF 3 , CH 2 F, CH 2 Cl, CH 2 CF 3 , CHFCH 3 , CHFCH 2 F, CF 2 CH 3 , CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, or CHClCHClCH3.
  • At embodiments, at least one of R31, R32, R34, and R35 is ethylenyl, propenyl, 2-propenyl, (E)- but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but- 2-enyl, (Z)-pent-2-enyl, or (E)-pent-1-enyl.
  • At least one of R 31 , R 32 , R34, and R35 is ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2- ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • at least one of R31, R32, R 34 , and R 35 is CN.
  • R 31 , R 32 , R 34 , and R 35 are 137 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 independently selected from the group consisting of CH3, CH2CH3, OH, F, Cl, Br, OCH3, [0376]
  • R 31 , R 32 , R 34 , and R 35 are H; and R 33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa.
  • R31, R32, R34, and R35 are H; and R33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SR a , NR a R b , or -C 1-4 alkyl-OR a .
  • R 31 , R 32 , R 34 , and R 35 are H; and R 33 is H or D.
  • R31, R32, R34, and R35 are H; and R33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, or -C1-4alkyl-ORa.
  • R31, R 32 , R 34 , and R 35 are H; and R 33 is H, D, halogen, or alkyl.
  • R 31 , R 32 , R 34 , and R 35 are H; and R 33 is OR a , SR a , or NR a R b .
  • R 31 , R 32 , R 34 , and R35 are H; and R33 is halogen.
  • Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • alkenyl include ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1- enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl.
  • Non-limiting examples of alkynyl include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent- 1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Non- limiting examples of halogen include F, Cl, Br, and I.
  • R 33 is alkyl (e.g., CH 3 , or CH 2 CH 3 ,), OR a , (e.g., OH or OCH 3 ), halogen (e.g., F, Cl, or Br), -C1-4alkyl-ORa (e.g., CH2OCH3), halogenated alkyl (CF3), CN, alkynyl (e.g., C ⁇ CH), or cycloalkyl (e.g., In some embodiments, R 33 is CH 3 , certain embodiments, R 33 is halogen (e.g., F, Cl, or Br). In some embodiments, R 33 is Cl. In some embodiments, R 33 is Br.
  • R 31 , R 32 , R 34 , and R 35 are H; and R 33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa.
  • R31, R32, R34, and R35 are H; R33 is CH3, CH2CH3, OH, F, Cl, Br, OCH3, 138 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 some embodiments, R31, R32, R34, and R35 are H; R 33 is halogen.
  • R 31 , R 32 , R 34 , and R 35 are H; R 33 is Cl. In some embodiments, R31, R32, R34, and R35 are H; R33 is F. In some embodiments, R31, R32, R34, and R35 are H; and R33 is Br.
  • the compound of Formula II has the structure of Formula IIc: wherein R 15a is H, D, alkyl, halogen, OR a , or fluorinated alkyl; R33 is H, D, halogen, alkyl, ORa, or NRaRb; selected from the group consisting R 11 is H, alkyl, aryl or heteroaryl; R12 is H, D, halogen, alkyl, or ORa; and R13 is H, D, halogen, alkyl, or ORa. [0380] In some embodiments, R11, R12, and R13 in Formula IIc are as defined above for the compound of Formula II.
  • R15a in Formula IIc is as defined above for the compound of Formula IIa.
  • R 33 in Formula IIc is as defined above for the compound of Formula IIb.
  • R a or R b for the compounds of Formulae I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc [0381] The following description of R a or R b is applicable for any one or more of the compounds of Formulas I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc.
  • At least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, 139 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 aryl, or heteroaryl.
  • at least one occurrence of Ra or Rb is independently H, D, alkyl, or cycloalkyl.
  • at least one occurrence of R a or R b is independently saturated heterocycle, aryl, or heteroaryl.
  • alkyl e.g., Me, Et, or Pr
  • -C 1-4 alkyl-OR a e.g., CH 2 OCH 3, CH 2 OH, or CH 2 CH 2 OH
  • at least one occurrence of Ra or Rb is H, Me, phenyl, , [0383]
  • Non- limiting examples of heterocycle include 140 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R x for the compounds of Formulae I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc [0384] The following description of R x is applicable for any one or more of the compounds of Formulas I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc.
  • each occurrence of Rx is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.
  • each occurrence of R x is independently H or alkyl.
  • alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl.
  • At least one occurrence of Rx is optionally substituted heterocycle.
  • each occurrence of Rx is independently H or Me.
  • the compound of Formula I is selected from the group consisting of compounds 1-5, 7-23, and 27-30 in Table 2.
  • the compound of Formula II is selected from the group consisting of compounds 6 and 24-26 in 141 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Table 2.
  • the compound is any one of the compounds described herein, or pharmaceutically acceptable salts thereof or an enantiomer thereof.
  • the enumerated compounds in Tables 1-2 and Examples 1-15 are representative and non-limiting compounds of the embodiments disclosed herein.
  • the compound is any one of the compounds described herein, or pharmaceutically acceptable salts thereof or an enantiomer thereof.
  • Schemes 1-7 below describe synthetic routes which may be used for the synthesis of compounds of the present invention, e.g., compounds having a structure of Formula I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, or IIc, or a precursor thereof.
  • Various modifications to these methods may be envisioned by those skilled in the art to achieve similar results to that of the inventions given below.
  • the synthetic route is described using compounds having the structure of Formula I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, or IIc, or a precursor thereof as examples.
  • bicyclic imide I-1 (Scheme 1) is via alkylation of a suitably substituted bicyclic imide I-3 with a halomethyl oxadiazole I-2 in the presence of a base such as potassium carbonate, optionally with a catalyst such as sodium iodide in a solvent such as DMF or NMP. RZ may be Cl or Br. Other substituents are defined herein.
  • Some bicyclic imides I-3 are commercially available or can be synthesized from commercial precursors by literature methods.
  • Oxadiazole I-2 can be prepared from a nitrile I-4 as shown in Scheme 2.
  • Nitrile I-4 is converted to the amide oxime I-5 by heating with hydroxylamine hydrochloride and a base such as sodium bicarbonate in a solvent such as ethanol.
  • hydroxylamine solution in water can be used without added base.
  • the amide oxime is reacted with a haloacetylchloride and a base such as triethylamine.
  • the resulting intermediate is cyclized to the halomethyl oxadiazole I-2 by heating in toluene, for example, at 100 °C.
  • One such chiral reducing agent is [N-[(1S,2S)-2-(amino- ⁇ N)-1,2- diphenylethyl]-4-methylbenzenesulfonamidato- ⁇ N]chloro[(1,2,3,4,5,6- ⁇ )-1,3,5- trimethylbenzene]-ruthenium (CAS [174813-81-1]) in a mixture of formic acid and triethylamine.
  • the alcohol I-7 is then converted to amide oxime I-8 and chloromethyl oxadiazole I-2a by the same methods used to prepare I-2 (Scheme 3).
  • An alternative way to construct the oxadiazole is shown in Scheme 4.
  • ester I-12 Reaction of ester I-12 with an isocyanate attached to a removable protecting group in the presence of a base such as triethylamine or sodium hydride in a solvent such as DMF or NMP gives the protected bicyclic imide I-13.
  • a base such as triethylamine or sodium hydride in a solvent such as DMF or NMP gives the protected bicyclic imide I-13.
  • One suitable protecting group is 4-methoxybenzyl. Removal of the protecting group then yields I-3.
  • PG is 4-methoxybenzyl
  • the protecting group may be removed with a mixture of trifluoromethanesulfonic acid and TFA, or by treatment with ceric ammonium nitrate (CAN) in a solvent such as acetonitrile. The same method can also be used starting from amide I-11 to give I-13.
  • CAN ceric ammonium nitrate
  • An alternative method is reaction of ester I-12 with TMS-isocyanate in a solvent such as DCM to form the primary urea I-14 that can be cyclized to I-3 by treatment with a base such as sodium t-butoxide in a solvent such as THF.
  • a base such as sodium t-butoxide
  • THF a solvent such as THF
  • the monocyclic imide I-15 is prepared in an analogous manner (Scheme 6) by reacting imide I-16 with halomethyl oxadiazole I-2 under the conditions used in Scheme 1.
  • Many imides I-16 are commercially available. When Z is NR11 and R11 is aryl, the required imide I-16a can be prepared as shown in Scheme 7.
  • compositions [0397] This invention also provides a pharmaceutical composition comprising at least one of the compounds as described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. [0398] In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one compound selected from the group consisting of compounds of Formula I as described herein and a pharmaceutically acceptable carrier or diluent. [0399] In certain embodiments, the compound in the composition is in the form of a hydrate, solvate or pharmaceutically acceptable salt.
  • composition can be administered to the 146 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 subject by any suitable route of administration, including, without limitation, oral and parenteral.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being comingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and 147 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 the like.
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non- toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like
  • organic acids such as acetic, butionic, succinic, glycolic, stearic,
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. See, e.g., Berge et al. (supra).
  • compositions can also be present in the compositions.
  • emulsifiers such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the compositions.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon 148 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 the host being treated and the particular mode of administration.
  • the amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary, or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerator
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0410]
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • compositions may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying proportions, to provide the desired release profile, other polymer matrices, liposomes, and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, 150 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol,
  • cyclodextrins e.g., hydroxybutyl- ⁇ -cyclodextrin
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams, and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the pharmaceutical agents in the proper medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions; or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, or solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • One strategy for depot injections includes the use of polyethylene oxide-polypropylene oxide copolymers wherein the vehicle is fluid at room temperature and solidifies at body temperature.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot-injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the compounds of the invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means.
  • the compounds may be used to treat arthritic conditions in mammals (e.g., humans, livestock, and domestic animals), racehorses, birds, lizards, and any other organism which can tolerate the compounds.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • the present invention provides a method for treating a condition in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from the group consisting of compounds of Formula I or II, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein the condition is selected from the group consisting of pain, a skin disorder, a respiratory disease, a fibrotic disease, an inner ear disorder, fever or another disorder of thermoregulation, a urinary tract or bladder disorder, an autoimmune disease, ischemia, a central nervous system (CNS) disorder, an inflammatory disorder, a gastroenterological disorder, and a cardiovascular disorder.
  • a therapeutically effective amount of at least one compound selected from the group consisting of compounds of Formula I or II, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof wherein the condition is selected from the group consisting of pain, a skin disorder, a respiratory disease, a fibrotic disease, an inner ear disorder, fever or another disorder of thermo
  • the pain is acute pain, chronic pain, complex regional pain syndrome, inflammatory pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteroarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, diabetic neuropathy, sciatica, HIV-related neuropathy, pos-herpetic neuralgia, fibromyalgia, nerve injury, post stock pain, or tooth and tooth injury-related pain.
  • the urinary tract or bladder disorder is pelvic hypersensitivity, urinary incontinence, cystitis, bladder instability, or bladder outlet obstruction.
  • the skin disorder is burns, psoriasis, eczema, or pruritus. In some embodiments, the skin disorder is atopic dermatitis or psoriasis-induced itching.
  • the respiratory disease is an inflammatory airway disease, airway hyperresponsiveness, an idiopathic lung disease, chronic obstructive pulmonary disease, asthma, chronic asthma, tracheobronchial or diaphragmatic dysfunction, or cough, or chronic cough.
  • the ischemia is CNS hypoxia or a disorder associated with reduced blood flow to CNS.
  • the autoimmune disease is rheumatoid arthritis or multiple sclerosis.
  • the central nervous system disorder is associated with neurodegeneration.
  • the gastroenterological disorder is an inflammatory bowel disease, esophagitis, gastroesophageal reflux disorder, irritable bowel syndrome, emesis, or stomach duodenal ulcer.
  • the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.
  • the mammalian species is human.
  • a method of inhibiting transient receptor potential ankyrin 1 (TRPA1) in a mammalian species in need thereof including administering to the mammalian species a therapeutically effective amount of at least one compound of Formula I or II or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • TRPA1 transient receptor potential ankyrin 1
  • the compounds described herein is selective in inhibiting TRPA1 with minimal or no off-target inhibition activities against potassium channels, or against calcium or sodium channels.
  • the compounds described herein do not block the hERG channels and therefore have desirable cardiovascular safety profiles.
  • Some aspects of the invention involve administering an effective amount of a composition to a subject to achieve a specific outcome.
  • the small molecule compositions useful according to the methods of the present invention thus can be formulated in any manner suitable for pharmaceutical use.
  • the formulations of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
  • an effective amount of the compound can be administered to a subject by any mode allowing the compound to be taken up by the appropriate target cells.
  • 154 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 “Administering” the pharmaceutical composition of the present invention can be accomplished by any means known to the skilled artisan.
  • Specific routes of administration include, but are not limited to, oral, transdermal (e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.).
  • An injection can be in a bolus or a continuous infusion.
  • the pharmaceutical compositions according to the invention are often administered by intravenous, intramuscular, or other parenteral means. They can also be administered by intranasal application, inhalation, topically, orally, or as implants; even rectal or vaginal use is possible.
  • Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin.
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with protracted release of active compounds in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners, or solubilizers are customarily used as described above.
  • the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of present methods for drug delivery, see Langer, R. (1990) Science 249:1527-33, which is incorporated herein by reference in its entirety.
  • compositions used in the methods of the invention can range from about 1 nM to about 100 ⁇ M. Effective doses are believed to range from about 10 picomole/kg to about 100 micromole/kg.
  • the pharmaceutical compositions are preferably prepared and administered in dose units. Liquid dose units are vials or ampoules for injection or other parenteral administration. Solid dose units are tablets, capsules, powders, and suppositories. For treatment of a patient, different doses may be necessary depending on activity of the compound, manner of administration, purpose of the administration (i.e., prophylactic or therapeutic), nature and severity of the disorder, and age and body weight of the patient.
  • compositions can be administered per se (neat) or in the form of a pharmaceutically acceptable salt.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can conveniently be used to prepare pharmaceutically acceptable salts thereof.
  • Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.
  • Suitable buffering agents include, but not limited to: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v).
  • Suitable preservatives include benzalkonium chloride (0.003- 0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v); and thimerosal (0.004-0.02% w/v).
  • compositions suitable for parenteral administration conveniently include sterile aqueous preparations, which can be isotonic with the blood of the recipient.
  • acceptable vehicles and solvents are water, Ringer’s solution, phosphate buffered saline, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed mineral or non-mineral oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • administrations can be found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA; incorporated herein by reference in its entirety.
  • the compounds useful in the invention can be delivered in mixtures of more than two such compounds.
  • a mixture can further include one or more adjuvants in addition to the combination of compounds.
  • a variety of administration routes is available. The particular mode selected will depend, of course, upon the particular compound selected, the age and general health status of the subject, the particular condition being treated, and the dosage required for therapeutic 156 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 efficacy.
  • compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the compounds into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • Other delivery systems can include time-release, delayed release, or sustained-release delivery systems.
  • release delivery systems can avoid repeated administrations of the compounds, increasing convenience to the subject and the physician.
  • Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer- based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides.
  • polymer-based systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides.
  • Microcapsules of the foregoing polymers containing drugs are described in, for example, U.S. Pat. No.5,075,109 (incorporated by reference herein in its entirety).
  • Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
  • lipids including sterols such as cholesterol, cholesterol esters and fatty acids, or neutral fats such as mono-di-and tri-glycerides
  • hydrogel release systems silastic systems
  • peptide-based systems such as wax, but are not limited to: (a) erosional systems in which an agent of the invention is contained in a form within a matrix such as those described in U.S. Pat.
  • Equivalents [0448] The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein.
  • Examples 1-11 describe various intermediates used in the syntheses of representative compounds of Formula I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, or IIc disclosed herein.
  • Example 1 describes various intermediates used in the syntheses of representative compounds of Formula I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, or IIc disclosed herein.
  • Example 1 describes various intermediates used in the syntheses of representative compounds of Formula I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, or IIc disclosed herein.
  • Example 1 describe various intermediates used in the syntheses of representative compounds of Formula I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, or IIc disclosed herein.
  • Step b [0451] A solution of (3S)-3-(4-chlorophenyl)-3-hydroxypropanenitrile (30.0 g, 165 mmol) and NH2OH (50% in water) (24 mL) in MeOH (300 mL) was stirred at 75 °C for 16 h.
  • Step c [0452] To a stirred solution of (3S)-3-(4-chlorophenyl)-N,3-dihydroxypropanimidamide (30.0 g, 140 mmol) and DIEA (45.2 g, 349 mmol) in NMP (300 mL) was added chloroacetyl chloride (17.4 g, 154 mmol) at 0 °C. The reaction was stirred at 0 °C for 2 h then heated at 95 °C for 4 h. The resulting mixture was quenched with water (500 mL) at 0 °C and extracted with EA (3 x 500 mL).
  • Step d [0453] To a solution of (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4- chlorophenyl)ethanol (0.250 g, 0.915 mmol) and TBSCl (0.275 g, 1.83 mmol) in DMF (5 mL) was added DIEA (0.354 g, 2.75 mmol). The reaction was stirred at room temperature 159 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 for 16 h, diluted with water (30 mL) and extracted with EA (3 x 30 mL).
  • Step b [0455] A solution of 1-tert-butyl 3-methyl 4-carbamoylpiperazine-1,3-dicarboxylate (1.00 g, 3.48 mmol) and t-BuONa (0.167 g, 1.74 mmol) in THF (15 mL) was stirred at room temperature for 16 h under nitrogen. The resulting mixture was acidified to pH 5 with aq. HCl (1 M) and extracted with EA (3 x 20 mL).
  • reaction mixture was stirred for 16 h under nitrogen, diluted with water (30 mL), and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Step b [0457] A solution of tert-butyl (2R)-2-(carbamoylmethyl)pyrrolidine-1-carboxylate (0.300 g, 1.31 mmol) in HCl in 1,4-dioxane (3 M, 3 mL) was stirred at room temperature for 2 h and concentrated under reduced pressure to afford 2-[(2R)-pyrrolidin-2-yl]acetamide as an off- white solid (0.300 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C6H12N2O [M + H] + : 129 found 129.
  • Step c [0458] To a stirred mixture of 2-[(2R)-pyrrolidin-2-yl]acetamide (0.300 g, 2.34 mmol) and K 2 CO 3 (1.62 g, 11.7 mmol) in THF (10 mL) was added CDI (0.750 g, 4.68 mmol) at room temperature under nitrogen. The reaction was stirred at room temperature for 2 h then warmed to 70 °C 16 h.
  • Step b [0460] To a stirred mixture of tert-butyl (2S,4R)-2-carbamoyl-4-hydroxypyrrolidine-1- carboxylate (5.00 g, 21.7 mmol) in DCM (50 mL) was added TFA (12.5 mL) at room temperature. After 1 h, the resulting mixture was concentrated under reduced pressure to afford (2S,4R)-4-hydroxypyrrolidine-2-carboxamide as a yellow oil (5.00 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C5H10N2O2 [M + H] + : 131 found 131.
  • Step c [0461] To a stirred solution of (2S,4R)-4-hydroxypyrrolidine-2-carboxamide (5.00 g, 38.4 mmol) and K2CO3 (10.6 g, 76.8 mmol) in THF (50 mL) was added CDI (6.23 g, 38.4 mmol) at room temperature.
  • Step d [0462] To a stirred solution of (6R,7aS)-6-hydroxy-tetrahydro-2H-pyrrolo[1,2-c]imidazole- 1,3-dione (15.0 g, 28.8 mmol, 30%) and imidazole (3.92 g, 57.6 mmol) in DMF (150 mL) was added TBSCl (5.21 g, 34.6 mmol) at room temperature. The reaction was stirred for 1 h, diluted with water (100 mL), and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Step b [0464] A solution of tert-butyl 3-(carbamoylmethyl)piperazine-1-carboxylate (0.300 g, 1.23 mmol) and CDI (0.240 g, 1.48 mmol) in ACN (5 mL) was stirred at 100 °C for 16 h.
  • Step b [0466] To a stirred solution of 7-[(4-methoxyphenyl)methyl]-tetrahydro-2H-pyrazino[1,2- c]pyrimidine-1,6,8-trione (0.150 g, 0.495 mmol) in TFA (2 mL) was added CF 3 SO 3 H (0.4 164 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 mL) at room temperature.
  • Step b [0468] To a solution of tert-butyl (2R)-2-(carbamoylmethyl)piperidine-1-carboxylate (0.850 g, 3.51 mmol) in dioxane (12 mL) was added aq. HCl (4 mL, 4 M) at room temperature. The reaction was stirred for 16 h and concentrated under reduced pressure. The residue was suspended in DCM (4 mL), filtered, and the filter cake washed with DCM (4 x 3 mL).
  • Step c [0469] To a solution of 2-[(2R)-piperidin-2-yl]acetamide hydrochloride (0.200 g, 1.41 mmol) in ACN (5 mL) was added CDI (0.342 g, 2.11 mmol). The reaction mixture was stirred at 80 °C for 16 h. The cooled mixture was diluted with water (30 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Step b 166 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0471] To a stirred solution of 2-[(4-methoxyphenyl)methyl]-tetrahydroimidazo[4,3- c][1,4]oxazine-1,3-dione (0.200 g, 0.720 mmol) in toluene (2 mL) was added AlCl3 (0.241 g, 1.81 mmol). The reaction was stirred at 50 °C for 4 h and concentrated under reduced pressure.
  • Step b [0473] To a stirred solution of 7-[(4-methoxyphenyl)methyl]-tetrahydro-1H-pyrimido[4,3- c][1,4]oxazine-6,8-dione (0.340 g, 1.17 mmol) in TFA (2 mL) and DCM (2 mL) was added 167 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 CF3SO3H (0.878 g, 5.85 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h and concentrated under reduced pressure.
  • Step b [0475] To a solution of methyl 4-hydroxypiperidine-2-carboxylate hydrochloride (1.50 g, 7.67 mmol) in DMF (15 mL) were added imidazole (1.57 g, 23.0 mmol) and TBSCl (1.73 g, 11.5 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h, diluted with water (100 mL), and extracted with EA (3 x 30 mL).
  • Step c [0476] To a solution of methyl 4-[(tert-butyldimethylsilyl)oxy]piperidine-2-carboxylate (0.500 g, 1.83 mmol) in DMF (15 mL) were added TEA (0.370 g, 3.66 mmol) and 1- (isocyanatomethyl)-4-methoxybenzene (0.358 g, 2.20 mmol) at room temperature. The reaction was stirred for 4 h, diluted with water (50 mL), and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (5 x 35 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Step d [0477] To a solution of 7-[(tert-butyldimethylsilyl)oxy]-2-[(4-methoxyphenyl)methyl]- tetrahydro-5H-imidazo[1,5-a]pyridine-1,3-dione (0.250 g, 0.620 mmol) in ACN (25 mL) and H2O (2.5 mL) was added CAN (1.70 g, 3.09 mmol) at room temperature.
  • Step e 169 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 [0478] To a solution of 7-hydroxy-hexahydroimidazo[1,5-a]pyridine-1,3-dione (0.300 g, 0.350 mmol, 20% purity) in DMF (5 mL) were added imidazole (96.0 mg, 1.41 mmol) and TBSCl (0.106 g, 0.710 mmol) at room temperature. The reaction was stirred for 16 h, diluted with water (50 mL), and extracted with EA (3 x 30 mL).
  • Step c [0481] To a stirred mixture of 2-[(1-methylpyrazol-4-yl)amino]acetamide (0.400 g, 2.59 mmol) and Boc 2 O (0.849 g, 3.89 mmol) in DCM (5 mL) was added TEA (0.525 g, 5.18 mmol) at room temperature. The reaction was stirred for 2 h, diluted with water (20 mL), and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step d [0482] To a stirred mixture of tert-butyl N-(carbamoylmethyl)-N-(1-methylpyrazol-4- yl)carbamate (0.100 g, 0.393 mmol) in DMF (2 mL) was added NaH (23.6 mg, 0.590 mmol, 60% in oil) at room temperature. The reaction was stirred for 1 h under nitrogen, quenched with saturated aq. NH 4 Cl (20 mL), and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Examples 12-15 describe the exemplified syntheses of representative compounds of Formula I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, or IIc disclosed herein. 171 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Example 12.
  • Example 13 Compound 2 (2-((3-((2S)-2-(4-Chlorophenyl)-2-hydroxyethyl)-1,2,4- oxadiazol-5-yl)methyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione isomer 1) and Compound 3 (2-((3-((2S)-2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5- yl)methyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione isomer 2) 172 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Step a: [0485] To a stirred mixture of (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4- chlor
  • the reaction was heated to 80 °C for 16 h.
  • the cooled mixture was diluted with EA (5 mL) and water (5 mL) and extracted with EA (3 x 5 mL).
  • the combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
  • Example 14 Compound 4 (7-( ⁇ 3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4- oxadiazol-5-yl ⁇ methyl)-tetrahydro-1H-pyrimido[4,3-c][1,4]oxazine-6,8-dione isomer 1) and Compound 5 (7-( ⁇ 3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5- yl ⁇ methyl)-tetrahydro-1H-pyrimido[4,3-c][1,4]oxazine-6,8-dione isomer 2) Step a: [0487] To a stirred solution of hexahydropyrimido[4,3-c][1,4]oxazine-6,8-dione (80.0 mg, 0.470 mmol) and (1S)-2-[5-(chloromethyl
  • the reaction was stirred for 16 h, diluted with water (30 mL) and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Example 15 Compound 6 (3-( ⁇ 3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4- oxadiazol-5-yl ⁇ methyl)-1-(1-methylpyrazol-4-yl)imidazolidine-2,4-dione) Step a: [0489] To a stirred mixture of (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4- chlorophenyl)ethanol (60.0 mg, 0.220 mmol) and 1-(1-methylpyrazol-4-yl)imidazolidine-2,4- dione (59.3 mg, 0.330 mmol) in DMF (2 mL) was added K2CO3 (60.7 mg, 0.440 mmol).
  • TRPA1 Inhibitor Activities This assay was used to evaluate the disclosed compounds’ inhibition activities against the human TRPA1 channel.
  • Cell culture [0492] CHO cells inducibly expressing human TRPA1 were grown in DMEM containing 10% heat-inactivated FBS, 1 mM sodium pyruvate, 2 mM L-glutamine, zeocin (100 ⁇ g/ml) and blasticidin (10 ⁇ g/ml). Expression was induced by addition of doxycycline (1 ⁇ g/ml) 24 hours before experiments. Cells used for electrophysiology were plated in plastic culture flasks and grown at 37°C in a 5% CO2-humidified tissue culture incubator per ChanPharm SOP.
  • the internal solution contained 10 mM CsCl, 110 mM CsF, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES, 4 mM MgATP, 0.25 mM NaGTP, and 4 mM BAPTA; pH adjusted to 7.2 with CsOH; 285-290 mOsm.
  • Compound stock solutions were freshly diluted 184 ACTIVEUS 204604250 Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 with external solution to concentrations of 3 nM, 10 nM 30 nM, 100 nM, 300 nM, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, and 30 ⁇ M.
  • the internal solution contained 10 mM KCl, 110 mM KF, 10 mM NaCl, 10 mM EGTA, and 10 mM HEPES; pH adjusted to 7.2 with KOH; 280-285 mOsm. All compounds were dissolved in DMSO at 30 mM. Compound stock solutions were freshly diluted with external solution to concentrations of 50 ⁇ M and 100 ⁇ M. The highest content of DMSO (0.15%) was present at 50 ⁇ M. Voltage protocol [0499] All experiments were performed at room temperature. Each cell acted as its own control.
  • intracellular solution was loaded into the intracellular compartments of the automated patch clamp platform SyncroPatch (Nanion) chip, and the cell suspension was pipetted into the extracellular compartments.
  • membrane current recordings, and compound application were enabled by means of the SyncroPatch.
  • hERG currents were elicited by a voltage pulse pattern with fixed amplitudes (depolarization: +20mV amplitude, 300 ms duration; repolarization: -50mV, 300 ms duration) repeated at 3 s intervals from a holding potential of -80 mV.
  • Data analysis [0500] Data acquisition and analysis were performed using DataControl384 (Nanion’s proprietary software).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un composé de formule I ou II ou un sel pharmaceutiquement acceptable de celui-ci, les substituants étant tels que définis dans la description. L'invention concerne également des compositions pharmaceutiques les comprenant et un procédé d'utilisation de celles-ci.
PCT/US2024/037153 2023-07-10 2024-07-09 Inhibiteurs bicycliques et monocycliques de trpa1 Pending WO2025014922A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100179128A1 (en) * 2005-08-10 2010-07-15 Richard Jonathan Daniel Hatley Xanthine derivatives as selective hm74a agonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100179128A1 (en) * 2005-08-10 2010-07-15 Richard Jonathan Daniel Hatley Xanthine derivatives as selective hm74a agonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE SUBSTANCE RECORD 25 April 2023 (2023-04-25), ANONYMOUS: "Z3531901823", XP093267767, Database accession no. SID 479388663 *
DATABASE Subtance record 3 June 2019 (2019-06-03), ANONYMOUS: "AKOS033987124", XP093267762, Database accession no. SID 379136156 *

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