Bicyclic and monocyclic trpa1 inhibitors

Abstract

A compound of Formula I or II or a pharmaceutically acceptable salt thereof, is described, where the substituents are as defined herein. Pharmaceutical compositions comprising the same and method of using the same are also described.

Description

Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 BICYCLIC AND MONOCYCLIC TRPA1 INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 512,813, filed on July 10, 2023, the content of which is incorporated herein by reference in its entirety. INCORPORATION BY REFERENCE

[0002] All documents cited herein are incorporated herein by reference in their entirety.

[0003] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights. FIELD OF THE INVENTION

[0004] The invention relates generally to the field of pharmaceutical science. More particularly, the invention relates to compounds and compositions useful as pharmaceuticals as potassium channel blockers. BACKGROUND

[0005] Transient receptor potential channels (TRP channels) are a family of voltage-gated ion channels located primarily on the plasma membrane of mammalian cells. There are approximately 30 structurally related TRP channels subdivided into several groups: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV. Transient receptor potential ankyrin 1 (TRPA1), a member of the TRPA subfamily, is a cation-selective, calcium-permeable ion channel (Montell, C., 2005, Sci. STKE, 272:re3).

[0006] 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. The TRPA1 protein also contains a C- terminal extension (Terrett, J.A. et al., 2021, J. Med. Chem.64, 7, 3843–3869). 1 ACTIVEUS 204604250Attorney 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. These sensory neurons are in the dorsal root and nodose ganglia and connect with skin, lung, small intestine, colon, pancreas, skeletal muscle, heart, brain, bladder, and several immune cells, including neutrophils, eosinophils, mast cells, dendritic cells, macrophages, and T and B- lymphocytes (Naert, R. et al., 2021, Int. J. Mol. Sci.22, 11460, 1-17). 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. et al., 2013, Curr. Top. Med. Chem.13, 3, 241-243). TRPA1 functions primarily as a sensor for environmental irritants and is thought to give rise to somatosensory modalities, such as pain, cold, and itch.

[0008] TRPA1 is activated by a range of endogenous and exogenous stimuli for pain and inflammation. Specifically, TRPA1 can be activated by external irritants, such as allyl isothiocyanate (AITC) and allicin. 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.

[0009] 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. A gain-of- function TRPA1 mutation in humans has been linked to familial episodic pain syndrome (FEPS) (Kremeyer, B. et al., 2010, Neuron 66, 5, 671-680). The discovery of a human genetic link between TRPA1 and FEPS suggests that TRPA1 plays a significant role in human pain. Patients carrying a single gain-of-function mutation in TRPA1 are known to experience debilitating upper body pain, triggered by fasting, cold, and fatigue. Several anesthetics are known to be TRPA1 agonists, including isoflurane (Matta, J.A. et al., 2008, PNAS 105, 25, 8784-8789), providing rationale for TRPA1 inhibitors for the relief of post- surgical pain.

[0010] 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 204604250Attorney 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. et al., 2021, J. Exp. Med.218, 4, e20201637, 1-23; van den Berg, M.P.M. et al., 2021, Respir. Res.22, 48, 1-15; Terrett, J.A. et al., 2021, J. Med. Chem.64, 7, 3843–3869). The cough can be associated with asthma, chronic pulmonary obstructive disease (COPD), and idiopathic pulmonary fibrosis (IPF). 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. Allergy 5, 24, 1-10; Grace, M.S. and Belvisi, M.G., 2011, Pulm. Pharmacol. Ther.24, 3, 286-288); however, TRPA-protective effects in IPF have also been reported (Virk, H.S. et al., 2021, Br J Pharmacol.178, 2948–2962). 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).

[0011] 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). Direct clinical support for relief of AITC-induced itch upon TRPA1 specific inhibition has also been reported (Balestrini, A. et al., 2021, J. Exp. Med.218, 4, e20201637, 1-23). Additionally, a TRPA1 antagonist is effective in a behavioral model of migraine-related allodynia (Edelmayer, R.M. et al., 2012, Pain 2012, 153, 9, 1949-1958).

[0012] TRPA1 expression is increased by inflammatory mediators and following nerve injury, suggesting a role for TRPA1 activity in inflammation. For example, TRPA1 is required for the observed hypersensitivity in inflammatory pain models (Bautista, D.M. et al. 2013, Annu. Rev. Physiol.75, 181–200, Julius, D.2013, Annu. Rev. Cell Dev. Biol.29, 355- 384). Disease models of diabetes indicate that 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. Studies further suggest that TRPA1 is implicated in migraine pain as a result from neurogenic inflammation (Edelmayer, R.M. et al., 2012, Pain 3 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 153, 9, 1949-1958). This may be due to the activation of trigeminal TG neurons through nasal application of TRPA1 activators.

[0013] 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. Ther.18, 185, 1-11; Horvath, A. et al., 2016, Arthritis Res. Ther.18, 6, 1-14). Additionally, TRPA1 KO mice have been shown to improve in weight bearing on the osteoarthritic limb in a knee swelling model (Horvath, A. et al., 2016, Arthritis Res. Ther.18, 6).

[0014] 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. Pharmacol.166, 4, 1444–1460). Additionally, colitis induced by dinitrobenzene sulphonic acid (DNBS) is attenuated after pharmacological blockade or genetic inactivation of TRPA1 (Engel, M.A. et al., 2011, Gastroenterology 141, 4, 1346-1358), suggesting that TRPA1 can be a target in GI inflammatory conditions, such as inflammatory bowel disease, Crohn’s disease, and ulcerative colitis (Cseko, K. et al., 2019, Pharmaceuticals 12, 48, 1-19; Blackshaw, L.A. et al., 2013, The Open Pain Journal 6, (Suppl 1: M4) 23-30).

[0015] 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. SUMMARY OF THE INVENTION

[0017] In one aspect, a compound useful as a TRPA1 inhibitor having a structure of Formula I 4 ACTIVEUS 204604250Attorney 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.

[0018] In one aspect, 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; Y2is a direct bond, CR4R4’, NR10, O, or S; wherein when Y1is NR9, O, or S, Y2is a direct bond or CR4R4’; and wherein when Y2is NR10, O, or S, Y1is a direct bond or CR3R3’; 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, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, 5 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R1’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; or alternatively,is –(C=O)–; or still alternatively, R1and R1’, together with the carbon atom that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R2 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, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R3 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; or alternatively, R2and R3, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents 6 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R3’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R4is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; or alternatively, R1 and R4, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; or alternatively, R3 and R4, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R4’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, 7 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R7is H, D, alkyl, or -C1-4alkyl-ORa; R7’ is H, D, alkyl, or -C1-4alkyl-ORa; R8 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, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R9 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; R10 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; A is an aryl or heteroaryl optionally substituted 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; L1is –(CR5R6)n–; each occurrence of R5is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; each occurrence of R6 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; n is 2 or 3; 8 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 each occurrence of Ra and Rb is independently selected from the group consisting of H, D, alkyl, (C=O)Rx, (C=O)N(Rx)2, SO2Rx, NRx(C=O)N(Rx)2, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Ra and Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0- 3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl in R1, R1’, R2, R2’, R3, R3’, R4, R4’, R5, R6, R7, R7’, R8, R8’, R9, R10, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1- 2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rx is independently H, D, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rxgroups together with the nitrogen atom that they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0019] In any one of the embodiments described herein, n is 2.

[0020] In any one of the embodiments described herein, each occurrence of R5 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0021] In any one of the embodiments described herein, each occurrence of R5 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0022] In any one of the embodiments described herein, each occurrence of R6 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0023] In any one of the embodiments described herein, each occurrence of R6 independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0024] In any one of the embodiments described herein, L1is selected from the group consisting of –CH2–CH2–, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH(OH)–CH2–, –CH2– 9 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0025] In any one of the embodiments described herein, L1is 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 embodiments described herein, the compound has the structure of Formula Ia:, wherein R5a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R5b is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R6ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; and R6bis H, D, alkyl, halogen, ORa, or fluorinated alkyl.

[0027] In any one of the embodiments described herein,has the structure of –CH2–10 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0028] In any one of the embodiments described herein, R7 is H, D, or alkyl.

[0029] In any one of the embodiments described herein, R7is H, D, CH3, or CH2CH3.

[0030] In any one of the embodiments described herein, R7’ is H, D, or alkyl.

[0031] In any one of the embodiments described herein, R7’ is H, D, CH3, or CH2CH3.

[0032] In any one of the embodiments described herein, is selected from the group consisting of –CH2–, –CH(CH3)–, –C(CH3)2–, and –CH(CH2CH3)–.

[0033] In any one of the embodiments described herein,is –CH2–.

[0034] In any one of the embodiments described herein, L1isis – CH2–. A

[0035] In any one of the embodiments described herein, is 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.

[0036] In any one of the embodiments described herein,is selected from the group11 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0038] In any one of the embodiments described herein,is 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. A

[0039] In any one of the embodiments described herein, is selected from the group

[0040] In any one of the embodiments described herein, 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; R6ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R6bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; R21is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; 12 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R22 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; R23 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; R24 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; and R25is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa.

[0041] In any one of the embodiments described herein, X is a direct bond.

[0042] In any one of the embodiments described herein, X is CR8R8’.

[0043] In any one of the embodiments described herein, 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 each occurrence of R21 is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; each occurrence of R22is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; each occurrence of R23is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; each occurrence of R24 is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; and each occurrence of R25is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa.

[0044] In any one of the embodiments described herein, R21, R22, R24, and R25 are H; and R23 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa.

[0045] In any one of the embodiments described herein, R23is CH3, CH2CH3, OH, F, Cl, Br,

[0046] In any one of the embodiments described herein, R23 is Cl.

[0047] In any one of the embodiments described herein, R8is H, D, or alkyl.

[0048] In any one of the embodiments described herein, R8is H, D, CH3, or CH2CH3.

[0049] In any one of the embodiments described herein, R8’ is H, D, or alkyl.

[0050] In any one of the embodiments described herein, R8’ is H, D, CH3, or CH2CH3.

[0051] In any one of the embodiments described herein, Y1is CR3R3’.

[0052] In any one of the embodiments described herein, R3is H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0053] In any one of the embodiments described herein, R3is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. 14 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0054] In any one of the embodiments described herein, R3’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0055] In any one of the embodiments described herein, R3’ H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0056] In any one of the embodiments described herein, Y1 is a direct bond.

[0057] In any one of the embodiments described herein, Y2 is CR4R4’.

[0058] In any one of the embodiments described herein, R4 is H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0059] In any one of the embodiments described herein, R4 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0060] In any one of the embodiments described herein, R4’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0061] In any one of the embodiments described herein, R4’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0062] In any one of the embodiments described herein, Y2 is NR10.

[0063] In any one of the embodiments described herein, R10 is H, alkyl, cycloalkyl, aryl, or alkylaryl.

[0064] In any one of the embodiments described herein, R10 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2.

[0065] In any one of the embodiments described herein, Y2 is O or S.

[0066] In any one of the embodiments described herein,selected from the15 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0067] In any one of the embodiments described herein, R1is H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0068] In any one of the embodiments described herein, R1 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0069] In any one of the embodiments described herein, R1 and R4, together with the carbon atoms that they are connected to, form a cyclopropyl group which is optionally substituted with D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0070] In any one of the embodiments described herein, R1’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0071] In any one of the embodiments described herein, is –(C=O)–.

[0072] In any one of the embodiments described herein, R2 is H, D, alkyl, halogen, or halogenated alkyl.

[0073] In any one of the embodiments described herein, R2 is H, D, CH3, CH2CH3, F, Cl, Br, or fluorinated alkyl.

[0074] In any one of the embodiments described herein, R2’ is H, D, alkyl, halogen, or halogenated alkyl.

[0075] In any one of the embodiments described herein, R2’ is H, D, CH3, CH2CH3, F, Cl, Br, or fluorinated alkyl. 16 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0076] In any one of the embodiments described herein,selected from the

[0077] In any one of the embodiments described herein, 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024R1 is H, D, halogen, alkyl, or ORa; R1’ is H, D, halogen, alkyl, or ORa; R2 is H, D, halogen, alkyl, or ORa; R3is H, D, halogen, alkyl, or ORa; R4is H, D, halogen, alkyl, or ORa; R4’ is H, D, halogen, alkyl, or ORa; R8 is H, D, or alkyl; and R10 is H or alkyl.

[0078] In another aspect, a compound of Formula II or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described,wherein 18 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Z is NR11, O, or S; Q is a direct bond or CR13R13’; R11is 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; R12is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R12’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R13is 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, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R14is H, D, alkyl, or -C1-4alkyl-ORa; R14’ is H, D, alkyl, or -C1-4alkyl-ORa;is an aryl or heteroaryl optionally substituted 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; L2 is –(CR15R16)m–; 19 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 each occurrence of R15 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; each occurrence of R16is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; m is 2 or 3; each occurrence of Raand Rbis independently selected from the group consisting of H, D, alkyl, (C=O)Rx, (C=O)N(Rx)2, SO2Rx, NRx(C=O)N(Rx)2, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Raand Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0- 3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl in R11, R12, R12’, R13, R13’, R14, R14’, R15, R16, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rxis independently H, D, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rxgroups together with the nitrogen atom that they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0079] In any one of the embodiments described herein, m is 2.

[0080] In any one of the embodiments described herein, each occurrence of R15 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0081] In any one of the embodiments described herein, each occurrence of R15 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0082] In any one of the embodiments described herein, each occurrence of R16is independently H, D, alkyl, halogen, ORa, or halogenated alkyl. 20 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0083] In any one of the embodiments described herein, each occurrence of R16 independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0084] In any one of the embodiments described herein, L2 is selected from the group consisting of –CH2–CH2–, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH(OH)–CH2–, –CH2–

[0085] In any one of the embodiments described herein, L2is selected from the group consisting of –CH2–CH2–, –CH(CH3)–CH2–, –CH2–CH(CH3)–, –CH2–C(CH3)2–, –C(CH3)2–

[0086] In any one of the embodiments described herein, the compound has the structure of Formula IIa:, wherein R15ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R15bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; R16a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; and R16b is H, D, alkyl, halogen, ORa, or fluorinated alkyl. 21 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0087] In any one of the embodiments described herein,has the structure of -CH2-CH2-, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH2–CH(CH2)–, –C(CH3)2–CH2–,

[0088] In any one of the embodiments described herein, R14 is H, D, or alkyl.

[0089] In any one of the embodiments described herein, R14is H, D, CH3, or CH2CH3.

[0090] In any one of the embodiments described herein, R14’ is H, D, or alkyl.

[0091] In any one of the embodiments described herein, R14’ is H, D, CH3, or CH2CH3.

[0092] In any one of the embodiments described herein,is selected from the group consisting of –CH2–, –CH(CH3)–, –C(CH3)2–, and –CH(CH2CH3)–.

[0093] In any one of the embodiments described herein,is –CH2–.

[0094] In any one of the embodiments described herein, L2is-CH2-.

[0095] In any one of the embodiments described herein,is 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.

[0096] In any one of the embodiments described herein,is selected from the group22 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024B

[0098] In any one of the embodiments described herein, is 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.

[0100] In any one of the embodiments described herein, the compound has the structure of Formula Ib:, 23 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 wherein R15ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R15bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; R16ais H, D, alkyl, halogen, ORa, 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, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R32 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; R33 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; R34 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; and R35is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa.

[0101] In any one of the embodiments described herein, R31, R32, R34, and R35 are H; and R33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa.

[0102] In any one of the embodiments described herein, R33 is CH3, CH2CH3, OH, F, Cl, Br,

[0103] In any one of the embodiments described herein, R33is Cl.

[0104] In any one of the embodiments described herein, Q is CR13R13’.

[0105] In any one of the embodiments described herein, R13 is H, D, or alkyl.

[0106] In any one of the embodiments described herein, R13 is H, D, CH3, or CH2CH3.

[0107] In any one of the embodiments described herein, R13’ is H, D, or alkyl.

[0108] In any one of the embodiments described herein, R13’ is H, D, CH3, or CH2CH3.

[0109] In any one of the embodiments described herein, Q is a direct bond.

[0110] In any one of the embodiments described herein, Z is NR11. 24 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0111] In any one of the embodiments described herein, R11 is H, alkyl, cycloalkyl, aryl, or heteroaryl.

[0112] In any one of the embodiments described herein, R11 is selected from the group consisting.

[0113] In any one of the embodiments described herein, Z is O or S.

[0114] In any one of the embodiments described herein,selected from the

[0115] In any one of the embodiments described herein, R12 is H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0116] In any one of the embodiments described herein, R12 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

[0117] In any one of the embodiments described herein, R12’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.

[0118] In any one of the embodiments described herein, R12’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. 25 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0120] In any one of the embodiments described herein, the compound has the structure of Formula IIc,, wherein R15a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R33is H, D, halogen, alkyl, ORa, or NRaRb;selected from the group consistingR11 is H, alkyl, aryl or heteroaryl; R12is H, D, halogen, alkyl, or ORa; and R13is H, D, halogen, alkyl, or ORa. 26 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0121] In any one of the embodiments described herein, at least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl.

[0122] In any one of the embodiments described herein, at least one occurrence of Ra or Rb is independently H, D, Me, Et, Pr, CH2CH2OH, phenyl, or a heterocycle selected from theheterocycle is optionally substituted by alkyl, OH, oxo, or (C=O)C1-4alkyl where valence permits.

[0123] In any one of the embodiments described herein, at least one occurrence of Raor Rbis H, Me, phenyl,

[0124] In any one of the embodiments described herein, 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.

[0125] In any one of the embodiments described herein, each occurrence of Rx is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.

[0126] In any one of the embodiments described herein, each occurrence of Rx is independently H or alkyl.

[0127] In any one of the embodiments described herein, each occurrence of Rx is independently H or Me.

[0128] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 1-5, 7-23, and 27-30 in Table 2.

[0129] In any one of the embodiments described herein, the compound is selected from the group consisting of compounds 6 and 24-26 in Table 2.

[0130] In another aspect, 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. 27 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0131] In yet another aspect, a method of treating a condition in a mammalian species in need thereof is described, 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.

[0132] In any one of the embodiments described herein, 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.

[0133] In any one of the embodiments described herein, a urinary tract disorder is pelvic hypersensitivity, urinary incontinence, or cystitis, bladder instability, or bladder outlet obstruction.

[0134] In any one of the embodiments described herein, 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.

[0137] In any one of the embodiments described herein, the ischemia is CNS hypoxia or a disorder associated with reduced blood flow to CNS.

[0138] In any one of the embodiments described herein, the autoimmune disease is rheumatoid arthritis or multiple sclerosis.

[0139] In any one of the embodiments described herein, the central nervous system disorder is associated with neurodegeneration. 28 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0140] In any one of the embodiments described herein, the gastroenterological disorder is an inflammatory bowel disease, esophagitis, gastroesophageal reflux disorder, irritable bowel syndrome, emesis, or stomach duodenal ulcer.

[0141] In any one of the embodiments described herein, the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.

[0142] In any one of the embodiments described herein, the mammalian species is human.

[0143] In yet another aspect, a method of inhibiting transient receptor potential A1 (TRPA1) in a mammalian species in need thereof is described, 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.

[0144] In any one of the embodiments described herein, the mammalian species is human.

[0145] 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. Such combination can be made in any one or more embodiments of the application described herein or any formula described herein. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0146] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It is to be understood that the terminology used herein is for the purpose of describing certain embodiments only and is not intended to be limiting.

[0147] The terms “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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 undecyl, dodecyl, and the like. The term “(C1-Cx)alkyl” or “C1-xalkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to x carbon atoms. For example, the term “(C1-C4)alkyl” or “C1-4alkyl” 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. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rcand Rdis independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rband Rctogether with the N to which they are bonded optionally form a heterocycle, and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.

[0148] The term “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. The term “C2-Cxalkenyl” or “C2-xalkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon double bond. For example, the term “C2-C6alkenyl” or “C2-6alkenyl” 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, (E)-hex-3- enyl, and (E)-hex-1,3-dienyl. “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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group bearing a single halogen substituent or multiple halogen substituents such as CF3or CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rcand Rdis independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rband Rctogether with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0149] The term “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. The term “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. For example, the term “C2-C6alkynyl” or “C2-6alknyl” 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. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Rais independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with 31 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 the N to which they are bonded optionally to form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0150] The term “cycloalkyl” refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. “C3-C7cycloalkyl” or “C3-7cycloalkyl” 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 include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rband Rctogether with the N to which they are bonded optionally to form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The 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.

[0151] The term “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 include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3or an alkyl group 32 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Rais independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc,and Rdis independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The 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.

[0152] The term “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). The term “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 include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Rais independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc 33 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The 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.

[0153] The term “biaryl” refers to two aryl groups linked by a single bond. The term “biheteroaryl” refers to two heteroaryl groups linked by a single bond. Similarly, the term “heteroaryl-aryl” refers to a heteroaryl group and an aryl group linked by a single bond and the term “aryl-heteroaryl” refers to an aryl group and a heteroaryl group linked by a single bond. In certain embodiments, 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. For example, 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.

[0154] The term “carbocycle” 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. The term “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. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. 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.

[0155] The terms “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 204604250Attorney 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. (The term “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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1- dioxothienyl, and the like. Exemplary 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, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0156] “Substituted heterocycle” and “substituted heterocyclic” (such as “substituted heteroaryl”) 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 include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, 35 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rdis independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rband Rctogether with the N to which they are bonded optionally form a heterocycle; and each occurrence of Reis independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The 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.

[0157] The term “oxo” refers tosubstituent group, which may be attached to a carbon ring atom on a carboncycle or heterocycle. When 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. For instance, a pyridine with a 2- oxo substituent group may have the structurewhich also includes its tautomeric form

[0158] The term “alkylamino” refers to a group having the structure -NHR’, wherein R’ is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of 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.

[0159] The term “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 204604250Attorney 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. Examples of 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. In certain embodiments, 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.

[0160] The terms “halogen” or “halo” refer to chlorine, bromine, fluorine, or iodine.

[0161] The term “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. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3or an alkyl group bearing CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, alkyl, halogen-substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc, and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rband Rctogether with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted. The term “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 204604250Attorney 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.

[0162] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0163] 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. In addition, 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.

[0164] 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 (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. 38 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0165] 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. 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.

[0166] 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.

[0167] 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.

[0168] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, 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. The 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 204604250Attorney 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.

[0169] 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. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0171] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0172] Definitions of specific functional groups and chemical terms are described in more detail herein. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0173] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0174] 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 204604250Attorney 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. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0175] 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. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H (D),3H (T),13C,11C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, 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 as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H (T), and carbon- 14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H (D), can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. 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.

[0176] If, for instance, a particular enantiomer of a compound of the present invention is desired, it 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. Alternatively, where 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. 41 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0177] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, 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. Furthermore, 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. The term “stable,” as used herein, 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.

[0178] As used herein, the terms “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. Diseases other than cancers may be associated with mutational alternation of component of Ras signaling pathways and the compound disclosed herein may be used to treat these non-cancer diseases. Such non-cancer diseases may include: neurofibromatosis; Leopard syndrome; Noonan syndrome; Legius syndrome; Costello 42 ACTIVEUS 204604250Attorney 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.

[0179] As used herein, “effective amount” refers to any amount that is necessary or sufficient for achieving or promoting a desired outcome. In some instances, 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.

[0180] As used herein, 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. In other embodiments, 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. Methods for synthesizing these compounds are also described herein. Pharmaceutical compositions and 43 ACTIVEUS 204604250Attorney 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.

[0183] In one aspect, 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; Y2is a direct bond, CR4R4’, NR10, O, or S; wherein when Y1is NR9, O, or S, Y2is 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; R1is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R1’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; 44 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 or alternatively,is –(C=O)–; or still alternatively, R1and R1’, together with the carbon atom that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R2 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, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R3is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; or alternatively, R2 and R3, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R3’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, 45 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R4is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; or alternatively, R1 and R4, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R4’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R7is H, D, alkyl, or -C1-4alkyl-ORa; R7’ is H, D, alkyl, or -C1-4alkyl-ORa; R8is 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, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R9 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; 46 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R10 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;is an aryl or heteroaryl optionally substituted 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; L1 is –(CR5R6)n–; each occurrence of R5is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; each occurrence of R6 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; n is 2 or 3; each occurrence of Ra and Rb is independently selected from the group consisting of H, D, alkyl, (C=O)Rx, (C=O)N(Rx)2, SO2Rx, NRx(C=O)N(Rx)2, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Ra and Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0- 3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl in R1, R1’, R2, R2’, R3, R3’, R4, R4’, R5, R6, R7, R7’, R8, R8’, R9, R10, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1- 2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rx is independently H, D, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rxgroups together with the nitrogen atom that 47 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0184] In some embodiments, n is 2. In other embodiments, n is 3.

[0185] In some embodiments, each occurrence of R5is 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, -C1-4alkyl-ORa, or CN. In other embodiments, each occurrence of R5is independently H, D, alkyl, halogen, ORa, or halogenated alkyl. In some embodiments, 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 R5is 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 R5is 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, at least one occurrence of R5 is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, at least one occurrence of R5is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, at least one occurrence of R5 is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, at least one occurrence of R5 is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include

[0187] In some embodiments, each occurrence of R5 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or halogenated alkyl (e.g., fluorinated alkyl). In some embodiments, each 48 ACTIVEUS 204604250Attorney 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. In certain embodiments, R5 is independently H, D, OH, F, Cl, or Br. In some embodiments, R5 is independently H, D, OH, or F. In further embodiments, R5is independently H, D, or OH.

[0188] In some embodiments, each occurrence of R6 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen. In some embodiments, each occurrence of R6is independently cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or CN. In other embodiments, each occurrence of R6is independently H, D, alkyl, halogen, ORa, or halogenated alkyl. In some embodiments, R6 is independently H, D, ORa(e.g., OH, OMe, or OEt), halogen (e.g., F, Cl, or Br). In some embodiments, at least one occurrence of R6is H or D. In some embodiments, at least one occurrence of R6 is ORa, e.g., OH, OMe, or OEt. In some embodiments, at least one occurrence of R6 is -C1-4alkyl-ORa, e.g., CH2OH, CH2CH2OH, or CH2OCH3. In some embodiments, at least one occurrence of R6is 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, at least one occurrence of R6 is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, at least one occurrence of R6is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, at least one occurrence of R6 is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, at least one occurrence of R6 is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include

[0189] In any one of the embodiments described herein, each occurrence of R6 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or halogenated alkyl (e.g., fluorinated alkyl). In some embodiments, each occurrence of R6 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In certain embodiments, R6 is independently H, D, OH, F, 49 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Cl, or Br. In some embodiments, 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–,,. In some embodiments, 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 embodiments, L1isIn some embodiments, L1ishalogenated alkylene, such as fluorinated alkylene, e.g., , , , or .

[0192] In some embodiments, 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– CH2–, –C(CH3)2–CH2–CH2–, –CH(OH)–CH2–CH2–, –CH2–CH(OH)–CH2–, and –CH2–CH2– CH(OH)–.

[0193] In some embodiments, R7 is H, D, alkyl, or -C1-4alkyl-ORa. In some embodiments, R7is H, D, or alkyl. In some embodiments, R7is H or D. In some embodiments, R7is H. In other embodiments, R7is D. In some embodiments, R7is 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 CH2CH3. In some embodiments, R7is H, CH3, or CH2CH3. In some embodiments, R7is – CH2–OH, –CH2–OCH3, –CH2–CH2–OH, –CH2–CH2–OMe, –CH2–CH2–CH2–OH, or –CH2– CH2–CH2–OMe. In some embodiments, R7 is H, D, CH3, CH2CH3, or CH2OCH3. In some embodiments, R7is H, D, CH3, or CH2OCH3. In some embodiments, R7is H, CH3, or CH2CH3.

[0194] In some embodiments, R7’ is H, D, alkyl, or -C1-4alkyl-ORa. In some embodiments, R7’ is H, D, or alkyl. In some embodiments, R7’ is independently H or D. In some embodiments, R7’ is H. In other embodiments, R7’ is D. In some embodiments, R7’ 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 CH2CH3. In some embodiments, R7’ is H, CH3, or CH2CH3. In some embodiments, R7’ is – CH2–OH, –CH2–OCH3, –CH2–CH2–OH, –CH2–CH2–OMe, –CH2–CH2–CH2–OH, or –CH2– CH2–CH2–OMe. In some embodiments, R7’ is H, D, CH3, CH2CH3, or CH2OCH3. In some embodiments, R7’ is H, D, CH3, or CH2OCH3. In some embodiments, R7’ is H, CH3, or CH2CH3. 51 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0195] In some embodiments, is selected from the group consisting of –CH2–, – CH(CH3)–, –C(CH3)2–, and –CH(CH2CH3)–. In certain embodiments,some embodiments,. In some embodiments,C(CH3)2.

[0196] In some embodiments, L1 is selected from the group consisting of –CH2–CH2–, –is –CH2–. In some embodiments, L1is selected from the group consisting of –CH2–some embodiments, L1 is –CH2–CH2– andis –CH2–. In some embodiments, L1 is selected from the group consistingsome embodiments,In some embodiments,

[0197] In some embodiments,is an optionally substituted aryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. In some embodiments,is 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- 52 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 A SRa, or -C1-4alkyl-ORa. In certain embodiments, is phenyl which is optionally substituted with by 1-5 substituents each independently selected from the group consisting of A H, D, halogen, alkyl, CN, ORa, SRa, or NRaRb. In some embodiments, is 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. 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. In some A embodiments, is phenyl which is optionally substituted with by 1-3 substituents each independently selected from the group consisting of -C1-4alkyl-SRa, or -C1-4alkyl-ORa. In A certain embodiments, is phenyl which is optionally substituted with by 1-3 substituents each independently selected from the group consisting of H, D, halogen, alkyl, CN, ORa, SRa, A or NRaRb. In some embodiments, is phenyl which is substituted with at least one substituent selected from the group consisting of H, D, 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., CF3), CN, alkynyl (e.g., C≡CH), and cycloalkyl (e.g.,In some embodiments, A A is phenyl which is substituted with at least one halogen. In some embodiments, is phenyl which is substituted with at least one alkyl or alkoxy.53 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0199] In someis phenyl substituted with 1-5 halogens, e.g.,embodiments,. In someembodiments,

[0200] In some embodiments,is a heteroaryl. In some embodiments,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 NRaRb, -C1-4alkyl-SRa, and -C1-4alkyl-ORa. In some embodiments, is a 5- or 6- membered heteroaryl which is optionally substituted with by 1-4 substituents each 54 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 independently selected from the group consisting of H, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, and -C1- A4alkyl-ORa. In some embodiments, is a 5- or 6-membered heteroaryl which is optionally substituted with by 1-4 substituents each independently selected from the group consisting of CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, and -C1-4alkyl-ORa. In some A embodiments, is a 5- or 6-membered heteroaryl containing 1-3 heteroatoms each A independently is N, O, or S. In further embodiments, is pyridine, thiophene, or furan. A In some embodiments, is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted by alkyl, halogen, or OH. Non-limiting examples of 5-membered55 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024is selected from the groupis selected from the group

[0202] In some embodiments,is a 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic aryl or heteroaryl which is each 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 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.

[0203] In some embodiments,is selected from the group consisting56 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024substituted 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.

[0204] In some embodiments, X is a direct bond. In some embodiments, X is CR8R8’.

[0205] In some embodiments, R8is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, R8 is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, aryl, heteroaryl, or halogenated alkyl. In some embodiments, R8 is alkynyl, halogenated alkynyl, saturated heterocycle, partially saturated heterocycle, alkylaryl, or alkylheteroaryl. In some embodiments, R8 is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R8is 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. In some embodiments, R8 is D. In some embodiments, R8 is cycloalkyl or halogenated cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Non-limiting examples of halogenated cycloalkylsubstituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, 57 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl include,the like. In some embodiments, R8is H. In some embodiments, R8 is aryl. In some embodiments, R8 is phenyl. In some embodiments, R8 is heteroaryl. In some embodiments, R8 is selected from the group consisting of,

[0206] In some embodiments, R8’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, R8’ is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, aryl, heteroaryl, or halogenated alkyl. In some embodiments, R8’ is alkynyl, halogenated alkynyl, saturated heterocycle, partially saturated heterocycle, alkylaryl, or alkylheteroaryl. In some embodiments, R8’ is halogen. 58 ACTIVEUS 204604250Attorney 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. In some embodiments, R8’ is D. In some embodiments, R8’ is cycloalkyl or halogenated cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Non-limiting examples of halogenated cycloalkylsome 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. In some embodiments, R8’ is H. In some embodiments, R8’ is aryl. In some embodiments, R8’ is phenyl. In some embodiments, R8’ is heteroaryl. In some embodiments, R8’ is selected from the group consisting of,59 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0207] In some embodiments, Y1is a direct bond, CR3R3’, NR9, O, or S. In some embodiments, Y1is a direct bond or CR3R3’. In some embodiments, Y1is NR9, O, or S. In some embodiments, Y1 is NR9 or O. In some embodiments, Y1 is NR9. In some embodiments, Y1is O.

[0208] In some embodiments, Y2 is a direct bond, CR4R4’, NR10, O, or S. In some embodiments, Y2is a direct bond or CR4R4’. In some embodiments, Y2is NR10, O, or S. In some embodiments, Y2is NR10or O. In some embodiments, Y2is NR10. 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’. In some embodiments, Y1 is CR3R3’; and Y2is CR4R4’, NR10, O, or S. In some embodiments, Y1is CR3R3’; and Y2is CR4R4’. In some embodiments, Y1is CR3R3’; and Y2is NR10. In some embodiments, Y1is CR3R3’; and Y2 is O, or S. In some embodiments, Y1 is NR9, O, or S; and Y2 is CR4R4’.

[0210] In some embodiments, Y2 is a direct bond; and Y1 is CR3R3’, NR9, O, or S. In some embodiments, Y2 is a direct bond; and Y1 is CR3R3’. In some embodiments, Y2 is CR4R4’; and Y1is CR3R3’, NR9, O, or S. In some embodiments, Y2is CR4R4’; and Y1is CR3R3’. In some embodiments, Y2is CR4R4’; and Y1is NR9. In some embodiments, Y2is CR4R4’; and Y1 is O, or S. In some embodiments, Y2 is NR10, O, or S; and Y1 is CR3R3’.

[0211] In some embodiments, R1is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R1is 60 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R1is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1- 3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R1is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R1is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0212] In some embodiments, R1 is H, D, or alkyl. In some embodiments, R1 is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R1is D. In some embodiments, R1is 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. In some embodiments, R1is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R1is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R1is halogenated alkyl. Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R1is halogenated cycloalkyl. Non-limiting examples of halogenated61 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0213] In some embodiments, R1 is ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl- CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R1is ORa, SRa, or NRaRb. In some embodiments, R1 is (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, or (C=O)ORa. In some embodiments, R1 is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.

[0214] In some specific embodiments, R1is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R1 is OH, CH2OH, or CH2CH2OH.

[0215] In still other embodiments, R1is 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 isoptionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, 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. Non-limiting examples of N-containing heterocycle, partially saturated heterocycle,62 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0216] In some embodiments, R1is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like.

[0217] In some embodiments, R1is selected from the group consisting of H, D, CH3, CH2CH3, OH, F, Cl, Br, I, OCH3, CF3, CH2F, CHF2, CN, NH2, NHCH3, N(CH3)2, ,63 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0218] In some embodiments, R1is selected from the group consisting of H, D, Cl, Br, F, I, CN, CH3, CH2CH3, CF3, CH2CH2CH3, CH(CH3)2, , , , and . In some embodiments, R1is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R1is H, D, Cl, Br, or F.

[0219] In some embodiments, R1’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1- 4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R1’ is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R1’ is saturated 64 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1- 3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R1’ is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R1’ is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0220] In some embodiments, R1’ is H, D, or alkyl. In some embodiments, R1’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R1’ is D. In some embodiments, 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. In some embodiments, R1’ is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R1’ is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R1’ is halogenated alkyl. Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R1’ is halogenated cycloalkyl. Non-limiting examples of halogenated

[0221] In some embodiments, R1’ is ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R1’ is ORa, SRa, or NRaRb. In some embodiments, R1’ is (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, or (C=O)ORa. 65 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 In some embodiments, R1’ is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.

[0222] In some specific embodiments, R1’ is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R1’ is OH, CH2OH, or CH2CH2OH.

[0223] In still other embodiments, 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. In further embodiments, R1’ isoptionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R1’ 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,66 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0224] In some embodiments, R1’ is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting

[0225] In some embodiments, R1’ is selected from the group consisting of H, D, CH3,67 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br,

[0226] In some embodiments, R1’ is selected from the group consisting of H, D, Cl, Br, F, I,some embodiments, R1’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In some embodiments, R1’ is H, D, Cl, Br, or F.

[0227] In some embodiments, is –(C=O)–.

[0228] In some embodiments, R1 and R1’, together with the carbon atom that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0- 3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7- membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0229] In some embodiments, 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). In certain embodiments,, 68 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024. In some embodiments, R1and R1’, 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). In some embodiments, 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).

[0230] In some embodiments, R2is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, R2 is H, D, or halogen. In some embodiments, R2is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R2is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R2is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, - (CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0231] In some embodiments, R2is H, D, or alkyl. In some embodiments, R2is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R2is D. In some embodiments, R2is 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. In some embodiments, R2is a cycloalkyl. 69 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R2 is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R2is halogenated alkyl. Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R2is halogenated cycloalkyl. Non-limiting examples of halogenated

[0232] In still other embodiments, R2is 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, R2 is selected from the group consisting of,optionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, 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 include70 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0233] In some embodiments, 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 includethe like.

[0234] In some embodiments, R2 is selected from the group consisting of H, D, Cl, Br, F, I, CH3, CH2CH3, CF3, CH2CH2CH3, or CH(CH3)2. In some embodiments, R2is H, D, Cl, Br, or F.

[0235] In some embodiments, R2’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, R2’ is H, D, or halogen. In some embodiments, R2’ is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R2’ is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 71 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R2’ is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, - (CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0236] In some embodiments, R2’ is H, D, or alkyl. In some embodiments, R2’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R2’ is D. In some embodiments, R2’ 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. In some embodiments, R2’ is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R2’ is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R2is halogenated alkyl. Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R2’ is halogenated cycloalkyl. Non-limiting examples of halogenated

[0237] In still other embodiments, 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. In further embodiments, R2’ is selected from the group consisting of, 72 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024optionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, 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,73 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0238] In some embodiments, 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 includethe like.

[0239] In some embodiments, R2’ is selected from the group consisting of H, D, Cl, Br, F, I, CH3, CH2CH3, CF3, CH2CH2CH3, or CH(CH3)2. In some embodiments, R2’ is H, D, Cl, Br, or F.

[0240] In some embodiments, R3 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1- 4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R3 is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R3 is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1- 3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R3is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R3 is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0241] In some embodiments, R3is H, D, or alkyl. In some embodiments, R3is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R3is D. In some embodiments, R3is alkynyl, wherein the alkynyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of 74 ACTIVEUS 204604250Attorney 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. In some embodiments, R3 is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R3 is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R3 is halogenated alkyl. Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R3 is halogenated cycloalkyl. Non-limiting examples of halogenated

[0242] In some embodiments, R3 is ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl- CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R3is ORa, SRa, or NRaRb. In some embodiments, R3 is (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, or (C=O)ORa. In some embodiments, R3 is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.

[0243] In some specific embodiments, R3is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R3 is OH, CH2OH, or CH2CH2OH.

[0244] In still other embodiments, R3is 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, R3 is selected from the group consisting of,75 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024optionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R3 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

[0245] In some embodiments, R3 is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like. 76 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0246] In some embodiments, R3 is selected from the group consisting of H, D, CH3,77 ACTIVEUS 204604250Attorney 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.

[0248] In some embodiments, R3’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R3’ is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R3’ is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1- 3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R3’ is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R3’ is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0249] In some embodiments, R3’ is H, D, or alkyl. In some embodiments, R3’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R3’ is D. In some embodiments, R3’ 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. In some embodiments, R3’ is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R3’ is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R3is halogenated alkyl. Non- 78 ACTIVEUS 204604250Attorney 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. In some embodiments, R3’ is halogenated cycloalkyl. Non-limiting examples of halogenated

[0250] In some embodiments, R3’ is ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R3’ is ORa, SRa, or NRaRb. In some embodiments, R3’ is (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, or (C=O)ORa. In some embodiments, R3’ is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.

[0251] In some specific embodiments, R3’ is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R3’ is OH, CH2OH, or CH2CH2OH.

[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, R3’ isoptionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R3’ is a N-containing heterocycle, partially saturated heterocycle, or 79 ACTIVEUS 204604250Attorney 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. Non-limiting examples of N-containing heterocycle, partially saturated heterocycle,

[0253] In some embodiments, R3’ is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like.

[0254] In some embodiments, R3’ is selected from the group consisting of H, D, CH3, CH2CH3, OH, F, Cl, Br, I, OCH3, CF3, CH2F, CHF2, CN, NH2, NHCH3, N(CH3)2, ,80 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024is 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. In some embodiments, R3’ is H, D, Cl, Br, or F. In some embodiments, R3’ is OH. 81 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0256] In some embodiments, R2 and R3, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0- 3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7- membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. 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, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.

[0257] In some embodiments, R2and R3, 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). In some embodiments, R2 and R3, 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, R2 and R3, together with the carbon atoms that they are connected to, form a cyclopropyl group. In some embodiments, the 3- to 7-membered cycloalkyl ring or saturated heterocycle formed by R2and R3together 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, ORx(e.g., OH, OCH3), -(CH2)1-2ORx(e.g., CH2OH), or N(Rx)2(e.g., NH2, NHCH3, N(CH3)2).

[0258] In some embodiments, R4 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1- 4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R4 is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - 82 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R4 is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1- 3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R4 is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R4 is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0259] In some embodiments, R4 is H, D, or alkyl. In some embodiments, R4 is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R4 is D. In some embodiments, 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. In some embodiments, R4 is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R4is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R4 is halogenated alkyl. Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R4 is halogenated cycloalkyl. Non-limiting examples of halogenated

[0260] In some embodiments, R4is ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl- CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R4is ORa, SRa, or NRaRb. In 83 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 some embodiments, R4 is (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, or (C=O)ORa. In some embodiments, R4 is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.

[0261] In some specific embodiments, R4 is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R4 is OH, CH2OH, or CH2CH2OH.

[0262] In still other embodiments, R4is 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 selected from the group consisting of,optionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, 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. Non-limiting examples of N-containing heterocycle, partially saturated heterocycle, and84 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0263] In some embodiments, R4is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting

[0264] In some embodiments, R4is selected from the group consisting of H, D, CH3,85 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024is 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, CH3, CH2CH3, CF3, CH2CH2CH3, CH(CH3)2, , , , and . In some embodiments, 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.

[0266] In some embodiments, R4’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R4’ is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R4’ is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1- 3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence 86 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 permits. In some embodiments, R4’ is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R4’ is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0267] In some embodiments, R4’ is H, D, or alkyl. In some embodiments, R4’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R4’ is D. In some embodiments, 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. In some embodiments, R4’ is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R4’ is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R4’ is halogenated alkyl. Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R4’ is halogenated cycloalkyl. Non-limiting examples of halogenated

[0268] In some embodiments, R4’ is ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R4’ is ORa, SRa, or NRaRb. In some embodiments, R4’ is (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, or (C=O)ORa. In some embodiments, R4’ is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. 87 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0269] In some specific embodiments, R4’ is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R4’ is OH, CH2OH, or CH2CH2OH.

[0270] In still other embodiments, R4’ 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’ isoptionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R4’ is an 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,88 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0271] In some embodiments, R4’ is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like.

[0272] In some embodiments, R4’ is selected from the group consisting of H, D, CH3,89 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br,

[0273] In some embodiments, R4’ is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like.

[0274] In some embodiments, R4’ is selected from the group consisting of H, D, Cl, Br, F, I,some embodiments, 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.

[0275] In some embodiments, R1and R4, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0- 3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7- membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. 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 204604250Attorney 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, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.

[0276] In some embodiments, R1and 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). In some embodiments, 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. In some embodiments, the 3- to 7-membered cycloalkyl ring or saturated heterocycle formed by R1and R4together 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, ORx(e.g., OH, OCH3), -(CH2)1-2ORx(e.g., CH2OH), or N(Rx)2(e.g., NH2, NHCH3, N(CH3)2).

[0277] In some embodiments, R3and R4, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0- 3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7- membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1- 2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. 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, CHBrCH3, CH2CH2CF3, and CHClCHClCH3.

[0278] In some embodiments, 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). In some embodiments, R3and R4, together with the carbon atoms they are connected to, form a 3- to 7-membered saturated heterocycle comprising 0-3 91 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, R3 and R4, together with the carbon atoms that they are connected to, form a cyclopropyl group. In some embodiments, 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., 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).

[0279] In some embodiments, R9is 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. In some embodiments, R9 is H, CF3, CH2F, CHF2, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl- CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle. In some embodiments, R9 is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R9 is alkyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R9 is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, - (CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0280] In some embodiments, R9 is H or alkyl. In some embodiments, R9 is H or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R9 is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R9is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R9is 92 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include

[0281] In some embodiments, 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.

[0282] In still other embodiments, 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. In further embodiments, R9isoptionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R9is 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, and93 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0283] In some embodiments, R9 is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like.

[0284] In some embodiments, R9 is selected from the group consisting of H, CH3, CH2CH3,94 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024. In some embodiments, R9is selected from the group consisting of H, CH3,

[0285] In some embodiments, R9is selected from the group consisting of H, CH3, CH2CH3,

[0286] In some embodiments, R10 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. In some embodiments, R10is H, CF3, CH2F, CHF2, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl- CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle. In some embodiments, R10is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R10is alkyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R10is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, - (CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0287] In some embodiments, R10is H or alkyl. In some embodiments, R10is H or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, 95 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 heptyl, and octyl. In some embodiments, R10 is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R10is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R10 is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include

[0288] In some embodiments, R10is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle.

[0289] In still other embodiments, R10is 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, R10 isoptionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 permits. Non-limiting examples of N-containing heterocycle, partially saturated heterocycle,

[0290] In some embodiments, R10 is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like.

[0291] In some embodiments, R10is selected from the group consisting of H, CH3, CH2CH3,97 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024. In some embodiments, 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 of98 ACTIVEUS 204604250Attorney 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 of99 ACTIVEUS 204604250Attorney 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; R5bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; R6ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; and R6b is H, D, alkyl, halogen, ORa, or fluorinated alkyl. A

[0297] In some embodiments, , X, Y1, Y2, R1, R1’, R2, R2’, R7, and R7’ in Formula Ia are as defined above for the compound of Formula I. Other substituents are defined herein.

[0298] In some embodiments, R5a is H or D. In some embodiments R5a is ORa, e.g., OH or OCH3. In some embodiments, R5a is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R5ais halogen, e.g., F, 100 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Cl, Br, or I. In some embodiments, R5a is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, or CF2CH3, or CH2CHF2.

[0299] In some embodiments, R5bis H or D. In some embodiments, R5bis ORa, e.g., OH or OCH3. In some embodiments, R5b is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R5b is halogen, e.g., F, Cl, Br, or I. In some embodiments, R5bis fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.

[0300] In some embodiments, R6a is H or D. In some embodiments, R6a is ORa, e.g., OH or OCH3. In some embodiments R6ais alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R6ais halogen, e.g., F, Cl, Br, or I. In some embodiments, R6a is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.

[0301] In some embodiments, R6bis H or D. In some embodiments, R6bis ORa, e.g., OH or OCH3. In some embodiments, R6b is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R6b is halogen, e.g., F, Cl, Br, or I. In some embodiments, R6bis fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.101 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 CH(CH2)–, or -C(CH3)2–CH2–. In some embodiments,has the structure of

[0303] In some embodiments, the compound of Formula I has the structure of Formula Ib:, wherein R5ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R5bis H, D, alkyl, halogen, ORa, 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, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R23 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; R24 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; and 102 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R25 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.

[0304] In some embodiments, X, Y1, Y2, R1, R1’, R2, R2’, R7, and R7’ in Formula Ib are as defined above for the compound of Formula I. In some embodiments, R5a, R5b, R6a, and R6bin Formula Ib are as defined above for the compound of Formula Ia. Other substituents are defined herein.

[0305] In some embodiments, at least one of R21, R22, R24, and R25is not H. In some embodiments, at least two of R21, R22, R24, and R25 are not H. In some embodiments, at least one of R21, R22, R24, and R25is H, D, alkyl, halogenated alkyl, or halogen. In some embodiments, at least one of R21, R22, R24, and R25is CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa. In some embodiments, at least one of R21, R22, R24, and R25 is ORa, SRa, or NRaRb. In some embodiments, at least one of R21, R22, R24, and R25 is H, D, halogen, fluorinated alkyl, alkyl, alkenyl, or alkynyl. In some embodiments, at least one of R21, R22,In some embodiments, at least one of R21, R22, R24, and R25is H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3. In some embodiments, at least one of R21, R22, R24, and R25 is OH, OCH3, CH2OCH3. In some embodiments, at least one of R21, R22, R24, and R25 is Cl, F, Br, or I. In some embodiments, at least one of R21, R22, R24, and R25is Cl. In some embodiments, at least one of R21, R22, R24, and R25is CF3, CH2F, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, or CHClCHClCH3. In some embodiments, atembodiments, 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. In some embodiments, at least one of R21, R22, 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. In some embodiments, at least one of R21, R22, R24, and R25is CN. In some embodiments, at least two of R21, R22, R24, and R25are 103 ACTIVEUS 204604250Attorney 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] In some embodiments, R21, R22, R24, and R25are H; and R23is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa. In some embodiments, R21, R22, R24, and R25 are H; and R23 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa. In certain embodiments, R21, R22, R24, and R25are H; and R23is H or D. In certain embodiments, R21, R22, R24, and R25 are H; and R23 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, or -C1-4alkyl-ORa. In certain embodiments, R21, R22, R24, and R25are H; and R23is H, D, halogen, or alkyl. In certain embodiments, R21, R22, R24, and R25are H; and R23is ORa, SRa, or NRaRb. In certain embodiments, R21, R22, R24, 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. Non-limiting examples of 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-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.

[0307] In some embodiments, R23is alkyl (e.g., CH3, or CH2CH3,), ORa, (e.g., OH or OCH3), 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, R23is CH3,certain embodiments, R23is halogen (e.g., F, Cl, or Br). In some embodiments, R23is Cl. In some embodiments, R23is Br.

[0308] In some embodiments, R21, R22, R24, and R25are H; and R23is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa. In some embodiments, R21, R22, R24, and R25 are H; R23 is CH3, CH2CH3, OH, F, Cl, Br, OCH3, 104 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024some embodiments, R21, R22, R24, and R25 are H; R23is halogen. In some embodiments, R21, R22, R24, and R25are H; R23is 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.

[0309] In some embodiments, the compound of Formula I has the structure of Formula Ic or Id:, wherein each occurrence of R5ais independently H, D, alkyl, halogen, ORa, or fluorinated alkyl; each occurrence of R5bis 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; each occurrence of R21 is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; each occurrence of R22is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; 105 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 each occurrence of R23 is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; each occurrence of R24is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; and each occurrence of R25is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa.

[0310] In some embodiments, 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. In some embodiments, R5a, R5b, R6a, and R6bin Formula Ic or Id are as defined above for the compound of Formula Ia. In some embodiments, R21, R22, R23, R24, and R25 in Formula Ic or Id are as defined above for the compound of Formula Ib.

[0311] In some embodiments, the compound of Formula I has the structure of Formula Ie:wherein R5ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R23is H, D, halogen, alkyl, ORa, or NRaRb;106 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024R1is H, D, halogen, alkyl, or ORa; R1’ is H, D, halogen, alkyl, or ORa; R2 is H, D, halogen, alkyl, or ORa; R3 is H, D, halogen, alkyl, or ORa; R4is H, D, halogen, alkyl, or ORa; R4’ is H, D, halogen, alkyl, or ORa; R8 is H, D, or alkyl; and R10 is H or alkyl.

[0312] In some embodiments, R1, R1’, R2, R3, R4, R4’ R8, and R10 in Formula Ie are as defined above for the compound of Formula I. In some embodiments, R5a in Formula Ie is as defined above for the compound of Formula Ia. In some embodiments, R23in Formula Ie is as defined above for the compound of Formula Ib.

[0313] In one aspect, a compound of Formula II or a pharmaceutically acceptable salt thereof, or a tautomer thereof is described,wherein Z is NR11, O, or S; Q is a direct bond or CR13R13’; 107 ACTIVEUS 204604250Attorney 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, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl- saturated heterocycle; R12 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R12’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R13 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, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R14 is H, D, alkyl, or -C1-4alkyl-ORa; R14’is H, D, alkyl, or -C1-4alkyl-ORa; B is an aryl or heteroaryl optionally substituted 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; L2is –(CR15R16)m–; each occurrence of R15is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; 108 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 each occurrence of R16 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; m is 2 or 3; each occurrence of Ra and Rb is independently selected from the group consisting of H, D, alkyl, (C=O)Rx, (C=O)N(Rx)2, SO2Rx, NRx(C=O)N(Rx)2, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Ra and Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0- 3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl in R11, R12, R12’, R13, R13’, R14, R14’, R15, R16, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rxis independently H, D, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rx groups together with the nitrogen atom that they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

[0314] In some embodiments, m is 2. In other embodiments, m is 3.

[0315] In some embodiments, each occurrence of R15 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen. In some embodiments, each occurrence of R15is independently cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or CN. In other embodiments, each occurrence of R15 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl. In some embodiments, R15is independently H, D, ORa(e.g., OH, OMe, or OEt), or halogen (e.g., F, Cl, or Br).

[0316] In some embodiments, at least one occurrence of R15 is H or D. In some embodiments, at least one occurrence of R15 is ORa, e.g., OH, OMe, or OEt. In some embodiments, at least one occurrence of R15is -C1-4alkyl-ORa, e.g., CH2OH, CH2CH2OH, or 109 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 CH2OCH3. In some embodiments, at least one occurrence of R15 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, at least one occurrence of R15is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, at least one occurrence of R15is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, at least one occurrence of R15is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, at least one occurrence of R15is halogenated cycloalkyl. Non-limiting examples of

[0317] In some embodiments, each occurrence of R15is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or halogenated alkyl (e.g., fluorinated alkyl). In some embodiments, each occurrence of R15 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In certain embodiments, R15is independently H, D, OH, F, Cl, or Br. In some embodiments, R15 is independently H, D, OH, or F. In further embodiments, R15 is independently H, D, or OH.

[0318] In some embodiments, each occurrence of R16is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen. In some embodiments, each occurrence of R16 is independently cycloalkyl, halogenated cycloalkyl, -C1-4alkyl-ORa, or CN. In other embodiments, each occurrence of R16 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl. In some embodiments, R16is 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 R16is ORa, 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 pentyl, hexyl, heptyl, and octyl. In some embodiments, at least one occurrence of R16 is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, at least one occurrence of R16 is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, at least one occurrence of R16 is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, at least one occurrence of R16 is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include,

[0320] In some embodiments, each occurrence of R16 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or halogenated alkyl (e.g., fluorinated alkyl). In some embodiments, each occurrence of R15is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. In certain embodiments, R16 is independently H, D, OH, F, Cl, or Br. In some embodiments, R16 is independently H, D, OH, or F. In further embodiments, R16 is independently H, D, or OH.

[0321] In some embodiments, L2 is selected from the group consisting of –CH2–CH2–, –. In some embodiments, L2is selected from the group consisting of –CH2–CH2–, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH(OH)– 111 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024In some embodiments, L2 is –CH2–CH2–. In some embodiments, L2isIn some embodiments, L2is halogenated alkylene, such as fluorinated alkylene, e.g.,.

[0323] In some embodiments, L2 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– CH2–, –C(CH3)2–CH2–CH2–, –CH(OH)–CH2– CH2–, –CH2–CH(OH)–CH2–, and –CH2– CH2–CH(OH)–.

[0324] In some embodiments, 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, R14is D. In some embodiments, R14is alkyl. Non-limiting examples 112 ACTIVEUS 204604250Attorney 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. In some embodiments, R14 is H, D, CH3, or CH2CH3. In some embodiments, R14is H, CH3, or CH2CH3. In some embodiments, R14is –CH2–OH, –CH2– OCH3, –CH2–CH2–OH, –CH2–CH2–OMe, –CH2–CH2–CH2–OH, or –CH2–CH2–CH2–OMe. In some embodiments, R14 is H, D, CH3, CH2CH3, or CH2OCH3. In some embodiments, R14 is H, D, CH3, or CH2OCH3. In some embodiments, R14is H, CH3, or CH2CH3.

[0325] In some embodiments, R14’ is H, D, alkyl, or -C1-4alkyl-ORa. In some embodiments, R14’ is H, D, or alkyl. In some embodiments, R14’ is independently H or D. In some embodiments, R14’ is H. In other embodiments, R14’ is D. In some embodiments, R14’ 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. In some embodiments, R14’ is –CH2–OH, –CH2–OCH3, –CH2–CH2–OH, –CH2–CH2–OMe, –CH2–CH2–CH2–OH, or – CH2–CH2–CH2–OMe. In some embodiments, R14’ is H, D, CH3, CH2CH3, or CH2OCH3. In some embodiments, R14’ is H, D, CH3, or CH2OCH3. In some embodiments, R14’ is H, CH3, or CH2CH3.

[0326] In some embodiments,is selected from the group consisting of –CH2–, – CH(CH3)–, –C(CH3)2–, and –CH(CH2CH3)–. In certain embodiments,In some embodiments,

[0327] In some embodiments, L2 is selected from the group consisting of –CH2–CH2–, –is –CH2–. In some embodiments, L2is selected from the group consisting of – 113 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024some embodiments, L2 is –CH2–CH2– and is –CH2–. In some embodiments, L2 is selected from the group consisting of; and

[0328] In some embodiments,is an optionally substituted aryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. In some embodiments,is 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, or -C1-4alkyl-ORa. In certain embodiments,is phenyl which is optionally substituted with by 1-5 substituents each independently selected from the group consisting of H, D, halogen, alkyl, CN, ORa, SRa, or NRaRb. In some embodiments,is 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. 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. In some embodiments,is phenyl which is optionally substituted with by 1-3 substituents each 114 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 independently selected from the group consisting of -C1-4alkyl-SRa or -C1-4alkyl-ORa. In B certain embodiments, is phenyl which is optionally substituted with by 1-3 substituents each independently selected from the group consisting of H, D, halogen, alkyl, CN, ORa, SRa, B or NRaRb. In some embodiments, is phenyl which is substituted with at least one substituent selected from the group consisting of H, D, 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., CF3), CN, alkynyl (e.g., C≡CH), and cycloalkyl (e.g.,In some embodiments, is phenyl which is substituted with at least one halogen. In some embodiments, is phenyl which is substituted with at least one alkyl or alkoxy.

[0330] In some embodiments,is phenyl substituted with 1-5 halogens, e.g.,115 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024some embodiments,

[0331] In some embodiments,is a heteroaryl. In some embodiments,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. In some embodiments, is 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- B4alkyl-ORa. In some embodiments, is a 5- or 6-membered heteroaryl containing 1-3 B heteroatoms each independently is N, O, or S. In further embodiments, is pyridine, thiophene, or furan. In some embodiments, is a 5-membered heteroaryl, wherein the heteroaryl is optionally substituted by alkyl, halogen, or OH. Non-limiting examples of 5- membered heteroaryl include. 116 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024117 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0333] In some embodiments,is a 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic aryl or heteroaryl which is each 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 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.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. 118 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0335] In some embodiments, Z is NR11. In some embodiments, Z is O. In some embodiments, Z is S.

[0336] In some embodiments, Q is a direct bond. In some embodiments, Q is CR13R13’.

[0337] In some embodiments, 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 CR13R13’.

[0338] In some embodiments, R11is 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. In some embodiments, R11is H, CF3, CH2F, CHF2, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl- CONRaRb, -C1-4alkyl-NRaCORb, or -C1-4alkyl-saturated heterocycle. In some embodiments, R11is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R11is alkyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, - (CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R11is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0339] In some embodiments, R11is H or alkyl. In some embodiments, R11is H or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R11is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R11 is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R11is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include119 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0340] In some embodiments, 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.

[0341] In still other embodiments, R11is 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, R11 isoptionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R11 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,120 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0342] In some embodiments, R11is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like. In some embodiments, R11is optionally substituted heteroaryl. Non-limiting examples of heteroaryl includethe like.

[0343] In some embodiments, R11 is selected from the group consisting of H, CH3, CH2CH3,121 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0344] In some embodiments, R11is selected from the group consisting of H, CH3, CH2CH3,

[0345] In some embodiments, R12 is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R12is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R12is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1- 3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R12is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R12is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. 122 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0346] In some embodiments, R12 is H, D, or alkyl. In some embodiments, R12 is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R12 is D. In some embodiments, 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. In some embodiments, R12is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R12is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R12is halogenated alkyl. Non- limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R12is halogenated cycloalkyl. Non-limiting examples of halogenated

[0347] In some embodiments, R12is ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R12 is ORa, SRa, or NRaRb. In some embodiments, R12is (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, or (C=O)ORa. In some embodiments, R12is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.

[0348] In some specific embodiments, R12 is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R12is OH, CH2OH, or CH2CH2OH.

[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. In further embodiments, R12is selected from the group consisting of, 123 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024optionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R12is 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,124 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0350] In some embodiments, R12 is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like.

[0351] In some embodiments, R12 is selected from the group consisting of H, D, CH3,125 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024some embodiments, R12is 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.

[0353] In some embodiments, R12’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R12’ is H, D, halogen, CN, CF3, CH2F, CHF2, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R12’ is saturated heterocycle, partially saturated heterocycle, or heteroaryl, each optionally substituted with 1- 3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R12’ is alkyl, alkenyl, or alkynyl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits. In some embodiments, R12 is cycloalkyl, aryl, alkylaryl, or alkylheteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, alkyl, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits.

[0354] In some embodiments, R12’ is H, D, or alkyl. In some embodiments, R12’ is H, D, or alkyl, wherein the alkyl is optionally substituted by OH, oxo, or NH2. Non-limiting examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, and octyl. In some embodiments, R12’ is D. In some embodiments, 126 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 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. In some embodiments, R12’ is a cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, R12’ is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R12’ is halogenated alkyl. Non-limiting examples of halogenated alkyl include CF3, CH2F, CHF2, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, and CHClCHClCH3. In some embodiments, R12’ is halogenated cycloalkyl. Non-limiting examples of halogenated cycloalkyl include,

[0355] In some embodiments, R12’ is ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb. In some embodiments, R12’ is ORa, SRa, or NRaRb. In some embodiments, R12’ is (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, or (C=O)ORa. In some embodiments, R12’ is -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl- COORa, -C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb.

[0356] In some specific embodiments, R12’ is NH2, CH2NH2, or CH2CH2NH2. In other specific embodiments, R12’ is OH, CH2OH, or CH2CH2OH.

[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. In further embodiments, R12’ is selected from the group consisting of, 127 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024optionally substituted by alkyl, OH, NH2, or oxo where valence permits. In some embodiments, R12’ 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,128 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0358] In some embodiments, R12’ is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl includethe like.

[0359] In some embodiments, R12’ is selected from the group consisting of H, D, CH3,129 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024is selected from the group consisting of H, D, CH3, CH2CH3, CF2H, CH2F, CF3, CN, Cl, Br,

[0360] 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.

[0361] In some embodiments, R13is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, R13 is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, aryl, heteroaryl, or halogenated alkyl. In some embodiments, R13 is alkynyl, halogenated alkynyl, saturated heterocycle, partially saturated heterocycle, alkylaryl, or alkylheteroaryl. In some embodiments, R13 is halogen. Non-limiting examples of halogen include F, Cl, Br, and I. In some embodiments, R13is 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. In some embodiments, R13 is D. In some embodiments, R13 is cycloalkyl or halogenated cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Non-limiting examples of halogenated cycloalkylsome embodiments, R13is optionally substituted aryl or alkylaryl. Non-limiting examples of aryl include phenyl, biphenyl, 130 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 naphthyl, anthracenyl, and the like. Non-limiting examples of alkylaryl include,the like. In some embodiments, R13is H. In some

[0362] In some embodiments, R13’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl. In some embodiments, R13’ is H, D, halogen, alkyl, cycloalkyl, halogenated cycloalkyl, aryl, heteroaryl, or halogenated alkyl. In some embodiments, R13’ is alkynyl, halogenated alkynyl, saturated heterocycle, partially saturated heterocycle, alkylaryl, or alkylheteroaryl. In some embodiments, R13’ is halogen. 131 ACTIVEUS 204604250Attorney 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. In some embodiments, R13’ is D. In some embodiments, R13’ is cycloalkyl or halogenated cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Non-limiting examples of halogenated cycloalkylsome 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. In some embodiments, R13’ is H. In some embodiments, R13’ is aryl. In some embodiments, R13’ is phenyl. In some embodiments, R13’ is heteroaryl. In some embodiments, R13’ is selected from the group consisting of132 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024. In some embodiments, R13’ is selected from the group consisting of H, R13’ isof H,selected from the group consisting of133 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0365] In some embodiments,selected from the group consisting of ,

[0366] In some embodiments, the compound of Formula II has the structure of Formula IIa:, wherein R15ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R15bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; R16a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; and R16b is H, D, alkyl, halogen, ORa, or fluorinated alkyl. B

[0367] In some embodiments, , Z, Q, R12, R12’, R14, and R14’ in Formula IIa are as defined above for the compound of Formula II. Other substituents are defined herein.

[0368] In some embodiments, R15ais H or D. In some embodiments, R15ais ORa, e.g., OH or OCH3. In some embodiments, R15ais alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R15a is halogen, e.g., F, Cl, Br, or I. In some embodiments, R15a is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, or CF2CH3, or CH2CHF2.

[0369] In some embodiments, R15b is H or D. In some embodiments, R15b is ORa, e.g., OH or OCH3. In some embodiments, R15b is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R15bis halogen, 134 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 e.g., F, Cl, Br, or I. In some embodiments, R15b is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.

[0370] In some embodiments, R16ais H or D. In some embodiments, R16ais ORa, e.g., OH or OCH3. In some embodiments, R16a is alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R16a is halogen, e.g., F, Cl, Br, or I. In some embodiments, R16ais fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.

[0371] In some embodiments, R16b is H or D. In some embodiments, R16b is ORa, e.g., OH or OCH3. In some embodiments, R16bis alkyl, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, pentyl, hexyl, heptyl, or octyl. In some embodiments, R16bis halogen, e.g., F, Cl, Br, or I. In some embodiments, R16b is fluorinated alkyl, e.g., CF3, CH2F, CHF2, CH2CF3, CHFCH3, CF2CH3, or CH2CHF2.135 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024.

[0373] In some embodiments, 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; R16bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; R31is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R32is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R33is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R34is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; and 136 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R35 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.

[0374] In some embodiments, Z, Q, R12, R12’, R14, and R14’ in Formula IIb are as defined above for the compound of Formula II. In some embodiments, R15a, R15b, R16a, and R16bin Formula IIb are as defined above for the compound of Formula IIa. Other substituents are defined herein.

[0375] In some embodiments, at least one of R31, R32, R34, and R35is not H. In some embodiments, at least two of R31, R32, R34, and R35 are not H. In some embodiments, at least one of R31, R32, R34, and R35is H, D, alkyl, halogenated alkyl, or halogen. In some embodiments, at least one of R31, R32, R34, and R35is CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa. In some embodiments, at least one of R31, R32, R34, and R35 is ORa, SRa, or NRaRb. In some embodiments, at least one of R31, R32, R34, and R35 is H, D, halogen, fluorinated alkyl, alkyl, alkenyl, or alkynyl. In some embodiments, at least one R31, R32, R34,some embodiments, at least one of R31, R32, R34, and R35is H, Me, Et, i-Pr, n-Bu, CF2H, CF2Cl, or CF3. In some embodiments, at least one of R31, R32, R34, and R35 is OH, OCH3, CH2OCH3. In some embodiments, at least one of R31, R32, R34, and R35 is Cl, F, Br, or I. In some embodiments, at least one of R31, R32, R34, and R35is Cl. In some embodiments, at least one of R31, R32, R34, and R35is CF3, CH2F, CH2Cl, CH2CF3, CHFCH3, CHFCH2F, CF2CH3, CHClCH3, CCl2CH3, CHBrCH3, CH2CH2CF3, or CHClCHClCH3. In some embodiments, atembodiments, 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. In some embodiments, at least one of R31, R32, 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. In some embodiments, at least one of R31, R32, R34, and R35is CN. In some embodiments, at least two of R31, R32, R34, and R35are 137 ACTIVEUS 204604250Attorney 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] In some embodiments, R31, R32, R34, and R35are H; and R33is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa. In some embodiments, R31, R32, R34, and R35 are H; and R33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa. In certain embodiments, R31, R32, R34, and R35are H; and R33is H or D. In certain embodiments, R31, R32, R34, and R35 are H; and R33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, or -C1-4alkyl-ORa. In certain embodiments, R31, R32, R34, and R35are H; and R33is H, D, halogen, or alkyl. In certain embodiments, R31, R32, R34, and R35are H; and R33is ORa, SRa, or NRaRb. In certain embodiments, R31, R32, R34, 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. Non-limiting examples of 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-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.

[0377] In some embodiments, R33is alkyl (e.g., CH3, or CH2CH3,), ORa, (e.g., OH or OCH3), 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, R33is CH3,certain embodiments, R33is halogen (e.g., F, Cl, or Br). In some embodiments, R33is Cl. In some embodiments, R33is Br.

[0378] In some embodiments, R31, R32, R34, and R35are H; and R33is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa. In some embodiments, R31, R32, R34, and R35 are H; R33 is CH3, CH2CH3, OH, F, Cl, Br, OCH3, 138 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024some embodiments, R31, R32, R34, and R35 are H; R33is halogen. In some embodiments, R31, R32, R34, and R35are H; R33is 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.

[0379] In some embodiments, the compound of Formula II has the structure of Formula IIc:wherein R15ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R33 is H, D, halogen, alkyl, ORa, or NRaRb;selected from the group consistingR11is 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. In some embodiments, R15a in Formula IIc is as defined above for the compound of Formula IIa. In some embodiments, R33in Formula IIc is as defined above for the compound of Formula IIb. Raor Rbfor the compounds of Formulae I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc

[0381] The following description of Raor Rbis applicable for any one or more of the compounds of Formulas I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc. In some embodiments, at least one occurrence of Ra or Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, 139 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 aryl, or heteroaryl. In some embodiments, at least one occurrence of Ra or Rb is independently H, D, alkyl, or cycloalkyl. In some embodiments, at least one occurrence of Raor Rbis independently saturated heterocycle, aryl, or heteroaryl.

[0382] In some embodiments, at least one occurrence of Raor Rbis independently H, D, alkyl (e.g., Me, Et, or Pr), -C1-4alkyl-ORa(e.g., CH2OCH3,CH2OH, or CH2CH2OH), arylwherein the heterocycle is optionally substituted by alkyl, OH, oxo, or (C=O)C1-4alkyl where valence permits. In some embodiments, at least one occurrence of Ra or Rb is independently H, D, Me, Et, Pr, CH2CH2OH, phenyl, or a heterocycle selected from the group consisting of ,substituted by alkyl, OH, oxo, or (C=O)C1-4alkyl where valence permits. In some embodiments described herein, at least one occurrence of Ra or Rb is H, Me, phenyl,,

[0383] In some embodiments, 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. Non- limiting examples of heterocycle include140 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024Rxfor the compounds of Formulae I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc

[0384] The following description of Rxis applicable for any one or more of the compounds of Formulas I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc.

[0385] In some embodiments, for a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, II, IIa, IIb, and IIc described herein, each occurrence of Rx is independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH. In some embodiments, each occurrence of Rxis independently H or 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, at least one occurrence of Rx is optionally substituted heterocycle. Non-with the nitrogen atom that they are connected to, form an optionally substituted heterocycle including the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S. In some embodiments, each occurrence of Rx is independently H or Me.

[0386] In some embodiments, the compound of Formula I is selected from the group consisting of compounds 1-5, 7-23, and 27-30 in Table 2. In some embodiments, the compound of Formula II is selected from the group consisting of compounds 6 and 24-26 in 141 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Table 2. In some embodiments, the compound is any one of the compounds described herein, or pharmaceutically acceptable salts thereof or an enantiomer thereof.

[0387] The enumerated compounds in Tables 1-2 and Examples 1-15 are representative and non-limiting compounds of the embodiments disclosed herein. In some embodiments, the compound is any one of the compounds described herein, or pharmaceutically acceptable salts thereof or an enantiomer thereof. Abbreviations ACN Acetonitrile Boc or boc Tert-butyloxycarbonyl CAN Ceric ammonium nitrate CDI Carbonyldiimidazole DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMF Dimethyl formamide DMSO Dimethyl sulfoxide EA Ethyl acetate EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOH Ethanol HATU Hexafluorophosphate azabenzotriazole tetramethyl uronium HOBT Hydroxybenzotriazole MeOH Methanol NMP N-Methyl-2-Pyrrolidone PE Petroleum ether T3P Propanephosphonic acid anhydride TBS Tert-butyldimethylsilyl TBSCl Tert-butyldimethylsilyl choloride TFA Trifluoroacetic acid TMS Trimethylsilyl THF Tetrahydrofuran Methods of Preparation

[0388] Following are general synthetic schemes for manufacturing compounds of the present invention. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture the compounds disclosed herein. Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrations, but not limitations of the preparation of some of the starting materials and compounds disclosed herein. 142 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0389] 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. In the embodiments 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. The general synthetic routes described in Schemes 1-7 and examples described in the Example section below illustrate methods used for the preparation of the compounds described herein.

[0390] One direct route to prepare 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.

[0391] 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. Alternatively, 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.

[0392] In certain compounds where L1is (S)-CH(OH)CH2, these compounds can be obtained 143 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 from ketonitrile I-6. Reduction of the ketone with a suitable chiral reducing agent gives the S-alcohol I-7. One such chiral reducing agent is [N-[(1S,2S)-2-(amino-κN)-1,2- diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-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).

[0393] An alternative way to construct the oxadiazole is shown in Scheme 4. Alkylation of bicyclic imide I-3 with a suitably substituted bromoacetic ester I-9 followed by hydrolysis of the ester yields carboxylic acid I-10. The alkylation step is carried out with a base such as potassium carbonate in a solvent such as DMF. The hydrolysis is achieved with an aqueous alkali such as lithium hydroxide. Acid I-10 is then reacted with amide oxime I-5 and a coupling reagent such as EDCI or T3P. The intermediate formed is cyclized by heating in a solvent such as toluene or DMF to give the oxadiazole I-1.144 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0394] Some bicyclic imides I-3 are commercially available. Others can be synthesized as shown in Scheme 5 starting either from an azaheterocyclic amide I-11 or from an azaheterocyclic ester I-12, both of which can be prepared from commercial precursors by standard methods. Reaction of I-11 with carbonyl diimidazole and optionally a base such as triethylamine in a solvent such as THF or acetonitrile provides I-3 directly. 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. One suitable protecting group is 4-methoxybenzyl. Removal of the protecting group then yields I-3. When 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. 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. When R1 or R1’ is OH, or Y1 or Y2 is N, it may be necessary to protect those groups with standard protecting groups; for example, TBS for OH or boc for NH.145 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0395] 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.

[0396] 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. Alkylation of aryl amine I-17 with a bromoacetic ester I-18 and a base such as potassium carbonate in a solvent such as DMF gives ester I-19, that is converted to primary amide I-20 by treatment with aqueous ammonia in a solvent such as dioxane. Reaction of I-20 with di-t-butyl dicarbonate and a base such as triethylamine in a solvent such as DCM provides Boc-protected amine I-21 that is cyclized to I-16a using a base such as sodium hydride in a solvent such as DMF.Pharmaceutical 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. The composition can be administered to the 146 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 subject by any suitable route of administration, including, without limitation, oral and parenteral.

[0400] The phrase “pharmaceutically acceptable carrier” as used herein 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. Some examples of 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; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. The term “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.

[0401] As set out above, certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt,” as used herein, refers to the relatively non-toxic, inorganic and organic acid salts of compounds of the present invention. These 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 the like. See, e.g., Berge et al., (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19 (incorporated herein by reference in its entirety).

[0402] 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. For example, 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.

[0403] In other cases, 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. The term “pharmaceutically acceptable salts” in these instances 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).

[0404] Wetting agents, emulsifiers, and lubricants, 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.

[0405] 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 204604250Attorney 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%.

[0406] 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. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0407] 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.

[0408] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), 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 accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymer; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of 149 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 capsules, tablets and pills, the pharmaceutical 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.

[0409] 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. They 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. Examples of embedding compositions, which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0411] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins, e.g., hydroxybutyl-β-cyclodextrin, may be used to solubilize compounds.

[0412] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

[0413] 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.

[0414] 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.

[0415] 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.

[0416] 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. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and butane.

[0417] 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.

[0418] Ophthalmic formulations, eye ointments, powders, solutions, and the like, are also contemplated as being within the scope of this invention. 151 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0419] Pharmaceutical 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.

[0420] In some cases, 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.

[0421] 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.

[0422] When 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.

[0423] 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. It 152 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another anticancer agents).

[0424] 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.

[0425] 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. Administration to a Subject / Methods of Treating a Condition

[0426] In yet another aspect, 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.

[0427] In some embodiments, 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.

[0428] In some embodiments, the urinary tract or bladder disorder is pelvic hypersensitivity, urinary incontinence, cystitis, bladder instability, or bladder outlet obstruction. In some 153 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 embodiments, the skin disorder is burns, psoriasis, eczema, or pruritus. In some embodiments, the skin disorder is atopic dermatitis or psoriasis-induced itching.

[0429] In some embodiments, 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.

[0430] In some embodiments, the ischemia is CNS hypoxia or a disorder associated with reduced blood flow to CNS. In some embodiments, the autoimmune disease is rheumatoid arthritis or multiple sclerosis. In some embodiments, the central nervous system disorder is associated with neurodegeneration. In some embodiments, the gastroenterological disorder is an inflammatory bowel disease, esophagitis, gastroesophageal reflux disorder, irritable bowel syndrome, emesis, or stomach duodenal ulcer. In some embodiments, the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy.

[0431] In some embodiments, the mammalian species is human.

[0432] In yet another aspect, a method of inhibiting transient receptor potential ankyrin 1 (TRPA1) in a mammalian species in need thereof is described, 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.

[0433] In some embodiments, 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. In some embodiments, the compounds described herein do not block the hERG channels and therefore have desirable cardiovascular safety profiles.

[0434] 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.

[0435] 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.

[0436] For use in therapy, 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 204604250Attorney 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.

[0437] For example 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.

[0438] The concentration of compounds included in compositions used in the methods of the invention can range from about 1 nM to about 100 μM. Effective doses are believed to range from about 10 picomole / kg to about 100 micromole / kg.

[0439] 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. The administration of a given dose can be carried out both by single administration in the form of an individual dose 155 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 unit or else several smaller dose units. Repeated and multiple administration of doses at specific intervals of days, weeks, or months apart are also contemplated by the invention.

[0440] The compositions can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine 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. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0441] 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).

[0442] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations, which can be isotonic with the blood of the recipient. Among the acceptable vehicles and solvents are water, Ringer’s solution, phosphate buffered saline, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed mineral or non-mineral oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, etc. administrations can be found in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA; incorporated herein by reference in its entirety.

[0443] 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.

[0444] 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 efficacy. The methods of this invention, generally speaking, can be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of response without causing clinically unacceptable adverse effects. Preferred modes of administration are discussed above.

[0445] The 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.

[0446] Other delivery systems can include time-release, delayed release, or sustained-release delivery systems. Such 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. 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. Specific examples include, 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. Nos.4,452,775, 4,675,189, and 5,736,152 (each incorporated herein by reference in its entirety), and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Pat. Nos.3,854,480, 5,133,974, and 5,407,686 (each incorporated herein by reference in its entirety). In addition, pump-based hardware delivery systems can be used, some of which are adapted for implantation. Assays for Effectiveness of TRPA1 Channel Inhibitors

[0447] In some embodiments, the compounds as described herein were tested for their activities against TRPA1 channel. In some embodiments, the compounds as described herein 157 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 were tested for their TRPA1 channel electrophysiology. In some embodiments, the compounds as described herein were tested for their hERG electrophysiology. 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. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, exemplification, and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof. EXAMPLES

[0449] 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. Intermediate 1 ((1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4- chlorophenyl)ethan-1-ol); Intermediate 2 (3-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-2-(4- chlorophenyl)ethyl]-5-(chloromethyl)-1,2,4-oxadiazole)Step a:

[0450] To a stirred solution of 3-(4-chlorophenyl)-3-oxopropanenitrile (50.0 g, 278 mmol) and 1,3,5-trimethylbenzene; N-[(1S,2S)-2-amino-1,2-diphenylethyl]-N-(chlororuthenio)-4- methylbenzene-1-sulfonamide (0.710 g, 1.14 mmol) in ACN (500 mL) was added formic acid triethylamine complex (5:2) (40 mL) at 0 °C. The mixture was stirred at room 158 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 temperature for 3 h under nitrogen, concentrated under reduced pressure, diluted with ice water (500 mL), and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (7:1) to afford (3S)-3-(4-chlorophenyl)-3-hydroxypropanenitrile as a yellow oil (35.0 g, 69.3%): LCMS (ESI) calc’d for C9H8ClNO [2M - 1]-: 361, 363 (3 : 1) found 361, 363 (3 : 1); 1H NMR (400 MHz, DMSO-d6) δ 7.45-7.42 (m, 4H), 6.03 (d, J = 4.6 Hz, 1H), 4.94-4.90 (m, 1H), 2.94-2.80 (m, 2H). 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 ℃ for 16 h. The cooled mixture was concentrated under reduced pressure to afford (3S)-3-(4-chlorophenyl)- N,3-dihydroxypropanimidamide as a brown oil (30.0 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C9H11ClN2O2 [M + H]+: 215, 217 (3 : 1), found 215, 217 (3 : 1);1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.38-7.35 (m, 4H), 5.40 (d, J = 4.2 Hz, 3H), 4.95-4.79 (m, 1H), 2.39-2.14 (m, 2H). 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 ℃. The reaction was stirred at 0 ℃ for 2 h then heated at 95 ℃ for 4 h. The resulting mixture was quenched with water (500 mL) at 0 ℃ and extracted with EA (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with PE / EA (5 / 1) to afford (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethanol as a yellow solid (15.0 g, 33.0%, over three steps): LCMS (ESI) calc’d for C11H10Cl2N2O2[M - H]-: 271, 273 (3 : 2) found 271, 273 (3 : 2);1H NMR (300 MHz, DMSO-d6) δ 7.47-7.33 (m, 4H),, 5.67 (d, J = 4.9 Hz, 1H), 5.09 (s, 2H), 5.02-5.00 (m, 1H), 3.11-2.96 (m, 2H). 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 204604250Attorney 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). The combined organic layers were washed with brine (5 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with PE / EA (3 / 1) to afford 3-[(2S)-2-[(tert-butyldimethylsilyl)oxy]- 2-(4-chlorophenyl)ethyl]-5-(chloromethyl)-1,2,4-oxadiazole as a colorless oil (0.200 g, 50.8%): LCMS (ESI) calc’d for C17H24Cl2N2O2Si [M + H]+: 387, 389 (3 : 2) found 387, 389 (3 : 2).1H NMR (400 MHz, DMSO-d6) δ 7.49-7.39 (m, 4H), 5.16 (d, J = 4.1 Hz, 1H), 5.10 (s, 2H), 3.12-2.96 (m, 2H), 0.73 (s, 9H), -0.14 (s, 3H), -0.23 (s, 3H). Example 2. Intermediate 3 (tert-Butyl 1,3-dioxohexahydroimidazo[1,5-a]pyrazine- 7(1H)-carboxylate)Step a:

[0454] A solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (1.00 g, 4.09 mmol) and isocyanatotrimethylsilane (0.471 g, 4.09 mmol) in DCM (15 mL) was stirred at room temperature for 12 h under nitrogen. The resulting mixture was concentrated under reduced pressure to afford 1-tert-butyl 3-methyl 4-carbamoylpiperazine-1,3-dicarboxylate as a light- yellow oil (1.10 g, 93.5%), which was used in the next step directly without purification: LCMS (ESI) calc’d C12H21N3O5 for [M + H - 56]+: 232 found 232. 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). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl 1,3-dioxo-tetrahydro-2H-imidazo[1,5-a]pyrazine-7- carboxylate as an off-white solid (0.600 g, 67.5%), which was used in the next step directly without purification: LCMS (ESI) calc’d C11H17N3O4 for [M - H]-: 254 found 254. Example 3. Intermediate 4 ((4aR)-Hexahydropyrrolo[1,2-c]pyrimidine-1,3-dione) 160 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024Step a:

[0456] To a stirred mixture of [(2R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]acetic acid (1.00 g, 4.36 mmol) and NH4OAc (1.68 g, 21.8 mmol) in DCM (10 mL) were added HOBT (0.880 g, 6.54 mmol), EDCI (1.02 g, 6.54 mmol), and TEA (1.32 g, 13.1 mmol) at room temperature. The 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. The residue was purified by reverse phase chromatography, eluting with 28% ACN in water (plus 10 mM NH4HCO3), to afford tert-butyl (2R)-2-(carbamoylmethyl)pyrrolidine- 1-carboxylate as a yellow solid (0.350 g, 35.1%): LCMS (ESI) calc’d for C11H20N2O3 [M + H]+: 229 found 229;1H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 6.78 (s, 1H), 3.98-3.87 (m, 1H), 3.27-3.10 (m, 2H), 2.52 (dd, J = 55.44, 14.41 Hz, 1H), 2.12-1.96 (m, 1H), 1.94-1.61 (m, 4H), 1.40 (s, 9H). 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 K2CO3(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. The cooled mixture was concentrated under reduced pressure and the residue purified by reverse phase chromatography, eluting with 17% ACN in water (plus 10 mM NH4HCO3) to afford (4aR)-hexahydropyrrolo[1,2-c]pyrimidine-1,3-dione as an off- white solid (0.200 g, 55.4%): LCMS (ESI) calc’d for C7H10N2O2 [M + H]+: 155 found 155;1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 3.74-3.63 (m, 1H), 3.43-3.36 (m, 1H), 3.31- 161 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 3.24 (m, 1H), 2.56 (dd, J = 16.07, 4.23 Hz, 1H), 2.41 (dd, J = 16.08, 13.00 Hz, 1H), 2.17- 2.07 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.71 (m, 1H), 1.59-1.46 (m, 1H). Example 4. Intermediate 5 ((6R,7aS)-6-[(tert-butyldimethylsilyl)oxy]-tetrahydro-2H- pyrrolo[1,2-c]imidazole-1,3-dione)Step a:

[0459] A solution of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (5.00 g, 20.4 mmol) in NH3·H2O (50 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure to afford tert-butyl (2S,4R)-2- carbamoyl-4-hydroxypyrrolidine-1-carboxylate as a colorless oil (5.00 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C10H18N2O4 [M + H]+: 231 found 231;1H NMR (400 MHz, DMSO-d6) δ 7.33 (d, J = 14.16 Hz, 1H), 6.87 (d, J = 29.12 Hz, 1H), 4.97 (s, 1H), 4.27-4.16 (m, 1H), 4.13-4.02 (m, 1H), 3.43-3.34 (m, 1H), 3.28-3.20 (m, 1H), 2.07-1.95 (m, 1H), 1.84-1.74 (m, 1H), 1.39 (d, J = 17.7 Hz, 9H). 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. The reaction was stirred for 16 h, concentrated under reduced pressure, 162 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 and the residue was purified by reverse phase chromatography, eluting with 5 % ACN in water (plus 10 mM NH4HCO3), to afford (6R,7aS)-6-hydroxy-tetrahydro-2H-pyrrolo[1,2- c]imidazole-1,3-dione as a yellow oil (15.0 g, mixed with imidazole): LCMS (ESI) calc’d for C6H8N2O3 [M + H]+: 157 found 157;1H NMR (400 MHz, DMSO-d6) δ 5.24-5.16 (m, 1H), 4.40-4.33 (m, 1H), 4.05 (dd, J = 9.85, 7.09 Hz, 1H), 3.61 (dd, J = 11.60, 5.26 Hz, 1H), 2.81 (dd, J = 11.51, 2.22 Hz, 1H), 1.91-1.83 (m, 1H), 1.71-1.60 (m, 1H). 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. The residue was purified by silica gel column chromatography, eluting with PE / EA (2 / 1) to afford (6R,7aS)-6-[(tert- butyldimethylsilyl)oxy]-tetrahydro-2H-pyrrolo[1,2-c]imidazole-1,3-dione as an off-white solid (0.55 g, 7.06%): LCMS (ESI) calc’d for C12H22N2O3Si [M + H]+: 271 found 271;1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 4.67-4.59 (m, 1H), 4.27 (dd, J = 9.66, 7.58 Hz, 1H), 3.70 (dd, J = 11.53, 4.92 Hz, 1H), 2.94-2.86 (m, 1H), 1.94-1.85 (m, 2H), 0.87 (s, 9H), 0.08 (d, J = 2.31 Hz, 6H). Example 5. Intermediate 6 (tert-Butyl 6,8-dioxo-hexahydropyrazino[1,2-c]pyrimidine-2- carboxylate)Step a:

[0463] A solution of tert-butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate hydrochloride (0.500 g, 1.70 mmol) in NH3·H2O (5 mL) was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 25% ACN in water (plus 10 mM NH4HCO3) to afford tert- butyl 3-(carbamoylmethyl)piperazine-1-carboxylate as an off-white solid (0.300 g, 72.7%): LCMS (ESI) calc’d for C11H21N3O3 [M + H]+: 244 found 244;1H NMR (400 MHz, DMSO- 163 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 d6) δ 8.16 (s, 1H), 7.62 (s, 1H), 7.10 (s, 1H), 3.94 (d, J = 13.48 Hz, 1H), 3.88-3.77 (m, 1H), 3.32-3.21 (m, 1H), 3.16-3.06 (m, 2H), 2.98-2.74 (m, 2H), 2.50-2.37 (m, 2H), 1.41 (s, 9H). 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. After cooling down to room temperature, the cooled mixture was concentrated under reduced pressure and the residue purified by reverse phase chromatography, eluting with 30% ACN in water (plus 0.05% TFA), to afford tert-butyl 6,8-dioxo-hexahydropyrazino[1,2-c]pyrimidine- 2-carboxylate as a light yellow solid (0.180 g, 54.2%): LCMS (ESI) calc’d for C12H19N3O4[M + Na]+: 292 found 292;1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 4.04-3.87 (m, 3H), 3.55-3.41 (m, 1H), 2.80-2.69 (m, 1H), 2.69-2.55 (m, 2H), 2.50-2.39 (m, 2H), 1.42 (s, 9H). Example 6. Intermediate 7 (Hexahydropyrazino[1,2-c]pyrimidine-1,6,8-trione)Step a:

[0465] To a stirred mixture of ethyl 2-(3-oxopiperazin-2-yl)acetate (0.500 g, 2.68 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (0.657 g, 4.02 mmol) in DMF (5 mL) was added TEA (0.543 g, 5.37 mmol) at room temperature under nitrogen. The reaction was stirred for 3 h and purified by reverse phase chromatography, eluting with 60% ACN in water (plus 10 mM NH4HCO3) to afford 7-[(4-methoxyphenyl)methyl]-tetrahydro-2H-pyrazino[1,2- c]pyrimidine-1,6,8-trione as an off-white solid (0.150 g, 18.4%): LCMS (ESI) calc’d for C15H17N3O4 [M + H]+: 304 found 304;1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 3.82 Hz, 1H), 7.24-7.16 (m, 2H), 6.88-6.81 (m, 2H), 4.75 (q, J = 14.46 Hz, 2H), 4.28 (dd, J = 12.51, 5.32 Hz, 1H), 4.11-4.04 (m, 1H), 3.72 (s, 3H), 3.31-3.14 (m, 3H), 2.97-2.81 (m, 2H). 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 CF3SO3H (0.4 164 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 mL) at room temperature. After 16 h, the resulting mixture was concentrated under reduced pressure to afford hexahydropyrazino[1,2-c]pyrimidine-1,6,8-trione as a red liquid (0.150 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C7H9N3O3 [M + H]+: 184 found 184;1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.17 (s, 1H), 4.28-4.14 (m, 1H), 4.06-3.92 (m, 1H), 3.30-3.03 (m, 3H), 2.77-2.62 (m, 2H). Example 7. Intermediate 8 ((R)-Hexahydro-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione)Step a:

[0467] To a solution of [(2R)-1-(tert-butoxycarbonyl)piperidin-2-yl]acetic acid (1.00 g, 4.11 mmol) and NH4Cl (1.10 g, 20.6 mmol) in DMF (10 mL) were added HATU (2.34 g, 6.16 mmol) and TEA (1.25 g, 12.3 mmol) at room temperature. The reaction was stirred for 3 h, diluted with water (80 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (5 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA, to afford tert-butyl (2R)-2-(carbamoylmethyl)piperidine-1- carboxylate as a light yellow oil (0.850 g, 85.0%): LCMS (ESI) calc’d for C12H22N2O3 [M + H]+: 243 found 243;1H NMR (400 MHz, DMSO-d6) δ 7.29 (s, 1H), 6.78 (s, 1H), 4.54-4.42 (m, 1H), 4.14-4.04 (m, 1H), 3.88-3.74 (m, 1H), 3.23-3.12 (m, 2H), 2.81-2.71 (m, 1H), 2.46- 2.36 (m, 1H), 2.19 (dd, J = 13.61, 6.53 Hz, 1H), 1.61-1.43 (m, 3H), 1.39 (s, 9H). 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). The filter cake was dried under reduced pressure to afford 2-[(2R)-piperidin-2-yl]acetamide hydrochloride as an off-white solid (0.440 g, 88.0%): LCMS (ESI) calc’d for C7H14N2O [M + H]+: 143 found 143;1H NMR (400 MHz, DMSO-d6) δ 9.13-8.78 (m, 2H), 7.67 (s, 1H), 7.12 165 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 (s, 1H), 3.37-3.25 (m, 1H), 3.25-3.13 (m, 1H), 2.92-2.78 (m, 1H), 2.56 (dd, J = 15.79, 5.97 Hz, 1H), 2.44 (dd, J = 15.77, 7.26 Hz, 1H), 1.82-1.56 (m, 4H), 1.52-1.41 (m, 2H). 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. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 5) to afford (R)- hexahydro-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as an off-white solid (40.0 mg, 17.0%): LCMS (ESI) calc’d for C8H12N2O2 [M + H]+: 169 found 169;1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 4.16-3.99 (m, 1H), 3.45-3.33 (m, 1H), 2.72-2.55 (m, 2H), 2.45- 2.31 (m, 1H), 1.80-1.58 (m, 3H), 1.45-1.13 (m, 3H). Example 8. Intermediate 9 (Tetrahydro-2H-imidazo[4,3-c][1,4]oxazine-1,3-dione)Step a:

[0470] To a stirred solution of methyl morpholine-3-carboxylate hydrochloride (0.500 g, 2.75 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (0.674 g, 4.13 mmol) in THF (5 mL) was added NaH (0.275 g, 6.88 mmol, 60% in oil) at room temperature. The reaction was stirred for 2 h, quenched with water (10 mL), and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 42% ACN in water (plus 10 mM NH4HCO3) to afford 2-[(4-methoxyphenyl)methyl]-tetrahydroimidazo[4,3- c][1,4]oxazine-1,3-dione as a colorless oil (0.368 g, 48.4%): LCMS (ESI) calc’d for C14H16N2O4[M + H]+: 277 found 277;1H NMR (400 MHz, CDCl3) δ 7.40-7.31 (m, 2H), 6.94-6.77 (m, 2H), 4.62 (s, 2H), 4.28 (dd, J = 11.31, 4.87 Hz, 1H), 4.11 (dd, J = 10.76, 4.88 Hz, 1H), 4.03 (dd, J = 13.50, 3.12 Hz, 1H), 3.94 (dd, J = 11.54, 3.97 Hz, 1H), 3.81 (s, 3H), 3.37 (td, J = 11.80, 3.22 Hz, 1H), 3.29-3.22 (m, 1H), 3.22-3.13 (m, 1H). Step b: 166 ACTIVEUS 204604250Attorney 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. The residue was purified by reverse phase chromatography, eluting with 5% ACN in water (plus 10 mM NH4HCO3) to afford tetrahydro-2H-imidazo[4,3-c][1,4]oxazine-1,3- dione as an off-white solid (0.900 g, 79.6%): LCMS (ESI) calc’d for C6H8N2O3[M + H]+: 157 found 157;1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 4.23-4.14 (m, 1H), 4.07-3.97 (m, 1H), 3.86-3.72 (m, 2H), 3.40-3.24 (m, 2H), 3.07-2.96 (m, 1H). Example 9. Intermediate 10 (Hexahydropyrimido[4,3-c][1,4]oxazine-6,8-dione)Step a:

[0472] To a stirred solution of methyl 2-(morpholin-3-yl)acetate hydrochloride (0.500 g, 2.56 mmol) in DMF (5 mL) was added NaH (0.122 g, 5.11 mmol, 60% in oil) in portions at 0 °C. The reaction was stirred for 30 min under nitrogen, then 1-(isocyanatomethyl)-4- methoxybenzene (0.625 g, 3.83 mmol) in DMF (1 mL) was added dropwise at 0 °C over 1 min. The reaction mixture was allowed to warm to room temperature. After 16 h, the mixture was quenched with saturated aq. NH4Cl (30 mL) at 0 °C and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2 / 1), to afford 7-[(4- methoxyphenyl)methyl]-tetrahydro-1H-pyrimido[4,3-c][1,4]oxazine-6,8-dione as an off- white solid (0.400 g, 53.9%): LCMS (ESI) calc’d for C15H18N2O4 [M + H]+: 291 found 291;1H NMR (300 MHz, DMSO-d6) δ 7.25-7.15 (m, 2H), 6.91-6.80 (m, 2H), 4.89-4.62 (m, 2H), 3.99-3.79 (m, 3H), 3.73 (s, 3H), 3.67-3.53 (m, 1H), 3.50-3.38 (m, 1H), 3.11 (t, J = 10.80 Hz, 1H), 2.98-2.83 (m, 1H), 2.66 (dd, J = 16.65, 4.87 Hz, 1H), 2.55 (d, J = 13.29 Hz, 1H). 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 204604250Attorney 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. The residue was purified by reverse phase chromatography, eluting with 20% ACN in water (plus 10 mM NH4HCO3), to afford hexahydropyrimido[4,3-c][1,4]oxazine-6,8-dione as an off-white solid (0.180 g, 90.3%): LCMS (ESI) calc’d for C7H10N2O3 [M + H]+: 171 found 171;1H NMR (300 MHz, DMSO- d6) δ 10.32 (s, 1H), 3.96-3.85 (m, 1H), 3.85-3.78 (m, 2H), 3.62-3.50 (m, 1H), 3.42 (td, J = 11.92, 2.81 Hz, 1H), 3.10 (dd, J = 11.37, 10.29 Hz, 1H), 2.84 (ddd, J = 13.37, 12.20, 3.85 Hz, 1H), 2.45 (d, J = 5.01 Hz, 1H), 2.35 (dd, J = 16.72, 12.13 Hz, 1H). Example 10. Intermediate 11 (7-[(tert-Butyldimethylsilyl)oxy]-hexahydroimidazo[1,5-Step a:

[0474] A solution of 1-tert-butyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate (2.00 g, 7.71 mmol) in HCl / MeOH (4 M, 10 mL) was stirred at room temperature for 16 h and concentrated under reduced pressure to afford methyl 4-hydroxypiperidine-2-carboxylate hydrochloride as an off-white solid (1.50 g, 99.0%): LCMS (ESI) calc’d for C7H13NO3[M + H]+: 160 found 160;1H NMR (300 MHz, DMSO-d6) δ 9.23 (brs, 2H), 4.88 (s, 1H), 4.25-4.06 (m, 1H), 3.84-3.68 (m, 4H), 3.34-3.22 (m, 1H), 2.99-2.82 (m, 1H), 2.28-2.14 (m, 1H), 1.96- 1.81 (m, 1H), 1.70-1.49 (m, 2H). 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). The combined organic layers were 168 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 washed with brine (5 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1 / 1), to afford methyl 4-[(tert-butyldimethylsilyl)oxy]piperidine-2- carboxylate as a colorless oil (0.550 g, 26.0%): LCMS (ESI) calc’d for C13H27NO3Si [M + H]+: 274 found 274;1H NMR (300 MHz, CDCl3) δ 3.80-3.68 (m, 4H), 3.41 (dd, J = 10.53, 3.35 Hz, 1H), 3.23 (dt, J = 12.73, 4.13 Hz, 1H), 2.72-2.58 (m, 1H), 2.23-2.13 (m, 1H), 1.89- 1.78 (m, 1H), 1.60-1.36 (m, 2H), 0.90 (s, 9H), 0.08 (s, 6H). 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. The residue was purified by silica gel column chromatography, eluting with PE / EA (5 / 1) to afford 7-[(tert- butyldimethylsilyl)oxy]-2-[(4-methoxyphenyl)methyl]-tetrahydro-5H-imidazo[1,5- a]pyridine-1,3-dione as a colorless oil (0.300 g, 41.0%): LCMS (ESI) calc’d for C21H32N2O4Si [M + H]+: 405 found 405;1H NMR (400 MHz, DMSO-d6) δ 7.41-7.32 (m, 2H), 6.91-6.82 (m, 2H), 4.60 (s, 2H), 4.27-4.16 (m, 1H), 3.90-3.73 (m, 5H), 2.88 (td, J = 13.39, 3.41 Hz, 1H), 2.40-2.28 (m, 1H), 1.93-1.81 (m, 1H), 1.49-1.35 (m, 1H), 1.34-1.22 (m, 1H), 0.89 (s, 9H), 0.09 (d, J = 1.38 Hz, 6H). 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. The solution was stirred for 16 h and purified by reverse phase chromatography, eluting with 5% ACN in water (plus 10 mM NH4HCO3), to afford 7-hydroxy-hexahydroimidazo[1,5-a]pyridine-1,3-dione as an off-white solid (0.300 g, crude), which was used in the next step directly without purification: LCMS (ESI) calc’d for C7H10N2O3[M - H]-: 169 found 169. Step e: 169 ACTIVEUS 204604250Attorney 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). The combined organic layers were washed with brine (5 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% ACN in water (plus 10 mM NH4HCO3), to afford 7-[(tert-butyldimethylsilyl)oxy]- hexahydroimidazo[1,5-a]pyridine-1,3-dione as a brown yellow oil (85.0 mg, 85.0% overall two steps): LCMS (ESI) calc’d for C13H24N2O3Si [M + H]+: 285 found 285;1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 4.04 (dd, J = 12.21, 4.21 Hz, 1H), 3.93-3.82 (m, 2H), 2.84 (td, J = 13.20, 3.42 Hz, 1H), 2.09-2.02 (m, 1H), 1.83-1.73 (m, 1H), 1.30-1.14 (m, 2H), 0.87 (s, 9H), 0.09 (d, J = 1.73 Hz, 6H). Example 11. Intermediate 12 (1-(1-Methylpyrazol-4-yl)imidazolidine-2,4-dione)Step a:

[0479] To a stirred mixture of 1-methylpyrazol-4-amine (0.550 g, 5.66 mmol) and ethyl bromoacetate (1.13 g, 6.79 mmol) in DMF (10 mL) was added K2CO3 (1.56 g, 11.3 mmol) at room temperature. The reaction was stirred for 2 h, diluted with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 35% ACN in water (plus 10 mM NH4HCO3), to afford ethyl 2-[(1-methylpyrazol-4-yl)amino]acetate as a light-yellow solid (1.00 g, 83.5%): LCMS (ESI) calc’d for C8H13N3O2 [M + H]+: 184 found 184;1H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 0.94 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J = 0.90 Hz, 1H), 4.24 (q, J = 7.14 Hz, 2H), 3.90 (s, 3H), 3.86 (s, 2H), 1.32-1.25 (m, 3H). 170 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Step b:

[0480] To a stirred solution of ethyl 2-[(1-methylpyrazol-4-yl)amino]acetate (0.500 g, 2.72 mmol) in dioxane (2 mL) was added NH3·H2O (6 mL) at room temperature. The reaction was stirred for 4 h and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 5% ACN in water (plus 10 mM NH4HCO3), to afford 2-[(1-methylpyrazol-4-yl)amino]acetamide as a light-yellow oil (0.460 g, 92.9%): LCMS (ESI) calc’d for C6H10N4O [M + H]+: 155 found 155. Step c:

[0481] To a stirred mixture of 2-[(1-methylpyrazol-4-yl)amino]acetamide (0.400 g, 2.59 mmol) and Boc2O (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 Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20 / 1), to afford tert-butyl N-(carbamoylmethyl)-N-(1-methylpyrazol-4-yl)carbamate as a light- yellow oil (0.110 g, 15.0%): LCMS (ESI) calc’d for C11H18N4O3[M + H]+: 255 found 255;1H NMR (300 MHz, DMSO-d6) δ 7.75-7.46 (m, 1H), 7.42-7.21 (m, 2H), 7.03 (s, 1H), 4.03 (s, 2H), 3.76 (s, 3H), 1.41 (s, 9H). 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. NH4Cl (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. The residue was purified by reverse phase chromatography, eluting with 31% ACN in water (plus 10 mM NH4HCO3) to afford 1-(1- methylpyrazol-4-yl)imidazolidine-2,4-dione as a light-yellow oil (60.0 mg, 76.2%): LCMS (ESI) calc’d for C7H8N4O2 [M + H]+: 181 found 181;1H NMR (300 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.41 (s, 1H), 4.01 (s, 2H), 3.78 (s, 3H).

[0483] 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 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 Example 12. Compound 1 ((4aR)-2-({3-[(2S)-2-(4-Chlorophenyl)-2-hydroxyethyl]-1,2,4- oxadiazol-5-yl}methyl)-tetrahydro-4H-pyrrolo[1,2-c]pyrimidine-1,3-dione)Step a:

[0484] To a stirred mixture of (4aR)-hexahydropyrrolo[1,2-c]pyrimidine-1,3-dione (50.8 mg, 0.330 mmol) and (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethanol (30.0 mg, 0.110 mmol) in DMF (0.5 mL) were added K2CO3 (45.5 mg, 0.330 mmol) and NaI (1.65 mg, 0.011 mmol) at room temperature. The reaction mixture was stirred for 2 h under nitrogen, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 36% ACN in water (plus 10 mM NH4HCO3), to afford (4aR)-2-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol- 5-yl}methyl)-tetrahydro-4H-pyrrolo[1,2-c]pyrimidine-1,3-dione as a yellow oil (22.9 mg, 53.3%): LCMS (ESI) calc’d for C18H19ClN4O4 [M + H]+: 391, 393 (3 : 1) found 391, 393 (3 : 1);1H NMR (400 MHz, DMSO-d6) δ 7.38-7.35 (m, 4H), 5.63 (d, J = 4.82 Hz, 1H), 5.12-4.92 (m, 3H), 3.83-3.69 (m, 1H), 3.54-3.46 (m, 1H), 3.46-3.36 (m, 1H), 3.05-2.91 (m, 2H), 2.86 (dd, J = 16.17, 3.96 Hz, 1H), 2.67 (dd, J = 16.20, 13.17 Hz, 1H), 2.24-2.14 (m, 1H), 2.05- 1.93 (m, 1H), 1.90-1.76 (m, 1H), 1.69-1.56 (m, 1H). 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 204604250Attorney 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- chlorophenyl)ethanol (90.0 mg, 0.330 mmol) and K2CO3(91.0 mg, 0.660 mmol) in DMF (1 mL) was added tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione (60.9 mg, 0.396 mmol) at room temperature under nitrogen. 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. The residue was purified by reverse phase chromatography, eluting with 50% ACN in water (plus 10 mM NH4HCO3), to afford 2-((3-((S)-2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5- yl)methyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione as an off-white solid (63.0 mg, 48.9%): LCMS (ESI) calc’d for C18H19ClN4O4 [M + H]+: 391, 393 (3 : 1) found 391, 393 (3 : 1);1H NMR (300 MHz, DMSO-d6) δ 7.37-7.35 (m, 4H), 5.63 (d, J = 4.8 Hz, 1H), 4.97 (dt, J = 7.8, 5.7 Hz, 1H), 4.90 (t, J = 2.8 Hz, 2H), 4.13 (dd, J = 11.9, 4.2 Hz, 1H), 3.96 (dd, J = 13.2, 4.7 Hz, 1H), 3.03-2.88 (m, 3H), 2.05 (d, J = 12.7 Hz, 1H), 1.88 (d, J = 13.1 Hz, 1H), 1.70 (d, J = 13.0 Hz, 1H), 1.49 (t, J = 13.1 Hz, 1H), 1.36-1.25 (m, 2H). Step b:

[0486] The product 2-((3-((S)-2-(4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5- yl)methyl)tetrahydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione (63.0 mg, 0.161 mmol) was separated by Prep Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH : DCM = 1 : 1; Flow rate: 20 mL / min; Gradient: 40% B to 40% B in 18 min; Wavelength: 220 / 254 nm; Retention Time 1 (min): 12.62; Retention Time 2 (min): 16.72; Sample Solvent: MeOH : DCM = 1 : 1. The faster-eluting enantiomer at 12.62 min was obtained 2-((3-((S)-2- (4-chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)tetrahydroimidazo[1,5- a]pyridine-1,3(2H,5H)-dione isomer 1 as an off-white solid (12.2 mg, 19.0%): LCMS (ESI) calc’d for C18H19ClN4O4 [M + H]+: 391, 393 (3 : 1) found 391, 393 (3 : 1);1H NMR (300 MHz, DMSO-d6) δ 7.39-7.35 (m, 4H), 5.63 (d, J = 4.89 Hz, 1H), 5.02-4.93 (m, 1H), 4.90 (d, J = 5.64 Hz, 2H), 4.13 (dd, J = 11.83, 4.21 Hz, 1H), 4.00-3.91 (m, 1H), 3.08-2.83 (m, 3H), 2.10-1.99 (m, 1H), 1.93-1.80 (m, 1H), 1.76-1.63 (m, 1H), 1.59-1.43 (m, 1H), 1.40-1.22 (m, 2H). The slower-eluting enantiomer at 16.72 min was obtained 2-((3-((S)-2-(4- chlorophenyl)-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)methyl)tetrahydroimidazo[1,5- 173 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 a]pyridine-1,3(2H,5H)-dione isomer 2 as an off-white solid (13.9 mg, 21.0%): LCMS (ESI) calc’d for C18H19ClN4O4 [M + H]+: 391, 393 (3 : 1) found 391, 393 (3 : 1);1H NMR (300 MHz, DMSO-d6) δ 7.39-7.35 (m, 4H), 5.63 (d, J = 4.85 Hz, 1H), 5.01-4.93 (m, 1H), 4.90 (s, 2H), 4.13 (dd, J = 11.87, 4.23 Hz, 1H), 4.00-3.91 (m, 1H), 3.06-2.80 (m, 3H), 2.11-1.96 (m, 1H), 1.93-1.81 (m, 1H), 1.75-1.64 (m, 1H), 1.58-1.42 (m, 1H), 1.39-1.20 (m, 2H). 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)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethanol (0.150 g, 0.560 mmol) in DMA (1 mL) was added K2CO3(0.130 g, 0.94 mmol) at room temperature. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 46% ACN in water (plus 10 mM NH4HCO3), to afford 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 as an off-white solid (30.0 mg, 15.7%): LCMS (ESI) calc’d for C18H19ClN4O5 [M + H]+: 407, 409 (3 : 1) found 407, 409 (3 : 1);1H NMR (400 MHz, DMSO-d6) δ 7.39-7.34 (m, 4H), 5.62 (d, J = 4.83 Hz, 1H), 5.24-4.91 (m, 3H), 3.99-3.88 (m, 2H), 3.85 (dd, J = 13.31, 2.56 Hz, 1H), 3.71-3.61 (m, 1H), 3.48 (td, J = 11.99, 2.82 Hz, 1H), 3.24-3.16 (m, 1H), 3.06-2.89 (m, 3H), 2.77 (dd, J = 16.90, 4.63 Hz, 1H), 2.65-2.55 (m, 1H). Step b: 174 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024

[0488] 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 (30.0 mg, 0.0740 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: Chiral ART Cellulose-SA, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH), Mobile Phase B: MeOH: DCM = 1: 1; Flow rate: 20 mL / min; Gradient: 40% B to 40% B in 17 min; Wavelength: 220 / 254 nm; Retention Time 1: 11.53 min; Retention Time 2: 15.18 min; Sample Solvent: EtOH: DCM = 1: 1. The faster eluting diastereomer at 11.53 min was obtained 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 as an off-white solid (2.40 mg, 8.00%): LCMS (ESI) calc’d for C18H19ClN4O5[M + H]+: 407, 409 (3 : 1) found 407, 409 (3 : 1);1H NMR (400 MHz, DMSO-d6) δ 7.39-7.34 (m, 4H), 5.64 (d, J = 4.79 Hz, 1H), 5.18-5.01 (m, 2H), 5.00- 4.92 (m, 1H), 3.99-3.88 (m, 2H), 3.88-3.80 (m, 1H), 3.72-3.61 (m, 1H), 3.53-3.43 (m, 1H), 3.19 (t, J = 10.87 Hz, 1H), 3.04-2.90 (m, 3H), 2.77 (dd, J = 16.90, 4.68 Hz, 1H), 2.60 (dd, J = 16.89, 12.51 Hz, 1H). And the slower eluting diastereomer at 15.18 min was obtained 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 as an off-white solid (16.1 mg, 53.7%): LCMS (ESI) calc’d for C18H19ClN4O5[M + H]+: 407, 409 (3 : 1) found 407, 409 (3 : 1);1H NMR (400 MHz, DMSO-d6) δ 7.39-7.34 (m, 4H), 5.63 (d, J = 4.86 Hz, 1H), 5.22-4.92 (m, 3H), 3.98-3.87 (m, 2H), 3.84 (dd, J = 13.52, 2.59 Hz, 1H), 3.71-3.61 (m, 1H), 3.48 (td, J = 12.00, 2.86 Hz, 1H), 3.19 (...

Claims

Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 CLAIMS 1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a tautomer thereof:wherein X is a direct bond or CR8R8’; Y1 is a direct bond, CR3R3’, NR9, O, or S; Y2is a direct bond, CR4R4’, NR10, O, or S; wherein when Y1is NR9, O, or S, Y2is a direct bond or CR4R4’; and when Y2is NR10, O, or S, Y1is a direct bond or CR3R3’; provided that Y1 and Y2 cannot both be direct bonds; R1is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R1’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; or alternatively, is –(C=O)–; or still alternatively, R1 and R1’, together with the carbon atom that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, 191 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R2is 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, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R3is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; or alternatively, R2 and R3, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R3’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R4is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; 192 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 or alternatively, R1 and R4, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; or alternatively, R3 and R4, together with the carbon atoms that they are connected to, form a 3- to 7-membered cycloalkyl ring or saturated heterocycle comprising 0-3 heteroatoms each selected from the group consisting of N, O, and S; wherein the 3- to 7-membered cycloalkyl ring or saturated heterocycle is optionally substituted by one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; R4’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R7is H, D, alkyl, or -C1-4alkyl-ORa; R7’ is H, D, alkyl, or -C1-4alkyl-ORa; R8is 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, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R9 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; 193 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R10 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;is an aryl or heteroaryl optionally substituted 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; L1 is –(CR5R6)n–; each occurrence of R5is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; each occurrence of R6 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; n is 2 or 3; each occurrence of Ra and Rb is independently selected from the group consisting of H, D, alkyl, (C=O)Rx, (C=O)N(Rx)2, SO2Rx, NRx(C=O)N(Rx)2, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Ra and Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0- 3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl in R1, R1’, R2, R2’, R3, R3’, R4, R4’, R5, R6, R7, R7’, R8, R8’, R9, R10, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1- 2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rx is independently H, D, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rxgroups together with the 194 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 nitrogen atom that they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

2. The compound of claim 1, wherein n is 2.

3. The compound of claim 1 or 2, wherein each occurrence of R5 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.

4. The compound of claim 3, wherein each occurrence of R5 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

5. The compound of any one of claims 1-4, wherein each occurrence of R6is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.

6. The compound of claim 5, wherein each occurrence of R6independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

7. The compound of claim 1, wherein L1is selected from the group consisting of –CH2–8. The compound of claim 1, wherein L1 is selected from the group consisting of –CH2–9. The compound of claim 1, wherein the compound has the structure of Formula Ia: 195 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024, wherein R5ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R5b is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R6a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; and R6b is H, D, alkyl, halogen, ORa, or fluorinated alkyl.

10. The compound of claim 9, whereinhas the structure of –CH2–CH2–, –11. The compound of any one of claims 1-10, wherein R7is H, D, or alkyl.

12. The compound of claim 11, wherein R7is H, D, CH3, or CH2CH3.

13. The compound of any one of claims 1-12, wherein R7’ is H, D, or alkyl.

14. The compound of claim 13, wherein R7’ is H, D, CH3, or CH2CH3.

15. The compound of any one of claims 1-10, whereinis selected from the group consisting of –CH2–, –CH(CH3)–, –C(CH3)2–, and –CH(CH2CH3)–.

16. The compound of any one of claims 1-10, whereinis –CH2–.

17. The compound of claim 1, wherein L1 isis –CH2–. A 18. The compound of any one of claims 1-17, wherein is phenyl which is optionally substituted with by 1-5 substituents each independently selected from the group 196 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 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.

19. The compound of claim 18, whereinis selected from the group consisting of21. The compound of any one of claims 1-17, whereinis 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.197 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 202423. The compound of claim 1, wherein 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; R6a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R6bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; R21is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R22is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R23is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R24is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; and R25 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.

24. The compound of any one of claims 1-23, wherein X is a direct bond.

25. The compound of any one of claims 1-23, wherein X is CR8R8’. 198 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 26. The compound of claim 1, wherein the compound has the structure of Formula Ic or Id:, wherein each occurrence of R5ais independently H, D, alkyl, halogen, ORa, or fluorinated alkyl; each occurrence of R5bis 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; each occurrence of R21 is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; each occurrence of R22is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; each occurrence of R23 is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; 199 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 each occurrence of R24 is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; and each occurrence of R25is independently H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa.

27. The compound of claim 23 or 26, wherein R21, R22, R24, and R25are H; and R23is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa.

28. The compound of claim 27, wherein R23 is CH3, CH2CH3, OH, F, Cl, Br, OCH3,29. The compound of claim 28, wherein R23 is Cl.

30. The compound of any one of claims 1-23 and 25-29, wherein R8 is H, D, or alkyl.

31. The compound of claim 30, wherein R8 is H, D, CH3, or CH2CH3.

32. The compound of any one of claims 1-23 and 25-31, wherein R8’ is H, D, or alkyl.

33. The compound of claim 32, wherein R8’ is H, D, CH3, or CH2CH3.

34. The compound of any one of claims 1-33, wherein Y1 is CR3R3’.

35. The compound of any one of claims 1-34, wherein R3 is H, D, alkyl, halogen, ORa, or halogenated alkyl.

36. The compound of claim 35, wherein R3 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

37. The compound of any one of claims 1-36, wherein R3’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.

38. The compound of claim 37, wherein R3’ H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

39. The compound of any one of claims 1-33, wherein Y1is a direct bond.

40. The compound of any one of claims 1-39, wherein Y2 is CR4R4’.

41. The compound of any one of claims 1-40, wherein R4 is H, D, alkyl, halogen, ORa, or halogenated alkyl.

42. The compound of claim 41, wherein R4 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. 200 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 43. The compound of any one of claims 1-42, wherein R4’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.

44. The compound of claim 43, wherein R4’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

45. The compound of any one of claims 1-39, wherein Y2 is NR10.

46. The compound of any one of claims 1-39 and 45, wherein R10 is H, alkyl, cycloalkyl, aryl, or alkylaryl.

47. The compound of claim 46, wherein R10 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, and CH(CH3)2.

48. The compound of any one of claims 1-39, wherein Y2 is O or S.

49. The compound of any one of claims 1-23 or 27, whereinselected201 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 202450. The compound of any one of claims 1-49, wherein R1is H, D, alkyl, halogen, ORa, or halogenated alkyl.

51. The compound of claim 50, wherein R1is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

52. The compound of any one of claims 1-38, 40, and 49, wherein R1 and R4, together with the carbon atoms that they are connected to, form a cyclopropyl group which is optionally substituted with D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

53. The compound of claim 52, wherein R1’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

54. The compound of any one of claims 1-49, wherein is –(C=O)–.

55. The compound of any one of claims 1-54, wherein R2is H, D, alkyl, halogen, or halogenated alkyl.

56. The compound of claim 55, wherein R2 is H, D, CH3, CH2CH3, F, Cl, Br, or fluorinated alkyl.

57. The compound of any one of claims 1-56, wherein R2’ is H, D, alkyl, halogen, or halogenated alkyl.

58. The compound of claim 57, wherein R2’ is H, D, CH3, CH2CH3, F, Cl, Br, or fluorinated alkyl. 202 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 59. The compound of any one of claims 1-23 or 27, whereinselected60. The compound of claim 1, wherein the compound has the structure of Formula Iewherein 203 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R5a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R23is H, D, halogen, alkyl, ORa, or NRaRb;R1 is H, D, halogen, alkyl, or ORa; R1’ is H, D, halogen, alkyl, or ORa; R2is H, D, halogen, alkyl, or ORa; R3 is H, D, halogen, alkyl, or ORa; R4 is H, D, halogen, alkyl, or ORa; R4’ is H, D, halogen, alkyl, or ORa; R8is H, D, or alkyl; and R10is H or alkyl.

61. A compound of Formula II, or a pharmaceutically acceptable salt thereof, or a tautomer thereof: 204 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024wherein Z is NR11, O, or S; Q is a direct bond or CR13R13’; R11is 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; R12is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R12’ is H, D, halogen, alkyl, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, alkylheteroaryl, CN, ORa, SRa, NRaRb, (C=O)NRaRb, NRb(C=O)Ra, (C=O)Ra, (C=O)ORa, -C1-4alkyl-ORa, -C1-4alkyl-SRa, -C1-4alkyl-NRaRb, -C1-4alkyl-COORa, - C1-4alkyl-CONRaRb, or -C1-4alkyl-NRaCORb; R13is 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, alkynyl, cycloalkyl, halogenated alkyl, halogenated alkynyl, halogenated cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; R14is H, D, alkyl, or -C1-4alkyl-ORa; R14’is H, D, alkyl, or -C1-4alkyl-ORa; 205 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024is an aryl or heteroaryl optionally substituted 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; L2is –(CR15R16)m–; each occurrence of R15 is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; each occurrence of R16is independently H, D, alkyl, halogenated alkyl, cycloalkyl, halogenated cycloalkyl, CN, ORa, -C1-4alkyl-ORa, or halogen; m is 2 or 3; each occurrence of Raand Rbis independently selected from the group consisting of H, D, alkyl, (C=O)Rx, (C=O)N(Rx)2, SO2Rx, NRx(C=O)N(Rx)2, cycloalkyl, halogenated alkyl, heteroalkyl, halogenated heteroalkyl, halogenated cycloalkyl, saturated heterocycle comprising 1-3 heteroatoms each selected from the group consisting of N, O, and S, aryl, and heteroaryl; or alternatively, Raand Rb, together with the carbon or nitrogen atom that they are connected to, form a cycloalkyl or saturated heterocycle comprising the nitrogen atom and 0- 3 additional heteroatoms each selected from the group consisting of N, O, and S; the alkyl, alkenyl, alkynyl, cycloalkyl, saturated heterocycle, partially saturated heterocycle, aryl, heteroaryl, alkylaryl, and alkylheteroaryl in R11, R12, R12’, R13, R13’, R14, R14’, R15, R16, Ra, or Rb, where applicable, are each optionally substituted by 1-4 substituents each independently selected from the group consisting of alkyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, halogen, CN, ORx, -(CH2)1-2ORx, N(Rx)2, -(CH2)1-2N(Rx)2, (C=O)Rx, (C=O)N(Rx)2, NRx(C=O)Rx, and oxo where valence permits; and each occurrence of Rxis independently H, D, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH; or alternatively, the two Rxgroups together with the nitrogen atom that they are connected to, form a heterocycle optionally substituted by alkyl and comprising the nitrogen atom and 0-3 additional heteroatoms each selected from the group consisting of N, O, and S.

62. The compound of claim 61, wherein m is 2. 206 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 63. The compound of claim 61 or 62, wherein each occurrence of R15 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.

64. The compound of claim 63, wherein each occurrence of R15 is independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

65. The compound of any one of claims 61-64, wherein each occurrence of R16 is independently H, D, alkyl, halogen, ORa, or halogenated alkyl.

66. The compound of claim 65, wherein each occurrence of R16 independently H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

67. The compound of claim 61, wherein L2is selected from the group consisting of – CH2–CH2–, –CH(CH3)–CH2–, –CH2–C(CH3)2–, –CH(OH)–CH2–, –CH2–CH(OH)–,68. The compound of claim 61, wherein L2is selected from the group consisting of – CH2–CH2–, –CH(CH3)–CH2–, –CH2–CH(CH3)–, –CH2–C(CH3)2–, –C(CH3)2–CH2–,69. The compound of claim 61, wherein the compound has the structure of Formula IIa:, wherein R15ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R15bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; 207 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 R16a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; and R16bis H, D, alkyl, halogen, ORa, or fluorinated alkyl.

70. The compound of claim 69, whereinhas the structure of –CH2–CH2–, –71. The compound of any one of claims 61-70, wherein R14 is H, D, or alkyl.

72. The compound of claim 71, wherein R14 is H, D, CH3, or CH2CH3.

73. The compound of any one of claims 61-72, wherein R14’ is H, D, or alkyl.

74. The compound of claim 73, wherein R14’ is H, D, CH3, or CH2CH3.

75. The compound of any one of claims 61-74, whereinis selected from the group consisting of –CH2–, –CH(CH3)–, –C(CH3)2–, and –CH(CH2CH3)–.

76. The compound of any one of claims 61-75, whereinis –CH2–.

77. The compound of claim 61, wherein L2 isis –CH2–.

78. The compound of any one of claims 61-77, whereinis 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.

79. The compound of claim 78, whereinis selected from the group consisting of208 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 202481. The compound of any one of claims 61-77, whereinis 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.

83. The compound of claim 1, wherein the compound has the structure of Formula IIb: 209 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024, wherein R15a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R15b is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R16ais H, D, alkyl, halogen, ORa, or fluorinated alkyl; R16bis H, D, alkyl, halogen, ORa, or fluorinated alkyl; R31is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R32is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R33is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; R34is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogenated cycloalkyl, halogenated alkyl, aryl, heteroaryl, CN, ORa, SRa, NRaRb, -C1-4alkyl-SRa, or -C1-4alkyl-ORa; and R35 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.

84. The compound of claim 83, wherein R31, R32, R34, and R35 are H; and R33 is H, D, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, CN, CF3, ORa, SRa, NRaRb, or -C1-4alkyl-ORa.

85. The compound of claim 84, wherein R33 is CH3, CH2CH3, OH, F, Cl, Br, OCH3,86. The compound of claim 85, wherein R33is Cl.

87. The compound of any one of claims 61-86, wherein Q is CR13R13’.

88. The compound of any one of claims 61-87, wherein R13 is H, D, or alkyl.

89. The compound of claim 88, wherein R13 is H, D, CH3, or CH2CH3.

90. The compound of any one of claims 1-89, wherein R13’ is H, D, or alkyl.

91. The compound of claim 90, wherein R13’ is H, D, CH3, or CH2CH3.210 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 92. The compound of any one of claims 61-86, wherein Q is a direct bond.

93. The compound of any one of claims 61-92, wherein Z is NR11.

94. The compound of any one of claims 61-93, wherein R11is H, alkyl, cycloalkyl, aryl, or heteroaryl.

95. The compound of claim 94, wherein R11is selected from the group consisting of H,. The compound of any one of claims 61-92, wherein Z is O or S.

97. The compound of any one of claims 61-86, whereinselected from98. The compound of any one of claims 61-97, wherein R12 is H, D, alkyl, halogen, ORa, or halogenated alkyl.

99. The compound of claim 98, wherein R12 is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl.

100. The compound of any one of claims 61-99, wherein R12’ is H, D, alkyl, halogen, ORa, or halogenated alkyl.

101. The compound of claim 100, wherein R12’ is H, D, CH3, CH2CH3, OH, F, Cl, Br, or fluorinated alkyl. 211 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 102. The compound of any one of claims 61-86, whereinselected from103. The compound of claim 61, wherein the compound has the structure of Formula IIcwherein R15a is H, D, alkyl, halogen, ORa, or fluorinated alkyl; R33 is H, D, halogen, alkyl, ORa, or NRaRb;selected from the group consistingR11 is H, alkyl, aryl or heteroaryl; R12 is H, D, halogen, alkyl, or ORa; and R13 is H, D, halogen, alkyl, or ORa.

104. The compound of any one of the claims 1-103, wherein at least one occurrence of Raor Rb is independently H, D, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl. 212 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 105. The compound of any one of claims 1-104, wherein at least one occurrence of Ra or Rb is independently H, D, Me, Et, Pr, CH2CH2OH, phenyl, or a heterocycle selected from theheterocycle is optionally substituted by alkyl, OH, oxo, or (C=O)C1-4alkyl where valence permits.

106. The compound of claim 105, wherein at least one occurrence of Raor Rbis H, Me,107. The compound of any one of claims 1-103, wherein 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.

108. The compound of any one of the proceeding claims, wherein each occurrence of Rxis independently H, alkyl, or heterocycle optionally substituted by alkyl, halogen, or OH.

109. The compound of claim 108, wherein each occurrence of Rx is independently H or alkyl.

110. The compound of claim 109, wherein each occurrence of Rx is independently H or Me.

111. The compound of claim 1, wherein the compound is selected from the group consisting of compounds 1-5, 7-23, and 27-30 in Table 2.

112. The compound of claim 61, wherein the compound is selected from the group consisting of compounds 6 and 24-26 in Table 2.

113. A pharmaceutical composition comprising at least one compound according to any one of claims 1-112 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

114. 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 213 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 compound according to any one of claims 1-112 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.

115. The method of claim 114, wherein 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, post-herpetic neuralgia, fibromyalgia, nerve injury, post stroke pain, or tooth and tooth injury-related pain.

116. The method of claim 114, wherein a urinary tract disorder is pelvic hypersensitivity, urinary incontinence, or cystitis, bladder instability, or bladder outlet obstruction.

117. The method of claim 114, wherein the skin disorder is burns, psoriasis, eczema, or pruritus.

118. The method of claim 114, wherein the skin disorder is atopic dermatitis or psoriasis- induced itching.

119. The method of claim 114, wherein 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.

120. The method of claim 114, wherein the ischemia is CNS hypoxia or a disorder associated with reduced blood flow to CNS.

121. The method of claim 114, wherein the autoimmune disease is rheumatoid arthritis or multiple sclerosis.

122. The method of claim 114, wherein the central nervous system disorder is associated with neurodegeneration.

123. The method of claim 114, wherein the gastroenterological disorder is an inflammatory bowel disease, esophagitis, gastroesophageal reflux disorder, irritable bowel syndrome, emesis, or stomach duodenal ulcer.

124. The method of claim 114, wherein the cardiovascular disorder is stroke, myocardial infarction, atherosclerosis, or cardiac hypertrophy. 214 ACTIVEUS 204604250Attorney Docket No.2206689.160WO1 Date of Deposit: July 9, 2024 125. The method of claim 114, wherein the mammalian species is human.

126. 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 claims 1-112 or a pharmaceutically acceptable salt thereof.

127. The method of claim 126, wherein the mammalian species is human. 215 ACTIVEUS 204604250

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