Inhibitors of integrated stress response pathway

FIELD

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

BACKGROUND

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, α, β and γ) becomes phosphorylated in its α-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 (GEF) activity), sequestering eIF2B in a complex with eIF2 and reducing general protein translation of most mRNA in 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 β-secretase BACE-1.

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

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

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).

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

FIG. 3A and FIG. 3B show percent recovery of protein synthesis in a stressed cell in the presence of one of several test compounds at a concentration of 100 nM (FIG. 3A) or 1 μM (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.

FIG. 4A shows representative levels of ATF4 expression and β-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).

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.

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 (fEPSP) slope, measured from 20 minutes prior to theta burst stimulation (TBS) to 60 minutes after TBS. FIG. 5B shows the responses recorded in the last 10 minutes after conditioning stimulation of the slices from the WT C57BL/6 and APP/PS1 mice treated with ISRIB (APP+ISRIB), and from APP/PS1 mice treated with compound 3 (APP+Cmp3), or compound 152 (APP+Cmp152), or the vehicle (APP).

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”). FIG. 6B shows levels of ATF4 expression normalized to β-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 β-actin expression in hippocampi extracted from mice treated with compound 3 versus a vehicle control (“Veh”).

FIG. 7A shows 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.

FIG. 8A shows protein synthesis in muscles from fasting mice or fasting mice treated with compound 3. Protein synthesis was normalized to β-actin expression and percentage was calculated as the percent relative to protein synthesis levels from control mice (Fed) which correspond to 100%. FIG. 8B shows 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.

FIG. 9A and FIG. 9B show gastrocnemius weight from mice that were fed, fasted, or fasted with compound 3 (FIG. 9A) 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 β-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 β-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.

FIG. 10A-C shows protein synthesis in the gastrocnemius (FIG. 10A), tibialis anterior (FIG. 10B) and quadriceps (FIG. 10C) muscles for the mobile hindlimb and the immobilized hindlimb (triggering immobilization-induced muscle atrophy) in mice with unilateral hindlimb immobilization, treated either with a vehicle control or compound 3. The levels were normalized to β-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.

FIG. 11A-C shows muscle weight of gastrocnemius (FIG. 11A), quadriceps (FIG. 11B), 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 shows percent protein synthesis (normalized to β-actin expression) in gastrocnemius (FIG. 11D), quadriceps (FIG. 11E), and tibialis anterior (FIG. 11F) 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 in the flank of each animal.

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.

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.

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.

FIG. 14C and FIG. 14D shows 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.

FIG. 15A shows an SDS-PAGE gel of secreted proteins from CHO cells cultured in the presence of 1 μm, 5 μm, or 10 μm 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

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

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”.

“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., C₁-C₁₀means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀alkyl”), having 1 to 10 carbon atoms (a “C₁-C₁₀alkyl”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkyl”), having 1 to 6 carbon atoms (a “C₁-C₆alkyl”), having 2 to 6 carbon atoms (a “C₂-C₆alkyl”), or having 1 to 4 carbon atoms (a “C₁-C₄alkyl”). 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-decyl, and the like.

“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-C₂₀alkylene”), having 1 to 10 carbon atoms (a “C₁-C₁₀alkylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkylene”), having 1 to 6 carbon atoms (a “C₁-C₆alkylene”), 1 to 5 carbon atoms (a “C₁-C₅alkylene”), 1 to 4 carbon atoms (a “C₁-C₄alkylene”) or 1 to 3 carbon atoms (a “C₁-C₃alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), butylene (—CH₂(CH₂)₂CH₂—), isobutylene (—CH₂CH(CH₃)CH₂—), pentylene (—CH₂(CH₂)₃CH₂—), hexylene (—CH₂(CH₂)₄CH₂—), heptylene (—CH₂(CH₂)₅CH₂—), octylene (—CH₂(CH₂)₆CH₂—), and the like.

“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 olefinic unsaturation (i.e., having at least one moiety of the formula C═C) and having the number of carbon atoms designated (i.e., C₂-C₁₀means two to ten carbon atoms). An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C₂-C₂₀alkenyl”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkenyl”), having 2 to 8 carbon atoms (a “C₂-C₈alkenyl”), having 2 to 6 carbon atoms (a “C₂-C₆alkenyl”), or having 2 to 4 carbon atoms (a “C₂-C₄alkenyl”). Examples of alkenyl group include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, and the like.

“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 “C₂-C₂₀alkenylene”), having 2 to 10 carbon atoms (a “C₂-C₁₀alkenylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkenylene”), having 2 to 6 carbon atoms (a “C₂-C₆alkenylene”), 2 to 4 carbon atoms (a “C₂-C₄alkenylene”) or 2 to 3 carbon atoms (a “C₂-C₃alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (—CH═CH—), propenylene (—CH═CHCH₂—), 1,4-but-1-enylene (—CH═CH—CH₂CH₂—), 1,4-but-2-enylene (—CH₂CH═CHCH₂—), 1,6-hex-1-enylene (—CH═CH—(CH₂)₃CH₂—), and the like.

“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 unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C₂-C₁₀means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C₂-C₂₀alkynyl”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkynyl”), having 2 to 8 carbon atoms (a “C₂-C₈alkynyl”), having 2 to 6 carbon atoms (a “C₂-C₆alkynyl”), or having 2 to 4 carbon atoms (a “C₂-C₄alkynyl”). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

“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 “C₂-C₂₀alkynylene”), having 2 to 10 carbon atoms (a “C₂-C₁₀alkynylene”), having 6 to 10 carbon atoms (a “C₆-C₁₀alkynylene”), having 2 to 6 carbon atoms (a “C₂-C₆alkynylene”), 2 to 4 carbon atoms (a “C₂-C₄alkynylene”) or 2 to 3 carbon atoms (a “C₂-C₃alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (—C≡C—), propynylene (—C≡CCH₂—), and the like.

“Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C₃-C₁₀means three to ten carbon atoms). Cycloalkyl 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-C₈cycloalkyl”), having 3 to 6 carbon atoms (a “C₃-C₆cycloalkyl”), or having from 3 to 4 annular carbon atoms (a “C₃-C₄cycloalkyl”). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

“Cycloalkylene” as used herein refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkylene”), having 3 to 6 carbon atoms (a “C₃-C₆cycloalkylene”), or having from 3 to 4 annular carbon atoms (a “C₃-C₄cycloalkylene”). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and the like. A cycloalkylene may attach to the remaining structures via the same ring carbon atom or different ring carbon atoms. When a cycloalkylene attaches 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.

“Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic non-aromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C═C) and having the number of carbon atoms designated (i.e., C₂-C₁₀means two to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

“Cycloalkenylene” as used herein refers to the same residues as cycloalkenyl, but having bivalency.

“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 anthryl) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “C₆-C₁₄aryl”). An aryl 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, 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.

“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 “C₆-C₁₄arylene”).

“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 ring (e.g., pyridyl, furyl) 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 heteroatoms 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.

“Heteroarylene” as used herein refers to the same residues as heteroaryl, but having bivalency.

“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 heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms 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 heteroatoms 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.

“Heterocyclylene” as used herein refers to the same residues as heterocyclyl, but having bivalency.

“Halo” or “halogen” refers to elements of the Group 17 series 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 (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-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 (—CF₃). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (—OCF₃).

“Carbonyl” refers to the group C═O.

“Thiocarbonyl” refers to the group C═S.

“Oxo” refers to the moiety ═O.

“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 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted.

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.

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.

As used herein, the term “effective 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 effective 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.

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

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.

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.

“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 in 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.

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, ethylcellulose, 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 microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl 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.

It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.

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.

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

Compounds

In one aspect, provided is a compound of formula (I):

embedded image

or a pharmaceutically acceptable salt thereof;

wherein:

- X¹and X², independently of each other, are CH or N;
- Y¹is selected from the group consisting of a bond, NR^Y1, and O; provided that when X¹is N, then Y¹is a bond;
- R^Y1is hydrogen or C₁-C₆alkyl;
- Y²is selected from the group consisting of a bond, NR^Y2, and O; provided that when X²is N, then Y²is a bond;
- R^Y2is hydrogen or C₁-C₆alkyl;
- m¹, m², n¹, n², p¹, p², q¹, and q², independently of each other, are 0 or 1;
- r and s, independently of each other, are 0, 1, or 2;
- A¹is selected from the group consisting of:
  - a substituent of formula (A¹-a)

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- - - wherein
      - *represents the attachment point to the remainder of the molecule; Z¹is selected from the group consisting of CR^Z1-1R^Z1-2, NR^Z1-2, O, S, and —CR^Z1-1═CR^Z1-1—;
      - wherein R^Z1_1 is H or R¹⁴; and R^Z1-2is H or R¹⁴;
      - Z²is selected from the group consisting of CR^Z2-1R^Z2-2, NR^Z2-2; O, S,
      - and —CR^Z2-1═CR^Z2-1—;
      - wherein R^Z2-1is H or R¹⁴; and R^Z2-2is H or R¹⁴;
      - Z³, independently at each occurrence, is C or N, provided that at least one Z³is C;
      - R¹³is hydrogen or R¹⁴, or R¹³and R^Z1-2are taken together to form a double bond between the carbon atom bearing R¹³and Z¹, or R¹³and R^Z2-2are taken together to form a double bond between the carbon atom bearing R¹³and Z²; and
      - x1 is 0, 1, 2, 3, or 4, provided than when one Z³is N, then x1 is not 4;
  - C₆-C₁₀aryl optionally substituted with one or more R¹⁴substituents; and
  - 5-10 membered heteroaryl optionally substituted with one or more R¹⁴substituents;
- R¹⁴is selected, independently at each occurrence, from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, —OH, —O(C₁-C₆alkyl), —O(C₁-C₆haloalkyl), —SH, —S(C₁-C₆alkyl), —S(C₁-C₆haloalkyl), —NH₂, —NH(C₁-C₆alkyl), —NH(C₁-C₆haloalkyl), —N(C₁-C₆alkyl)₂, —N(C₁-C₆haloalkyl)₂, —NR^14-aR^14-b, —CN, —C(O)OH, —C(O)O(C₁-C₆alkyl), —C(O)O(C₁-C₆haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)NH(C₁-C₆haloalkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)N(C₁-C₆haloalkyl)₂, —C(O)NR^14-aR^14-b, —S(O)₂OH, —S(O)₂O(C₁-C₆alkyl), —S(O)₂O(C₁-C₆haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆haloalkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂N(C₁-C₆haloalkyl)₂, —S(O)₂NR^14-aR^14-b, —OC(O)H, —OC(O)(C₁-C₆alkyl), —OC(O)(C₁-C₆haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆alkyl), —N(H)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆alkyl)C(O)H, —N(C₁-C₆alkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆alkyl)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆haloalkyl)C(O)H, —N(C₁-C₆haloalkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆haloalkyl)C(O)(C₁-C₆haloalkyl), —OS(O)₂(C₁-C₆alkyl), —OS(O)₂(C₁-C₆haloalkyl), —N(H)S(O)₂(C₁-C₆alkyl), —N(H)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆alkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆haloalkyl)S(O)₂(C₁-C₆alkyl), and —N(C₁-C₆haloalkyl)S(O)₂(C₁-C₆haloalkyl);
  - wherein R^14-aand R^14-bare taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
- A²is selected from the group consisting of:
  - a substituent of formula (A²-a)

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- - - wherein
      - represents the attachment point to the remainder of the molecule; Z⁴is selected from the group consisting of CR^Z4-1R^Z4-2, NR^Z4-2, O, S, and —CR^Z4-1═CR^Z4-1—;
      - wherein R^Z4-1is H or R¹⁶; and R^Z4-2is H or R¹⁶;
      - Z⁵is selected from the group consisting of CR^Z5-1R^Z5-2, NR^Z5-2; O, S, and —CR^Z5-1═CR^Z5-1—;
      - wherein R^Z5-1is H or R¹⁶; and R^Z5-2is H or R¹⁶;
      - Z⁶, independently at each occurrence, is C or N, provided that at least one Z⁶is C;
      - R¹⁵is hydrogen or R¹⁶, or R¹⁵and R^Z4-2are taken together to form a double bond between the carbon atom bearing R¹⁵and Z⁴, or R¹⁵and R^Z5-2are taken together to form a double bond between the carbon atom bearing R¹⁵and Z⁵; and
      - x2 is 0, 1, 2, 3, or 4, provided than when one Z⁶is N, then x2 is not 4;
  - C₆-C₁₀aryl optionally substituted with one or more R¹⁶substituents; and
  - 5-10 membered heteroaryl optionally substituted with one or more R¹⁶substituents;
- R¹⁶is selected, independently at each occurrence, from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, —OH, —O(C₁-C₆alkyl), —O(C₁-C₆haloalkyl), —SH, —S(C₁-C₆alkyl), —S(C₁-C₆haloalkyl), —NH₂, —NH(C₁-C₆alkyl), —NH(C₁-C₆haloalkyl), —N(C₁-C₆alkyl)₂, —N(C₁-C₆haloalkyl)₂, —NR^16-aR^16-b, —CN, —C(O)OH, —C(O)O(C₁-C₆alkyl), —C(O)O(C₁-C₆haloalkyl), —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), —C(O)NH(C₁-C₆haloalkyl), —C(O)N(C₁-C₆alkyl)₂, —C(O)N(C₁-C₆haloalkyl)₂, —C(O)NR^16-aR^16-b, —S(O)₂OH, —S(O)₂O(C₁-C₆alkyl), —S(O)₂O(C₁-C₆haloalkyl), —S(O)₂NH₂, —S(O)₂NH(C₁-C₆alkyl), —S(O)₂NH(C₁-C₆haloalkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂N(C₁-C₆haloalkyl)₂, —S(O)₂NR^16-aR^16-b, —OC(O)H, —OC(O)(C₁-C₆alkyl), —OC(O)(C₁-C₆haloalkyl), —N(H)C(O)H, —N(H)C(O)(C₁-C₆alkyl), —N(H)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆alkyl)C(O)H, —N(C₁-C₆alkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆alkyl)C(O)(C₁-C₆haloalkyl), —N(C₁-C₆haloalkyl)C(O)H, —N(C₁-C₆haloalkyl)C(O)(C₁-C₆alkyl), —N(C₁-C₆haloalkyl)C(O)(C₁-C₆haloalkyl), —OS(O)₂(C₁-C₆alkyl), —OS(O)₂(C₁-C₆haloalkyl), —N(H)S(O)₂(C₁-C₆alkyl), —N(H)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆alkyl), —N(C₁-C₆alkyl)S(O)₂(C₁-C₆haloalkyl), —N(C₁-C₆haloalkyl)S(O)₂(C₁-C₆alkyl), and —N(C₁-C₆haloalkyl)S(O)₂(C₁-C₆haloalkyl);
  - wherein R^16-aand R^16-bare taken together with the nitrogen atom which bears them to form a 3-10 membered heterocycle;
- R^1aand R^1bare independently selected from the group consisting of hydrogen, C₁-C₆alkyl, and halogen;
- R^2aand R^2bare independently selected from the group consisting of hydrogen, C₁-C₆alkyl, and halogen;
- when present, R^3aand R^3bare independently at each occurrence selected from the group consisting of hydrogen, C₁-C₆alkyl, and halogen;
- when present, R^4aand R^4bare independently at each occurrence selected from the group consisting of hydrogen, C₁-C₆alkyl, and halogen;
- or alternatively, R^1aand R^2aare taken together to form a C₁-C₆alkylene moiety;
- or alternatively, R^1aand an R^3amoiety, when present, are taken together to form a C₁-C₆alkylene moiety, and R^1band the R^3bin the geminal position to the R^3ataken together with R^1a, are both hydrogen;
- or alternatively, an R^3amoiety, when present, and an R^4amoiety, when present, are taken together to form a C₁-C₆alkylene moiety, and the R^3bin the geminal position to the R^3ataken together with the R^4amoiety and the R^4bin the geminal position to the R^4ataken together with the R^3amoiety, are both hydrogen;
- when present, R^5aand R^5bare taken together to form an oxo (═O) substituent or an imido (═NH) substituent, or alternatively, R^5aand R^5bare both hydrogen;
- when present, R^6ais selected from the group consisting of hydrogen, —OR^6a-a, and —NR^6a-bR^6a-c;
- when present, R^6bis hydrogen;
- or alternatively, R^6aand R^6bare taken together to form a moiety selected from the group consisting of —O—CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—, and —CH₂—CH₂—CH₂—CH₂—O—;
- when present, R^7aand R^7bare both hydrogen;
- when present, R^8aand R^8bare taken together to form an oxo (═O) substituent, or alternatively, R^8aand R^8bare both hydrogen;
- when present, R^9aand R^9bare taken together to form an oxo (═O) substituent or an imido (═NH) substituent, or alternatively, R^9aand R^9bare both hydrogen;
- when present, R^10ais selected from the group consisting of hydrogen, —OR^10a-a, and —NR^10a-bR^10a-c;
- when present, R^10bis hydrogen;
- or alternatively, R^10aand R^10bare taken together to form a moiety selected from the group consisting of —O—CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—CH₂—O—CH₂—, and —CH₂—CH₂—CH₂—CH₂—O—;
- when present, R^11aand R^11bare both hydrogen;
- when present, R^12aand R^12bare taken together to form an oxo (═O) substituent, or alternatively, R^12aand R^12bare both hydrogen;
- R^6a-ais selected from the group consisting of hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R^10a-ais selected from the group consisting of hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl;
- or R^6a-aand R^Y1may be taken together to form a carbonyl (C═O) moiety;
- or R^10a-aand R^Y2may be taken together to form a carbonyl (C═O) moiety;
- R^6a-band R^6a-c, independently of each other, are selected from the group consisting of hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl; and
- R^10a-band R^10a-c, independently of each other, are selected from the group consisting of hydrogen, C₁-C₆alkyl, and C₁-C₆haloalkyl.

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

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or a pharmaceutically acceptable salt thereof;

wherein:

- A¹is a substituent of formula (A¹-a)

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A²is a substituent of formula (A²-a)

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- and wherein R^Y1, R^Y2, r, s, Z¹, R^Z1-1, R^Z1-2, Z², R^Z2-1, R^Z2-2, Z³, x1, Z⁴, R^Z4-1, R^Z4-2, Z⁵, R^Z5-1, R^Z5-2, Z⁶, x2, R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R¹³, R¹⁴, R¹⁵, and R¹⁶are as defined in compounds of formula (I).

In some embodiments of the compounds of formula (1-1), (A¹-a) is selected from the group consisting of:

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In some embodiments of the compounds of formula (1-1), (A¹-a) is (A¹-b).

In some embodiments of the compounds of formula (1-1), (A¹-a) is (A¹-c).

In some embodiments of the compounds of formula (1-1), (A¹-a) is (A¹-d).

In some embodiments of the compounds of formula (1-1), (A¹-a) or (A¹-b) is selected from the group consisting of:

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wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A¹-a) or (A¹-b) is selected from the group consisting of:

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

In some embodiments of the compounds of formula (1-1), (A¹-a) or (A¹-c) is selected from the group consisting of:

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wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A¹-a) or (A¹-c) is selected from the group consisting of:

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

In some embodiments of the compounds of formula (1-1), (A²-a) is selected from the group consisting of:

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In some embodiments of the compounds of formula (1-1), (A²-a) is (A²-b).

In some embodiments of the compounds of formula (1-1), (A²-a) is (A²-c).

In some embodiments of the compounds of formula (1-1), (A²-a) is (A²-d).

In some embodiments of the compounds of formula (1-1), (A²-a) or (A²-b) is selected from the group consisting of:

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wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A²-a) or (A²-b) is selected from the group consisting of:

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

In some embodiments of the compounds of formula (1-1), (A²-a) or (A²-c) is selected from the group consisting of:

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wherein the * represents the attachment point to the remainder of the molecule. In some embodiments, (A²-a) or (A²-c) is selected from the group consisting of:

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

In some embodiments, (A¹-a) or (A¹-b) is selected from the group consisting of:

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wherein the * represents the attachment point to the remainder of the molecule; and (A²-a) or (A²-b) is selected from the group consisting of:

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

In some embodiments, (A¹-a) or (A¹-b) is selected from the group consisting of:

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wherein the * represents the attachment point to the remainder of the molecule; and (A²-a) or (A²-b) is selected from the group consisting of:

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

In some embodiments, (A¹-a) or (A¹-b) is selected from the group consisting of:

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wherein the * represents the attachment point to the remainder of the molecule; and (A²-a) or (A²-c) is selected from the group consisting of: