INHIBITORS OF INTEGRATED STRESS RESPONSE PATHWAY

CROSS REFERENCE TO RELATED APPLICATIONS

[QQQI] This application claims the priority benefit of U.S. Provisional Patent Application Nos. 62/598,377, filed December 13, 2017, and 62/690,857, filed June 27, 2018, the disclosures of which are incorporated herein by reference in their entireties.

FIELD

[0002] The present disclosure relates generally to therapeutic agents that may be useful as inhibitors of Integrated Stress Response (ISR) pathway.

BACKGROUND

[0003] Diverse cellular conditions and stresses activate a widely conserved signaling pathway termed the Integrated Stress Response (ISR) pathway. The ISR pathway is activated in response to intrinsic and extrinsic stresses, such as viral infections, hypoxia, glucose and amino acid deprivation, oncogene activation, UV radiation, and endoplasmic reticulum stress. Upon activation of ISR by one or more of these factors, the eukaryotic initiation factor 2 (eIF2, which is comprised of three subunits, a, b and g) becomes phosphorylated m its a-subunit and rapidly reduces overall protein translation by binding to the eIF2B complex. This phosphorylation inhibits the eIF2B~mediated exchange of GDP for GTP (i.e., a guanine nucleotide exchange factor (GET) activity), sequestenng eIF2B in a complex with eIF2 and reducing general protein translation of most mRNA m the cell. Paradoxically, eIF2a phosphorylation also increases translation of a subset of mRNAs that contain one or more upstream open reading frames (uORFs) in their 5’ untranslated region (UTR). These transcripts include the transcriptional modulator activating transcription factor 4 (ATF4), the transcription factor CHOP, the growth arrest and DNA damage-inducible protein GADD34 and the b-secretase BACE-l.

[0004] In animals, the ISR modulates a broad translational and transcriptional program involved in diverse processes such as learning memory, immunity, intermediary metabolism, insulin production and resistance to unfolded protein stress in the endoplasmic reticulum, among others. Activation of the ISR pathway has also been associated with numerous pathological conditions including cancer, neurodegenerative diseases, metabolic diseases (metabolic syndrome), autoimmune diseases, inflammatory diseases, musculoskeletal diseases (such as myopathy), vascular diseases, ocular diseases, and genetic disorders. Aberrant protein synthesis through eIF2a phosphorylation is also characteristic of several other human genetic disorders, cystic fibrosis, amyotrophic lateral sclerosis, Huntington disease and prion disease.

BRIEF SUMMARY

[0005] Inhibitors of the Integrated Stress Response (ISR) pathway are described, as are methods of making and using the compounds, or salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[QQQ6] FIG. 1 shows percentage of ATF4 inhibition after induction with thapsigargin (Tg) in the presence of certain test compounds. Percentage of ATF4 inhibition was calculated as the percent reduction normalized to Tg treatment (0% inhibition) and untreated cells ( 100% inhibition).

[0007] FIG. 2 shows protein synthesis levels in the presence of media alone or certain test compounds unstressed cells. The levels were normalized to the media alone condition, which correspond to 100% protein synthesis.

[0008] FIG. 3A and FIG. 3B show percent recover} of protein synthesis in a stressed cell in the presence of one of several test compounds at a concentration of 100 nM (FIG. 3 A) or 1 mM (FIG. 3B). The levels were normalized to the media alone and to Tg alone conditions, which correspond to 100% and 0% respectively. FIG. 3C shows percent ATF4 inhibition for select compounds against percent recovery of protein synthesis.

[0009] FIG. 4A shows representative levels of ATF4 expression and b-actin expression (control) in SH-SY5Y cells after being treated with cell culture media conditioned using wild-type CHO cells (wtCM) or 7PA2 CHO cells (7PA2CM).

[0010] FIG. 4B shows percent inhibition of ATF4 expression in SH-5Y5Y cells after incubation with conditioned media from 7PA2 CHO cells and one of several test compounds. The levels were normalized to the media alone and to conditioned media from 7PA2 CHO cells alone, which correspond to 100% and 0% respectively. [0011] FIG. 5A shows long-term potentiation (LTP) of a stimulated hippocampal slice from a WT C57BL/6 mouse or a transgenic APP/PS1 mouse with or without incubation with ISRIB. LTP was based on field excitatory postsynaptic potential (ffiPSP) slope, measured from 20 minutes prior to theta burst stimulation (TBS) to 60 minutes after TBS. FIG. 5B show's the responses recorded in the last 10 minutes after condi tioning stimulation of the slices fro the WT C57BL/6 and APP/PS1 mice treated with ISRIB (APP+ISRIB), and from APP/PSi mice treated with compound 3 (APP + Cmp3), or compound 152 (APP+Cmpl 52), or the vehicle (APP).

[0012] FIG. 6A shows results of an 8-arm radial water maze (RAWM) task used to measure learning in aged mice treated with compound 3 versus a vehicle control (“Veh”). F1G.6B show's levels of ATF4 expression normalized to b-actin expression in hippocampi extracted from mice treated with compound 3 versus a vehicle control (“Veh”). FIG. 6C shows individual data points for the levels of ATF4 expression normalized to b-actin expression hippocampi extracted from mice treated with compound 3 versus a vehicle control (“Veh”).

[0013] FIG. 7A show's learning memory test results of mice without a traumatic brain injury (TBI), with TBI and untreated, and with TBI treated with compound 3. FIG. 7B shows long term memory test results of mice without a traumatic brain injury (TBI), with TBI and untreated, and with TBI treated with compound 3. FIG. 7C shows social behavior (indicated by time spent with a companion mouse) of mice without a traumatic brain injury (TBI), with TBI and untreated, and with TBI treated with compound 3.

[0014] FIG. 8A show's protein synthesis in muscles from fasting mice or fasting mice treated with compound 3. Protein synthesis was normalized to b-actin expression and percentage was calculated as the percent relative to protein synthesis levels from control mice (Fed) which correspond to 100%. FIG. 8B show's visualization of a muscle fiber cross-sectional area (CSA) stained with puromycin from a fed mouse, a fasting mouse, and a fasting mouse treated with compound 3.

[0015] FIG. 9A and FIG. 9B show gastrocnemius weight from mice that w'ere fed, fasted, or fasted with compound 3 (FIG. 9 A) or compound 152 (FIG. 9B) administration. FIG. 9C and FIG. 9D show percent of protein synthesis from mice that were fed, fasted, or fasted with compound 3 (FIG. 9C) or compound 152 (FIG. 9D) administration, normalized to b-actin expression and percentage calculated as the percent relative to protein synthesis levels from fed mice FIG 9E and FIG. 9F shows Atrogin-1 expression in gastrocnemius from mice that were fed, fasted, or fasted and treated with compound 3 (FIG. 9E) or compound 152 (FIG. 9F), normalized to b-actin expression and fold change calculated as the levels relative to the expression levels from fed mice. FIG. 9G shows visualization of a muscle fiber cross-sectional area (CSA) stained for ATF4 from a fed mouse, a fasting mouse, and a fasting mouse treated with compound 152.

[0016] FIG. 10A-C shows protein synthesis in the gastrocnemius (FIG. 10A), tibialis anterior (FIG. 10B) and quadriceps (FIG. I OC) muscles for the mobile hindlirnb and the immobilized hindlirnb (triggering immobilization-induced muscle atrophy) in mice with unilateral hindlirnb immobilization, treated either with a vehicle control or compound 3. The levels were normalized to b-actin expression and percentage was calculated as the percent relative to protein synthesis levels from mobile limb of control mice (vehicle-treated) which correspond to 100%. FIG. 10D shows visualization of a muscle fiber cross-sectional area (CSA) of gastrocnemius from mobile or immobile hind limbs stained for ATF4.

[0017] FIG. 11A-C show's muscle weight of gastrocnemius (FIG. 11 A), quadriceps (FIG.

1 IB), and tibialis anterior (FIG. 11C) muscles of control, mice with cachexia induced muscle atrophy, and mice with cachexia induced muscle atrophy treated with compound 3. FIG. 11D-F show's percent protein synthesis (normalized to b-actin expression) in gastrocnemius (FIG. 1 ID), quadriceps (FIG. 1 I E), and tibialis anterior (FIG. 1 IF) muscles of control, mice with cachexia induced muscle atrophy, and mice with cachexia induced muscle atrophy treated with compound 3. Cachexia was induced by injecting mice with CT26 colon carcinoma cells m the flank of each animal.

[0018] FIG. 12A-12C shows tumor volume (FIG. 12A), tumor weight (FIG. 12B), and tumor density (FIG. 12C) of a subcutaneously injected CT26 colon carcinoma cell line tumor from untreated (vehicle) mice or mice treated with compound 3 for 13 days, starting 6 days post tumor injection.

[0019] FIG. 13A shows relative fluorescence intensity (RFU) of GFP resulting from cell- free expression in a system treated with compound 152, compound 153, or a vehicle control.

FIG. 13B compares the RFU from GFP cell-free expression systems treated with compound 152, compound 153, or vehicle control after 6 hours. [QQ2Q] FIG. 14A and FIG. 14B show an SDS-PAGE gel of yeast cells engineered to express phospholipase C (PLC) under a methanol-inducible promoter (pAOX-PLC; FIG. 14A) or a constitutive promoter (pGAP-PLC; FIG. 14B), cultured in the presence of compound 152 or a control. The arrow' in each figure indicates PLC.

[0021] FIG. 14C and FIG. 14D show's activity of PLC secreted from yeast cells engineered to express phospholipase C (PLC) under a methanol-inducible promoter (pAOX-PLC; FIG.

14C) or a constitutive promoter (pGAP-PLC; FIG. 14D), cultured in the presence of compound 152 or a control, and indicated by fold-change relative to the control.

[QQ22] FIG. 15A show's an SDS-PAGE gel of secreted proteins from CLIO cells cultured in the presence of 1 pm, 5 pm, or 10 pm of compound 152 or compound 153 for 24 hours. The secreted proteins were quantitated relative to a control, as shown in FIG. 15B.

DETAILED DESCRIPTION

Definitions

[0023] For use herein, unless clearly indicated otherwise, use of the terms“a”,‘ ^‘ an” and the like refers to one or more.

[0024] Reference to“about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to“about X” includes description of“X”.

[QQ25] “Alkyl” as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., C _J -C _JO means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a“C3-C20 alkyl”), having 1 to 10 carbon atoms (a“Ci~Cio alkyl”), having 6 to 10 carbon atoms (a“Ce-Cio alkyl”), having 1 to 6 carbon atoms (a“Ci-C ₆ alkyl”), having 2 to 6 carbon atoms (a“C ₂ -C ₆ alkyl”), or having 1 to 4 carbon atoms (a“C ₁ -C ₄ alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-deey!, and the like.

[0026] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 20 carbon atoms (a“C1-C20 alkylene”), having 1 io 10 carbon atoms (a“Ch-Cho alkylene”), having 6 to 10 carbon atoms (a“C ₆ -Cio alkylene”), having 1 to 6 carbon atoms (a“Ci-C ₆ alkylene”), 1 to 5 carbon atoms (a“Cr-Cs alkylene”), 1 to 4 carbon atoms (a“Ci-Cty alkylene”) or 1 to 3 carbon atoms (a“Ci-Cty alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), isopropylene (-CEtyCEtyCHU)-), butylene (-CH ₂ (CH ₂ ) ₂ CH ₂ -), isobutylene (-CH ₂ CH(CH ₃ )CH ₂ -), pentylene (-CH ₂ (CH ₂ ) ₃ CH ₂ -), hexylene (-CH ₂ (CH ₂ ) ₄ CH ₂ -), heptylene (-CH ₂ (CH ₂ ) ₅ CH ₂ -), octylene (-CH ₂ (CH ₂ ) ₆ CH ₂ -), and the like.

[QQ27] “Alkenyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e. , unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefimc unsaturation (i.e., having at least one moiety of the formula O C) and having the number of carbon atoms designated (i.e., C ₂ -C _lo means two to ten carbon atoms). An alkenyl group may have“cis” or“trans” configurations, or alternatively haveΈ” or“Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C ₂ -C ₂₀ alkenyl”), having 6 to 10 carbon atoms (a“( C ₁₀ alkenyl”), having 2 to 8 carbon atoms (a“C ₂ -Cg alkenyl”), having 2 to 6 carbon atoms (a“C ₂ -C ₆ alkenyl”), or having 2 to 4 carbon atoms (a“C ₂ -C ₄ alkenyl”). Examples of alkenyl group include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2-methylbuta-l,3-dienyl, pent-l-enyl, pent-2-enyl, hex- 1-enyl, hex-2-enyl, hex-3-enyl, and the like.

[0028] “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkenylene groups are those having 2 to 20 carbon atoms (a“C ₂ -C ₂ o alkenylene”), having 2 to 10 carbon atoms (a“C ₂ -Cio alkenylene”), having 6 to 10 carbon atoms (a“C ₆ -C ₁₀ alkenylene”), having 2 to 6 carbon atoms (a“C ₂ -C ₆ alkenylene”), 2 to 4 carbon atoms (a“C ₂ -C ₄ alkenylene”) or 2 to 3 carbon atoms (a“C ₂ -C ₃ alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH ₂ -), 1 ,4-but- 1 -enylene (-CH=CH-CH ₂ CH ₂ -), l,4-but-2-enylene

(-CH ₂ CH=CHCH ₂ -), 1 ,6-hex- 1 -enylene (-CH=CH-(CH ₂ ) ₃ CH ₂ -), and the like.

[QQ29] “Alkynyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic u saturation (i.e., havin at least one moiety of the formula CºC) and having the number of carbon atoms designated (i.e., C ₂ -C ₁₀ means two to ten carbon atoms). Particular alkyny] groups are those having 2 to 20 carbon atoms (a“C2-C20 alkynyl”), having 6 to 10 carbon atoms (a“Cft-C o alkynyl”), having 2 to 8 carbon atoms (a“C ₂ - C ₈ alkynyl’'), having 2 to 6 carbon atoms (a“C ₂ -C ₆ alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetyienyi), prop-1 -ynyl, prop-2-ynyi (or propargyl), but-l-ynyl, but-2-ynyl, but-3- ynyl, and the like.

[0030] “Alkynylene” as used herein refers to the same residues as alkynyl, but having bivalency. Particular alkynylene groups are those having 2 to 20 carbon atoms (a“C ₂ -C _2Q alkynylene”), having 2 to 10 carbon atoms (a“C _2~ Cio alkynylene”), having 6 to 10 carbon atoms (a“C _f -C o alkynylene”), having 2 to 6 carbon atoms (a“C ₂ -C ₆ alkynylene”), 2 to 4 carbon atoms (a“C2-C4 alkynylene”) or 2 to 3 carbon atoms (a“C2-C3 alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-CºC-), propynyiene (-CºCCH2-), and the like.

[QQ31] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (/.<?., C3- Cio means three to ten carbon atoms). Cycloalkyd can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a“C3-C8 cycloalkyd”), having 3 to 6 carbon atoms (a“C ₃ -Ce cycloalkyP’), or having from 3 to 4 annular carbon atoms (a‘ ^' C3-C4 cycloalkyd”). Examples of cycloalkyd include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, and the like.

[0032] “Cyeloalkylene” as used herein refers to the same residues as cycloalkyl, but having bivalency. Cyeloalkylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cyeloalkylene groups are those having from 3 to 12 annular carbon atoms. A preferred cyeloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a“Cg-Cg cyeloalkylene”), having 3 to 6 carbon atoms (a“C -Ce cyeloalkylene”), or having from 3 to 4 annular carbon atoms (a“C3-C4 cyeloalkylene”).

Examples of cyeloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyc!opentydene, cyclohexylene, cycloheptylene, norbomyl ene, and the like. A cyeloalkylene may atach to the remaining structures via the same ring carbon atom or different ring carbon atoms. When a cycloalkylene ataches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis- or trans- to each other. For example, cyclopropylene may include 1 ,1-cyclopropylene and 1 ,2-cyclopropylene (e.g., cis- 1 ,2-cyclopropylene or trans- 1 ,2-cyclopropylene), or a mixture thereof.

[QQ33] “Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of o!efimc unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C ₂ -Cio means two to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbomenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a“C Cg

cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cydobutenyl, cyciopentenyl, cyclohexenyl, norbomenyl, and the like.

[QQ34] “Cycioalkenylene” as used herein refers to the same residues as cydoalkenyl, but having bi valency.

[QQ35] “Aryl” or“Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthry!) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a“( C _M aryl”). An and group having more than one ring where at least one nng is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.

[0036] “Arylene” as used herein refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a“C _ft -Cw arylene”).

[0037] “Heteroaryl” as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur. A heteroaryl group may have a single nng (e.g., pyridyl, fury!) or multiple condensed rings (e.g, indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatorns independently selected from nitrogen, oxygen, and sulfur. In one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.

In another variation, particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heteroaryl group having more than one ring where at least one ring is non aromatic may be connected to the parent structure at either an aromatic ring position or at a non- aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0038] “Heteroaiylene” as used herein refers to the same residues as heteroaryl, but having bi valency.

[0039] “Heterocycle”,‘ ^‘ heterocyclic”, or“heterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof, but excludes heteroaryl. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatorns independently selected from nitrogen, oxygen and sulfur,

3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatorns independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatorns independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatorns independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatorns independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.

[QQ4Q] “Heterocyclylene” as used herein refers to the same residues as heterocyclyl, but having bi valency.

[0041] “Halo” or“halogen” refers to elements of the Group 17 senes having atomic number 9 to 85 Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc refer to aryl and alkyl substituted with two (“di”) or three (“hi”) halo groups, which may be but are not necessarily the same halogen; thus 4 -chi oro-3 -fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a“perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl (-CF ₃ ).

Similarly,“perhaloa!koxy” refers to an a!koxy group in which a halogen takes the place of each H m the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF ₃ ).

[0042] “Carbonyl” refers to the group 0=0.

[0043] “Thiocarbonyl” refers to the group 0=8.

[0044] “Qxo” refers to the moiety =0.

[0045] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has I to 2, 1 to 3, 1 to 4, I to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted. [0046] Unless clearly indicated otherwise,“an individual’' as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.

[0047] As used herein,“treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. The methods of the present disclosure contemplate any one or more of these aspects of treatment.

[0048] As used herein, the term“effecti ve amount” intends such amount of a compound of the invention which should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e. , a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effecti ve amount may be considered in the context of administering one or more therapeutic agents (e.g. , a compound, or

pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0049] A“therapeutically effective amount” refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome.

[0050] As used herein,“unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.

[0051] As used herein, by“pharmaceutically acceptable” or“pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g, the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0052] “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.

Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ m the manufacturing process, or by separately reacting a purified compound of the present disclosure in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0053] The term“excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral

administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethyicellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc =“directly compressible”), honey dc, lactose (anhydrate or monohydrate;

optionally in combination with aspartame, cellulose, or microciystalline cellulose), starch dc, sucrose, etc ; disintegrants include, e.g., croscarmellose sodium, gel lan gum, sodium starch glycolate, etc ; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium steaiyi fumarate, etc.; materials for chewable tablets include, e.g, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0054] It is understood that aspects and embodiments described herein as '‘comprising” include“consisting of’ and“consisting essentially of’ embodiments.

[0055] When a composition is described as“consisting essentially of” the listed components, the composition contains the components expressly listed, and may contain other components which do not substantially affect the disease or condition being treated such as trace

impurities. However, the composition either does not contain any other components which do substantially affect the disease or condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the disease or condition being treated, the composition does not contain a sufficient concentration or amount of those extra components to substantially affect the disease or condition being treated. When a method is described as“consisting essentially of’ the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the disease or condition being treated, but the method does not contain any other steps which substantially affect the disease or condition being treated other than those steps expressly listed.

[0056] When a moiety is indicated as substituted by“at least one” substituent, this also encompasses the disclosure of exactly one substituent.

Compounds

[0057] In one aspect, pro vided is a compound of formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

X ¹ and X ² , independently of each other, are CH or N;

Y ¹ is selected from the group consisting of a bond, NR ^Y ', and O; provided that when X ¹ is N, then Y ¹ is a bond;

R is hydrogen or Ci-Ce alkyl;

Y ^z is selected from the group consisting of a bond, NR ^Y2 , and O; provided that when X ² is N, then Y ² is a bond;

R ^Y2 is hydrogen or CrC ₆ alkyl;

m ¹ , rn ² , n ¹ , n , p ¹ , p ^z , q ¹ , and q ² , independently of each other, are 0 or 1 ;

r and s, independently of each other, are 0, 1, or 2;

A ¹ is selected from the group consisting of:

a substituent of formula (A -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹ is selected from the group consisting of NR ^{21 2} , O, S, and -CR ^{Z1 1} =CR

wherein

Z is selected from the group consisting of CR' ^~ , NI¾Y ; O, S, and -CR^ ^CR ²² - ¹ -;

wherein R ^{22 1} is H or R ¹⁴ ; and R ^{Z2 z} is H or R ¹⁴ ;

Z ³ , independently at each occurrence, is C or N, provided that at least one Z ³ is C; R" is hydrogen or R ¹⁴ , or R ³ and R ^{Z1 2} are taken together to form a double bond between the carbon atom bearing R ^{! i} and Z ^! , or R ¹³ and R ^{Z2 2} are taken together to form a double bond between the carbon atom bearing R ^l3 a d Z ² ; and

xl is 0, 1, 2, 3, or 4, provided than when one Z ³ is N, then xl is not 4; t C o aryl optionally substituted with one or more R ¹⁴ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ¹⁴

substituents;

R ¹⁴ is selected, independently at each occurrence, from the group consisting of halogen, CrCe alkyl, Ci-C ₆ hafoalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci- C ₆ alkyl), -8iC C,, haloalkyl), -NH ₂ , -NH(C C ₆ alkyl), -NH(CI-C ₆ haloalkyl), ~N(C _r alkyl) ₂ , -\(C haloalkyl) ₂ , -NR^R ¹⁴ *, -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl), -C(0)0(C _r C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(C C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) _? ., -C(0)NR ^{14 3} R ^{14 b} , -S(0) _? 0H, -S(0) ₂ 0(Ci-C ₆ alkyl), -S(0) ₂ 0(Ci~C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(C _I -C ₆ alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyl), -S(0) ₂ N{Ci-C ₆ alkyl) ₂ , 8((); ₂ N{ ( ^' ···( ^' ,. haloalkyl) _? ., -S(0) ₂ NR ^{14 a} R ^{14 b} ,-0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-OP OK ( -( ,, haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl)

haloalkyl), -N(C C ₆ alkyl)C(0)H, AiC _r( ^' , alkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ alk}'l)C(0)(Ci-C ₆ haloalkyl), -N(C -C ₆ haloalkyl)C(0)H, -N(CI-C ₆

haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CrC ₆ haloalkyl)C(0)(Ci-C ₆ haloalky l),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (C ₁ -C ₆ alkyl),

N(l I }8{ ⁽⁾ )?{ ^{( '} ·· ^{( '} .·. haloalkyl), AitVC, alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(CI-C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(C C ₆ haloaliy d)S(0) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{l4 a} and R ^{14 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A is selected from the group consisting of:

a substituent of formula (A ^z -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ⁴ is selected from the group consisting of CR^R ^{24 2} , NR ^{24 2} , O, S, and -CR ^{Z ! :} CR ^/

wherein R

Z ⁵ is selected from the group consisting of CR ^{Z i} R ^{25 2} , NR ^Z5 ; O, S, and -CR ^{Z5 1} =CR ^{Z5 1} -;

wherein R ^{25 1} is H or R ¹⁶ ; and R ^{Z3 z} is H or R ^!t> ;

Z°, independently at each occurrence, is C or N, provided that at least one Z ⁶ is C;

R ¹³ is hydrogen or R , or R ¹³ and R ^{24 2} are taken together to form a double bond between the carbon atom bearing R ¹⁵ and Z ⁴ , or R ¹³ and R ^{25 2} are taken together to form a double bond between the carbon atom bearing R ⁱ⁵ and Z ⁵ ; and

x2 is 0, 1, 2, 3, or 4, provided than when one Z ⁶ is N, then x2 is not 4; Ce-Cio aryl optionally substituted with one or more R ¹⁶ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ¹⁶

substituents;

R ¹⁶ is selected, independently at each occurrence, from the group consisting of halogen,

CrC ₆ alkyl, C C ₆ haloalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), ·CP ·, -M 1{ ^{( '} ··· ⁽ ). alkyl), -NH(C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) ₂ , -NR ^{16 a} R ^{16 b} , -CN, -C(0)0H, -C(0)0(C C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(C _] -C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{16 a} R ^{16 b} ,

-S(0) ₂ 0H, -S(0) ₂ 0(CrC ₆ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(CrC ₆ alkyl), -S(0) ₂ NH(C _I -C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl)?, -S(Q) ₂ N(CrC ₆ haloalkyl) _? alkyl),

-0C(0)(CrC ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyi), -N(C C ₆ alky])C(0)H, -N(CI-C ₆ alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyi), -N(CrC ₆ haloalkyl)C(0)H, -N(Ci-C ₆

haloaJkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyi),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyi), -N(H)S(0) ₂ (Ci-C ₆ alkyl),

-N(H)S(0) ₂ (CI-C ₆ haloalkyi), -N(C -C ₆ alk\ )S(0) ₂ (C _l -C ₆ alkyl), ~N(C I~C ₆ alkyl)S(0) ₂ (C _l -C ₆ haloalkyi), -N(CI-C ₆ haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -NfC -Ce haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyi);

wherein R and : 1 16-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^la and R ^lb are independently selected from the group consisting of hydrogen, C -Ce alkyl, and halogen;

R ^2a and R ^2b are independently selected from the group consisting of hydrogen, Ci-C ₆ alky _' l, and halogen;

when present, R ^ia and R ^ib are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R* ^a and R* ^b are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

or alternatively, R ^a and R ^2a are taken together to form a Ci-Ce alkylene moiety;

or alternatively, R ^a and an R ^a moiety, when present, are taken together to form a Ci-Ce alky ene moiety, and R ^lb and the R ^3b in the gennnal position to the R ³ taken together with R ^ia , are both hydrogen;

or alternatively, an R ^3a moiety, when present, and an R ^¾J moiety, when present, are taken together to form a Ci-Ce alkylene moiety, and the R ^3b in the geminal position to the R ^3a taken together with the R ^4a moiety and the R ^4b in the geminal position to the R ^4a taken together with the R ^3a moiety, are both hydrogen;

when present, R ^5a and R ^5b are taken together to form an oxo (=0) substituent or an irnido (=NH) substituent, or alternatively, R ^5a and R ^5b are both hydrogen;

when present, R ^6a is selected from the group consisting of h drogen, -OR ^{6a a} ,

and -NR ^{6a b} R ^{6a c} ;

when present, R ^bb is hydrogen;

or alternatively, R ^6a and R ^6b are taken together to form a moiety selected from the group consisting of -0~CH _2~ CH _2~ , -CH ₂ -0-CH ₂ -, -CH ₂ -CH ₂ -0-, -0-CH ₂ -CH ₂ -CH ₂ -, -CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-CH2-O-, -O-CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -0-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -0-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -0-CH _2~ , and

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -0-;

when present, R ^7a and R ^7b are both hydrogen;

when present, R ^8a and R ^8b are taken together to form an oxo (=0) substituent, or

alternatively, R and R are both hydrogen;

when present, R ^9a and R ^9b are taken together to form an oxo (=0) substituent or an iinido (=NH) substituent, or alternatively, R ^9a and R ^9b are both hydrogen; when present, R ^10a is selected from the group consisting of hydrogen, ~OR ^{l0a a} ,

and -NR ^{10a b} R ^{10a c} ;

when present, R ^10b is hydrogen;

or alternatively, R ^0a and R ^0b are taken together to form a moiety selected from the

group consisting of -O-CH2-CH2-, -CH ₂ -0-CH ₂ -, -CH ₂ -CH ₂ -0-, -O-CH2-CH2-CH2-, ('I I _' ·0·(Ί 1 ·-('! 1 ···. - ( Ί 1 - - { Ί i -·-()-( 1 l·-. -CH ₂ -CH ₂ -CH ₂ -0-, -O-ίΊ I -C! S ·-{'! ! ,-P 1 -CH ₂ -0-CH _2~ CH _2~ CH _2~ , -CH ₂ -CH ₂ -0-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -0-CH ₂ -, and

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -0-;

when present, R ^lla and R ^llb are both hydrogen;

when present, R ^12a and R ^12b are taken together to form an oxo (=0) substituent, or

alternatively, R ^{l a} and R ^{l b} are both hydrogen;

R ^{6a a} is selected from the group consisting of hydrogen, C -Ce alky l, and C -Ce haloalkyl; R ^{10a a} is selected from the group consisting of hydrogen, Ci-Ce alkyl, and CrC ₆ haloalkyl; or R ^{6a a} and R ⁷ may be taken together to form a carbonyl (C ^:=: 0) moiety ⁷ ;

or R ^{lua a} and R ^{' 2} may be taken together to form a carbonyl (C=0) moiety :

R ^{ba b} and R ^6a_t , independently of each other, are selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and C1-C6 haloalkyl; and

R ^{10a b} and R ^{lt,a c} , independently of each other, are selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and CVC _f , haloalky!.

[0058] In some embodiments, the compound of formula (I) is a compound of formula (1 -1 ):

or a pharmaceutically acceptable salt thereof;

wherein:

A ⁵ is a substituent of formula (A^a)

A ² is a substituent of formula (A -a)

n compounds of formul a (I)

In some embodiments of the compounds of formula (1-1), (A‘-a) is selected from the group consisting of:

[0061] In some embodiments of the compounds of formula (1 -1), (A'-a) is (A^-c).

[0062] In some embodiments of the compounds of formula (1 -1), (A -a) is (A ^-d). [QQ63] In some embodiments of the compounds of formula (1 -1 ), (A'-a) or (A ¹ -! ) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ¹ -a) or (A*-b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. In some embodiments, (A ¹ -a) or (A ^] -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ³ -a) or (A ³ -b) is selected from the group consisting of: wherein the * represents the atachment point to th e remainder of the molecule.

[0064] In some embodiments of the compounds of formula (1 -1), (A ^f -a) or (A ^! -c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule some embodiments, (A ³ -a) or (A ³ -c) is selected from the group consisting of:

*

; wherein the * represents the attachment point to the remainder of the molecule.

[0065] In some embodiments of the compounds of formula (1-1), (A ² -a) is selected from the group consisting of:

In some embodiments of the compounds of formula (1 -1 ), (A -a) is (A -b).

[006'; In some embodiments of the compounds of formula (1 -1), (A ² -a) is (A -c).

[0068] In some embodiments of the compounds of formula (1 -1), (A -a) is (A ~d).

[0069] In some embodiments of the compounds of formula (1-1), (A ² -a) or (A ² -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ² -a) or (A -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ² ~a) or (A -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A -a) or (A -b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecul

[QQ7Q] In some embodiments of the compounds of formula (1-1), (A ² -a) or (A ² -c) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ² -a) or (A -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0071] In some embodiments, (A ^! -a) or (A ¹ -!)) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0072] In some embodiments, (A ^! -a) or (A ^! -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0073] In some embodiments, (A^a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from th< group consisting of: wherein the * represents the atachment point to the remainder of the molecule.

[0074] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0075] In some embodiments, (A ^! -a) or (A ² -b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and (A ^? -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0076] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

to the remainder of the molecul e.

[QQ77] In some embodiments, (A ^! -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ^z -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule.

is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0079] In some embodiments, (A ^! -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0080] In some embodiments, the compound of formula (I) is a compound of formula (1-2):

or a pharmaceutically acceptable salt thereof;

wherein:

A ⁵ is a substituent of formula (A^a)

A ² is selected from the group consisting of:

a substituent of formula (A ² -a)

C6-C10 aryl optionally substituted with one or more R ¹⁶ substituents; and 5-10 membered heteroaryl optionally substituted with one or more R ^!o

substituents;

R ^{i0a c} , R ^10b , R ¹² , R ¹⁴ , R”, and R ¹⁶ are as defined in compounds of formula (I).

In some embodiments of the compounds of formula (1-2), X ^“ is CH. In some embodiments, r is 1 and s is 1.

[0082] In some embodiments of the compounds of formula (1-2), X ² is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.

[QQ83] In some embodiments of the compounds of formula (1-2), (A ^f -a) is selected from the group consisting of:

[0084] In some embodiments of the compounds of formula (1 -2), (A'-a) is (A^b).

[0085] In some embodiments of the compounds of formula (1 -2), (A'-a) is (A^-c).

[0086] In some embodiments of the compounds of formula (1 -2), (A -a) is (A^-d).

[0087] In some embodiments of the compounds of formula (1-2), (A ¹ -a) or (A ^f -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecul e. In some embodiments, (A ¹ -a) or (A ^] -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A -a) or (A -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[QQ88] In some embodiments of the compounds of formula (1-2), (Aha) or (A‘-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule some embodiments, (A ¹ -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0089] In some embodiments of the compounds of formula (1-2):

q is 1;

R ⁹³ and R ^9b are taken together to form an oxo ( ^:=: 0) substituent or an unido (=NH)

substituent, or alternatively, R/ ^a and R ^9b are both hydrogen;

R ^1Ja is selected from the group consisting of hydrogen, ~OR ^{i0a a} , and -NR ^{]0a b} R ^{0a c} ;

R ^l0b is hydrogen;

or alternatively, R ^iGa and R ^iGb are taken together to form a -CH ₂ -0-CH ₂ - moiety; and A ² is Ce-Cio ai l optionally substituted with one or more R ⁱ⁶ substituents, or 5-10

membered heteroaryl optionally substituted with one or more R ^l ° substituents.

[QQ9Q] In some embodiments of the compounds of formula (1-2):

R ^9a and R ^9b are taken together to form an oxo ( ^:=: 0) substituent or an unido (=NH)

substituent;

R ^IOa is selected from the group consisting of hydrogen, -OR ^{10a a} , and -NR ^{iua b} R ^{,0a c} ;

R ^10b is hydrogen; and

A ² is Ce-Cio aiyl optionally substituted with one or more R ¹⁰ substituents, or 5-10

membered heteroaryl optionally substituted with one or more R ¹⁶ substituents.

[QQ91] In some embodiments of the compounds of formula (1-2), R ^9a and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments of the compounds of formula (1 -2), R ^9a and R ^9b are taken together to form an imido (=NH) substituent. In some embodiments, R ^iua is hydrogen.

[0092] In some embodiments of the compounds of formula (1-2):

R ⁹³ and R ^9b are both h drogen; and

R ^10a and R ^10b are taken together to form a ~CH _~ 0-CH ₂ - moiety' .

[0093] In some embodiments of the compounds of formula (1-2):

R ^9a and R ^9b are both hydrogen; and

R ^10a and R ^10b are both hydrogen.

[QQ94] In some embodiments of the compounds of formula (1 -2): X ² is CH;

R ^Yl is hydrogen or Ci-C ₆ alkyl;

Y ² is selected from the group consisting of NR ² and O;

R ^Y2 is hydrogen or Ci-Ce alkyl;

q ² is 1;

r and s, independently of each other, are 0, 1, or 2;

A ¹ is a substituent of formula (A^a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹ is selected from the group consisting of CR ^{Zl l} R ^{Z1 2} , NR ^{Z1 2} , O, S, and -CR ^{Z1 1} =CR

wherein

Z" is selected from the group consisting of CR- R ^Z~ , NI¾C ^Z ; O, S, and -CR^-^CR ^{22 1} -;

wherein R ^{22 1} is H or R ¹⁴ ; and R ^{Z2 z} is H or R ¹⁴ ;

Z ³ , independently at each occurrence, is C or N, provided that at least one Z ³ is C;

R ^l3 is hydrogen or R ¹⁴ , or R ^1J and R ^Z1~2 are taken together to form a double bond between the carbon atom bearing R ^~ and Z , or R and R are taken together to form a double bond between the carbon atom bearing R ⁱ³ and Z ² ; and

xl is 1 , 2, 3, or 4, and at least one R ^l4 is halogen;

R ¹⁴ is selected, independently at each occurrence, from the group consisting of halogen, C -C ₆ alkyl, C C ₆ hatoalkyl, -OH, -0(C C ₆ alkyl), -0(C C ₆ haloalkyl), -SH, -S(Ci- C ₆ alkyl), -SiCrCe, haloalkyl), ~NH ₂ , -NH(C C ₆ alkyl), ~NH(C C ₆ haloalkyl), -N(C _r alkyl) ₂ , -\(C haloalkyl) ₂ , -NR ¹⁴ ¾ ¹⁴ *, -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl), -C(0)0(C _r C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(C C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) _? ., -C(0)NR ^{14 3} R ^{14 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _I -C ₆ alkyl), -S(0) ₂ 0(Ci~C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(C _I -C ₆ alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyl), -S(()} .\{( _r C,, alkyl) ₂ , -S(0) ₂ N(C _I -C ₆ haloalkyl) _? ., -S(0) _? NR ^14~a R ^14~b ,-OC(0)H, -0C(0)(Ci-C ₆ alkyl),

-()( ( OK ( -( ,, haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl)

haloalkyl), -N(C C ₆ alkyl)C(0)H, AiC _r( ^' , alkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ alk}'l)C(0)(Ci-C ₆ haloalkyl), -N(C -C ₆ haloalkyl)C(0)H, -N(CrC ₆

haioalkyl)C(0)(CrC ₆ alkyl), -N(CrC ₆ haioalkyl)C(0)(CrC ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (C ₁ -C ₆ alkyl),

-N(H)S(0) ₂ (CI-C ₆ haloalkyl), -N(C _r C ₆ alkyJ)S(0) ₂ (Ci-C ₆ alkyl), -\iC _r C,, alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), haloaikyl)S(0)?.(Ci-C ₆ alkyl), and -N(CI-C ₆ haloalliy'l)S(0) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{l4 a} and R ^14_b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A is Ce-Cio aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ⁱ⁶ substituents;

R ^lb is selected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, CrCe haloalkyl, -OH, -OlC -Ce alkyl), -0(C -Ce haloalkyl), -SH, -S(Ci~ C _ft alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , - H(C -C ₆ alkyl),-NH(C -C ₆ haloalkyl), -N(C·,- C ₆ alkyl) _? ., -N(C C ₆ haloalkyl) ₂ , -NR ^{16 3} R ^{16 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl ) . -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0) R ^{16 3} R ^{l6 b} , -S(0) _? 0H, -S(0) ₂ 0(C _r C ₆ alkyl), -S(0) ₂ 0(C C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(CI-C ₆ alkyl), -S(0) ₂ NH(C _r C ₆ haloalkyl), -S(0) ₂ N(CrC ₆ alkyl)?,

-S(0) ₂ N(C -C ₆ haloalkyl) ₂ alkyl),

-0C(0)(C _r C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(C C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C C ₆ alkyl)C(0)(CrC ₆ alkyl), -N(C C ₆ aik\ I }( (()}·; ( -( ,. haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haloalkyl)C(0)(Ci-C ₆ alkyl), ~MC _r C., haloalkyl )CiO)i( _r C,, haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), - (H)S(0) _? .(Ci-C ₆ alkyl),

-N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(CI-C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloatkyl), -N(C C ₆ haloalkyi)S(0) ₂ (Ci-C ₆ alkyl), and -N(C C ₆ haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R' ^{6 3} and R ^{16 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^la and R ^lb are independently selected from the group consisting of hydrogen, Ci-C ₆ alky _' l, and halogen;

R ^2a and R ^2b are independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

when present, R’ ^a and R’ ^b are independently at each occurrence selected from the group consisting of hydrogen, Ci-C _& alkyl, and halogen;

when present, R ^4a and R ^4b are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

or alternatively, R ^a and R ^2a are taken together to form a C -Ce alkylene moiety;

or alternatively, R ^ia and an R ^3a moiety, when present, are taken together to form a Ci-Ce alkylene moiety, and R ^lb and the R ^b in the geminal position to the R ^3a taken together with R ^la , are both hydrogen;

or alternatively, an R ^3a moiety, when present, and an R ^4a moiety, when present, are taken together to form a Ci-Cg alkylene moiety, and the R ^b in the geminal position to the R ^Ja taken together with the R ^4a moiety' and the R ^4b in the geminal position to the R ^4a taken together with the R ^3a moiety , are both hydrogen;

R ^9a and R ^9b are taken together to form an oxo ( ^:=: 0) substituent or an imido (=NH)

substituent, or alternatively, R ^9a and R ^9b are both hydrogen;

hydrogen; and

hydrogen.

[0095] In some embodiments of the compounds of formula (1-2), R ^Yi is hydrogen. In some embodiments of the compounds of formula (1-2), R^ ¹ is Ci-Cg alkyl.

[0096] In some embodiments of the compounds of formula (1-2), Y ² is NR ² . In some embodiments of the compounds of formula (1-2), R ^Y is hydrogen. In some embodiments of the compounds of formula (1-2), R ^¾2 is Ci-Ce alkyl.

[QQ97] In some embodiments of the compounds of formula (1 -2), Y is O. [QQ98] In some embodiments of the compounds of formula (1 -2), R ^la and R ^lb are independently selected from the group consisting of hydrogen and Ci-Cr, alkyl. In some embodiments of the compounds of formula (1-2), R ^‘ and R ^‘ are both hydrogen.

[0099] In some embodiments of the compounds of formula (1-2), R ^2a and R ^2b are independently selected from the group consisting of hydrogen and Ci-Cg alkyl. In some embodiments of the compounds of formula (1-2), R ²³ and R ^2b are both hydrogen.

[Q1QQ] In some embodiments of the compounds of formula (1-2), R ^la and R ^2a are taken together to form a Ci-C ₆ alkylene moiety

[0101] In some embodiments of the compounds of formula (1 -2), r is 1 and s is 1. In some embodiments, R ^3a and R ^3b are independently selected from the group consisting of hydrogen and Ci-C _ft alkyl. In some embodiments, R ^3a and R ^3b are both hydrogen. In some embodiments, R ^4a and R ^4b are independently selected from the group consisting of hydrogen and C1-C0 alkyl. In some embodiments, R ^4a and R ^4b are both hydrogen. In some embodiments, R ^ia and R ^3a are taken together to form a Ci-C ₆ alkylene moiety, and R ^lb and R ^3b are both hydrogen. In some embodiments, R ³³ and R ⁴³ are taken together to form a C.-Ce alkylene moiety, and R ^,b and R ^4b are both hydrogen.

[0102] In some embodiments of the compounds of formula (1 -2), R ^9a and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments of the compounds of formula (1-2), R ^9a and R ^9b are taken together to form an imido (=NH) substituent.

[0103] In some embodiments of the compounds of formula (1-2), (A ^x -a) is selected from the group consisting of:

[0104] ln some embodiments of the compounds of formula (1-2), (A ^x -a) is (A ³ -b).

[0105] ln some embodiments of the compounds of formula (1-2), (A ^f -a) is (A ³ -e).

[0106] In some embodiments of the compounds of formula (1 -2), (A ^f -a) is (A ³ -d).

[0107] In some embodiments of the compounds of formula (1 -2), (A ^x -a) or (A ^x -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments xl is 1 , 2, 3, or 4, and at least one ^l4 is halogen. In some embodiments, xl is 1 and R ¹⁴ is halogen. In some embodiments, xl is 2 and at least one R ¹⁴ is halogen. In some embodiments, xl is 3 and at least one R ¹⁴ is halogen. In some embodiments, xl is 4 and at least one R ¹⁴ is halogen. In some embodiments, (A ^! -a) or (A ¹ -!)) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. In some embodiments, (A ^] -a) or (A^b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments xl is 1, 2, 3, or 4, and at least one R ¹⁴ is halogen. In some embodiments, xl is 1 and R ¹⁴ is halogen. In some embodiments, xl is 2 and at least one R ⁴ is halogen. In some embodiments, xl is 3 and at least one R ¹⁴ is halogen. In some embodiments, xl is 4 and at least one R ¹⁴ is halogen. In some embodiments, (Ai-a) or

(A -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0108] In some embodiments of the compounds of formula (1-2), (A‘-a) or (A ^x -c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A*-a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. [Q1Q9] In some embodiments of the compounds of formula (1 -2), A ^z is Cg-Cio aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹ ” substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ⁶ substituents.

[0110] In some embodiments of the compounds of formula (1-2), A ² is C ₆ -C _lo ar l optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is C^-Cio and substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of;

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A is phenyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ^z is phenyl substituted by at least one halogen substituent and optionally further substituted with one or more R ^lb substituents. In some embodiments, A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the mol ecule.

[0111] In some embodiments of the compounds of formula (1-2), A ² is 5-10 membered heteroaryl optionally substituted with one or more R ⁱ⁶ substituents. In some embodiments, A ² is 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of: ; w herein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ² is pyridyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is pyridyl substituted by at least one halogen substituent and optionally further substituted with one or more R ^l6 substituents. In some embodiments, wherein the * represents the atachment point to the remainder of the molecule.

[0112] In some embodiments of the compounds of formula (1-2):

q ² is 0;

R ^9a and R ^9b are both hydrogen;

R ^IOa is -OR ^{10a a} or -NR ^{i0a b} R ^{10a c} ; and

R ^10b is hydrogen.

[0113] In some embodiments of the compounds of formula (1-2):

R ^10a is~OR ^{l0a a} or -NR ^{i0a b} R ^{!0a c} ; and

A is a substituent of formula (A ² -a)

[0114] In some embodiments of the compounds of formula (1 -2), R ^10a is -OR ^{10a a} .

[0115] In some embodiments of the compounds of formula (1 -2), (A ² -a) is selected from the group consisting of:

In some embodiments of the compounds of formula (1 -2), (A ² -a) is (A -b).

In some embodiments of the compounds of formula (1-2), (A ² -a) is (A ^z -c).

In some embodiments of the compounds of formula (1-2), (A ² -a) is (A ^z -d).

In some embodiments of the compounds of formula (1-2), (A ² -a) or (A ² -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. In some embodiments, (A ^z -a) or is selected from the group consisting of;

wherein the * represents the attachment point to ths remainder of the molecule. In some embodiments, (A ² -a) or (A ^z -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments of the compounds of formula (1-2), (A -a) or (A ^z -c) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ~a) or (A ² -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0121] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0122] In some embodiments, (A ^! ~a) or (A ¹ -!)) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A ² -a.) or is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0123] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A -a) or (A ² -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0124] In some embodiments, (A ^x -a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to th e remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0125] In some embodiments, (A ^! -a) or (A ^! -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -h) is selected from the group consisting of;

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

to the remainder of the molecule.

[0127] In some embodiments, (A ^! ~a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, (A*-a) or (A*-c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A -a) or (A ~b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, (A^a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from the group consisting of:

[0130] wherein the * represents the attachment point to the remainder of the molecule.

[0131] In some embodiments, (A^a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[0134] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

nts the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0135] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and A ² is selected from the group consisting of

wherein the * represents the atachment point to the remainder of the molecule. [0136] In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0137] In some embodiments, or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0138] In some embodiments, (A ^x -a) or (A^b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ^! -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

In some embodiments, (A ^! -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

In some embodiments, (A’-a) or (A ^l -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: ; wherein the * represents the attachment point

io the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

[0143] In some embodiments, the compound of formula (1) is a compound of formula (1-3):

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is a substituent of formula (A*-a)

A is Ce-Cio aryl optionally substituted with one or more R ^{i 6} substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ^lb substituents; and wherein X ² , R ^Y1 , Y ² , R ^Y2 , r, s, Z ^l , R ^{21 1} , R ^{21 2} , Z ² , R ^{22 1} , R ^{22 2} , Z ³ , xl,

R ^b . R ^;a . R ^3b R ⁴³ , R ^4b , R ^9a , R ^9b , R ^10a R ^{103 3} , R ^{!0a b} , R ^{10a c} . R ^l0b , R ^i2a , R ^12b . R ¹³ . R ^{! l} .

defined in compounds of formula (1).

In some embodiments of the compounds of formula (1-3), X ² is CH. In some embodiments, r is 1 and s is 1

[0145] In some embodiments of the compounds of formula (1-3), X ² is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2 [0146] In some embodiments of the compounds of formula (1 -3), (A'-a) is selected from the group consisting of:

In some embodiments of the compounds of formula (1-3), (A ^! -a) is (A^b). In some embodiments of the compounds of formula (1-3), (A ¹ -a) is (A^c). In some embodiments of the compounds of formula (1-3), (A ^x -a) is (A^d).

[0150] In some embodiments of the compounds of formula (1-3), (A'-a) or (A'-b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ^! -a) or is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecul e. In some embodiments, (A ¹ -a) or (A ^] -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A -a) or (A -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0151] In some embodiments of the compounds of formula (1-3), (Aha) or (A‘-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule some embodiments, (A ¹ -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0152] In some embodiments of the compounds of formula (1-3):

R ^9a and R ^9b are taken together to form an oxo (=0) substituent or an imido (=NH)

substituent, or alternatively, R ^9a and R ^9b are both hydrogen;

R ^K '“ is selected from the group consisting of hydrogen, ~OR ^{i0a a} , and -NR ^{10a b} R ^0a ;

R ¹ '* is hydrogen; and

R ^{l a} and R ^{l b} are both hydrogen.

[0153] In some embodiments of the compounds of formula (1-3), R ^9a and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments, R ^10a is hydrogen. In some embodiments, R ^10a is -OR ^{10a a} In some embodiments, R ^1Ja is NR ^{l0a b} R ^{!0a £:} .

[0154] In some embodiments of the compounds of formula (1-3), R ^9a and R ^9b are taken together to form an imido (=NH) substituent. In some embodiments, R ^10a is hydrogen. In some embodiments, R ^10a is -OR ^10a~a . In some embodiments, R ^10a is -NR ^{i0a b} R ^{10a c} .

[0155] In some embodiments of the compounds of formula (1 -3), R ^9a and R ^9b are both hydrogen. In some embodiments, R ^10a is hydrogen. In some embodiments, R ^l0a is -OR ^{iua a} . In some embodiments, R ^10a is -NR ^{lua b} R ^{30a c} .

[0156] In some embodiments of the compounds of formula (1-3):

X ² is CH or N;

R ^x '‘ is hydrogen or C -C ₆ alkyd;

Y ^z is selected from the group consisting of a bond, NR* ² , and O; provided that when X ² is N, then Y ^z is a bond;

R ^Y2 is hydrogen or Ci-C ₆ alkyl;

r and s, independently of each other, are 0, 1, or 2;

A ¹ is selected from the group consisting of:

a substituent of formula (A^a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹ is selected from the group consisting of CR ^{Zl 1} R ^{Z3 2} , NR ^{21 2} , O, S, and -CR ^{Z I :} CR'" ¹ -.

wherein R ^{z, !} is H or R ⁱ⁴ ; and R ^Zi is H or R ¹⁴ ;

Z is selected from the group consisting of CR' ^{~ ~} , NR O, S, and -CR^-^CR ^{22 1} -;

wherein R ^{22 1} is H or R ¹⁴ ; and R ^{22 z} is H or R ¹⁴ ;

Z ³ , independently at each occurrence, is C or N, provided that at least one Z ³ is C;

R ^l3 is hydrogen or R ¹⁴ , or R ^1J and R ^{21 2} are taken together to form a double bond between the carbon atom bearing R and Z , or R and R are taken together to form a double bond between the carbon atom bearing R ⁱ³ and Z ² ; and

xl is 1 , 2, 3, or 4, and at least one R ^l4 is halogen;

R ¹⁴ is selected, independently at each occurrence, from the group consisting of halogen, C -C ₆ alkyl, C C ₆ haloalkyl, -OH, -0(C C ₆ alkyl), -0(C C ₆ haloalkyl), -SH, -S(C ₃ - r

haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C _I -C ₆ alkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ alk}'i)C(0)(Ci-C ₆ haloalkyl), - fC -C _f , haloalkyl)C(0)H, -N(C _I -C ₆

haloalkyl)C(0)(CrC ₆ alkyl), -N(CrC ₆ haloalkyl)C(0)(CrC ₆ haloalky l), -0S(0) ₂ (Ci~C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), haloalkyl), -N(C _r C ₆ alkyJ)S(0) ₂ (Ci-C ₆ alkyl), -N(C _I -C ₆

alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(CI-C ₆ haloalliy'l)S(0) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{l4 a} and R ^14_b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A is Ce-Cio aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ⁱ⁶ substituents;

R ^lb is selected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, Ci-Ce haloalkyl, -OH, -OiC -Ce alkyl), -0(C -Ce haloalkyl), -SH, -S(Ci~ C _ft alkyl), S(Ci-C ₆ haloalkyl), -NH ₂ , -NHfC -Cc, alkyl),-NH(C _] -C ₆ haloalkyl), -N(Cr C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl) ₂ , -NR ^{16 3} R ^{16 b} , -CN, -C(0)0H, -C<0)0(Ci-C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -HOl iC C,, alkyl) ₂ , -C(0)N(C C ₆ haloalky ) ₂ , -C(0)NR ^{16 3} R ^{l6 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl), -S(0) ₂ 0(CrC ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(C _I -C ₆ alkyl), -S(0) ₂ NH(C C ₆ haloalkyl), -S(0) ₂ N(C C ₆ alkyl) ₂ , -S(0) ₂ N(CrC ₆ haloalkyl) ₂ alkyl),

-0C(0)(C _r C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(C C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C C ₆ alkyi)C(0){Ci-C ₆ alkyl), -N(C C ₆ aik\ i )( (()}·; ( -( ,, haloalkyl), ~N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CJ-C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl),

-N(H)S(0) ₂ (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0) ₂ (C ₁ -C ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci~C ₆ haloalkyl), haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -N(C -C ₆ haloalky )S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ^{i6 3} and R ^{16 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^la and R ^lb are independently selected from the group consisting of hydrogen, C -Ce alkyl, and halogen; R ^a and R *’ are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R ^,a and R ^,b are independently at each occurrence selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

when present, R ^4a and R ^4b are independently at each occurrence selected from the group consisting of hydrogen, Cj-C ₆ alkyl, and halogen;

or alternatively, R ^ia and R ^a are taken together to form a Ci-Cg alkylene moiety;

or alternatively, R ^ia and an R ^3a moiety, when present, are taken together to form a Ci-Cty alkylene moiety', and R ^!b and the R ^3b in the geminal position to the R ^3a taken together with R ^ia , are both hydrogen;

or alternatively, an R ^3a moiety, when present, and an R ^4a moiety, when present, are taken together to form a Cj-Ce alkylene moiety, and the R ^b in the geminal position to the R ^3a taken together with the R ^4a moiety' and the R ^4b in the geminal position to the R ^4a taken together with the R ^3a moiety, are both hydrogen;

R ^9a and R ^9b are taken together to form an oxo (==0) substituent or an imido (=NH)

substituent, or alternatively, R ^9a and R ^9b are both hydrogen;

R ^10a is selected from the group consisting of hydrogen, -OR ^{10a a} , and -NR ^{3ua b} R ^! ° ^a~c ;

R ^10b is hydrogen;

R ^!2a and R ^!2b are taken together to form an oxo (=0) substituent, or alternatively, R ^{l a} and R ^,2b are both hydrogen;

R ^{10a a} is selected from the group consisting of hydrogen, (ty-Cty alkyl, and Ci-Ce haloalkyl; or R ^{i0a a} and R ^Y2 may be taken together to form a carbonyl (0=0) moiety; and

R ^{l0a b} and R ^{l0a c} , independently of each other, are selected from the group consisting of hydrogen, Ci-Ce alkyl, and (ty-Cs haloalkyl.

[0157] In some embodiments of the compounds of formula (1-3), R ^Yi is hydrogen. In some embodiments of the compounds of formula (1-3), ^ ¹ is Ci-Cg alkyl.

[0158] In some embodiments of the compounds of formula (1-3), X ² is CH and Y ² is NR^ ² .

In some embodiments of the compounds of formula (1-2), R ^Y2 is hydrogen. In some

embodiments of the compounds of formula (1-3), R ^Y2 is Cty-Cty alkyl.

[0159] In some embodiments of the compounds of formula (1 -3), X is CH and Y ^“ is O.

[0160] In some embodiments, X ^z is N and Y ² is a bond. [0161] In some embodiments of the compounds of formula (1 -3), R ^la and R ^lb are independently selected from the group consisting of hydrogen and Ci-Cr, alkyl. In some embodiments of the compounds of formula (1-3), R ^‘ and R ^‘ are both hydrogen.

[0162] In some embodiments of the compounds of formula (1-3), R ^2a and R ^2b are independently selected from the group consisting of hydrogen and Ci-Cg alkyl. In some embodiments of the compounds of formula (1-3), R ^2a and R ^2b are both hydrogen.

[0163] In some embodiments of the compounds of formula (1-3), R ^la and R ²³ are taken together to form a Ci-C ₆ alkylene moiety.

[0164] In some embodiments of the compounds of formula (1 -3), r is 1 and s is 1. In some embodiments, R ^3a and R ^3b are independently selected from the group consisting of hydrogen and Ci-C _ft alkyl. In some embodiments, R ^3a and R ^3b are both hydrogen. In some embodiments, R ^4a and R ^4b are independently selected from the group consisting of hydrogen and C1-C0 alkyl. In some embodiments, R ^4a and R ^4b are both hydrogen. In some embodiments, R ^ia and R ^3a are taken together to form a Ci-C ₆ alkylene moiety, and R ^!b and R ^3b are both hydrogen. In some embodiments, R ³³ and R ⁴³ are taken together to form a Ci-Ce alkylene moiety, and R ^,b and R ^4b are both hydrogen.

[0165] In some embodiments of the compounds of formula (1 -3), R ^9a and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments of the compounds of formula (1-3), R ^9a and R ^9b are taken together to form an imido (=NH) substituent. In some embodiments of the compounds of formula (1-3), R ^9a and R ^9b are both hydrogen.

[0166] In some embodiments of the compounds of formula (1-3), R ^10a is hydrogen and R ^10b is hydrogen.

[0167] In some embodiments of the compounds of formula (1 -3), R ^10a is -OR ^{10a a} and R ^10b is hydrogen. In some embodiments, R ^{l0a a} is selected from the group consisting of hydrogen and Ci-C _f , alkyl. In some embodiments, R ^{10a a} is hydrogen. In some embodiments, R ^{10a a} is C -Ce alkyl. In some embodiments, R ^{lua a} and R. ^'32 may be taken together to form a carbonyl (C=0) moiety.

[0168] In some embodiments of the compounds of formula (1-3), R ^10a is -NR ^1J “ ^b R ^{1Jd t} and

R ^10b is hydrogen. In some embodiments, R ^{1Ja b} and R ^{0a c} , independently of each other, are selected from the group consisting of hydrogen and CrCg alky]. In some embodiments, R ¹⁰ “ ^b and R ^{i0a c} are hydrogen. In some embodiments, R ^{!0a b} and R ¹⁰ⁱ are Ci-Cr, alkyl.

[0169] In some embodiments of the compounds of formula (1-3):

X ² is i l l;

R is hydrogen;

Y ² is NR ^Y2 ;

R ^{Y 2} is hydrogen;

R ^9a and R ^9b are both hydrogen;

R ^10a is -OR ¹⁰ **;

R ^{t0a a} is hydrogen;

R ^10b is hydrogen; and

R ^!2a and R ^!2b are both hydrogen.

[0170] In some embodiments of the compounds of formula (1-3):

X ² is CH;

Y ² is NR* ² ;

R ^9a and R ^9b are both hydrogen;

R ^IOa is -OR ^{10a a} ;

R ^12a and R ^12b are both hydrogen; and

R ^{10a a} and R ^Y are taken together to form a carbonyl (OΌ) moiety

[0171] In some embodiments of the compounds of formula (1-3):

X ² is CH;

R ' ^! is hydrogen;

Y ² IS NR ^Y2 ;

R ^Y2 is hydrogen;

R ^9a and R ^9b are both hydrogen;

R ^10a is -OR ^{10a a} ;

R ^10b is hydrogen;

R ^{! a} and R ^{! b} are both hydrogen; and

R ^{103 3} and R ² are taken together to form a carbonyl (C=0) moiety.

[0172] In some embodiments of the compounds of formula (1 -3):

X ² is CH; R ^{Y l} is hydrogen;

Y ² is NR ^Y2 ;

R ^Y2 is hydrogen;

R ^9a and R ^9b are both hydrogen;

R ^10a is hydrogen;

R ^!0b is hydrogen; and

R ^12a and R ^12b are both hydrogen.

[0173] In some embodiments of the compounds of formula (1 -3):

X ² is N;

R ^Yl is hydrogen;

Y ² is a bond;

R ^9a and R ^9b are both hydrogen;

R ^!0a is -OR ^{10a a} ;

R ^{10a a} is hydrogen;

R ^10b is hydrogen; and

R ^12a and R ^12b are both hydrogen.

[0174] In some embodiments of the compounds of formula (1-3):

X ² is N;

R ^Yi is hydrogen;

Y ² is a bond;

R ⁹³ and R ^9b are both hydrogen;

R ^10a is hydrogen;

R ^10b is hydrogen; and

R ^l2a and R ^l2b are both hydrogen.

[0175] In some embodiments of the compounds of formula (1-3);

X ² is (1 1;

R ^Y is hydrogen;

Y ² is NR ^Y2 ;

R ^Y2 is hydrogen;

r and s are both 1 ;

R ^9a and R ^9b are both hydrogen; R ^10a is -OR ¹⁰ **;

R ^{l0a a} is hydrogen;

R ^10b is hydrogen; and

R ^12a and R ^12b are both hydrogen.

[0176] In some embodiments of the compounds of formula (1-3):

X ² is Cl !:

Y ² is NR · ^'

r and s are both 1 ;

R ^9a and R ^9b are both hydrogen;

R ^10a is -OR ^{10a a} ;

R ^12a and R ^12b are both hydrogen; and

R ^{10a a} and R ^Y/ are taken together to form a carbonyl (OΌ) moiety.

[0177] In some embodiments of the compounds of formula (1-3):

X ² is Cl !:

R ^{' 1} is hydrogen;

Y ² is NR ^Y2 ;

R ^Y2 is hydrogen;

r and s are both 1 ;

R ^9a and R ^9b are both hydrogen;

R ^!0a is -OR ^{10a a} ;

R ^10b is hydrogen;

R ^12a and R ^12b are both hydrogen; and

R ^{10a a} and R ^Y2 are taken together to form a carbonyl (C=0) moiety.

[0178] In some embodiments of the compounds of formula (1 -3):

X ² is CH;

R ^Yi is hydrogen;

Y ² is NR* ² ;

R' ¹² is hydrogen;

r and s are both 1 ;

R ^9a and R ^9b are both hydrogen;

R ^10a is hydrogen; R ^10b is hydrogen; and

R ^{l a} and R ^{l b} are both hydrogen.

[0179] In some embodiments of the compounds of formula (1-3):

X ² is N;

R^ is hydrogen;

Y is a bond;

r and s are both 1 ;

R ⁹ “ and R ^9b are both hydrogen;

R ^10a is -OR ^{10a a} ;

R ^{IOa a} is hydrogen;

R ^10b is hydrogen; and

R ^!2a and R ^!2b are both hydrogen.

[0180] In some embodiments of the compounds of formula (1-3):

X ² is N;

R ^{' 1} is hydrogen;

Y ^z is a bond;

r and s are both 1 ;

R ^9a and R ^9b are both hy drogen;

R ^10a is hydrogen;

R ^10b is hydrogen; and

R ^{1 3} and R ^{l b} are both hydrogen.

[0181] R ^32a and R ^12b are both hydrogen.In some embodiments of the compounds of formula (1 -3), A is C6-C10 aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ^lb substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ^lb substituents.

[0182] In some embodiments of the compounds of formula (1-3), A ² is C ₆ -C _lo aryl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is C^-C o aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is phenyl optionally substituted with one or more R ^lb substituents. In some embodiments, A is phenyl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, A ² is 5-10 membered heteroaryl optionally substituted with one or more R ³⁶ substituents. In some embodiments, A ² is 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ² is pytidyl optionally substituted with one or more R ⁱ⁶ substituents. In some embodiments. A ² is pyridyl substituted by at least one halogen substituent and optionally further substituted with one

or more R' ⁶ substituents. In some embodiments, wherein the * represents the attachment point to the remainder of the molecule.

[0183] In some embodiments, (A ^! ~a) or (A ³ -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0184] In some embodiments, (A ^! ~a) or (A ¹ -!)) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A ² -a.) or is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the diments, (A ^! ~a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A -a) or (A ² -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0186] In some embodiments, (A ^x -a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to th e remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0187] In some embodiments, (A ^! -a) or (A ^! -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -h) is selected from the group consisting of;

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

to the remainder of the molecule.

[0189] In some embodiments, (A ^! ~a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0190] In some embodiments, (A ^! ~a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A -a) or (A ~b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, (A^a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from the group consisting of:

_ , wherein the * represents the attachment point to the remainder of the molecule.

[0193] In some embodiments, (A -a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[0196] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

nts the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0197] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and A ² is selected from the group consisting of

wherein the * represents the atachment point to the remainder of the molecule. [0198] In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0199] In some embodiments, or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0200] In some embodiments, (A ^x -a) or (A^b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ^! -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

In some embodiments, (A ^! -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

[0203] In some embodiments, (A ^! ~a) or (A ^l -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0204] In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: wherein the * represents the attachment point

to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0205] In some embodiments, the compound of formula (1) is a compound of formula (1-4):

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is a substituent of formula (A ³ -a)

A is Ce-Cio aryl optionally substituted with one or more R ⁱ⁶ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ^lb substituents;

R ^lla and R ^llb are both hydrogen;

R ^lza and R ^lzb are both hydrogen;

and wherein X ² , R ^{V i} . Y ² , R ^Y2 , r, s, A ¹ , z\ R ^Z1_1 , R ^{/ j} " ^' . Z". R ^Z2 , R ^{7 '} ". Z\ xl, R ^!a , R ^lb ,

_R 2a _R ?.b_ _R 3a_ _R 3b R ⁴³ , R ^4b , R ³³ , R‘ ⁴ , and R ^l ° are as defined in compounds of formula (I).

[0206] In some embodiments of the compounds of formula (1-4), X is CH. In some embodiments, r is 1 and s is 1.

[0207] In some embodiments of the compounds of formula (1-4), X ^z is N and Y ² is a bond.

In some embodiments, r is 1 and s is 1 In some embodiments, r is 0 and s is 2. [Q2Q8] In some embodiments of the compounds of formula (1 -4), (A'-a) is selected from the group consisting of:

In some embodiments of the compounds of formula (1-4), (A ^! -a) is (A ¹ -!)).

[0210] In some embodiments of the compounds of formula (1-4), (A ¹ -a) is (A^c).

[0211] In some embodiments of the compounds of formula (1-4), (A ^x -a) is (A^d).

[0212] In some embodiments of the compounds of formula (1-4), (A^a) or (A'-b) is selected from the group consisting of

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecul e. In some embodiments, (A ¹ -a) or (A ^] -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A -a) or (A -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0213] In some embodiments of the compounds of formula (1-4), (Aha) or (A‘-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule some embodiments, (A ¹ -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0214] In some embodiments of the compounds of formula (1-4), A ² is C ₆ -C _lo aryl optionally substituted with one or more R ¹⁶ substituents. In some embodiments. A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is phenyl optionally substituted with one or more R ^lb substituents. In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments of the compounds of formula (1-4), A ^z is 5-10 membered heteroaryl optionally substituted with one or more R ^l6 substituents. In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is pyridyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ¹ -!)) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0217] In some embodiments, (A ^! ~a) or (A ¹ -!)) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A ² -a.) or (A ~b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the diments, (A ^! ~a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A -a) or (A ² -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0219] In some embodiments, (A ^x -a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to th e remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0220] In some embodiments, (A ^! -a) or (A ^! -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -h) is selected from the group consisting of;

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

to the remainder of the molecule.

In some embodiments, (A ^! ~a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the atachment point to the remainder of the molecule.

In some embodiments, (A*-a) or (A*-c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A -a) or (A ~b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0224] In some embodiments, (A^a) or (A ^! -c) is selected from the group consisting of: : wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0226] In some embodiments, (A^a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[0229] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

nts the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0230] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and A ² is selected from the group consisting of

wherein the * represents the atachment point to the remainder of the molecule. [0231] In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[Q232] In some embodiments, or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0233] In some embodiments, (A ^x -a) or (A^b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ^! -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

[0235] In some embodiments, (A ^! -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

In some embodiments, (A’-a) or (A ^l -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0237] In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: ; wherein the * represents the attachment point

io the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, the compound of formula (1) is a compound of formula

(2-2):

(2-2)

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is selected from the group consisting of:

a substituent of formula (A -a)

Ce-Cio aryl optionally substituted with one or more R ¹⁴ substituents; and 5-10 membered heteroaryl optionally substituted with one or more R ¹⁴

substituents;

A ² is selected from the group consisting of:

a substituent of formula (A ² -a)

Ce-Cio aryl optionally substituted with one or more R ¹⁶ substituents; and

5-10 mernbered heteroaryl optionally substituted with one or more R ³⁶

substituents;

l

compounds of formula (I).

[Q239] In some embodiments of the compounds of formula (2-2), X ³ is CH and X ^z is CH. In some embodiments, r is 1 a d s is 1.

[0240] In some embodiments of the compounds of formula (2-2), X ³ is CH, X ² is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2,

[0241] In some embodiments of the compounds of formula (2-2), X ³ is N, Y ¹ is a bond, and X ² is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.

[0242] In some embodiments of the compounds of formula (2-2), X ¹ is N, Y ¹ is a bond, X ^z is N and Y ^"z is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2

[0243] In some embodiments of the compounds of formula (2-2):

q ¹ is 1;

A ³ is selected Cg-Cio aryl optionally substituted with one or more R ³⁴ substituents; or 5-

10 mernbered heteroaryl optionally substituted with one or more R ¹⁴ substituents; A ² is selected from the group consisting of:

a substituent of formula (A -a)

Ce-Cio aryl optionally substituted with one or more R ¹⁰ substituents; and 5-10 membered heteroaryl optionally substituted with one or more R ¹⁶ substituents;

R ^5a and R ^5b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent, or alternatively, R ^5a and R ^5b are both hydrogen;

R ^6a is selected from the group consisting of hydrogen, -OR ^{oa a} , and ~NR ^{6a b} R ^{6a L} ;

R ^6b is hydrogen;

or alternatively, R ^6a and R ^6b are taken together to form a -CH ₂ -0-CH ₂ - moiety;

R ^9a and R ^9b are both hydrogen;

R ^IOa is selected from the group consisting of-OR ^lua_a , and -NR ^{,0a b} R ^{10a c} ; and

R ^10b is hydrogen;

or alternatively, R ^Ga and R ^Gb are taken together to form a -CH ₂ -0~CH _2~ moiety.

[0244] In some embodiments of the compounds of formula (2-2):

R ^5a and R ^5b are taken together to form an oxo (=0) substituent;

R ⁶³ is hy drogen;

R ^ub is hydrogen;

R ^9a and R ^9b are both hydrogen;

R ^10a is selected from the group consisting of-OR ^{lua a} , and -NR ^{l0a b} R ^{10a c} ; and

R ^10b is hydrogen;

or alternatively, R ^0a and R ^0b are taken together to form a -CH ₂ -0~CH _2~ moiety.

[0245] In some embodiments of the compounds of formula (2-2):

q ² is l;

A is Ce-Cio aryl optionally substituted with one or more R ¹⁶ substituents; or 5-10 membered heteroaryl optionally substituted with one or more R ¹⁶ substituents; and R ^IOa and R ^IOb are taken together to form a -CH ₂ -0-CH ₂ - moiety .

[0246] In some embodiments of the compounds of formula (2-2), A ² is C C _{J O} aryl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is phenyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0247] In some embodiments of the compounds of formula (2-2), A ^z is 5-10 membered heteroaryl optionally substituted with one or more R ^l6 substituents. In some embodiments, A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is pyridyl optionally substituted with one or more R ¹ ” substituents. In some embodiments, A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[0248] In some embodiments of the compounds of formula (2-2):

q ² is 0;

A ² is a substituent of formula (A -a)

R ^10a is -OR ^{10a a} ; and

R ^{! 0b} is hydrogen.

[Q249] In some embodiments of the compounds of formula (2-2), (A ² -a) is selected from the group consisting of:

In some embodiments of the compounds of formula (2-2), (A -a) is (A -b).

In some embodiments of the compounds of formula (2-2), (A ² -a) is (A ² -c).

[0252] In some embodiments of the compounds of formula (2-2), (A ² -a) is (A -d).

[0253] In some embodiments of the compounds of formula (2-2), (A ² -a) or (A ^? -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ² -a) or (A -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ² ~a) or (A -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A -a) or (A -b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecul

[Q254] In some embodiments of the compounds of formula (2-2), (A ² -a) or (A ² -c) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ² -a) or (A -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0255] In some embodiments of the compounds of formula (2-2):

R ^5a and R ^5b are both hydrogen;

R ^6a and R ^6b are taken together to form a -CH ₂ -0-CH ₂ - moiety;

R ^10a is selected from the group consisting of -OR ^{103 3} , and -NR ^{iGa b} R ^{10a c} ; and

R ^10b is hydrogen;

or alternatively, R ^l0a and R ^l0b are taken together to form a -CH ₂ -0-CH ₂ - moiety .

[0256] In some embodiments of the compounds of formula (2-2):

q ² is 1 ;

A ² is Ce-Cio aryl optionally substituted with one or more R ⁱ⁶ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ^lb substituents; and R ^10a and R ^10b are taken together to form a -CH ₂ -0-CH ₂ - moiety.

[Q257] In some embodiments of the compounds of formula (2-2), A is Cg-Cio aryl optionally substituted with one or more R ^{i 6} substituents. In some embodiments. A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule. In some embodiments, A ² is phenyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ^“ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the mol ecule.

[0258] In some embodiments of the compounds of formula (2-2), A ² is 5-10 membered heteroaryl optionally substituted with one or more R ⁱ⁶ substituents. In some embodiments, A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule. In some embodiments, A is pyridyl optionally substituted with one or more R ³⁶ substituents. In some embodiments, A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[Q259] In some embodiments of the compounds of formula (2-2):

q is 0;

A is a substituent of formula (A ² -a)

R ^IOa is -OR ^{10a a} ; and

R ^10b is hydrogen.

In some embodiments of the compounds of formula (2-2), (A -a) is selected from the group consisting of:

In some embodiments of the compounds of formula (2-2), (A ~a) is (A ^z -b). In some embodiments of the compounds of formula (2-2), (A ^? -a) is (A ² -e). In some embodiments of the compounds of formula (2-2), (A ² -a) is (A ² -d).

[0264] In some embodiments of the compounds of formula (2-2), (A ² -a) or (A ² -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. In some embodiments, (A ^z -a) or is selected from the group consisting of;

wherein the * represents the attachment point to ths remainder of the molecule. In some embodiments, (A ² -a) or (A ^z -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments of the compounds of formula (2-2), (A -a) or (A ^z -c) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ~a) or (A ² -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[Q266] In some embodiments of the compounds of formula (2-2), A ¹ is Ce-Cio aryl optionally substituted with one or more R ¹⁴ substituents. In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is phenyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments of the compounds of formula (2-2), A ¹ is 5-10 membered heteroaryl optionally substituted with one or more R ^l4 substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is pyridyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ⁴ -a) or (A ¹ -!)) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecul e; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A -a) or (A"-b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, (A^a) or (A ^! -b) is selected from the group consisting of:

ts the

attachment point to the remainder of the molecule; and (A ² -a) or (A ^? ~c) is selected from th« group consisting of: _, wherein the * represents fte attachment point to the remainder of the molecule.

[0271] In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0272] In some embodiments, (A^a) or (A^b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0273] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of: wherein the * represents the attachment point to th e remainder of the molecule; and (A ^? -a) or (A ² -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (AX) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -h) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -h) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, (A^a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from the group consisting of:

_ , wherein the * represents the attachment point to the remainder of the molecule.

[0278] In some embodiments, (A -a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[0281] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

nts the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0282] In some embodiments, (A ^x -a) or (A^b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule.

[0283] In some embodiments, (A ^l -a) or (A’-b) is selected from the group consisting of: wherein the * represents the attachment point to th e remainder of the molecule; and A is selected from the group consisting of: wherein th< represents the attachment point to the remainder of the molecule.

[0284] In some embodiments, (A ^! ~a) or (A ¹ -b) is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the represents the attachment point to the remainder of the molecule.

[0285] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

[Q286] In some embodiments, (A ^! -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

In some embodiments, (A ^l -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

In some embodiments, (A’-a) or (A ^l -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: ; wherein the * represents the attachment point

io the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

[0290] In some embodiments, A ^! is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A ² ~a) or (A ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0291] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and or is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0293] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. lected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A'-b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A"-c) is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecul

In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² ~a) or (A"-b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecuk

[Q298] In some embodiments, A is selected from the group consisting of: ; herein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A"-c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0299] In some embodiments, ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ^? ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0300] In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. [Q3Q1] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0302] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0303] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A" is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0304] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of; ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

[0306] In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[Q3Q8] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the

remainder of the molecule; ; wherein the represents the attachment point to the remainder of the molecule.

[0309] In some embodiments, A ¹ is selected from the group consisting of:

represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0310] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0312] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the *

represents the attachment point to the remainder of the molecule;

wherein the * represents the attachment point to the remainder of the molecule.

[0313] In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. [0314] In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

[0315] In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0316] In some embodiments. ; wherein the * represents the

attachment point to the remainder of the molecule; and A ² is wherein the * represents the attachment point to the remainder of the mol ecule.

[0317] In some embodiments, the compound of formula (I) is a compound of formula

(2-3):

or a pharmaceutically acceptable salt thereof;

wherein:

A is selected from the group consisting of:

a substituent of formula (A ¹ -a)

( C 10 aryl optionally substituted with one or more R ¹⁴ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ¹⁴

substituents;

A is Ce-Cio aryl optionally substituted with one or more R ^{i 6} substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ^lb substituents;

ia

Rl° _a -c _{R l} 0b_

l ^12a , R ^12b , R ¹³ , R ⁱ⁴ , and R ¹⁶ are as defined in compounds of formula (I).

[0318] In some embodiments of the compounds of formula (2-3), X ¹ is CH and X ² is CH. In some embodiments, r is 1 and s is 1

[0319] In some embodiments of the compounds of formula (2-3), X ¹ is CH, X is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.

[0320] In some embodiments of the compounds of formula (2-3), X ¹ is N, Y ¹ is a bond, and X ² is CH In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2

[0321] In some embodiments of the compounds of formula (2-3), X ⁵ is N, Y ¹ is a bond, X ^z is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2, [Q322] In some embodiments of the compounds of formula (2-3):

q ¹ is 1;

A ³ is selected (X-Cio aryl optionally substituted with one or more R ³⁴ substituents; or 5- 10 membered heteroaryl optionally substituted with one or more R ¹⁴ substituents;

A ² is Ce-Cio aryl optionally substituted with one or more R ³⁶ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ^l ° substituents;

R ^5a and R ^5b are taken together to form an oxo ( ^:=: 0) substituent or an imido (=NH)

substituent, or alternatively, R ^5a and R ^5b are both hydrogen;

R ^oa is selected from the group consisting of hydrogen, -OR ^{68 8} , and -NR ^{6a b} R ^{6a c} ; and R ^bb is hydrogen;

or alternatively, R ^6a and R ^6b are taken together to form a -CH ₂ -0-CH ₂ - moiety.

[0323] In some embodiments of the compounds of formula (2-3):

R ^5a and R ^5b are taken together to form an oxo (=0) substituent;

R ⁶³ is hydrogen; and

R ^ub is hydrogen.

[0324] In some embodiments of the compounds of formula (2-3):

R ^5a and R ^5b are both hydrogen; and

R ^ba and R ^bb are taken together to form a -CH ₂ -0-CH ₂ - moiety.

[0325] In some embodiments of the compounds of formula (2-3):

X ¹ and X ² , independently of each other, are CH or N; provided that at least one of X ¹ and X ² is CH;

Y ¹ is selected from the group consisting of a bond, NR ^! , and O; provided that when X ¹ is N, then Y ¹ is a bond;

R ^Yl is hydrogen or Ci-C ₆ alkyl;

Y ² is selected from the group consisting of a bond, NR ^Y2 , and O; provided that when X ² is N, then Y ² is a bond;

R* ² is hydrogen or Ci-C ₆ alkyl;

q ³ is 1;

r and s, independently of each other, are 0, 1, or 2;

A ¹ is C ₆ -C _IG aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents;

R ¹⁴ is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, C C ₆ haloalkyl, -OH, -0(C C ₆ alkyl), -0(C C ₆ haloalkyl), -SH, -S(Ci- C¾ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -NH(C _I -C ₆ haloalkyl), -N(Cr C ₆ alky 1) ₂ , -N(Ci-C ₆ haloalkyl) ₂ , -NR ^{i4 a} R ^{!4 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl), -C(Q)0{C _I -C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(C C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{14 a} R ^{14 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci-C ₆ alkyl), -S(0) ₂ 0(Ci~C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

S(();;N1 !{( ^' ·( ^' :, alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -S(0) ₂ N(C _I -C ₆ haloalkyi) ₂ alkyl), -OHOKH-tV haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), Ail j )C iO)iCVC,, haloalkyl), -N(C C ₆ alkyl)C(0)H, Ait U-P, alkyl)C(0)(C _r C ₆ alkyl), -N(C _t -C ₆ alkyi)C(0)(CrC ₆ haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haloalkyl)C(0)(CrC ₆ alkyl), -N(C C ₆ haloalkyl)C(0)(CrC ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -OSiOpiC VH, haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl),

-N(H)S(0) ₂ (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0) ₂ <Ci-C ₆ alkyl), A,( ⁽ _r C, alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), A(( ₍ ,, haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and AiCVC,. haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ^{l4 a} and R ^{l4 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ^z is C ₆ -C _IG aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ⁶ substituents;

R ¹⁶ is sel ected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, C C ₆ haloalkyl, -OH, -0(C,-C ₆ alkyl), -0(C,-C ₆ haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), Ai k -NH(C C ₆ alkyl), -NH(C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , AiOC,, haloalkyl) ₂ , -NR ^{16 a} R ^{16 b} , -CN, -C(0)0H, -C(0)0(C C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(Q)NH ₂ , -C (O)NH(C i-C ₆ alkyl), -C(0)NH(C i-C ₆ haloalkyl), -HO AiCVC V. alkyl ) ·.. -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{16 a} R ^{16 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _I -C ₆ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _I~ C ₆ alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyl), -S(0) ₂ N(C C ₆ alkyl) ₂ , -S(0) ₂ N(C _I -C ₆ haloalkyi) ₂ alkyl), -0C(0)(Ci-C ₆ haloalkyl), -Ni l I )( ^' {(>)! !. -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(G)(Ci-Cg haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C _I -C ₆ alkyl)C(0)(C ₁ -C ₆ alkyl), -\!( ₍ ,, alk l)C(0)(Ci-C ₆ haloalkyl), -N(CrC ₆ haloalkyl)C (0)H, -N(Ci-Cg

haloalkyl)C(Q)(CrCg alkyl), -N(C -C ₆ haloalkyl)C(0)(CrCg haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl),

-N(H)S(0) ₂ (C ₁ -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0) ₂ (C C ₆ alkyl), -N{C alkyi)SiO) ₂ (C -Cg haloalkyl), -N(C _J -C ₆ haloalkyl)S(0) ₂ (C C ₆ alkyl), and ~N(C _I~ C ₆ haloalkyl)S(0) ₂ (C _] -Cg haloalkyl);

wherein R ^l6 “ and R ^{lu b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^!a and R ^!b are independently selected from the group consisting of hydrogen, C -Cg alkyl, and halogen;

R ^a and *’ are independently selected from the group consisting of hydrogen, Ci-Cg alkyl, and halogen;

when present, R ^,a and R ^,b are independently at each occurrence selected from the group consisting of hydrogen, (ty-Cg alkyl, and halogen;

when present, R ^4a and R ^4b are independently at each occurrence selected from the group consisting of hydrogen, C -C ₆ alkyl, and halogen;

or alternatively, R ^ia and R ^2a are taken together to form a C -Cg alkylene moiety;

or alternatively, R ^ia and an R ^a moiety, when present, are taken together to form a (ty-Cg alkylene moiety, and R ^!b and the R ^b in the geminal position to the R ^3a taken together with R ^ia , are both h drogen;

or alternatively, an R ^3a moiety, when present, and an R ^4a moiety, when present, are taken together to form a C -Cg alkylene moiety, and the R ^b in the geminal position to the R ^a taken together with the R ^4a moiety' and the R ^4b in the geminal position to the R ^4a taken together with the R ^3a moiety, are both hydrogen;

R ^5a and R ^5b are taken together to form an oxo (=0) substituent or an imido ( ^: =NH)

substituent;

R ^ba is hydrogen;

R ^bb is hydrogen; R ^9a and R ^9b are taken together to form an oxo (==0) substituent or an imido ( ^: =NH) substituent, or alternatively, R ^9a and R ^9b are both hydrogen;

R ^10a is selected from the group consisting of hydrogen, -OR ^{10a a} , and -NR ^{!ua b} R ^l0M ;

R ^10b is hydrogen;

R ^!2a and R ^!2b are taken together to form an oxo (=0) substituent, or alternatively, R ^{l a} and R ^,2b are both hydrogen;

R ^{10a a} is selected from the group consisting of hydrogen, Ci-Ce alkyl, and CrC ₆ haloalkyl; or R ^{i0a a} and R ^Y2 may be taken together to form a carbonyl (C ^:=: 0) moiety;

R ^{IOa b} and R ^{,0a c} , independently of each other, are selected from the group consisting of hydrogen, C -Ce alkyl, and C -Ce haloalkyl; and

provided that when X ² is N, then:

A ¹ is Ce-Cio aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ^l4 substituents; and

A ² is Ce-Cio aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ⁶ substituents.

[Q326] In some embodiments of the compounds of formula (2-3), R ^!a and R ^!b are

independently selected from the group consisting of hydrogen and Cj-Ce alkyl. In some embodiments of the compounds of formula (2-3), R ^a and R ^b are both hydrogen.

[0327] In some embodiments of the compounds of formula (2-3), R^ ^* and R ⁴ ' are

independently selected from the group consisting of hydrogen and Ci-C ₆ alkyl. In some embodiments of the compounds of formula (2-3), R ^2a and R ^2b are both hydrogen.

[0328] In some embodiments of the compounds of formula (2-3), R ^lcl and R ^“ “ are taken together to form a Ci-Cg alkylene moiety

[0329] In some embodiments of the compounds of formula (2-3), r is 1 and s is 1. In some embodiments, ⁴³ and R ^<b are independently selected from the group consisting of hydrogen and Cj-Cg alkyl. In some embodiments, R ^a and R ^b are both hydrogen. In some embodiments, R ^4a and R ^4b are independently selected from the group consisting of hydrogen and Ci-Cg alkyl. In some embodiments, R ^4a and R ^4b are both hydrogen. In some embodiments, R ^ia and R ^Ja are taken together to form a Ci-Ce alkylene moiety, and R ^lb and R ^,b are both hydrogen. In some embodiments, R ^,a and R ^4a are taken together to form a C-.-Ce alkylene moiety, and R and R ^4b are both hydrogen

[0330] In some embodiments of the compounds of formula (2-3):

X ¹ is Cl !:

X ² is (Ί 1:

Y ¹ is selected from the group consisting of NR ^{Y 1} and O;

R ^{Y l} is hydrogen or Ci-C ₆ alkyl;

Y ² is selected from the group consisting of NR ^Y and O:

R ^Y2 is hydrogen or Ci-C ₆ alkyl;

q ^! and q ² are each 1 ; a d

r and s are both 1.

[0331] In some embodiments of the compounds of formula (2-3):

X ¹ is (Ί 1:

X ² is CH;

Y ¹ is NR ^Y1 ;

R ^Yi is hydrogen;

V ^' is NR ^' ·’:

R ^Y2 is hydrogen;

ql is 1; and

r and s are both 1.

[Q332] In some embodiments of the compounds of formula (2-3), R ⁹ “ and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments of the compounds of formula (2-3), R ^9a and il ^9b are taken together to form an imido (=NH) substituent. In some embodiments of the compounds of formula (2-3), R ^9a and R ^9b are both hydrogen.

[0333] In some embodiments of the compounds of formula (2-3), R ^10a is hydrogen and R ^10b is hydrogen.

[Q334] In some embodiments of the compounds of formula (2-3), R ^!0a is -OR ^{10a a} and R ^10b is hydrogen. In some embodiments, R ^{30a a} is selected from the group consisting of hydrogen and Ci-Ce alkyl. In some embodiments, R ^10a~a is hydrogen. In some embodiments, R ^10a~a is Ci-Cg alkyl. In some embodiments, R ^{i0a a} and R ^Y2 may be taken together to form a carbonyl (0=0) moietyr

[0335] In some embodiments of the compounds of formula (2-3), R ^IOa is -NR ^{i0a b} R ³ ° ^{3 c} and R ^llJb is hydrogen. In some embodiments, R ^{10a b} and R ^{l0a c} , independently of each other, are selected from the group consisting of hydrogen and Ci-Cg alkyl. In some embodiments, R ^{10a b} and R ^{l0a 1} are hydrogen. In some embodiments, R ^{l0a b} and R ^{3ua c} are Ci-Ce alkyl.

[Q336] In some embodiments of the compounds of formula (2-3), A ¹ is Ce-Cio aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroary] substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents.

[0337] In some embodiments of the compounds of formula (2-3), A ³ is C C _{J O} aryl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is Ce-C o aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ³⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is phenyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is phenyl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is 5-10 membered heteroary] optionally substituted with one or more R ³⁴ substituents. In some embodiments. A ¹ is 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule. In some embodiments, A ¹ is pyridyl optionally substituted with one or more R ³⁴ substituents. In some embodiments, A ¹ is pyridyl substituted by at least one halogen substituent and optionally further substituted with one

or more R ¹⁴ substituents. In some embodiments, wherein the represents the atachment point to the remainder of the molecule.

[0338] In some embodiments of the compounds of formula (2-3), A ^z is Cs-Cio aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ⁱ⁶ substituents.

[0339] In some embodiments of the compounds of formula (2-3), A ² is Cy-Cio aryl optionally substituted with one or more R ³⁶ substituents. In some embodiments, A ² is Ce.-C o aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ³⁶ substituents. In some embodiments, A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A is phenyl optionally substituted with one or more R ^lb substituents. In some embodiments, A ^z is phenyl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule. In some embodiments, A ² is 5-10 membered heieroary] optionally substituted with one or more R ^{i 6} substituents. In some embodiments. A ² is 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of: ; wherein the represents the attachment point to the remainder of the molecule. In some embodiments, A ² is pyridyl optionally substituted with one or more R ¹⁰ substituents. In some embodiments. A ² is pyridyl substituted by at least one halogen substituent and optionally further substituted with one

or more R ^,b substituents. In some embodiments, wherein the * represents the attachment point to the remainder of the molecule.

[0340] In some embodiments of the compounds of formula (2-3):

X ¹ is N;

X ² is Cl !:

Y ¹ is a bond;

Y is selected from the group consisting of NR ^{Y z} and O;

R ^Y2 is hydrogen or Ci-C ₆ alkyl;

ql is 1; and

r and s are both 1.

[0341] In some embodiments of the compounds of formula (2-3):

X ¹ is N;

X ² is Cl !:

Y ¹ is a bond;

Y ² is NR ^Y2 ;

R ^Y2 is hydrogen;

ql is 1 ; and

r and s are both 1 . [Q342] In some embodiments of the compounds of formula (2-3), R ^9a and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments of the compounds of formula (2-3), R ^9a and R ^9b are taken together to form an imido (=NH) substituent. In some embodiments of the compounds of formula (2-3), R ^9a and R ^9b are both hydrogen.

[0343] In some embodiments of the compounds of formula (2-3), R ^10a is hydrogen and R ^10b is hydrogen.

[Q344] In some embodiments of the compounds of formula (2-3), R ^10a is -OR ^{10a a} and R ^10b is hydrogen. In some embodiments, R ^{10a a} is selected from the group consisting of hydrogen and Ci-Ce alkyl. In some embodiments, R ^{i0a a} is hydrogen. In some embodiments, R ^{10a a} is Ci-Cg alkyl. In some embodiments, R ^{iU3 3} and R ^{¾ 2} may be taken together to form a carbonyl (C=0) moiety.

[0345] In some embodiments of the compounds of formula (2-3), R ^10a is -NR ^{10a b} R ^{10a c} and R ^10b is hydrogen. In some embodiments, R ^{1Ja b} and R ^{0a c} , independently of each other, are selected from the group consisting of hydrogen and C i-C , alkyl. In some embodiments, R ^{30a b} and R ^l0a< are hydrogen. In some embodiments, R ^{10a b} and R ^{3ua c} are Ci-Ce alkyl.

[0346] In some embodiments of the compounds of formula (2-3), A ¹ is Cs-Cio aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents.

[0347] In some embodiments of the compounds of formula (2-3), A ¹ is C ₆ -C _lo ar l optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is C^-Cjo aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ³⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is phenyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is phenyl substituted by at least one halogen substituent and optionally further substituted with one or more R ^la substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is 5-10 membered heteroaryl optionally substituted with one or more R ¹⁴ substituents. In some embodiments. A ¹ is 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^] is pyridyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is pyridyl substituted by at least one halogen substituent and optionally further substituted with one

or more R ⁴ substituents. In some embodiments. ; wherein the * represents the attachment point to the remainder of the molecule.

[0348] In some embodiments of the compounds of formula (2-3), A ² is Ce-Cho aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁰ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ^t! substituents.

[Q349] In some embodiments of the compounds of formula (2-3), A is Ce-Cio aryl optionally substituted with one or more R ¹ " substituents. In some embodiments. A

aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A is phenyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ^z is phenyl substituted by at least one halogen substituent and optionally further substituted with one or more R ^lb substituents. In some embodiments. A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the mol ecule.

In some embodiments. A ² is 5-10 membered heteroaryl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ⁱ⁰ substituents. In some embodiments, A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments. A ² is pyridyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments. A ² is pyridyl substituted by at least one halogen substituent and optionally further substituted with one

or more R ^l6 substituents. In some embodiments. wherein the * represents the attachment point to the remainder of the molecule.

[0350] In some embodiments of the compounds of formula (2-3):

X ¹ is Cl !:

X ² is N;

Y ^] is selected from the group consisting of NR ^Y1 and O;

R ^Yl is hydrogen or CrC ₆ alkyl;

Y ² is a bond;

ql is 1 ;

r and s are both 1 ;

A ¹ is Ce-Cio aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents; and

A ² is C _fi -C o aryl substituted by at least two halogen substituents and optionally further substituted with one or more R substituents, or 5-10 mernbered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ^,b substituents.

[0351] In some embodiments of the compounds of formula (2-3):

X ¹ is CH;

X ² is N;

Y ¹ is NR ^Y1 ;

R ^Yi is hydrogen;

Y ² is a bond;

ql is 1;

r and s are both 1 ;

A ¹ is C ₆ -C _IG aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 mernbered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents; and

A ² is Ce-Cio aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ^!o substituents, or 5-10 mernbered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ^l6 substituents.

[0352] In some embodiments of the compounds of formula (2-3), R ^9a and R ^9b are both hydrogen.

[0353] In some embodiments of the compounds of formula (2-3), R ^10a is hydrogen and R ^10b is h drogen.

[0354] In some embodiments of the compounds of formula (2-3), R ^10a is -OR ^{10a a} and R ^10b is hydrogen. In some embodiments, R ^{i0a a} is selected from the group consisting of hydrogen and Cj-Ce alkyl ln some embodiments, R ^{10a a} is hydrogen. In some embodiments, R ^103'3 is Ci-C ₆ alkyl. In some embodiments, R ^10a“3 and R ^Y2 may be taken together to form a carbonyl (0=0) moietyr [0355] In some embodiments of the compounds of formula (2-3), R ^10a is -N ^{10a b} R ^10a< and R ^{i ub} is hydrogen. In some embodiments, R ^{! 0a b} and R ^{l0a c} , independently of each other, are selected from the group consisting of hydrogen and C -Ce alkyl. In some embodiments, R 10a-b and R ^{lt,a L} are hydrogen. In some embodiments, R ^K '“ ^b and ! are Ci-Cg alkyl.

[0356] In some embodiments of the compounds of formula (2-3), A ¹ is C ₆ -C _lo aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ³⁴ substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents.

[Q357] In some embodiments of the compounds of formula (2-3), A ¹ is C ₆ -C _lo aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents. In some embodiments. A ¹ is phenyl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents. In some

embodiments, ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents.

[0358] In some embodiments of the compounds of formula (2-3), A ² is Ce-Cio aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁶ substituents.

[0359] In some embodiments of the compounds of formula (2-3), A ² is C ₆ -C o aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁰ substituents. In some embodiments. A" is phenyl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁶ substituents. In some

embodiments, wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is 5-10 membered heteroaryl substituted by at least two halogen substituent and optionally further substituted with one or more R ¹⁶ substituents.

[0360] In some embodiments of the compounds of formula (2-3), A ¹ is C C _{J O} aryl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is phenyl optionally substituted with one or more R ^1'* substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0361] In some embodiments of the compounds of formula (2-3), A ¹ is 5-10 membered heteroaiyl optionally substituted with one or more R’ ⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is pyridyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is ; wherein the * represents the attachment point to the remainder of the molecule.

[0362] In some embodiments of the compounds of formula (2-3):

q ^! is 0;

A ¹ is a substituent of formula (A ³ -a)

R ^6a is OR"" ": and

R ^ob is hydrogen.

[0363] In some embodiments of the compounds of formula (2-3):

R ^ia and R ^ib are taken together to form an oxo ( ^: =0) substituent;

R ^6a is hydrogen; and

R ^6b is hydrogen.

[Q364] In some embodiments of the compounds of formula (2-3), (A -a) is selected from the group consisting of:

[Q365] In some embodiments of the compounds of formula (2-3), (A‘-a) is (A ¹ -!)).

[0366] In some embodiments of the compounds of formula (2-3), (A -a) is (A^-c).

[0367] In some embodiments of the compounds of formula (2-3), (A‘-a) is (A^d).

[0368] In some embodiments of the compounds of formula (2-3), (A ^! -a) or (A ^f -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ^! ~a) or (A ¹ -b) is selected from the group consisting of:

nts the attachment point to the remainder of the molecul e. In some embodiments, (A^a) or (A ^] -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ^] -a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to th e remainder of the molecule.

[Q369] In some embodiments of the compounds of formula (2-3), (A ^f -a) or (A'-c) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ¹ -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0370] In some embodiments of the compounds of formula (2-3):

R ^9a and R ^9b are taken together to form an oxo ( ^: =0) substituent or an imido (=NH)

substituent, or alternatively, R ^a and R ^b are both hydrogen;

R ^!0a is selected from the group consisting of hydrogen, -OR ^{10a a} , and -NR ^{10a b} R ^{l0a c} ;

R ^10b is hydrogen; and

R ^a and ^b are both hydrogen.

[0371] In some embodiments of the compounds of formula (2-3), R ^9a and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments, R ^IOa is hydrogen. In some embodiments, R ^10a is -OR ^{10a a} In some embodiments, R ^10a is -NR ^l0a~b R ^{10a c}

[0372] In some embodiments of the compounds of formula (2-3), R ^9a and R ^9b are taken together to form an imido (=NH) substituent. In some embodiments, R ^10a is hydrogen. In some embodiments, R ^10a is -OR ^{10a a} . In some embodiments, R ^10a is -NR ^{i0a b} R ^{10a c} . [Q373] In some embodiments of the compounds of formula (2-3), R ^9a and R ^9b are both hydrogen. In some embodiments, R ^10a is hydrogen. In some embodiments, R ^l0a is -OR ¹⁰ **. In some embodiments, R ^10a is -NR ^{lua b} R ^{30a c} .

[0374] In some embodiments of the compounds of formula (2-3):

X ² is CH;

Y ² is NR ^Y2 :

R ⁹³ and R ^9b are both hydrogen;

R ^10a is -OR ¹⁰ **;

R ^a and R ^b are both hydrogen; and

R ^{IOa a} and R ^Y are taken together to form a carbonyl (C=0) moiety.

[0375] In some embodiments of the compounds of formula (2-3), A ² is CtyCio aryl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ² is phenyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0376] In some embodiments of the compounds of formula (2-3), A ² is 5-10 membered heteroaryl optionally substituted with one or more R ^,b substituents. In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A is pyridyl optionally substituted with one or more R ³⁶ substituents. In some embodiments, A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[Q377] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0378] In some embodiments, (A^a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0379] In some embodiments, (A^a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from th< group consisting of: wherein the * represents the atachment point to the remainder of the molecule.

[0380] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0381] In some embodiments, (A ^! -a) or (A ² -b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and (A ^? -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0382] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

to the remainder of the molecul e.

l-c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ^z -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule.

is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0385] In some embodiments, (A ^l -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -e) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0387] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecul e; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. or (A ^! -b) is selected from the group consisting of:

nts the attachment point to the remainder of the molecul e; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

In some embodiments, (A -a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0390] In some embodiments, (A ^! -a) or (A ¹ -!)) is selected from the group consisting of:

nts the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0391] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

wherein the * represents the attachment point to th e remainder of the molecule; and A is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0392] In some embodiments, (A ^! ~a) or (A ¹ -b) is selected from the group consisting of

; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0393] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[Q394] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

remainder of the molecule.

[0395] In some embodiments, (A^a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ^! -a) or (A ^l -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[Q397] In some embodiments, (A ^! -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. is selected from the group consisting of: ; wherein the * represents the attachment point

to the remainder of the molecule; ; wherein the * represents the attachment point to the remainder of the molecule.

[0399] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A"-b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule; and or selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecuk

[0401] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A"-a) or (A ² -C) is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A'-a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of:

; wherein the * represents the atachment point to the remainder of the molecule. In some embodiments. A ¹ is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule; selected from the group consisting of: and wherein the * represents the atachment point to the remainder of the molecule.

In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments. A ¹ is selected from the group consisting of: ; wherein the represents the atachment point to the remainder of the molecule; and (A"-a) or (A -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0408] In some embodiments wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule.

[0410] In some embodiments, A ^! is selected from the group consisting of

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0411] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0412] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0413] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[0414] In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the atachment point to the

remainder of the molecule; ; wherein the * represents the attachment point to the remainder of the molecule. [0418] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0419] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the mol ecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0420] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0421] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the *

represents the attachment point to the remainder of the molecule;

wherein the * represents the attachment point to the remainder of the molecule.

; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

wherein the * represents the

attachment point to the remainder of the molecule; ; wherein the * represents the attachment point to the remainder of the molecule

In some embodiments, the compound of formula (I) is a compound of formula

(2-4):

(2-4)

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is selected from the group consisting of:

a substituent of formula (A^a)

C C o aryl optionally substituted with one or more R ¹⁴ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ¹⁴

substituents; A ^z is C ₆ -CIG aryl optionally substituted with one or more R ¹⁶ substituents; or 5-10 membered heteroaryl optionally substituted with one or more R ¹⁶ substituents;

R ^{l la} and R ^{l lb} are both hydrogen;

R ^12a and R ^1¾ are both hydrogen;

Z ³ , xl , R ^la , are as defined m compounds of formula (I).

In some embodiments of the compounds of formula (2-4), X is CH and X ^z is CH. In some embodiments, r is 1 a d s is 1.

[0428] In some embodiments of the compounds of formula (2-4), X ³ is CH, X ² is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.

[0429] In some embodiments of the compounds of formula (2-4), X ¹ is N, Y ¹ is a bond, and X ² is CH. In some embodiments, r is 1 and s is 1 In some embodiments, r is 0 and s is 2.

[0430] In some embodiments of the compounds of formula (2-4), X ¹ is N, Y ¹ is a bond, X is N and Y ^z is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2

[0431] In some embodiments of the compounds of formula (2-4):

q ¹ is 1;

A ³ is selected CY-Cio aryl optionally substituted with one or more R ³⁴ substituents; or 5- 10 membered heteroary] optionally substituted with one or more R ¹⁴ substituents; R ^5a and R ^5b are taken together to form an oxo (=0) substituent or an imido (=NH)

substituent, or alternatively, R ^,a and R ^'b are both hydrogen;

R ⁶³ is selected from the group consisting of hydrogen, -OR ^{63 3} , and -NR ^{ba b} R ^{oa c} ; and R ^6b is hydrogen;

or alternatively, R ^6a and R ^6b are taken together to form a -CH ₂ -0-CH ₂ - moiety.

[0432] In some embodiments of the compounds of formula (2-4), R ^5a and R ^5b are both hydrogen; and R ^6a and R ^6b are taken together to form a -CH ₂ -0-CH ₂ - moiety.

[0433] In some embodiments of the compounds of formula (2-4), A ³ is C ₆ -C _lo ar l optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is phenyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments of the compounds of formula (2-4), A ¹ is 5-10 membered heteroaryl optionally substituted with one or more R ^l4 substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ is pyridyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is wherein the * represents the attachment point to the remainder of the molecule.

[0435] In some embodiments of the compounds of formula (2-4), A is Cg-Cio aryl optionally substituted with one or more R ⁱ⁶ substituents. In some embodiments. A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ² is phenyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments of the compounds of formula (2-4), A ^z is 5-10 membered heteroaryl optionally substituted with one or more R ^l6 substituents. In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is pyridyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is ; wherein the * represents the attachment point to the remainder of the moiecuf some embodiments, (A ^! -a) or (A ¹ -!)) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, (A^a) or (A ¹ -!)) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ^z -a) or (A -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecul

[0440] In some embodiments, (A ¹ -a) or (A ^l -b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A -a) or (A -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule.

[0441] In some embodiments, (A ^! -a) or (A ^! -b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the

[0442] In some embodiments, (A ^x -a) or (A^b) is selected from the group consisting of: wherein the * represents the attachment point to the remain der of the molecule; and (A ² -a) or (A ^z -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of die molecule. [Q443] In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A -a) or (A ^z -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0445] In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecul e; and ( . v’-a ) or (A ² -c) is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule.

[0447] In some embodiments, (A ^! -a) or (A ¹ -!)) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0448] In some embodiments, (A ^! ~a) or (A ¹ -b) is selected fro the group consisting of:

nts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~h) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0450] In some embodiments, (A^a) or (A ^! ~h) is selected from the group consisting of:

wherein the * represents the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0451] In some embodiments, (A^a) or (A^b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0452] In some embodiments, (A^a) or (A ^! ~h) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. [Q453] In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the mol ecule.

[Q454] In some embodiments, or (A ^l -b) is selected from the group consisting of:

remainder of the molecule.

In some embodiments. (A^a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. [0456] In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of:

represents the attachment point

to the remainder of the molecul e; and A ² is selec ted from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A^c) is selected from the group consisting of; ; wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[Q458] In some embodiments, (A^a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point

to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0459] In some embodiments, A ^! is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and or (A ² ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule; and or selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecuk

[0461] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A"-a) or (A ² -C) is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A'-a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of:

; wherein the * represents the atachment point to the remainder of the molecule. In some embodiments. A ¹ is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule; selected from the group consisting of: and wherein the * represents the atachment point to the remainder of the molecule.

In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments. A ¹ is selected from the group consisting of: ; wherein the represents the atachment point to the remainder of the molecule; and (A"-a) or (A -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0468] In some embodiments wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule.

[0470] In some embodiments, A ^! is selected from the group consisting of

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0471] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[Q472] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0473] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[0474] In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0477] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the atachment point to the

remainder of the molecule; ; wherein the * represents the attachment point to the remainder of the molecule. [Q478] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0479] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the mol ecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0480] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0481] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the *

represents the attachment point to the remainder of the molecule;

wherein the * represents the attachment point to the remainder of the molecule.

; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

wherein the * represents the

attachment point to the remainder of the molecule; ; -wherein the * represents the attachment point to the remainder of the molecule

[0487] In some embodiments, the compound of formula (I) is a compound of formula o-o)·

(3-3)

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is Ce-Cio aryl optionally substituted with one or more R ¹⁴ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ¹⁴ substituents;

A ^z is Ce-Cio aryl optionally substituted with one or more R ³⁶ substituents; or 5-10

membered heteroaiyl optionally substituted with one or more R ³⁶ substituents;

R ³⁶ are as defined in compounds of formula (I).

[0488] In some embodiments of the compounds of formula (3-3), X ³ is CH and X ² is CH. In some embodiments, r is 1 and s is 1. [Q489] In some embodiments of the compounds of formula (3-3), X ⁵ is CH, X ² is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2

[0490] In some embodiments of the compounds of formula (3-3), X ¹ is N, Y ¹ is a bond, and X ² is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.

[0491] In some embodiments of the compounds of formula (3-3), X ¹ is N, Y ¹ is a bond, X ² is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.

[0492] In some embodiments of the compounds of formula (3-3):

R ⁵ “ and R ^5b are taken together to form an oxo (==0) substituent or an imido ( ^: =NH)

substituent, or alternatively, R ^5a and R ^5b are both hydrogen;

R ^ba is selected from the group consisting of hydrogen, -QR ^{6a a} , and -NR ^{6a b} R ^{6a c} ;

R ^10b is hydrogen; and

R ^!2a and R ^!2b are both hydrogen.

[0493] In some embodiments of the compounds of formula (3-3), R ^9a and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments, R ^10a is hydrogen. In some embodiments, R ^10a is -OR ^10a~a . In some embodiments, R ^10a is -NR ^{i0a b} R ^{10a c} .

[0494] In some embodiments of the compounds of formula (3-3), R ^9a and R ^9b are taken together to form an imido (=NH) substituent. In some embodiments, R ^10a is hydrogen. In some embodiments, R ^10a is -OR ^{10a a} . In some embodiments, R ^10a is -NR ^! ° ^a~b R ^{10a c}

[0495] In some embodiments of the compounds of formula (3-3), R ^9a and R ^9b are both hydrogen. In some embodiments, R ^i0a is hydrogen. In some embodiments, R ^0a is -OR ^{10a a} In some embodiments, R ^i0a is -NR^R ^{108 6} .

[0496] ln some embodiments of the compounds of formula (3-3), A ¹ is Ce-Cio aryl optionally substituted with one or more R ¹⁴ substituents. In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ⁵ is phenyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0497] In some embodiments of the compounds of formula (3-3), A ^] is 5-10 membered heteroaryl optionally substituted with one or more R ^l4 substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^] is pyridyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is ; wherein the * represents the attachment point to the remainder of the molecule.

[0498] In some embodiments of the compounds of formula (3-3):

X ² is CH;

Y ² is N R ^' "’;

R ^9a and R ^9b are both hydrogen;

R ^{! 0a} is -OR ^{10a a} ;

R ^{1 3} and R ^{l b} are both hydrogen; and

R ^1Ja “ and ^¾2 are taken together to form a carbonyl (C=0) moiety.

[0499] In some embodiments of the compounds of formula (3-3), A ² is C ₆ -C o aryl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is phenyl optionally substituted with one or more R ^lb substituents. In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments of the compounds of formula (3-3), A ^z is 5-10 membered heteroaryl optionally substituted with one or more R ^l6 substituents. In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A is pyridyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ² -a) or (A ¹ -!)) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecul e; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A -a) or (A"-b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0503] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

ts the

attachment point to the remainder of the molecule; and (A ² -a) or (A ^? ~c) is selected from th« group consisting of: _, wherein the * represents fte attachment point to the remainder of the molecule.

[0504] In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, (A ^A -a) or (A^b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0506] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of: wherein the * represents the attachment point to th e remainder of the molecule; and (A ^? -a) or (A ² -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (AX) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -h) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0508] In some embodiments, (A^a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -h) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0509] In some embodiments, (A^a) or (A ^! -c) is selected from the group consisting of: : wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

0511 In some embodiments, (A^a) or (A^b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[0514] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

nts the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0515] In some embodiments, (A ^x -a) or (A^b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule.

[0516] In some embodiments, (A ^l -a) or (A ^! ~h) is selected from the group consisting of: wherein the * represents the attachment point to th e remainder of the molecule; and A is selected from the group consisting of: wherein th< represents the attachment point to the remainder of the molecule.

[0517] In some embodiments, (A ^! ~a) or (A ¹ -b) is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the represents the attachment point to the remainder of the molecule.

[0518] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ^! -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

In some embodiments, (A ^! -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

[0521] In some embodiments, (A ^! ~a) or (A ^l -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: ; wherein the * represents the attachment point

io the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

[0523] In some embodiments, A ^! is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A ² ~a) or (A ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0524] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and or is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0526] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. lected from the group consisting of ; wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A'-b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A"-c) is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecul

[0529] In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² ~a) or (A"-b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A is selected from the group consisting of: ; herein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A"-c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0532] In some embodiments, ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ^? ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. [Q534] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0535] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0536] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A" is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0537] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[0538] In some embodiments, A is selected from the group consisting of; ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[0541] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the

remainder of the molecule; ; wherein the represents the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is selected from the group consisting of:

represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0543] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, A is selected from the group consisting of: ; wherein the *

represents the attachment point to the remainder of the molecule;

wherein the * represents the attachment point to the remainder of the molecule.

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. [0547] In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the represents the attachment point to the remainder of the molecule.

; wherein the * represents the

attachment point to the remainder of the molecule; and A wherein the * represents the attachment point to the remainder of the mol ecule.

[0551] In some embodiments, the compound of formula (I) is a compound of formula (3-4):

(3-4)

or a pharmaceutically acceptable salt thereof;

wherein:

A ³ is C ₆ -C _IG aryl optionally substituted with one or more R ¹⁴ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ³⁴ substituents;

A ² is C _fi -C o aryl optionally substituted with one or more R ¹ " substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ^lu substituents;

R ¹¹³ and R ^!!b are both hydrogen;

R ^{3 a} and R ^{3 b} are both hydrogen;

and wherein X ³ , X ² , Y ¹ , R ^Yi , Y ² , R ^Y2 , r, s, R ^la , R ^lb , R ^2a , R ^2b , R ^3a , R ^3b , R ⁴³ , R ^4b , R ^5a , R ^sb , R ⁶³ , R ^{6a a} , R ^{6a b} , R ^{6a c} , R ^6b , R ^8a R ^sb , R ¹⁴ , and R ¹⁶ are as defined in compounds of formula (I).

[0552] In some embodiments of the compounds of formula (3-4), X ³ is CH and X ^z is CH. In some embodiments, r is 1 and s is 1.

[0553] In some embodiments of the compounds of formula (3-4), X ³ is CH, X is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2,

[0554] In some embodiments of the compounds of formula (3-4), X ¹ is N, Y ¹ is a bond, and X ² is CH. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.

[0555] In some embodiments of the compounds of formula (3-4), X ¹ is N, Y ¹ is a bond, X ^z is N and Y ^z is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2

[0556] In some embodiments of the compounds of formula (3-4):

R ⁵³ and R ^5b are taken together to form an oxo (=0) substituent or an imido (=NH)

substituent, or alternatively, R ⁵³ and R ^5b are both hydrogen;

R ⁶³ is selected from the group consisting of hydrogen, -OR ^{03 3} , and NR ^{6a b} R ^{6a L} ;

R ^30b is hydrogen; and

R ¹²³ and R ^{l b} are both hydrogen. [0557] In some embodiments of the compounds of formula (3-4), R ^9a and R ^9b are taken together to form an oxo (=0) substituent. In some embodiments, R ^l0a is hydrogen. In some embodiments, R ^10a is -OR ^{103 3} . In some embodiments, R ¹⁰³ is -NR ^! ° ^{a b} R ^{10a c}

[0558] In some embodiments of the compounds of formula (3-4), R ^9a and R ^9b are taken together to form an imido (=NH) substituent. In some embodiments, R ^IOa is hydrogen. In some embodiments, R ^30a is -OR ^{10a a} . In some embodiments, R ^IOa is -NR ^{l0a b} R ^{10a c} .

[Q559] In some embodiments of the compounds of formula (3-4), R ⁹³ and R ^9b are both hydrogen. In some embodiments, R ^lua is hydrogen. In some embodiments, R ^l0a is -OR ^{103 3} In some embodiments, R ^10a is -NR ^{!0a b} R ^{30a c} .

[0560] In some embodiments of the compounds of formula (3-4):

X ³ is Ci l;

Y ¹ is NR ^Y1 ;

R ^5a and R ^5b are both hydrogen;

R ^6a is -OR ^{63 3} ;

R ⁸³ and R ^8b are both hydrogen; and

R ^ua “ and ^{¾ 1} are taken together to form a carbonyl (C=0) moiety.

[0561] In some embodiments of the compounds of formula (3-4), A ³ is C ₆ -C o aryl optionally substituted with one or more R ³⁴ substituents. In some embodiments, A ³ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule. In some embodiments, A ³ is phenyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ³ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. [Q562] In some embodiments of the compounds of formula (3-4), A ³ is 5- 10 membered heteroaryl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^] is pyridyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is ; wherein the * represents the attachment point to the remainder of the molecule.

[0563] In some embodiments of the compounds of formula (3-4), A ^z is C ₆ -C o aryl optionally substituted with one or more R ³⁶ substituents. In some embodiments, A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments. A ² is phenyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0564] In some embodiments of the compounds of formula (3-4), A ² is 5-10 membered heteroaryl optionally substituted with one or more R ⁶ substituents. In some embodiments. A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule. In some embodiments, A is pyridyl optionally substituted with one or more R ³⁶ substituents. In some embodiments, A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[Q565] In some embodiments, (A ³ -a) or (A ^l -b) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. [Q566] In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0567] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule.

[0568] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0569] In some embodiments, (A ^! -a) or (A ² -b) is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule; and (A ^? -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0570] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

to the remainder of the molecul e.

!-c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ^z -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

[0572] In some embodiments, (A ^! -a) or is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0573] In some embodiments, (A ^l -a) or is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -e) is selected from the group consisting of:

[0574] wherein the * represents the attachment point to the remainder of the molecule.

[0575] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecul e; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. or (A ^! -b) is selected from the group consisting of:

nts the attachment point to the remainder of the molecul e; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

[Q577] In some embodiments, (A -a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0578] In some embodiments, (A ^! -a) or (A ¹ -!)) is selected from the group consisting of:

nts the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0579] In some embodiments, (A ^! ~a) or (A^b) is selected from the group consisting of:

wherein the * represents the attachment point to th e remainder of the molecule; and A is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0580] In some embodiments, (A ^! ~a) or (A ¹ -b) is selected from the group consisting of

; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0581] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[Q582] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

remainder of the molecule.

In some embodiments, (A^a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ^! -a) or (A ^l -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[Q585] In some embodiments, (A ^! -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0586] In some embodiments, (A ^! -a) or is selected from the group consisting of: ; wherein the * represents the attachment point

to the remainder of the molecule; ; wherein the * represents the attachment point to the remainder of the molecule.

[0587] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A"-b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule; and or selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecuk

[Q589] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A"-a) or (A ² -C) is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule.

[0590] In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A'-a) or (A -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0591] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of:

wherein the * represents the atachment point to the remainder of the molecule. In some embodiments. A ¹ is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule; selected from the group consisting of: and wherein the * represents the atachment point to the remainder of the molecule.

In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

In some embodiments. A ¹ is selected from the group consisting of: ; wherein the represents the atachment point to the remainder of the molecule; and (A"-a) or (A -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0595] In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0596] In some embodiments wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. [0597] In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A ^! is selected from the group consisting of

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[Q599] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[Q6QQ] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0601] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the atachment point to the

remainder of the molecule; ; wherein the * represents the attachment point to the remainder of the molecule. [0606] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0607] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the mol ecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0608] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0609] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the *

represents the attachment point to the remainder of the molecule;

wherein the * represents the attachment point to the remainder of the molecule.

[Q61Q] In some embodiments. ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

OH] In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0612] In some embodiments. wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0613] In some embodiments, wherein the * represents the

attachment point to the remainder of the molecule; ; wherein the * represents the attachment point to the remainder of the molecule

In some embodiments, the compound of formula (I) is a compound of formula

(4-4):

(4-4)

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is Ce-Cio aryl optionally substituted with one or more R ¹⁴ substituents; or 5-10 membered heteroaryl optionally substituted with one or more R ¹⁴ substituents; A is Ce-Cio aryl optionally substituted with one or more R ^{i 6} substituents; or 5-10 membered heteroaryl optionally substituted with one or more R ^lb substituents; R'“ and R' ^b are both hydrogen;

R ^8a and R ^8b are both hydrogen;

R ^{l la} and R ^{l lb} are both hydrogen;

R ^12a and R ^1¾ are both hydrogen;

and wherein

R ¹⁶ are as defined in compounds of formula (1). [0615] In some embodiments of the compounds of formula (4-4), X ⁵ is CH and X is CH. In some embodiments, r is 1 and s is 1.

[0616] In some embodiments of the compounds of formula (4-4), X ³ is CH, X is N and Y ² is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2.

[0617] In some embodiments of the compounds of formula (4-4), X ¹ is N, Y ¹ is a bond, and X ² is CH. In some embodiments, r is 1 and s is 1 In some embodiments, r is 0 and s is 2.

[0618] In some embodiments of the compounds of formula (4-4), X ¹ is N, Y' ¹ is a bond, X is N and Y ^L is a bond. In some embodiments, r is 1 and s is 1. In some embodiments, r is 0 and s is 2

[0619] In some embodiments of the compounds of formula (4-4), A ^] is C ₆ -C o aryl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ^! is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule. In some embodiments, A ³ is phenyl optionally substituted with one or more R ¹⁴ substituents. In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0620] In some embodiments of the compounds of formula (4-4), A ³ is 5-10 membered heteroaryl optionally substituted with one or more R ⁴ substituents. In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments. A ¹ is pytidyl optionally substituted with one or more R ⁱ⁴ substituents. In some embodiments. A ¹ is ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments of the compounds of formula (4-4), A ^z is Ce-Cio aryl optionally substituted with one or more R ^l0 substituents. In some embodiments. A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A is phenyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ^z is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecule.

In some embodiments of the compounds of formula (4-4), A is 5-10 membered heteroaryl optionally substituted with one or more R ^l6 substituents. In some embodiments, A is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^z is pyridyl optionally substituted with one or more R ¹⁶ substituents. In some embodiments, A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[0623] In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0624] In some embodiments, (A ^! ~a) or (A ¹ -!)) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A ² -a.) or is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the diments, (A ^! ~a) or (A^b) is selected from the group consisting of:

nts the attachment point to the remainder of the molecule; and (A -a) or (A ² -c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0626] In some embodiments, (A ^x -a) or (A ^! -b) is selected from the group consisting of:

wherein the * represents the attachment point to th e remainder of the molecule; and (A ^? -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0627] In some embodiments, (A ^! -a) or (A ^! -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -h) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

to the remainder of the molecule.

In some embodiments, (A ^! ~a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0630] In some embodiments, (A ^! ~a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A -a) or (A ~b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0631] In some embodiments, (A^a) or (A ^! -c) is selected from the group consisting of: : wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -c) is selected from the group consisting of:

[0632] : wherein the * represents the attachment point to the remainder of the molecule.

[0633] In some embodiments, (A^a) or (A ² -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[Q636] In some embodiments, (A ^! -a) or (A^b) is selected from the group consisting of:

nts the

attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule

[0637] In some embodiments, (A ^x -a) or (A^b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0638] In some embodiments, (A ^l -a) or (A ^! ~h) is selected from the group consisting of: wherein the * represents the attachment point to th e remainder of the molecule; and A is selected from the group consisting of: wherein th< represents the attachment point to the remainder of the molecule.

[0639] In some embodiments, (A ^! ~a) or (A ¹ -b) is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the represents the attachment point to the remainder of the molecule.

[0640] In some embodiments, (A^a) or (A ^! -b) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A ^! -a) or (A^c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molec ule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

In some embodiments, (A ^! -a) or (A ^! -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ^z is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

[0643] In some embodiments, (A ^! ~a) or (A ^l -c) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, (A^a) or (A ^! ~c) is selected from the group consisting of: ; wherein the * represents the attachment point

io the remainder of the molecule; wherein the * represents the attachment point to the remainder of the molecule.

[0645] In some embodiments, A ^! is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A ² ~a) or (A ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0646] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and or is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0648] In some embodiments. A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. lected from the group consisting of ; wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A'-b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0650] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; and (A -a) or (A"-c) is selected from the group consisting of: wherein the * represents the atachment point to the remainder of the molecul

[0651] In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² ~a) or (A"-b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0652] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the diments, A is selected from the group consisting of: ; herein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A"-c) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

; wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ^? ~b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule.

[0655] In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and (A ² -a) or (A ² -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. [Q656] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0657] In some embodiments. A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0658] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A" is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0659] In some embodiments, A ¹ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule; and A ² is ; wherein the * represents the attachment point to the remainder of the molecule.

[0660] In some embodiments, A is selected from the group consisting of; ; wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the mol ecule.

[0661] In some embodiments, A ¹ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the molecule.

lected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule.

[Q663] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the attachment point to the

remainder of the molecule; ; wherein the represents the attachment point to the remainder of the molecule.

[0664] In some embodiments, A ¹ is selected from the group consisting of:

represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0665] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the * represents the atachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

In some embodiments, A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule; A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0667] In some embodiments, A ¹ is selected from the group consisting of: ; wherein the *

represents the attachment point to the remainder of the molecule;

wherein the * represents the attachment point to the remainder of the molecule.

Oosj In some embodiments, wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. wherein the * represents the attachment point to the remainder of the molecule; and A ² is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule

[0670] In some embodiments. wherein the * represents the attachment point to the remainder of the molecule; and A is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule.

[0671] In some embodiments. ; wherein the * represents the

attachment point to the remainder of the molecule; and A ² is wherein the * represents the attachment point to the remainder of the mol ecule.

[0672] In one aspect, provided is a compound of formula (II):

or a pharmaceutically acceptable salt thereof;

wherein:

m3 is 0 or 1 ;

n3 is 0 or 1 ;

r2 is 0, 1 , or 2;

X ⁴ is (Ί 1 or N;

provided that at least one of X ³ and X ⁴ is CH;

Y ^J is selected from the group consisting of a bond, XR ' \ and O;

wherein R ^Y3 is hydrogen or CrC ₆ alkyl;

Y ⁴ is selected from the group consisting of a bond, NR ^Y4 , and O;

wherein R ^{Y 4} is hydrogen or Ci-Ce alkyl;

provided that:

when X ³ is N, then Y ⁵ is a bond and m3 is 1 ;

when X ⁴ is N, then Y ⁴ is a bond and n3 is 1;

A ^J is selected from the group consisting of:

a substituent of the formula (A ³ -a)

wherein

* represents the attachment point to the remainder of the molecule; Z ⁷ is selected from the group consisting of CR ^Z R ^Z ' ² , NR ^Z7 f O, S, and -CR^ ^CR ^{27 1} -; wherein

R ² IS H or R ² '; and

R ^{Z7 2} is H or R ²⁷ ;

Z ⁸ is selected from the group consisting of NR ^{Z8 2} ; O, S, and -CR ^{Z8 !} =CR ^{Z8 1} -;

wherein

R ^{28 1} is H or R '; and

R ²⁸ ’ is H or R ²⁷ ;

Z ⁹ , independent!}' at each occurrence, is C or N, provided that at least one Z ⁹ is C;

R ²⁶ is hydrogen or R ² ', or R ²⁶ and R ^z ' ^~2 are taken together to form a double bond between the carbon atom bearing R ^z6 and Z'; and

x3 is 0, 1, 2, 3, or 4, provided than when one Z ⁹ is N, then x3 is not 4; Ce-Cio aryl optionally substituted with one or more R ² ' substituent; and

5-10 rnembered heteroaryl optionally substituted with one or more R ^z ' substituent;

R ² ' is selected, independently at each occurrence, from the group consisting of halogen, C1-C0 alkyl, Ci-Ce haloaikyi, -OH, -OCCi-Ce alkyl), -0(Ci-C ₆ haloaikyi), -SH, -S(Ci-C,. alkyl), ~S(Ci~C ₆ haloaikyi), -NH ₂ , -NH(Ci-C ₆ alkyl),-NH(Ci-C ₆ haloalk>'l),-N(C r C ₆ alkyl) ₂ , -N(Ci-Ce haloalkyl) ₂ , -NR ^27_a R ^{27 b} , -CN, -C(0)0H, -C(0)0(C _r C ₆ alkyl),

-C(0)0(Ci-C ₆ haloaikyi), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C C ₆ haloaikyi), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆

haloaikyi)? alkyl),

-S(0) ₂ 0(Ci-C ₆ haloaikyi), -S(0) ₂ NH ₂ , -SiO) ₂ NH(Ci-C ₆ alkyl),

-S(0) ₂ NH(C _I -C ₆ haloaikyi), -S(0) ₂ N(Ci-C ₆ alkyi) ₂

haloalkyi) ₂ alkyl),

-0C(0)(Ci-C ₆ haloaikyi), -N(H)C(0)H, -N(H)C(0)(CrC ₆ alkyd),

-N(H)C(0)(C r C ₆ haloaikyi), -N(C C ₆ alkyi)C(0)H, -N(C C ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyi)C(0)(C ₁ -C ₆ haloaikyi), -N(C _I -C ₆ haloa!kv'!)C(0)H, ~N(C _I~ C ₆ haloa!ky!)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ haloaikyi), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloaikyi), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloaikyi), - Ci-C,. alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C -C6 haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -NlCi-C, haloalkyl)S(0) ₂ (C _l -C6 haloalkyl);

wherein R ^2/ “ and R ^z ' ^b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ⁴ is selected from the group consisting of:

a substituent of the formula (A ⁴ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁰ is selected from the group consisting of CR ²¹⁰ ^ ^{230 2} , NR ^{Z10 2} , O, S, and -CR ^{/ |:} '- ^: CR ^{/ ;} ' ^:· '-.

wherein

R ^{210 1} is H or R ^z9 ; and

R ^Z1G~2 is H or R ²⁹ ;

Z ¹¹ is selected from the group consisting of NR ^{Z11 2} ; O, S, and ~CR ^{21 ] i} =CR ^ZH · ¹ -;

wherein

R ^{233 1} is H or R ²⁹ ; and

R ^Zii‘2 is H or R ²⁹ ;

Z ¹² , independently at each occurrence, is C or N, provided that at least one Z ⁱ² is C;

R ²⁸ is hydrogen or R ^z9 , or R ²⁸ and R ^{Z30 2} are taken together to form a double bond between the carbon atom bearing R ²⁸ and Z ^!u ; and x4 is 0, 1, 2, 3, or 4, provided than when one Z ¹² is N, then x4 is not 4; C6-C10 aryl optionally substituted with one or more R ^z9 substituent; and

5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-Ce alkyl, Cj-Cg haloalkyl, -OH, -0(( ^' i-( ^' _ό alkyl), -OiCrCe haloalkyl), -SH, -S(C C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(Ci-Ce alkyl),-NH(Ci-C ₆ haloalkyl), -N(C -C ₆ alkyl) , -N(Ci-C ₆ haloalkyl) ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alky 1 ) ·. -C(0)N(Ci-C ₆ haloally 1 alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(()) ₂ NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -S(0) N(Ci~C ₆ alkyl) ₂ , -S« ⁾ ).N( ^{( '} i- ⁽ \. haloally. I ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(0)(C _I -C ₆ haloalkyl) alkyl)C(0)H, -N(C _I -C ₆

alkyl)C(0)(Ci-C ₆ alkyl), alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C _I -C ₆ haloalkyl)C(0)H, - (C _J -C ₆ haloallyd)C(0)(Ci-C ₆ alkyl), -N(C _J -C ₆ haloalkyl)C( ⁽⁾ )(CrC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) _? (C ₁ -C ₆ haloalkyl),

-N(C _I -C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -\{i _r C„ alkyl)S(0) _? (Ci-C ₆ haloalkyl), -N(CrC ₆ haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(C _I -C ₆ haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ^{29 a} and R ^{29 b} are taken together with the nitrogen atom winch bears them to form a 3-10 membered heterocycle;

R ^{1 ,a} and R ^17b are independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

R ^ISa and R ^ISb are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R ^19a and R ^19b are independently at each occurrence selected from the group consisting of hydrogen, C -Ce alkyl, and halogen;

when present, R ^20a and R ^20b are independently at each occurrence selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

or alternatively, R ^l7a and R ^l8a are taken together to form a Ci-Ce alkylene moiety;

or alternatively, R ^l7a and an R ^l9a moiety, when present, are taken together to form a C·,- Ce alkylene moiety, and R ^17b and the R ^l9b in the geminal position to the R ^19a taken together with R ^{1 /a} , are both hydrogen; or alternatively, an R ^l9a moiety, when present, and an R ^20a moiety, when present, are taken together to form a Ci-C ₆ alkylene moiety, and the R ^l9b in the geminal position to the R ^i9a taken together with the R ^2ua moiety and the R ^20b m the geminal position to the R ^20a taken together with the R ^9a moiety, are both hydrogen;

R ^!a and R ^!b are taken together to form an oxo (=0) substituent or an miido (=NH) substituent, or alternatively, R ^ia and R ^lb are both hydrogen;

when present, R ^22a and R ^22b are both hydrogen;

R ^3a and R ^3b are taken together to form an oxo (=0) substituent or an irnido (=NH) substituent, or alternatively, R ^23a and R ^23b are both hydrogen;

when present, R ^24a is selected from the group consisting of hydrogen, -OH, and -NH ₂ ; or alternatively, R ^24a and R ^Y4 are taken together to form a #-C(=0)-0- group, wherein # represent the attachment point to the nitrogen atom bearing R^ ⁴ ;

when present, R ^24b is hydrogen; and

when present, R ^2:a and R ^2:b are both hydrogen;

or alternatively, R ^25a , when present, and one R ²⁹ of A ⁴ are taken together with the atoms connecting them to form a 5-6 membered heterocycloalkenyi optionally substituted with one or more R ²⁹ substituent, and R ^2sb is H;

or alternatively, R ^2¾J , when present, R ^25b , when present, and one R ⁹ of A ⁴ are taken together with the atoms connecting them to form a 5-6 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

and further provided that one of (i), (ii), (iii) and (iv) applies:

(i) when m3 is 0 and n3 is 0, then:

X ³ is CH and Y ³ is NR ^Y3 ;

X ⁴ is CH and Y ⁴ is NR ^Y4 ;

R ^21a and R ^21b are taken together to form an oxo (=0) substituent;

il ^{2 ,a} and il ^{2 ,b} are taken together to form an oxo (=0) substituent;

A ³ is a substituent of the formula (A ³ -a)

* represents the attachment point to the remainder of the molecule;

Z' is selected from the group consisting of CR ^{Z/ 1} R ^Z/ · ² , NR ^Z/ \ O, S, and -CR ^{Z :} CR' ^{" 1} -.

wherein

R ²⁷¹ is H or R '; and

R ^Z72 is H or R ²⁷ ;

Z ⁸ is selected from the group consisting of CR ^Z81 R ^Z52 , NR ^Z8z ; O, S, and -CR ^/81 =CR ^Z81 -;

wherein

R ²⁸¹ is H or R ²⁷ ; and

R ^Z82 is H or R ²⁷ ;

Z ⁹ , independently at each occurrence, is C or N, provided that at least one Z ⁹ is C;

R ^2t> is hydrogen or Rf or R ²⁶ and R ² ' ² are taken together to form a double bond between the carbon atom bearing R ²⁶ and Z ⁷ ;

R ^{2 '} is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-Ce, alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), ~NH, N1 !· ^(' ··· ⁽ .. alkyl), -NH(C _] -C ₆ haloalkyl), -N(C _I -C ₆ aikyl) ₂ , -N(C C ₆ haloalkyl) _? , -NR ^27a R ^27b , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(C _] -C ₆ alkyl) ₂ , -C(0)N(C _] -C ₆ haloalkyl) _? . alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), ~S(0) ₂ NH ₂ , -S(0) ₂ NH(C C ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -S(0) ₂ N(CrC ₆ alkyl) , -S(0) N(CI-C ₆ haloally 1 alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, ·N(P) ⁽ (<)}! ⁽ ··<). alkyl), -N(H)C(0)(C rCe haloalkyl), -N(C C ₆ alky ^] )C(0)H, -N(C _I -C ₆

alk l)C(0)(C -C ₆ alkyl), -N(C _I -C ₆ alkyl)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(CI-C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ haloalky 1)C(0)(C _r C ₆ haloalkyl), -0S(0) ₂ (C C ₆ alkyl), -0S(0) ₂ (C ₁ -C ₆ haloalkyl), -N(H)S(0) ₂ (C _l -C ₆ alkyl), -N(H)S(0) ₂ (C]-C ₆ haloalkyl), -\iC -CY. alkTl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(G) ₂ (Ci-C ₆ haloalkyl), -N(C C ₆ haloalky l)S(0) ₂ (Ci-C ₆ alkyl), and -N(C _I -C ₆ haloallyl)S(O) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{2/ a} and R ^{27 b} are taken together with the nitrogen atom which hears them to form a 3-10 membered heterocycle;

x3 is 0, I , 2, 3, or 4, provided than when one Z ⁹ is N, then x3 is not 4;

A ⁴ is a substituent of the formula (A ⁴ ~a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁰ is selected from the group consisting of€K ^Zi0 ¾ ^{ZΪ0 2} , NR ^{Z10 2} , O, S, and -CR ^{Z!0 i=} CR ^{Zi0 !} -;

wherein

R ^ZilM is H or R ²⁹ ; and

R ^{Z10 2} is H or R ²⁹ ;

Z is selected from the group consisting of CR ^“ Ά NR O, S, and -CR ^{Z11 1} =CR ^{Z11 1} -;

wdierein

Z ^l , independently at each occurrence, is C or N, provided that at least one Z ^!2 is C;

R ²⁸ is hydrogen or R ^z9 , or R ²⁸ and R ^{Z 3 u'2} are taken together to form a double bond between the carbon atom bearing R ²⁸ and Z ¹⁰ ; R ²⁹ is selected, independent!} _' at each occurrence, from the group consisting of halogen, Ci-Cr, alkyl, Ci-Cc, haloalkyl, -OH, -0(C -C ₆ alkyl), oalkyl), -NH ₂ , 2, -N(CI-C ₆ alkyl),

CiOK iC i-C, haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C{())NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{29 3} R ^{29 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci~C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(CrC ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -S(0) ₂ N(C _] -C ₆ haloalkyl) ₂ , -S(0) ₂ NR ^{29 3} R ^{29 b} ,-0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-0C(0)(Ci C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alky ),

- (H)C(Q)(CrC ₆ haloalkyl), -N(Ci-C ₆ alkyl)C(0)H, -N(CrC ₆ alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C I-C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), ~N(CI~C ₆ haioalkyl)C(0)(C i-C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C _I -C ₆ alk l)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ alk> !)S(0} ₂₍ ⁽ r,.

haloalkyl), -N(Ci-Ce haioalkyl)S(0) ₂ (CrC ₆ alkyl), and -NfCi-Ce haloalkyl)S(0) ₂ (C _] -C ₆ haloalkyl);

wherein R ^{9 3} and R ^{29 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x4 is 0, l, 2, 3, or 4, provided than when one Z ¹² is N, then x4 is not 4; and

provided that A ² and A ⁴ are not both simultaneously a moiety selected from group consisting of:

sents the attachment point to the remainder of the molecule;

(ii) when m3 is 0 and n3 is 1, then:

r2 is I or 2;

s2 is 1 or 2;

X ³ is C ^' i I and Y ³ is NR ^Y3 ;

R ^21a and R ^21b are taken together to form an oxo (=0) substituent;

R ^z'*a is selected from the group consisting of hydrogen, -OH, and -NH ₂ ;

A ⁰ is a substituent of the formula (A ³ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z' is selected from the group consisting of CR ^ZM R ^Z, \ NR ^Z, , O, S, and -CR ^Z71 =CR ^Z71 -;

wherein

R ²⁷¹ is H or R ^2/ ; and

R ²⁷² is H or R ²⁷ ;

Z ⁸ is selected from the group consisting of CR ²⁸ ^ ²⁸² , NR ^Z8z ; O, S, and CR ^Z81 = ^: CR ^Z81 -;

wherein

R ²⁸¹ is H or R ^2/ ; and

R ²⁸² is H or R ²⁷ ; Z ⁹ , independently at each occurrence, is C or N, provided that at least one Z ⁹ is C;

R ^J is hydrogen or R ', or R and R are taken together to form a double bond between the carbon atom bearing R ^“u and Z';

R ²⁷ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), 0(( rC,. haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), Al l ,. -M-RCrCe aikv!l Ai !(( ,-( ,, haloalkyl), -N(C C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl) alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)M-i(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(C ₁ -C ₆ alkyl) ₂ , -C{0)\(Ci- ⁽ ..

haloalkyl) ₂ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(O) A! !{( V(V. alkyl),

-S(0) ₂ NH(C ₁ -C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -SlOfAiC i-C, haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(())(C _r C ₆ haloalkyl), -N(C _I -C ₆ alkyl)C(())H, -N(C C ₆

alkyl)C(0)(C ₁ -C ₆ alkyl), -N(CrC ₆ alkyl)C(O)(C ₁ -C ₆ haloalkyl), AiC _r C„ haloalkyl)C(0)H, -N(Ci-Ce haloalkyd)C(0)(CrC ₆ alkyl), -N(Ci-C ₆ haloally 1 )( ( ())(( ^' _: haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl),

-NiCi-Ce alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆

haloalkyl), -N(C -C6 haloalkyl)S(0) ₂ (Ci-C6 alkyl), and -N(CI-C6

haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ² and R"' ^b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x3 is 0, 1, 2, 3, or 4, provided than when one Z ⁹ is N, then x3 is not 4;

A ⁴ is C ₆ - Cio aryl optionally substituted with one or more R ²⁹ substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, Ci-C _f, haloalkyl, -OH, -OfC -Ce alkyl),

-0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NHiCi-Ce alky 1),-NH(C _! -Cg haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C _I -C ₆

haloalkyl ) alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)M-i(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0) ( ,-G,. alkyl) ₂ haloa!ky! -C(0)NR ²⁹ - ^a R ²⁹ - ^b , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -StOi _. A! Hi VCY. alkyl),

-S(0) NI Hi VC,·, haloalkyl), -S(0) ₂ N(Ci-C ₆ aikyl} ₂ , -S(0) ₂ N(CrC ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl),

-N(H)C(0)(C, -C _& haloalkyl), -N(C _I -C ₆ alkyl)C(())H, -N(C _I -C ₆

alkyl)C(0)(C ₁ -C ₆ alkyl), ~N(C _I~ C ₆ alkyl)C(O)(C ₁ -C ₆ haloalkyl), -\!( C,, haloalkyl)C(0)H, -N(C _I -C ₆ haloaHy l)C(0)(CrC ₆ alkyl), -N(Ci-C ₆ haloaikyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -MCi-C,. alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C -C ₆ haloalk l)S(0) ₂ (Ci-C ₆ alkyl), and -NlCi-C, haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ²⁹ “ and R" ^{9 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

provided that when R ^3a and R ^3b are taken together to form an oxo (=0) substituent, then R ^4a is -OH or -NH ₂ ;

(iii) when m3 is 1 and n3 is 0, then:

X ⁴ is CH and Y ⁴ is NR ^Y4 ;

R ^zla and R ^zlb are taken together to form an oxo (=0) substituent or an imido (=NH) substituent;

ll ^{2 ,a} and il ^{2 ,b} are taken together to form an oxo (=0) substituent;

A ³ is C ₆ - Cio aryl optionally substituted with one or more R ² ' substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ² ' substituent;

R ² ' is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, Ci-tk haloalkyl, -OH, -OfC -Ce alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NHiCi-Ce alky 1),-NH(C _! -Cg haioalkyi), -N(C _r C ₆ alkyl) ₂ , -N(C _I -C ₆ haioalkyi ) alkyl),

-C(0)0(Ci-C ₆ haioalkyi), -C(0)NH ₂ , -C(0)M-i(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haioalkyi), -C(0) ( Ί-G,, alkyl) ₂

haloalkyl>2, -C(0)NR ^{27 a} R ^{27 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haioalkyi), -S(0) ₂ NH ₂ , -StOfA! Hi VCY. alkyl),

-S(()} A! !{( ^' : ·( ^' , haioalkyi), -S(0) ₂ N(Ci-C ₆ aikyi} ₂ , -S(0) ₂ N(CrC ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haioalky ), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl),

-N(H)C(0)(C, -C _& haioalkyi), -N(C _I -C ₆ alkyl)C(())H, -N(C _I -C ₆

alkyl)C(0)(C ₁ -C ₆ alkyl), -N(CrC ₆ alkyl)C(O)(C ₁ -C ₆ haioalkyi), -\!( C,, haloa!ky!)C(0)H, -N(C _I -C ₆ haloalk\'l)C(0)(CrC ₆ alkyl), -N(Ci-C ₆ haIoalkyl)C(0)(C C ₆ haioalkyi), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haioalkyi), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haioalkyi),

-NiC Ce alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆

haioalkyi), -N(CVC ₆ haloalk l)S(0) ₂ (Ci-C ₆ alkyl), and -NlCi-C, haloaikyl)S(0) ₂ (Ci-C ₆ haioalkyi);

wherein R ^2/ “ and R"' ^b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ⁴ is a substituent of the formula (A ^’ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁰ is selected from the group consisting of CR ^Zl(M R ^{0 2} , NR ^{ZI0 2} , O, S, and -CR ^{Z10 1} =CR ^{Z10 1} -;

wherein

R ^{210 1} is H or R ²⁹ ; and

R ^{Z10 2} is H or R ²⁹ ; Z ¹¹ is selected from the group consisting of NR ^{Z11 2} ; O, S, and -CR ^Z! =CR ^{Zi i !} -;

wherein

R ^Zi is H or R ²⁹ ; and

R ^{Zii 2} is H or R ²⁹ ;

Z ^!2 , independently at each occurrence, is C or N, provided that at least one Z ⁱ² is C;

R ²⁸ is hydrogen or R"· ⁹ , or R ²⁸ and R ^{Z10 2} are taken together to form a double bond between the carbon atom bearing R ²⁸ and Z ^!u ;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-Ce, alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), ~NH , N1 !· ( ^' ···( .. alkyl), -NH(C _] -C ₆ haloalkyl), -N(C _I -C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) _? , -NR ^{29 a} R ^{29 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _J -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) _? . alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), ~S(0) ₂ NH ₂ , -S(0) ₂ NH(C C ₆ alkyl),

-S(0) ₂ NH(Ci-Ce haloalkyl), -S(0) ₂ N(CrC ₆ alkyl) , -S(0) N(C _I -C ₆ haloally 1 alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, - i i ( ⁽⁾ }{ ⁽ . ⁽ ,. alkyl),

-N(H)C(0)(C _r C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C _I -C ₆

alk}'i)C(0)(C -C ₆ alkyl), -N (Ci-Ce alkyi)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(C C ₆ haloalkyl)C(0)(C ₁ -C ₆ alkyl), -N(C C ₆ haloalky 1)C(0)(C _r C ₆ haloalkyl), -0S(0) ₂ (C C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (C -C ₆ haloalkyl),

-NiC i-e, alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ aHy )S(0) ₂ (Ci-C ₆ haloalkyl), -N(C C ₆ haloalky l)SiO) ₂ (Ci-C ₆ alkyl), and -N! ( >·<).

haloallyd)S(O) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{29 3} and R ^{29 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x4 is 0, ! , 2, 3, or 4, provided than when one Z ¹ " is N, then x4 is not 4; (iv) when m3 is 1 and n3 is 1, then:

R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido

(=NH) substituent;

A ^J is Ce-Cio aryl optionally substituted with one or more R substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ²⁷ substituent:

R ² ' is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), ~SH, -S(Ci-C ₆ alkyl), -S(CrC ₆ haloalkyl), -NH ₂ , -NH(CI-C ₆ alkyl),-NH(Ci-C ₆ haloalkyl), -N(CI-C ₆ alkyl) ₂ , -N(CI-C ₆ haloalkyl) ,. alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , ~C (0)X! li(V( ,, alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(C C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) _? alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(0) ₂ NH(CrC ₆ haloalkyl), -S(0) ₂ N(C _I -C ₆ alkyl) ₂ , -S(0) ₂ N(Ci-C ₆ haloalkyl) _? . ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(0)(C -C ₆ haloalkyd), -N(C _I -C ₆ alkyl)C(0)H, -N(C _I -C ₆

alk}d)C(0)(CrC ₆ alkyl), -N(C _r C ₆ alkyl)C(0)(C _l -C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (C!-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyd), -N(H)S(0) ₂ (C _J -C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyd),

-N(C _I -C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl)

haloalkyl), -N(CrC ₆ haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(C C ₆ haloalkyd)S(0) ₂ (Ci-C ₆ haloalkyd);

wherein R ^7~a and ll ^{2 / b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ⁴ is Ce-Cio aryl optionally substituted with one or more R ²⁹ substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, C1-C0 alkyl, Ci-Ce haloalkyl, -OH, ~0(C i~C ₆ alkyl), -OiC i-C,. haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(Ci-Ce alkyl),-NH(Ci-C ₆ haloalkyl), -N(C -C ₆ alkyl) , -N(Ci-C ₆ haloalkyl) ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alky 1 ) ·. -C(0)N(Ci-C ₆ haloally 1 alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(()) ₂ NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(0) ₂ NH(C _I -C ₆ haloalkyl), -S(0) _? N(Ci~C ₆ alkyl) ₂ ,

haloally. I ) _' . -S(0) ₂ NR ^{29 a} R ^{29 b} ,-0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ ally !),

-N(H)C(0)(C _I -C ₆ haloalkyl) alkyl)C(0)H, -N(C _I -C ₆

alkyl)C(0)(Ci-C ₆ alkyl), AίG ,-G, alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C _I -C ₆ haloalkyl)C(0)H, - (C _J -C ₆ haloallyd)C(0)(Ci-C ₆ alkyl), -N(C _J -C ₆ haloalkyl)C( ⁽⁾ )(CrC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) _? (C ₁ -C ₆ haloalkyl),

-N(C _I -C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -\{i _r C„ alkyl)S(0) _? (Ci-C ₆ haloalkyl), -N(CrC ₆ haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(C _I -C ₆ haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ^{29 a} and R ^{29 b} are taken together with the nitrogen atom winch bears them to form a 3-10 membered heterocycle;

provided that:

when one of X ³ or X ⁴ is N, then r2 is 1 or 2 and s2 is 1 or 2; and when ⁱ³ and R ^ib are taken together to form an oxo (=0) substituent, then R ²⁴³ is -OH or -NH ₂ .

In some embodiments of compounds of formula (II):

m3 is 0 or 1;

n3 is 0 or 1 ;

r2 is 0, 1, or 2;

s2 is 0, 1 , or 2;

X ³ is CH or N;

X ⁴ is CH or N;

provided that at least one of X’ and X ⁴ is CH; Y ^J is selected from the group consisting of a bond, NR ^Y3 , and O;

wherein R ^Y3 is hydrogen or Ci-C ₆ alkyl;

Y ⁴ is selected from the group consisting of a bond, NR ^Y4 , and O;

wherein R ^{Y 4} is hydrogen or Ci-Ce alkyl;

provided that:

when X ³ is N, then Y ³ is a bond and m3 is 1 ;

when X ⁴ is N, then Y ⁴ is a bond and n3 is 1 ;

A ^J is selected from the group consisting of:

wherein

* represents the attachment point to the remainder of the molecule;

Z' is selected from the group consisting of CR ² ' ^ ^{7 2} , NR ^{27 2} , O, S, and -CR ^{Z7 !:} = ^: CR ^ZM -;

wherein

Z ⁸ is selected from the group consisting of CR ^{Z8 1} R ^{Zs 2} , NR ^{Z8 z} ; O, S, and -CR ^{Z8 1} =CR ^{Z8 1} -:

wherein

R ^{28 1} is H or R ²⁷ ; and

R ^Z8~2 is H or R ²⁷ ;

R ^z is hydrogen or R ' , or R and R are taken together to form a double bond between the carbon atom bearing R ²⁶ and Z '; and x3 is 0, 1, 2, 3, or 4;

C, Cio aryl optionally substituted with one or more R ² ' substituent; and

5-10 membered heteroaryl optionally substituted with one or more R ² ' substituent;

R ²⁷ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -C ₆ haloalkyl, -OH, -0(Ci-C ₆ alkyl), 0(( rC,. haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(C C ₆ haloalkyl), -M l, -NH(CrC ₆ alky 1),-NH(C _! -Cg haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)M-i(Ci-C ₆ alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(C ₁ -C ₆ alkyl) ₂ , ~C{0}\ii ⁽ C

haloalkyl) ₂ , -C(0)NR ^{27 a} R ^{27 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S{C.» ! Hi VCY. alkyl),

S(<)} A1 !{( ^' : ·( ^' ,, haloalkyl), -S(0) ₂ N(Ci-C ₆ aikyl) ₂ , -S(0) ₂ N(CrC ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl),

-N(H)C(0)(C, -C _& haloalkyl), -N(C _I -C ₆ alkyl)C(())H, -N(C _I -C ₆ alkyl)C(0)(C ₁ -C ₆ alkyl), ~N(C _I~ C ₆ alkyl)C(O)(C ₁ -C ₆ haloalkyl), -\{( C,, haloalkyl)C(0)H, -N(C _I -C ₆ ha!oalky!)C(Q)(CrC ₆ alkyl), -N(Ci-C ₆ haloally 1 )( ( ())(( ^' _: haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ <Ci-C ₆ haloalkyl),

-NiC Ce alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C -C ₆ haloalk l)S(0) ₂ (Ci-C ₆ alkyl), and -N(C _I -C ₆

haloalk l)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ^2/ “ and R"' ^b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ⁴ is selected from the group consisting of:

a substituent of the formula (A ⁴ -b)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁰ is selected from the group consisting of CR ^Zl(M R ^{/ 0 2} , NR ^{ZI0 2} , O, S, uo-i .

and -CR ^Z10_1 =CR ^;

R ^ZKM is H or R ²⁹ ; and

R ^{Z10 2} is H or R ²⁹ ; group consisting of CR ^{Zl l 1} R ^{Z] 2} , NR ,^Z ¹ l ¹ l-2;. O, S

wherein

R ^{Zi i_1} is

R ^{Zii 2} is

R ²⁸ is hydrogen are taken together to form a double bond between the carbon atom bearing R ²⁸ and Z ¹⁰ ; and

x4 is 0, 1, 2, 3, or 4;

Ce-Cio aryl optionally substituted with one or more R ²⁹ substituent; and

5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -C ₆ ha!oalkyl, -OH, -0(Ci~C ₆ alkyl), -0(C _] -C ₆ haloalkyl), -SH, -S(C C ₆ alkyl), -S(C _r C ₆ haloafkyl), -NH ₂ , -NH(C I-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C C ₆

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -Ni l ! )( (( ⁾ }·; ( -( ,. alkyl),

-N(H)C(0)(CI-C ₆ haloalkyl), -N(CI-C ₆ alkyl)C(0)H, -N(Ci-C ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C C ₆ haloa]kyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ haloalkyl)C(0)(CrC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (C _] -C ₆ haloalkyl), N(( ·{ ^' , alkyi)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(CrC ₆ haloalkyl)S(0) ₂ (Ci-C6 alkyl), and -NfCi-Ce ha!oalkx i )S(()j .(( _| -( .·. haloalkyl);

wherein R ^{29 3} and R ^{29 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle; R ^{1 ,a} and R ^{1 /b} are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

R ^1Sa and R ^1Sb are independently selected from the group consisting of hydrogen, Ci-C _& alkyl, and halogen;

when present, R ^19a and R ^19b are independently at each occurrence selected from the group consisting of hydrogen, C -Ce alkyl, and halogen;

when present, R “ and R are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

or alternatively, R ^l7a and R ^l8a are taken together to form a Ci-CV, alkylene moiety;

or alternatively, R ^{1 /a} and an R ^l9a moiety, when present, are taken together to form a (>,- C ₆ alkylene moiety, and R ^17b and the R ^l9b in the geminal position to the R ¹⁹³ taken together with R ^{l 7a} , are both hydrogen;

or alternatively, an R ^l9a moiety, when present, and an R ^20a moiety, when present, are taken together to form a Ci-Ce alkylene moiety, and the R ^19b in the geminal position to the R ^l9a taken together with the R ^/0a moiety and the R ^t,b in the geminal position to the R ^20a taken together with the R ^l9a moiety, are both hydrogen;

R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent, or alternatively, R ^{2 a} and R ^{2 b} are both hydrogen;

when present, R ^22a and R ^22b are both hydrogen;

R ^23a and R ^23b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent, or alternatively, R ^23a and R ^23b are both hydrogen;

when present, R ^¾a is selected from the group consisting of hydrogen, -OH, and -NH ₂ ; or alternati ely, R ^24a and R ^Y4 are taken together to form a #-C(=O)-0- group, wherein # represent the attachment point to the nitrogen atom bearin R ^¾4 ;

when present, R ^4b is hydrogen; and

when present, R ^25a and R ^25b are both hydrogen;

or alternatively, R ^sa , when present, and one R ²⁹ of A ⁴ are taken together with the atoms connecting them to form a 5-6 membered heterocycloalkenyl optionally substituted with one or more R ²⁹ substituent, and R ² * is H; or alternatively, R ^5a , when present, R ^/5b , when present, and one R ²⁹ of A ^¾ are taken together with the atoms connecting them to form a 5-6 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

and further provided that one of (i), (ii), (iii) and (iv) applies:

(i) when m3 is 0 and n3 is 0, then:

X ³ is CH and Y ³ is NR ^Y3 ;

X ⁴ is CH and Y ⁴ is NR ^Y4 ;

R ^{2 la} and R ^{2 lb} are taken together to form an oxo (=0) substituent;

R ^23a and R ^23b are taken together to form an oxo (=0) substituent;

A’ is a substituent of the formula (A’-b)

wherein

* represents the attachment point to the remainder of the molecule;

Z ⁷ is selected from the group consisting of CR ^Z R ^{Z ; 2} , NR ^Z7_ , O, S, and -CR^ ^CR ^{27 1} -;

wherein

R ^{27 1} is H or R ²⁷ ; and

R ^{Z7 2} is H or R ²⁷ ;

Z ⁸ is selected from the group consisting of CR ^{Z8 1} R ^{zs 2} , NR ^{Z8 2} ; O, S, and -CR ^{Z8 !:=:} CR ^{Z8 1} -;

wherein

R ^{28 1} is H or R ²⁷ ; and

R ^Z8~2 is H or R ²⁷ ;

R ²⁰ is hydrogen or R ', or R ²⁶ and R ² ' ² are taken together to form a double bond between the carbon atom bearing R ²⁶ and Z ⁷ ;

R ^'' is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-Ce, alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH , -NH(C I-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(C _] -C ₆ alkyl)?.

haloalkyl) _? alkyl),

-S(0) _? 0(Ci~C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _J -C ₆ alkyl),

SiO)A! l{(V-( ^' ,, haloalkyl), -S(0) _? N(C C ₆ alkyl ),. -S(0) ₂ N(CrC ₆ haloalkyl) alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N i l l )( (( ⁾ )! ( -( ,, alkyl), -N(H)C(0)(CrCe haloalkyl), -N(C -Ce alkyl)C(0)H, -N(Ci-C ₆

alkyl)C(0)(C _] -C ₆ alkyl), -N(CI-C ₆ alkyl)C(0)(C _] -C ₆ haloalkyl), -N(CI-C ₆ haloalkyl)C(0)H, -N(C C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ haloalky )C(0)(CrC ₆ haloalkyl), -0S(0) ₂ (C C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (C _r C ₆ alkyl), -N(H)S(0) ₂ (C -C ₆ haloalkyl),

N(( VC,. alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (CrC ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -NfCi-Ce haloalkx i )S(()j .(( _| -( ,·, haloalkyl);

wherein R ^{2 3} and R ^{27 b} are taken together with the nitrogen atom which hears them to form a 3-10 membered heterocycle;

x3 is 0, 1, 2, 3, or 4;

A ⁴ is a substituent of the formula (A ^’ -b)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁰ is selected from the group consisting of NR ^{Z1J 2} , O, S, and -CR ^{Z10 1} =CR ^{Z10 1} -;

wherein

R ^{210 1} is H or R ²⁹ ; and

R ^{Z10 2} is H or R ²⁹ ; group consisting of CR ^{Zl l 1} R ^{Z] 2} , NR ^{Z11 2} ; O, S,

wherein

R ^{Zi i_1} is

R ^{Zii 2} is

R ²⁸ is hydrogen are taken together to form a double bond between the carbon atom bearing R ²⁸ and ZrlO.

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cr, alkyl, Ci-Cc, haloalkyl, -OH, -0(C -C ₆ alkyl),

-0(Ci-C ₆ haloalkyl), -SH, -S(( alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CI-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(CI-C ₆ haloalkyl) ₂ alkyl),

CiOK iC i-C, haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(C C ₆ haloalkyl) ₂ , -C(0)NR ^{29 3} R ^{29 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci~C ₆ alkyl),

~S(0) ₂ 0(Ci-Ce haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci~C ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -SiO^N^-Ce aikyl) ₂ , -S(0) ₂ N(C _I -C ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyd), - (H)C(0)(CrC ₆ haloalkyl), -N(Ci-C ₆ alkyl)C(0)H, -N(CrC ₆

aIkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (C -C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(Q) ₂ (CI-C ₆ haloalkyl),

-N(CI-C ₆ alk l)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ ally i )S(OWi C,,

haloalkyl), -NfC -Ce haioalkyl)S(0) ₂ (CrC ₆ alkyl), and -N(CI-C ₆

haloalkyl)S(0) ₂ (C _] -C ₆ haloalkyl);

wherein R ^{9 3} and R ^{29 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x4 is 0, 1, 2, 3, or 4; and

provided that A ³ and A ⁴ are not both simultaneously a moiety selected from group consisting of:

sents the attachment point to the remainder of the molecule;

(ii) when m3 is 0 and n3 is 1, then:

r2 is I or 2;

s2 is 1 or 2;

X ³ is CH and Y ³ is NR ^Y3 ;

R ^21a and R ^21b are taken together to form an oxo (=0) substituent;

R" ^'*a is selected from the group consisting of hydrogen, -OH, and -NH ₂ ;

A ⁰ is a substituent of the formula (A ³ -b)

wherein

* represents the attachment point to the remainder of the molecule; Z' is selected from the group consisting of NR ^Z ' , O, S,

wherein

R ^Z is H or R ²⁷ ; and

R ^Z72 is H or R ²⁷ ;

Z ⁸ is selected from the group consisting of CR ^{Zf Z82} , NR ^Z8z ; O, S, and CR N-· _CR /S-I_.

wherein

R ²⁸¹ is H or R ²⁷ ; and

R ²⁸² is H or R ²⁷ ; R ^2t> is hydrogen or R6', or R ²⁶ and R ² ' ² are taken together to form a double bond between the carbon atom bearing R ⁶ and Z ⁷ ;

R ^{2 '} is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-Ce, alkyl), -0(Ci-C ₆ haloalky ), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , N1 !· ( ^' ···( .. alkyl), -NH(C _] -C ₆ haloalkyl), -N(C _I -C ₆ alkyl) _? ., -N(C C ₆ haloalkyl) ₂ , -NR ^{27 a} R ^{27 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _J -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) _? . ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(0) ₂ NH(Ci-Ce haloalkyl), -S(0) ₂ N(CrC ₆ alkyl) , -S(0) ₂ N(C _I -C ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), alkyl),

-N(H)C(0)(C rCe haloalkyl), -N(C C ₆ a)kyl)C(0)H, -N(C _I -C ₆

alky )C(0)(C -C ₆ alkyl), -N(C _I -C ₆ alkyl)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(C C ₆ haloalkyl)C(0)(C ₁ -C ₆ alkyl), -N(C C ₆ haloalky 1)C(0)(C _r C ₆ haloalkyl), -0S(0) ₂ (C C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (C -C ₆ haloalkyd), NiC rC, alkyl)S(Q) ₂ (CrC ₆ alkyd), -N(C C ₆ alkyd)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C C ₆ haloalky l)SiO) ₂ (Ci-C ₆ alkyl), and -N! ( >·<).

haloalliyd)S(O) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{2 / a} and R ^{27 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x3 is 0, 1, 2, 3, or 4;

A ⁴ is C Cio aryl optionally substituted with one or more R"· ⁹ substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent:

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(C -C ₆ alkyl), -S(Ci-Ce haloalkyl), -NH _¾ -NH(CI-C ₆ aikyl),-NH(Ci-C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) _? . ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(()) _' NHiC haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) _? , -S(0) _? N(C _l -C ₆ haloalkyl) _? alkyl),

-0C(0)(C i-C ₆ haloalkyl), alkyl),

-N(H)C(0)(C _r C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C _I -C ₆

alkyl)C(Q)(C -C ₆ alkyl), -N(C _I -C ₆ alkyl)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(CI-C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ haloalky 1)C(0)(C _r C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C _! -C ₆ haloalkyl), -N(H)S(0) ₂ (C _l -C ₆ alkyl), -N(H)S(0) ₂ (C -C ₆ haloalkyl),

-NiC i-CY. alkyl)S(0)2(CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (C _l -C6

haloalkyl), -N(C C ₆ haloalky l)S(0) _? (Ci-C ₆ alkyl), and -N(C _I -C ₆

haloally )S(O) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{29 3} and R ^{29 b} are taken together with the nitrogen atom which hears them to form a 3-10 membered heterocycle;

provided that when R ^" " ^3* and ·" ³¹¹ are taken together to form an oxo (=0) substituent, then R ^24a is -OH or -NH _? ;

(iii) when m3 is 1 and n3 is 0, then:

X ⁴ is CH and Y ⁴ is NR ^Y4 ;

R ^{2i a} and R ^2ib are taken together to form an oxo (=0) substituent or an imido

(=NH) substituent;

R" ^3a and R" ^3b are taken together to form an oxo ( ^:: =0) substituent;

A ^J is Ce-Cio aryl optionally substituted with one or more R ' substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ²⁷ substituent;

R ² ' is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(C -C ₆ alkyl), -S(CrC ₆ haloalkyl), -NH _¾ -NH(C _I -C ₆ alkyl),-NH(CrC ₆ haloaik}d),-N(C _r C ₆ alkyl) _? , -N(C C ₆ haloalkyl) _? , -NR ^{27 3} R ^{27 b} , -CN, -( (0)01 1. -C(0)0(Ci-C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) _? . ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(0) _? M i(C -( ^’ .·, haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) _? , -S(0) _? N(C _l -C ₆ haloalkyl) _? alkyl),

-0C(0)(C i-C ₆ haloalkyl), -N(H)C(0)H, -Nil ! }( «}}!( >( ,. alkyl),

-N(H)C(0)(C _r C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(CI-C ₆

alkyl)C(0)(C -C ₆ alkyl), -N(C _I -C ₆ alkyl)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(CI-C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ haloalky 1)C(0)(C _r C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C _! -C ₆ haloalkyl), -N(H)S(0) ₂ (C _l -C ₆ alkyl), -N(H)S(0) ₂ (C -C ₆ haloalkyl), -N(C _] -C ₆ alkyl)S(0)2(CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (C _l -C6

haloalkyl), -N(C C ₆ haloalky l)S(0) _? (Ci-C ₆ alkyl), and -N(CI-C ₆ haloally )S(O) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{2/ a} and R ^{27 b} are taken together with the nitrogen atom which hears them to form a 3-10 membered heterocycle;

A ⁴ is a substituent of the formula (A ⁴ ~b)

wherein

* represents the attachment point to the remainder of the molecule;

Z ^lu is selected from the group consisting of CR ² ' ^{0 1} ^ ^{10 2} , NR ^{Z10 2} , (), S, and ~CR ^{/ In ;} CR ^{/ :n} '~:

wherein

Z ^!i is selected from the group consisting of CR ^{Z! ! l} R ^{zl1 2} , NR ^{211 2} ; O, S, and -CR ^ZU_1 =CR ^{Z11 1} -;

wherein R ^{211 1} is H or R ^/9 ; and

R ^{Z11 2} is H or R ²⁹ ;

R-' is hydrogen or R . or R-' and R are taken together to form a double bond between the carbon atom bearing R" ⁸ and Z ^1u ;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), 0(( rC,. haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NHtCrCe aikv!}.-Ni !(( ,-( ,, haloalkyl), -N(C C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)M-i(Ci-C ₆ alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(C ₁ -C ₆ alkyl) ₂ , -C{0)\ii .

haloalkyl>2, -C(0)NR ²⁹ - ^a R ²⁹ - ^b , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _] -C ₆ alkyl),

-S(0) ₂ NH(C ₁ -C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ aikyl} ₂ , -S(0) ₂ N(CrC ₆ haloalkyl) ₂ , -S(0) ₂ NR ^{29 a} R ²⁹ - ^b ,-0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(()){C _I -C ₆ haloalkyl), -N(C ₃ -C ₆ alkyl)C(())H, -N(C _I -C ₆ alkyl)C(0)(C ₁ -C ₆ alkyl), ~N(C _I~ C ₆ alkyl)C(O)(C ₁ -C ₆ haloalkyl), ~\!C _r C„ haloalkyl)C(0)H, -N(C _I -C ₆ haloalkyl)C(G)(CrC ₆ alkyl), -N(Ci-C ₆ haloally 1 )( ^' ( ())(( ^' _: haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -NiC Ce alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C -C6 haloalkyl)S(0) ₂ (Ci-C6 alkyl), and -N(CI-C6

haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ²⁹ “ and R" ^{9 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x4 is 0, 1, 2, 3, or 4;

(iv) when m3 is 1 and n3 is 1 , then:

R ^2ia and R ^2ib are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; A ³ is Ce-Cio aryl optionally substituted with one or more R ²⁷ substituent, or 5-10 memhered heteroaryl optionally substituted with one or more R ² ' substituent;

R ^{2 '} is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-Ce, alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci~C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH _? , N1 !· ( ^' ···( .. alkyl), -NH(C _] -C ₆ haloalkyl), -N(C _I -C ₆ alkyl) _? , -N(C C ₆ haloalkyl) ₂ , -NR ^{27 a} R ^{27 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _J -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) _? . ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) _? NH(Ci-C ₆ alkyl),

-S(0) ₂ NH(C _I -C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) _? , -S(0) _? N(C _l -C ₆ haloallyl) _? alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -Nil ! }( «)}!( >( , alkyl), -N(H)C(0)(C rCe haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C _I -C ₆ alkyl)C(0)(C -C ₆ alkyl), -N(C _I -C ₆ alkyl)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(C C ₆ haloalkylX OXC C _? alkyl), -N(C C ₆ haloalky 1)C(0)(C _r C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -OSCO) ₂ (Ci~C ₆ haloalkyl), -N(H)S(0) _? (Ci-C ₆ alkyl), -N(H)S(0) ₂ (C -C ₆ haloalkyl), Ni(V(V. alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ allyd)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C C ₆ haloalky l)S(0) _? (Ci-C ₆ alkyl), and -N(C _I -C ₆ haloallyd)S(O) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{2 / a} and R ^{27 b} are taken together with the nitrogen atom which hears them to form a 3-10 memhered heterocycle;

A ⁴ is Ce-Cio aryl optionally substituted with one or more ^" " ⁹ substituent, or 5-10 memhered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, -OH, -0(( ^' i-( ^' _ό alkyl), -OiCrCe haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH _? , -NH(Ci-Ce alkyl), -NH(C _I -C ₆ haloalkyl), -N(C -C ₆ alkyl) _? , -N(CrC ₆ haloalkyl) _? ,. alkyl),

-C(0)0(Ci-C ₆ haloalkyl), alkyl), -C(0)NH(C C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyffe, -C(0)N(Ci-C ₆

-0C(0)(C -C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(C J -C6 alkyl),

-N(H)C(0)(C r C ₆ haloalkyl), -N(CI-C ₆ alkyl)C(0)H, -N(C C ₆

alkyI)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(CI-C ₆ haloalkyl)C(0)H, ~N(CI~C ₆ haloalkyl)C(0)(Ci~C ₆ alkyl), -N(CI-C ₆ haloalky 1)C(0)(C -€, haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -N(CI-C ₆ alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci~C ₆

haloalkyl), -NfC-.-Ce haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -N(C J -C6 haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ^{/9 3} and R ^{9 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

provided that:

when one of X ^J or X ⁴ is N, then r2 is 1 or 2 and s2 is 1 or 2; and when R2 ^¾l and R ^3b are taken together to form an oxo (=0) substituent, then R ^24a is -OH or -NH ₂ .

[0674] In some embodiments the compound of formula (II) is a compound of formula (III):

compounds of formula (II);

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.

[0676] In some embodiments the compound of formula (II) is a compound of formula (V):

or a pharmaceutically acceptable salt thereof.

[0677] In some embodiments of the compounds of formula (II), (III), (IV), or (V), R ^{3 /a} and R ^{3 /b} are independently hydrogen or C -Cg alkyl. In some embodiments, R ^{3 /a} and R ^{3 /b} are both hydrogen. In some embodiments, R ^{1 ,a} and R ^17b are both C _r Cg alkyl. In some embodiments, R ^{1 ,a} and R ^{i b} are both methyl. In some embodiments, R ^/a is hydrogen and R ^{3 /b} is C -Cg alkyl. In some embodiments, R ^l7a is hydrogen and R ^l7b is methyl.

[Q678] In some embodiments of the compounds of formula (II), (III), (IV), or (V), R ^1Sa and R ^18b are independently hydrogen or Ci-Cg alkyl. In some embodiments, R ^18a and R ^18b are both hydrogen. In some embodiments, R ^18a and R ^18b are both Ci-C ₆ alkyl. In some embodiments, R ^{i Ba} and R ^{i Bb} are both methyl. In some embodiments, R ^l8a is hydrogen and R ^18b is Ci-Cr, alkyl.

In some embodiments, R ^!8a is hydrogen and R ^l8b is methyl.

[0679] In some embodiments of the compounds of formula (II), (III), (IV), or (V), R ¹⁷³ , R ^1?b , R ^18a , and R ^iBb are hydrogen.

[0680] In some embodiments of the compounds of formula (II), (III), (IV), or (V), R ^{1 ,a} , R ^{3 /b} , R ^1Sa , and R ^3Bb are independently Cj-C ₆ alky . In some embodiments, R ^{1 /a} , R ^{1 /b} , R ^18a , and R ^lsb are methyl.

[0681] Tn some embodiments of the compounds of formula (II), (III), (IV), or (V), R ^{1 ,a} and R ^i8a are independently Cj-Ce alkyl, and R ^{i 7b} and R ^18b are both hydrogen. R ^{3 /a} and R ^i8a are both methyl, and R ^17b and R ^18b are both hydrogen.

[0682] In some embodiments of the compounds of formula (II), (III), (IV), or (V), R ^{3 73} and R ¹⁸³ are taken together to form a Ci-C ₆ alkylene moiety, and R ^{1 /b} and R ^18b are both hydrogen. In some embodiments, R ^{3 /a} and R ^38a are taken together to form an ethylene (-CH ₂ -CH ₂ -) moiety, and R ^{i /b} and R ^lsb are both hydrogen. In some embodiments, R ^{3 /a} and R ³⁸³ are taken together to form a propylene (-CH2-CH2-CH2-) moiety, and R ^{1 ,b} and R ^18b are both hydrogen.

In some embodiments of the compounds of formula (II), (III), (TV), or (V), r2 is 1 and s2 is 1. In some embodiments, R ^{i 7a} and R ^{i 7b} are independently hydrogen or Ci-CV, alkyl. In some embodiments, R ¹ ' ³ and R ^{1 /b} are both hydrogen. In some embodiments, R ^{1 /a} and R ^{! /b} are both Ci-Ce alky]. In some embodiments, R ^{1 ,a} and R ^{1 ,b} are both methyl. In some embodiments, R ^{1 ,a} is hydrogen and R ^{1 ,b} is Ci-C ₆ alkyl. In some embodiments, R ^17a is hydrogen and R ^{1 ,b} is methyl. In some embodiments, R ^{3 83} and R ^{! 8b} are independently hydrogen or CVC _f , alkyl. In some embodiments, R and R ^' are both hydrogen. In some embodiments, R and R ^* are both C -C ₆ alkyl. In some embodiments, R ^!8a and R ^!8b are both methyl. In some embodiments, R ^{i 8a} is hydrogen and R ^{i 8b} is CrC ₆ alkyl. In some embodiments, R ^]8a is hydrogen and R ^]8b is methyl. In some embodiments, R , R ' , R" , and R ^{* '} are hydrogen. In some embodiments, R ^17a , R ^17b , R ^18a , and R ^i8b are independently Ci-C ₆ alkyl. In some embodiments, R ¹ ' ³ , R ^17b , R ^l8a , and R ^l8b are methyl. In some embodiments, R ^{1 /a} and R ^lba are independently Cj-Ce alkyl, and R ¹⁷¹ ’ and R ^lsb are both hydrogen. R ^{! 7a} and R ^{! 8a} are both methyl, and R ^{1 /b} and R ^{i 8b} are both hydrogen. In some embodiments, R ^{3 /a} and R ^3Ba are taken together to form a Ci-Ce alkylene moiety, and R ^i,b and R ^18b are both hydrogen. In some embodiments, R ^{1 ,a} and R ^18a are taken together to form an ethylene (-CH ₂ -CH ₂ -) moiety, and R ^{1 ,b} and R ^{i sb} are both hydrogen. In some embodiments, R ^{l ,a} and R ^ISa are taken together to form a propylene (-CH2-CH2-CH2-) moiety, and R ^{! /b} and R ^18b are both hydrogen. In some embodiments, R ^19a and R ^19b are independently hydrogen or Ci-Ce alkyl. In some embodiments, R ^19a and R ^19b are both hydrogen. In some embodiments, R ^!9a and R ^!9b are both Ci-C ₆ alky . In some embodiments, R ^l9a and R ^!9b are both methyl. In some embodiments, R ^{! 9a} is hydrogen and R ^{! 9b} is CVC _f , alkyl. In some embodiments, R ^19a is hydrogen and R ^19b is methyl. In some embodiments, R ^0a and R ^0b are independently hydrogen or Ci-Ce alkyl. In some embodiments, R ^0a and R ^0b are both hydrogen. In some embodiments, R ^0a and R ^0b are both Ci-Ce alkyl. In some embodiments, R ^20a and R ^0b are both methyl. In some embodiments, R ^20a is hydrogen and R ^20b is C-.-Ce alkyl. In some embodiments, R ^2lJa is hydrogen and R ^2ub is methyl. In some embodiments, R ^9a , R ^l9b , R ^20a , and R ^z9b are hydrogen. In some embodiments, R ^{i a} , R ^19b , R ^0a , and R ^20b are independently CrC ₆ alkyl. In some embodiments, R ^{i 9a} , R ^19b , R ^20a , and Il ^20b are methyl. In some embodiments, R ^{i 9a} and R ^20a are independently Ci-Ce alkyl, and R ^19b and R ^2ub are both hydrogen. In some embodiments, R ^i9a and R ^20a are both methyl, and R ^19b and R ^z0b are both hydrogen. In some embodiments, R ^l9a and R ^2ua are taken together to form a C -Ce alkylene moiety, and R ^l9b and R ^0b are both hydrogen. In some embodiments, R ^19a and R ^z0a are taken together to form an ethylene (-CH2-CH2-) moiety, and R ^l9b and R ^z9b are both hydrogen. In some embodiments, R ^19a and R ^0a are taken together to form a propylene (-CH2-CH2-CH2-) moiety, and R ^l9b and R ^20b are both hydrogen. In some embodiments. t ^{! 7a} and R ^{! 9a} are taken together to form a C -C ₆ alkylene moiety, and R ^{l ,b} and

R ^19b are both hydrogen. In some embodiments, R ^17a and R ^19a are taken together to form an ethylene (-CH ₂ -CH ₂ -) moiety, and R ^{1 ?b} and R ^l 9b ⁰ are both hydrogen. In some embodiments, R and R ^{, 9a} are taken together to form a propylene (-CH ₂ -CH ₂ -CH ₂ -) moiety, and R ^l7b and R ^l9b are both hydrogen.

[0684] In some embodiments of the compounds of formula (II), (III), (IV), or (V), r2 is 2 and s2 is 0. In some embodiments, R ^{1 ,a} and R ^{1 ,b} are independently hydrogen or Ci-Ce alkyl . In some embodiments, R ^{1 /a} and R ^{1 /b} are both hydrogen. In some embodiments, R ^{i 7a} and R ^l7b are both C -Cg alkyl. In some embodiments, R ^{1 ,a} and R ^{1 ,b} are both methyl. In some embodiments, R ^{1 /a} is hydrogen and R ^{1 /b} is CrC ₆ alkyl. In some embodiments, R ^{1 /a} is hydrogen and R ^{1 /b} is methyl . In some embodiments, R ^18a and R ^18b are independently hydrogen or C -Ce alkyl. In some embodiments, R ^18a and R ^18b are both hydrogen. In some embodiments, Il ^18a and Il ^,8b are both Ci-Ce alkyl. In some embodiments, R ¹⁸³ and R ^18b are both methyl. In some embodiments, R ^lba is hydrogen and R ^lbb is CrC ₆ alkyl. In some embodiments, R ^18a is hydrogen and R ^lbb is methyl . In some embodiments, R ^{l ,a} , R ^17b , R ^,8a , and R ^l8b are hydrogen. In some embodiments, R ^{1 /a} , R ^1?b , R ^18a , and R ^18b are independently Ci-Ce alkyl. In some embodiments, R ¹ ' ³ , R ^17b , R ^38a , and R ^l8b are methyl. In some embodiments, R ^{1 /a} and R ^18a are independently Ci-Ce alkyl, and R ^{1 /b} and R ^lsb are both hydrogen. R ^{1 ?a} and R ^!8a are both methyl, and R ^{3 /b} and R ^18b are both hydrogen. In some embodiments, R ^{3 /a} and R ³⁸³ are taken together to form a C -Ce alkylene moiety, and R ^{1 /b} and R ^38b are both hydrogen. In some embodiments, R ^17a and R ^18a are taken together to form an ethylene (-City-City-) moiety, and R ^{1 ,b} and R ^{i sb} are both hydrogen. In some embodiments, R ^{l ,a} and R ^ISa are taken together to form a propylene (-CH ₂ -CH ₂ -CH ₂ -) moiety , and R ^{! /b} and R ^18b are both hydrogen. In some embodiments, R ^19a and R ^19b are independently at each occurrence hydrogen or Ci-Ce alkyl. In some embodiments, R ¹⁹³ and R ^19b are

independently at each occurrence hydrogen or methyl. In some embodiments, R ^!9a and R ^!9b are both at each occurrence hydrogen. In some embodiments, R ^39a and R ^39b are both at each occurrence Ci-Ce alkyl. In some embodiments, R ¹⁹³ and R ^39b are both at each occurrence methyl . In some embodiments, R ^19a is at each occurrence hydrogen and R ^b is at each occurrence Ci-Ce alkyl. In some embodiments, R ^19a is at each occurrence hydrogen and R ^19b is at each occurrence methyl. In some embodiments, R ¹⁹³ is at each occurrence hydrogen and R ^39b is at each occurrence methyl. In some embodiments, one R ¹⁹ “ is hydrogen and the other R ^19a is C -Ce alkyl and R ^b is at each occurrence hydrogen. In some embodiments, one R ^!9a is hydrogen and the other R ^l9a is methyl, and R ^{i 9b} is at each occurrence hydrogen. In some embodiments, R ^19a is at each occurrence hydrogen, one R ^l9b is hydrogen, and the other R ^l9b is Ci-Ce alkyl. In some embodiments, R ^i9a is at each occurrence hydrogen, one R ^{i b} is hydrogen, and the other R ^{! 9b} is methyl. In some embodiments, R ^l7a and an R ^l9a moiety are taken together to form a Ci-Ce alk lene moiety, and R ^{1 /b} and the R ^19b in the geminal position to the R ^19a taken together with R ^{1 /a} , are both hydrogen. In some embodiments, R ^{1 ,a} and an R ^19a moiety are taken together to form an ethylene (-City-City-) moiety, and R ^{l ?b} and the R ^l9b in the geminal position to the R ^39a taken together with R ^{3 /a} , are both hydrogen. In some embodiments, R ^{1 ,a} and an R ^19a moiety are taken together to form a propylene (-Q-ty-CI-ty-CI-ty-) moiety, and R ^17b and the R ^19b in the geminal position to the R ^!9a taken together with R ^{1 ?a} , are both hydrogen.

[0685] In some embodiments of the compounds of formula (II), (III), (IV), or (V), R ^{z /} , independently at each occurrence, is halogen. In some embodiments, R ² ', independently at each occurrence, is selected from the group consisting of fluoro and chloro. [Q686] In some embodiments of the compounds of formula (II), (III), (TV), or (V), R ^/9 , independently at each occurrence, is halogen. In some embodiments, R ²⁹ , independently at each occurrence, is selected from the group consisting of fluoro and chloro.

[0687] In some embodiments of the compounds of formula (II), (III), (IV), or (V):

m3 is 0 and n3 is 0;

X ³ is CH and Y ³ is NR ^Y3 ;

X ⁴ is CH and Y ⁴ is NR ^Y4 ;

R ^" " ^1* and R ^“lb are taken together to form an oxo (=0) substituent;

R and R"· ³¹³ are taken together to form an oxo (=0) substituent;

A is a substituent of the formula (A ³ -b)

wherein

* represents the attachment point to the remainder of the molecule;

Z ⁷ is selected from the group consisting of CR ²⁷ ^ ² ' ² , NR ^{7 2} , O, S, and -CR^-^CR ^{27 1} -;

wherein

R ² ' ¹ is H or R ^{z /} ; and

R ^{27 2} is H or R ²⁷ ;

Z ^s is selected from the group consisting of CR ^{Z8 1} R ^{Z8 2} , NR ^{Z8 2} ; O, S, and

CR ^{ZS :} CR ^{/n 1} -.

wherein

R ^{28 1} is H or R ^z ) and

R ^{28 2} is H or R ²⁷ ;

R ^2t> is hydrogen or R ^z ) or R ²⁶ and R ² ' ² are taken together to form a double bond between the carbon atom bearing R ²⁶ and Z ⁷ ;

R ^{2 '} is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-Ce, alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH , alkyl), -NH(C _] -C ₆ haloalkyl), -N(C _I -C ₆ aikyl) ₂ , -N(C C ₆ haloalkyl) ₂ , -XR ^{" ::} R ^{" b} . -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(C _] -C ₆ alkyl)?.

haloalkyl) _? alkyl),

-S(0) _? 0(Ci~C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _J -C ₆ alkyl),

SiO)A! l{(V-( ^' ,, haloalkyl), -S(0) _? N(C C ₆ alkyl ),. -S(0) ₂ N(CrC ₆ haloalkyl) alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -Xi H )( (())! ( -( ,, alkyl), -N(H)C(0)(CrCe haloalkyl), -N(C -Ce alkyl)C(0)H, -N(Ci-C ₆

alkyl)C(0)(C _] -C ₆ alkyl), -N(CI-C ₆ alkyl)C(0)(C _] -C ₆ haloalkyl), -N(CI-C ₆ haloalkyl)C(0)H, -N(C C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haloalky )C(0)(CrC ₆ haloalkyl), -0S(0) ₂ (C C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl),

N(( VC,. alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (CrC ₆ haloalkyl), -N(CrC ₆ haloalkyl)S(0) ₂ (Ci-C6 alkyl), and -NfCi-Ce haloalkx i )S(()j .(( _| -C,·, haloalkyl);

wherein R ^{2 3} and R ^{27 b} are taken together with the nitrogen atom which hears them to form a 3-10 membered heterocycle;

x3 is 0, 1, 2, 3, or 4;

substituent of the formula (A ⁴ -b)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁰ is selected from the group consisting of NR ^{Z1J 2} , O, S, and -CR ^{Z10 1} =CR ^{Z10 1} -;

wherein

R ^{210 1} is H or R ²⁹ ; and

R ^{Z10 2} is H or R ²⁹ ; group consisting of CR ^{Zl l 1} R ^{Z] 2} , NR ^{Z11 2} ; O, S,

wherein

R ^{Zi i_1} is

R ^{Zii 2} is

R ²⁸ is hydrogen are taken together to form a double bond between the carbon atom bearing R ²⁸ and ZrlO.

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cr, alkyl, Ci-Cc, haloalkyl, -OH, -0(C -C ₆ alkyl),

-0(Ci-C ₆ haloalkyl), -SH, -S(( alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CI-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(CI-C ₆ haloalkyl) ₂ alkyl),

CiOK iC i-C, haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(C C ₆ haloalkyl) ₂ , -C(0)NR ^{29 3} R ^{29 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci~C ₆ alkyl),

~S(0) ₂ 0(Ci-Ce haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci~C ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -Sty^NiC Ce aikyi) ₂ , -S(0) ₂ N(C _I -C ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyd), -N(H)C(0)(CrC ₆ haloalkyl), -NtyVCc, alkyl)C(0)H, -N(CrC ₆ aIkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (C -C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(Q) ₂ (CI-C ₆ haloalkyl), -N(CI-C ₆ alk l)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ a!k> l )S(0) ₂₍ ⁽ r,.

haloalkyl), -NfC -Ce haioalkyl)S(0) ₂ (CrC ₆ alkyl), and -N(CI-C ₆ haloalkyl)S(0) ₂ (C _] -C ₆ haloalkyl);

wherein R ^{9 3} and R ^{29 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x4 is 0, 1, 2, 3, or 4; and

provided that A ^z and A ⁴ are not both simultaneously a moiety selected from group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule.

[0688] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0 and n3 is 0, X ³ is CH, Y ³ is NR^, X ⁴ is CH, Y ⁴ is NR* ⁴ , R ^a and R ^b are taken together to form an oxo (=0) substituent, and R ^½ and R ^zb are taken together to form an oxo (=0) substituent; (A ³ -b) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ³ -b) is selected from the group consisting of:

; wherein t the * representts the attachment point to the remainder of the molecule. In some embodiments, (A ³ -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. In some embodiments, (A ³ -h) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule.

[0689] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0 and n3 is 0, X ³ is CH, Y ³ is NR ^{* 3} , X ⁴ is CH, Y ⁴ is NR ⁴ , R ^2!a and R ^2!b are taken together to form an oxo (=0) substituent, and R ^½ and R ^3b are taken together to form an oxo (=0) substituent; (A ⁴ -b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ⁴ -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ⁴ -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ⁴ ~b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecul

[Q69Q] In some embodiments of the compounds of formula (II), (III), (IV), or (V):

m3 is 0 and n3 is 1;

r2 is 1 or 2;

R ^21a and R ^21b are taken together to form an oxo (=0) substituent;

R ^24a is selected from the group consisting of hydrogen, -OH, and -NH ₂ ;

R ^25a and R ^25b are both hydrogen:

A ³ is a substituent of the formula (A’-b)

wherein

* represents the attachment point to the remainder of the molecule; Z ' is selected from the group consisting of O, S, and -CR ^{Z7 1} =CR ^{Z7 1} -;

wherein

R ^ZM is H or R ² ' ; and

R ^{Z7 2} is H or R ²⁷ ; Z ⁸ is selected from the group consisting of CR ²⁸ ^ ^{25 2} , NR ^{Z8 z} ; O, S, and -CR ^{28 1} =CR ^{Z8 1} -;

wherein

R ^{28 1} is H o

R ^{28 2} is H o

R ²⁶ is hydrogen or are taken together to form a double bond between the carbon atom bearing R ²⁶ and Z ';

R ² ' is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cr, alkyl, Ci-Cc, haloalkyl, -OH, -0(C -C ₆ alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S( ⁽ Ί-C, alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CI-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(CI-C ₆ haloalkyl) ₂ , -NR ^{27 a} R ^{27 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

CiOKJiC i-C, haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C{())NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ aikyl) ₂ , -C(0)N(C C ₆ haloalkyl) ₂ , -C(0)NR ^{27 a} R ^{27 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _! -C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(CrC ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -S(0) ₂ NiC C ₆ alkyl) ₂ , -SiO) ₂ N(Ci-C ₆ haloalkyl) ₂ , ~S(0) ₂ NR ^{27 a} R ^{27 b} ,~0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyd), - (H)C(0)(CrC ₆ haloalkyl), -N(CVC ₆ alkyl)C(0)H, -N(CrC ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haloalkyi)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (C -C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C _I -C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ a!k> l )S(0} ₂₍ ⁽ r,,

haloalkyl), -NfC -Ce haloalkyl)S(0) ₂ (Ci-C ₆ alkyd), and -N(C _I -C ₆

haloalkyl)S(0) ₂ (C _] -C ₆ haloalkyl);

wherein R ^{/ a} and R ^{27 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x3 is 0, 1, 2, 3, or 4; and

A ⁴ is C _fi -C o aryl optionally substituted with one or more R ^z9 substituent, or 5-10

membered heteroaryl optionally substituted with one or more R ²⁹ substituent; R ²⁹ is selected, independent!} _' at each occurrence, from the group

consisting of halogen, Ci-Cr, alkyl, Ci-Cc, haloalkyl, -OH, -0(Ci-C ₆ alkyl),

oalkyl), -NH ₂ , 2, -N(CI-C ₆ alkyl),

CiOK iC i-C, haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C{())NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(C C ₆ haloalkyl) ₂ , -C(0)NR ^{29 3} R ^{29 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci~C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(CrC ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -S(0) ₂ N(C _] -C ₆ haloalkyl) ₂ , ~S(0) ₂ NR ^{29 3} R ^{29 b} ,~0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-0C(0)(Ci C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alky ), - (H)C(Q)(CrC ₆ haloalkyl), -NfCi-Cc, alkyl)C(0)H, -N(CrC ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), ~N(C _I~ C ₆ haioalkyl)C(0)(C rC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(Q) ₂ (C _I -C ₆ haloalkyl),

-N(CI-C ₆ alk l)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ alk> !)S(0} ₂₍ ⁽ r,.

haloalkyl), -N(Ci-Ce haioalkyl)S(0) ₂ (CrC ₆ alkyl), and -NfCi-Ce

haloalkyl)S(0) ₂ (C _] -C ₆ haloalkyl);

wherein R ^{9 3} and R ^{29 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle.

[0691] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X ³ is CH, Y’ is NR ^Y3 , R ^la and R ^21b are taken together to form an oxo (=0) substituent, R ²⁴³ is selected from the group consisting of hydrogen, -OH, and -NH ₂ , and R ²³³ and R ^23b are both hydrogen; X ⁴ is CH. In some embodiments, Y ^* is a bond. In some embodiments, Y ⁴ is a NR ^Y4 . In some embodiments, R ^Y4 is hydrogen. In some embodiments, R ^¾4 is Ci-Ce alkyl. In some embodiments, R’" ⁴ is methyl. In some embodiments, R ^Y'* is ethyl. In some embodiments, Y ⁴ is a O. In some embodiments, R ^{2 3} and R ^{2 b} are taken together to form an oxo (=0) substituent and R ²⁴³ is -OH or -NH ₂ . In some embodiments, R ²⁴³ is -OH. In some embodiments, R ^<! is -NH ₂ . In some embodiments, R’ and R’ are taken together to form an imido (=NH) substituent. In some embodiments, R ^¾a is hydrogen. In some embodiments, R ^4a is -OH. In some embodiments, R ^¾a is -NH ₂ .

[0692] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X ³ is CH, Y ^J is NR ^Y3 , R ^21a and R ^21b are taken together to form an oxo (=0) substituent, R ^24a is selected from the group consisting of hydrogen, -OH, and -NH ₂ , and R ^21a and R ^21b are both hydrogen; X ⁴ is N. In some embodiments, R ^3a and R ^3b are taken together to form an oxo ( ^:=: 0) substituent and R ^4a is -OH or -NH ₂ . In some embodiments, R ^z4a is -OH. In some embodiments, R ^z'*a is -NH ₂ . In some embodiments, R ^23a and R ^{2 b} are taken together to form an imido (=NH) substituent. In some embodiments, R ^24a is hydrogen. In some embodiments, R ^4a is -OH. In some embodiments, Il ^4a is -NH ₂ . In some embodiments, R ^{2 a} and R ^{2 b} are both hydrogen. In some embodiments, R ^4a is hydrogen. In some embodiments, R ^z4a is -OH. In some embodiments, R ^24a is -NH ₂ .

[0693] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X’ is CH, Y ³ is NR ’, R ^21a and R ^21b are taken together to form an oxo (=0) substituent, R ^24a is selected from the group consisting of hydrogen, -OH, and -NH ₂ , and R ^5a and R ^5b are both hydrogen; (A ³ -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ³ -b) is selected from the group consisting of:

; wherein t the * representts the attachment point to the remainder of the molecule. In some embodiments, (A ³ -b) is selected from the group consisting of:

ts the attachment point to the remainder of the molecule. In some embodiments, (A ³ -h) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule.

[0694] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X ^J is CH, Y ^J is NR ^Y , R ^la and R ^21b are taken together to form an oxo (=0) substituent, R ^4a is selected from the group consisting of hydrogen, -OH, and -NH ₂ , and R ^5a and R ^5b are both hydrogen; A ^¾ is C ₆ -Cio and optionally substituted with one or more R ²⁹ substituent. In some embodiments, A ⁴ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[0695] In some embodiments of the compounds of formula (II), (HI), (IV), or (V), wherein m3 is 0, n3 is 1, r2 is 1 or 2, s2 is 1 or 2, X ³ is CH, Y ³ is NR ^" * ³ , R ^{! a} and R ^2!b are taken together to form an oxo (=0) substituent, R ^24a is selected from the group consisting of hydrogen, -OH, and -NH ₂ , and R" ^5a and R" ^5b are both hydrogen; A ⁴ is 5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent. In some embodiments, A ⁴ is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the mol ecule.

[0696] In some embodiments of the compounds of formula (II), (III), (IV), or (V):

m3 is 1 and n3 is 0;

X ⁴ is CH and Y ⁴ is NR ^Y4 ;

R ^zla and R"· ¹ * ⁵ are taken together to form an oxo (=0) substituent or an irnido ί Ni l ) substituent;

R ^{2 ,a} and R ^{2 ,b} are taken together to form an oxo (=0) substituent;

A ³ is Ce-Cio aryl optionally substituted with one or more R ^' substituent, or 5-10

membered heteroaryl optionally substituted with one or more R ²⁷ substituent;

R ²⁷ is selected, independently at each occurrence, from the group consisting of halogen, Ci-Ce alkyl, C -Cg haloalkyl, -OH, -0(( ^' i-( ^' _ό alkyl), -OiCrCe haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(Ci-Ce aikyl),-NH(Ci-C6 haloalkyl),-N(Ci-C6 alkyl)?, -N(Ci-C6 haloalkyl) ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) _? , -C(0)N(CI-C ₆ haloalkyl) ₂ , -C(0)NR ^{27 a} R ^{27 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci-C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _I~ C ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -S(0) ₂ N(C _] -C ₆ haloalkyl) ₂ , ~S(0) ₂ NR ^{27 a} R ^{27 b} ,~0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-0C(0)(Ci C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), - (H)C(0)(CrC ₆ haloalkyl), -N(CVC ₆ alkyl)C(0)H, ~N(CrC ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haioalkyl)C(0)(C rC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl),

-N(C _I -C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ a!k> l)S(OH ⁽ r,, haloalkyl), -NiC -Ce haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(C _I -C ₆ haloalkyl)S(0) ₂ (C _] -C ₆ haloalkyl);

wherein R ^{/ a} and R ^{27 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ⁴ is a substituent of the formula (A ⁴ ~h)

wherein

* represents the attachment point to the remainder of the molecule;

Z ^!0 is selected from the group consisting of CR ^{Z!0 I} R ^{Z10 2} , NR ^{Z10 2} , O, S, and -CR ^{zl! ,} =CR ^ZiiM -;

wherein

R ^Z1( is H or R ²⁹ ; and

Z ^u is selected from the group consisting of NR ^{ZI1 2} ; O, S, and -CR ^{zll 1} =CR ^{zl1 1} -;

wherein

R ^Zi is H or R ²⁹ ; and

R ^{Z11 2} is H or R ²⁹ ; R ²⁸ is hydrogen or R"· ⁹ , or R ²⁸ and R ^{Z10 2} are taken together to form a double bond between the carbon atom bearing R ²⁸ and Z ^!u ;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-Ce, alkyl), -0(Ci-C ₆ haloalky ), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , N1 !· ( ^' ···( .. alkyl), -NH(C _] -C ₆ haloalkyl), -N(C _I -C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) ₂ , -NR ^{29 a} R ^{29 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _J -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆

), I-C ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -Xi P }( (<>}!( >( ,. alkyl),

-N(H)C(0)(C rCe haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C _I -C ₆

alky )C(0)(C -C ₆ alkyl), -N(C _I -C ₆ alkyl)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(C C ₆ haloalkyl)C(0)(C ₁ -C ₆ alkyl), -N(C C ₆ haloalky 1)C(0)(C _r C ₆ haloalkyl), -0S(0) ₂ (C C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (C -C ₆ haloalkyd), NiC rC, alkyl)S(Q) ₂ (CrC ₆ alkyd), -N(C C ₆ alkyd)S(G) ₂ (Ci-C ₆ haloalkyl), -N(C C ₆ haloalky l)S(0) ₂ (Ci-C ₆ alkyl), and -N! ( >·<).

haloalliyd)S(O) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{29 3} and R ^{29 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x4 is 0, 1, 2, 3, or 4.

[0697] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 0, X ⁴ is CH, Y ⁴ is NR ^Y4 , R ^la and R ^lb are taken together to form an oxo (=0) substituent or an imido (=NH) substituent, and R ² ’ ³ and R ^2,b are taken together to form an oxo (~0) substituent; X ³ is CH. In some embodiments, Y ³ is a bond. In some embodiments, Y ³ is a NR ^Y . In some embodiments, R ^Y is hydrogen. In some embodiments, alkyd. In some embodiments, R^ ³ is methyl. In some embodiments, R ^Y3 is ethyl. In some embodiments, Y ^"3 is a (). In some embodiments, X ³ is N. In some embodiments, R ²¹³ and R ^21b are taken together to form an oxo (=0) substituent. In some embodiments, R ^zla and R ^21b are taken together to form an imido (=NH) substituent.

[0698] In some embodiments of the compounds of formula (11), (111), (IV), or (V), wherein m3 is 1 , n3 is 0, X ⁴ is CH, Y ⁴ is NR ^Y4 , R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent, and R ^3a and R ^z3b are taken together to form an oxo (=0) substituent; A ³ is Ce-Oo aryl optionally substituted with one or more R ^{2 '} substituent. In some embodiments, A ³ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[Q699] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 0, X ⁴ is CH, Y ⁴ is NR’ ⁴ , R ^zla and R ^zlb are taken together to form an oxo (=0) substituent or an imido (=NH) substituent, and R ^{2 a} and R ^{2 b} are taken together to form an oxo (=0) substituent; A ³ is 5-10 membered heteroaryl optionally substituted with one or more R ² ' substituent. In some embodiments, A ⁴ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0700] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 0, X ⁴ is CH, Y ⁴ is NR ^Y4 , R ^23a and R ^23b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent, and R ^3* and R ^z3b are taken together to form an oxo (=0) substituent; (A ⁴ ~b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ⁴ -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ⁴ -b) is selected from the group consisting of:

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ⁴ ~b) is selected from the group consisting of: ; wherein the * represents the attachment point to the remainder of the molecul

[0701] In some embodiments of the compounds of formula (II), (III), (IV), or (V):

m3 is 1 and n3 is 1;

Rf ^la and R ^“lb are taken together to form an oxo (=0) substituent or an imido ( ^: =NH) substituent;

A is C _fi -C o aryl optionally substituted with one or more R ' substituent, or 5-10

membered heteroaryl optionally substituted with one or more R ^{2 /} substituent;

R ²⁷ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -C ₆ haloalkyl, -OH, -0(Ci-C ₆ alkyl), 0(( rC,. haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(C _r C ₆ haloalkyl), -M l , -M-RCrCe aikv! } -Ni !(( ,-( ,, haloalkyl), -N(C C ₆ alkyl) ₂ , -N(CI-C ₆ haloalkyl)?, -NR ^{2 / a} R ^{2 , b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(C _r C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{27 a} R ^{27 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci-C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C]-C ₆ alkyl),

-S«)pM 1{C -C„ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -S(0) ₂ N(Ci-C ₆ haloalkyl)? alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(Q)(C C ₆ haloalkyl), -N(C -C ₆ alkyl)C(0)H, -N(CrC ₆ alkyi)C(0)iCi-C ₆ alkyl), -N(CI-C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, ~N(C _I~ C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haioalkyl)C(0)(C rC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl),

-N(CI-C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ a!k\ DSiOWOC,.

haloalkyl), -NiC -Ce haioalkyl)S(0) ₂ (CrC ₆ alkyl), and -N(C _I -C ₆ haloalkyl)S(Q) ₂ (CrC ₆ haloalkyl);

wherein R ^{/ a} and R ^{27 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heierocycle;

A ⁴ is Ce-Cio aryl optionally substituted with one or more R ⁹ substituent, or 5-10

membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -C ₆ haloalkyl, -OH, -0(Ci~C ₆ alkyl), -0(C _] -C ₆ haloalkyl), -SH, -S(C C ₆ alkyl), -S(C _r C ₆ haloalkyl), -NH¾ -NH(C I-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C _r C ₆ alkyi) ₂ , -N(C C ₆

wherein R ^{29 3} and R ^{29 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle; provided that:

when one of X ³ or X ⁴ is N, then r2 is 1 or 2 and s2 is 1 or 2; and

when R ^{2 ,a} and R ^{2 ,b} are taken together to form an oxo (==()) substituent, then R ^24a is -OH or -NH ₂ .

[0702] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R ^2ia and R ^2ib are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; X’ is CH. In some embodiments, Y ³ is a bond. In some embodiments, Y ³ is aNR ³ ( In some embodiments, R ^Y is hydrogen. In some embodiments, ^Y is CrC ₆ alkyl. In some embodiments, R ^{~ 3} is methyl. In some embodiments, R ^Y3 is ethyl. In some embodiments, Y ³ is a O.

[0703] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1 , n3 is 1, and R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; X ³ is N. In some embodiments, R ^{2 a} and R ^{2 b} are taken together to form an oxo (=0) substituent. In some embodiments, R ^zia and R ^zib are taken together to form an imido (=NH) substituent.

[Q7Q4] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is I, n3 is 1, and R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; X ⁴ is CH. In some embodiments, Y ⁴ is a bond. In some embodiments, Y ⁴ is aNR ²⁴ . In some embodiments, R ^Y4 is hydrogen. In some embodiments, R ^Y4 is Ci-Cs alkyl. In some embodiments, R ^Y<* is methyl. In some embodiments, R ^Y4 is ethyl. In some embodiments, Y ⁴ is a O. In some embodiments, R ^3a and R ^3b are taken together to form an oxo (=0) substituent and R ^24a is -OH or -NH ₂ . In some embodiments, R ^24a is -OH. In some embodiments, R ^4a is -NH ₂ . In some embodiments, R ^{2 a} and R ^{2 b} are taken together to form an imido (=NH) substituent. In some embodiments, R ^24a is hydrogen. In some embodiments, R ^4a is -OH. In some embodiments, R ^z4a is -NH _2. In some embodiments, R ^z3a and R ^z3b are both hydrogen. In some embodiments, R ^4a is hydrogen. In some embodiments, R ^24a is -OH. In some

embodiments, R ^24a is -NH ₂ .

[0705] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, ii3 is 1, and R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; X ⁴ is N. In some embodiments, R ^3a and R ^3b are taken together to form an oxo (=0) substituent and R ^24a is -OH or -NH ₂ . In some embodiments, R ^24a is -OH. In some embodiments, Rr“ is -NH ₂ . In some embodiments, R “ are taken together to form an imido (=NH) substituent. In some embodiments, R ^24a is hydrogen. In some embodiments, R ²⁴³ is -OH. In some embodiments, R ^4a is -NH ₂ . In some embodiments, R ²³³ and R ^23b are both hydrogen. In some embodiments, R ^4a is hydrogen. In some embodiments, R ^24a is -OH. In some embodiments, R ^z4a is -NH ₂ .

[Q7Q6] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; A ^J is Ce-Cio aryl optionally substituted with one or more R ^“ ' substituent. In some embodiments, A ³ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[Q7Q7] In some embodiments of the compounds of formula (II), (III), (TV), or (V), wherein m3 is i, n3 is 1, and R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; A ⁵ is 5-10 membered heteroaryl optionally substituted with one or more R ² ' substituent. In some embodiments, A ³ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0708] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; A ⁴ is CVCio aryl optionally substituted with one or more R ⁱ⁹ substituent. In some embodiments, A ⁴ is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule.

[O709] In some embodiments of the compounds of formula (II), (III), (IV), or (V), wherein m3 is 1, n3 is 1, and Il ^21a and Il ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent; A ⁴ is 5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent. In some embodiments, A ⁴ is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule.

[0710] In one aspect, provided is a compound of formula (X-l ):

or a pharmaceutically acceptable salt thereof;

wherein:

R ⁰ and R ³¹ are, independently of each other and independently at each occurrence, halogen;

x5 and x6 are independently of each other 0, 1, 2, 3, 4 or 5;

Q ¹ is selected from the group consisting of:

wherein * represents the point of atachment to the

moiety, and # represents the point of atachment to the

moiety; and

R and R ³³ are both hydrogen, or R’ ² and R ³³ are taken together to form an oxo (=0) substituent.

In some embodiments of the compounds of formula (X-l), Q ¹ is

are both hydrogen.

In some embodiments of the compounds of formula (X-l), Q ¹ is

, are taken together to form an oxo (=0) substituent.

odiments of the compounds of formula (X-l), Q ¹ is

[0714] In some embodiments of the compounds of formula (

[0715] In some embodiments of the compounds of formula (X-l), Q ¹ is [0716] In some embodiments of the compounds of formula (X-l), Q ¹ is

[0717] In some embodiments of the compounds of formula (X-l ), R’° and R ¹ are, independently of each other and independently at each occurrence, selected from fluoro and chloro.

[0718] In some embodiments of the compounds of formula (X-l), x5 and x6 are both 1. In some embodiments, x5 is 1 and x6 is 2. In some embodiments, x5 is 2 and x6 is 1. In some embodiments, x5 and x6 are both 2,

[0719] In one aspect, provided is a compound of formula (X-2):

or a pharmaceutically acceptable salt thereof;

wherein:

R ³⁴ and R ^' are, independently of each other and independently at each occurrence, halogen;

x7 and x8 are, independently of each other, 0, 1, 2, 3, 4, or 5;

A ⁵ is a 5-12 membered heteroaryl;

Q is selected from the group consisting of:

wherein * represents the point of attachment to the H moiety, and #

represents the point of attachment to the moiety;

R ^,b and R’ ' are both hydrogen, or R ³⁶ and R” are taken together to form an oxo (=0) substituent;

R ^S and R ³⁹ are both hydrogen, or R ³⁸ and R ⁹ are taken together to form a propylene

(-CH2-CH2-CH2-) moiety ; and

T ¹ is -CR ⁴⁰ R ⁴¹ - or S(=0) ₂ -, wherein R ⁴⁰ is selected from the group consisting of

hydrogen, -OH, and -NH ₂ ; and R ⁴¹ is hydrogen.

[O720] In some embodiments of the compounds of formula (X-2), Q ² is are both hvdroeen.

In some embodiments of the compounds of formula (X-2), Q is are taken together to form an oxo (= substituent.

[Q722] In some embodiments of the compounds of formula (X-2), Q ² is are both hydrogen.

[0723] In some embodiments of the compounds of formula (X-2), Q ² is , are taken together to form an oxo (=0) substituent. [Q724] In some embodiments of the compounds of formula (X-2), Q ² is

are both hydrogen. In some embodiments, T ³ is -CR ⁴⁰ R ⁴¹ -. In some embodiments, T ⁴ is -CR ⁴⁰ R ⁴¹ -, and R ⁴⁰ is selected from the group consisting of hydrogen, -OH, and -NH ₂ ; and R ⁴¹ is hydrogen. In some embodiments, T ¹ is - CR ⁴⁰ R ⁴¹ -, R ⁴⁰ is hydrogen and R ⁴¹ is hydrogen. In some embodiments, T ¹ is -CR ⁴ °R ⁴¹ -, R ⁴⁰ is -OH, and R ⁴¹ is hydrogen. In some embodiments, T ¹ is -CR ⁴⁰ R ⁴³ -, R ⁴⁰ is -NH ₂ , and R ⁴¹ is hydrogen. In other embodiments, T ¹ is S(=0) ₂ -.

[0725] In some embodiments of the compounds of formula (X-2), Q ² is

, are taken together to form a propylene (-CH ₂ -

CH2-CH2-) moiety. In some embodiments, T ¹ is -CR ⁴⁰ R ⁴¹ -. In some embodiments, T ¹ is - CR ⁴⁰ R ⁴¹ -, and R ⁴⁰ is selected from the group consisting of hydrogen, -OH, and ~NH ₂ ; and R ⁴¹ is hydrogen. In some embodiments, T ¹ is -CR ⁴ °R ⁴¹ -, R ⁴⁰ is hydrogen and R ⁴³ is hydrogen. In some embodiments, T ¹ is -CR ⁴⁰ R ⁴³ -, R ⁴⁰ is -OH, and R ⁴ ' is hy drogen. In some embodiments, T ¹ is -CR ⁴⁰ R ⁴¹ -, R ⁴⁰ is -NH ₂ , and R ⁴¹ is hydrogen. In other embodiments, T ¹ is S( ^: =0) ₂ -.

[0726] In some embodiments of the compounds of formula (X-2), R ⁴ and R ⁵ are, independently of each other and independently at each occurrence, selected from fluoro and chioro.

[0727] In some embodiments of the compounds of formula (X-l ), x7 and x8 are both 1. In some embodiments, x7 is 1 and x8 is 2. In some embodiments, x7 is 2 and x8 is 1. In some embodiments, x7 and x8 are both 2.

[Q728] ln one aspect, provided is a compound of formula (X-3):

or a pharmaceutically acceptable salt thereof;

wherein:

R ^4“ and R ⁴³ are, independently of each other and independently at each occurrence,

halogen;

x9 and xlO are, independently of each other, 0, 1, 2, 3, 4, or 5;

R ⁴⁴ and R ⁴³ are both hydrogen, or R ^'*'* and R ⁴⁵ are taken together to form an ethylene t ~Ci I ~Ci 1 -) moiety;

A ⁶ is a 5-12 membered heteroaryl;

A' is (A-Cio aryl or 5-12 membered heteroaryl;

Q ^J is selected from the group consisting of:

wherein * represents the point of attachment to the moiety, and # represents the point of attachment to the moiety: and

provided that one of (i) or (n) applies:

O

[0729] In some embodiments of the compounds of formula (X-3), q3 is 0, Q ³ is and A ⁷ is 5-12 membered heteroaryl.

O

[Q73Q] In some embodiments of the compounds of formula (X-3), q3 is 1 , Q ³ is

or OH , and A' is C ₆ -C _lo aryl. In some embodiments of the compounds of formula

compounds of formula (X-3), q3 is I, Q ³ is OH , and A ⁷ is Ce-Cio aryl. In some embodiments, A' is phenyl.

[0731] In some embodiments of the compounds of formula (X-3), R ⁴⁴ and R ⁴⁵ are both hydrogen. In some embodiments of the compounds of formula (X-3), R ⁴⁴ and R ⁴⁵ are taken together to form an ethylene (-CH ₂ -CH ₂ -) moiety .

[0732] In some embodiments of the compounds of formula (X-3), R ⁴² and ⁴ⁱ are, independently of each other and independently at each occurrence, selected from fluoro and chloro.

[0733] In some embodiments of the compounds of formula (X-3), x9 and xlO are both 1. In some embodiments, x9 is 1 and xlO is 2. In some embodiments, x9 is 2 and xlO is 1. In some embodiments, x9 and xlO are both 2.

[Q734] In one aspect, provided is a compound of formula (X-4):

or a pharmaceutically acceptable salt thereof; wherein:

R ⁴ ° and R ⁴ ' are, independently of each other and independently at each occurrence, halogen;

x 11 and x!2 are, independently of each other, 0, 1, 2, 3, 4, or 5;

R ⁴⁸ is hydrogen or -OH;

Q ⁴ is selected from the group consisting of:

wherein * represents the point of attachment to the

moiety, and # represents the point of attachment to the

are,

independently of each other, hydrogen or C -C ₆ alkyl.

hyl,

56 53

and R R ⁵² , R ³³ , R ³⁴ , R ³³ , and R ³⁰ are all hydrogen. In some embodiments, R ³³ and R ³³ are both

C -Ce alkyl, and R ⁴⁹ , R ⁵⁰ , R”, R ^3z , R ⁵⁴ , and R ⁵⁶ are all hydrogen. In some embodiments, R ³ and R ⁵⁵ are both methyl, and R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ³² , R ³⁴ , and R ⁵⁶ are all hydrogen. In some embodiments, R ⁴⁹ , R ³ °, R ⁵¹ , and R ³² are all Ci-C ₆ alkyl, R ⁵³ , R ³⁴ , R ³³ , and R ³⁶ are all hydrogen. In some embodiments, R ⁴⁹ , R ⁵⁰ , R ⁵¹ , and R ³² are all methyl, R ⁵³ , R ⁵⁴ , R ³³ , and R ^3b are all hydrogen. In some embodiments, R ⁴⁹ , R ⁵⁰ , R ³ , and R ³² are all hydrogen, R ⁵³ , R ³⁴ , R ³³ , and R ⁵ " are ail C .-Cc, alkyl. In some embodiments, R ⁴⁹ , R ⁵⁰ , R ⁵¹ , and R ⁵ " are all hydrogen, R ⁵ , R ⁵⁴ , R ⁵⁵ , and R ⁵⁶ are all methyl. In some embodiments, R ⁴⁹ , R ⁵⁰ , R ⁵¹ , R ³² , R ⁵³ , R ⁵⁴ , R ⁵⁵ , and R ³⁰ are all hydrogen.

[Q736] In some embodiments of the compounds of formula (X-4), Q ⁴ is

. In some embodiments, R ³ ', R ⁵⁸ , R ⁵⁹ , and R ⁶⁰ are all CrCg alkyl . In some embodiments, R ⁵ ', R ³⁸ , R ⁵⁹ , and R ⁶⁰ are all methyl. In some embodiments, R ⁵⁷ and R ⁵⁹ are both C -Ce alkyl, and R ⁵⁸ and R ^o0 are both hydrogen. In some embodiments, R ^{3 /} and R ⁵⁹ are both methyl, and R ⁵⁸ and R ⁶⁰ are both hydrogen. In some embodiments, R ⁵⁷ , R ⁵⁸ , R ³⁹ , and R ^o0 are all hydrogen.

[0737] In some embodiments of the compounds of formula (X-4), Q ⁴ is

, , , R ⁶³ , and R ⁶⁴ are all Ci-C ₆ alkyl . In some embodiments, R ⁶ⁱ , R ^b2 , R ⁶³ , and R ⁶⁴ are all methyl. In some embodiments, R ⁶¹ and R ⁶³ are both C -Ce alkyl, and R ⁶² and R° ⁴ are both hydrogen. In some embodiments, R ⁶ ‘ and R ⁶² are both methyl, and R ⁶² and R ⁶⁴ are both hydrogen. In some embodiments, R ⁶¹ , R ^u2 , R ⁶³ , and R° ⁴ are all hydrogen.

[0738] In some embodiments of the compounds of formula (X-4), R ⁴⁸ is hydrogen.

[0739] In some embodiments of the compounds of formula (X-4), R ⁴⁸ is -OH.

[0740] In some embodiments of the compounds of formula (X-4), R ⁴⁶ and R ⁴⁷ are, independently of each other and independently at each occurrence, selected from fluoro and chloro. [0741] In some embodiments of the compounds of formula (X-4), xl 1 and x 12 are both 1. In some embodiments, xl 1 is 1 and x!2 is 2. In some embodiments, xl 1 is 2 and x!2 is 1. In some embodiments, xl l and xl2 are both 2.

In one aspect, pro vided is a compound of formula (X-5):

(X-5)

or a pharmaceutically acceptable salt thereof;

wherein:

R ⁶⁵ and R ⁶⁶ are, independently of each other and independently at each occurrence, halogen;

xl3 and x! 4 are, independently of each other, 0, 1 , 2, 3, 4, or 5;

Q ^' is selected from the group consisting of:

wherein * represents the point of attachment to the

moiety, and # represents the

point of attachment to the moietv;

R ⁶ ' and R ⁶⁸ are both hydrogen, or R ^{b /} and R ⁶⁸ are taken together to form an imino (=NH) substituent; and

R ⁶⁹ is hydrogen or -NH?. [Q743] In some embodiments of the compounds of formula (

[0744] in some embodiments of the compounds of formula (

some embodiments, R ⁶ ' and R ⁶⁸ are both hydrogen, and R ⁶⁹ is hydrogen or -NH ₂ . In some embodiments, R ⁶ ' and R ⁸ are both hydrogen, and R ⁹ is hydrogen. In some embodiments, R ⁶ ' and R ^b8 are both hydrogen, and R ^b9 is -NH ₂ . In some embodiments, R ⁶⁷ and R° ⁸ are taken together to form an imino (=NH) substituent, and R° ⁹ is hydrogen or -NH ₂ . In some embodiments, R ⁶⁷ and R ⁶⁸ are taken together to form an imino (=NH) substituent, and R ⁶⁹ is hydrogen. In some embodiments, R ⁶ ' and R ⁶⁸ are taken together to form an imino ί Ni l ) substituent, and R ⁶⁹ is-NH .

[0745] In some embodiments of the compounds of formula (X-5), R ⁶⁵ and R ⁶⁶ are, independently of each other and independently at each occurrence, selected from fluoro and chi or o.

[0746] In some embodiments of the compounds of formula (X-5), x!3 and xl4 are both 1. In some embodiments, xl3 is 1 and xl4 is 2. In some embodiments, xl3 is 2 and xl4 is 1. In some embodiments, x! 3 and x !4 are both 2.

[0747] In one aspect, provided is a compound of formula (X-6):

CX-6)

or a pharmaceutically acceptable salt thereof;

wherein:

R ⁷⁰ and R ⁷¹ are, independently of each other and independently at each occurrence, halogen;

x!5 and x! 6 are, independently of each other, 0, 1, 2, 3, 4, or 5; n4 is 1 or 2;

T ² is O or NH; and

A ⁸ is a 5-12 membered heteroaryl.

[0748] In some embodiments of the compounds of formula (X-6), n4 is 1.

[0749] In some embodiments of the compounds of formula (X-6), n4 is 2.

[0750] In some embodiments of the compounds of formula (X-6), T ² is O.

[0751] In some embodiments of the compounds of formula (X-6), T ² is NH.

[0752] In some embodiments of the compounds of formula (X-5), R ⁷⁰ and R' ¹ are, independently of each other and independently at each occurrence, selected from fluoro and chi or o.

[0753] In some embodiments of the compounds of formula (X-5), xl 5 and xl6 are both 1. In some embodiments, xl5 is 1 and xl6 is 2. In some embodiments, xl5 is 2 and xl6 is 1. In some embodiments, xl5 and xl6 are both 2.

[0754] In one aspect, provided is a compound of formula (X-7):

(X-7)

or a pharmaceutically acceptable salt thereof;

wherein:

R ⁷² and R ⁷³ are, independently of each other and independently at each occurrence, halogen;

xl 7 and xl 8 are, independently of each other, 0, I , 2, 3, 4, or 5;

A ⁹ is a 5-12 membered heteroaryl; and

A ^1u is a 5-12 membered heteroaryl;

provided that A ⁹ and A ¹⁰ are not both simultaneously a moiety selected from group consisting of:

epresents the attachment point to the remainder of the molecule.

[0755] In some embodiments of the compounds of formula (X-7), R ⁷² and R' ³ are, independently of each other and independently at each occurrence, selected from fluoro and chloro.

[Q756] In some embodiments of the compounds of formula (X-7), xl 7 and x 18 are both 1.

In some embodiments, xl 7 is 1 and xl 8 is 2. In some embodiments, xl 7 is 2 and xl 8 is 1. In some embodiments, x!7 and xl8 are both 2.

[0757] In one aspect, pro vided is a compound of formula (X-8):

or a pharmaceutically acceptable salt thereof;

wherein:

R' ⁴ and R ° are, independently of each other and independently at each occurrence, halogen;

xl9 and x20 are, independently of each other, 0, 1, 2, 3, 4, or 5;

A ¹¹ is C _ft -Cio aryl or 5-12 membered heteroaryl;

Q° is selected from the group consisting of:

(R ⁷⁴ ) _{x-j c}

wherein * represents the point of attachment to the

moiety, and # represents the point of attachment to the -A ¹¹ -( ' ^: ’) _X2 o moiety

T is O or NR;

Ί is O or NR;

R' ⁶ is selected from hydrogen, -OH, and -NH ₂ ;

R' ' is selected from hydrogen, -OH, and -NH ₂ ;

R' ^s is hydrogen or -OH; and

provided that one of (i) or (ii) applies:

(i) when A ^{1 1} is C ₆ -C _lo ar l, Q ⁶ is selected from the group consisting of:

(ii) when A ¹¹ is 5-12 membered heteroaryl,

[0758] In some embodiments of the compounds of formula (X-8), A ¹¹ is Ce-Cio aryl, and Q ⁶ is selected from the group consisting of:

[0759] In some embodiments of the compounds of formula (X-8), A ¹¹ is C0-C10 aryl, and Q°

some embodiments, A ¹¹ is phenyl.

[0760] In some embodiments of the compounds of formula (X-8), A ¹¹ is C y-Cio aryl, and Q ⁶

some embodiments, R ⁷⁶ is hydrogen. In some embodiments, R' ^b is -OH. In some embodiments, R' ⁶ is -NH ₂ . In some embodiments, A ¹¹ is phenyl. [0761] In some embodiments of the compounds of formula (X-8), A 11 is Ce,-Cio aryl, and Q'

,

embodiments, R ^{? ?} is -OH In some embodiments, R" is NH?. In some embodiments, A ¹¹ is phenyl.

e compounds of formula (X-8), A ¹¹ is C ₆ -Cio and, and some embodiments, A is phenyl.

[0764] In some embodiments of the compounds of formula (X-8), A ¹¹ is C C _{J O} aryl, and Q ⁶

In some embodiments, T is O. In some embodiments, T ⁴ is

NH. In some embodiments. A ¹¹ is phenyl

11

[0765] In some embodiments of the compounds of formula (X-8), A is Cg-Cio and, and Q

some embodiments, T ⁴ is O. In some embodiments, T ⁴ is

NH. In some embodiments, A is phenyl. [0766] In some embodiments of the compounds of formula (X-8), A ¹¹ is 5-12 membered

heteroaryl,

[0767] In some embodiments of the compounds of formula (X-8), A ¹¹ is 5-12 membered

heteroaryl,

In some embodiments of the compounds of formula (X-8), A ¹¹ is 5-12 membered

heteroaryl, . In some embodiments, R' ⁸ is hydrogen. In some embodiments, R' ⁸ is-QH

[0769] In some embodiments of the compounds of formula (X-8), R ' ⁴ and R ⁷⁵ are, independently of each other and independently at each occurrence, selected from fluoro and chloro.

[0770] In some embodiments of the compounds of formula (X-8), x!9 and x20 are both 1. in some embodiments, xi9 is 1 and x20 is 2. In some embodiments, xl9 is 2 and x20 is 1. In some embodiments, x!9 and x20 are both 2.

[0771] In one aspect, provided is a compound of formula (X-9):

or a pharmaceutically acceptable salt thereof;

wherein:

R' ⁹ and R ⁸⁰ are, independently of each other and independently at each occurrence, halogen; x21 and x22 are, independently of each other, 0, 1 , 2, 3, 4, or 5;

A ¹² is Ce-C o aryl or 5-12 membered heteroaryl;

Q-' is selected from the group consisting of:

wherein * represents the point of attachment to the

moiety , and # represents the point of attachment to the -A ^lz -(R ^8t ') _X 22 moiety; T ⁵ is O or NH;

T ⁶ is O or NH;

R ⁸¹ is selected from hydrogen, -OH, and -NH ₂ ;

R ⁸ is selected from hydrogen, -OH, and M 1 ·:

R ⁸⁵ is hydrogen or -OH; and

provided that one of (i) or (ii) applies:

(i) when A ¹² is Ce-Cio aryl, Q' is selected from the group consisting of:

(ii) when A ¹² is 5-12 membered heteroaryl,

[Q772] In some embodiments of the compounds of formula (X-9), A ¹² is Ce.-Cio aryl, and Q' is selected from the group consisting of:

[0773] In some embodiments of the compounds of formula (X-9), A ¹² is Cg-Cio an , and Q '

some embodiments, R ⁸¹ is hydrogen in some embodiments, R ^8! is selected from -OH. In some embodiments, R ⁸ ’ is selected from -NH _2. In some embodiments, A ¹² is phenyl.

[Q774] In some embodiments of the compounds of formula (X-9), A ¹² is Ce.-Cio aryl, and Q' . In some embodiments, R ⁸² is hydrogen. In some embodiments, R ^S is selected from -OH. in some embodiments, R ⁸² is selected from -NH ₂ . In some embodiments, A ¹² is phenyl.

[0775] In some embodiments of the compounds of formula (X-9), A ¹² is C0-C10 aryl, and Q '

In some embodiments, A ¹² is phenyl. [0776] In some embodiments of the compounds of formula (X-9), A ¹² is Ce.-Cio aryl, and Q'

some embodiments. T ³ is O. In some embodiments, T is

NH. In some embodiments, A is phenyl.

e compounds of formula (X-9), A ¹² is C ₆ -Cio aryl, and Q

some embodiments. T° is O. In some embodiments. ’ is

NH. In some embodiments, A ¹² is phenyl.

[0778] In some embodiments of the compounds of formula (X-9), A ¹² is 5-12 membered

heteroaryl,

[0779] In some embodiments of the compounds of formula (X-9), A ¹ " is 5-12 membered

heteroaryl,

In some embodiments of the compounds of formula (X-9), A ¹² is 5-12 membered

heteroaryl, In some embodiments, R ⁸³ is hydrogen. In some embodiments, R ⁸³ is-QH

[0781] In some embodiments of the compounds of formula (X-9), R ^'9 and R ⁸⁰ are, independently of each other and independently at each occurrence, selected from fluoro and chloro. [Q782] In some embodiments of the compounds of formula (X-9), x2l and x22 are both 1. In some embodiments, x2l is 1 and x22 is 2. In some embodiments, x2 l is 2 and x22 is 1. In some embodiments, x2l and x22 are both 2.

[0783] In one aspect, provided is a compound of formula (XX):

or a pharmaceutically acceptable salt thereof;

wherein:

X ⁵ is CH or N;

Y ^J is selected from the group consisting of a bond, NR ^Y5 , and O; provided that when X ⁵ is N, then Y ⁵ is a bond;

R' is hydrogen or Ci-C ₆ alkyl;

R ^N is hydrogen or C -C ₆ alkyl;

m ⁴ , n ⁵ , p ³ , and q ⁴ , independently of each other, are 0 or 1 ;

r3 and s3, independently of each other, are 0, 1 , or 2;

A ¹ is selected from the group consisting of:

C, Cio aryl optionally substituted with one or more R ^9J substituents; and 5-10 membered heteroaryl optionally substituted with one or more R ⁹⁵

substituents;

R ⁹⁵ is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, C C ₆ haloalkyl, -OH, -0(C ₃ -C ₆ alkyl), -0<C ₃ -C ₆ haloalkyi), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(C C ₆ aihvi f-Xi haloalkyl), -N(Ci- C ₆ alkyl) ₂ , -N(CI-C ₆ haloalkyl) , -NR ^{95 3} R ^{95 b} , -CN, -C(0)0H, -C(0)0(C]-C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(C _] -C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(C ₃ -C ₆ alkyl) _? , -C(0)N(C ₃ -C ₆ haloalkyl) , -C(0)NR ^{95 a} R ^{95 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _I -C ₆ alkyl), -S(0) ₂ 0(Ci~C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(C _I -C ₆ alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyl), -S<0) _. .\{C _r C _I alkyl) ₂ , -S(0) ₂ N(C _I -C ₆ haloalkyl) _? . alkyl),

-()( ( OK ( -( ,, haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl)

haloalkyl), -N(C C ₆ alkyl)C(0)H, AiC _r( ^' , alkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ alk}'l)C(0)(Ci-C ₆ haloalkyl), -N(C -C ₆ haloalkyl)C(0)H, -N(CrC ₆

haioalkyl)C(0)(CrC ₆ alkyl), -N(CrC ₆ haioalkyl)C(0)(CrC ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (C ₁ -C ₆ alkyl),

-N(H)S(0) ₂ (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyJ)S(0) ₂ (Ci-C ₆ alkyl), -\iC _r C,, alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), haloaikyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(CI-C ₆ haloalliy'l)S(0) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{95 a} and R ^{95 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^84a and R ^84b are independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

R ^S5a and R ^85b are independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

when present, R ^86a and R ^86b are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R ^87a and R ^87b are independently at each occurrence selected from the group consisting of hy drogen, Ci-Ce alkyl, and halogen;

or, R ^84a and R ^85a are taken together to form a Ci-Ce, alkylene moiety;

or, R ^84a and an R ^86a moiety , when present, are taken together to form a C -Ce alkylene moiety;

or, an R ^8oa moiety, when present, and an R ^8/a moiety, when present, are taken together to form a Ci-C ₆ alkydene moiety ;

R ⁸⁸ is selected from the group consisting of hydrogen, C -C _f , alkyl, C -C ₆

haloalkyl, -C(0)(Ci-C ₆ alkyl), -C(0)(C ₃ -C ₆ haloalkyl), -C(0)0H, -C(0)0(Ci-C ₆ alkyl), ~C(0)0(Ci~C ₆ haloalkyl), -C(0)NH ₂ , -( ^' {OVM Kί ,-G,, alkyl),

~C(0)NH(CrC ₆ haloalkyl), -C(0)N(C _I~ C ₆ alk\l) ₂ , -C(G)N(C _I~ C ₆ haloalkyl) ₂ , -C(0)NR ^{ss a} R ^{88 b} , -S(0) _? 0H, -S(0) ₂ 0(Ci-C ₆ alkyl), -S(0) ₂ 0(C C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(CI-C ₆ alkyl), -S(0) ₂ NH(C C ₆ haloalkyl), -S(0) ₂ N(CrC ₆ alkyl) ₂ , -S(0) ₂ N(Ci-C ₆ haloalkyl) ₂ , and -SiO) A R ^{KK :!} R ^{KS h} :

wherein R ^{ss a} aid R ^{88 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ⁸⁹ is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, C -Ce alkyl, C -Ce haloalkyl, -OH, -0(C _] -C ₆ alkyl), -QlCrCc, haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(CI-C ₆ alkyl), -NH(C C ₆ haloalkyl), -N(CI-C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) ₂ , -NR ^{89 a} R ^{89 b} , -CN, -C(0)0H,

-H OKK (VC,, alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(C _] -C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{89 a} R ^89b , -S(0) ₂ 0H, -S(0) ₂ 0(CrC ₆ alkyl), -SiOkOKVC, haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _I -C ₆ alkyl), -S(0) ₂ NH(CrC ₆ haloalkyl), -S(0) ₂ N(C _I -C ₆ ally I k. -S(0) ₂ N(Ci-C ₆ haloalkyl) ₂ , -S(0) ₂ NR ^{89 a} R ^{89 b} 0C(0)H, -0C(0)(Ci-C ₆ alkyl), -0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(0)(CrC ₆ haloalkyl), alkyl)C(0)H, -N(C C ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N( alkyl)C(0)(Ci-C ₆ haloalkyl), -N(CI-C ₆ haloalkyi)C(0)H, -N( ⁽ _r C, haloalkyl)C(0)(Ci-C ₆ alkyl), -NiCi-Ce

haloalkyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆

haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C _I~ C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ aHyd)S(0) ₂ (CrC ₆ haloalkyl), -N(C C ₆ haloaikyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(Ci-C ₆ haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl); wherein R ^{s a} and R ^{89 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

when present, R ^90a and R ^90b are taken together to form an oxo (==()) substituent or an

imido (=NH) substituent, or alternatively, R ^90a and R ^90b are both hydrogen;

when present, R ^9la is selected from the group consisting of hydrogen, -GR ^{1a a} , and - \R ^i|::b R ^{'' i3} V

when present, R ^91b is hydrogen:

or alternatively, R ⁹¹³ and R ^9lb are taken together to form a moiety selected from the

group consisting of -0-CH ₂ -CH ₂ -, -CH ₂ -G-CH _2~ , -CH _2~ CH _2~ 0-, -0-CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -O-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -O-CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -O-, -O-CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH2-O-CH2-CH2-CH2-, -CH2-CH2-O-CH2-CH2-, -CH2-CH2-CH2-O-CH2-, and -CH2-CH2-CH2-CH2-O-;

when present, R ^92a and R ^92b are both hydrogen;

when present, R ^{9 a} and R ^{9 b} are taken together to form an oxo (=0) substituent, or

alternatively, R ^93a and R ^93b are both hydrogen;

R ^{9! a a} is selected from the group consisting of hydrogen, CiAty alkyl, and CVC _f , haloalkyl; or R ^{9l3 3} and R ^Y5 may be taken together to form a carbonyl (0=0) moiety; and

R ^{91a b} and R ^{a c} , independently of each other, are selected from the group consisting of hydrogen, C -Ce alkyl, and O-Ce haloalkyl;

provided that when m ⁴ is 0, n ³ is 0, and q ⁴ is 0, then A ¹³ is a substituent of formula (A ^l3 -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁴ is selected from the group consisting of CR ^Zl4_1 R ^{Z14 2} , NR ^{Z14 2} ,

wherein R ^Zl4_l is hydrogen or R ^l6 ; and R ^{ZI4 2} is hydrogen or R ⁹⁵ ·

Z ¹⁵ is selected from the group consisting of CR ²¹⁵ ^ ²¹³

wherein R ^Zl3_1 is hydrogen or R ⁹ ’; and R ^{Z15 2} is hydrogen or R ⁹⁵ ; Z ¹⁶ , independently at each occurrence, is CH, CR ⁹³ , or N;

R ⁹⁴ is hydrogen or R ⁹⁵ , or R ^a and R ^{Z14 2} are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ^!4 , or R ^9’ and R ^{Z15 Z} are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ¹³ ; and

x23 is 0, 1, 2, 3, or 4.

In some embodiments of the compounds of formula (XX):

X ⁵ is CH or N; Y ³ is selected from the group consisting of a bond, NR ^Y5 , and O; provided that when X ³ is N, then Y ³ is a bond;

R ^Y5 is hydrogen or Ci-C _& alkyl;

R ^N is hydrogen or Ci-Ce alkyl;

nr, n ⁵ , p ³ , and q ⁴ , independently of each other, are 0 or 1;

r3 and s3, independently of each other, are 0, 1, or 2;

A ¹³ is selected from the group consisting of:

Cg-Cio aryl optionally substituted with one or more R ⁹⁵ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ⁹⁵

substituents;

R ⁹³ is selected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, CrCe haloalky!, -OH, -0(Ci-C ₆ alkyl), -0(Ci-Ce ha!oa!kyl), -SH, -S(Ci~ C _ft alkyl), S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CVC6 alkyl),-NH(C _] -C6 haloalkyl), -N(Cr C ₆ alkyl) _? ., -N(C _I -C ₆ haloalkyl) ₂ , - alkyl), -C(0)0(Ci-C ₆ haloalkyl) alkyl), -C(0)NH(Ci-C ₆ haloalkyl), ~C(0)N(C C ₆ alkyl) _? , ~C(0)N(C C ₆ haloalkyl) _? , -C(0)NR ^{95 3} R ^9Yb , -S(0) _? 0H, -S(0) _? 0(CrC ₆ alkyl), -S(0) _? 0(CrC ₆ haloalkyl), -S(0) _? NH _? ,

-S(0) _? NH(CrC ₆ alkyl), -S(0) ₂ NH(C _r C ₆ haloalkyl), -S(0) _? N(C C ₆ alkyl) _? ,

-S(0) _? N(C _I -C ₆ haloalkyl) _? alkyl), -0C(0)(C _r C ₆ haloalkyl), -N(H)C(OJH, -N(H)C(0)(C C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C C ₆ alkyl)C(0)(CrC ₆ alkyl), -N(C C ₆ aik\ i )( (()}·; ( -( ,, haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CJ-C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyl),

-0S(0)?(Ci-C ₆ alkyl), -0S(0)?(Ci-C ₆ haloalkyl), -N(H)S(0)?(Ci-C ₆ alkyl),

-N(H)S(0) _? (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0)?(C ₁ -C6 alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci~C ₆ haloalkyl), ~\(C ~C,·, haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -N(C -C ₆ haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ^{95 3} and R ^{95 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^84a and R ^S4b are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen; R ^85a and R ^85b are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R ^Sba and R ^Sbb are independently at each occurrence selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

when present, R ' and R ' are independently at each occurrence selected from the group consisting of hydrogen, C -C ₆ alkyl, and halogen;

or, R ^84a and R ^85a are taken together to form a Ci-Ce alkylene moiety;

or, R ^84a and an R ^86a moiety, when present, are taken together to form a Ci-Ce alkylene moiety;

or, an R ^8oa moiety, when present, and an R ^{8 /a} moiety, when present, are taken together to form a C -C alkylene moiety;

R ⁸⁸ is selected from the group consisting of hydrogen, CrC ₆ alkyl, CrCe

haloalkyl, -C(0)(C _] -C ₆ alkyl), -C(0)(Ci-C ₆ haloalkyl), -C(0)0H, -C(0)0(Ci-C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(C C ₆ alkyl) ₂ , -C(0)N(C C ₆ haloalkyl) ₂ , alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _I -C ₆ alkyl), -S(0) ₂ NH(C C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyfty -S(0) ₂ N(Ci-C ₆ haloalkyl) ₂ , and -S(0) ₂ NR ^{88 a} R ^{88 b} ;

wherein R ^{88 3} and R ^{88 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ⁸⁹ is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, Ci~C ₆ alkyl, Ci-C ₆ haloalkyl, -OH, -()(( ]-( ^' ,. alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CI-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C i-C ₆ alkyl) ₂ , -N! ( >·< ,. haloalkyl) _? ., -NR ^{89 a} R ^{89 b} , -CN, -C(0)0H, -C(0)0(CrC ₆ alkyl), -C(0)0(C ₁ -C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alktyK -C(0)N(Ci-C ₆ haloalkyl) ₂ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , SiO) _? i(Cx-C _e alkyl), -S(0) ₂ NH(C C ₆ haloalkyl),

-S(0) ₂ N(CrC ₆ alkyl)?, -S(0) ₂ N(Ci~C ₆ haloalkyl) _? , -S(0) ₂ NR ^{89 a} R ^{89 b} ,-0C(0)H, -0C(0)(C -C ₆ alkyl), -0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(0)(C _I -C ₆ haloalkyl), -NiCVCY. alkyl)C(0)H, -N(C C ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(CI-C ₆ hal oalkyl)C(0)H, -N(C C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆

haloalkyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci~C ₆

haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -N VC, alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ ally i)S(OHi C,, haloalkyl), -\!( ₍ ,, haloalk l)S(0) ₂ (Ci~C ₆ alkyl), and -N(C _I -C ₆ haJoalkyl)S(0) ₂ (CrC ₆ haloalkyl); wherein R ^{89 a} and ll ^{89 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

when present, R ^90a and R ^90b are taken together to form an oxo (=0) substituent or an

imido (=NH) substituent, or alternatively, R ^90a and R ^90b are both hydrogen;

when present, R ^91a is selected from the group consisting of hydrogen, -OR ^91a_a , and - NR ^91a~b R ^{91a c} ;

when present, R ^9lb is hydrogen;

or alternatively, R ^{9 ,a} and ll ^{9 ,b} are taken together to form a moiety selected from the

group consisting of -0-CH ₂ -CH ₂ -, -Ci h-O-Ci l·-. -CH ₂ -CH ₂ -0-, -0-CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -O-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -O-CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -O-, -O-CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -0-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -0-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -0-CH ₂ -, and

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -0-;

when present, R ^92a and R ^92b are both hydrogen;

when present, R ^93a and R ^93b are taken together to form an oxo (=0) substituent, or

alternatively, R ^93a and R ^93b are both hydrogen;

R ^{91a a} is selected from the group consisting of hydrogen, Ci-Ce alkyl, and CrC ₆ haloalkyl; or R ^{ia a} and R ^Ya may be taken together to form a carbonyl (0=0) moiety; and

R ^{9la b} and R ^{9 ,a c} , independently of each other, are selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Cs haloalkyl;

provided that when m ⁴ is 0, n ^s is 0, and q ⁴ is 0, then p ^J is 1 and A ¹³ is a substituent of formula (A ^l3 ~a)

wherein

* represents the attachment point to the remainder of the molecule; r!4 is selected from the group consisting of CR ^Zl41 R ^Z]42 , NR ,Z14-2

wherein R ^{Z 4_1} is hydrogen or R ⁶ ; and R ^Z142 is hydrogen or R ⁹⁵ ; Z ¹⁵ is selected from the group consisting of CR ^{Z i} R ^Z152 , NR ^l52 ,

C (R ^{z 151} R ^{z 152} ) N (R ^{z 152} ) , O, C(R ^Z151 R ^Z152 )0, S. C<R ^/I R ^/I< "’)S.

and -CR ^Z151 =CR ^z151 -:

wherein ^ «Z15-1 is hydrogen or R”; and R ^Z152 is hydrogen or R ^’

Z ¹⁶ , independently at each occurrence, is CH, CR ⁹⁵ , or N;

R ⁹⁴ is hy drogen or R ⁹⁵ , or R ⁹⁴ and R ^Z142 are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ¹⁴ , or R ^9'* and R ^zl32 are taken together to form a doubl e bond between the carbon atom bearing R ⁹⁴ and Z ¹⁵ ; and

x23 is 0, 1, 2, 3, or 4.

[Q785] In some embodiments, the compound of formula (XX) is a compound of formula

(XX-I)

or a pharmaceutically acceptable salt thereof;

wherein R ^N , R ^Y5 , m ⁴ , n ⁵ , pi q ⁴ , r3, s3, A ¹³ , R ^84a , R ^84b , R ^85a , R ^85b , R ^86a , R ^86b , R ^87a , R ^87b , R ⁸⁸ , R ⁸⁹ , R ^90a , R ^wb , R ^91a , R ^9lb , R ⁹²³ , R ^92b , R ^93a , and R ^93b are as defined for the compounds of formula (XX).

In some embodiments, the compound of formula (XX) is a compound of formula

(XX-II)

or a pharmaceutically acceptable salt thereof;

wherein R ^N , m ⁴ , n ⁵ , p ³ , q ⁴ , r3, s3, A ¹³ , R ^84a , R ^m , R ^8Sa , R ^85b , R ^86a , R ^m , R ^87a R ^87b , R ⁸⁸ , R ⁸⁹ , R ^90a , R ^90b , R ^9ia , R ^91b , R ^92a R ^/b , R ^93a , and R ^93b are as defined for the compounds of formula (XX).

ts of the compounds of formulae (XX), (XX-1), and (XX-11), the

wherein # represents the attachment point to the remainder of

the molecule, wherein # represents the attachment point to the remainder of the molecule.

[0788] In some embodiments, the compound of formula (XX) or the compound of formula (XX-I) is a compound of formula (XX-I-1 ):

(CC-ί-1)

or a pharmaceutically acceptable salt thereof;

wherein R ^N , R’ R ⁸⁸ , R ⁸⁹ , R ^93a , and R ^93b are as defined in the compounds of formula (XX), and wherein A ¹ is a substituent of formula (A ¹³ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁴ is selected from the group consisting of CR ^{Zl4 l} R ^{Z14 2} , NR ^{214 2} ,

wherein R Z ⁷ 14 ⁴ -J ¹ is hydrogen or R ^G ; and R ^l4 is hydrogen or i 95. Z.) ' is selected from the group consisting of CR ^{z , i} R ^{215 2} , NR ^{Z! 5 2} ,

wherein R ² * ^{5 1} is hydrogen or R ⁹⁵ ; and R ^{215 2} is hydrogen or R ⁹⁵ ; Z ¹⁶ , independently at each occurrence, is CH, CR ⁹⁵ , or N;

R ⁹⁴ is hydrogen or R ⁹⁵ , or R ⁹⁴ and R ^{Z14 2} are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ¹⁴ , or R ⁹⁴ and R ^{211 2} are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ¹⁵ ;

x23 is 0, 1, 2, 3, or 4; and

R ³ is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, Ci-tX haloalkyl, -OH, -OfC -Ce alkyl), -OiC i-C,. haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(Ci-Ce alkyl),-NH(Ci-C ₆ haloalkyl), -N(C -C ₆ alkyl) , -N(Ci-C ₆ haloalkyl) ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , ~i i O}M !{( VCV alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alky 1 ) ·. -C(0)N(Ci-C ₆ haloally 1 alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) _? NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(0) ₂ NH(C _I -C ₆ haloalkyl), -S(0) _? N(Ci~C ₆ alkyl) ₂ , haloally. I ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ ally !),

-N(H)C(0)(C _I -C ₆ haloalkyl) alkyl)C(0)H, -N(C _I -C ₆

alkyl)C(0)(Ci-C ₆ alkyl), Lί ⁽ _G ^(' ·. alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C _I -C ₆ haloalkyl)C(0)H, -N(C _J -C ₆ haloalkyl)C(0)(C -C ₆ alkyl), -N(C _J -C ₆ haloalkyl)C( ⁽⁾ )(CrC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) _? (C ₁ -C ₆ haloalkyl),

-N(C _I -C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -\{i _r C„ alkyl)S(0) _? (Ci-C ₆ haloalkyl), -N(CrC ₆ haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(C _I -C ₆ haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl).

[0789] In some embodiments of the compounds of formula (CC-I-G), R ^N is hydrogen or Ci~

Ce alkyl. In some embodiments of the compounds of formula (XX-1- is hydrogen.

[Q79Q] In some embodiments of the compounds of formula (XX-1-1), R ^Y5 is hydrogen or Ci-

Ce alkyl. In some embodiments of the compounds of formula (XX-I-l), R ^Y5 is hydrogen.

[0791] In some embodiments of the compounds of formula (XX-I-l), R ⁸⁸ is hydrogen, C -Cg alkyl, or Ci-C _f , haloalkyl. In some embodiments, R ⁸⁸ is hydrogen.

[0792] In some embodiments of the compounds of formula (XX-I-l), R ⁸⁹ is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, Ci-Cg alkyl, and Ci-Cg haloalkyl. In some embodiments of the compounds of formula (XX-I-l ), R ⁸⁹ is, independently at each occurrence, hydrogen or halogen. In some embodiments, R ⁸⁹ is, independently at each occurrence, hydrogen, fluoro or chloro. In some embodiments, one R ⁸⁹ is chloro and the remaining R ⁸⁹ substituents are hydrogen. [Q793] In some embodiments of the compounds of formula (XX-I-1), R ^{9 a} and R ^{9 b} are taken together to form an oxo (=0) substituent. In some embodiments of the compounds of formula (XX-I-1), R ⁹³³ and R ^93b are both hydrogen.

[0794] In some embodiments of the compounds of formula (XX-I-1), (A ⁱ³ -a) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ¹³ -a) is selected from the group consisting of:

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A ^L, -a) is selected from the group consisting of: wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, is ; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, wherein the represents the attachment point to the remainder of the molecule.

[0795] In some embodiments of the compounds of formula (XX-I-1), the moiety

, , r of the molecule.

[Q796] In some embodiments, the compound of formula (XX) or the compound of formula (XX-I) is a compound of formula (XX-I-2):

or a pharmaceutically acceptable salt thereof;

wherein R ^N , R ^Y5 , A ^l , R ⁸⁸ , and R ^8y are as defined m the compounds of formula (XX). [Q797] In some embodiments of the compounds of formula (XX-I-2), R ^N is hydrogen or Ci- alkyl. In some embodiments of the compounds of formula (XX-I-2), R ^N is hydrogen.

[0798] In some embodiments of the compounds of formula (XX-I-2), R’ is hydrogen or C - C ₆ alkyl. In some embodiments of the compounds of formula (XX-I-2 hydrogen.

[0799] In some embodiments of the compounds of formula (XX-I-2), R ⁸⁸ is hydrogen, Ci-C ₆ alkyl, or C -C ₆ ha!oalkyl. In some embodiments, R ⁸⁸ is hydrogen.

[0800] In some embodiments of the compounds of formula (XX-I-2), R ⁸⁹ is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and CrC ₆ haloalkyl. In some embodiments of the compounds of formula (XX-I-2), R ⁸⁹ is, independently at each occurrence, hydrogen or halogen. In some embodiments, R ⁸⁹ is, independently at each occurrence, hydrogen, fluoro or chloro. In some embodiments, one R ⁸⁹ is chioro and the remaining R ⁸⁹ substituents are hydrogen.

[0801] In some embodiments of the compounds of formula (XX-I-2), A ³ is selected from the group consisting of C ₆ -C _l4 aryl optionally substituted with one or more R ⁹ ’ substituents; and 5-14 membered heteroaryl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, aryl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, A ¹³ is Ce-Cio aryl optionally substituted with one or more R ^w substituents.

wherein the * represents the attachment point to the remainder of the mol ecule. In some embodiments, A ¹ is phenyl optionally substituted with one or more R ⁹⁵ substituents. In some

embodiments, A ¹³ is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^l is the * represents the attachment point to the remainder of the

molecule. In some embodiments. A ^L ’ is the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ ' is naphthyl optionally substituted with one or more R” substituents. In some embodiments. A ¹³ is selected

from the group consisting of ; wherein the

* represents the attachment point to the remainder of the molecule. In some embodiments, A ¹³ wherein the * represents the attachment point to the remainder of the

molecule. In some embodiment: wherein the * represents the attachment point to the remainder of the molecule.

[0802] In some embodiments of the compounds of formula (XX-I-2), A ¹³ is 5-14 membered heteroaryl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments. A ¹³ is 5-10 membered heteroaiyl optionally substituted with one or more R ⁹³ substituents. In some embodiments, A 13 is selected from the group consisting wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹ ’ is pyridyl optionally

substituted with one or more R ⁹⁵ substituents. In some embodiments,

wherein the * represents the attachment point to the remainder of the mol ecule. In some embodiments, A ^{5 3} is quinoimyl optionally substituted with one or more A ¹ ’ substituents. In

some embodiments, A ¹³ is selected from the group consisting of ; and ; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, A ^l is wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ³ is and ; wherein the * represents the attachment point to the remainder of the molecule. odiments of the compounds of formula (XX-I-2), the moiety

, wherein # represents the attachment point to the remainder of the

molecule, i , wherein # represents the attachment point to the remainder of the molecule.

[0804] In some embodiments, the compound of formula (XX) or the compound of formula (XX-I) is a compound of formul a (XX-I-2b):

(XX-I-2b)

or a pharmaceutically acceptable salt thereof;

wherein R ^N , R ^' . A ¹³ , R ⁸⁸ , and R ⁸⁹ are as defined m the compounds of formula (XX).

[Q8Q5] In some embodiments of the compounds of formula (XX-l-2b), R ^N is hydrogen or Ci-

Ce alkyl. In some embodiments of the compounds of formula (XX-I-2b), R ^N is hydrogen.

[Q8Q6] In some embodiments of the compounds of formula (XX-I-2b), R ^Y5 is hydrogen or Ci-C _f , alkyl. In some embodiments of the compounds of formula (XX-I-2b), R ^Y: is hydrogen.

[0807] In some embodiments of the compounds of formula (XX-I-2b), R ⁸⁸ is hydrogen, CV

C ₆ alkyl, or C -C ₆ haloalkyl. In some embodiments, R ⁸⁸ is hydrogen. [Q8Q8] In some embodiments of the compounds of formula (XX-I-2b), R ^s9 is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, C]-C ₆ alkyl, and Ci-C _f , ha!oalkyl. In some embodiments of the compounds of formula (XX-I-2b), R ⁸⁹ is, independently at each occurrence, hydrogen or halogen. In some embodiments, R ⁸⁹ is, independently at each occurrence, hydrogen, fluoro or chloro. In some embodiments, one R ⁸⁹ is chloro and the remaining R ⁸⁹ substituents are hydrogen.

[0809] In some embodiments of the compounds of formula (XX-I-2b), A ^{! 3} is selected from the group consisting of Cg-CA aryl optionally substituted with one or more ⁹³ substituents; and 5-14 membered heteroaryl optionally substituted with one or more R ⁹³ substituents. In some embodiments, A ^{5 3} is C C _M aryl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, A ^l is Ce-C-.o aryl optionally substituted with one or more R ⁹⁵ substituents.

In some embodiments, A ^l is selected from the group consisting of ·

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹³ is phenyl optionally substituted with one or more R ⁹⁵ substituents. In some

embodiments, A ^{1 3} is selected from the group consisting

; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, A ^l is ; wherein the * repress

attachment point to the remainder of the molecule. In some embodiments, A ^{5 3} is ; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, A ¹ ’ is ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ^l is naphthyl optionally substituted with one or more R ⁹³ substituents. In some embodiments. A ¹³ is selected

from the group consisting of ; wherein the

* represents the attachment point to the remainder of the molecule. In some embodiments, A ^! wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, 13 is wherein the * represents the attachment point to the remainder of the molecule.

[0810] In some embodiments of the compounds of formula (XX-I-2b), A ¹³ is 5-14 membered heteroaiyi optionally substituted with one or more R ⁹³ substituents. In some embodiments, A ¹³ is 5-10 membered heteroaryl optionally substituted with one or more R ⁹³ substituents. In some embodiments, A” is selected from the group consisting of ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments. A ¹³ is pyridyl optionally substituted with one or more substituents. In some embodiments. A ¹³ is ; wherein the * represents the attachment point to the remainder of th* molecule. In some embodiments, A ^l is quinolinyl optionally substituted with one or more A substituents. In some embodiments, A ¹³ is selected from the group consisting of wherein the * represents the attachment

point to the remainder of the molecule. In some embodiments, A ^l is

wherein the * represents the attachment point to the remainder of the molecule. In some

embodiments, wherein the * represents the attachment point to the remainder of the molecule.

[0811] In some embodiments of the compounds of formula (XX-I-2b), the moiety

, , r of the molecule.

[0812] In some embodiments, the compound of formula (XX) or the compound of formula (XX-T) is a compound of formula (XX-T-3):

or a pharmaceutically acceptable salt thereof;

wherein R ^N , R ^¾5 , A ¹⁸ , R ⁸⁸ , and R ⁸⁹ are as defined in the compounds of formula (XX);

R _t 9 ^y 1 ⁱ a ^a is selected from the group consisting of hydrogen, and -NR ^{y a} a-b ^i:! Rr ^: 91a-c.

R > 91 ⁱ a ^a -a ^a is selected from the group consisting of hydrogen, C]-C ₆ alkyl, and Ci-Ce lialoalkyl; or R ^{93a a} and R ^Y ’ may he taken together to form a carbonyl (0=0) moiety; and

R ^{91a b} and R ^9ia~L , independently of each other, are selected from the group consisting of hydrogen, Ci-Cr, alkyl, and Ci-C ₆ haloalkyl.

[0813] In some embodiments of the compounds of formula (XX-I-3), R is hydrogen or Ci- Ce alkyl. In some embodiments of the compounds of formula (XX-I-3), R ^N is hydrogen.

[0814] In some embodiments of the compounds of formula (XX-I-3), R ³ is hydrogen or Ci- Ce alkyl. In some embodiments of the compounds of formula (XX-I-3), R' ^' is hydrogen.

[0815] In some embodiments of the compounds of formula (XX-I-3), R ^8B is hydrogen, Ci-C ₆ alkyl, or Ci-Cs haloalkyl. In some embodiments, R ⁸⁸ is hydrogen.

[0816] In some embodiments of the compounds of formula (XX-I-3), R ⁸⁹ is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, Ci-Ce alkyl, and Cj-Ce haloalkyl. In some embodiments of the compounds of formula (XX-I-3), R ⁸⁹ is, independently at each occurrence, hydrogen or halogen. In some embodiments, R ⁸⁹ is, independently at each occurrence, hydrogen, fluoro or chloro. In some embodiments, one R ⁸⁹ is chloro and the remaining R ⁸⁹ substituents are hydrogen.

[0817] In some embodiments of the compounds of formula (XX-I-3), R ^9ia is hydrogen or -0R ^{91a a} . In some embodiments, R ^9ia is hydrogen. In some embodiments, R ^9ia is -0R ^{y3a a} , wherein R ^{9 a a} is selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and Ci-Ce haloalkyl; or R ^{1a a} and R ^Y3 may be taken together to form a carbonyl (C=0) moiety'. In some embodiments, R ^9!a is -0R ^{91a a} , wherein R ^{91a a} is hydrogen. [0818] In some embodiments of the compounds of formula (XX-I-3), A ¹³ is selected from the group consisting of Ce-Cw aryl optionally substituted with one or more R ⁹⁵ substituents; and 5-14 membered heteroaryl optionally substituted with one or more R ⁹ ’ substituents. In some embodiments, A ¹³ is C ₆ -C _l4 aryl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, A ¹³ is Cs-C o ary! optionally substituted with one or more R ³ substituents.

In some embodiments, A ¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹³ is phenyl optionally substituted with one or more R ⁹⁵ substituents. In some

embodiments, A ¹³ is selected from the group consisting

and wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments. A ¹³ is ; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments. ; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments. A ¹³ is naphthyl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, A ¹ 1 ³ 3 is selected from the group consisting of ; wherein the

* represents the attachment point to the remainder of the molecule. In some embodiments, A”

IS wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, A ^l is wherein the * represents the attachment point to the remainder of the molecule

In some embodiments of the compounds of formula (XX-I-3), A ¹³ is 5-14 membered heteroaryl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, A ⁵ is 5-10 membered heteroaryl optionally substituted with one or more R ⁹⁵ substituents. In some

embodiments, A ⁵³ is selected from the group consisting

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments. A ¹³ is pyridyl optionally

substituted with one or more R ⁹³ substituents. In some embodiments,

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹³ is quinolinyl optionally substituted with one or more A ¹³ substituents. In

some embodiments, A ¹ ’ is selected from the group consisting of and ; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, A ^l is wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ⁵ is and ; wherein the * represents the attachment point to the remainder of the molecule.

[0820] In some embodiments of the compounds of formula (CC-Ϊ-3), the moiety

, r of the molecule.

[0821] In some embodiments, the compound of formula (XX) or the compound of formula (XX-1) is a compound of formula (XX-11-3):

or a pharmaceutically acceptable salt thereof;

wherein R ^N , R ^{Y J} , A ¹³ , R ⁸⁸ , and R ⁸⁹ are as defined in the compounds of formula (XX);

R ^91a is selected from the group consisting of hydrogen, -OR ^{91a a} , and NR ^{9ia b} R ^{91a c} ;

R ^{91a a} is selected from the group consisting of hydrogen, Cj-Ce alkyl, and Ci-Ce haloalkyl; or R ^{9i3 3} and R’ may be taken together to form a carbonyl (C=0) moiety; and

R ^{9l3 b} and R ^{9*3 0} , independently of each other, are selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and C1-C6 haloalkyl.

[0822] In some embodiments of the compounds of formula iXX-H-3). R is hydrogen or Ci~ Ce alkyl. In some embodiments of the compounds of formula (XX-II-3), R is hydrogen.

[0823] In some embodiments of the compounds of formula (XX-II-3), R ^ss is hydrogen, C·,- C , alkyl, or Ci-C ₆ haloalkyl. In some embodiments, R ⁸⁸ is hydrogen.

[Q824] In some embodiments of the compounds of formula (XX-II-3), R ^s9 is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, C]-C ₆ alkyl, and Ci-Ce haloalkyl. In some embodiments of the compounds of formula (XX-II-3), R ⁸⁹ is, independently at each occurrence, hydrogen or halogen. In some embodiments, R ⁸⁹ is, independently at each occurrence, hydrogen, fluoro or chloro. In some embodiments, one R ⁸⁹ is chloro and the remaining R ⁸⁹ substituents are hydrogen.

[0825] In some embodiments of the compounds of formula (XX-II-3), R ^91a is hydrogen or -OR ^{91a a} In some embodiments, R ^9ia is hydrogen. In some embodiments, R ^9ia is -OR ^{913 3} , wherein R ^{913 3} is selected from the group consisting of hydrogen, CrCe alkyl, and CrC ₆ haloalkyl; or R ^{913 3} and R ^Y5 may be taken together to form a carbonyl (C=0) moiety . In some embodiments, R ⁹¹³ is -OR ^{913 3} , wherein R ^{91a 3} is hydrogen. [Q826] In some embodiments of the compounds of formula (CC-P-3), A ¹³ is selected from the group consisting of Ce-Cw aryl optionally substituted with one or more R ⁹⁵ substituents; and 5-14 membered heteroaryl optionally substituted with one or more R ⁹ ’ substituents. In some embodiments, A ¹³ is C6-C _l4 aryl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, A ¹³ is C^-Cio aryl optionally substituted with one or more R ³ substituents.

In some embodiments, A ¹³ is selected from the group consisting of

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹³ is phenyl optionally substituted with one or more R ⁹⁵ substituents. In some

embodiments, A ¹³ is selected from the group consisting

; and wherein the * represents the attachment point to the remainder of the

attachment point to the remainder of the molecule. In some embodiments. A ¹³ is ; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, A ¹³ is represents the attachment point to the remainder of the molecule. In some embodiments. A ¹³ is naphthyl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, A ^l is selected from the group consisting of ; wherein the

* represents the attachment point to the remainder of the molecule. In some embodiments, A”

IS wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, A ^l is wherein the * represents the attachment point to the remainder of the molecule

[0827] In some embodiments of the compounds of formula (XX-II-3), A ¹³ is 5-14 membered heteroaryl optionally substituted with one or more R ⁹⁵ substituents. In some embodiments, A ⁵ is 5-10 membered heteroaryl optionally substituted with one or more R ⁹⁵ substituents. In some

embodiments, A ⁵³ is selected from the group consisting

; wherein the * represents the attachment point to the remainder of the molecule. In some embodiments. A ¹³ is pyridyl optionally

substituted with one or more R ⁹³ substituents. In some embodiments,

wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ¹³ is quinolinyl optionally substituted with one or more A ¹³ substituents. In

some embodiments, A ¹ ’ is selected from the group consisting of and ; wherein the * represents the attachment point to the remainder of the

molecule. In some embodiments, A ^l is wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, A ⁵ is and

,

molecule, , wherein # represents the attachment point to the remainder of the molecule.

[0829] In the descriptions herein, it is understood that every description, variation, embodiment or aspect of a moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every' description, variation, embodiment or aspect provided herein with respect to X ¹ of formula (I) may be combined with every' description, variation, embodiment or aspect of m ^‘ , nr, n , n , p ^‘ , p , q , qri r, s, X , Y ^‘ ,

Y ² , A ¹ , A ² , R ^ia , R , R , R , R ^3a , R ^b , R ^4a , R ^4b , R ^Sa , Rty R ^ua , R ^bb , R' ^a , R' ^b , R ^8a , R ^8b , R ^9a , R R ^10a , R ^10b , R ^{l la} , R ^{l lb} , R ^12a , and R ^i/b the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments or aspects of formula (1), where applicable, apply equally to any of formulae (1-1), (1-2), (1-3), (1 -4), (2-2), (2-3), (2-4), (3-3), (3-4), and (4-4) detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. Similarly, every description, variation, embodiment or aspect pro vided herein with respect to X ³ of formula (II) may be combined with every description, variation, embodiment or aspect of m ³ , n ^J , r ² , s ² , X ⁴ , Y ³ , Y ^'* , A ³ , A ⁴ , R ^{1 ,a} , R ^17b , the same as if each and every combination were specifically and individually listed. It is also understood that ail descriptions, variations, embodiments or aspects of formula (II), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for ail formulae. For example, ail descriptions, variations, embodiments or aspects of formula (II) where applicable, apply equally to any of formulae (III), (IV), and (V) detailed herein, and are equally described, the same as if each and every description, variation. embodiment or aspect were separately and individually listed for all formulae. Similarly, every description, variation, embodiment or aspect provided herein with respect to X ^s of formula (XX) may be combined with every description, variation, embodiment or aspect of R ^N , Y ⁵ , IY5 , m 4

R ^92a , R ^9zb , R ^93a , and R ^{9 ,b} the same as if each and ever ' combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (XX), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments or aspects of formula (XX) where applicable, apply equally to any of formulae (XX-I), (XX-II), (XX-I-1), (XX-I-2), (XX-I-2b), (XX-I-3), and (XX-II-3) detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. [Q83Q] Also provided are salts of compounds referred to herein, such as pharmaceutically acceptable salts. The present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described. Thus, if a particular stereochemical form, such as a specific enantiomeric form or diastereomeric form, is depicted for a given compound, then it is understood that any or ail stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of that same compound are herein described and embraced by the invention.

[0831] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1% or 0.5% impurity .

[0832] In some embodiments, provided is compound selected from compounds m Table 1, or a stereoisomer, tautomer, solvate, prodrug or salt thereof. Although certain compounds described in Table 1 are presented as specific stereoisomers and/or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of Table 1 are herein described.

Pharmaceutical Compositions and Formulations

[0833] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a salt thereof and a pharmaceutically acceptable earner or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

[0834] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.

[Q835] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically accep table carrier. In another variation, methods of administering a compound are provided.

The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[Q836] A compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g , nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0837] One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable earner, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition,

pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 ^th ed. (2000), which is incorporated herein by reference.

[Q838] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable earners for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emul gators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0839] Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a salt thereof can be formulated as a 10 mg tablet.

[0840] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.

Methods of Use and Uses

[0841] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays

[0842] Provided herein is a method of treating a disease or disorder in an individual m need thereof comprising administering a compound describes herein or any embodiment, variation, or aspect thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound, pharmaceutically acceptable salt thereof, or composition is administered to the individual according to a dosage and/or method of administration described herein.

[0843] The compounds or salts thereof described herein and compositions described herein are believed to be effective for treating a variety of diseases and disorders. In some

embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating a disease or disorder mediated by an integrated stress response (ISR) pathway. In some embodiments, the disease or disorder is mediated by eukaryotic translation initiation factor 2a (eIF2a) or eukaryotic translation initiation factor 2B (elF2B). In some embodiments, the disease or disorder is mediated by phosphorylation of eIF2a and/or the guanine nucleotide exchange factor (GEF) activity of eIF2B.

[Q844] In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating a disease or disorder, wherein the disease or disorder is a neurodegenerative disease, an inflammatory disease, an autoimmune disease, a metabolic syndrome, a cancer, a vascular disease, a musculoskeletal disease (such as a myopathy), an ocular disease, or a genetic disorder.

[0845] In some embodiments, the disease or disorder is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is vanishing white matter disease, childhood ataxia with CNS hypomyelination, intellectual disability syndrome, Alzheimer’s disease, prion disease, Creutzfe!dt-iakob disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) disease, Pelizaeus-Merzbacher disease, a cognitive impairment, a traumatic brain injury, a postoperative cognitive dysfunction (PCD), a neuro-otological syndrome, hearing loss, Huntington’s disease, stroke, chronic traumatic encephalopathy, spinal cord injury, dementia, frontotemporal dementia (FTD), depression, or a social behavior impairment. In some embodiments, the cognitive impairment is triggered by ageing, radiation, sepsis, seizure, heart attack, heart surgery, liver failure, hepatic encephalopathy, anesthesia, brain injury, brain surgery , ischemia, chemotherapy, cancer treatment, critical illness, concussion, fibromyalgia, or depression. In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is ageing-related cognitive impairment. In some embodiments, the neurodegenerative disease is a traumatic brain injury.

[0846] In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating Alzheimer’s disease. In some

embodiments, neurodegeneration, cognitive impairment, and/or amyloidogenesis is decreased.

[Q847] In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the inflammatory disease is arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, asthma, allergic asthma, bronchial asthma, tuberculosis, chronic airway disorder, cystic fibrosis, glomerulonephritis, membranous nephropathy, sarcoidosis, vasculitis, ichthyosis, transplant rejection, interstitial cystitis, atopic dermatitis, or inflammatory bowel disease. In some embodiments, the inflammatory' bowel disease is Crohn’ disease, ulcerative colitis, or celiac disease.

[0848] In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, or rheumatoid arthritis.

[0849] In some embodiments, the disease or disorder is a metabolic syndrome. In some embodiments, the metabolic syndrome is alcoholic liver steatosis, obesity', glucose intolerance, insulin resistance, hyperglycemia, fatty liver, dyslipiderma, hyperlipidemia,

hyperhomocysteinemia, or type 2 diabetes.

[0850] In some embodiments, the disease or disorder is a cancer. In some embodiments, the cancer is pancreatic cancer, breast cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, urothelial cancer, endometrial cancer, ovarian cancer, cervical cancer, renal cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), multiple myeloma, cancer of secretory cells, thyroid cancer, gastrointestinal carcinoma, chronic myeloid leukemia, hepatocellular carcinoma, colon cancer, melanoma, malignant glioma, glioblastoma, glioblastoma multiforme, astrocytoma, dysplastic gangliocytoma of the cerebellum, Ewing’s sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, ductal adenocarcinoma, adenosquamous carcinoma, nephroblastoma, acinar cell carcinoma, neuroblastoma, or lung cancer. In some embodiments, the cancer of secretory cells is non-Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmacytoma, lymphoplasmacytic lymphoma or acute lymphoblastic leukemia.

[0851] In some embodiments, the disease or disorder is a musculoskeletal disease (such as a myopathy). In some embodiments, the musculoskeletal disease is a myopathy, a muscular dystrophy, a muscular atrophy, a muscular wasting, or sarcopenia. In some embodiments, the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker’s disease, myotonic dystrophy, X-hnked dilated cardiomyopathy, spinal muscular atrophy (SMA), or metaphyseal chondrodysplasia, Schmid type (MCDS). In some embodiments, the myopathy is a skeletal muscle atrophy. In some embodiments, the musculoskeletal disease (such as the skeletal muscle atrophy) is triggered by ageing, chronic diseases, stroke, malnutrition, bedrest, orthopedic injury, bone fracture, cachexia, starvation, heart failure, obstructive lung disease, renal failure, Acquired Immunodeficiency Syndrome (AIDS), sepsis, an immune disorder, a cancer, ALS, a bum injury, denervation, diabetes, muscle disuse, limb immobilization, mechanical unload, myositis, or a dystrophy.

[0852] In some embodiments, the disease or disorder is a genetic disorder, such as Down syndrome or MEHMO syndrome (Menial retardation, Epileptic seizures, Hypogenitalism, Microcephaly, and Obesity).

[0853] In some embodiments, a compound or salt thereof described herein or a composition described herein may be used in a method of treating musculoskeletal disease. In some embodiments, skeletal muscle mass, quality and/or strength are increased. In some

embodiments, synthesis of muscle proteins is increased. In some embodiments, skeletal muscle fiber atrophy is inhibited.

[Q854] In some embodiments, the disease or disorder is a vascular disease. In some embodiments, the vascular disease is atherosclerosis, abdominal aortic aneurism, carotid artery disease, deep vein thrombosis, Buerger’s disease, chronic venous hypertension, vascular calcification, telangiectasia or lymphoedema.

[0855] In some embodiments, the disease or disorder is an ocular disease. In some embodiments, the ocular disease is glaucoma, age-related macular degeneration, inflammatory retinal disease, retinal vascular disease, diabetic retinopathy, uveitis, rosacea, Sjogren's syndrome, or neovascularization in proliferative retinopathy. [Q856] In some embodiments, provided herein is a method of inhibiting an ISR pathway.

The compounds or salts thereof described herein and compositions described herein are believed to be effective for inhibiting an ISR pathway. In some embodiments, the method of inhibiting an ISR pathway comprises inhibiting the ISR pathway in a cell by administering or delivering to the cell a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the method of inhibiting an ISR pathway comprises inhibiting the ISR pathway in an individual by administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Inhibition of the ISR pathway can be determined by methods known in the art, such as western blot, immunohistochemistry, or reporter cell line assays.

[0857] In some embodiments, the inhibition of the ISR pathway comprises binding eIF2B

In some embodiments, the inhibition of the ISR pathway comprises increasing protein translation, increasing guanine nucleotide exchange factor (GEF) activity of eIF2B, delaying or preventing apoptosis in a cell, and/or inhibiting translation of one or more mRNAs comprising a 5’ untranslated region (5’UTR) comprising at least one upstream open reading frame (uORF).

[0858] In some embodiments, provided herein are methods of increasing protein production using a compound or salt described herein. The protein production is increased relative to the same condition without the compound or salt. Protein production can be increased either in vivo or in vitro. For example, protein production can be increased in vivo by administering the compound or salt to an individual. In some embodiments, protein production is increased in vitro using the compound or salt with a cell-free protein synthesis system (CFPS) or a cell-based protein expression system. The protein produced can be a heterologous protein (e.g., a recombinant protein) or a native protein. Heterologous protein production can be achieved using a recombinant nucleic acid encoding the protein. In some embodiments, the protein produced is an antibody or a fragment thereof. Other exemplary proteins can include, but are not limited to, enzymes, allergenic peptides or proteins (for example, for use as a vaccine), recombinant protein, cytokines, peptides, hormones, erythropoietin (EPO), interferons, granulocyte-colony stimulating factor (G-CSF), anticoagulants, and clotting factors. The increase in protein production can be determined by methods known in the art, such as western blot or immunohistochemistry. [Q859] Cell-free protein synthesis (CFPS) systems are generally known, and include cellular machinery for protein expression in an in vitro environment. In some embodiments, the CFPS system includes a cellular extract (such as a eukaryotic cellular extract), which includes protein expression machinery. In some embodiment, the cellular machinery' in the CFPS system comprises eukaryotic cellular machinery', such as eukaryotic initiation factor 2 (eIF2) and/or eukaryotic initiation factor 2B (eIF2B), or one or more subunits thereof.

[0860] In some embodiments, there is a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with a compound or salt as described herein. In some embodiments, the protein is an antibody or a fragment thereof. Other exemplary' proteins can include, but are not limited to, enzymes, allergenic peptides or proteins (for example, for use as a vaccine), recombinant protein, cytokines, peptides, hormones, erythropoietin (EPO), interferons, granulocyte-colony stimulating factor (G-CSF), anticoagulants, and clotting factors. In some embodiments, the CFPS system comprises a cell extract comprising the eIF2. In some embodiments, the CFPS system further comprises eIF2B

[0861] In some embodiments, there is a method of producing a protein, comprising contacting a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with a compound or salt thereof as described herein. In some embodiments, the protein is an antibody or a fragment thereof. Other exemplary' proteins can include, but are not limited to, enzymes, allergenic peptides or proteins (for example, for use as a vaccine), recombinant protein, cytokines, peptides, hormones,

erythropoietin (EPO), interferons, granulocyte-colony stimulating factor (G-CSF),

anticoagulants, and clotting factors. In some embodiments, the CFPS system comprises a cell extract comprising the eIF2. In some embodiments, the CFPS system further comprises eIF2B. In some embodiments, the method comprises purifying the protein.

[0862] In some embodiments, there is a method of producing a protein, comprising contacting a eukaryotic cell comprising a nucleic acid encoding the protein with a compound or salt as described herein. In some embodiments, the method comprises culturing the cell in an in vitro culture medium comprising the compound or salt. In some embodiments, the nucleic acid encoding the protein is a recombinant nucleic acid. In some embodiments, the eukaryotic cell is a human embryonic kidney (HEK) cell or a Chinese hamster ovary (CHO) cell in other embodiments, the eukaryotic ceil is a yeast ceil (such as Saccharomyces cerevisiae or Pichia pastoris), a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell (such as a HeLa cell), a baby hamster kidney cell (such as BHK21 cells), a murine myeloma cell (such as NSO or Sp2/0 cells), an HT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood derived leukocyte. In some embodiments, the protein is an antibody or a fragment thereof. Other exemplary proteins can include, but are not limited to, enzymes, allergenic peptides or proteins (for example, for use as a vaccine), recombinant protein, cytokines, peptides, hormones, erythropoietin (EPO), interferons, granulocyte-colony stimulating factor (G- CSF), anticoagulants, and cloting factors. In some embodiments, the method comprises purify ing the protein.

[0863] In some embodiments, there is a method of culturing a eukaryotic cell comprising a nucleic acid encoding a protein, comprising contacting the eukaryotic cell with an in vitro culture medium comprising a compound or salt as described herein. In some embodiments, the nucleic acid encoding the protein is a recombinant nucleic acid. In some embodiments, the eukaryotic cell is a human embryonic kidney (HEK) cell or a Chinese hamster ovary' (CHO) cell. In other embodiments, the eukaryotic cell is a yeast cell (such as Saccharomyces cerevisiae or Pichia pastoris), a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell (such as a HeLa cell), a baby hamster kidney cell (such as BHK21 cells), a murine myeloma cell (such as NSO or Sp2/0 cells), an HT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood derived leukocyte. In some embodiments, the protein is an antibody or a fragment thereof. Other exemplary proteins can include, but are not limited to, enzymes, allergenic peptides or proteins (for example, for use as a vaccine), recombinant protein, cytokines, peptides, hormones, erythropoietin (EPO), interferons, granulocyte-colony stimulating factor (G-CSF), anticoagulants, and clotting factors. In some embodiments, the method comprises purifying the protein.

[0864] In some embodiments, there is an in vitro cell culture medium, comprising the compound or salt described herein, and nutri ents for cellular growth. In some embodiments, the culture medium comprises a eukaryotic cell comprising a nucleic acid encoding a protein. In some embodiments, the culture medium further comprises a compound for inducing protein expression. In some embodiments, the nucleic acid encoding the protein is a recombinant nucleic acid. In some embodiments, the protein is an antibody or a fragment thereof. Other exemplary' proteins can include, but are not limited to, enzymes, allergenic peptides or proteins (for example, for use as a vaccine), recombinant protein, cytokines, peptides, hormones,

erythropoietin (EPO), interferons, granulocyte-colony stimulating factor (G-CSF),

anticoagulants, and dotting factors. In some embodiments, the eukaryotic cell is a human embryonic kidney (HEK) cell or a Chinese hamster ovary' (CHO) cell. In other embodiments, the eukaryotic cell is a yeast cell (such as Saccharomyces cerevisiae or Pichia pastor is), a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell (such as a HeLa cell), a baby hamster kidney cell (such as BHK21 cells), a murine myeloma cell (such as NSO or Sp2/0 cells), an HT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood derived leukocyte.

[0865] In some embodiments, provided herein is a method of increasing protein translation in a cell or cell free expression system. In some embodiments, the cell was stressed prior to administration of the compound, salt thereof, or composition. In some embodiments, protein translation is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 100%, 125%, 150%, 175%, 200%, 250%, or 300% or more. In some embodiments, protein translation is increased by about 10% to about 300% (such as about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 125%, about 125% to about 150%, about 150% to about 175%, about 175% to about 200%, about 200% to about 250%, or about 250% to about 300%) In some embodiments, protein translation is increased as compared to prior to the administration of the compounds, salt thereof, or composition. In some embodiments, protein translation is increased as compared to an unstressed cell, a basal condition where cells are not subjected to a specific stress that activates the ISR In some embodiments, protein translation is increased as compared to a stressed cell where ISR is active.

[0866] Some of the compounds described herein increase protein synthesis in a cell without full inhibition of ATF4 translation, under ISR-stressed or non-ISR stressed conditions.

Exemplary compounds include compound 150, compound 153, and compound 30, or a salt thereof. Despite ATF4 participation in various pathologies, the ATF4 protein is an important factor for restoring cellular homeostasis m stressed ceils, for example during oxidative stress response, cholesterol metabolism, protein folding amino acid synthesis, and autophagy. Thus, for certain treatments, it may be preferable to limit ATF4 inhibition. In some embodiments, the compound is used to increase protein synthesis by about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, about 125% or more, about 150% or more, about 175% or more, about 200% or more, about 250% or more, or about 300% or more wherein ATF4 protein expression is inhibited by about 75% or less, about 50% or less, about 40% or less, about 30% or less, about 20% or less, about 10% or less, or about 5% or less. In some embodiments the compound is used to increase protein synthesis by about 10% to about 300%» (such as about 10% to about 2014, about 20% to about 3014, about 30% to about 4014, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 125%, about 125% to about 150%, about 15014 to about 175%, about 17514 to about 200%, about 200% to about 25014, or about 250% to about 300%), wherein ATF4 protein expression is inhibited by about 75% or less (such as about 50% or less, about 40% or less, about 30% or less, about 20% or less, about 10% or less, or about 5% or less).

[0867] In some embodiments, provided herein is a method of increasing protein translation in a cell. In some embodiments, the cell was stressed prior to administration of the compound, salt thereof, or composition. In some embodiments, protein translation is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 100%, 125%, 150%,

175%, 20014, 250%, or 300% or more. In some embodiments, protein translation is increased as compared to prior to the administration of the compounds, salt thereof, or composition. In some embodiments, protein translation is increased as compared to an unstressed cell, a basal condition where cells are not subjected to a specific stress that activates the ISR. In some embodiments, protein translation is increased as compared to a stressed cell where ISR is active.

[0868] In some embodiments, provided herein is a method of increasing guanine nucleoti de exchange factor (GEF) activity of eIF2B in cells. In some embodiments, provided herein is a method of delaying or preventing apoptosis in a cell. In some embodiments, provided herein is a method of inhibiting translation of one or more mRNAs comprising a 5 untranslated region (5’UTR) that contains at least one upstream open reading frame (uORF), encoding proteins with translational preferences, including but not limited to ATF4, ATF2, ATF5, CHOP, GADD34, BACE-l, C _/ ΈBRa, or MAP1LC3B. In some embodiments, the mRNA encodes ATF4, BACE-1, GADD34, or CHOP. In some embodiments, the mRNA encodes ATF4. [Q869] In some embodiments, expression of ATF4, BACE-l , GADD34 or CHOP is inhibited. In some embodiments, expression of ATF4 is inhibited. In some embodiments, expression of Ab is inhibited. ATF4 increases expression of, among others, GADD45A, CDKN1A, and EIF4EBP1, which encode DDIT-l , p2l, and 4E-BP1 , respectively. These proteins induce musculoskeletal disease (such as skeletal muscle atrophy), and can be modulated by inhibiting expression of ATF4. Accordingly, in some embodiments, expression of one or more of CDKN1 A, GADD45A, or EIF4EBP1 is inhibited.

[0870] In some embodiments, the compound, salt thereof, or composition inhibits translation of one or more mRNAs comprising a 5’ untranslated region (5’UTR) comprising at least one upstream open reading frame (uORF) with an IC50 of less than about 1 mM, such as less than about 750 nM, 600 nM, 500 nM, 300 nM, 200 nM, 100 nM, 80 nM, 60 nM, 40 nM, 25 nM, or less. In some embodiments, the compound, salt thereof, or composition inhibits translation of one or more mRNAs comprising a 5’ untranslated region (5’UTR) comprising at least one upstream open reading frame (uORF) with an IC ₅₀ between about 1 nM and 1 mM, such as between about 10 nM and 600 nM, 15 nM and 200 nM, or 20 nM and 180 nM.

[0871] In some embodiments, the compound, salt thereof, or composition inhibits expression of ATF4 with an IC50 of less than about 1 mM, such as less than about 750 nM, 600 nM, 500 nM, 300 nM, 200 nM, 100 nM, 80 nM, 60 nM, 40 nM, 25 nM, or less. In some embodiments, the compound, salt thereof, or composition inhibits expression of ATF4 with an IC50 between about 1 nM and 1 mM, such as between about 2 nM and 800 nM, 10 nM and 600 nM, 15 nM and 200 nM, or 20 nM and 180 nM.

[0872] In some aspects, the half maximal inhibitory concentration (IC50) is a meas ure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. In some aspects, the IC ₅₀ is a quantitative measure that indicates how much of an inhibitor is needed to inhibit a given biological process or component of a process such as an enzyme, cell, cell receptor or microorganism by half. Methods of determining IC50 in vitro and in vivo are known the art.

[0873] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, bovine, ovine, porcine, equine, canine, feline, rabbit, or rodent. In some embodiments, the individual is a human. In some embodiments, the individual has any of the diseases or disorders disclosed herein. In some embodiments, the individual is a risk for developing any of the diseases or disorders disclosed herein.

[0874] In some embodiments, the individual is human. In some embodiments, the human is at least about or is about any of 21, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 12, 10, 8, 6, 5, 4, 3, 2, or 1 years old.

[0875] Also provided herein are uses of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is for the treatment of a disorder or disease described herein. In some embodiments, the manufacture of a medicament is for the prevention and/or treatment of a disorder or disease mediated by an ISR pathway. In some embodiments, the manufacture of a medicament is for the prevention and/or treatment of a disorder or disease mediated by eIF2a or eIF2B. In some embodiments, the manufacture of a medicament is for the prevention and-'or treatment of a disorder or disease mediated by phosphorylation of eIF2a and/or the GEF activity of eIF2B.

Combinations

[Q876] In certain aspects, a compound described herein is administered to an individual for treatment of a disease in combination with one or more additional pharmaceutical agents that can treat the disease. For example, in some embodiments, an effective amount of the compound is administered to an individual for the treatment of cancer in combination with one or more additional anticancer agents.

[0877] In some embodiments, activity of the additional pharmaceutical agent (such as additional anticancer agent) is inhibited by an activated ISR pathway. An ISR inhibitor, such as one of the compounds described herein, can inhibit the ISR pathway to enhance function ality of the additional pharmaceutical agent. By way of example, certain BRAF inhibitors (e.g., vemurafenib or dabrafenib) activate the ISR pathway in BRAF-mutated melanoma cells (e.g., BRAF with a V600F mutation) through the expression of ATF4. In some embodiments, there is a method of treating cancer comprising administering to an individual with cancer an effective amount of a compound described herein in combination with an effective amount of a BRAF inhibitor. In some embodiments, there is a method of treating a BRAF-mutated melanoma comprising administering to an individual with a BRAF-mutated melanoma an effective amount of a compound described herein in combination with an effective amount of a BRAF inhibitor.

In some embodiments, there is a method of treating a BRAF-mutated melanoma comprising administering to an individual with a BRAF-mutated melanoma an effective amount of a compound described herein in combination with an effective amount of vemurafemb or dabrafenib.

[0878] As another example, certain anticancer agents (such as ubiquitin-proteasome pathway inhibitors (such as bortezomib), Cox-2 inhibitors (e.g , celecoxib), platinum-based antineoplastic drugs (e.g., cisplatin), anthracychnes (e.g. doxorubicin), or topoisomerase inhibitors (e.g., etoposide)) are used to treat cancer, but may have limited functionality against solid tumors. Resistance in certain solid tumors (e.g., breast cancers) has been associated with ATF4 stabilization and induction of autophagy. In some embodiments, an effective amount of an ISR inhibitor compound as described herein is administered to an individual with cancer to increase sensitivity to one or more anticancer agents.

[0879] In some embodiments, there is a method of treating a refractory cancer (such as a solid tumor) in an individual, comprising administering to the individual an effective amount of a compound described herein in combination with an effective amount of an anticancer agent.

In some embodiments, there is a method of treating a refractory cancer (such as a solid tumor) in an individual, comprising administering to the individual an effective amount of a compound described herein in combination with an effective amount of an ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based antineoplastic drug (e.g., cisplatin), an anthracy cline (e.g. doxorubicin), or a topoisomerase inhibitor (e.g., etoposide). In some embodiments, the refractor} _' cancer is breast cancer. In some embodiments, the refractor _} cancer is melanoma.

[0880] In some embodiments, a compound described herein is used to treat cancer in combination with one or more anti-cancer agents, such as an anti-neoplastic agent, an immune checkpoint inhibitor, or any other suitable anti-cancer agent. Exemplar _}' immune checkpoint inhibitors include anti-PD-l, anti-PD-Ll, anti G!TR, anti-OX-40, anti-LAG3, anti-TIM-3, anti- 41BB, anti-CTLA-4 antibodies. Exemplar} anti-neoplastic agents can include, for example, anti-microtubule agents, platinum coordination complexes, alkylating agents, topoisomerase II inhibitors, topoisomerase I inhibitors, antimetabolites, antibiotic agents, hormones and hormonal analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. Other anti-cancer agents can include one or more of an immuno-stimulant, an antibody or fragment thereof (e.g., an anti-CD20, anti-HER2, anti-CD52, or anti-VEGF antibody or fragment thereof), or an immunotoxin (e.g., an anti~CD33 antibody or fragment thereof, an anti-CD22 antibody or fragment thereof, a eaiicheamicin conjugate, or a pseudomonas exotoxm conjugate).

[0881] ATF4-mediated expression of CHOP has also been shown to regulate the function and accumulation of myeloid-derived suppressor cells (MDSCs) in tumors. MDSCs in tumors reduce the ability' to prime T cell function and reduce antitumora! or anticancer responses. Certain immunotherapeutic agents (such as anti-PD-l, anti PD-L1, anti-GITR, anti-OX-40, anti- LAG3, anti-TIM-3, anti-41 BB, or anti-CTLA-4 antibodies) have been used to boost the immune response against cancer. ATF4-mediated expression of AXL has been associated with poor response to anti -PD 1 therapy in melanoma. In some embodiments, an effective amount of an ISR inhibitor compound as described herein is administered to an individual with cancer to increase sensitivity to one or more immunotherapeutic agents. In some embodiments, there is a method of treating a refractory cancer (such as a melanoma) in an individual, comprising administering to the individual an effective amount of a compound described herein in combination with an effective amount of an immunotherapeutic agent (e.g. anti-PD-l, anti PD- L i , anti-GITR, anti-OX-40, anti-LAG3, anti-TIM-3, anti-4lBB, or anti-CTLA-4 antibodies). In some embodiments, the refractory' cancer is melanoma.

Dosing and Method of Administration

[Q882] The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount.

[0883] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight. An exemplar' dose is in the range of about from about 0 7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1 75 g daily, or about 1.75 to 7 g daily

[0884] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.

[0885] A compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g , about a once weekly dosing. The dosing frequency can be more than once daily, e.g, tw ce or three times daily. The dosing frequency can also be intermittent, including a‘drug holiday’ (e.g , once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.

Articles of Manufacture and Kits

[0886] The present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.

[0887] The present disclosure further provides kits for carrying out the methods of the present disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer

[0888] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.

[Q889] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0890] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g. magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual.

General Synthetic Methods

[0891] The compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

[0892] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereo eric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization a d the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High-Performance Liquid

Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

[0893] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

[0894] Solvates and/or polymorphs of a compound provided herein or a salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density', hardness, crystal shape, optical and electrical properties, stability, and/or solubility . Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0895] Chromatography, recry stallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

[0896] General methods of preparing compounds according to the present disclosure are depicted in the schemes below.

G

H N 3 3 *P o r ^p G _» H (C-4)

PG: protecting group Ar ¹ : aryl or H Ai^O^Br H

(B-4)

(C-1 ) heteroaryl o Y ^N ·'· "Ό .Ar

(C-2) Ar _1·0^LN ^

H (C-5)

Ar ² aryl or Ar

H (C-6) heteroaryl

[0897] Compounds disclosed herein, such as compounds of formula (C-3), (C-4), (C-5), and (C-6), for example, can he synthesized according to the general method described in the scheme above. A compound of formula (C-1) is reacted with a carboxylic acid (B-la), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-lb), under suitable conditions to give a compound of formula (C-2). The compound of formula (C-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-2b), to gi ve a compound of formula (C-3). The compound of formula (C-2), which may first be optionally deprotected, is reacted with an oxirane derivative of formula (B-3) to give a compound of formula (C-4). The compound of formula (C-2), which may first be optionally deprotected, is reacted with a haloaJkyl derivative, such as a bromoalkyl compound of formula (B-4), to give a compound of formula (C-5). The compound of formula (C-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-5a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-5b), to give a compound of formula (C-6).

or

O optional Ar ₂ 0 _^ ^<9

(B-3) o r N ^' Ύ ^' Ό .Ar ²

Ar ^' °~ ^A C! deprotection A, ' O 4 OH N PG (B-1 b) o N ^PG H (D-4)

H,N ^' - ^step

A

PG: pr

Ar ^2A Ci

(B-5b) _¾ O r' ^"' N ^A Ar ²

Ar ² : aryi or Ar ^

H (D-6) heteroaryi

[0898] Compounds disclosed herein, such as compounds of formula (D-3), (D-4), (D-5), arid (D-6), for example, can he synthesized according to the general method described in the scheme above. A compound of formula (D-1) is reacted with a carboxylic acid (B-la), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-lb), under suitable conditions to give a compound of formula (D-2). The compound of formula (D-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-2b), to give a compound of formula (D-3). The compound of formula (D-2), which may first be optionally deprotected, is reacted with an oxirane derivative of formula (B-3) to give a compound of formula (D-4) The compound of formula (D-2), which may first be optionally deprotected, is reacted with a ha!oalkyl derivative, such as a bromoa!ky! compound of formula (B-4), to give a compound of formula (D-5). The compound of formula (D-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-5a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-5b), to give a compound of formula (D-6).

Ar ² : aryl or VY ^N -

O (E-6) heteroaryi

[0899] Compounds disclosed herein, such as compounds of formula (E-3), (E-4), (E-5), and (E-6), for example, can be synthesized according to the general method described in the scheme above. A compound of formula (E-1) is reacted with a carboxylic acid (B-1 a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-lb), under suitable conditions to give a compound of formula (E-2). The compound of formula (E-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-2b), to give a compound of formula (E-3). The compound of formula (E- 2), which may first be optionally deprotected, is reacted with an oxirane derivative of formula (B-3) to give a compound of formula (E-4). The compound of formula (E-2), which may first be optionally deprotected, is reacted with a haloalkyl derivative, such as a bromoalky! compound of formula (B-4), to give a compound of formula (E-5). The compound of formula (E-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-5a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-5b), to give a compound of formula (E-6). O

_Ar2 -0^ A _jO - _H

(B-2a)

or

O

A ₍

Ar ² "°^C

⁰ (B-2b)

A _I · ^{1" n} '^ΌH _AG i 0^ _N ΰ _¾ AG ²

(B-1a)

O optional Ar ^{2 '} ®;A ⁱ O rih OH

Ar^O^G. I deprotection ^{d d)}

(B-1 b) AG

ste ^{1 0} ^ N^^^° _Ai - ²

[0900] Compounds disclosed herein, such as compounds of formula (F-3), (F-4), (F-5), and (F-6), for example, can be synthesized according to the general method described in the scheme above. A compound of formula (F-1) is reacted with a carboxylic acid (B-la), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-lb), under suitable conditions to give a compound of formula (F-2). The compound of formula (F-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-2b), to give a compound of formula (F-3). The compound of formula (F- 2), which may first be optionally deprotected, is reacted with an oxirane derivati ve of formula (B-3) to give a compound of formula (F-4). The compound of formula (F-2), which may first be optionally deprotected, is reacted with a haloa!ky! derivative, such as a bromoalky! compound of formula (B-4), to give a compound of formula (F-5). The compound of formula (F-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-5a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-5b), to give a compound of formula (F-6).

[0901] Compounds disclosed herein, such as compounds of formula (G-3), (G-4), (G-5), and (G-6), for example, can be synthesized according to the general method described in the scheme above. A compound of formula (G-1) is reacted with a carboxylic acid (B-1 a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-lb), under suitable conditions to give a compound of formula (G-2). The compound of formula (G-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-2a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-2b), to give a compound of formula (G-3). The compound of formula (G-2), which may first be optionally deprotected, is reacted with an oxirane derivative of formula (B-3) to give a compound of formula (G-4). The compound of formula (G-2), which may first be optionally deprotected, is reacted with a haloalkyl derivative, such as a bromoa!ky! compound of formula (B-4), to give a compound of formula (G-5). The compound of formula (G-2), which may first be optionally deprotected, is reacted with a carboxylic acid (B-5a), or a carboxylic acid derivative (e.g. an acyl chloride of formula (B-5b), to give a compound of formula (G-6).

ENUMERATED EMBODIMENTS

[Q9Q2] The following enumerated embodiments are representative of some aspects of the invention. Embodiment 1 . A compound of formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

X ¹ and X ² , independently of each other, are CH or N;

Y ¹ is selected from the group consisting of a bond, NR* ', and O; provided that when X ¹ is N, then Y ¹ is a bond;

R ^{Y l} is hydrogen or Ci-C ₆ alkyl;

Y ² is selected from the group consisting of a bond, NR ^Y2 , and O; provided that when X ² is N, then Y ² is a bond;

R ^{Y 2} is hydrogen or Ci-C ₆ alkyl;

m ¹ , m ² , n ¹ , n ^z , p ¹ , p , q ¹ , and q ² , independently of each other, are 0 or 1 ;

r and s, independently of each other, are 0, 1, or 2;

A ¹ is selected from the group consisting of:

a substituent of formula (A ⁵ -a)

wherein

* represents the attachment point to the remainder of the molecule; Z ¹ is selected from the group consisting of CR ²¹ ^ ^{1 2} , NR ^{Z1 2} , O, S, and -CR ^{Z1 1} =CR ^{Z1 1} -;

wherein R ² ' ¹ is H or R ¹⁴ ; and R ^Zi is H or R ¹⁴ ;

Z ² is selected from the group consisting of€¾ ^Z ¾ ^{Z ~2} , NR ^Z2 ; O, S, and -CR ^{Z 2} CR ^{2 ' 2} -:

wherein R ² ’ ¹ is H or R ¹⁴ ; and R ^{22 2} is H or R’ ⁴ ; Z ³ , independently at each occurrence, is C or N, provided that at least one Z ³ is C;

R ^! ’ is hydrogen or R ¹⁴ , or R ^!J and R ^{Z1 2} are taken together to form a double bond between the carbon atom bearing R ¹³ and Z ¹ , or R ¹³ and R ^z are taken together to form a doubl e bond between the carbon atom bearing R ¹³ and Z ² ; and

xl is 0, 1, 2, 3, or 4, provided than when one Z ^J is N, then xl is not 4; Cg-Cio aryl optionally substituted with one or more R ¹⁴ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ¹⁴

substituents;

R ¹⁴ is selected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, Ci-Ce haloalkyl, -OH, -OiC -Ce alkyl), -0(C -Ce haloalkyl), -SH, -S(Ci~ C _ft alkyl), S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CVC ₆ alkyl),-NH(C _] -C ₆ haloalkyl), -N(C - C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl) ₂ , -NR ^{14 3} R ^{14 b} , -CN, -C(0)0H, -C<0)0(Ci-C ₆ alkyl),

-0C(0)(C _r C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(C C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ alkyi)C(0)H, -N(C C ₆ alkyl)C(0)(CrC ₆ alkyl), -N(C C ₆ aik\ i }( (()}·; ( -( ,, haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haioalkyl)C(0)(Ci-C ₆ alkyl), -N(CJ-C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ <Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl),

-N(H)S(0) ₂ (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ alk\d)S(0) ₂ (Ci-C ₆ haloalkyl), ~N( _{] ~} C ^' .., haloalkyl)S(0) ₂ (C]-C ₆ alkyl), and -N(C]-C ₆ haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl):

wherein R ^{14 3} and R ^{14 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ² is selected from the group consisting of:

a substituent of formula (A ² -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ⁴ is selected from the group consisting of CR^R ^{24 2} , NR ^{24 2} , O, S, and -CR ^{Z ! :} CR ^/

wherein R

Z ⁵ is selected from the group consisting of CR ^{Z i} R ^{25 2} , NR ^Z5 ; O, S, and -CR ^{Z5 1} =CR ^{Z5 1} -;

wherein R ^{25 1} is H or R ¹⁶ ; and R ^{Z3 z} is H or R ^!t> ;

Z°, independently at each occurrence, is C or N, provided that at least one Z ⁶ is C:

R ¹³ is hydrogen or R , or R ¹³ and R ^{24 2} are taken together to form a double bond between the carbon atom bearing R ¹⁵ and Z ⁴ , or R ¹³ and R ^{25 2} are taken together to form a double bond between the carbon atom bearing R ⁱ⁵ and Z ⁵ ; and

x2 is 0, 1, 2, 3, or 4, provided than when one Z ⁶ is N, then x2 is not 4; Ce-Cio aryl optionally substituted with one or more R ¹⁶ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ¹⁶

substituents;

R ¹⁶ is selected, independently at each occurrence, from the group consisting of halogen,

Ci-C _f , alkyl, C C ₆ haloalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), ·CP ·, -M 1{ ^{( '} ··· ⁽ ). alkyl), -NH(C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) ₂ , -NR ^{16 a} R ^{16 b} , -CN, -C(0)0H, -C(0)0(C C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(C _] -C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{16 a} R ^{16 b} ,

-S(0) ₂ 0H, -S(0) ₂ 0(CrC ₆ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(CrC ₆ alkyl), -S(0) ₂ NH(C _I -C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl)?, -S(Q) ₂ N(CrC ₆ haloalkyl) _? alkyl),

-0C(0)(CrC ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyi), -N(C C ₆ alky])C(0)H, -N(CI-C ₆ alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyi), -N(CrC ₆ haloalkyl)C(0)H, -N(Ci-C ₆

haloaJkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyi),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyi), -N(H)S(0) ₂ (Ci-C ₆ alkyl),

-N(H)S(0) ₂ (CI-C ₆ haloalkyi), -N(C -C ₆ alk\ )S(0) ₂ (C _l -C ₆ alkyl), ~N(C I~C ₆ alkyl)S(0) ₂ (C _l -C ₆ haloalkyi), -N(CI-C ₆ haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -NfC -Ce haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyi);

wherein R and : 1 16-b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^la and R ^lb are independently selected from the group consisting of hydrogen, C -Ce alkyl, and halogen;

R ^2a and R ^2b are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R ^ia and R ^ib are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R* ^a and R* ^b are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

or alternatively, R ^a and R ^2a are taken together to form a Ci-Ce alkylene moiety;

or alternatively, R ^a and an R ^a moiety, when present, are taken together to form a Ci-Ce alkylene moiety, and R ^lb and the R ^3b in the gennnal position to the R ³ taken together with R ^ia , are both hydrogen;

or alternatively, an R ^3a moiety, when present, and an R ^¾J moiety, when present, are taken together to form a Ci-Ce alkylene moiety, and the R ^3b in the geminal position to the R ^3a taken together with the R ^4a moiety and the R ^4b in the geminal position to the R ^4a taken together with the R ^3a moiety, are both hydrogen;

when present, R ^5a and R ^5b are taken together to form an oxo (=0) substituent or an irnido (=NH) substituent, or alternatively, R ^5a and R ^5b are both hydrogen;

when present, R ^6a is selected from the group consisting of h drogen, -OR ^{6a a} ,

and -NR ^{6a b} R ^{6a c} ;

when present, R ^bb is hydrogen;

or alternatively, R ^6a and R ^6b are taken together to form a moiety selected from the group consisting of -0~CH _2~ CH _2~ , -CH ₂ -0-CH ₂ -, -CH ₂ -CH ₂ -0-, -0-CH ₂ -CH ₂ -CH ₂ -, -CH2-O-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-CH2-O-, -O-CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -0-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -0-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -0-CH _2~ , and

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -0-;

when present, R ^7a and R ^7b are both hydrogen;

when present, R ^8a and R ^8b are taken together to form an oxo (=0) substituent, or

alternatively, R and R are both hydrogen;

when present, R ^9a and R ^9b are taken together to form an oxo (=0) substituent or an iinido (=NH) substituent, or alternatively, R ^9a and R ^9b are both hydrogen; when present, R ^10a is selected from the group consisting of hydrogen, ~OR ^{l0a a} ,

and -NR ^{10a b} R ^{10a c} ;

when present, R ^10b is hydrogen;

or alternatively, R ^0a and R ^0b are taken together to form a moiety selected from the

group consisting of -O-CH2-CH2-, -CH ₂ -0-CH ₂ -, -CH ₂ -CH ₂ -0-, -O-CH2-CH2-CH2-, ('I I _' ·0·(Ί 1 ·-('! 1 ···. - ( Ί 1 - - { Ί i -·-()-( 1 1 ··. -CH ₂ -CH ₂ -CH ₂ -0-, -O-ίΊ I -C! S -C! ! ,-P 1 -CH ₂ -0-CH _2~ CH _2~ CH _2~ , -CH ₂ -CH ₂ -0-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -0-CH ₂ -, and

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -0-;

when present, R ^lla and R ^llb are both hydrogen;

when present, R ^12a and R ^12b are taken together to form an oxo (=0) substituent, or

alternatively, R ^{l a} and R ^{l b} are both hydrogen;

R ^{6a a} is selected from the group consisting of hydrogen, C -Ce alky l, and C -Ce haloalkyl; R ^{10a a} is selected from the group consisting of hydrogen, Ci-Ce alkyl, and CrC ₆ haloalkyl; or R ^{6a a} and R ⁷ may be taken together to form a carbonyl (C ^:=: 0) moiety ⁷ ;

or R ^{lua a} and R ^{' 2} may be taken together to form a carbonyl (C=0) moiety :

R ^{ba b} and R ^6a_t , independently of each other, are selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and C1-C6 haloalkyl; and

R ^{10a b} and R ^{lt,a c} , independently of each other, are selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and CVC _f , haloalky!.

Embodiment 2, The compound of embodiment 1 , wherein the compound of formula (I) is a compound of formula (1-1):

or a pharmaceutically acceptable salt thereof;

wherein:

A ⁵ is a substituent of formula (A^a)

and

A ² is a substituent of formula (A ^z -a)

Embodiment 3 The compound of embodiment i, wherein the compound of formula (I) is a compound of formula (1-2):

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is a substituent of formula (A^a)

and

A ² is selected from the group consisting of:

a substituent of formula (A ² -a)

C6-C10 aryl optionally substituted with one or more R ¹⁶ substituents; and 5-10 membered heteroaryl optionally substituted with one or more R ^!o substituents.

Embodiment 4. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (1-3):

or a pharmaceutically acceptable salt thereof;

wherein:

A ³ is a substituent of formula (A ³ -a)

and A ¹ is C ₆ -C _IG aryl optionally substituted with one or more R ¹⁶ substituents; or 5-10 membered heteroaryl optionally substituted with one or more R ¹⁶ substituents.

Embodiment 5 The compound of embodiment 1, wherein the compound of formula (1) is a compound of formula (1-4):

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is a substituent of formula (A^a)

A ^z is C ₆ -C _IG aryl optionally substituted with one or more R ¹⁶ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ¹⁶ substituents; R ^lla and R ^llb are both hydrogen; and

R ^12a and R ^1¾ are both hydrogen.

Embodiment 6. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (2-2):

or a pharmaceutically acceptable salt thereof;

wherein:

A ³ is selected from the group consisting of:

a substituent of formula (A ³ -a)

C _fi -Cio atyl optionally substituted with one or more R ¹⁴ substituents; and 5-10 membered heteroaryl optionally substituted with one or more R ¹⁴

substituents;

and

A ² is selected from the group consisting of:

a substituent of formula (A ² -a)

C6-C10 atyl optionally substituted with one or more R ¹⁶ substituents; and 5-10 membered heteroaryl optionally substituted with one or more R ^!o

substituents.

Embodiment 7. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (2-3):

(2-3)

or a pharmaceutically acceptable salt thereof;

wherein: A ⁵ is selected from the group consisting of:

a substituent of formula (A ⁵ -a)

( C io aryl optionally substituted with one or more R ¹⁴ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ¹⁴

substituents;

and

A is Ce-Cio aryl optionally substituted with one or more R ¹⁶ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ¹⁶ substituents.

Embodiment 8. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (2-4):

(2-4)

or a pharmaceutically acceptable salt thereof;

wherein:

A ¹ is selected from the group consisting of:

a substituent of formula (A*-a)

Cg-Cio aryl optionally substituted with one or more R ¹⁴ substituents; and 5-10 membered heteroaryl optionally substituted with one or more R ¹⁴

substituents; A ^z is C ₆ -CIG aryl optionally substituted with one or more R ¹⁶ substituents; or 5-10 membered heteroaryl optionally substituted with one or more R ¹⁶ substituents;

R ^{l la} and R ^{l lb} are both hydrogen; and

R ^12a and R ^1¾ are both hydrogen.

Embodiment 9. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (3-3):

(3-3)

or a pharmaceutically acceptable salt thereof;

wherein:

A ⁵ is C ₆ -CIQ aryl optionally substituted with one or more R ¹⁴ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ¹⁴ substituents; and

A ² is Ce-Cio aryl optionally substituted with one or more R ¹⁰ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ¹⁶ substituents.

Embodiment 10. The compound of embodiment l , wherein the compound of formula (I) is a compound of formula (3-4):

or a pharmaceutically acceptable salt thereof;

wherein: A ⁵ is C ₆ -C _IG aryl optionally substituted with one or more R ¹⁴ substituents; or 5-10 membered heteroaryl optionally substituted with one or more R ¹⁴ substituents; A ² is C _fi -C o aryl optionally substituted with one or more R ¹ " substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ^lu substituents; R ^lla and R ^llb are both hydrogen; and

R ^{! a} and R ^{! b} are both hydrogen.

Embodiment 1 1. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (4-4):

(4-4)

or a pharmaceutically acceptable salt thereof;

wherein:

A ³ is C _fi -C o aryl optionally substituted with one or more R ¹⁴ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ¹⁴ substituents; A ² is Ce-Cio aryl optionally substituted with one or more R ³⁶ substituents; or 5-10

membered heteroaryl optionally substituted with one or more R ^!o substituents; R' ^a and R' ^b are both hydrogen;

R ^8a and R ^8b are both hydrogen;

R ^lla and R ^llb are both hydrogen; and

R ¹²³ and R ^12b are both hydrogen.

Embodiment 12. A compound of formula (II):

or a pharmaceutically acceptable salt thereof;

wherein:

m3 is 0 or 1 ;

n3 is 0 or 1 ;

r2 is 0, 1 , or 2;

s2 is 0, I, or 2;

X ³ is CH or N;

X ⁴ is CH or N;

provided that at least one of X ³ and X ⁴ is CH;

Y ^J is selected from the group consisting of a bond, XR ' \ and O;

wherein R ^Y3 is hydrogen or CrC ₆ alkyl;

Y ⁴ is selected from the group consisting of a bond, NR ^Y4 , and O;

wherein R ^{Y 4} is hydrogen or Ci-Ce alkyl;

provided that:

when X ³ is N, then Y ⁵ is a bond and m3 is 1 ;

when X ⁴ is N, then Y ⁴ is a bond and n3 is 1;

A ^J is selected from the group consisting of:

a substituent of the formula (A ³ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ⁷ is selected from the group consisting of NR ^{7 2} , O, S, and -CR^-^CR ^{27 1} -; wherein

R ² IS H or R ² '; and

R ^{Z7 2} is H or R ²⁷ ;

Z ⁸ is selected from the group consisting of NR ^{Z8 2} ; O, S, and -CR ^{Z8 !} =CR ^{Z8 1} -;

wherein

R ^{28 1} is H or R '; and

R ²⁸ ’ is H or R ²⁷ ;

Z ⁹ , independent!}' at each occurrence, is C or N, provided that at least one Z ⁹ is C;

R ²⁶ is hydrogen or R ² ', or R ²⁶ and R ^z ' ^~2 are taken together to form a double bond between the carbon atom bearing R ^z6 and Z'; and

x3 is 0, 1, 2, 3, or 4, provided than when one Z ⁹ is N, then x3 is not 4; Ce-Cio aryl optionally substituted with one or more R ² ' substituent; and

5-10 rnembered heteroaryl optionally substituted with one or more R ^z ' substituent;

R ² ' is selected, independently at each occurrence, from the group consisting of halogen, C1-C0 alkyl, Ci-Ce haloaikyi, -OH, -OCCi-Ce alkyl), -0(Ci-C ₆ haloaikyi), -SH, -S(Ci-C,. alkyl), ~S(Ci~C ₆ haloaikyi), -NH ₂ , -NH(Ci-C ₆ alkyl),-NH(Ci-C ₆ haloalk>'l),-N(C r C ₆ alkyl) ₂ , -N(Ci-Ce haloalkyl) ₂ , -NR ^27_a R ^{27 b} , -CN, -C(0)0H, -C(0)0(C _r C ₆ alkyl),

-C(0)0(Ci-C ₆ haloaikyi), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C C ₆ haloaikyi), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆

haloaikyi)? alkyl),

-S(0) ₂ 0(Ci-C ₆ haloaikyi), -S(0) ₂ NH ₂ , -S( ^{) )2NH(C _I -C ₆ alkyl),

-S(0) ₂ NH(C _I -C ₆ haloaikyi), -S(0) ₂ N(Ci-C ₆ alkyi) ₂

haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloaikyi), -N(H)C(0)H, -N(H)C(0)(CrC ₆ alkyd),

-N(H)C(0)(C r C ₆ haloaikyi), -N(C C ₆ alkyl)C(0)H, -N(C C ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyi)C(0)(C ₁ -C ₆ haloaikyi), -N(C _I -C ₆ haloa!kv'!)C(0)H, ~N(C _I~ C ₆ haloa!ky!)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haloalkyl)C(0)(Ci-C ₆ haloaikyi), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloaikyi), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloaikyi), - C i-C,. alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C -C6 haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -NlCi-C,

haloalkyl)S(0) ₂ (C _l -C6 haloalkyl);

wherein R ^2/ “ and R ^z ' ^b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ⁴ is selected from the group consisting of:

a substituent of the formula (A ⁴ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁰ is selected from the group consisting of CR ^Zl( R ^10·2 , NR ^{Z10 2} , O, S, and -CR ^{Z10 !:=:} CR ^{z10 1} -;

wherein

Z ¹¹ is selected from the group consisting of CR ^z “ ¹ R ^{l 1 2} , NR ^{211 2} ; O, S, and ~CR ^{21 ] i} =CR ^ZH · ¹ -;

wherein

R ^{211 1} is H or R ²⁹ ; and

R ^{211 2} is H or R ²⁹ ;

Z ¹² , independently at each occurrence, is C or N, provided that at least one Z ⁱ² is C;

R is hydrogen or R ^z , or R and R are taken together to form a double bond between the carbon atom bearing R ²⁸ and Z ^!u ; and x4 is 0, 1, 2, 3, or 4, provided than when one Z ¹² is N, then x4 is not 4; C6-C10 aryl optionally substituted with one or more R ^z9 substituent; and

5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), ~SH, -S(Ci-C ₆ alkyl), -S(CrC ₆ haloalkyl), -NH ₂ , -NHiCi-Ce alky 1),-NH(C _! -Cg haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)M-i(Ci-C ₆ alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0) ( ,-G,. alkyl) ₂

haloa!ky! -C(0)NR ^{29 a} R ^{29 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -StOfA! Hi VCY. alkyl),

-S(0) NI Hi VC,·, haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyi} ₂ , -S(0) ₂ N(CrC ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl),

-N(H)C(0)(C, -C _& haloalkyl), -N(C _I -C ₆ alkyl)C(())H, -N(C _I -C ₆

alkyl)C(0)(C ₁ -C ₆ alkyl), ~N(C _I~ C ₆ alkyl)C(O)(C ₁ -C ₆ haloalkyl), ~\f ( _r C,, haloalkyl)C(0)H, -N(C _I -C ₆ haloaHy l)C(0)(CrC ₆ alkyl), -N(Ci-C ₆ haloaikyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -MCi-C,. alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C -C ₆ haloalk l)S(0) ₂ (Ci-C ₆ alkyl), and -NlCi-C, haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ²⁹ “ and R" ^{9 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^{! 7a} and R ^{! 7b} are independently selected from the group consisting of hydrogen, C -C ₆ alkyl, and halogen;

R ^18a and R ^18b are independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

when present, R ^19a and R ^19b are independently at each occurrence selected from the group consisting of hydrogen, Ci-Cg alkyl, and halogen;

when present, R ^0a and R ^0b are independently at each occurrence selected from the group consisting of hydrogen, C -Ce alkyl, and halogen;

or alternatively, R ^{1 /a} and R ^l8a are taken together to form a Ci-Cg alkylene moiety;

or alternatively, R ^{l 7a} and an R ^l9a moiety, when present, are taken together to form a CC Ce alkylene moiety, and R ^{i 7b} and the R ^!9b in the geminal position to the R ^19a taken together with R ^{! /a} , are both hydrogen; or alternatively, an R ^l9a moiety, when present, and an R ^20a moiety, when present, are taken together to form a Ci-C ₆ alkylene moiety, and the R ^l9b in the geminal position to the R ^i9a taken together with the R ^2ua moiety and the R ^20b m the geminal position to the R ^20a taken together with the R ^9a moiety, are both hydrogen;

R ^!a and R ^!b are taken together to form an oxo (=0) substituent or an miido (=NH) substituent, or alternatively, R ^ia and R ^lb are both hydrogen;

when present, R ^22a and R ^22b are both hydrogen;

R ^3a and R ^3b are taken together to form an oxo (=0) substituent or an irnido (=NH) substituent, or alternatively, R ^23a and R ^23b are both hydrogen;

when present, R ^24a is selected from the group consisting of hydrogen, -OH, and -NH ₂ ; or alternatively, R ^24a and R ^Y4 are taken together to form a #-C(=0)-0- group, wherein # represent the attachment point to the nitrogen atom bearing R^ ⁴ ;

when present, R ^24b is hydrogen; and

when present, R ^2:a and R ^2:b are both hydrogen;

or alternatively, R ^25a , when present, and one R ²⁹ of A ⁴ are taken together with the atoms connecting them to form a 5-6 membered heterocycloalkenyi optionally substituted with one or more R ²⁹ substituent, and R ^2sb is H;

or alternatively, R ^2¾J , when present, R ^25b , when present, and one R ⁹ of A ⁴ are taken together with the atoms connecting them to form a 5-6 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

and further provided that one of (i), (ii), (iii) and (iv) applies:

(i) when m3 is 0 and n3 is 0, then:

X ³ is CH and Y ³ is NR ^Y3 ;

X ⁴ is CH and Y ⁴ is NR ^Y4 ;

R ^21a and R ^21b are taken together to form an oxo (=0) substituent;

il ^{2 ,a} and il ^{2 ,b} are taken together to form an oxo (=0) substituent;

A ³ is a substituent of the formula (A ³ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z' is selected from the group consisting of CR ^{Z/ 1} R ^Z/ · ² , NR ^Z/ \ O, S, and -CR ^{Z :} CR' ^{" 1} -.

wherein

R ²⁷¹ is H or R '; and

R ^Z72 is H or R ²⁷ ;

Z ⁸ is selected from the group consisting of CR ^Z81 R ^Z52 , NR ^Z8z ; O, S, and -CR ^Z81 =CR ^Z81 -;

wherein

R ²⁸¹ is H or R ²⁷ ; and

R ^Z82 is H or R ²⁷ ;

Z ⁹ , independently at each occurrence, is C or N, provided that at least one Z ⁹ is C;

R ^2t> is hydrogen or Rf or R ²⁶ and R ² ' ² are taken together to form a double bond between the carbon atom bearing R ²⁶ and Z ⁷ ;

R ^{2 '} is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, -OH, -0(Ci-Ce, alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -SICi-Cr, haloalkyl), ~NH, N1 !· ^(' ··· ⁽ .. alkyl), -NH(C _] -C ₆ haloalkyl), -N(C _I -C ₆ alkyl) _? , -N(C C ₆ haloalkyl) ₂ , -NR ^27a R ^27b , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alky l) ·. -C(0)N(Ci-C ₆

), _I -C ₆ haloally 1 alkyl),

-0C(0)(Ci-C ₆ haloalkyl), alkyl),

-N(H)C(0)(C rCe haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(CI-C ₆

alkyl)C(0)(C-C ₆ alkyl), -NfCi-Ce alkyl)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(C _r C ₆ haloally1)C(0)(C C ₆ alkyl), -N(C C ₆ haloalky 1)C(0)(C i-C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (C ₁ -C ₆ alkyl), -N(H)S(0) ₂ (Ci~C ₆ haloalkyl), -N(C _I -C ₆ alkyl)S(0) ₂ {Ci-C ₆ alkyl), ~\{i _r C„ alky )S(0) ₂ (Ci-C ₆ haloalkyl), -N(CI-C ₆ haloalkyl)S(0) ₂ iCi-C ₆ alkyl), and -N(CI-C ₆ haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ^{27 a} and R ^{2 , b} are taken together with the nitrogen atom winch bears them to form a 3-10 membered heterocycle;

x3 is 0, 1, 2, 3, or 4, provided than when one Z ⁹ is N, then x3 is not 4;

A ⁴ is a substituent of the formula (A ⁴ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ^!0 is selected from the group consisting of NR ^{Z10 2} , O, S, and -CR ^{zl0 i=} CR ^Zi(M -;

wherein

R ^{210 1} is H or R ²⁹ ; and

Z ^u is selected from the group consisting of CR ^Zl R ‘ , NR ^{ZI1 2} ; O, S, and -CR ^{Z11 1} =CR ^{Z11 1} -;

wherein

R ^Zi is H or R ²⁹ ; and

R ^{211 2} is H or R ²⁹ ;

Z ¹² , independently at each occurrence, is C or N, provided that at least one Z ⁱ² is C;

R is hydrogen or R % are taken together to form a double bond between the carbon atom bearing R ⁸ and Z ^lu ;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -Ce haloalkyl, -OH, -0(Ci~C ₆ alkyl), -0(C _] -C ₆ haloalkyl), -SH, -S(C C ₆ alkyl), -S(C _r C ₆ haloalkyl), -NH ₂ , -NH(CrC ₆ alky 1),-NH(C _! -Cg haloalkyl), -N(C C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(C _r C ₆ haloalkyl) _? . ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(()) _' N Hi C haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) _? , -S(0) _? N(C _l -C ₆ haloalkyl) _? alkyl),

-0C(0)(C i-C ₆ haloalkyl), -N(H)C(0)H, -Nil 1}( «)}!( >( , alkyl),

-N(H)C(0)(C _r C ₆ haloalkyl), -N(C C ₆ alky])C(0)H, -N(CI-C ₆

alkyl)C(0)(C -C ₆ alkyl), -N(CI-C ₆ alkyl)C(0)(C -C ₆ haloalkyl), -N(Ci-C ₆ haloalkyl)C(0)H, -N(CI-C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ haloalky l)C(0)(C _r C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C _! -C ₆ haloalkyl), -N(H)S(0) ₂ (C _l -C ₆ alkyl), -N(H)S(0) ₂ (C -C ₆ haloalkyl),

Ni ⁽ VC, alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(G) _? (Ci-C ₆ haloalkyl), -N(C C ₆ haloalky l)S(0) _? (Ci-C ₆ alkyl), and -N! ( >·( ,.

haloallyd)S(O) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{29 3} and R ^{29 b} are taken together with the nitrogen atom which hears them to form a 3-10 membered heterocycle; x4 is 0, I , 2, 3, or 4, provided than when one Z ¹ " is N, then x4 is not 4; and

provided that A’ and A ⁴ are not both simultaneously a moiety selected from group consisting of:

, ents the attachment point to the remainder of the molecule;

(ii) when m3 is 0 and n3 is 1, then:

r2 is 1 or 2;

s2 is 1 or 2; X ³ is CH and Y ³ is NR ^Y3 ;

R ^2ia and R ^2ib are taken together to form an oxo (=0) substituent;

R ^24a is selected from the group consisting of hydrogen, -OH, and -NH ₂ ;

A ^J is a substituent of the formula (A ^J ~a)

wherein

* represents the attachment point to the remainder of the molecule;

Z' is selected from the group consisting of CR ^Z R ^Z ' ^~2 , NR ^Z ' , O, S, and -CR^ ^CR ^{27 1} -;

wherein

R ^Z is H or R ²⁷ ; and

R ^{27 2} is H or R ²⁷ ;

Z ⁸ is selected from the group consisting of O, S, and C R N- · _{C R /} S- I _.

wherein

Z ⁹ , independently at each occurrence, is C or N, provided that at least one Z ⁹ is C;

R ²⁶ is hydrogen or R ²⁷ , or R ²⁶ and R ^{/ / 2} are taken together to form a double bond between the carbon atom bearing R ^2b and Z';

R ² ' is selected, independently at each occurrence, from the group consisting of halogen, Ci-Cr, alkyl, Ci-Cc, haloalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(C _] -Ce alkyl), -S(CrCe haloalkyl), -NH ₂ , -NH(CI-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C _r C ₆ aikyi) ₂ , -N(CI-C ₆ haloalkyl) alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ aikyl) ₂ , -C(0)N(C C ₆ haloalkyl) ₂ , -C(0)NR ^{27 a} R ^{27 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci-C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _I~ C ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -S(0) ₂ N(C _] -C ₆ haloalkyl) ₂ , ~S(0) ₂ NR ^{27 a} R ^{27 b} ,~0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-0C(0)(Ci C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), - (H)C(0)(CrC ₆ haloalkyl), -N(CVC ₆ alkyl)C(0)H, ~N(CrC ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, ~N(C _I~ C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ haioalkyl)C(0)(C rC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(Q) ₂ (C _I -C ₆ haloalkyl),

-N(C _I -C ₆ alk l)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ ally i)S(OHi C,, haloalkyl), -NiC -Ce haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(C _I -C ₆

haloalkyl)S(0) ₂ (C _] -C ₆ haloalkyl);

wherein R ^/~a and R ^{27 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x3 is 0, 1, 2, 3, or 4, provided than when one Z ⁹ is N, then x3 is not 4;

A ⁴ is Ce-Cio ay I optionally substituted with one or more R ²⁹ substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), 0(( ·{ ^' ,. haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(CrC ₆ aikv!} -M !(( ,-( ,, haloalkyl), -N(C.-C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl) ₂ , -NR ^{29 a} R ^{29 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(C C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(C ₁ -C ₆ alkyl) ₂

haloalkyl) ₂ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _] -C ₆ alkyl),

-S(0) ₂ NH(C ₁ -C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -S(0) ₂ N(CrC ₆ haloalkyl) ₂ , -S(0) ₂ NR ^{29 a} R ²⁹ - ^b ,-0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl),

-N(H)C(0)(C _I -C ₆ haloalkyl), -N(C -C ₆ alkyl)C(0)H, -N(C C ₆ aik\ i }( (( ⁾ }·;( -( ,. alkyl), -N(C _I -C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C _I -C ₆ haloalkyl)C(0)H, ~N(C _I~ C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆

haioalkyl)C(0)(C rC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl),

-N(C _I -C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ a!k\ DSiOWOC,.

haloalkyl), -NiC -Ce haloalkyl)S(0) ₂ (CrC ₆ alkyl), and -N(C _I -C ₆ haloalkyl)S(Q) ₂ (CrC ₆ haloalkyl);

wherein R ^{9 3} and R ^{29 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heierocycle;

provided that when R ^2ia and R ^2ib are taken together to form an oxo (=0) substituent, then R ^24a is -OH or -NH ₂ ;

(iii) when m3 is 1 and n3 is 0, then:

X ⁴ is CH and Y ⁴ is NR ^Y4 ;

R ^21a and R ^21b are taken together to form an oxo (=0) substituent or an imido (=NH) substituent;

R ^22a and R ^22b are taken together to form an oxo (=0) substituent;

A’ is Ce-Cio and optionally substituted with one or more R ² ' substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ^/ substituent;

R ⁷ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), 0(( rC,. haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(C C ₆ haloalkyl), -M l, -NH(CrC ₆ alky 1),-NH(C _! -Cg haloalkyl), -N(C.-C ₆ alkyl) ₂ , -N(C _I -C ₆ haioaikvib. -NR ^{27 a} R ^{27 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl),

-C(0)0(C C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(C ₁ -C ₆ alkyl) ₂ , -i ( 0)N( 1 , -C haloalkyl) ₂ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -StOpM H( XV. alkyl),

-S(0) ₂ NH(C ₁ -C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ , -S!0) ₂ NiC i-C,.

haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl),

-N(H)C(0)(C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)C(0)H, -N(C C ₆ aik\ i )( (( ⁾ }·;( -( ,. alkyl), -N(C _I -C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C _I -C ₆ haloalkyl)C(0)H, ~N(C _I~ C ₆ haloalkyl)C(0)(Ci~C ₆ alkyl), -N(C _I -C ₆ haioalkyl)C(0)(C rC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C _I -C ₆ alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ ally DSiOWf G, haloalkyl), -NiC -Ce haloalkyl)S(0) ₂ (CrC ₆ alkyl), and -N(C _I -C ₆ haloalkyl)S(Q)2(C -C6 haloalkyl);

wherein R ^/~a and R ^{27 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heierocycle;

A ⁴ is a substituent of the formula (A ⁴ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ^!0 is selected from the group consisting of CR ^{Z 0 i} R ^{Z10 2} , NR ^* · ^{10 2} , O, S, and -CR ^{zl0 i=} CR ^Zi(M -;

wherein

R ^{210 1} is H or R ²⁹ ; and

Z ^u is selected from the group consisting of CR ^Zl R ‘ , NR ^{ZI1 2} ; O, S, and -CR ^{Z11 1} =CR ^{Z11 1} -;

wherein

R ^Zi is H or R ²⁹ ; and

R ^{211 2} is H or R ²⁹ ;

Z ¹² , independently at each occurrence, is C or N, provided that at least one Z ⁱ² is C;

R is hydrogen or R y or R and R are taken together to form a double bond between the carbon atom bearing R ²⁸ and Z ^llJ ;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), 0(( rC,. haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -M l, -NHiCi-Ce alky 1),-NH(C _! -Cg haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)M-i(Ci-C ₆ alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0) ( ,-G,. alkyl)

haloa!ky! -C(0)NR ^{29 a} R ^{29 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -StOpM Hi VCY. alkyl),

-S(0) NI Hi VC,·, haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) _? , -S(0) ₂ N(CrC ₆ haloalkyl) ₂ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl),

-N(H)C(0)(C, -C _& haloalkyl), -N(C _I -C ₆ alkyl)C(())H, -N(C _I -C ₆

alkyl)C(0)(C ₁ -C ₆ alkyl), ~N(C _I~ C ₆ alkyl)C(O)(C ₁ -C ₆ haloalkyl), -\!( C,, haloalkyl)C(0)H, -N(C _I -C ₆ haloaHy l)C(0)(CrC ₆ alkyl), -N(Ci-C ₆ haloaikyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl),

-MCi-C,. alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C -C ₆ haloalk l)S(0) ₂ (Ci-C ₆ alkyl), and -NlCi-C, haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ²⁹ “ and R" ^{9 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

x4 is 0, 1, 2, 3, or 4, provided than when one Z ¹² is N, then x4 is not 4;

(iv) when m3 is 1 and n3 is 1 , then:

R ^{2i a} and R ^2ib are taken together to form an oxo (=0) substituent or an imido (=NH) substituent;

A ^J is Ce-Cio aryl optionally substituted with one or more R ^“ ' substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ⁷ substituent;

R ²⁷ is selected, independently at each occurrence, from the group consisting of halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, -OH, -0(( ^' i-( ^' _ό alkyl),

2,

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(C _J -C ₆ alkyl),

-N(H)C(0)(C r C ₆ haloalkyl), -N(CI-C ₆ alkyl)C(0)H, -N(C C ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(CI-C ₆ haloalkyl)C(0)H, L( ⁽ _G ⁽ \, haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ haloalky 1)C(0)(C -€, haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl),

-N(CI-C ₆ alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci~C ₆

haloalkyl), -NlC-.-Ce haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -N(C _J -C ₆

haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ^{z/ a} and R ^{7 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ⁴ is Ce-Cio aryl optionally substituted with one or more R ²⁹ substituent, or 5-10 membered heteroaryl optionally substituted with one or more R ²⁹ substituent;

R ²⁹ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -Ce haloalkyl, -OH, -0(Ci-C ₆ alkyl), 0(( rC,. haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(CrC ₆ alky 1),-NH(C _! -Cg haloalkyl), -N(C C ₆ alkyl) ₂ , -N(CI-C ₆ haloalkyl)? alkyl),

-C(Q)0{C _I -C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0)\(( ,-G,. alkyl) _? , -i ( 0)N( 1 , -C haloalkyl) ₂ alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -StOpM H< VO. alkyl),

-S(0) ₂ NH(C ₁ -C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) _? , -S(0) ₂ N(CrC ₆ haloalkyl)? alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl),

-N(H)C(0)(C _I -C ₆ haloalkyl), -N(C]-C ₆ alkyl)C(0)H, -N(C C ₆ aik\ i )( (( ⁾ )·;( -( ,. alkyl), -N(CI-C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(CI-C ₆ haloalkvl)C(0)H, -NiCi-CY haloalkyl)C(0)(Ci-C ₆ alkyl), ~N(C _I~ C ₆ haioalkyl)C(0)(C rC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyl), -N(CI-C ₆ alk l)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ ally I sSiOWi C,, haloalkyl), -N(Ci-Ce haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(C _I -C ₆ haloalkyl)S(0) ₂ (C _] -Ce haloalkyl);

wherein R ^{9 3} and R ^{29 1} ’ are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

provided that:

when one of X’ or X ⁴ is N, then r2 is 1 or 2 and s2 is 1 or 2; and when R ^z3cl and R ^z3b are taken together to form an oxo (=0) substituent, then R ^z4a is -OH or -NH ₂ .

Embodiment 12. A compound of formula (XX):

or a pharmaceutically acceptable salt thereof;

wherein:

X ^s is ( 1 1 or N;

Y ⁵ is selected from the group consisting of a bond, NR* ³ , and O; provided that when X ⁵ is N, then Y ⁵ is a bond;

R ^Y5 is hydrogen or Ci-C ₆ alkyl;

R is hydrogen or CrC ₆ alkyl;

m ⁴ , n ⁵ , p ³ , and q ⁴ , independently of each other, are 0 or 1;

r3 and s3, independently of each other, are 0, 1, or 2; A ⁱ is selected from the group consisting of:

Ce-Cio aryl optionally substituted with one or more R ^9' substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ⁹⁵

substituents;

R ⁹⁵ is sel ected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, C C ₆ haloalkyl, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -M l ·, -M I{ ⁽ V<). alkyl), -NH(CI-C ₆ haloalkyl), -N(C _r C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) ₂ , -CN, -C(0)0H, -C(0)0(C C ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C (O)NH(C i-C ₆ alkyl), -C(0)NH(C i-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{95 a} R ^{95 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(CrC ₆ alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl)?, -S(Q) ₂ N(CrC ₆ haloalkyl) _? alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N{H)C{0)(C C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(CI-C ₆ alkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ alky liHOKC haloalkyl), -N(CrCe haloalkyl)C(0)H, -N(Ci-C ₆

haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆ haloalkyl)C(0)(C C ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl),

-N(H)S(0) ₂ (CI-C ₆ haloalkyl), -N(C -C ₆ alkyl)S(0) ₂ (Ci~C ₆ alkyl), ~N(C I~C ₆ alkyl)S(0) ₂ (C _l -C ₆ haloalkyl), -N(C _I -C ₆ haloalkyl)S(0) _? (C -C ₆ alkyl), and -NfC -Ce haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ^a and R ^{95 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^84a and R ^S4b are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

R ^85a and R ^85b are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyd, and halogen;

when present, R ^86a and R ^86b are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R ^{S /a} and R ^8/b are independently at each occurrence selected from the group consisting of hydrogen, CrC ₆ alkyl, and halogen;

or, R ^84a and R ^85a are taken together to form a C1-C0 alk lene moiety; or, R ^84a and an R ^86a moiety, when present, are taken together to form a Ci-Ce alk lene moiety;

or, an R ^8oa moiety, when present, and an R ^8/a moiety, when present, are taken together to form a C -C alkylene moiety;

R ⁸⁸ is selected from the group consisting of hydrogen, CrC ₆ alkyl, Ci-Ce

haloalkyl, -C(0)(C _] -C ₆ alkyl), -C(0)(Ci-C ₆ haloalkyl), -C(0)0H, -C(0)0(Ci-C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(C C ₆ alkyl) ₂ , -C(0)N(C C ₆ haloalkyl) , alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C I-C ₆ alkyl), -S(0) ₂ NH(C C ₆ haloalkyl), -S(0)?N(Ci-C ₆ alkyl) ₂ , -S(0) ₂ N(Ci-C ₆ haloalkyl) ₂ , and -S(0) ₂ NR ^{88 a} R ^{88 b} ;

wherein R ^{88 3} and R ^{88 b} are taken together with the nitrogen ato which bears them to form a 3-10 membered heterocycle;

R ⁸⁹ is selected, independently at each occurrence, from the group consisting of hy drogen, halogen, Ci~C ₆ alkyl, Ci-Ce haloalkyl, -OH, -()(( -( ^' ,. alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(C i~C ₆ alkyl), -S(C -C ₆ haloalkyl), -NH ₂ , -NH(C _I -C ₆ alkyl), -NH(C _I -C ₆ haloalkyl), -N(C i-C ₆ alkyl) ₂ , -N(CI-C ₆ haloalkyl) _? ., -NR ^{89 a} R ^{89 b} , -CN, -C(0)0H, -C(0)0(CrC ₆ alkyl), -C(0)0(C ₁ -C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(C I-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkwK -C(0)N(Ci-C ₆ haloalkyl) ₂ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , SiO) _? i(Cx-C _e alkyl), -S(0) ₂ NH(CrC ₆ haloalkyl),

-S(0) ₂ N(CrC ₆ alkyl)?, -S(0) ₂ N(Ci~C ₆ haloalkyl) _? , -S(0) ₂ NR ^{89 a} R ^{89 b} ,-0C(0)H, OCtOKC ! · ⁽ „ alkyl), -OCiGKCh-Ci, haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(())(C C ₆ haloalkyl), -N(CI-C ₆ alkyl)C(0)H, -N(C C ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N{C alkyl)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ haloalkyl)C(0)H, -N(C C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆

haloalkyl K iOHC i-C, haloalkyl), -0S(0) ₂ (C _r C ₆ alkyl), -0S(0) ₂ (C _] -C ₆

haloalkyl), -N(H)S(0) ₂ (C _I -C ₆ alkyl), -N(H)S(0) ₂ (C C ₆ haloalkyl), -N(C C ₆ alkyl)S(0) ₂ (CrC ₆ alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(CI-C ₆ haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -N(C -Ce haloalkyl)S(0) (Ci-C ₆ haloalkyl); wherein R ^{8y a} and R ^{89 b} are taken together with the nitrogen atom winch bears them to form a 3-10 membered heterocycle; when present, R ^90a and R ^90b are taken together to form an oxo (==0) substituent or an imido (=NH) substituent, or alternatively, R ^90a and R ^90b are both hydrogen;

when present, R ^91a is selected from the group consisting of hydrogen, -OR ^91a_a , and - NR ^91a~b R ^{91a c} ;

when present, R ^91b is hydrogen;

or alternatively, R ^{9 ,a} and ll ^{9 ,b} are taken together to form a moiety selected from the

group consisting of -0-CH ₂ -CH ₂ -, -Ci h-O-CS l·-. -CH ₂ -CH ₂ -0-, -0-CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -0-CH _2~ CH _2~ , -CH ₂ -CH ₂ -O-CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -O-, -O-CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -0-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -0-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -0-CH ₂ -, and

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -0-;

when present, R ^92a and R ^92b are both hydrogen;

when present, R ^93a and R ^93b are taken together to form an oxo (=0) substituent, or

alternatively, R ^93a and R ^93b are both hydrogen;

R ^{91a a} is selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloaikyl; or R ^{ia a} and R ^Ya may be taken together to form a carbonyl (0=0) moiety; and

R ^{9la b} and R ^{9 ,a c} , independently of each other, are selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Cg haloaikyl;

provided that when m ⁴ is 0, n ^s is 0, and q ⁴ is 0, then p ^J is 1 and A ¹³ is a substituent of formula (A ^l3 ~a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁴ is selected from the group consisting of CR ²¹⁴ ^ ^{214 2} , NR ^{214 2} ,

wherein R is hydrogen or R , and , Z14-2 is hydrogen or R’ 95. wherein R ^Zl5-1 is hydrogen or R ⁹⁵ ; and R ^{Z 15 "2} is hydrogen or R ⁹⁵ ;

Z ¹⁶ , independently at each occurrence, is CH, CR ⁹⁵ , or N;

R ⁹⁴ is hydrogen or R ⁹⁵ , or R ⁹⁴ and R ^{Z 14"2} are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ¹⁴ , or R ^9'* and R ^{Z1 Z} are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ¹⁵ ; and

x23 is 0, 1, 2, 3, or 4.

Embodiment 13. A compound selected from the group consisting of a compound of Table 1 , or a pharmaceutically acceptable salt thereof.

Embodiment 14. A pharmaceutical composition comprising a compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 15. A method of treating a disease or disorder mediated by an integrated stress response (I SR) pathway in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, or a therapeutically effecti ve amount of a pharmaceutical composition of embodiment 14.

Embodiment 16. The method of embodiment 14, wherein the compound, the

pharmaceutically acceptable salt, or the pharmaceutical composition is administered in combination with a therapeutically effective amount of one or more additional anti-cancer agents.

Embodiment 17. The method of embodiment 15, wherein the disease or disorder is mediated by phosphorylation of eIF2a and/or the guanine nucleotide exchange factor (GEE) activity of eIF2B. Embodiment 18. The method of any one of embodiments 15-17, wherein the disease or disorder is mediated by a decrease in protein synthesis.

Embodiment 19. The method of any one of embodiments 15-18, wherein the disease or disorder is mediated by the expression of ATF4, CHOP or BACE-l .

Embodiment 20. The method of any of embodiments 15-19, wherein the disease or disorder is a neurodegen erative disease, an inflammatory disease, an autoimmune disease, a metabolic syndrome, a cancer, a vascular disease, an ocular disease, a musculoskeletal disease, or a genetic disorder.

Embodiment 21. The method of embodiment 20, wherein the disease is vanishing white matter disease, childhood ataxia with CNS hypomyeimation, intellectual disability syndrome, Alzheimer’s disease, prion disease, Creutzfeldt- Jakob disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) disease, cognitive impairment, frontotemporal dementia (FTD), traumatic brain injury, postoperative cognitive dysfunction (PCD), neuro-otologicai syndromes, hearing loss, Huntington’s disease, stroke, chronic traumatic encephalopathy, spinal cord injury, dementias or cognitive impairment, arthritis, psoriatic arthritis, psoriasis, j uvenile idiopathic arthritis, asthma, allergic asthma, bronchial asthma, tuberculosis, chronic airway disorder, cystic fibrosis, glomerulonephritis, membranous nephropathy, sarcoidosis, vasculitis, ichthyosis, transplant rejection, interstitial cystitis, atopic dermatitis or inflammatory bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, alcoholic liver steatosis, obesity, glucose intolerance, insulin resistance, hyperglycemia, fatty liver, dyslipidemia, hyperlipidemia, type 2 diabetes, pancreatic cancer, breast cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, urothelial cancer, endometrial cancer, ovarian cancer, cervical cancer, renal cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), multiple myeloma, cancer of secretory cells, thyroid cancer, gastrointestinal carcinoma, chronic myeloid leukemia, hepatocellular carcinoma, colon cancer, melanoma, malignant glioma, glioblastoma, glioblastoma multiforme, astrocytoma, dyspiastic gang!iocytoma of the cerebellum, Ewing’s sarcoma, rhabdomyosarcoma,

ependymoma, medulloblastoma, ductal adenocarcinoma, adenosquamous carcinoma, nephroblastoma, acinar cell carcinoma, lung cancer, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmocytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, Pelizaeus-Merzbacher disease, atherosclerosis, abdominal aortic aneurism, carotid arter' disease, deep vein thrombosis, Buerger's disease, chronic venous hypertension, vascular calcification, telangiectasia or !ymphoedema, glaucoma, age-related macular degeneration, inflammatory retinal disease, retinal vascular disease, diabetic retinopathy, uveitis, rosacea, Sjogren's syndrome or neovascularization in proliferative retinopathy, hyperhomocysteinemia, skeletal muscle atrophy, myopathy, muscular dystrophy, muscular wasting, sarcopenia,

Duchenne muscular dystrophy (DMD), Becker’s disease, myotonic dystrophy, X-linked dilated cardiomyopathy, spinal muscular atrophy (SMA), Down syndrome, MEHMO syndrome, metaphyseal chondrodysplasia, Schmid type (MCDS), depression, or social behavior impairment.

Embodiment 22. A method of producing a protein, comprising contacting a eukaryotic cell comprising a nucleic acid encoding the protein with the compound or salt of any one of embodiments 1-13.

Embodiment 23. The method of embodiment 22, comprising culturing the cell in an in vitro culture medium comprising the compound or salt.

Embodiment 24. A method of culturing a eukaryotic cell comprising a nucleic acid encoding a protein, comprising contacting the eukaryotic cell with an in vitro culture medium comprising a compound or salt of any one of embodiments 1-13.

Embodiment 25. The method of any one of embodiments 22-24, wiierem the nucleic acid encoding the protein is a recombinant nucleic acid.

Embodiment 26. The method of any one of embodiments 22-25, wherein the ceil is a human embryonic kidney (HEK) cell or a Chinese hamster ovary (CHO) cell

Embodiment 27. The method of any one of embodiments 22-25, wherein the cell is a yeast cell, a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell, a baby hamster kidney cell, a murine myeloma cell, an HT-1080 cell, a PE .C6 cell, a plant cell, a hyhridoma cell, or a human blood derived leukocyte

Embodiment 28. A method of producing a protein, comprising contacting a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with the compound or salt of any one of embodiments 1-13.

Embodiment 29. The method of any one of embodiments 22-28, wherein the protein is an antibody or a fragment thereof.

Embodiment 30. The method of any one of embodiments 22-28, wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor.

Embodiment 31. The method of any one of embodiments 22-30, comprising purifying the protein.

Embodiment 32. An in vitro cell culture medium, comprising the compound or salt of any one of embodiments 1-13 and nutrients for cellular growth.

Embodiment 33. The cell culture medium of embodiment 32, comprising a eukaryotic cell comprising a nucleic acid encoding a protein.

Embodiment 34. The cell culture medium of embodiment 32 or 33, further comprising a compound for inducing protein expression.

Embodiment 35. The cell culture medium of any one of embodiments 32-34, wherein the nucleic acid encoding the protein is a recombinant nucleic acid.

Embodiment 36. The cell culture medium of any one of embodiments 32-35, wherein the protein is an antibody or a fragment thereof. Embodiment 37. The cell culture medium of any one of embodiments 32-35, wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor.

Embodiment 38. The cell culture medium of any one of embodiments 32-37, wherein the eukaryotic cell is a human embryonic kidney (HEK) cell or a Chinese hamster ovar' (CHO) cell.

Embodiment 39. The cell culture medium of any one of embodiments 32-37, wherein the cell is a yeast cell, a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell, a baby hamster kidney cell, a murine myeloma cell, an HT- 1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood derived leukocyte

Embodiment 40. A cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with the compound or salt of any one of embodiments 1-13.

Embodiment 41. The CFPS system of embodiment 40, comprising a eukaryotic cell extract comprising elF2.

Embodiment 42, The CFPS system of embodiment 40 or 41, further comprising eIF2B

Embodiment 43. The CFPS system of any one of embodiments 40-42, wherein the protein is an antibody or a fragment thereof.

Embodiment 44. The CFPS system of any one of embodiments 40-43, wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor.

Embodiment 1 A. A compound of formula (1 -2):

or a pharmaceutically acceptable salt thereof;

wherein:

X ² is CH;

R ^Yl is hydrogen or Ci-C ₆ alkyl;

Y ² is selected from the group consisting of NR ² and O;

R ^Y2 is hydrogen or Ci-Ce alkyl;

q ² is 1;

r and s, independently of each other, are 0, 1, or 2;

A ¹ is a substituent of formula (A^a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹ is selected from the group consisting of CR ^{Zl l} R ^{Z1 2} , NR ^Z1 \ O, S, and -CR ^{Z1 1} =CR

wherein

Z" is selected from the group consisting of CR- R ^Z~ , NI¾C ^Z ; O, S, and -CR^ ^CR ²² - ¹ -;

wherein R ^{22 1} is H or R ¹⁴ ; and R ^{Z2 z} is H or R ¹⁴ ;

Z ³ , independently at each occurrence, is C or N, provided that at least one Z ³ is C;

R ^l3 is hydrogen or R ¹⁴ , or R ^1J and R ^Z1~2 are taken together to form a double bond between the carbon atom bearing R and Z , or R and R are taken together to form a double bond between the carbon atom bearing R‘ and Z ² ; and

xl is 1, 2, 3, or 4, and at least one R ⁱ⁴ is halogen;

R ¹⁴ is selected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, CrCe haloalky!, -OH, -OiC -Ce alkyl), -0(C -Ce ha!oa!kyl), -SH, -S(C _3~ C _ft alkyl), S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CVC6 alkyl),-NH(C _] -C6 haloalkyl), -N(C ₃ - C ₆ alkyl) _? ., -N(C ₃ -C ₆ haloalkyl) ₂ , -NR ^{14 3} R ^{14 b} , -CN, -C(0)0H, -C(0)0(C C ₆ alkyl),

-0C(0)(C _r C ₆ haloalkyl), -N(H)C(OJH, -N(H)C(0)(C C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C C ₆ alkyl)C(0)(CrC ₆ alkyl), -N(C _I -C ₆ aik\ i )( (()}·; ( -( ,, haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C _J -C ₆ haloalkyl )CiO)iC _r C,, haloalkyl),

-0S(0)?(Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0)?(Ci-C ₆ alkyl),

-N(H)S(0) _? (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0)?(C ₁ -C6 alkyl), -N(C C ₆ alkyl)S(0) _? (Ci~C ₆ haloalkyl), haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -N(C -C ₆ haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl):

wherein R ^{i4 3} and R ^{14 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

A ² is C Cio aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ⁶ substituents;

R ¹⁶ is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, C C ₆ haloalkyl, -OH, -0(C C ₆ alkyl), -0(C _r C ₆ haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH _? , -NH(C C ₆ aih\i}.-Xi KC rC,, haloalkyl), -N(Ci- C ₆ alkyl) _? , -N(C _I -C ₆ haloalkyd) _? , -NR ^{io 3} R ^{!o b} , -CN, -C(0)0H, -C(0)0(Ci-Ce alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH _? , -C(0)NH(C _] -C ₆ alkyl), -C(0)NH(C C ₆ haloalkyl), -C(0)N(C ₃ -C ₆ alkyl) _? , -C(0)N(C ₃ -C ₆ haloalkyl) _? , -C(0)NR ^{16 a} R ^{16 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _I -C ₆ alkyl), -S(0) ₂ 0(Ci~C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(C _I -C ₆ alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyl), -S(()} .\{( _r C,, alkyl) ₂ , -S(0) ₂ N(C _I -C ₆ haloalkyl) _? ., -S(0) ₂ NR ^{16 a} R ^{16 b} ,-0C(0)H, -0C(0)(Ci-C ₆ alkyl),

-()( ( OK ( -( ,, haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl)

haloalkyl), -N(C C ₆ alkyl)C(0)H, AiC _r( ^' , alkyl)C(0)(Ci-C ₆ alkyl), -N(C _I -C ₆ alk}'l)C(0)(Ci-C ₆ haloalkyl), -N(C -C ₆ haloalkyl)C(0)H, -N(CrC ₆

haioalkyl)C(0)(CrC ₆ alkyl), -N(CrC ₆ haioalkyl)C(0)(CrC ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (C C ₆ haloalkyl), -N(H)S(0) ₂ (C ₁ -C ₆ alkyl),

-N(H)S(0) ₂ (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -\iC _r C,, alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(CI-C ₆ haloalliy )S(0) ₂ (C ₁ -C ₆ haloalkyl);

wherein R ^{l6 a} and R ^16_b are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^la and R ^lb are independently selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

R ^a and R ^Jb are independently selected from the group consisting of hydrogen, Ch-Ce alkyl, and halogen;

when present, R ^a and R ^b are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R ^’a and R ^’b are independently at each occurrence selected from the group consisting of hy drogen, Ci-Ce alkyl, and halogen;

or alternatively, R ^ia and R ^a are taken together to form a Ci-Ce alkylene moiety;

or alternatively, R ^la and an R ^3a moiety , when present, are taken together to form a C -Ce alkylene moiety, and R ^lb and the R ^¾ in the geminal position to the R ^3a taken together with R ^a , are both hydrogen;

or alternatively, an R ^a moiety , when present, and an R ^4a moiety, when present, are taken together to form a C -Ce alkydene moiety , and the R ^,h in the geminal position to the R ^3a taken together with the R ^4a moiety and the R ⁴¹ ’ in the geminal position to the R ^4a taken together with the R ^Ja moiety, are both hydrogen;

R ^9a and R ^9b are taken together to form an oxo (=0) substituent or an irnido (=NH)

substituent;

R ^10a is hydrogen; and R ^1,,b is hydrogen.

Embodiment 2A. The compound of embodiment 1 A, or a pharmaceutically acceptable salt thereof, wherein xl is 1 and R ¹⁴ is halogen.

Embodiment 3 A. A compound of formula (1-3):

or a pharmaceutically acceptable salt thereof;

wherein:

X ² is Cl 1 or X:

R ^{Y l} is hydrogen or Ci-C ₆ alkyl;

Y ² is selected from the group consisting of a bond, NR ^Y2 , and O; provided that when X ² is N, then Y ² is a bond;

R ^{Y 2} is hydrogen or Ci-Ce alkyl;

r and s, independently of each other, are 0, 1 , or 2;

A ¹ is selected from the group consisting of:

a substituent of formula (A^a)

wherein

* represents the attachment point to the remainder of the molecule; Z ¹ is selected from the group consisting of CR ^{Zl 1} R ^{Z3 2} , NR ^{Z1 2} , O, S, and -CR ^{Z1 1} =CR ^{Z1 1} -;

wherein K ^z ’ ⁴ is H or R ⁱ⁴ ; and R ^{l 2} is H or R ^l4 ; 7J is selected from the group consisting of€K ^Z ¾ ^Z/ , NR ^{Z2 z} ; O, S, and ~CR ^{Z2 i} =CR ^{Z2 i} -;

wherein R ^Z2_1 is H or R ¹⁴ ; and R ^{Z2 2} is H or R‘ ⁴ ;

Z ^J , independently at each occurrence, is C or N, provided that at least one Z is C;

R ¹³ is hydrogen or R ¹⁴ , or R ¹³ and R ² are taken together to form a double bond between the carbon atom bearing R ^l and Z ¹ , or R ^l and R ^Z2~2 are taken together to form a double bond between the carbon atom bearing R” and Z ² ; and

xl is 1, 2, 3, or 4, and at least one R ⁱ⁴ is halogen;

R ¹⁴ is selected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, CrCe haloalky!, -OH, -OfC -Ce alkyl), -0(C -Ce ha!oa!kyl), -SH, -S(Ci~ C _ft alkyl), S(Ci-C ₆ haloalkyl), -NH ₂ , -NHfC -Cc, alkyl),-NH(C _] -C ₆ haloalkyl), -N(Cr C ₆ alkyl) _? ., -N(C _I -C ₆ haloalkyl) ₂ , -NR ^{14 3} R ^{14 b} , -CN, -C(0)0H, -C(0)0(C C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) _? , -C(0)N(C C ₆ haloalkyl) _? , -C(0)NR ^{14 3} R ^{l4 b} , -S(0) _? 0H, -S(0) ₂ 0(C _r C ₆ alkyl), -S(0) _? 0(CrC ₆ haloalkyl), -S<0) XI ! _? .

-S(0) _? NH(CrC ₆ alkyl), -S(0) ₂ NH(C _r C ₆ haloalkyl), -S(0) _? N(C C ₆ alkyl) _? , -S(0) ₂ N(CrC ₆ haloalkyl) _? alkyl), -0C(0)(C _r C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(C C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -XiiVC,·, alkyl)C(0)(CrC ₆ alkyl), -N(C C ₆ aik\ i )( (()}·; ( -( ,, haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haioaikyl)C(0)(CrC ₆ alkyl), -N(CJ-C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyl),

-0S(0) _? (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) _? (Ci-C ₆ alkyl),

-N(H)S(0) _? (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0) ₂ (C ₁ -C ₆ alkyl), -N(C C ₆ alkyl)S(0) _? (Ci~C ₆ haloalkyl), haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -N(C -C ₆ haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl):

wherein R ^{i4 3} and R ^{14 b} are taken together with the nitrogen atom which bears them to form a 3-10 rnemhered heterocycle;

A ² is Ce-Cio aryd substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ^l6 substituents;

R ^lb is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, C C ₆ haloalkyl, -OH, -0(C C ₆ alkyl), -0(C C ₆ haloalkyl), -SH, -S(Ci- C¾ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(Ci-C ₆ alkyl), -NH(C _I -C ₆ haloalkyl), -N(Cr C ₆ alky 1) ₂ , -N(C _I -C ₆ haloalkyl) ₂ , -NR ^{i6 a} R ^{!6 b} , -CN, -C(0)0H, -C(0)0(Ci-C ₆ alkyl), -C(Q)0{C _I -C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(C C ₆ haloalkyl), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{16 a} R ^{16 b} , -S(0) ₂ 0H, -S(0) ₂ 0(Ci-C ₆ alkyl), -S(0) ₂ 0(Ci~C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

S(();;N1 !{( ^' ·( ^' , alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyl) ₂ ,

alkyl), )C(0){C _r C„ haloalkyl), -N(C C ₆ alkyl)C(0)H, Ait U-P. alkyl)C(0)(C _r C ₆ alkyl), -N(C _I -C ₆ alkyi)C(0)(CrC ₆ haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haloalkyl)C(0)(CrC ₆ alkyl), -N(C C ₆ haloaikyl)C(0)(CrC ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -OSiOpiC VH haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl),

-N(H)S(0) ₂ (C _I -C ₆ haloalkyl), -N(C _r C ₆ aiky3)S(0) ₂ (C ₃ -C ₆ alkyl), A,(( _r C, alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), A(( ₍ ,, haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and AiCVC,. haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ^{l6 a} and R ^{lo b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^la and R ^lb are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

R ^2a and R ^2b are independently selected from the group consisting of hydrogen, C-.-Cs alkyl, and halogen;

when present, R ^3a and R ^3b are independently at each occurrence selected from the group consisting of hydrogen, C -C ₆ alkyl, and halogen;

when present, R ^4a and R ^4b are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

or alternatively, R ^la and R ^2a are taken together to form a Ci-C _f , alkylene moiety'; or alternatively, R ^ia and an R ^3a moiety, when present, are taken together to form a Ci-Ce alkylene moiety , and R ^!b and the R ^b in the gemina! position to the R ^3a taken together with R ^ia , are both h drogen;

or alternatively, an R ^3a moiety, when present, and an R ^4a moiety, when present, are taken together to form a C -Ce alkylene moiety, and the R ^b in the geminal position to the R ^a taken together with the R ^4a moiety' and the R ^4b in the geminal position to the R ^4a taken together with the R ^3a moiety, are both hydrogen;

R ^9a and R ^9b are taken together to form an oxo (==0) substituent or an imido ( ^: =NH)

substituent, or alternatively, R ^9a and R ^9b are both hydrogen;

R ^10a is selected from the group consisting of hydrogen, -OR ^{10a a} , and -NR ^{3ua b} R ^! ° ^a~c ;

R ^10b is hydrogen;

R ^!2a and R ^!2b are taken together to form an oxo (=0) substituent, or alternatively, R ^l2a and R ^,2b are both hydrogen;

R ^{10a a} is selected from the group consisting of hydrogen, Ci-Ce alkyl, and CrC ₆ haloalkyl; or R ^{i0a a} and R ^Y2 may be taken together to form a carbonyl (C ^:=: 0) moiety; and

R ^{IOa b} and R ^{,0a c} , independently of each other, are selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Cs haloalkyl.

Embodiment 4 A. The compound of embodiment 3 A, or a pharmaceutically acceptable salt thereof, wherein xl is 1 and R ¹⁴ is halogen.

Embodiment 5 A. A compound of formula (2-3):

or a pharmaceutically acceptable salt thereof;

wherein:

X ³ and X ^z , independently of each other, are CH or N; provided that at least one of X ¹ and X ² is CH; Y ^] is selected from the group consisting of a bond, NR ^{Y l} , and O; provided that when X ¹ is N, then Y ¹ is a bond;

R ^Yi is hydrogen or Ci-C _& alkyl;

Y ² is selected from the group consisting of a bond, NR ^Y2 , and O; provided that when X ² is N, then Y ² is a bond;

R ^Y2 is hydrogen or C -C ₆ alkyl;

ql is 1;

r and s, independently of each other, are 0, 1, or 2;

A ¹ is Ce-Cio aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ^¾ substituents;

R ¹⁴ is selected, independently at each occurrence, from the group consisting of halogen, Ci-C ₆ alkyl, C C ₆ haloalkyl, -OH, -0(C ₃ -C ₆ alkyl), -0<C ₃ -C ₆ haJoalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(C C ₆ alkv!) -NH(( ₍ ,, haloalkyl), -N(Ci- C ₆ alkyl) ₂ , -N(C _I -C ₆ haloalkyl) , -NR ^{14 3} R ^{14 b} , -CN, -C(0)0H, -C(0)0(Cj-C ₆ alkyl), -C{0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(Ci-C ₆ haloalkyl), -C(0)N(C _3~ C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ , -C(0)NR ^{14 a} R ^{14 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _I -C ₆ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(C C ₆ alkyl), -S(0) ₂ NH(C ₃ -C ₆ haloalkyl), -S(0) ₂ N(C _r C ₆ alkyl },.

-S(0) ₂ N(C ₃ -C ₆ haloalkyl),, -S(0) ₂ NR ^{14 a} R ^{i4 b} ,-0C(0)H, -0C(0)(Ci-C ₆ alkyl), -0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyl), -N(C _J -C ₆ alky I K (0)1 f. -NUY-iti alkyl }( (()}{( i-Cti alkyl), -N(C _I -C ₆ alkyl)C(0)(CrC ₆ haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haloalkyl)C(0)(C C ₆ alkyl), -N(C C ₆ haloa ^] kyl)C(0)(C C ₆ haloalkyl),

-0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (CrC ₆ haloalkyl), ~N(H)S(0) ₂ (C -C ₆ alkyl),

-N(H)S(0) ₂ (C _] -C ₆ haloalkyd), -N(C -C ₆ alkyl)S(0) ₂ (C _l -C ₆ alkyl), -N(C _I -C ₆ alkyl)S(0) ₂ (Ci-C ₆ haloalkyl), -N(C C ₆ haloalky3)S(0) ₂ (C ₃ -C ₆ alkyl), and -N(C ₃ -C ₆ haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl);

wherein R ^{,4 a} and R ^{!4 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle; A ^z is C -C aryl substituted by at least one halogen substituent and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least one halogen substituent and optionally further substituted with one or more R ⁶ substituents;

R ¹⁶ is sel ected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, C C ₆ haloalkyi, -OH, -0(Ci-C ₆ alkyl), -0(Ci-C ₆ haloalkyi), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyi), ·CP ·, -\1 1{(VC, alkyl), -NH(C _I -C ₆ haloalkyi), -N(C _r C ₆ alkyl) ₂ , -N(C C ₆ haloalkyl) ₂ , -NR ^{16 a} R ^{16 b} , -CN, -C(0)0H, -C(0)0(C C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyi), -C(0)NH ₂ , -C (O)NH(C i-C ₆ alkyl), -C(0)NH(C i-C ₆ haloalkyi), -C(0)N(Ci-C ₆ alkyl) ₂ , -C(0)N(Ci-C ₆ haloalkyl) ₂ -C(0)NR ^{16 a} R ^{16 b} , -S(0) ₂ 0H, -S(0) ₂ 0(C _r C ₆ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyi), -S(0) ₂ NH ₂ ,

-S(0) ₂ NH(CrC ₆ alkyl), -S(0) ₂ NH(Ci-C ₆ haloalkyi), -S(0) ₂ N(Ci-C ₆ alkyl)?,

wherein R and : are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^la and R ^lb are independently selected from the group consisting of hydrogen, C-.-Cs alkyl, and halogen;

R ^2a and R ^2b are independently selected from the group consisting of hydrogen, Ci-C ₆ alky _' l, and halogen;

when present, R ^ia and R ^ib are independently at each occurrence selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R* ^a and R* ^b are independently at each occurrence selected from the group consisting of hydrogen, CrC ₆ alkyl, and halogen;

or alternatively, R ^a and R ^2a are taken together to form a Ci-Ce alkylene moiety; or alternatively, R ^ia and an R ^a moiety, when present, are taken together to form a Ci-Ce alkyiene moiety , and R ^!b and the R ^b in the gemina! position to the R ^3a taken together with R ^ia , are both hydrogen;

or alternatively, an R ^3a moiety, when present, and an R ^4a moiety, when present, are taken together to form a C -Ce alkyiene moiety, and the R ^b in the geminal position to the R ^a taken together with the R ^4a moiety' and the R ^4b in the geminal position to the R ^4a taken together with the R ^3a moiety, are both hydrogen;

R ^5a and R ^5b are taken together to form an oxo (==0) substituent or an imido ( ^: =NH)

substituent;

R ^ba is hydrogen;

R ^bb is hydrogen;

R ^9a and R ^9b are taken together to form an oxo (=0) substituent or an imido (=NH)

substituent, or alternatively, R ^9a and R ^9b are both hydrogen;

R ^10a is selected from the group consisting of hydrogen, -OR ^10a~a , and -NR ^{10a b} R ^{i0a c} ;

R ^10b is hydrogen;

R ^{l a} and R ^{l b} are taken together to form an oxo (=0) substituent, or alternatively, R ^,2a and R ^i2b are both hydrogen;

R ^{10a a} is selected from the group consisting of hydrogen, Ci-Ce alkyl, and C -C ₆ haloalkyl; or R ^{10a a} and R ² may be taken together to form a carbonyl (C=G) moiety;

R ^{!0a b} and R ^l0i , independently of each other, are selected from the group consisting of hydrogen, C1-C0 alkyl, and Ci-Ce haloalkyl; and

provided that when X ² is N, then:

A ¹ is Ce-Cio aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ^a substituents; and

A is Ce-Cio aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ^lb substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁶ substituents. Embodiment 6A. The compound of embodiment 5 A, or a pharmaceutically acceptable salt thereof, wherein X ¹ is CH and X ^’ is CH.

Embodiment 7A. The compound of embodiment 5 A, or a pharmaceutically acceptable salt thereof, wherein X ¹ is N and X ² is CH.

Embodiment 8A. The compound of embodiment 5A, or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is CH;

X ² is N;

A ¹ is Ce-Cio ar l substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁴ substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ^l4 substituents; and

A ^z is C ₆ -C _IG aryl substituted by at least two halogen substituents and optionally further substituted with one or more R ¹⁶ substituents, or 5-10 membered heteroaryl substituted by at least two halogen substituents and optionally further substituted with one or more R ⁶ substituents.

Embodiment 9 A. A compound of formula (XX):

or a pharmaceutically acceptable salt thereof;

wherein:

X is CH or N; Y ³ is selected from the group consisting of a bond, NR ^Y5 , and O; provided that when X ³ is N, then Y ³ is a bond;

R ^Y5 is hydrogen or Ci-C _& alkyl;

R ^N is hydrogen or Ci-Ce alkyl;

nr, n ⁵ , p ³ , and q ⁴ , independently of each other, are 0 or 1;

r3 and s3, independently of each other, are 0, 1, or 2;

A ¹³ is selected from the group consisting of:

Cg-Cio aryl optionally substituted with one or more R ⁹⁵ substituents; and

5-10 membered heteroaryl optionally substituted with one or more R ⁹⁵

substituents;

R ⁹³ is selected, independently at each occurrence, from the group consisting of halogen, CrC ₆ alkyl, CrCe haloalky!, -OH, -0(Ci-C ₆ alkyl), -0(Ci-Ce ha!oa!kyl), -SH, -S(Ci~ C _ft alkyl), S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CVC6 alkyl),-NH(C _] -C6 haloalkyl), -N(Cr C ₆ alkyl) _? ., -N(C _I -C ₆ haloalkyl) ₂ , - alkyl), -C(0)0(Ci-C ₆ haloalkyl) alkyl), -C(0)NH(Ci-C ₆ haloalkyl), ~C(0)N(C C ₆ alkyl) _? , ~C(0)N(C C ₆ haloalkyl) _? , -C(0)NR ^{95 3} R ^9Yb , -S(0) _? 0H, -S(0) _? 0(CrC ₆ alkyl), -S(0) _? 0(CrC ₆ haloalkyl), -S(0) _? NH _? ,

-S(0) _? NH(CrC ₆ alkyl), -S(0) ₂ NH(C _r C ₆ haloalkyl), -S(0) _? N(C C ₆ alkyl) _? ,

-S(0) _? N(C _I -C ₆ haloalkyl) _? alkyl), -0C(0)(C _r C ₆ haloalkyl), -N(H)C(OJH, -N(H)C(0)(C C ₆ alkyl), -N(H)C(0)(Ci-C ₆ haloalkyl), -N(C C ₆ alkyl)C(0)H, -N(C C ₆ alkyl)C(0)(CrC ₆ alkyl), -N(C C ₆ aik\ i )( (()}·; ( -( ,, haloalkyl), -N(C _r C ₆ haloalkyl)C(0)H, -N(C C ₆

haloalkyl)C(0)(Ci-C ₆ alkyl), -N(CJ-C ₆ haloalkyl)C(0)(Ci-C ₆ haloalkyl),

-0S(0)?(Ci-C ₆ alkyl), -0S(0)?(Ci-C ₆ haloalkyl), -N(H)S(0)?(Ci-C ₆ alkyl),

-N(H)S(0) _? (C _I -C ₆ haloalkyl), -N(C _r C ₆ alkyl)S(0)?(C ₁ -C6 alkyl), -N(C C ₆ alkyl)S(0) ₂ (Ci~C ₆ haloalkyl), ~\(C ~C,·, haloalkyl)S(0) ₂ (C -C ₆ alkyl), and -N(C -C ₆ haloalkyl)S(0) ₂ (C _l -C ₆ haloalkyl);

wherein R ^{95 3} and R ^{95 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ^84a and R ^S4b are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen; R ^85a and R ^85b are independently selected from the group consisting of hydrogen, Ci-C ₆ alkyl, and halogen;

when present, R ^Sba and R ^Sbb are independently at each occurrence selected from the group consisting of hydrogen, Ci-Ce alkyl, and halogen;

when present, R ' and R ' are independently at each occurrence selected from the group consisting of hydrogen, C -C ₆ alkyl, and halogen;

or, R ^84a and R ^85a are taken together to form a Ci-Ce alkylene moiety;

or, R ^84a and an R ^86a moiety, when present, are taken together to form a Ci-Ce alkylene moiety;

or, an R ^8oa moiety, when present, and an R ^{8 /a} moiety, when present, are taken together to form a C -C alkylene moiety;

R ⁸⁸ is selected from the group consisting of hydrogen, CrC ₆ alkyl, CrCe

haloalkyl, -C(0)(C _] -C ₆ alkyl), -C(0)(Ci-C ₆ haloalkyl), -C(0)0H, -C(0)0(Ci-C ₆ alkyl), -C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl),

-C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(C C ₆ alkyl) ₂ , -C(0)N(C C ₆ haloalkyl) ₂ , alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , -S(0) ₂ NH(C _I -C ₆ alkyl), -S(0) ₂ NH(C C ₆ haloalkyl), -S(0) ₂ N(Ci-C ₆ alkyfty -S(0) ₂ N(Ci-C ₆ haloalkyl) ₂ , and -S(0) ₂ NR ^{88 a} R ^{88 b} ;

wherein R ^{88 3} and R ^{88 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

R ⁸⁹ is selected, independently at each occurrence, from the group consisting of hydrogen, halogen, Ci~C ₆ alkyl, Ci-C ₆ haloalkyl, -OH, -()(( ]-( ^' ,. alkyl), -0(Ci-C ₆ haloalkyl), -SH, -S(Ci-C ₆ alkyl), -S(Ci-C ₆ haloalkyl), -NH ₂ , -NH(CI-C ₆ alkyl), -NH(CI-C ₆ haloalkyl), -N(C i-C ₆ alkyl) ₂ , -N! ( >·<!. haloalkyl) _? ., -NR ^{89 a} R ^{89 b} , -CN, -C(0)0H, -C(0)0(CrC ₆ alkyl), -C(0)0(C ₁ -C ₆ haloalkyl), -C(0)NH ₂ , -C(0)NH(Ci-C ₆ alkyl), -C(0)NH(C _I -C ₆ haloalkyl), -C(0)N(Ci-C ₆ alktyK -C(0)N(Ci-C ₆ haloalkyl) ₂ alkyl), -S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) ₂ NH ₂ , SiO) _? i(Cx-C _e alkyl), -S(0) ₂ NH(C C ₆ haloalkyl),

-S(0) ₂ N(CrC ₆ alkyl)?, -S(0) ₂ N(Ci~C ₆ haloalkyl) _? , -S(0) ₂ NR ^{89 a} R ^{89 b} ,-0C(0)H, -0C(0)(C -C ₆ alkyl), -0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ alkyl), -N(H)C(0)(C _I -C ₆ haloalkyl), -NiCVCY. alkyl)C(0)H, -N(C C ₆

alkyl)C(0)(Ci-C ₆ alkyl), -N(CI-C ₆ alkyl)C(0)(Ci-C ₆ haloalkyl), -N(CI-C ₆ ha ^] oalkyl)C(0)H, -N(C C ₆ haloalkyl)C(0)(Ci-C ₆ alkyl), -N(C C ₆

haloalkyl)C(0)(Ci-C ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ (Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (Ci-C ₆ alkyl), -N(H)S(0) ₂ (Ci-C ₆ haloalkyi), -N(CI -C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C C ₆ ally i)S(OHi C,, haloalkyl), -\!( ₍ ,, haloalk l)S(0) ₂ (Ci~C ₆ alkyl), and -N(CrC ₆ haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl); wherein R ^{89 a} and il ^{S9 b} are taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;

when present, R ^90a and R ^90b are taken together to form an oxo (=0) substituent or an

imido (=NH) substituent, or alternatively, R ^90a and R ^90b are both hydrogen;

when present, R ^91a is selected from the group consisting of hydrogen, -OR ^91a_a , and - NR ^91a~b R ^{91a c} ;

when present, R ^9lb is hydrogen;

or alternatively, R ^{9 ,a} and ll ^{9 ,b} are taken together to form a moiety selected from the

group consisting of -0-CH ₂ -CH ₂ -, -Ci k-O-Ci l·-. -CH ₂ -CH ₂ -0-, -0-CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -O-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -O-CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -O-, -O-CH ₂ -CH ₂ -CH ₂ -CH ₂ -,

-CH ₂ -0-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -0-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -0-CH ₂ -, and

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -0-;

when present, R ^92a and R ^92b are both hydrogen;

when present, R ^93a and R ^93b are taken together to form an oxo (=0) substituent, or

alternatively, R ^93a and R ^93b are both hydrogen;

R ^{91a a} is selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Ce haloalkyl; or R ^{ia a} and R ^Y:! may be taken together to form a carbonyl (0=0) moiety; and

R ^{9la b} and R ^{9 a c} , independently of each other, are selected from the group consisting of hydrogen, Ci-Ce alkyl, and Ci-Cs haloalkyl;

provided that when m ⁴ is 0, n ^s is 0, and q ⁴ is 0, then p ^J is 1 and A ¹³ is a substituent of formula (A ^l3 ~a)

wherein

* represents the attachment point to the remainder of the molecule; r!4 is selected from the group consisting of CR ^Zl41 R ^Z]42 , NR Z14-2

wherein R ^{Z 4_1} is hydrogen or R ⁶ ; and R ^Z142 is hydrogen or R ⁹⁵ ; Z ¹⁵ is selected from the group consisting of CR ^{Z i} R ^Z152 , NR ^l52 ,

C (R ^{z 151} R ^{z 152} ) N (R ^{z 152} ) , O, C(R ^Z151 R ^Z152 )0, S. C<R ^/I R ^/I< "’)S. and -CR ^Z151 =CR ^z151 -:

wherein R is hydrogen or R ^_ ; and R is hydrogen or R . Z ¹⁶ , independently at each occurrence, is CH, CR ⁹⁵ , or N;

R ⁹⁴ is hy drogen or R ⁹⁵ , or R ⁹⁴ and R ^Z142 are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ¹⁴ , or R ^9'* and R ^zl32 are taken together to form a doubl e bond between the carbon atom bearing R ⁹⁴ and Z ¹⁵ ; and

x23 is 0, 1 2, 3, or 4.

Embodiment 10A. The compound of embodiment 9 A, wherein the compound of formula

(XX) is a compound of formula (XX-I):

or a pharmaceutically acceptable salt thereof.

Embodiment 11 A. The compound of embodiment 10A, wherein the compound of formula (XX-I) is a compound of formula (XX-I- 1):

(CC-ί-1)

or a pharmaceutically acceptable salt thereof;

wherein R ^N , R’ R ⁸⁸ , R ⁸⁹ , R ^93a , and R ^93b are as defined in the compounds of formula (XX), and wherein A ¹ is a substituent of formula (A ¹³ -a)

wherein

* represents the attachment point to the remainder of the molecule;

Z ¹⁴ is selected from the group consisting of CR ^{Zl4 1} R ^{14 2} , NR ^{Z14 2} ,

wherein R ^{214 1} is hydrogen or R ^l6 ; and R ^{Z14 2} is hydrogen or R ⁹⁵ ; Z ¹⁵ is selected from the group consisting of NR ^{215 2} ,

wherein R ^{Z 5_1} is hydrogen or R ⁹⁵ ; and R ^{Z15 2} is hydrogen or R ⁹⁵ ; Z ^!6 , independently at each occurrence, is CH, CR ⁹¹ , or N;

R ⁹⁴ is hydrogen or R ⁹⁵ , or R ⁹⁴ and R ^{Z14 2} are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z ¹⁴ , or R ⁹⁴ and R ^{l5 2} are taken together to form a double bond between the carbon atom bearing R ⁹⁴ and Z”;

x23 is 0, 1, 2, 3, or 4; and

R ⁹³ is selected, independently at each occurrence, from the group consisting of halogen, C -Ce alkyl, C -Ce ha!oa!kyl, -OH, -0(Ci~C ₆ alkyl), -OiC i-C,. haloalkyl), -SH, -S(C C ₆ alkyl), -S(C C ₆ haloalkyl), -NH ₂ , -NH(Ci-Ce alkyl),-NH(Ci-C ₆ haloalkyl), -N(C -C ₆ alkyl) , -N(Ci-C ₆ haloalkyl) ₆ alkyl),

-C(0)0(Ci-C ₆ haloalkyl), -C(0)NH ₂ , ~i i ⁽ >}\l !{( VCV alkyl),

-C(0)NH(CI-C ₆ haloalkyl), -C(0)N(Ci-C ₆ alky 1 ) ·. -C(0)N(Ci-C ₆ haloally 1 alkyl),

-S(0) ₂ 0(Ci-C ₆ haloalkyl), -S(0) _? NH ₂ , -S(0) ₂ NH(Ci-C ₆ alkyl),

-S(0) ₂ NH(CI-C ₆ haloalkyl), -S(0) N(Ci~C ₆ alkyl) ₂ , -S« ⁾ ) .N( ^{( '} i- ⁽ \. haloally. I ₆ alkyl),

-0C(0)(Ci-C ₆ haloalkyl), -N(H)C(0)H, -N(H)C(0)(Ci-C ₆ ally !), -N(H)C(0)(C _I -C ₆ haloalkyl) alkyl)C(0)H, ~N(C _I~ C ₆

alkyl)C(0)(Ci-C ₆ alkyl), Lί ⁽ _G ^{( '} ·. alkyl)C(0)(Ci-C ₆ haloalkyl), -N(CI-C ₆ haloalkyl)C(0)H, - (C _J -C ₆ haloallyd)C(0)(Ci-C ₆ alkyl), -N(C -C ₆ haloalkyl)C( ⁽⁾ )(CrC ₆ haloalkyl), -0S(0) ₂ (Ci-C ₆ alkyl), -0S(0) ₂ {Ci-C ₆ haloalkyl), -N(H)S(0) ₂ (C C ₆ alkyl), -N(H)S(0) _? (C ₁ -C ₆ haloalkyl),

-N(CI-C ₆ alkyl)S(0) ₂ (Ci-C ₆ alkyl), -N(C _J -C ₆ alkyl)S(0) _? (Ci-C ₆ haloalkyl), -N(CrC ₆ haloalkyl)S(0) ₂ (Ci-C ₆ alkyl), and -N(CI-C ₆ haloalkyl)S(0) ₂ (Ci-C ₆ haloalkyl).

Embodiment 12A. The compound of embodiment 10A, wherein the compound of formula

(XX-I) is a compound of formula (XX-I-2):

or a pharmaceutically acceptable salt thereof.

Embodiment 13 A. The compound of embodiment ! 0A, wherein the compound of formula

(XX-I) is a compound of formula (XX-I-2b):

or a pharmaceutically acceptable salt thereof.

Embodiment 14A. The compound of embodiment 10A, wherein the compound of formula

(XX-I) is a compound of formula (XX-I-3):

(XX-I-3)

or a pharmaceutically acceptable salt thereof.

Embodiment 15 A. The compound of embodiment 9 A, wherein the compound of formula

(XX) is a compound of formula (XX-II):

(XX-II)

or a pharmaceutically acceptable salt thereof. Embodiment 16A. The compound of embodiment 15 A, wherein the compound of formula (XX-II) is a compound of formula (XX-II-3):

(XX-II-3)

or a pharmaceutically acceptable salt thereof.

Embodiment 17A. A compound selected from the group consisting of a compound of Table 1, or a pharmaceutically acceptable salt thereof.

Embodiment 18A. A pharmaceutical composition comprising a compound of any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Embodiment 19A. A method of treating a disease or disorder mediated by an integrated stress response (I SR) pathway in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of embodiments 1 A to G7A, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of embodiment 18A

Embodiment 20A. The method of embodiment 19 A, wherein the compound, the

pharmaceutically acceptable salt, or the pharmaceutical composition is administered m combination with a therapeutically effective amount of one or more additional anti-cancer agents. Embodiment 21 A. The method of embodiment 19A, wherein the disease or disorder is mediated by phosphorylation of eIF2a and/or the guanine nucleotide exchange factor (GEF) activity of eIF2B.

Embodiment 22A. The method of any one of embodiments 19A-21A, wherein the disease or disorder is mediated by a decrease in protein synthesis.

Embodiment 23 A. The method of any one of embodiments 19A-22A, wherein the disease or disorder is mediated by the expression of ATF4, CHOP or BACE-1.

Embodiment 24A. The method of any of embodiments 19A-23A, wherein the disease or disorder is a neurodegenerative disease, an inflammatory disease, an autoimmune disease, a metabolic syndrome, a cancer, a vascular disease, an ocular disease, a musculoskeletal disease, or a genetic disorder.

Embodiment 25A. The method of embodiment 24A, wherein the disease is vanishing white matter disease, childhood ataxia with CNS hypomyelination, intellectual disability syndrome, Alzheimer’s disease, prion disease, Creutzfel dt- Jakob disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) disease, cognitive impairment, frontotemporal dementia (FTD), traumatic brain injury, postoperative cognitive dysfunction (PCD), neuro-otological syndromes, hearing loss, Huntington’s disease, stroke, chronic traumatic encephalopathy, spinal cord injury, dementias or cognitive impairment, arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, asthma, allergic asthma, bronchial asthma, tuberculosis, chronic airway disorder, cystic fibrosis, glomerulonephritis, membranous nephropathy, sarcoidosis, vasculitis, ichthyosis, transplant rejection, interstitial cystitis, atopic dermatitis or inflammatory bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, alcoholic liver steatosis, obesity, glucose intolerance, insulin resistance, hyperglycemia, fatty liver, dyslipiderma, hyperlipidemia, type 2 diabetes, pancreatic cancer, breast cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, urothelial cancer, endometrial cancer, ovarian cancer, cervical cancer, renal cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), multiple myeloma, cancer of secretory cells, thyroid cancer, gastrointestinal carcinoma, chronic myeloid leukemia, hepatocellular carcinoma, colon cancer, melanoma, malignant glioma, glioblastoma, glioblastoma multiforme, astrocytoma, dysplastic gangliocytoma of the cerebellum, Ewing’s sarcoma, rhabdomyosarcoma,

ependymoma, medulloblastoma, ductal adenocarcinoma, adenosquamous carcinoma, nephroblastoma, acinar cell carcinoma, lung cancer, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy of undetermined significance (MGUS), piasmoeytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, Pelizaeus-Merzbacher disease, atherosclerosis, abdominal aortic aneurism, carotid artery disease, deep vein thrombosis, Buerger’s disease, chronic venous hypertension, vascular calcification, telangiectasia or lymphoedema, glaucoma, age-related macular degeneration, inflammatory retinal disease, retinal vascular disease, diabetic retinopathy, uveitis, rosacea, Sjogren's syndrome or neovascularization in proliferative retinopathy, hyperhomocysteinemia, skeletal muscle atrophy, myopathy, muscular dystrophy, muscular wasting, sarcopenia,

Duchenne muscular dystrophy (DMD), Becker’s disease, myotonic dystrophy, X-imked dilated cardiomyopathy, spinal muscular atrophy (SMA), Down syndrome, MEHMO syndrome, metaphyseal chondrodysplasia, Schmid type (MCDS), depression, or social behavior impairment.

Embodiment 26A. A method of producing a protein, comprising contacting a eukaryotic cell comprising a nucleic acid encoding the protein with the compound or salt of any one of embodiments 1 A- 17 A.

Embodiment 27A. The method of embodiment 26A, comprising culturing the cell m an in vitro culture medium comprising the compound or salt.

Embodiment 28A. A method of culturing a eukaryotic cell comprising a nucleic acid encoding a protein, comprising contacting the eukaryotic cell with an in vitro culture medium comprising a compound or salt of any one of embodiments 1-G7A.

Embodiment 29A. The method of any one of embodiments 26A-28A, wherein the nucleic acid encoding the protein is a recombinant nucleic acid.

Embodiment 30A. The method of any one of embodiments 26A-29A, wherein the ceil is a human embryonic kidney (HEK) cell or a Chinese hamster ovary (CHO) cell. Embodiment 31 A. The method of any one of embodiments 26A-29A, wherein the cell is a yeast cell, a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell, a baby hamster kidney cell, a murine myeloma cell, an HT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood derived leukocyte

Embodiment 32A. A method of producing a protein, comprising contacting a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with the compound or salt of any one of embodiments 1A-17A.

Embodiment 33A. The method of any one of embodiments 26A-32A, wherein the protein is an antibody or a fragment thereof.

Embodiment 34A. The method of any one of embodiments 26A-32A, wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor.

Embodiment 35A. The method of any one of embodiments 26A-34A, comprising purifying the protein.

Embodiment 36A. An in vitro cell culture medium, comprising the compound or salt of any one of embodiments 1 A-17A and nutrients for cellular growth.

Embodiment 37A. The cell culture medium of embodiment 36A, comprising a eukaryotic cell comprising a nucleic acid encoding a protein.

Embodiment 38. The cell culture medium of embodiment 36A or 37A, further comprising a compound for inducing protein expression.

Embodiment 39A. The cell culture medium of any one of embodiments 36A-38A, wherein the nucleic acid encoding the protein is a recombinant nucleic acid. Embodiment 40A. The cell culture medium of any one of embodiments 36A-39A, wherein the protein is an antibody or a fragment thereof.

Embodiment 41 A. The cell culture medium of any one of embodiments 36A-39A, wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor.

Embodiment 42A. The cell culture medium of any one of embodiments 36A-41A, wherein the eukaryotic cell is a human embryonic kidney (HEK) cell or a Chinese hamster ovary (CHO) cell.

Embodiment 43A. The cell culture medium of any one of embodiments 36A-41A, wherein the cell is a yeast cell, a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell, a baby hamster kidney cell, a murine myeloma cell, an HT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood derived leukocyte

Embodiment 44A. A cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with the compound or salt of any one of embodiments 1A-17A.

Embodiment 45A. The CFPS system of embodiment 40 A, comprising a eukaryotic cell extract comprising eIF2.

Embodiment 46A. The CFPS system of embodiment 44A or 45A, further comprising eIF2B.

Embodiment 47A. The CFPS system of any one of embodiments 44A-46A, wherein the protein is an antibody or a fragment thereof.

Embodiment 48A. The CFPS system of any one of embodiments 44A-47A, wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor.

[0903] Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled m the art without departing from the spirit and scope of the invention, as defined by the claims.

[Q9Q4] The chemical reactions in the Examples described can be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds of this disclosure are deemed to be within the scope of tins disclosure. For example, the synthesis of non-ex empli lied compounds according to the present disclosure can be successfully performed by modifications apparent to those skilled m the art, e.g , In

appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.

[0905] In some cases, stereoisomers are separated to give single enantiomers or

diastereomers as single, unknown stereoisomers, and are arbitrarily drawn as single isomers. Where appropriate, information is given on separation method and elution time and order. In the biological examples, compounds tested w¾re prepared in accordance to the synthetic procedures described therein. For any given compound of unknown absolute stereochemistry for which specific rotation is available, biological data for that compound was obtained using the enantiomer or diastereoisomer associated with said specific rotation.

[0906] In some cases, optical rotation w¾s determined on Jasco DIP-360 digital polanmeter at a wavelength of 589 nm (sodium D line) and are reported as [ojj, for a given temperature T (expressed in °C). Where appropriate, information is given on solvent and concentration (expressed as g/lOGmL).

[0907] Abbreviations: br. s. Broad singlet

chloroform-d Deuterated chloroform

methanol-d ₄ Deuterated methanol

DIAD Diisopropyl azodi carboxy late

DCM Dichloromethane

DEA Diethylamine

DIPEA Diisopropy lethy lamine

DMF N,N-Di methy lformami de

DMSO-de Deuterated dimethylsulfoxide

d Doublet

EDC.HC1 l-Ethyl-3-(3-dimethylaminopropy])carbodiimide hydrochloric acid

EtOAc Ethyl acetate

EiOH Ethanol

g Gram

HATU (0-(7-azabenzotriazol - 1 -yl)-N,N,N \N’ -tetramethyluronium hexafl uorophosphate)

HOST Hydroxy benzotri azole

HPLC High Performance Liquid Chromatography

L Litre

LCMS Liquid Chromatography Mass Spectrometry

MeCN Acetonitrile

MeOH Methanol

mg Milligram

mL Millilitre

mmol Millimoles

m multiplet

NMR Nuclear Magnetic Resonance

/PrOH Isopropanol

q quartet

RT Room temperature

singlet Supercritical Fluid Chromatography

TFA trifluoroacetic acid

THF T etr ahy dr of uran

TLC Thin layer chromatography

t

[0908] To a stirred solution of ira¾s-./V-(4-aminocydohexyl)-2-(4-chlorophenoxy)acetamido trifluoroacetate salt (100 mg, 0.252 mmol, 1 equiv) in MeCN (10 mL), was added 2-((4~ chlorophenoxy)methyl)oxirane (84 mg, 0.454 mmol, 1.8 equiv) and K ₂ C0 ₃ (70 mg, 0.504 mmol, 2 equiv) at RT. The reaction mixture was stirred overnight at 90 °C. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (100 mL x 2). The organic layer was washed with water (50 mL) and brine solution (50 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase HPLC to obtain fra --2-(4~chlorophenoxy)-N-(4-((3-(4~ chlorophenoxy)2-hydroxypropyl)amino)cyclohexyl)acetamide (Compound 1 - 6 mg, 5%) as an off white solid compound. LCMS: 467 [M+H] ⁺ ; 1HNMR (400 MHz, DMSO-de) d 8.26 (s, 1H), 7.92 (d, J= 8.1 Hz, 11 1 }. 7.33 (t, J= 8.2 Hz, 41 1 ). 6.96(d, J ------ 8.5 Hz, 41 1 ). 4.44 (s, 2H), 3.91 (dq,

J ----- 29.5, 6.4, 5 7 Hz, 3H), 3.57 (d, J 1 1 4 Hz, 21 !}. 2.81-2.72 (m, 2H), 1.95-1.85 (m, 2H), 1.75

(dd, J= 11.9, 4.6 Hz, 2H), 1.35-1.21 (m, 3H), 1.13 (t, J= 12.6 Hz, 2H). Synthesis of trans-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3-fluo rophenoxy)-

Step 1 Synthesis of 2-(4-chloro-3-fluorophenoxy)acetic acid:

[Q9Q9] To a stirred mixture of 4-chloro-3-fluorophenol (1 g, 0.068 mol, 1 equiv) and 2- chloroacetic acid (2 5 g, 0.273 mol, 4 equiv) in water (20 mL), was added NaOH (1.08 g, 0 273 mol, 4 equiv) and the reaction mixture was heated at 100 °C overnight. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was neutralized by using 3N HCI (20 mL). The resultant solid w¾s filtered off and residue was washed with water and dried under vacuum to obtain 2-(4-chloro-3-fluorophenoxy)acetic acid (700 mg, 51%) as white solid. LCMS: 204 [M+Hf

Step 2 - Synthesis of trans-tert-butyl (4-(2- (4-chloro-3- fluorophenoxy)acetamido)cyelohexyl)carhamate:

[0910] To a stirred mixture of 2-(4-Chloro-3-fluorophenoxy (acetic acid (500 mg, 2,43 mmol, 1 equiv) in DMF (5 mL), was added DIPEA (1.6 mL, 9.76 mmol, 4 equiv), HOBT (540 mg, 3.18 mmol, 1.5 equiv) and EDC.HCI (702 mg, 3.66 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 30 min and then trans-tert-butyl 4-aminocyclohexylcarbamate (838 mg, 9 76 mmol, 4 equiv) was added. The resultant reaction mixture was stirred at RT overnight.

The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered off and the residue was washed with water and dried under vacuum to obtain trans- tert- butyl (4-(2-(4-ch]oro-3-fluorophenoxy)acetamido)cyclohexyl)carbama te (170 mg, 18%) as white solid. LCMS: 399 [M+H]\ Step 3 Synthesis of trans~N-(4-aminocyclohexyl)~2~(4-chloro~3~fluorophenoxy)acet amide trifluoroacetate salt:

[0911] To a stirred solution of trans-tert- butyl (4-(2-(4-chloro-3-fluorophenoxy)acetamido) cyclohexyl)carbamate (150 mg, 0.395 mmol, 1 equiv) in DCM (5 mL) was added trifluoroacetic acid (3 mL) and the resultant reaction mixture was stirred at RT for 1 hr under nitrogen atmosphere. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain a sticky crude compound which was triturated with hexane (10 ml.) and diethyl ether and dried under vacuum to obtain /ra '-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamid e trifluoroacetate salt (100 mg, 89%) as brown solid. LCMS: 300 [M+H] ⁺ .

Step 4 Synthesis of trans-2-( 4-chloro-3-fluorophenoxy)-N-( 4-( 63-( 4-chloro-3-fluorophenoxy)- 2-hydroxypropyl)amino)cyclohexyl)acetamide :

[0912] To a stirred solution of /ra ’-N-(4-aminocyclohexyl)-2-(4-chloro-3- fluorophenoxy)acetamide trifluoroacetate salt (100 mg, 0.24 mmol, 1 equiv), and 2-((4-chloro-3- iluorophenoxy)methyl)oxirane (67 mg, 0.338 mmol, 1.4 equiv) in MeCN (5 mL), was added K2CO3 (99 rng, 0.72 mmol, 3 equiv). The resultant reaction mixture was heated at 90 °C overnight. The reaction was monitored by TLC and LCMS. After completion of the reacti on, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 * 50 mL) and washed with water (2 ^c 20 mL), brine solution (2 ^c 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude mixture which w¾s purified by reversed-phase HPLC to obtain /ra¾s-2-(4-chloiO-3-fluorophenoxy)-N-(4-((3-(4-chloro~3- fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide (Compound 2 - 7 mg, 4%) as light greenish solid. LCMS: 503 | VI 1 1 i 4 1 NMR (400 MHz, DMSO-de) d 7.92 id. J 6.36 Hz, 2H), 7.37-7.57 (m, 21 1 ). 7.06 (d, ./ 11.74 Hz, 21 1 ). 6 83 (m, 2H), 4.48 (s, 4H), 3.97 (m.,

1H), 3.89 (d, J= 6.85 Hz, 1H), 3.80 (m, 11 1). 3.55 (m, 3H), 1.85 (m, 1H), 1.77 (d, J = 14.18 Hz, 31 1 ). 1.35 (br. s , 11 1). 1.23 (hr. s., 2H).

Step 1 - Synthesis of tert-butyl (l~(3~(4~chlorophenoxy)-2-hydrox>propyl)piperidin-4~ yl)carbamate:

[0913] To a stirred solution of tert- butyl piperidin-4-ylcarbamate (0.500 g, 2.500 mmol, 1.0 equiv) in DMF (5 mL) was added 2-((4-chlorophenoxy)methyl)oxirane (0.460 g, 2.500 mmol, 2.0 equiv) at RT. The resulting reaction mixture was heated at 100 °C for 12 hr. Progress of the reaction was monitored by ^! H NMR. Reaction w¾s quenched by adding water and the resulting precipitate was filtered off. Tire obtained solid was washed with w¾ter (25 mL ^c 2) and dried under vacuum to obtain tert- butyl (l -(3-(4-chlorophenoxy)-2-hydroxypropy])piperidin-4- yl)carbamate (0.700 g, 73 % Yield) as a white solid. LCMS 386.3 [M+H] ⁺ ; ⁱ H NMR (400 MHz, DMSO-d _fi ) d 7.26-7.38 (m, J= 8.77 Hz, 2H), 6.89-7.01 (m, J= 8.77 Hz, 2H), 6.74 id. ./ 7 45 Hz, I I I). 4.84 (d, J 4.38 Hz, i l l ). 3.82-3 99 (m, 31 1). 3.17 id. ./ 5.26 Hz, 11 1). 2.75-2.92

(m, 2H), 2.25-2.41 (m, 2H), 1.91-2.07 (m, 21 1 ). 1.65 (d, J= 10.52 Hz, 2H), 1.37 (s, Oi l )

Step 2 - Synthesis of l-(4-aminopiperidin-l-yl)-3-(4-chlorophenoxy)propan-2-ol trifluoroacetate salt:

[0914] To a stirred solution of tert- butyl (l-(3-(4-chlorophenoxy)-2- hydroxypropyl)piperidin-4-yl)carbamate (0.700 g, 21.822 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroacetie acid (5 mL) at RT. The reaction mixture was allowed to stir at RT overnight. DCM and excess of trifluoroacetie acid were removed under reduced pressure to obtain l-(4-aminopiperidin-l -yl)-3-(4-chlorophenoxy)propan-2-ol trifluoroacetate salt (0 800 g, 100 % Yield) as an oil. ’HVY!R (400 MHz, DMSO-de) d 9.61 (br. s., i l l ). 8 18 (br. :s . 2H), 7.27-7.45 Or, J = 9.21 Hz, 2H), 6.92-7.04 Or, J = 8.77 Hz, 2H), 4.24-4.33 Or, I I I ). 3.62 (d, J = 10 96 Hz, 2H), 3 04-3 33 (m, 5H), 2.01 -2.20 (rn, 2H), 1.86-1.96 (m, H I). 1.78 (d, ./= 13.15 Hz, 1H).

Step 3 - Synthesis of 2-(4-chlorophenoxy)-N-(l-(3-(4-chlorophenoxy)-2 - hydroxypropyl)piperidm-4-yl)acetamide:

[0915] To a solution of l-(4-aminopiperidin-l-yl)-3-(4-chlorophenoxy)propan-2-ol trifluoroacetate salt (0.700 g, 1 758 mmol, 1.0 equiv) in DMF (10 ml,) was added 2-(4- chlorophenoxy)acetic acid (0.396 g, 1.934 mmol, 1.1 equiv) and HATH (1.340 g, 3.517 mmol, 2.0 equiv) at RT. The reaction mixture was stirred for 10 minutes and then DIPEA (1.6 mL, 8 793 mmol, 5.0 equiv) was added. The resultant reaction mixture was allowed to stir at RT overnight. Progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with water (50 mL. ^c 4), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound which was purified by reverse phase HPLC to obtain 2-(4-chlorophenoxy)-N-(l-(3-(4-chlorophenoxy)-2-hydroxypropy l)piperidin-4- yl)acetamide (Compound 5 - 0.550 g, 70 % Yield) as an off-white solid. LCMS: 453.1 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-de) d 8.09-8.16 (m, 1 H), 7.34 (d, J= 8 77 Hz, 2H), 6.90-7.01 (m, 2H), 5.59 (br. s, H I ). 4.48 (s, 2H), 4.14 (br. s., 1 1 1 ). 3.94 (dq , ./ = 4.60, 10.01 Hz, 1 1 1 ). 3 78 (br. s.. 1H), 2.90 (br. s, 2H), 1.82 id. ./ 10.09 Hz, 1H), 1.58-1.75 (m, 1 1 1 ).

Example 4

Step 1 Synthesis of trans-N-(4-(2-( 4-chlorophenoxy)acetamido)cyclohexyl)oxirane-2- carboxamide:

[0916] To a stirred mixture of , ⁱ ra«s~N-(4-aminocycloliexyl)-2-(4-chlorophenoxy)acetam ide (300 mg, 1.063 mmol, 1 equiv) in DMF (15 mL), was added triethylamine (0.5 mL, 4.252 mmol, 4 equiv), HOBT (144 mg, 1.595 mmol, 1.5 equiv) and EDC.HC1 (305 mg, 1 595 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 30 mm. Oxirane-2-carboxylic acid (140 mg, 1.595 mmol, 1.5 equiv) was then added. The resultant reaction mixture was stirred at RT overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, water (50 mL) was added and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with water (30 mL), brine solution (2 ^c 30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain ira«5 ^, -N-(4-(2-(4- chlorophenoxy)acetamido)cyclohexyl)oxirane-2-carboxamide (300 mg) as a white solid which was taken for the next step without any further purification. LCMS: 353 [M+H] T

Step 2 - Synthesis of trans-3-(4-chlorophenoxy)-N-(4-(2-(4 - chlorophenoxy)acetamido)cyclohexyl)-2-hydroxypropcmamide:

[0917] To a stirred solution of /ra -N-(4-(2-(4- chlorophenoxy)acetamido)cyclohexyT)oxirane-2-carboxamide (300 mg, 0.849 mmol, 1 equiv) and 4-chlorophenol (108 mg, 0.849 mmol, 1 equiv) in DMF (10 mL), was added K TO; (234 mg, 1.698 mmol, 2 equiv) and the resultant reaction mixture was heated at 100 °C overnight. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with water (30 mL), brine solution (30 mL ^c 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude mixture which was purified by reversed-phase HPLC to obtain /rans-3-(4-chlorophenoxy)-N-(4-(2-(4- chlorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide (Compound 8 - 50 mg) as white solid. LCMS 481 [M+H] ¹ ; ¹ HNMR (400 MHz, DMSO-de) d 7 94 (d, ,/ 8.77 Hz, 1 1 1). 7.69 (d, .7=8 77 Hz, 1 H), 7 34 (d, .7=9.21 Hz, 4 H), 6.97 (d, .7=9.21 Hz, 4 H), 5.94 (d, 7=5 70 Hz, 1 H), 4.45 (s, 2 H), 4.19 {or. s., 1 H), 4.01-4.12 (m, 2 H), 3.58 (br. s., 2 H), 1.74 (br. s., 4 H), 1.23 (br. s., 4 H).

fluorophenox )acetamido)cyclohexyl)-2-hydroxypropanamide

Step 1 Synthesis of trans-N-( 4-(2-( 4-chloro-3-fluorophenoxy)acetamido)cydohexyl)oxirane-2- carhoxamide:

[0918] To a stirred mixture of /ram-N-(4-aminocyclohexyl)-2-(4-chloro-3- fluorophenoxy)acetamide (1000 mg, 3.18 mmol, 1 equiv) in DMF (30 mL), was added triethylamine (1.8 mL, 12.72 mmol, 3 equiv), HOBT (643 mg, 4.77 mmol, 1.5 equiv) and EDC.HCI (643 mg, 4.77 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 30 min. Qxirane-2-carboxylic acid (420 mg, 4.77 mmol, 1.5 equiv) was added and the resultant reaction mixture was stirred at RT overnight. Reaction w¾s monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with w¾ter (100 mL) and extracted with EtOAc (2 x 100 mL) and washed with water and brine solution (2 ^c 50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain /ra¾s-N-(4-(2-(4-chloiO-3- fluorophenoxy)acetamido)cyciohexyl)oxirane-2-carboxamide (220 mg, 20 % Yield ) as a white solid. LCMS; 370

Step 2 Synthesis of trans-3~(4~chloro-3-fluoropkenoxy)~N~(4~(2-(4-chloro~3~

fluorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide:

[0919] To a stirred solution of /ra/¾’- -(4-(2-(4-chloro-3- fluorophenoxy)acetamido)cyclohexyl)oxirane-2-carboxamide (100 mg, 0.27 mmol, 1 equiv) in DMF (10 mL) was added K C O; (75 mg, 0.54 mmol, 2 equiv) followed by the addition of 4- chloro-3-fluorophenol (40 mg, 0.27 mmol, 1 equiv). The resultant reaction mixture w¾s heated at 100 °C overnight. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with waiter (50 mL) and extracted with EtOAc (2 ^c 50 mL) and washed with water and brine solution (2 x 30 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude mixture which was purified by reversed-phase HPLC to obtain fra ’-3-(4-chloro-3-fluorophenoxy)-N-(4-(2-(4-chloro-3- fluorophenoxy)acetamido)cyclohexyl)-2-hydroxypropanamide (Compound 9 - 60 mg, 48 % Yield) as a white solid LCMS: 517 I M l 11 : 4 IN. MR (400 MHz, DMSO-de) d 7.97 (d, .7=7.89 Hz, 1 H), 7.70 (d, ,7=8.33 Hz, 1 H), 7.41-7.57 (m, 2 H), 7.00-7.13 (m, 2 H), 6.84 (d, .7=8.33 Hz, 2 H), 5.98 (br. s, 1 H), 4.49 (s, 2 H), 4.04-4.25 (m, 2 H), 3.58 (br. s, 2 H), 1.74 (s, 4 H), 1.23-1.45 (m, 4 H).

Example 6

Synthesis oftrans-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloropheno xy)-

[Q92Q] To a stirred solution of /ra».s-N-(4-aminocyclohexyl)-2-(4-chloro-3- fluorophenoxy (acetamide trill uoroacetate salt (200 mg, 0.63 mmol, 1 equiv) in DMF (10 mL) was added K ₂ C0 ₃ (264 rng, 1.9 mmol, 3 equiv) followed by the addition of 2-((4- chlorophenoxy)methyl)oxirane (175 mg, 0.95 mmol, 1 equiv). The resultant reaction mixture was heated at 100 °C overnight. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was diluted with water (70 mL) and extracted with EtOAc (2 x 50 mL) and washed with w¾ter and brine solution (2 ^c 30 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude mixture which -was purified by reversed-phase HPLC to obtain /raiJS-2-(4-chloro-3-iluorophenoxy)-N- (4-((3-(4-chlorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)ac etamide (Compound 10 - 20 mg, 15 % Yield) as a white solid. LCMS: 485 ] \ 1 1 f : d lNV!R (400 MHz, DMSO-d ₆ ) d 7.92 (d, J= 8.33 Hz, 2 H), 7.49 (t, J=8.55 Hz, 1 H), 7.31 (d, J= 8.77 Hz, 2 H), 7.06 (d, J= 8.77 Hz, 1 H), 6.96 (d, ,/ 8.33 Hz, 2 H), 6.84 (d, ./ 8.77 Hz, 1 H), 4.48 (s, 2 H), 3.94 (d, ./ 5.26 Hz, 1 H), 3.85 (s, 2 H), 3.56 (br. s., 2 H), 1.90 (s, 4 H), 1.75 (s, 4 H).

Step 1 - Synthesis of tert-butyl (( 3S)-l-(3-(4-chloro-3-fluorophenoxy)-2 - hydroxypropyl)pipendin-3-yl)carbamate:

[0921] To a stirred solution of tert-butyl (S)-piperidin-3-ylcarbamate (0.500 g, 2.47 mmol, 1.0 equiv) in DMF (5 mL) was added 2-((4~ch!oro-3-fluorophenoxy)methyl)oxirane (0.602 g, 2.98 mmol, 2.0 equiv) at RT. The resulting reaction mixture was heated at 100° C for 12 hr. Product formation was confirmed by hi NMR spectroscopy. The reaction was stopped by adding water and the resulting precipitate was filtered off. The obtained solid was washed with water (25 mL ^c 2) and dried under vacuum to obtain ferZ-butyl ((3S)-l-(3-(4-chloro-3- fluorophenoxy)-2-hydroxypropyl)piperidin-3-yl)carbamate. (1.0 g 95 % Yield, as a white solid). LMCS 403 j M i i

Step 2 Synthesis of i-(((3S)-l-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)pip eridin-3-yl)- ) -azanyl)-2 2, 2-trifluoroethan-l -one trifluoroacetate salt:

[Q922] To a stirred solution of fc/7-butyl ((3S)-l-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperi din-3 -yl)carbamate (1.0 g, 2.48 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroacetic acid (5 mL) at RT. The reaction mixture was allowed to stir at RT overnight. DCM and excess trifluoroacetic acid was removed under reduced pressure to obtain l-(((3S)-l-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)pip eridin-3-yl)-? _*, ⁴ -azanyl)-2,2,2- trifluoroethan-l -one trifluoroacetate salt (1.3 g, 100 % Yield as an yellow' oil). LCMS 303

[M+Hf Step 3 Synthesis of 2-(4-chloro-3-fluorophenoxy)-N-((3S)-I-(3-(4-chloro-3-fluoro phenoxy)-2- hydroxypropyl)piperidin-3-yl)acetamide:

[0923] To a solution of l-(((3S)-l-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin-3-yl)-L ⁴ -azanyl)-2,2,2-trifluoroethan-l-one trifluoroaceiate salt (1.0 g, 2 48 mmol, 1.0 equiv) in DMF (15 ml.) was added 2-(4-chloro-3-fluorophenoxy)acetic acid (0.607 g, 2.97 mmol, 1.2 equiv) and HATH (1.89 g, 4.96 mmol) at RT. The resulting reaction mixture was stirred for 10 minutes, and DIPEA (2.1 mL, 12.4 mmol) was added. The reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL ^c 2) The combined organic extracts were washed with w ter (50 mL ^c 4), dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified by reverse phase HPLC to obtain 2-(4-chloro-3-fluorophenoxy)-N-((3S)-l-(3-(4-chloro-3-fIuoro phenoxy)-2- hydroxypropyl)piperidin-3-yl)acetamide (Compound 11 - 30 mg, as an off-white solid). LCMS 489 j M i i | ; TiNMR (400 MHz, DMSO-de) d 7.90 i d. ./ 7.02 Hz, 1H), 7.30-7.54 (m, 2H),

7.03 (ra, 21 1 ). 6 69-6.92 (m, 21 1). 4.93 (br s., 1 1 !}. 4.51 (s, i l l). 4.00 (d, J= 7.02 Hz, i l l }. 3.84- 3.94 (m, 2H), 3 81 (br. s., 1H), 2.69 (d, ./= 12.72 Hz, 1H), 2.27-2.42 (m, 2H), 2.16 (m., 2H), 1.75 (br. s., i l l). 1.62 (d, J= 9.21 Hz, 2H), 1.46 (d, J= 7.02 Hz, i l l). 1.32 (br. s., i l l ). 1.23 (br. s., 1H).

Example 8

Synthesis of 2-(4~chlore~3~fluorophenoxy)-N~((3R)~l~(3-(4~chloro~3-fluero phenoxy)~2~

Step 1 - Synthesis of tert-butyl ((3R)-l-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin-3-yl)carbamate:

[0924] To a stirred solution of tert- butyl (R)-piperidin-3-ylcarbamate (0.500 g, 2.47 mmol, 1.0 equiv) in DMF (5 mL) was added 2-((4-chloro-3-fluorophenoxy)methyl)oxirane (0.602 g, 2.98 mmol, 2,0 equiv) at RT. The resulting reaction mixture was heated at 100° C for 12 h. Product formation was confirmed by ^! H NMR spectroscopy. Reaction was stopped by adding water and the resulting precipitate was filtered off. Obtained solid was washed with water (25 mL X 2) and dried under vacuum to obtain tert- butyl ((3R)-l -(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin~3~yl)carbamate. (1.1 g as an white solid). LCMS: 403 | Vi ! I i .

Step 2 - Synthesis of l-( ( ( 3R)-l-( 3-( 4-chloro-3-flnorophenoxy)-2-hydroxypropyl)piperidin-3-yl)- l ⁴ -azcmyl)-2, 2, 2-trifluoroethan-l-one trifluoroaeetate salt:

[0925] To a stirred solution of tert-butyl ((3R)-1 -(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin-3-yl)carbamate (1.0 g, 2.48 mmol, 1.0 equiv) in DCM (30 mL) was added tnfluoroacetic acid (5 mL) at RT. the reaction mixture was allowed to stir at RT overnight. DCM and excess tnfluoroacetic acid was remo ved under reduced pressure to obtain

1-(((3R)-l-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl) piperidin-3-yl)-L ⁴ -azanyl)-2,2,2- trifluoroethan-i-one trifluoroaeetate salt (1.4 g, as an oil). LCMS: 303 [M+H] ⁺ .

Step 3 - Synthesis of 2-(4-chloro-3-fluorophenoxy)-N-((3R)-l-(3-(4-chloro-3-fluoro phenoxy)-2- hydroxypropyl)piperidin-3-yl)acetarnide:

[0926] To a solution of 1 -(((3R)-l-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin-3-yl)-L ⁴ -azanyl)-2,2,2-trifluoroethan-l-one trifluoroaeetate salt (1.0 g, 2.48 mmol, 1.0 equiv) in DMF (15 mL) was added 2-(4-chloro-3-fluorophenoxy)acetic acid (0.607 g, 2.97 mmol, 1.2 equiv) and HATH (1.89 g, 4.96 mmol) at RT. The resulting reaction mixture was stirred for 10 minutes and then DIPEA (2.1 ml,, 12,4 mmol) was added. The reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with water (50 ml, x 4), dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified by reverse phase HPLC to obtain 2-(4-chloro-3-fluorophenoxy)-N-((3R)-l-(3-(4-ehloro-3-fluoro phenoxy)-

2-hydroxy propyl)piperi din-3 -yl)acetamide (Compound 12 - 10 mg, as an off-white solid).

LCMS : 489 | M H i : ¹ HNMR (400 MHz, DMSO~d ₆ ) 6 7.90 (d, J 7.02 Hz, 11 1). 7.30-7.54 (ra. 211} 7.03 (ra, 2H), 669-6.92 (m, 2H), 4.93 (br. s., ill).451 (s, ill).400 (d../ 7.02 Hz, III).

3.84-3.94 (m, 2H), 3.81 (br. s, ill).2.69 (d, J= 12.72 Hz, ill).2.27-2.42 (m, 211).2.16 (m, 2H), 1.75 (br. s., 111).1.62 (d, ./ 9.21 Hz, 2H), 1.46 (d, ./ 7.02 Hz, 1H), 1.32 (br. s..111).1.23

(br s., 1H).

Step 1 Synthesis of tert-butyl ( I-(3-(4-ch!oro-3-fluorophenoxy)-2-hydroxypropy!)piperidin-4 - yl)carbamate:

[Q927] To a stirred solution of tert- butyl piperidin-4-yl carbamate (0.500 g, 2500 mmol, 1.0 equiv) m DMF (5 niL) was added 2-((4-chloro-3-fluorophenoxy)methyl)oxirane (0.507 g, 2.500 mmol, 1.0 equiv) at RT. The resulting reaction mixture was heated at 100 °C for 12 hr.

Progress of the reaction was monitored by Ή NMR. The reaction was stopped by adding water and the resulting precipitate was filtered off. The obtained solid was washed with water (23 rnL x 2) and dried under vacuum to obtain fe/7-butyl (l-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin-4-yi)carbamate (1.000 g, 99 % Yield) as a white solid. LCMS: 403.3 [M+H] ⁺ ; ¹ HNMR (400 MHz, D.MSO-d,.} d 7.45 (t, ./ 8.77 Hz, III).7.05 (dd, ./ 2.63, 11.40

Hz, 1H), 6.84 (dd, J= 1.75, 877 Hz, 1H), 6.74 (d, J= 7.45 Hz, 111).4.86 (d, J= 3.95 Hz, 111). 3.98 (d, J= 6.58 Hz, 1H), 3.82-3.93 (m, 2H), 3.17 (br. s., 1H), 2.74-2.90 (m, 2H), 2.26-2.42 (m, 2H), 1.90-2.09 (m, 2H), 1.60-1.70 (m, 2H), 1.37 (s, 9H). Step 2 - Synthesis of 1 ~(4-aminopiperidin~l-yl)~3~(4-chloro~3~fluorophenoxy)propan- 2-ol trifluoroacetate salt:

[0928] To a stirred solution of tert- butyl (l-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin-4-yl)carbamate (1.00 g, 2.48 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroacetic acid (5 mL) at RT. The reaction mixture was allowed to stir at RT overnight. DCM and excess trifluoroacetic acid was removed under reduced pressure to obtain l-(4-aminopiperidin-l-yl)-3-(4-chloro-3-fluorophenoxy)propan -2-ol trifluoroacetate salt (1.00 g, 96 % Yield) as an yellow oil. 4 IN VI R (400 MHz, DMSO-de) d 9.60 (hr. s , 1 H), 8.15 (br. s., 2H), 7.50 (t, J = 9.21 Hz, 1H), 7.09 (d, J= 11.40 Hz, GH), 6.85 (d, ,/= 7.89 Hz, 1H), 5.75 (br. s., 1H), 4.29 (br. s., 1H), 4.00 (br. s., 2H), 3.62 id. ./ 10.96 Hz, 2H), 3.28 (br. s., 2H), 3.18 (d, J =

10.52 Hz, 3H), 2.07 id. ./ 11.84 Hz, 2H), 1.83-2.01 (m, 2H).

Step 3 - Synthesis of 2-(4-chloro-3-fluorophenoxy)-N-(l-(3-(4-chloro-3-jluoropheno xy)-2- hydroxypropyl)piperidin-4-yl)acetamide:

[Q929] To a solution of l-(4-aminopiperidin-l-yl)-3-(4-chloro-3-fluorophenoxy)propan -2-ol trifluoroacetate salt (1.00 g, 2.40 mmol, 1.0 equiv) in DMF (10 mL) was added 2-(4-chloro-3- iluorophenoxy (acetic acid (0.540 g, 2.64 mmol, 1.1 equiv) and HATH ( 1 .830 g, 4.80 mmol, 2.0 equiv) at RT. The reaction mixture was stirred for 10 minutes and then DIPEA (1.7 mL, 9.41 mmol, 5.0 equiv) was added. The resultant reaction mixture was allowed to stir at RT overnight. Progress of the reaction was monitored by LCMS. Tire reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with water (50 mL ^c 4), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound which was purified by reverse phase HPLC to obtain 2-(4- chloro-3-f!uorophenoxy)-N-(i-(3-(4-chloro-3-fluorophenoxy)-2 -hydroxypropyl)piperidin-4- yl)acetamide (Compound 13 - 0.500 g, 43 % Yield) as an off-white solid. LCMS: 489.2

[M+Hf; ^l HNMR (400 MHz, DMSO-d ₆ ) d 7.97 (d, J= 7.89 Hz, 1H), 7.45 (t, J= 8.77 Hz, 1H), 7.49 (t, ./= 8.99 Hz, 1H), 7.05 (d, J = 2.63 Hz, 1H), 7.07 (d, J= 2.63 Hz, 1H), 6.84 (d, ./= 8 77 Hz, 2H), 4.87 (br. s., 1H), 4.50 (s, 2H), 4.00 (d, J= 6.58 Hz, M l). 3.83-3.95 (m, 2H), 3.60 (d, J = 7.45 Hz, 1H), 2.74-2.98 (m, 2H), 2.27-2.46 (m, 2H), 1.99-2.15 (m, 2H), 1.65 (br. s., 2H), 1. SS- l .S? (m, 2H).

Synthesis of2-(4-chloro-3-fluorophenoxy)-l-(4-((3-(4-chloro-3-fluoroph enoxy)-2- hy rox propyl)amino)piperidin-l-yl)ethan-l-one

Step 1 Synthesis of tert-butyl (l-(2-(4-chloro-3-fluorophenoxy)acetyl)piperidin-4-y!)carbam ate:

[0930] To a solution of tot-butyl piperidin-4-ylcarbamate (0.250 g, 1.25 mmol, 1.0 equiv) in DMF (10 mL) was added 2-(4-chloro-3-fluorophenoxy)acetic acid (0.281 g, 1.37 mmol, 1.1 equiv) and HATH (0.950 g, 2.50 mmol, 2.0 equiv) at RT. The reaction mixture was stirred for 10 minutes and then DIPEA (0.7 mL, 3.75 mmol, 5.0 equiv) was added. The resultant reaction mixture was allowed to stir at RT overnight. Progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL ^c 2). Combined organic layer was washed with water (25 mL ^c 4), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain the crude compound which w¾s crystallized in hexane to obtain tert- butyl (l-(2-(4-chloro-3-fluorophenoxy)acetyl)piperidin-4-yl)carbam ate (0 480 g, 100 % Yield) as an off-white solid LCMS: 387.3 [M+Hf ; ^l HNMR (400 MHz, DMSO-de) 67.46 (t, J= 8.99 Hz, 11 1). 7.05 (dd, J= 2.85, 11.62 Hz, 1H), 6.91 (d. ./ 7.02 Hz,

I f !) 6.80 (dd, J 2 41 , 8.99 Hz, i l l ). 4 87 (q, J = 14.62 Hz, 2H), 4 15 (d, J = 13.59 Hz, 1H),

3.72 (d, ./= 14.03 Hz, i l l ). 3.48 (br. s., 1 1 1 ). 3 07 (t, ./= 11.62 Hz. 1H), 2.68-2 78 (m, 1H), 1.74 (br. s., 2H), 1.38 (s, 9H), 1.16-1.26 (m, 2H). Step 2 Synthesis of l-(4-aminopiperidin-l-y!)-2-(4-chloro-3-fluorophenoxy)ethan- l-one trifluoroacetate salt:

[0931] To a stirred solution of tert- butyl (l-(2-(4-chloro-3-fluorophenoxy)acetyl)piperidin- 4-yi)carbamate (0.480 g, 1.24 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroacetic acid (3 mL) at RT. the reaction mixture was allowed to stir at RT overnight. DCM and excess trifluoroacetic acid was removed under reduced pressure to obtain l-(4-aminopiperidin-l-yl)-2- (4-chioro-3-fluorophenoxy)ethan-l-one trifluoroacetate salt (1.00 g, 100 % Yield) as an yellow oil. ¹ HNMR (400 MHz, DMSO-de) d 7 93 (hr. s . 31 1). 7.47 (t, J = 8.77 Hz, 1H), 7.05 (dd, ./ 2.85, 11.62 Hz, 1H), 6.81 (dd, ./ = 1.97, 8.99 Hz, 1H), 4.96 (d, ./= 14.47 Hz, 1H), 4.87 (d , ./ = 14.91 Hz, 1H), 4.32 (d, J= 13.59 Hz, 1H), 3.82 (d , J = 14.03 Hz, 1H), 3.27 (br. s., 1H), 3.08 (t, J ------ 12.72 Hz, 11 1 ). 2.63-2.79 (m, 2H), 1.91 (br. s., 2H), 1.39-1.57 (m, i l l ). 1.25-1.38 (m, 21 1).

Step 3 Synthesis of 2-(4-chloro-3-fluorophenoxy)-l-(4-((3-(4-chloro-3-jluorophen oxy)-2- hydroxypropyl)a:mino)piperidin-l-yl)ethan-l-one:

[Q932] To a stirred solution of l-(4-aminopiperidin-l-yl)-2-(4-chloro-3- fluorophenoxy)ethan-l-one trifluoroacetate salt (0.500 g, 1.25 mmol, 1.0 equiv) in DMF (10 mL) was added K ₂ C03 (0.518, 3.75 mmol, 3.0 equiv) followed by the addition of 2-((4-chloro- 3-fluorophenoxy)methyl)oxirane (0.355 g, 1 75 mmol, 2.0 equiv) at RT. The resulting reaction mixture was heated at 100° C for 12 hr. Product formation was confirmed by LCMS. The reaction was stopped by adding water (70 mL) and extracted with EtOAc (2 ^c 50 mL). The combined organic layer was washed with water (5 ^c 30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude mixture which was purified by reverse phase HPLC to obtain 2-(4-chloro-3-fluorophenoxy)-l-(4-((3-(4-chloro-3- iluorophenoxy)-2-hydroxypropy])amino)piperidin-l-yl)ethan-l- one (Compound 14 - 120 mg, 20 % Yield) as an off-white solid. LCMS: 489.3 [M+H] ⁺ ; ^! HNMR (400 MHz, DMSO-de) d 7.48 (q, J ----- 9.21 Hz, 21 1 ). 6 98-7.1 1 (m, 21 1 ). 6.81 (d, J= 8 77 Hz, l i t). 6.85 (d, J 8 77 Hz, 1 1 1).

5.61 (br. s., 11 1). 4 81-5.01 (m, 31 1). 4.29 (d, J= 13.16 Hz, 11 1 ). 3.95-4.08 (m, 31 1 ). 3 82 (d, ./ 13.15 Hz, 1H), 2.97-3.16 (m, 3H), 2.81-2.97 (m, 2H), 2.63-2.78 (m, 2H), 1.97 (br. s., 2H), 1.45 (br. s., 2H), 1.26 (d, J ------ 19.29 Hz, 2H). Example 11

Synthesis of tram-5-ehktro-N-(4-(2-(4-chloro-3- fluorophenoxy)acetamido)cvclohexyl)benzofuran-2-carboxamide

Step 1 - Synthesis of trans-ter (-butyl (4-(S-chlorobemofuran-2- carhoxamidojcyclohexyijcar hamate:

[Q933] To a solution of 5-e.hlorobenzofuran-2-earboxylic acid (0.274 g, 1.4 mmol, 1.5 equiv) m DMF (10 mL) was added DIPEA (0.5 mL, 2.7 mmol, 3.0 equiv) followed by the addition of HATU (0.706 g, 1.8 mmol, 2,0 equiv) and the resultant reaction mixture was stirred for 30 min. Trans -tert-butyi (4-aminocyclohexyl)carbamate (0.200 g, 0.90 mmol, 1.0 equiv) was added and the reaction mixture was allowed to stir overnight at RT and the resulting precipitate was filtered off and washed with excess methanol to obtain trans-ter (-butyl (4-(5-chlorobenzofuran-2- carboxamido)cyc!ohexy!)carbamate (350 mg, 64 % Yield) as an off-white solid. LCMS: 393 [M+Hf.

Step 2 - Synthesis of trans-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamide trifluoroacetate salt :

[0934] To a stirred solution of (rans~(ert~lwiy\ (4-(5-chlorohenzofuran-2- carboxamido)cyclohexyl)carbamate (350 mg, 0.89 mmol, 1 equiv) in DCM (10 mL) was added tnfluoroacetic acid (5 mL) and the resultant reaction mixture was stirred at RT for 1 h under nitrogen atmosphere. Reaction was monitored by LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain sticky crude compound which was triturated with hexane (10 mL) and diethyl ether and dried under vacuum to obtain /ra«.s-N-(4-aminocyclohexyl)-5-chlorobenzofuran~2-carhoxami de trifluoroacetate salt (500 mg, quantitative yield) as an off- white solid. LCMS: 293 [M+H] ⁺ .

Step 3 Synthesis of trans-5-chloro-N-(4-(2-(4-chloro-3- fluorophenox})acetamido)cyclohexyl)benzofurcm-2-carboxamide:

[0935] To a solution of /ra -N-(4-aminocyclohexyl)-5-chlorobenzofuran-2-carboxamide trifluoroacetate salt (0.200 g, 0.51 mmol, 1.0 equiv) in DCM (10 mL) was added DIPEA (0.3 mL, 1.5 mmol, 3.0 equiv) followed by the addition of HATU (0.388 g, 1.02 mmol, 2.0 equiv), The resulting mixture was stirred for 30 min 2-(4-chloro-3-fluorophenoxy)acetic acid (0.164 g, 0.76 mmol, 1.5 equiv) was added and the reaction mixture was allowed to stir overnight at RT and the resulting precipitate was filtered off and washed with excess methanol to obtain trans-5- chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexy l)benzofuran-2-carboxaniide (Compound 17 - 100 mg, 42 % Yield) as an off-white solid. LCMS: 479 1 VI · 1 11 : ¾NMR (400 MHz, DMSO-d _fi ) d 8.61 (d, J= 7.89 Hz, 1H), 8.01 (d, J= 8.33 Hz, 1H), 7.87 (d, J= 2.19 Hz, i l l ). 7.69 (d, ./ 8.77 Hz, 1 1 1 ). 7.32 - 7.60 On. 3H), 7.07 (dd, J = 2.63, 11.40 Hz, 11 1 ). 6.85

(d, J= 10.96 Hz, 1H), 4.51 (s, 21 1). 3.76 (d, J= 9.21 Hz, i l l ). 3 60 (hr. s . i l l ). 1.73 - 1.98 (m, 4H), 1.28 - 1.54 (m, 4H).

Synthesis of trans-6-chloro-N-(4-(2-(4-chloro-3- fluorophenoxy)acetamido)cyclohexyl)benzo[d]thiazole-2-carbox amide

Step 1 Synthesis of trans-tert-butyl (4-(6-chlorobenzo[d]thiazole-2- carboxamido)cyclohexyl)carbamate:

[Q936] To a solution of 6-chlorobenzo[d]thiazole-2-carboxylic acid (0.025 g, 0.11 mmol, 1.0 equiv) m DMF (10 mL) was added DIPEA (0.2 mL, 0.33 mmol, 3.0 equiv) followed by the addition of HATU (0.089 g, 0.23 mmol, 2.0 equiv) and the resulting mixture was stirred for 30 mm. Trans-tert- butyl (4-aminocyclohexyl)carbamate (0.025 g, 0.11 mmol, 1.0 equiv) was added and the reaction mixture was allowed to stir overnight at RT and the resulting precipitate was filtered off and washed with excess methanol to obtain trans-tert-butyl (4-(6- chlorobenzo[d]thiazole-2-carboxamido)cyclohexyl)carbamate (60 mg, quantitative yield) as an off-white solid. LCMS: 410 [M+Hf ; 'i iW!R (400M1 !/.. DMSO-d ₆ ) d 9 04 (d, J = 8.3 Hz, 1 H), 8.39 (s, 1 H), 8.11 (d, ./= 8.8 Hz, 1 H), 7.66 (d, J= 9.2 Hz, 1 H), 6.75 (d, J= 7.0 Hz, 1 H), 3.71 (hr. s., 2 H), 3.18 (br. s., 2 H), 1.80 id../ 12.7 Hz, 3 H), 1.54 (d, J= 9.6 Hz, 2 H), 1.38 (s,

9 H), 1.25 id. ./ 11.4 Hz, 2 H).

Step 2 Synthesis of trans-N-(4-aminocydohexyl)-6-chlorobemo[d]thiazole-2-carhoxa mide trifluoroacetate salt:

[Q937] To a stirred solution of trans-tert-butyl (4-(6-chlorobenzo[d]thiazole-2- carboxamido)cyclohexyl)carbamate (60 mg, 0.16 mmol, 1 equiv) in DCM (2 mL) was added trifluoroacetic acid (3 mL) and the resultant reaction mixture was stirred at RT for 1 h under nitrogen atmosphere. Reaction was monitored by LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain stick}' erode compound which was triturated with hexane (10 mL), diethyl ether (10 mL) and dried under vacuum to obtain *ra/w-N-(4-ammocyclohexyl)-6-chlorobenzo[d]thiazole-2-carbox amide trifluoroacetate salt (70 mg, quantitative yield) as an off- white solid. LCMS: 310 [M+H] ⁺ ;‘HNMR (400MHz, DMSO-de) d 9.12 (d, J 8.3 Hz, 1 H), 8.40 (s, 1 H), 8.12 (d, J 8.8 Hz, 1 H), 7.76 (br. s., 2 H), 7.67 (dd, J ----- 2 2, 8.8 Hz, 1 H), 3.75 (br s., 2 H), 2.98 (br s., 2 H), 1 97 (d, J = 1 1.0 Hz, 2 H), 1.89 (d, ./= 10.5 Hz, 2 H), 1.68 - 1.47 (m, 2 H), 1.47 - 1.34 (m, 2 H).

Step 3 - Synthesis of trans-6-chloro-N-(4-(2-(4-chloro-3- fluorophenoxy)acetamido)cyclohexyl)benåo[d]thiazole-2-carbo xamide:

[0938] To a solution of /ra«5 ^, -N-(4-aminocyclohexyl)-6-chlorobenzo[d]thiazole-2- carboxamide trifluoroacetate salt (0 070 g, 0.15 mmol, 1 0 equiv) in DMF (10 mL) was added DIPEA (0.1 mL, 0.45 mmol, 3.0 equiv) followed by the addition of HATU (0.114 g, 0.30 mmol, 2.0 equiv) and the resulting mixture was stirred for 30 min. 2-(4-chloro-3-fluorophenoxy)acetic acid (0.40 g, 0.18 mmol, 1.5 equiv) was added and the reaction mixture was allowed to stir overnight at RT and the resulting precipitate was filtered off and washed with excess methanol to obtain tra¾s-6-chloro-N-(4-(2-(4-chloro-3- fluorophenoxy)acetamido)cyclohexyl)benzo[d]thiazole-2-carbox amide (Compound 18 - 15 mg, 18 % Yield) as a white solid. LCMS: 497 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-d6) d 9.05 (d, I = 9.21 Hz, i l l ). 8 39 (br. s . H I). 8.12 (d, I = 8.33 Hz, 11 1 ). 7.99 (d, 1 = 8.33 Hz, H I). 7.66 (d, I = 8.77 Hz, 1 1 1 ). 7 50 (t, I = 8.77 Hz, H I ). 7.07 (d, J = 13.59 Hz, 1H), 6.86 id. J = 1 1.40 Hz, 11 1). 4.51 (s, 21 I K 3.77 (br. s., 11 1). 3.60 (br. s. 11 1 }. 1.81 (d, J = 13.59 Hz, 41 1). 1.59 (d, J = 11.40 Hz, 21 1 ). 1.39 (d, J = 1 1.84 Hz, 21 1 )

Example 13

Synthesis oftrans-5-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido )cyclohexyl)-2,3-

Step 1 - Synthesis of trans-tert-butyl (4-(5-chloro-2,3-dihydrobenzofuran-2- carboxamido)cyclohexyl)carbamate:

[0939] To a solution of 5-chloro-2,3-dihydrobenzofuran-2-carboxyiic acid (0.050 g, 0.25 mmol, 1.0 equiv) in DMF (05 mL) was added DIPEA (0.2 mL, 0 75 mmol, 3.0 equiv) followed by the addition of HATU (0.190 g, 0.50 mmol, 2.0 equiv) and the resulting mixture was stirred for 30 mm. Trans-tert-bvAyl (4-aminocyclohexyl)carbamate (0.200 g, 0.90 mmol, 1.0 equiv) was added and the reaction mixture was allowed to stir overnight at RT and the resulting precipitate was filtered off and washed with excess methanol to obtain trans-tert- butyl (4-(5- chloro-2,3-dihydrobenzofuran-2-carboxamido)cyclohexyl)carbam ate (100 mg, quantitative yield) as an off-white solid. LCMS; 394 [M+H] * .

Step 2 - Synthesis of trans-N-(4-aminocydohexyl)-5-chloro-2,3-dihydrobenzojuran-2- corboxamide trifluoroacetate salt:

[Q94Q] To a stirred solution of trans-tert-butyl (4-(5-chloro-2,3-dihydrobenzofuran-2- carboxamido)cyclohexyl)carbamate (100 mg, 0.25 mmol, 1 equiv) in DCM (10 mL) was added irifluoroacetic acid (5 L) and the resultant reaction mixture was stirred at RT for 1 h under nitrogen atmosphere. Reaction was monitored by LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain sticky crude compound which was triturated with hexane (10 mL) and diethyl ether and dried under vacuum to obtain rra«.s-N-(4-aminocyclohexyl)-5~chloro~2,3-dihydrobenzofuran ~2-carboxamide trifluoroacetate salt (100 mg, quantitative yield) as an off- white solid. LCMS: 294 [M+H] ⁺ .

Step 3 - Synthesis of trans-5-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)c yclohexyl)- 2 3-dikydrobemofiiran-2-carboxamide:

[0941] To a solution of /ra¾s~N~(4~aminocyclohexyl)-5~chloro~2,3-dihydrobenzofuran~ 2~ earboxamide trifluoroacetate salt (0.100 g, 0.25 mmol, 1.0 equiv) in DMF (10 mL) w¾s added D1PEA (0.13 mL, 0.75 mmol, 3.0 equiv) followed by the addition of HATH (0.190 g, 0.50 mmol, 2.0 equiv), The resulting mixture was stirred for 30 min. 2-(4-chloro-3- fluorophenoxy)acetic acid (0.083 g, 0.38 mmol, 1.5 equiv) was added and the reaction mixture was allowed to stir overnight at RT and the resulting precipitate was filtered off and w^ashed with excess methanol to obtain f.o -5-chloro-N-(4-(2-(4~chloro~3~

fluorophenoxy)acetamido)cyclohexyl)-2,3-dihydrobenzofuran -2-carboxamide (Compound 19 - 70 mg, 60 % Yield) as an off-white solid. LCMS: 481 | \ 1 1 1 G ; ⁱ HNMR (400 MHz, DMSO-de) 6 8.03 (d, ./ 7.45 Hz, 11 1). 7.96 (d, J= 8.33 Hz, I I I ). 7.49 (t, J= 8.99 Hz, 1 1 1). 7.26 (br. s., 1H), 7 15 (d, ./ 8.77 Hz, 1H), 7.04 (d, d 4.38 Hz, I I I). 6.84 (d, J 8.33 Hz, 21 1). 5.06 - 5.17 (ra,

11 1). 4.49 (s, 2H), 3.56 (br s., 21 1 ). 3.43 (d, J= 10.09 Hz, i l l ). 3.18 (br. s., 1 1 1). 1.77 (br. s., 4H), 1.32 (br. s, 4H).

Synthesis of 5-i;hloro~N~n~i3~(4-ckloro-3-fluoronkenoxv}-2-hvdroxvnronvl) mnerMm-4-vl)-

[0942] To a solution of 1 -(4-aminopiperidin-l-yl)-3-(4-chloro-3-fluorophenoxy)propan- 2-ol triiluoroacetate salt (0.105 g, 0.25 mmol, 1.0 equiv) in DMF (10 mL) was added 5-chloro-2,3- dihydrobenz.ofuran-2-carboxylic acid (0.050 g, 0.25 mmol, 1.0 equiv) and HATU (0.190 g, 9.0 mmol, 2.0 equiv) at RT. The resulting reaction mixture was stirred for 10 min and then DIPEA (0.2 mL, 0.75 mmol, 3.0 equiv) was added. The reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by LCMS. The reaction mixture w ^? as diluted with water (50 mL) and extracted with ethyl acetate (100 mL ^c 2). Combined organic extracts were washed with water (50 mL x 4), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude which was purified by reversed phase HPLC to obtain 5-chloro-N-(l-(3- (4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)-2 ,3-dihydrobenzofuran-2- carboxamide (Compound 20 - 10 mg) as an off-white solid. LCMS: 483 [M+H] ⁺ ; ¹ HNMR (400MHz, DMSO-d _fi ) d 8.05 (d, J= 8.3 Hz, 1 H), 7.46 (t, ./ 8.8 Hz, 1 H), 7.26 (br. s., 1 H), 7.15 (d, J= 7.9 Hz, 1 H), 7.06 (d, J= 11.0 Hz, 1 H), 6.83 (d, ./ 8.3 Hz, 2 H), 5.08 - 5.17 (m, 1 H), 4.87 (br s., 1 H), 4 00 (d, J= 6.6 Hz, 1 H), 3.89 (br. s., 1 H), 3.57 (br. s„ 1 H), 3.45 (dd, .7=16.2, 11 0 Hz, 2 H), 3.14 - 3.23 (m, 1 H), 2.80 (br s., 2 H), 2.33 (br. s., 2 H), 2.06 (d, .7=17.1 Hz, 2 H), 1.65 (br. s., 2 H), 1.48 ppm (d, .7=12.3 Hz, 2 H). Example IS

[0943] To a solution of l-(4-aminopiperidin-l-yl)-3-(4-chloro-3-fluorophenoxy)propan -2-ol trifluoroacetate salt (0.202 g, 0.485 mmol, 1.0 equiv) in DMF (10 ml,) was added 6-chloro-2- naphthoic acid (0.100 g, 0.485 mmol, 1.0 equiv) and HATU (0.369 g, 0.970 mmol, 2.0 equiv) at RT. The resulting reaction mixture was allowed to stir for 10 mm. DIPEA (187 mg, 1.48 mmol, 3.0 equiv) was added and the resultant reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL·) and extracted with ethyl acetate (100 mL ^c 2). Combined organic extracts were washed with water (50 mL. ^c 4), dried over anhydrous Na ₂ S0 ₄ and concentrated to obtain crude which was purified by reversed phase HPLC to obtain 6-chloro-N~(l-(3-(4-chloro-3-fluorophenoxy)~2~ hydroxypropyl)piperidin-4-yl)-2-naphthamide (Compound 21 - 60 mg, 26 % Yield) as an off- white solid. LCMS: 491 j M S S | ; TlNMR (400MHz, DMSO-de) d 8.40 - 8.53 (m, 2 H), 8.05 - 8 18 (m, 2 H), 7 98 i s. 2 H), 7.60 (dd, .7=8.8, 1.8 Hz, 1 H), 7.47 (t, =8.8 Hz, 1 H), 7.08 (dd, .7=11 8, 2.6 Hz, 1 H), 6.86 (d, .7=8 8 Hz, 1 H), 4 91 - 5.07 (m, 1 H), 3 98 - 4.11 im. 2 1 1 ). 3 79 - 3.98 (m, 2 H), 2.93 - 3.10 (m, 3 H), 2.31 (d, ./ 13.6 Hz, 3 H), 1.85 (d, ,7=11.0 Hz, 2 H), 1.66 (d,7=11.8 Hz, 2 H).

[0944] To a solution of i-(4-aminopiperidin~l~}'l)-3-(4-chloro-3-fluorophenoxy)propa n~2-ol (0.138 g, 0.48 mmol, 1.0 equiv) in DMT (10 L) was added 6-chloroquinohne-2-carboxyiic acid (0.100 g, 0.48 mmol, 1.0 equiv) and HATU (0.365 g, 0 96 mmol, 2,0 equiv) at RT. The resulting reaction mixture was stir for 10 min. DIPEA (0.24 mL, 1.44 mmol, 3.0 equiv) was added and the resultant reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 2). Combined organic extracts were washed with water (50 mL ^c 4), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude which was purified by reversed phase HPLC to obtain 6-chloro-N-(l-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropy])piperidin-4-yl)quinoline-2-carboxamide (Compound 22 - 15 mg, 6.5 % Yield) white solid. LCMS: 492 (400MHz, DMSQ~d ₆ ) 5 8.68 id. J = 8.3 Hz, 1 H), 8.53 (s, 1 H), 8.24 (d, J = 2.2 Hz, 1 H), 8.17 (dd, J = 4.8, 8.8 Hz, 2 H), 7.88 (dd, J = 2.4, 9.0 Hz,

1 H), 7.47 (t, J = 9.0 Hz, 1 H), 7.06 (d, J = 3.1 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 1 H), 4.90 (br. s., 1 H), 4.04 (d, J = 7.0 Hz, 1 H), 3 95 - 3.86 (m, 2 H), 3 85 (br. s , 1 H), 3.00 - 2.82 (m, 2 H), 2.40 - 2.27 (m, 2 H), 2.20 - 2.05 (m, 2 H), 1.79 (br s., 2 H), 1.71 (d, J = 1 1.0 Hz, 2 H).

Example 17

Synthesis oftram-6-chloro-N-(4-(2-(4-chloro-3-

[0945] To a solution of ira«5 ^, -N-(4-aminocyclohexyl)-2-(4-chloro-3- fluorophenoxy (acetamide (0.200 g, 0.6 mmol, 1.0 equiv) in DMF (10 mL) was added 6- chloroquinoline-2-carboxylic acid (0.138 g, 0.6 mmol, 1.0 equiv) and HATH (0.456 g, 1.2 mmol, 2.0 equiv) at RT. The reaction mixture was stir for 10 mm. DIPEA (0.31 mL, 1.8 mmol, 3.0 equiv) was added and the resultant reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 2). Combined organic extracts were washed with water (50 mL. ^c 4), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude which was purified by reversed phase HPLC to obtain fra¾w6-chloro-N-(4-(2-(4- chloro~3~fluorophenoxy)aceiamido)cyelohexyl)quinoline-2-carb oxamide (Compound 23 - 110 mg, 34 % Yield) as an off-white solid. LCMS: 490 [M+Hf ; 'HNMR (400MHz, DMSO-de) d 8.66 (d, J ------ 8.3 Hz, 1 H), 8.54 id. ./ 8.3 Hz, 1 H), 8.33 - 8.14 (m, 3 H), 8.01 (d, J ------ 7.9 Hz, 1

H), 7.88 (d, J--- 9.2 Hz, 1 H), 7 50 (t, J -- 8 8 Hz, 1 H), 7.11 - 7.01 (m, 1 H), 6.86 (d, J= 8.3 Hz,

1 H), 4.52 (s, 2 H), 3 83 (d, ./ 7.5 Hz, 1 H), 3.65 (hr. s., 1 H), 2.01 - 1.71 (m, 4 H), 1.69 - 1.53 (m, 2 H), 1.47 - 1.32 (m, 2 H).

Example 18

Synthesis oftrans-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohex yl)fiiro[2,3-

[Q946] To a solution of /ran.9-N-(4-aminocyclohexyl)-2-(4-chloro-3- fluorophenoxy)acetamide (0.200 g, 0.6 mmol, 1.0 equiv) in DMF (10 mL) was added furo[2,3- c|pyridine-2-carboxylic acid (0.108 g, 0.6 mmol, 1.0 equiv) and HATU (0.456 g, 1.2 mmol, 2.0 equiv) at RT. The reaction mixture was stir for 10 min. DIPEA (0.31 mL, 1.8 mmol, 3.0 equiv) was added and the resultant reaction mixture continued stirring at RT for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with w¾ter (50 mL) and extracted with ethyl acetate (100 mL ^c 2). Combined organic extracts ivere washed w th w¾ter (50 mL x 4), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude which was purified by reversed phase HPLC to obtain ir ’-N-(4-(2-(4-chloro-3- fluorophenoxy)acetamido)cyclohexyl)furo[2,3-c]pyridine-2-car boxamide (Compound 24 - 90 mg, 30 % Yield) as an off white solid. LCMS: 446 j YM I | . ¹ HNMR (400MHz, DMSG-d ₆ ) d 9 04 (s, 1 H), 8.79 (d, ,/= 7 9 Hz, 1 H), 8.47 (d, ./= 5.3 Hz, 1 H), 8 01 (d, J= 8.3 Hz, 1 H), 7.81 (d, J = 5.3 Hz, 1 H), 7.60 (s, 1 H), 7.50 (t, J = 9.0 Hz, 1 H), 7.13 - 7.00 (m, 1 H), 6.86 (d, .7= 8.3 Hz, 1 H), 4.51 (s, 2 H), 3.78 (br. s., 1 H), 3.63 (br. s., 1 H), 1.82 (d, J = 16.2 Hz, 4 H), 1.57 - 1.30 (m, 4 H).

Example 19

Step 1 Synthesis of l-(4-amino-2, 2, 6.6-tetramethylpiperidin-l -y!)-3-(4-chloro-3- fhiorophenoxy)propan-2-ol:

[0947] To a stirred solution of 2,2,6,6-tetramethylpiperidin-4-amine (1.00 g, 6.39 mmol, 1.0 equiv) in DMF (10 mL) was added 2-((4-chloro-3-iluorophenoxy)methyl)oxirane (1.19 g, 6.39 mmol, 1.0 equiv) at RT. The resulting reaction mixture was heated at 100 °C for 12 h. Progress of the reaction was monitored by 1H NMR. Reaction was quenched by adding water and extracted with ethyl acetate (100 mL ^c 2). Combined organic layer was washed with water (50 mL x 4), dried over anhydrous Na ₂ SG ₄ and concentrated under reduced pressure. The resulting crude material was triturated with hexane and diethyl ether to obtain 1 ~(4-amino-2, 2,6,6- tetramethylpiperidin-l-yl)-3-(4-chloro-3-fluorophenoxy)propa n-2-ol (0.330 g, 15 % Yield) as an off-white solid LCMS: 359.3 | M I ! | ; ¹ HNMR (400MHz, D.MSO-d,.} d 7 51 - 7.39 (m, 1 H), 7 06 (dd, J= 2.9, 11.6 Hz, 1 H), 6.83 (dd, J= 1.8, 8.8 Hz, 1 H), 4.97 (hr. s., 1 H), 4.05 - 3.95 (m, 1 H), 3.89 (dd, J = 5.9, 9.9 Hz, 1 H), 3.85 - 3.74 (m, 1 H), 2.81 - 2.57 (m, 3 H), 1.69 (d , J = 11.4 Hz, 2 H), 1.13 - 1.06 (m, 6 H), 1.01 - 0 88 (m, 6 H).

Step-2: Synthesis of 2-(4-chloro-3-fluorophenoxy)-N-( I -(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)-2, 2, 6, 6-tetramethylpiperidin-4-yl)acetamide:

[0948] To a solution of 1 -(4-amino-2, 2, 6, 6-tetramethylpiperidin-l -yl)-3-(4-chloro-3- fiuorophenoxy)propan-2-o! (0.169 g, 0.472 mmol, 1.0 equiv) in DMF (2 mL) was added 2-(4- chloro-3-fluorophenoxy)acetic acid (0 096 g, 0.472 mmol, 1.0 equiv) and HATU (0 358 g, 0.944 mmol, 2.0 equiv) at RT. The reaction mixture was stirred for 10 mm and then DIPEA (0.4 mL, 2.36 mmol, 5.0 equiv) was added. The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL ^c 2). Combined organic layer was washed with water (50 mL x 4), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain the crude compound which was purified by reversed phase HPLC to obtain 2- (4-chloro-3-iluorophenoxy)-N-(l -(3-(4-chloro-3-fiuorophenoxy)-2-hydroxypropyl)-2,2,6,6- tetramethy]piperidin-4-y!)acetamide (Compound 25 - 0.015 g, 6 % Yield) as an off-white solid. I.CViS: 545.3 | \M 1 | ; 4 IN MR (400MHz, DMSO-de) d 7.54 - 7.38 (m, 2 H), 7.09 (d, J = 9.6 Hz, 1 H), 6.98 id. J = 13.6 Hz, 1 H), 6.88 - 6.73 (m, 2 H), 5.76 (br. s., 1 H), 5.08 (d, J= 15.3 Hz, 1 H), 5.01 - 4.85 (m, 2 H), 4 00 (br. s , 2 H), 1.69 (br. s., 2 H), 1.23 (br. s„ 12 H).

Synthesis of2-(4-ehloro-3-fluorophenox )-N-(l-(3-(4-chloro-3-

Step 1 - Synthesis of 4-(3-bromopropoxy)-2-chloro-l-fluorobenzene:

[Q949] To solution of 3-chloro-4-fluorophenol (0.100 g, 0.68 mmol, 1.0 equiv) in ethanol (5 mL) was added K ₂ C0 ₃ (0.187 g, 1.36 mmol, 2.0 equiv) followed by the addition of 3-chloro-4- fluorophenol (0.151 g, 0.75 mmol, 1.1 equiv). The resulting reaction mixture was heated at 80 °C for overnight. Product formation was confirmed by NMR spectroscopy. After completion of reaction the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 2). Combined organic layer was washed with water (20 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain the crude compound which was purified by flash chromatography (0-30 % ethyl acetate in hexane as an eluent) to obtain 4-(3- bromopropoxy)-2-chloro-l-fluorobenzene (0.090 g, 50 % Yield) as a yellow semi-solid. ^] HNMR (400MHz, DMSO-dc,) 57.57 - 7.33 (m, 1 H), 7.14 - 7.03 (m, 1 H), 6.90 - 6.76 (m, 1 H), 4.22 - 3 96 (m, 3 H), 3.71 - 3 55 (m, 1 H), 2.30 - 2 09 (m, 1 H), 1.10 (f J= 7 0 Hz, 2 H).

Step 2 - Synthesis of tert-hutyl ( l-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4 - yl) carbamate:

[Q95Q] To solution of tert- butyl piperidin-4-ylcarbamate (0.067 g, 0.36 mmol, 1.0 equiv) in DMF (1 mL) was added K ₂ C0 ₃ (0.059 g, 0.430 mmol, 1.2 equiv) followed by the addition of 4- (3-bromopropoxy)-2-chloro-l-fluorobenzene (0.090 g, 0.36 mmol, 1.0 equiv). The resulting reaction mixture was heated at 100 °C for overnight. Product formation was confirmed by NMR spectroscopy. After completion of reaction the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 ml. ^c 2). Combined organic layer was washed with water (20 mL x 4), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain _<¾ r/-butyl (l-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-yl)carbam ate (0.056 g, 50 % Yield) as a crude which was used for next step without any further purification. LCMS: 387.3 [M+Hf; ^! HNMR (400MHz, DMSO-de) d 7.55 - 7.36 (m, 1 H), 7.1 1 - 7 03 (m, 1 H), 6 83 (t, ./ = 8.8 Hz, 1 H), 6.71 (d, J= 7.5 Hz, 1 H), 4.14 ( ·../ 6.4 Hz, 1 H), 4.08 - 3.93 (m, 1 H), 3.17 (br. s., 2 H), 2.76 (br. s., 1 H), 2.27 - 2.05 (m, 2 H), 1.89 - 1.77 (m, 2 H), 1.64 (br. s., 3 H), 1.57 - 1 44 (m, 1 H), 1.37 (s, 9 H).

Step 3 Synthesis of l-(3-(4-chloro-3fluorophenoxy)propyl)piperidin-4-amine trifluoroacetate salt:

[0951] To a stirred solution of fc/7-butyl (l-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin- 4-yl)carbamate (0.056 g, 0.145 mmol, 1.0 equiv) in DCM (30 mL) was added trifluoroacetic acid (1 mL) at RT. The reaction mixture was allowed to stir at RT overnight. DCM and excess of trifluoroacetic acid was removed under reduced pressure to obtain l-(3-(4-chloro-3- fluorophenoxy)propyl)piperidin-4-amine trifluoroacetate salt (0.100 g, quantitative yield) as an oil. LCMS: 287.3 [M+Hf; 11NMR (400MHz, DYlSO-d,.) d 8 24 (br. s., 2 H), 7.52 - 7.41 (m, 1 H), 7.16 - 6.98 (m, 1 H), 6.84 (d, ./= 6.6 Hz, 1 H), 4.21 - 3 95 (m, 1 H), 3.55 (d, J= 1 1.0 Hz, 1 H), 3.32 (br. s., 2 H), 3.09 (br. s., 2 H), 3.02 (br. s., 1 H), 2.95 (br. s., 1 H), 2.23 - 1.96 (m, 4 H), 1.78 (d. ./ 11.0 Hz, 2 H), 1.67 (d, J= 11.8 Hz, 1 H). Step 4 Synthesis of 2-(4-chloro-3-fluorophenoxy)-N-(l-(3-(4-chloro-3- fluorophenoxy)propyl)piperidin-4-yl)acetamide:

[0952] To a solution of l-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin-4-amine trifluoroacetate salt (0.627 g, 1.93 mmol, 1.0 equiv) in DMF (5 mL) was added 2-(4-chloro-3- fluorophenoxy)acetic acid (0.394 g, 1.93 mmol, 1.0 equiv) and HATU (1.46 g, 3.86 mmol, 2.0 equiv) at RT. The reaction mixture was stirred for 10 minutes and then DIPEA (1 mL, 5.79 mmol, 5.0 equiv) was added. The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL ^c 2). Combined organic layer was washed with water (50 mL x 4), dried over anhydrous Na ₂ SC>4 and concentrated under reduced pressure to obtain the crude compound which was purified by reversed phase HPLC to obtain 2- (4-chloro-3-iluorophenoxy)-N-(l -(3-(4-chloro-3-fiuorophenoxy)propy])piperidin-4-yl)acetamid e (Compound 28 - 0.020 g, 3 % Yield) as an off-white solid. LCMS: 473.2 [M+H] ^÷ ; ^l HNMR (400MHz, DMSO-de) d 7.98 (d, J = 7.9 Hz, 1 H), 7.57 - 7.41 (m, 2 H), 7.04 (s, 1 H), 7.07 (s, 1 1 1). 6.83 (t, ,/ 9.6 Hz, 2 H), 4 50 (s, 2 H), 4.01 (t, J 6.1 Hz, 2 H), 3.60 (hr. s., 1 H), 2.80 (d, ./

= 1 1.4 Hz, 2 H), 2.38 (t, J= 6.8 Hz, 2 H), 1.95 (t, J= 10.7 Hz, 2 H), 1.92 - 1.82 (m, 2 H), 1.68 (d, J= 9.6 Hz, 2 H), 1.54 - 1.42 (m, 2 H).

Synthesis of 5-chloro-N-(l-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl) piperidin-4- yl)henzofuran-2-carboxamide

[Q953] To a solution of l-(4-aminopiperidin-l-yl)-3-(4-chloro-3-fluorophenoxy)propan -2-ol trifluoroacetate salt (0.200 g, 0.48 mmol, 1.0 equiv) in DMF (10 mL) was added 5- chlorobenzofuran-2-carboxylic acid (0.095 g, 0.48 mmol, 1.0 equiv) and HATH (0.364 g, 0 96 mmol, 2.0 equiv) at RT. The resulting reaction mixture was stir at RT for 10 min and DIPEA (0.3 mL, 1.44 mmol, 3.0 equiv) was added. The reaction mixture was allowed to stir at RT overnight Product formation was confirmed by LCMS. After completion of reaction the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL * 2). Combined organic extracts were washed with water (50 mL ^c 4), dried over anhydrous Na ₂ S04 and concentrated. The crude product was purified by reverse phase HPLC to obtain 5-chloro-N- (l-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4 -yl)benzofuran-2-carboxamide (Compound 29 - 50 mg, 21 % yield) as a white solid. LCMS: 481.2 [M+H] ¹ HNMR (500 MHz, DMSO-t/6) 6 8 65 (d, ./ 7.9 Hz, I I I). 7.87 (d, J 2.3 Hz, i l l). 7.70 (d, ./ 8.8 Hz,IH),

7.55 - 7.43 (m, 31 1 ). 7 08 (dd, ./ 11.5, 2.9 Hz, ! 1 1 ). 6.89 - 6.82 (m, 1 1 1). 4 92 (s, i l l). 4.02 (dd,

J= 9.6, 3.0 Hz, I I I ). 3.95 - 3.86 (m, 31 1 ). 3.76 (s, i l l ). 3.34 (s, 91 1 ). 2.94 (d, J = 11.6 Hz, I I I ). 2 88 (s, 1H), 2.10 (t , J= 12.7 Hz, 2H), 1.74 (s, 2H), 1 63 (t, J 12 3 Hz, 2H).

Example 22

Synthesis of trans-6-chloro-N-( 4-((3-(4-chloro-3-fluorophenoxy)-2-

Step 1 Synthesis of tr ans -ter t-buty l (4-(6-chloroquinoline-2- carboxamidojcyciohexyljcarhamate :

[0954] To a stirred mixture of 6-chloroquinoline-2-carboxylic acid (100 mg, 0.48 mmol, 1 equiv) and trawx-tert-butyl (4~aminocyclohexyl)carbamate (103 mg, 0.48 mmol, 1 equiv) in DMF (5 mL) was added HATH (365 mg, 0.96 mmol, 2 equiv) and continued stir at RT for 30 min. DIPEA (0.3 ml, 1.44 mmol, 3 equiv) was added and again stirred at RT for overnight. Reaction progress was monitored by LCMS. After completion of reaction, the reaction mixture was poured into water (50 mL), the resulting yellow precipitate was filtered off and again washed with water (20 mL x 2). Thus obtained solid was dried under vacuum to obtain trans- tert-hutyl (4-(6-ch!oroquinoiine-2-carboxamido)cyclohexyl)carhamate (120 mg , 71.85 %) as a yellow solid LCMS: 404.6 j VI · 1 11

Step 2 - Synthesis of trans-N-(4-cminocyclohexyl)-6-chloroquinoline-2-carboxamide trifluoroacetate salt:

[0955] To a stirred solution of irats-tert-butyl (4-(6-chloroquinoline-2- carboxamido)cyclohexyl)carbamate (120 mg, 0.297 mmol, 1 equiv) in DCM (5 mL) _, was added TFA (0.5 mL) and the resultant reaction mixture was stirred at RT for overnight under nitrogen atmosphere. Reaction was monitored by LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain frans-N-(4-aminocycIohexyl)-6- chloroquinoline-2-carboxamide trifluoroacetate salt (130 rng, quant yield) as a light pink solid. LCMS: 304 4

Step 3 - Synthesis of trans-6-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)amino)cyclohexyl)quinoline-2-carboxamide:

[Q956] To a stirred mixture of /ram-N-(4-aminocyclohexyl)-6-chloroquinoline-2- carboxamide trifluoroacetate salt (130 mg, 0.311 mmol, 1 equiv) and K ₂ C0 ₃ (130 mg, 0.935 mmol, 3 equiv) in DMF (10 mL) was stirred at RT for 30 minute. 2-((4-chloro-3- fluorophenoxy)methyl)oxirane (63 mg, 0.311 mmol, 1 equiv) was added and heated at 70 °C for overnight Reaction was monitored by LCMS. After completion of reaction, the reaction mixture was poured into ice cold water (50 ml) and extracted with EtOAc (2 x 30 mL).

Combined organic layer was washed with w¾ter (4 x 20 mL), brine solution (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product which was purified by reversed-phase HPLC to obtain /rans-6-chloro-N-(4-((3-(4-chloro-3- fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)quinoline-2- carboxamide (Compound 30 - 35 mg, 30%) as an off white solid. LCMS: 506.4 (500 MHz, DMSO-ae) d 8 65 (d, J= 8.5 Hz, I I I). 8.54 (d, .7= 8.6 Hz, 11 1). 8.32 (s, !H), 8.25(d, J = 2.5 Hz, 1H), 8. 1 7 U. ·/ = 8.7 Hz, 2H), 7.88 (dd, J= 9 0, 2.5 Hz, 1H), 7 47 (t, ./= 8 8 Hz, 1 1 1). 7.09 (dd, J= 11.5, 2.9 Hz, 1H), 6.85 (dd, .7= 8.9, 2.8 Hz, i l l ). 4.00 (d, .7= 7.1Hz, 1H), 3.92 (d. ./ 8.8 Hz. 21 1 ). 3.81 (d , J =

10.9 Hz, 11 1 ). 2.79 (d , J= 11.8 Hz, 1 1 1). 2.69(d. ./ 8.6 Hz, i l l ). 1.98 !d../ 11.9 Hz, 2H), 1.92

- 1 85 (m, 2H), 1.58 - 1.47 (m, 2H), 1.21 (q, ./= 12.9, 11.8 Hz, 31 1 ). Example 23

Synthesis oftram-6-chloro-N-(4-((2-(4-chloro-3-

Step 1 - Synthesis of trans-tert-butyl (4-(6~chloroquinoline-2- carboxamido)cyclohexyl)carbamate:

[Q957] To a stirred mixture of 6-chl oroquinoline-2-carhoxy lie acid (100 mg, 0 48 mmol, 1 equiv) and rra ’-tert-butyl (4-aminocyclohexyl)carbamate (103 mg, 0 48 mmol, 1 equiv) in DMF (5 mL) was added HATU (365 mg, 0 96 mmol, 2 equiv) and continued stir at RT for 30 min. DIPEA (0.3 ml, 1.44 mmol, 3 equiv) was added and again stirred at RT for overnight. Reaction progress was monitored by LCMS. After completion of reaction, the reaction mixture was poured into water (50 ml), the resulting yellow precipitate was filtered off and again washed with water (20 mL ^c 2). The obtained solid was dried under vacuum to obtain t reins - tert-butyl (4-(6-chloroquinoline-2-carboxamido)cyclohexyl)carbamate (120 mg, 71.85 %) as a yellow solid. LCMS: 404 6 [M+H]

Step 2 - Synthesis of trans-N-( 4-aminocyclohexyl)-6-chloroquinoline-2-carboxamide trifluoroacetate salt:

[0958] To a stirred solution of ira/i -tert-butyl (4-(6-chloroquinohne-2- carboxamido)cyciohexyi)carbamate (120 mg, 0.297 mmol, 1 equiv) in DCM (5 mL) _, was added TEA (0.5 mL) and the resultant reaction mixture was stirred at RT for overnight under nitrogen atmosphere. Reaction was monitored by LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain /ra '-N-(4-aminocyclohexyl)-6- chloroquinoline-2-carboxamide trifluoroacetate salt (130 mg, quant yield) as a light pink solid. LCMS : 304.4 j M - ! f |

Step 3 - Synthesis of trans~6~chioro-N-(4~((2-(4-chIoro~3- fluorophenoxy)ethyl)amino)cyclohexyl)quinoline-2-carboxamide :

[0959] To a stirred solution of /ran.9-N-(4-aminocyclohexyl)-6-chloroquinoline-2- carboxamide trifluoroacetate salt (130 mg, 0.311 mmol, 1 equiv) in DMF (10 rnL) was added K ₂ C0 ₃ (130 mg, 0.935 mmol, 3 equiv) and allowed to stir at RT for 30 mm. 4-(2-bromoethoxy)- l-chloro-2-fluorobenzene (80 mg, 0.311 mmol, 1 equiv) was added and heated at 80 °C for overnight Reaction progress was monitored by LCMS. After completion of reaction, the reaction mixture was poured into ice cold water (50 ml) and extracted with EtOAc (2 ^c 30 mL). Combined organic layer washed with water (4 ^c 20 mL), brine solution (1 ^c 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude which was purified by reversed-phase HPLC to obtain /ra^-6-chloro-N-(4~((2-(4-chloro-3- fluorophenoxy)ethyl)amino)cyclohexyl)quinoline-2-carboxamide (Compound 31 - 5 mg, 3.3%) as an off white solid. LCMS: 476.4 (500 MHz, DMSO-ae) d 8.64 (d, J= 8.5 Hz, 11 1 ). 8.54 (d, J= 8 6 Hz, 1H), 8.39 - 8.33 (m, 2H),8.25 (d, ./= 2 4 Hz, i l l ). 8.17 it. J 8 6 Hz, 2H), 7.88 (dd, J = 9.0, 2.4 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H),7.09 (dd, J = 11.5, 2.9 Hz, 1H), 6.85 (dd, J ----- 8.8, 2.8 Hz, I I I ). 4.04 (t, J 5.6 Hz, 2H), 3.81 (dq, J= 11.0,7.1, 6.1 Hz, I I I ). 2.92 0. ./ 5.6 Hz, 2H), 1.99 - 1.92 (m, 21 1} 1.87 (d , J= 12 4 Hz, 21 !}. 1.56 - 1 47 (m,2H), 1.23 (s,

U S). 1.18 - 1.09 (m, 2H).

Example 24

Synthesis of tram-5-chloro-N-(4-((2-(4-chloro-3

Step 1 - Synthesis of trans-tert-hutyl N-f 4-[ (5-chlorobenzofiiran-2- carbonyl)amino jcydohexyl ] carbamate:

[0960] To a solution of 5-chlorobenzofuran-2-carboxylic acid (0.300 g, 1.53 mmol, 1.0 equiv) in DMF (5 mL) was added HATU (0.872 g, 2.3 mmol, 1.3 equiv) and /ra '-tert-butyl N- (4-aminocyelohexyl)carbamate (0.327 g, 1.53 mmol, 1 equiv) followed by the addition of DIPEA (0.395 g, 3.06 mmol, 2.0 equiv). The reaction mixture was allowed to stir at RT for overnight Product formation was confirmed by LCMS. After completion of reaction the reaction mixture was diluted with water and the resulting precipitate was filtered off and the obtained crude product was crystallized in MeOH to obtain mms-tert-butyl N-[4-[(5- chlorobenzofuran-2-carbonyl)amino]cyclohexyl [carbamate (0.450 g, 75 % Yield) as an off- white solid. LCMS: 393 3 I VI i ! |

Step 2 Synthesis of trans-N-( 4-aminocyclohexyl)-5-chlorobenzofuran-2-carhoxamide trifluoroacetate salt:

[0961] To a stirred solution of iraras-tert-butyl N-[4-[(5-chlorobenzofuran-2- carbonyl)amino]cyclohexyl]carbamate (0.450 g, 1.15 mmol, 1.0 equiv) in DCM (10 mL), was added Trrfluoroacetic acid (4mL). The reaction mixture was allowed to stir at RT for 1 h.

Product formation was confirmed by LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain /ra«s-N-(4-aminocyclohexyl)-5- chlorobenzofuran-2-carboxamide triiluoroacetate salt (0.450 g, Quant. Yield). LCMS: 292,3 [M+Hf

Step 3 Synthesis of 4-(2-bromoethoxy)-l-chloro-2-fluoro-benzene:

[Q962] To a stirred solution 4-chloro-3-fluoro-phenol (1.00 g, 6.83 mmol, 1.0 equiv) in EtOH (30 mL), w¾s added K .CO- (1.414 g, 10.25 mmol, 1.5 equiv), followed by the addition of 1,2-dibromoethane (1.284 g, 6.83 mmol, 1.0 equiv) and the mixture was allowed to stir at 80°C for overnight Product formation was confirmed by LCMS and TLC. After completion of reaction, reaction mixture was concentrated under reduced pressure. The residue w¾s diluted with water and extracted with ethyl acetate (50 mL ^c 3). Combined organic layer was washed with brine (15 mL), dried over anhydrous Na S0 ₄ and concentrated. The crude product obtained was purified by flash chromatography (0-40% Ethyl acetate hexane as an eluent) to obtain 4- (2-bromoethoxy)-l-chioro-2-fluoro-benzene (0.60 g, 35 % Yield). LCMS: 252.3 [M+Hf

Step 4 Synthesis of irans-5-chloro-N-(4-((2-(4-ckioro-3- fluorophenoxy)ethyl)amino)cyclohexyI)benzoJuran-2-carboxamid e:

[0963] To a stirred solution of /ra¾s~N-(4~amiiiocyclohexyl)-5-chlorobenzofuran-2- carboxamide triiluoroacetate salt (0.100 g, 0.25 mmol, 1.0 equiv) in DMF (3 mL), was added K CO ₃ (0.053 g, 0.38 mmol, 1.5 equiv), followed by the addition of 4-(2-bromoethoxy)-l- chloro-2-f!uoro-benzene (0.063 g, 0.25 mmol, 1.0 equiv) and the mixture was allowed to stir at 60°C for overnight. Product formation was confirmed by LCMS and TLC. After completion of reaction the mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (30 mL x 3). Combined organic layer was washed w th water (15 mL ^c 6), dried over anhydrous Na SC and concentrated. The crude product obtained w¾s purified by reverse phase HPLC to obtain fra«s-5-chloro-N-(4-((2-(4-chloro-3- fluorophenoxy)ethyl)amino)cyclohexyl)benzofuran-2-carboxamid e (Compound 32 - 8.6 mg, 7.5% Yield) as an off-white solid LCMS: 465.3 [M+Hf; 'HNMR (400 MHz, DMSO-de) d 8 57 (d, J ---- 8.1 Hz, I I I). 7.86 (d, J 2.3 Hz, 11 1). 7.69 (d, ./ 8.8 Hz,IH), 7 52 (s, 1H), 7 46 (t, J

= 8.8 Hz, 2H), 7.07 (dd, J= 11 6, 2.8 Hz, 11 1). 6 88 - 6 80 (m, 1H), 4.02 (t, J= 5 4 Hz, 2H), 3.81 - 3 67 (m, I I I). 2.90 (s, 2H), 1.98 - 1.90 (rn, 21 !}. 1.87 - 1 79 (m, 2H), 1.42 Uj. ,/ 12.8. 12,3 Hz, 2H), 1.23 (s, 1H), 1.10 (q , ./= 12 4 Hz, 2H)

[0964] The enantiomers, (+)-2-(4-chlorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2- hydroxypropyi)amino)cyc!ohexyl)acetamide (Compound 3 - [a] ° = 12.47° (c = 0.109, MeOH); elution time: 6 89 min) and (-)-2-(4-chlorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2- hydroxypropy!)amino)cyelohexyl)acetamide (Compound 4 - [a]„ = -13.5° (c = 0.0976, MeOH); elution time: 12.75 min), were separated by chiral SFC (Dai cel Chiral cel ^ OD-H, 250 ^c 4.6 mm, 5pm). Isocratic program with analytical grade liquid carbon dioxide and HPLC grade MeOH (0.2% DEA).

Chiral resolution of tram-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3-fluor ophenoxy)~

[0965] The enantiomers, (+)-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4-chloro-3- fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl)acetamide (Compound 6 - [a]“ ^::: 15.55° (c = 0.1075, MeOH); elution time: 12.16 min) and (-)-2-(4-chloro-3-fluorophenoxy)-N-(4-((3-(4- chloiO-3-fluorophenoxy)-2-hydiOxypropyl)amino)cyclohexyl)aee tamide (Compound 7 - [a]^ ^' = -8.41 ° (c = 0.1067, MeOH); elution time: 16.97 min), were separated by chiral SFC (Daicel Chiralcel ^¾ OD-H, 250 ^c 4.6 mm, 5mih). Isocratic program with analytical grade liquid carbon dioxide and HPLC grade MeOH (0.2% DBA). LCMS: 503 [M+H] ⁺ ; ¹ HNMR (400 MHz, DMSO-de) 57.92 (d, ./= 6 36 Hz, 2H), 7.37-7.57 (m, 2H), 7.06 (d, ./ = 11.74 Hz, 2H), 6.83 (m, 2H), 4.48 (s, 4H), 3.97 (m, i l l). 3.89 (d, J= 6.85 Hz, 1H), 3.80 (m, 1H), 3.55 (m, 3H), 1.85 (m I I I ). 1.77 {d. ,/ 14.18 Hz, 3H), 1.35 (br. s., I I I ). 1.23 (br. s., 2H).

Example 27

[0966] The enantiomers, (-)-2-(4-chlorophenoxy)-N-(l-(3-(4-chlorophenoxy)-2- hydroxypropyl)piperidm-4-yl)acetamide (Compound 15 - elution time: 16.39) and (+)-2-(4- chlorophenoxy)-N-(l-(3-(4-chlorophenoxy)-2-hydroxypropyl)pip eridin-4-yl)acetamide (Compound 16 - [a]^ = 7.91 ° (c = 0.1045, MeOH); elution time: 24.53 min), were separated by chiral SFC (Daicel Chiralcel ^® AD-H, 250 ^c 4.6 mm, 5pm). Isocratic program with analytical grade liquid carbon dioxide and HPLC grade EtOH (0.2% DEA). Example 28

Chiral resolution of2-(4-chloro-3-fluorophenoxy)-N-(l-(3-(4-chloro-3-fluorophe noxy)-2-

[0967] The enantiomers (-)-2-(4-chloro-3-fluorophenoxy)-N-(l -(3-(4-chloro-3- fluorophenoxy)-2~hydroxypropy!)piperidin~4~yl)acetamide (Compound 26 - [a]’ ⁰ -7.23° (c = 0 1098, MeOH); elution time: 9.15 min) and (+)-2-(4-chloro-3-fluorophenoxy)-N-(l-(3-(4- chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)aceta mide (Compound 27 - [a],) ⁰ 7.84° ( c = 0.1012, MeOH); elution time: 12 52 min) were separated by dural SFC

(CHIRALPAK-AD-H, 250 x 20 mm, 5pm). Isocratie Program with analytical grade liquid carbon dioxide and HPLC grade EtOH (0 1% trifluoroacetic acid).

[0968] To a solution of /ra«s-N-(4-aminocycJohexyl)-2-(4-chJoro-3- fluorophenoxy)acetamide 2,2,2-tiifluoroacetate (0 100 g, 0.241 mmol, 1.0 equiv) in DMF (5 mL) was added 6~chloro-2 -naphthoic acid (0.050 g, 0.241 mmol, 1.0 equiv) and HATU (0.137 g, 0.36 mmol, 1.50 equiv) at RT. Tire reaction mixture was stir for 10 mm. DIPEA (0.5 mL) was added and the resultant reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 2) Combined organic extracts were washed with water (50 rnL ^c 4), dried over anhydrous Na ₂ S0 ₄ and concentrated under reduced pressure to obtain crude which was crystallized in MeOH to obtain ?r ws-6-chloro-N-(4-(2-(4-chlorQ-3- fiuorophenoxy)acetamido)cyclohexyl)-2-naphthamide (Compound 145 - 60 mg, 51.28 % Yield) as an off-white solid. LCMS: 489.3 | \ 1 1 11 : 1H NMR (400MHz ,DMSO-d ₆ ) d 8 57 - 8.37 (m, 2 H), 8.11 (s, 1 H i. 8.09 - 7.95 (m, 3 H i. 7.59 (d, J ------ 8.8 Hz, 1 1 1 }. 7.50 (t, J= 9.0 Hz, 1 H i. 7.08

(dd, ./= 2.6, 11.4 Hz, 1 H), 6.86 (d, J= 7.5 Hz, 1 H), 4.52 (s, 2 H), 3.81 (br s., 1 H), 3 63 (br. s , 1 H), 1.91 (br. s., 2 H), 1.85 (br. s., 2 H), 1.53 - 1.29 (m, 4 H).

Synthesis of 6-chloro-N-(l-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin- 4-yl)quinoline-2- carboxatnide

[0969] To a stirred solution 6-chloro-N-(piperidin-4-yl)quinoline-2-carboxamide 2,2,2- trifluoroacetate (0.100 g, 0.247 mmol, 1.0 equiv) in DMF (5 mi), was added K CO ; (0.102 g, 0.742 mmol, 3.0 equiv), followed by the addition of 4-(3-bromopropoxy)-l-chloro-2- fluorobenzene (0.072 g, 0.272 mmol, 1.0 equiv) and the mixture was allowed to stir at 80°C for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water and extracted with ethyl acetate (30 mL ^c 3). Combined organic extracts were washed with water (15 mL ^c 4), dried over anhydrous Na ₂ S0 ₄ and concentrated. The crude product obtained was purified by reverse phase HPLC to obtain 6-chloro-N-(l-(3-(4-chloro-3- f!uorophenoxy)propyl)piperidin-4-y!)quinoiine-2-earboxamide (Compound 146 - 25 mg, 21% Yield) as an off-white solid. LCMS: 476.3 ! M 1 11 ⁺ ; ' l l NMR (400MHz ,DMSG-d ₆ ) 6 9.55 (br s., 1 H), 9 01 (d, J= 7.5 Hz, 1 H), 8.55 (d, J= 8.8 Hz, 1 H), 8.27 (br s., 1 H), 8.19 (d, ./ =

6.6 Hz, 1 H), 7.95 - 7.85 (m, 1 H), 7.51 (t, .7= 9.0 Hz, 1 H), 7.10 (d, = 11.4 Hz, 1 H), 6.86 (d, J = 9.2 Hz, 1 H), 4.11 (br. s., 2 H), 3.60 (d, J= 11.4 Hz, 2 H), 3.27 - 3.07 (m, 3 H), 2.17 (br. s., 2 H), 2.12 - 1.88 (m, 3 H).

[0970] To a stirred solution /ra«s-N-(4-aminocyclohexyl)-5-chlorobenzofuran-2- carboxamide 2,2,2-trifluoroacetate (0 250 g, 0.62 mmol, 1 0 equiv) in DMF (3 ml·} was added K ₂ C0 ₃ (0.128 g, 0.93 mmol, 1.5 eqmv), followed by the addition of 2-[(4-chloro-3-fluoro- phenoxy)methyl]oxirane (0.125 g, 0.62 mmol, 1.0 equiv) and the mixture was allowed to stir at 80°C for overnight. Product formation was confirmed by LCMS. Tire reaction mixture was diluted with water and extracted with ethyl acetate (30 ml, X 3). Combined organic extracts were washed with water (15 mL X 4), dried over anhydrous Na ₂ S0 ₄ and concentrated. The crude product obtained was purified by reverse phase HPLC to obtain fra¾v-5~chloro~N-(4-((3~ (4-chloro-3-fluorophenoxy)-2-hydroxypropyl)amino)cyclohexyl) benzofuran-2-carboxamide (Compound 147 - 35 mg, 11.5% Yield) as an off-white solid. LCMS 495.2 [M+H] ⁺ ; ^! H NMR (400 MHz, DMSO-d6) 6 8.57 id. I = 8.1 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1 1 1 ). 7.69 (d, J = 8.8 I iz. i l l ). 7 54 - 7.41 (m, 3H), 7.08 (dd, I = 1 1.3, 2.9 Hz, 1 H), 6.84 (dd, I = 8.7, 3.0 Hz, 1 H), 4.01 (ddd, J =9.0, 6.0, 3 7 Hz, 1H), 3.95 3.82 (m, 21 1 3 76 (dd, I = 13 7, 7.7 Hz, 1 1 1 2 74 (s, 1 1 1 1.94 (d, J = 11.6Hz, 2H), 1.84 (d, I = 12.2 Hz, 21 1 ). 1.41 (q, J = 12.6 Hz, 2H), 1.23 (s, 1H), 1.14 (d, J = 12.2 Hz, 21 1 ).

Example 32

Synthesis of 5-chloro-N-(l-(3-(4-chloro-3-fluorophenoxy)propyl)piperidin- 4-yl)benzofi*ran-2-

[0971] To a stirred solution 5-chloro-N-(piperidin-4-yl)benzofuran-2-carboxamide

hydrochloride (0 200 g, 0.63 mmol, 1 0 equiv) in DMF (3 mL), was added K ₂ C0 ₃ (0.131 g, 0.95 mmol, 1.5 equiv), followed by the addition of 4-(3-bromopropoxy)-l-chloro-2-fluoro-benzene (0.168 g, 0.63 mmol, 1.0 equiv) and the mixture was allowed to stir at 60°C for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water and stirred at RT for 10 min and resulting solid was filtered off, washed with excess water. Obtained solid material was dried under vacuum and washed with hexane to obtain 5-chloro-N-(l-(3-(4- chloro-3-iluorophenoxy)propyl)piperidin-4-y])benzofuran-2-ca rboxamide (Compoundl48 - 180 mg, 61% Yield). LCMS 465 3 [M+H] ⁺ ; H NMR (400 MHz, DMSO-d6) d 8.62 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.8 l lz. l H ). 7.52 (s, 1H), 7.46 (dd, J = 11.3, 7.7 Hz, 21 1 ). 7.06 (dd, J = 11.6, 2.9 Hz, i l l ). 6.83 (dd, J = 8.9, 2.81 1/. 11 1 ). 4.03 (t, J = 6.3 Hz, 21 1 ). 3 76 (did, J = 13.8, 10 1 , 9.6, 4.4 Hz, 1H), 2.88 (d, J = 11.2 Hz, 2H),2.41 (t, J = 7.1 Hz, 2H), 1.98 (t, J = 11.5 Hz, 2H), 1.86 (p, J = 6.6 Hz, 2H), 1.81 - 1.72 (m, 2H), 1.61 (qd, J = 12.1, 3.6 Hz, 2H), 1.24 id. J 5 1 Hz, 2H).

Synthesis of trans-2-(3-chloro-4-fluorophenoxy)-N-(4-(((6-chloroquinolin- 2-

Step 1 Synthesis of 2-(bromomethyl)-6-chloroqumoline:

[0972] To a stirred solution of 6-chloro-2-methylquinoline (1.0 g, 5.6 mmol, 1 equiv) in CCLflO mL) was added NBS (1.1 g, 6.18 mmol, 1.1 equiv) and AIBN (0.10 g, 0.56 mmol, 0.1 equiv). The reaction mixture was heated at 80°C for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with aqueous solution of sodium bicarbonate (15 L) and extracted with DCM (25 mL ^c 3).

Combined organic layer was washed with brine (40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Crude product was purified by flash chromatography (0 to 50 % ethyl acetate in hexane as an eluent) to obtain 2-(bromornethy!)-6-ch!oroquinoline (0.400 g). LCMS 255.9 [M+Hf

Step 2 Synthesis of trans-2-(3-chloro-4-flmrophenoxy)-N-(4-(((6-chloroquinolin-2 - yl)methyl)amino)cyclohexyl)acetamide:

[Q973] To a stirred solution of /ra '~N~(4~armnocyc]ohexy])-2-(3~chloro~4~

fluorophenoxy)acetamide 2,2,2-trifluoroacetate(0.566 g, 1.37 mmol, 0.1 equiv), in DCM (10 mL) was TEA (0.212 g, 2.1 mmol, 1.5 equiv) followed by the addition of added2- (bromomethyl)-6-chloroquinoline (0.35 g, 1.37 mmol, 1 equiv). The reaction mixture was allowed to stir at RT for 3h. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with DCM (25 mL x 3). Combined organic layer was washed with water (15 mL ^c 4), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Crude compound was purified by reversed phase HPLC to obtain iram ^, -2-(3-chloro-4-fluorophenoxy)-N-(4-(((6-chloroquinolin -2- yi)methyl)amino)cyclohexyl)acetamide (Compound 151 - 0.040 g, 6 % Yield) as an off-white solid. LCMS 476.2 [M+H] ⁺ ; 4 1 NMR (400 MHz, DMSO-de) d 8 30 i d. J = 6.5 Hz, 1H), 8 09 (s, 1H), 7.97 (s, 1H), 7.89 (d, J = 7.9Hz, IH), 7 71 (t, J= 12 6 Hz, 2H), 7.48 (t, J = 8 8 Hz, 1H), 7.05 id. ./ 12.0 Hz, 11 1). 6.83 (d, J = 8.9 1 1 r.1 1 1). 4.48 (s, 2H), 4.01 (s, 2H), 3.58 (d, J= 10.4

Hz, 11 1 ). 3.17 (s, 1 1 1 ). 2.39 (s, 2H), 1.93 (dd , J= 16.3,10.2 Hz, 2H), 1.76 {cl. -/ 12.3 Hz, 2H),

1.28 - 1.09 On. 5H). Example 34

Synthesis oftrans-6-chloro-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohex yl)-3,4-dihydro-2H-

[Q974] To a solution of 2-((5-chloropyridin-2-yl)oxy)acetic acid (1.0 g, 4.67 mmol, 1.0 equiv) in DMF (10 mL) was added DIPEA (2.5 mL, 14.01 mmol, 3.0 equiv) followed by the addition of HATH (3.5 g, 9.34 mmol, 3.0 equiv). The resulting mixture was stirred for 30 min. /ra¾wN-(4-aminoeycioliexyi)-2-(4-chlorophenoxy)acetamide 2,2,2-trifluoroacetate (1.7 g, 4.67 mmol, 2.0 equiv) was added and the reaction mixture was allowed to stir overnight at RT. The resulting precipitate was filtered off and washed with excess methanol to obtain tram- 6-chloro- N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-3,4-dihydro~2 H~benzo[b][] ,4]oxazine-2- carboxamide (Compound 156 - 700 mg, 31 % Yield) as an off-white solid. LCMS 478 [M+H] ^r ; 'l l NMR (400MHz .DMSO-d,.} 6 7.94 id. J = 7.9 Hz, 1 H), 7.82 (d, ./ 7.9 Hz, 1 H), 7.39 - 7.25

(m, J = 8 8 Hz, 2 H), 7 03 - 6.88 (m, J= 8.8 Hz, 2 H), 6.78 (d, ,/= 8 3 Hz, 1 H), 6.59 (s, 1 H), 6.50 (d, J= 8.3 Hz, 1 H), 6.18 (br. s., 1 H), 4.50 - 4.37 (m, 3 H), 3.57 (br. s., 2 H), 3.44 (d, J = 11.8 Hz, 1 H), 3.22 - 3.10 (m, 1 H), 1.76 (hr. s., 4 H), 1.34 (d, J = 9.2 Hz, 4 H).

Jiiral resolution of 5-chloro-N-i 1 -i3-(4-chloro-3-fluornnhennxv)-2-hvdroxvnronvl)mneridin-

[0975] The enantiomers, (+)-5-chloro-N-(l-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin-4-yl)benzofuran-2-carboxamide (Compound 149 - [a]), ⁰ = -13.09 (c = 0.1016 w/v%, MeOH); elution time: 15.61 min) and (-)-5-chloro-N-(l-(3-(4-chloro-3- fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)benzofiiran-2- carboxamide (Compound 150 - [a]“ = +13.16 (c = 0.1006 w/v%, MeOH); elution time: 17.32 min), were separated by chiral SFC (Daicel Chiralcel ^® OD-H, 250 x 4.6 mm, 5 pm). Isocratic program with analytical grade liquid carbon dioxide and HPLC grade MeOH (0.2% DBA).

Example 36

[0976] The enantiomers, (+)-6-chloro-N-(l -(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropy!)piperidin~4~yl)quinoline-2-carboxamide (Compound 152 - [a] = -95.75 (c = 0.1036, w/v%, MeOH); elution time: 22.17 min) and (-)-6-chloro-N-(l-(3-(4-chloro-3- fluorophenoxy)-2-hydroxypropyl)piperidin-4-yi)quinoiine-2~ca rboxamide (Compound 153 - [a] ,° = +113.73 (c = 0.1016, w/v%, MeOH); elution time: 27.55 min), were separated by chiral SFC (Chiralpak AD-H, 250 ^c 4.6 mm, 5pm). Isocratic Program with analytical grade liquid carbon dioxide and HPLC grade EtOH (0.2% DEA).

Example 37

Chiral resolution. oftrans-5-chloro-N-(4-((3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)amino)cyclohexyl)benzofuran-2-carboxamide

[0977] The enantiomers, (+)-/ra¾s-5-chloro-N-(4-((3-(4-chloro-3-lIuorophenoxy)-2- hydroxypropyl)amino)cyc!ohexyi)benzofuran~2~carboxamide (Compound 154 - [a] ^u = +13.91 (c ------ 0.1049, w/v%, MeOH); elution time: 1 1.77 min) and (-)-/ra -5-chloro-N-(4-((3-(4-chloro-3- iluorophenoxy)-2-hydroxypropy!)amino)cyclohexyl)benzofuran-2 -carboxamide (Compound 155 - [a]), ⁰ = -12.46 (c = 0.1011 w/v%, MeOH); elution time: 18.08 min), were separated by chiral SFC (Daicel Chiralcel ^® ' OD-H, 250 x 4.6 mm, 5pm). Isocratic Program with analytical grade liquid carbon dioxide and HPLC grade MeOH (0.2% DEA).

[0978] The enantiomers, (+)-/ra«s-6-chloro-N-(4-(2-(4- chlorophenoxy)acetamido)cyclohexyl)~3,4-dihydro-2H-benzo[b][ ! ,4]oxazine-2~carhoxamide (Compound 158 - [a] ⁰ = +26.68 (c = 0.053, w/v%, MeOH); elution time: 11.45 min) and (-)- ra«s~6~chloro~N~(4~(2~(4-chlorophenoxy)acetamido)cyclohexyl )-3,4~dihydro-2H- benzo[b][l ,4]oxazine-2-carboxamide (Compound 157 - [a]„ = -15.97 (c ------ 0.063 w/V%, MeOH). elution time: 10.09 min), were separated by chiral SFC (Daicei Chiralcel ^® OD-H, 250 ^c 20 mm, 5 pm). Isocraiic Program with analytical grade liquid carbon dioxide and HPLC grade /PrOH (0.2% DBA).

Synthesis oftrans-2-(4-chlorophenoxy)-N-(4-(5-((4-chlorophenoxy)methyl )-2-oxooxazolidin-

[Q979] To a stirred solution of /ra -2-(4-chlorophenoxy)-N-(4-((3-(4-chlorophenoxy)-2- hydroxypropyl)amino)cyclohexyl)acetamide (100 mg, 0 21 mmol, 1 equiv) in DCM (5 mL), was added Et ₃ N (0.2 mL, 1.1 mmol, 5 eqmv). The mixture was allowed to stir for 15 min. under nitrogen atmosphere. Isoindoline (26 mg, 1.05 mmol, 5 equiv) was added to the mixture and the reaction mixture was cooled to 0°C. Phosgene (20% in toluene, 1 mL) was added to the mixture dropwise. The temperature was allowed to rise to RT and the reaction mixture stirred overnight at RT. Progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with DCM (50 mL x 2) The organic layer was washed with water (50 mL), brine solution (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound, which was purified by reversed phase HPLC to obtain /ra -2-(4-chlorophenoxy)-N- (4-(5-((4~chlorophenoxy)methyl)-2-oxooxazolidin-3-yl)cyclohe xyl)acetamide (Compound 159 25 mg, 24 % Yield) as a white solid. LCMS 493.2 [M+Hf ; 4 i NMR (400 MHz, DMSO-r 6) d 7.97 (d, J= 8.0 Hz, 11 1 }. 7.34 id. ./ 8.4 Hz, 41 1 }. 7.01 - 6.93 (m, 41 P.4.84 (h, J = 4.5 Hz, i l l ).

4.45 (s, 2H), 4.18 (dd, J= 10 9, 3.2 Hz, i l l }. 4 08 (dd, J= 10.9, 5.2 Hz, 1H),3.64 (t, J= 8 9 Hz, 2H), 3.54 - 3.42 (m, 1H), 3.37 (dd, ./ 8.7. 5.9 Hz, i l l ). 1.86 - 1.77 (m, 21 1 ). 1 74 -1.66 (m,

21 i ). 1.57 {q. ,/ 12.7, 12.3 Hz, 21 1 ). 1.38 (tt , J = 13.1, 6.5 Hz, 2H).

BIOLOGICAL EXAMPLES

Example B1—ATF4 Expression Inhibition Assay

[0980] HEK293T cells were maintained at 37 °C and 5% C0 ₂ in Dulbecco’s Modified Eagle’s Media (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U/ml penicillin, and 100 .ug/rnl streptomycin. After reaching 80% of confluence, cells ere detached and seeded on 6 well plates in complete media, allowed to recover overnight and treated for 3 hours with 100 nM thapsigargin (Tg) in the presence of 100 nM or 1 mM concentration of a test compound (percent inhibition assays) or various concentrations ranging from 1 nM to 1 mM (IC ₅ o assay), Cells without treatment or cells treated with Tg alone were used as controls.

[0981] After 3 hours of treatment with Tg and the test compound, cells were lysed with SDS-PAGE lysis buffer. Lysates were transferred to 1.5 ml tubes and sonicated for 3 min, and total protein amounts were quantified using BCA Protein Assay Kit (Pierce). Equal amount of proteins were loaded on SDS-PAGE gels. Proteins were transferred onto 0.2 prn PVDF membranes (BioRad) and probed with primary antibodies diluted in Tris-buffered saline supplemented with 0.1% Tween 20 and 3% bovine serum albumin.

[0982] ATF4 (11815) antibody was used as primary antibody (Cell Signaling Technologies). A horseradish peroxidase (HRP)-conjugated secondary antibody (Rockland) was employed to detect tmmune-reactive bands using enhanced chemiluminescence (ECL Western Blotting Substrate, Pierce). Quantification of protein bands was done by densitometr' using Image!.

[0983] Percentages of ATF4 inhibition after induction with Tg in the presence of 100 nM or 1 mM of certain test compounds are shown in Table 2 and FIG. 1. Percentage of ATF4 inhibition was calculated as the percent reduction normalized to Tg treatment (0% inhibition) and untreated cells ( 100% inhibition). Also shown in Table 2 is the calculated IC ₅₀ for the test compounds. Under IS stressed conditions (resulting from treatment with Tg), ATF4 expression is generally upregulated. Accordingly, inhibition of ATF4 expression as a result of the test compound indicates suppression of the ISR pathway.

[Q984] CHO cells were maintained at 37 °C and 5% C0 ₂ in DMEM supplemented with 10% fetal bovine serum (FBS), 2 mM L-g!utamine, 100 U/ml penicillin, and 100 pg/ml streptomycin. After reaching 80% of confluence, cells were detached and seeded on 6 well plates in complete media, allowed to recover overnight and treated for 2 hours with 1 mM of the test compound (to assess protein synthesis levels in unstressed condition), or for 1 hour with 100 nM and 1 mM of the test compound and then co-treated with 300 nM Tg and 100 nM and 1 mM of the test compound (to assess the recovery of protein synthesis in a stressed condition). Cells treated with Tg alone were used as controls. [Q985] After the 2 hours treatments, media were replaced by adding 10 pg/ml puromycin (Sigma Aldrich) in complete media for 30 min. Media were removed and cells were lysed with SDS-PAGE lysis buffer. Lysates were transferred to 1.5 ml tubes and sonicated for 3 minutes and total protein amount were quantified using BCA Protein Assay Kit (Pierce). Equal amount of protein (30 pg) was loaded on SDS-PAGE gels. Proteins were transferred onto 0.2 pm PVDF membranes (BioRad) and probed with primary antibodies diluted in Tris-buffered saline supplemented with 0.1% Tween 20 and 3% bovine serum albumin.

[0986] Puromycin (12010) antibody was used as primary _' antibody (Merck Millipore). A HRP-conj ugated secondary' antibody (Rockland) was employed to detect immune-reactive bands using enhanced chemiluminescence (ECL Western Blotting Substrate, Pierce). Quantification of protein bands was done by densitometry' using Image!

[0987] Percent increase of protein synthesis in unstressed cells (without Tg treatment) in the presence of media alone or certain test compounds is shown m Table 3 and FIG. 2. The percentage levels w'ere normalized to the media alone condition, which correspond to 100% protein synthesis. All compounds stimulated protein synthesis above baseline, indicating that the test compounds result in increased protein synthesis in unstressed cells.

[0988] Percent recovery of protein synthesis in stressed cells (w ith Tg treatment) due to the test compounds at 100 nM or 1 pM is shown in FIG. 3A and 3B, respectively, and in Table 3.

The levels were normalized to the media alone and to Tg alone conditions, which correspond to 100% and 0% respectively.

Table 3

[0989] Data summarized in Tables 2 and 3 show that some compounds have differential activity in ATF4 inhibition and protein synthesis under ISR-inducing conditions. That is, some compounds are able to effectively inhibit ATF4 expression but do not restore protein synthesis. Other compounds effectively restore protein synthesis but do not inhibit ATF4 expression under ISR-inducing conditions. Still other compounds inhibit ATF4 expression and restore protein synthesis. Certain compounds (such as compounds 30, 150, 153) show' increased protein translation with limited (less than 50%) ATF4 inhibition. FIG. 3C shows percent ATF4 inhibition (see Example Bl) for select compounds against percent reco very of protein synthesis. This differential modulation of activities represents a unique characteristic that can be exploited when selecting specific compounds for a desired use.

[0990] Chinese hamster ovary (CHO) cells that stably express human APP751 incorporating the familial Alzheimer's disease mutation V717F were used as a source of Ab monomer and low-n oligomers. These cells, referred to as 7PA2 CHO cells, were cultured in 100 m dishes with Dulbecco's modified Eagle's medium (DMEM) containin 10% fetal bovine serum, 2 raM L-glutamine, 100 U/rnl penicillin, and 100 pg/ml penicillin, streptomycin and 200 pg/ml G418. Upon reaching 90-100 % conflueney, cells were washed with 5 mL of glutamine- and serum- free DMEM and incubated for approximately 16 h in 5 mL of the same DMEM. Conditioned media (CM) was collected.

SH-SY5Y cells were maintained at 37°C and 5% CO in RPMI 1640 media supplemented with 10% fetal bovine serum (FBS), penicillin and streptomycin. After reaching 80% of confluence, ceils were detached and seeded on 6 well plates in complete media, allowed to recover 48h and treated for 16 hours with CM from WT CHO cells or 7PA2 CHO cells in the presences of 1 mM of test compounds 3, 6, 15, 17, 23, 149, 152, or 153.

[Q992] After 16 hours treatment, culture media were removed and cells were lysed with SDS-PAGE lysis buffer. Lysates were transferred to 1.5 ml tubes and sonicated for 3 min. Total protein amount were quantified using BCA Protein Assay Kit (Pierce). Equal amount of proteins (30 pg) was loaded on SDS-PAGE gels. Proteins were transferred onto 0.2 pm P VDF membranes (Bio Rad) and probed with primary antibodies diluted in Tris-buffered saline supplemented with 0.1 % Tween 20 and 3% bovine serum albumin.

[0993] ATF4 (11815) antibody was used as primary antibody (Cell Signaling Technologies). A b-aetin antibody was used as a control primary antibody. An HRP-conjugated secondary antibody (Rockland) was employed to detect immune-reactive bands using enhanced chemiluminescence (ECL Western Blotting Substrate, Pierce). Quantification of protein bands was done by densitometry _' using Image!.

[0994] Representative levels of ATF4 expression from the treatment with CM from WT CHO cells (wtCM) or 7PA2 CHO cells (7PA2CM) are shown in FIG. 4A. The levels were normalized to b-actin expression and fold change was calculated as the levels relative to the ATF4 expression level from wtCM-treated SH-SY5Y cells (normalized to 1). Percent inhibition of ATF4 expression in SH-SY5Y cells after incubation with CM from the 7PA2 CHQ cells as a result of the test compounds is shown in FIG. 4B Percentage of

ATF4 inhibition was calculated as the percent reduction normalized to CM from 7PA2 CHO cells treatment (0% inhibition) and CM from WT CHO cells treatment (100% inhibition).

Example B4— Eleetrophysiology and Long-Term Potentiation

[0996] Hippocampal slices were prepared as described in Ardiles et al., Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice. Front Cell Neurosci, vol.

8, art. 326 (2014). Six to eleven-month-old WT C57BL/6 or transgenic APP/PS 1 mice (Jackson Lab 34829-JAX) were deeply anesthetized with isoflurane and their brains were quickly removed. 5-10 slices (350 pm) from each animal were dissected in ice-cold dissection buffer using a vibratome (Leica VT1200S, Leiea Microsystems, Nussloch, Germany). Slices were incubated with 5 mM 1SRIB, 5 pM compound 3, 1 mM compound 152, or a vehicle (complete medium containing 0.1% DMSO) 20 min before conditioning stimulation. Synaptic responses were evoked by stimulating the Schaffer collaterals with 0.2 ms pulses delivered through concentric bipolar stimulating electrodes, and recorded extracellularly in the stratum radiatum of the CAi subfield. Long-term potentiation (LTP) was induced by four-theta burst stimulation (TBS) (10 trains of four pulses at 100 Hz; 5 Hz inter-burst interval) delivered at 0.1 Hz. LTP magnitude based on field excitatory postsynaptic potential (fEPSP) was calculated as the average (normalized to baseline) of the responses recorded 60 min after conditioning stimulation. Similar experiments can be performed using a different test compound in place of ISR1B, compound 3, or compound 152.

[0997] Results for ISRIB are shown in FIG. 5 A. Treatment of the slices from both the WT C57BL/6 and APP/PSl mice treated with the vehicle (empty circles and empty triangles, respectively) resulted in LTP 60 minutes after stimulation, with the APP/PSl sample showing significantly reduced LTP. Treatment of the slices from the APP/PSl mouse w ith ISRIB (black triangles), however, resulted in partial LTP recovery' (FIG. 5 A) FIG. 5B shows the responses recorded in the last 10 minutes after conditioning stimulation of the slices from the WT

C57BL/6 and APP/PSl mice treated with ISRIB (APP+ISRIB), and from APP/PSl mice treated with compound 3 (APP + Cmp3), or compound 152 (APP+Cmpl 52), or the vehicle (APP). Example BS Learning memory in aged mice

[0998] Wild type 19-month old male C57B1/6J mice were used in an 8-arm radial water maze (RAWM) to measure the hippocampal-mediated learning memory. The maze involved a pool 118.5 cm in diameter and 25 cm high with 8 arms, each 41 cm in length, and an escape platform that could be moved. The pool was filled with water that was rendered opaque by adding white paint (Crayola, 54-2128-053). The escape platform remains hidden during the experiment. Visual cues were placed around the room such that they were visible to animals exploring the maze.

[0999] 9 mice were intraperitoneally injected with 5 mg/kg of compound 3 formulated in

50% Polyethylene glycol (PEG-400) in distilled water and other 9 animals were intraperitoneally injected with the vehicle 50% PEG-400 m distilled water as a control group. Animals ran 6 trials a day for two days. Animals were allowed 1 minute to locate the escape platform. On successfully finding the platform, animals remained there for 10 seconds before being returned to their holding cage. On a failed trial, animals were guided to the escape platform and then returned to their holding cage 10 seconds later.

[1QQQ] Behavioral tests were recorded and scored using a video tracking and analysis setup (Ethovision XT 8.5, No!dus Information Technology). The progra automatically analyzed the number of incorrect arm entries (termed number of errors) made per trial. Last three trials were averaged to determine learning memory after training.

[1001] At the end of the behavioral test, animals were sacrificed and the hippocampi were extracted and immediately frozen in liquid nitrogen and then stored at -80°C. The frozen samples were then homogenized with a T 10 basic ULTRA-TURRAX (IKa) in ice-cold buffer lysis (Cell Signaling 9803) and protease and phosphatase inhibitors (Roche). Lysates were sonicated for 3 minutes and centrifuged at 13,000 rpm for 20 minutes at 4°C. Protein concentration m supernatants was determined using BCA Protein Assay Kit (Pierce). Equal amount of proteins was loaded on SDS-P AGE gels. Proteins were transferred onto 0.2 pm PVDF membranes (BioRad) and probed with primary antibodies diluted in Tris-buffered saline supplemented with 0.1% Tween 20 and 3% bovine serum albumin. [1002] ATF4 (1 1815) antibody (Cell Signaling Technologies) and b-actin (Sigma- Aldrich) antibodies were used as primary antibodies. A HRP -conjugated secondary antibody (Rockland) was employed to detect immune-reactive bands using enhanced chemiluminescence (ECL Western Blotting Substrate, Pierce). Quantification of protein bands was done by densitometry using Image! software.

[1003] Results of RAWM task are shown in FIG. 6A. Aged animals with vehicle progressively learned the location of the escape platform during the trials. Interestingly, aged animals with compound 3 performed better than vehicle-treated animals suggesting an enhanced learning memory . Levels of ATF4 expression normalized to b-actin expression in hippocampi are shown in FIG. 6B, with individual data points being shown in FIG. 6C. Animals that received compound 3 showed lower levels of ATF4 expression compared with vehicle-treated animals. There is a clear trend indicating that the ISR pathway is being inhibited and a better performance in a learning memory task.

Example 116 Learning memory, long-term memory and social behavior after traumatic brain injury (TBI)

[1004] Wild type three-month-old male C57B1/6J mice were randomly assigned to TBI or sham surgeries. Animals were anesthetized and maintained at 2% isofiurane and secured to a stereotaxic frame with nontraumatic ear bars. The hair on their scalp was removed, and eye ointment and betadine were applied to their eyes and scalp, respectively. A midline incision was made to expose the skull. A unilateral TBI was induced m the right parietal lobe using the controlled cortical impact model (Nat Neurosci. 2014 Aug; 17(8): 1073-82). Mice received a 3.5- mm diameter craniectomy, a removal of part of the skull, using an electric microdrill. The coordinates of the craniectomy were: anteroposterior, -2.00 mm and mediolateral, +2.00 mm with respect to bregma. After the craniectomy, the contusion was induced using a 3-mm convex tip attached to an electromagnetic impactor (Leica). The contusion depth was set to 0.95 mm from dura with a velocity of 4.0 m/s sustained for 300 ms. These injury parameters were chosen to target, but not penetrate, the hippocampus. Sham animals received craniectomy surgeries but without the focal injury . After focal TBI surgery, the scalp was sutured and the animal was allowed to recover m an incubation chamber set to 37 °C. Animals were returned to their home cage after showing normal walking and grooming behavior. All animals fully recovered from the surgical procedures as exhibited by normal behavior and weight maintenance monitored throughout the duration of the experiments.

[1005] After 28 days post injury (dpi), animals were tested on the RAWM assay (see above). Animals ran 12 trials during learning test and 4 trials during memory test. Last three trials from learning test and all four trials from memor' test were averaged to determine learning memory (learning test) and long-term memory _' (memory _' test).

[1QQ6] Animals w'ere intrapentoneally injected with 5 mg/kg of compound 3 formulated in 50% PEG-400 in distilled water (h=10) or vehicle (50% PEG-400 in distilled water; n=10 for TBI group and n=8 for sham group) starting the day prior to behavior tests (27 dpi), after each of the final trials of the learning-test days (28 and 29 dpi) and before the social behavior test (42 dpi, see below) for a total of four injections. No injections were given when long-term memory was tested on day 35 dpi.

[1007] To quantitate social tendencies of the treated mice, the time spent with a novel conspecific mouse was measured in a Crawley's three-chamber box (J Vis Exp. 2011; (48):

2473). Treated animals were left to explore all three empty chambers freely for 10 minutes for habituation. Social pair mouse was placed in the housing cage at one side of the apparatus and treated animals in opposite chamber so that the mouse can freely explore the entire apparatus for 10 minutes. The time spent with the never-before-met animal was recorded. Direct contact between the treated mouse and the housing cage or stretching of the body of the subject mouse m an area 3-5 cm around the housing cage is counted as an active contact.

[1008] Learning memory and long-term memory' after TBI in mice are shown in FIG. 7 A and 7B respectively. Compared with vehicle-treated animals (squares), compound 3-treated animals (triangles) made significantly less errors over the course of training (FIG. 7A) and a similar trend was seen when memory was tested 7 days (35 dpi) after training (FIG. 7B).

[1009] Social behavior results are shown in FIG. 7C. Vehicle-treated TBI-injured animals spent significantly less time in the compartment with the novel animal compared to vehicle- treated animals from sham group indicating impairment in sociability. Interestingly, compound 3-treated TBI-injured animals spent more time with the novel mouse at levels similar to those animals from sham group indicating normal sociability', social motivation and affiliation.

Individual values and mean ± SEM are shown in FIG. 7C. Statistical analyses were performed using GraphPad Prism software and significant difference was assessed by t test (* < 0.05, ** <

0.01, and *** < 0.001).

[1010] Wild type eight-weeks-old male Baib/c mice obtained from the vivarium Fundacion Ciencia & Vida Chile (Santiago, Chile) were used. Mice were housed in independent plastic cages in a room maintained at 25°C with a 12-h: 12-h lightdark cycle

[1011] Twenty -four hours before and during the 2 days of fasted procedures, animals received oral administration via feeding tubes (15 gauge) of vehicle (50% Polyethylene glycol 400 (Sigma- Aldrich P3265) in distilled water or 10 mg/kg of compound 3 formulated in vehicle solution.

[1012] After 2 days of fasting the animals were sacrificed and muscles were removed from both hindlimbs. Mice with feed and water ad libitum were used as control.

[1013] For in vivo measurements of protein synthesis, puromycin (Sigma-Aldrich, P8833) was prepared at 0.04 pmol/g body weight in a volume of 200 pL of PBS, and subsequently administered into the animals via IP injection, 30 min prior to muscle collection.

[1014] Upon collection, muscles were immediately frozen in liquid nitrogen and then stored at -80°C. The frozen muscles were then homogenized with a T 10 basic ULTRA-TURRAX (IKa) in ice-cold buffer lysis (Cell Signaling 9803) and protease and phosphatase inhibitors (Roche). Lysates were sonicated for 3 min and centrifuged at 13,000 rpm for 20 minutes at 4°C. Protein concentration in supernatants was determined using BCA Protein Assay Kit (Pierce). Equal amount of proteins was loaded on SDS-PAGE gels. Proteins were transferred onto 0.2 iim PVDF membranes (BioRad) and probed with primary antibodies diluted in Tris-buffered saline supplemented with 0.1% Tween 20 and 3% bovine serum albumin.

[1015] Puromycin (12D1 Q) (Merck Millipore) and b-actin (Sigma-Aldrich) antibodies were used as primary antibodies. A HRP-conjugated secondary' antibody (Rockland) w¾s employed to detect immune-reactive bands using enhanced chemiluminescence (ECL Western Blotting S ubstrate, Pierce). Quantification of protein hands w¾s done by densitometry using Image! software. [1016] For immunohistochemical analysis of cross-sectional area (CSA), muscles from control (Fed) and fasted animals were submerged individually in optimal cutting temperature (OCT) compound (Tissue-Tel Sakura) at resting length, and frozen in isopentane cooled with liquid nitrogen. Cross-sections (l O-pm thick) from the mid-belly of the muscles were obtained with a cryostat (Leica) and immunostained with puromycin antibody (121)10) (Merck

Millipore). A HRP- polymer conjugated secondary antibody (Biocare Medical, MM620L) followed by diaminobenzidine substrate incubation (ImmPACT DAB - Vector, SK-4105) were employed to detect puromycinylated structures in CSA

[1017] Percent of protein synthesis in fasted muscles is shown in FIG. 8A for compound 3 and the vehicle control. The levels were normalized to b-actin expression and percentage was calculated as the percent relative to protein synthesis levels from control mice (Fed) which correspond to 100%.

[1018] Muscle fiber CSA were visualized with a Zeiss Axio Lab.Ai microscope and an Axiocam (Zeiss) digital camera. Puromycin staining in CSA is shown in FIG. 8B for compound 3. Muscle sections from control mice (fed) shows fibers stained with puromycin indicating de novo protein synthesis. No staining was detected in vehicle-treated fasted mice indicating a significant reduction of protein synthesis. Fasted mice treated with compound 3, however, showed a partial staining in muscle fibers indicating a partial recovery of protein synthesis as seen in FIG. 8A.

[1019] Gastrocnemius weight from control (fed) and fasted animals treated with compound 3 or compound 152 are shown in FIG. 9A and FIG. 9B respectively. Percent of protein synthesis from control (fed) or fasted animals treated with compound 3 or compound 152 are shown m FIG. 9C and FIG. 9D respectively. The levels were normalized to b-actin expression and percentage was calculated as the percent relative to protein synthesis levels from control mice (fed) which correspond to 100%. Atrogin-1 expression in gastrocnemius from control (fed) and fasted animals treated with compound 3 or compound 152 are shown in FIG. 9E and FIG. 9F respectively. The levels were normalized to b-actin expression and fold change was calculated as the levels relative to the expression levels from control mice (fed) which corresponds to 1. Data was shown as individual values and mean + standard error of mean (SEM). Statistical analyses were performed using GraphPad Prism software and significant difference was assessed by l test (* < 0.05, ** < 0.01 , *** < 0.001). [1020] Muscle fiber CSAs were visualized with a Zeiss Axio Lab. A 1 microscope and an Axiocam (Zeiss) digital camera. ATF4 staining in CSA is shown in FIG. 9G. Histological muscle sections from fasted mice treated with vehicle show fibers containing positive ATF4 staining, indicating the activation of the ISR. No staining was detected in control (fed) or in fasted mice treated with compound 152, indicating a complete inhibition of the ISR pathways in the muscle of these animals.

[1021] Wild type eight-weeks-old male Balb/e mice obtained from the vivarium Fundacion Ciencia & Vida Chile (Santiago, Chile) were used. Mice were housed in independent plastic cages, fed ad libitum in a room maintained at 25°C with a 12-h: l2-h light: dark cycle.

[1022] Twenty-four hours before and during the 3 days of immobilization procedures, animals received oral administration via feeding tubes (15 gauge) of vehicle (50% Polyethylene glycol 400 (Sigma- Aldrich P3265) in distilled water or 10 rng/kg of compound 3 formulated in vehicle.

[1023] One hindlimb was immobilized with a plastic stick placed over and under the limb and fixed with a medical adhesive bandage. Animals w ere daily monitored. The immobilization procedure prevented movement of the immobilized leg alone. After 3 days, the animals were sacrificed and gastrocnemius, quadriceps and tibialis anterior muscles were removed from both hindlimbs, the contralateral, non-immobilized leg being used as an internal control.

[1024] For in vivo measurements of protein synthesis, puromycin (Sigma- Aldrich, P8833) was prepared at 0.04 pmol/g body weight in a volume of 200 pL of PBS, and subsequently administered into the animals via intraperitonea! injection, 30 min prior to muscle collection.

[1025] Upon collection, muscles were immediately frozen in liquid nitrogen and then stored at -80°C. The frozen muscles w¾re then homogenized with a T 10 basic ULTRA-TURRAX (IKa) in ice-cold buffer lysis (Cell Signaling 9803) and protease and phosphatase inhibitors (Roche). Lysates were sonicated for 3 min and centrifuged at 13,000 rpm for 20 minutes at 4°C. Protein concentration in supernatants was determined using BCA Protein Assay Kit (Pierce). Equal amount of proteins w ^? as loaded on SDS-PAGE gels. Proteins were transferred onto 0.2 um PVDF membranes (BioRad) and probed with primar antibodies diluted in Tris-buffered saline supplemented with 0.1% Tween 20 and 3% bovine serum albumin. [1026] Puromycin (12D10) (Merck Millipore) and b-actin (Sigma- Aldrich) antibodies were used as primar antibodies. A HRP-conjugated secondary' antibody (Rockland) was employed to detect immune-reactive bands using enhanced chemiluminescence (ECL Western Blotting Substrate, Pierce). Quantification of protein bands was done by densitometry' using Image! software.

[1027] Percent of protein synthesis in mobile and immobile hind limbs sections from gastrocnemius, tibialis anterior, and quadriceps are shown in FIG. 10A, 10B and 10C respectively as mean ± SEM Statistical analyses were performed using GraphPad Prism software and significant difference was assessed by t test (* < 0.05 and ** < 0.01). The levels were normalized to b-actm expression and percentage was calculated as the percent relative to protein synthesis levels from mobile limb of control mice (vehicle-treated) which correspond to 100%. In all three immobilized muscles from vehicle-treated mice there is a significant reduction of protein synthesis. Interestingly, there is a complete recovery' of protein synthesis in tibialis anterior and quadriceps and a partial recovery of protein synthesis in gastrocnemius from compound-3-treated immobilized hindlimbs, suggesting that compound 3 could inhibits the ISR- induced repression of protein synthesis.

[1028] For immimohistoehemical analysis of cross-sectional area (CSA), gastrocnemius from mobile and immobile hind limbs were submerged individually in optimal cutting temperature (OCT) compound (Tissue-Tek; Sakura) at resting length, and frozen in isopentane cooled with liquid nitrogen. Cross-sections (lO-pm thick) from the mid-belly of the muscle was obtained with a cryostat (Leica) and immunostained with ATF4 antibody (Abeam). A HRP- polymer conjugated secondary' antibody (Biocare Medical, MM62QL) followed by

diaminobenzidine substrate incubation (ImmPACT DAB - Vector, SK-4105) -were employed to detect puromycinylated structures in CSA.

[1029] Muscle fiber CSAs were visualized with a Zeiss Axio Lab.Al microscope and an Axiocam (Zeiss) digital camera. ATF4 staining in CSA is shown in FIG. 10D. Histological muscle sections from immobilized hind limb show' fibers stained with ATF4, indicating the activation of the ISR. As expected, there is a strong correlation between the activation of the ISR pathway and the reduction of protein synthesis m immobilized muscles. Example B9 - Cachexia-induced muscle atrophy

[1030] Wild type six-weeks-old male Balb/c mice obtained from the vivarium Fundacion Ciencia & Vida Chile (Santiago, Chile) were used. Mice were housed in independent plastic cages m a room maintained at 25°C with a 12-h: 12-h light: dark cycle.

[1031] 1x10 ⁶ CT26 colon carcinoma cell line (ATCC #CRL-2638, ATCC Manassas, VA) were injected subcutaneously in the right lower flank of each animal for induction of cachexia- induced muscle atrophy as described (Nat Commun. 2012 Jun 12;3:896). Non-injected animals were used as controls. At day 6 post tumor-cell injection, animals were randomized into two groups and treated with 10 mg/kg of compound 3 formulated in 50% Polyethylene glycol (PEG- 400) in distilled water, or with vehicle (50% PEG-400 in distilled water) by daily oral gavage for 13 days.

[1032] For in vivo measurements of protein synthesis, 30 min before the study ends, animals were injected intraperitoneally with puromycin (Sigma- Aldrich, P8833) at 0.04 pmol/g body weight in a volume of 200 pL of PBS. After 13 days of daily dosage, the animals were sacrificed and gastrocnemius, quadriceps and tibialis anterior muscles were dissected and weighed from both hindlimbs to assess muscle atrophy.

[1033] Upon collection, muscles were immediately frozen in liquid nitrogen and then stored at -80°C. The frozen muscles were then homogenized with a T 10 basic ULTRA-TURRAX (IKa) in ice-cold buffer lysis (Cell Signaling 9803) and protease and phosphatase inhibitors (Roche). Lysates were sonicated for 3 min and centrifuged at 13,000 rpm for 20 minutes at 4°C. Protein concentration in supernatants was determined using BCA Protein Assay Kit (Pierce). Equal amount of proteins was loaded on SDS-PAGE gels. Proteins were transferred onto 0.2 um PVDF membranes (BioRad) and probed with primary antibodies diluted in Tris-buffered saline supplemented with 0.1% Tween 20 and 3% bovine serum albumin.

[1034] Puromycin (12D10) (Merck Millipore) and b-actin (Sigma- Aldrich) antibodies were used as primary antibodies. A FIRP-conjugated secondary' antibody (Rockland) w¾s employed to detect immune-reactive bands using enhanced chemiluminescence (ECU Western Blotting Substrate, Pierce). Quantification of protein bands was done by densitometry' using Image! software. [1035] Gastrocnemius, quadriceps, and tibialis anterior muscle weight from animals injected with CT26 tumor cells and treated with either vehicle or compound 3 are shown in FIG. 11 A, 11B, and 11C respectively. Treatment with compound 3 prevented the CT26-induced muscle weight loss.

[1036] Percent of protein synthesis in gastrocnemius, quadriceps and tibialis anterior from animals injected with CT26 tumor cells and treated with either vehicle or compound 3 are shown in FIG. 1 ID, 1 IE and 1 IF respectively. The levels were normalized to b-actin expression and percentage was calculated as the percent relative to protein synthesis levels from muscle section of control mice which correspond to 100%. Data is shown as individual values and mean ± standard error of mean (SEM). Statistical analyses were performed using GraphPad Prism software and significant difference was assessed by t test (* < 0.05). Treatments with compound 3 in tumor-induced muscle-w ⁷ asting animals significantly increase protein synthesis in quadriceps and tibialis anterior compared to vehicle-treated tumor-injected animals.

[1037] Wild type six-weeks-old male Balb/c mice obtained from the vivarium Fundacion Ciencia & Vida Chile (Santiago, Chile) were used. Mice were housed in independent plastic cages in a room maintained at 25°C with a 12-h: 12-h light: dark cycle.

[1038] IxiO ⁶ CT26 colon carcinoma cell line (ATCC #CRL-2638, A ^' TCC Manassas, VA) were injected subcutaneously in the right lower flank of each animal as described (Nat

Commun. 2012 Jun 12;3:896). Non-injected animals were used as controls. At day 6 post tumor-cell injection, mean tumor volume was about 100 mm ³ , animals were weighed and randomized into two groups and treated with 10 mg/kg of compound 3 formulated m 50% Polyethylene glycol (PEG-400) in distilled water, or with vehicle (50% PEG-400 in distilled water) by daily oral gavage for 13 days.

[1039] At the end of the study, tumors were measured with digital caliper and tumors volumes, expressed in mm’, were calculated with the following formula:

Tumor volume (mm ³ ) ^::: (a x b ² )/2

where“a’' is the largest perpendicular diameter and“b” is the smallest diameter. Animals were then sacrificed and tumors were extracted and weighed. The volumes and weight of the tumors of each animal are shown in FIG. 12A and 12B respectively. Tumor density was calculated as weight/volume ratio for each animal and is shown in FIG. I 2C. Bars represent mean + SEM. Statistical analyses were performed using GraphPad Prism software and significant difference was assessed by / test (* < 0.05).

[1040] As shown in FIGS. 12A-12C, compound 3 does not reduce tumor volume but significantly reduce the tumor density, suggesting that treatment with ISR-inhibitor compounds could make tumors less compact and hence more accessible to some tumor-directed therapies such as checkpoints inhibitors, adoptive cell transfer, monoclonal antibodies or cytokines that boost immune system.

Example Bll - Protein synthesis with a cell-free system

[1041] The expression of the green fluorescence protein (GFP) was evaluated using the 1-Step Human In vitro Protein Expression Kit based on HeLa cell lysates (ThermoFisher Scientific). HeLa lysate, accessor}' proteins, reaction mix and pCFE-GFP plasmid from the kit were thawed in ice. Reactions were prepared at room temperature in a 96-well optical plate by adding 12.5 pL of HeLa lysate, 2 5 pL accessor _}' proteins, 5 mΐ, reaction mix, 1 pg of pCFE-GFP plasmid and 1 mM of test compounds in 5 pL or 5 pL of distilled H ₂ 0 as a basal expression of GFP (vehicle). A well with dH ₂ 0 instead of pCFE-GFP plasmid was used as basal

autofluorescence of the reaction. All reactions were made in duplicated. Fluorescence intensity was measured by a multi-mode microplate reader (Synergy-4; Biotek) during 6-hour treatments and capturing fluorescence at 15-minute intervals with 485/20 and 528/20 excitation and emission filters.

[1042] Relative fluorescence intensity (RFU) of GFP resulting from cell-free expression treated with compounds 152 or 153 or vehicle are shown in FIG. 13A. Comparison of RFU of GFP at 6 hours is shown in FIG 13B. The addition of compounds 152 or 153 to the kit’s reaction mix increase the expression of GFP and hence its fluorescence up to 4-fold compared to the expression obtained using the kit’s reagents alone.

Example B12 Protein synthesis with a yeast cell-based assay

[1043] Two GS115H Pichia pastoris yeast strains that stably express phospholipase C protein (PLC) under the control of a methanol-inducible promoter (pAOX-PLC) or a constitutive promoter (pGAP-PLC) were used to assess the secretion levels of PLC and its enzymatic activity. pAOX-PLC and pGAP-PLC yeast single colonies were inoculated in 2 ml of YPD (1% yeast extract, 2% peptone, 2% glucose) and grown at 30°C in a deep 24-well microplate in a shaking incubator for 16-18 h at 250 rpm. These cultures were diluted to an OD600 of 1 in 2 ml of YPM (1% yeast extract, 2% peptone, 100 rnM phosphate buffer pH 6 and 0.5% methanol) or 2ml of YPM containing IOmM of compound 152 to induce gene expression and incubated at 30°C in a shaking incubator at 250 rpm. Methanol was added every 24 h in order to maintain 0.5% methanol concentration. Condition without compound 152 was used as a control for basal secretion and subsequent activity assessment of PLC. After 72 h of induction, cells were harvested by centrifugation and the supernatant analyzed for protein expression by SDS-PAGE and PLC activity.

[1044] Gels were stained with 0.1% Coomassie Blue R250 in 10% acetic acid, 50% methanol, and 40% ILO for 20 minutes. Stained gel was then washed twice for 2 hours with 10% acetic acid, 50% methanol and 40% dH Q until the Coomassie Blue background w¾s nearly dear. Photographs of the gels were taken m a gel imaging system. The secretion of PLC for pAOX-PLC or pGAP-PLC strains in the presence or absence of compound 152 are shown by the arrows in FIG. 14A and 14B. Secretion of PLC under the compound 152-treatment is shown in duplicates.

[1045] PLC activity was measured in 96 well microplates using 1 mM

0-(4-Nitrophenylphosphoryl)choline as a substrate. The assay was carried out at 50°C in a 96 micro well plate by incubating 10 pL of culture supernatant, 10 pL 100 mM NPPC and 80 pL of 250 mM HEPES pH 7, 60% sorbitol, 0.1 mM ZnCl _2. Absorbance at 405 nm was monitored every 30 s for 1 h at 50°C m a Synergy HT microplate reader (Biotek). 1 PLC unit is defined as the amount of enzyme releasing 1 nmol of p-nitrophenol per minute. Activity of PLC secreted from pAOX-PLC or pGAP-PLC strains in the presence or absence of compound 152 is shown in FIG. 14C and 14D respectively as mean + SEM. Fold change was calculated as the activity relative to the activity levels from untreated yeasts. Statistical analyses were performed using GraphPad Prism software and significant difference was assessed by t test (* < 0.05).

[1046] Results show that treatment with an ISR-inhibitor compound increases the synthesis of a heterologous protein and also its secretion in a cell-based system. In addition, the activity of the over expressed protein also increases during these conditions as shown in FIG. 14C and 14D. Example B13—Protein synthesis with a CHO cell-based assay

[1047] CHO cells were maintained at 37 °C and 5% C0 ₂ in DMEM supplemented with 10% fetal bovine serum (FBS), 2 mM L -glutamine, 100 U/ml penicillin, and 100 pg/rnl streptomycin. After reaching 80% of confluence, cells w¾re detached and seeded on 6wvell plates in complete media, allowed to recover for 48h. Cells were then washed three times with PBS and treated with compound 152 and 153 at 1 mM, 5 mM or 10 mM in 1 mL of media without FBS for 24h. Treatment with 0.1% DMSO 'as used as control (vehicle). After 24h treatment, supernatant (SN) which contains secreted proteins was extracted and protease and phosphatase inhibitors (Roche) were added to each sample. SN were centrifuged at 2,000 g for 10 min to discard any cellular debris and 900 pL SN were transferred to empty microtubes with 400 pL methanol by mixing well. 200 p.L of chloroform was added to the mix and then samples w'ere centrifuged at 14,000 g for 2 minutes. Top aqueous layer was discarded by pipetting off and 400 pL methanol was added to each sample by mixing well. Samples were then centrifuged at 17,000 g for 8 minutes and methanol was discarded by pipetting off without disturbing the protein pellet.

Samples were left dr ' at room temperature and pellets w'ere resuspended with SDS-PAGE sample buffer. Secreted proteins were analyzed by SDS-PAGE and Coomassie staining. Gels were stained with 0.1% Coomassie Blue R250 in 10% acetic acid, 50% methanol, and 40% H ₂ 0 for 20 minutes. Stained gel was then washed twice for 2 hours with 10% acetic acid, 50% methanol and 40% dH ₂ 0 until the Coomassie Blue background was nearly clear. Photographs of the gels were taken in a gel imaging system.

[1048] Total protein secretion from CHO cells treated with compound 152 or 153 at the indicated concentration or vehicle alone for 24 hours are shown in FIG. 15 A. Quantification of protein bands from the gel was done by densitometry using Image!. Percent of secreted proteins in each treatment is shown in FIG. 15B. Percentage was calculated as the percent relative to protein secretion levels from vehicle-treated CHO cells winch correspond to 100%. Treatment with ISR-inhibitor compounds can increase the secretion of proteins in a cell-based assay and could be used as enhancers of recombinant proteins in those systems.

[1049] All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference m their entireties.