[go: up one dir, main page]

WO2025038783A1 - Adenosine ligands for the treatment of neurological disorders or chronic heart failure - Google Patents

Adenosine ligands for the treatment of neurological disorders or chronic heart failure Download PDF

Info

Publication number
WO2025038783A1
WO2025038783A1 PCT/US2024/042362 US2024042362W WO2025038783A1 WO 2025038783 A1 WO2025038783 A1 WO 2025038783A1 US 2024042362 W US2024042362 W US 2024042362W WO 2025038783 A1 WO2025038783 A1 WO 2025038783A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
hydrogen
substituted
alkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/042362
Other languages
French (fr)
Inventor
Dario Doller
Guiying Li
Casey Mccomas
Amy Ripka
Allen T. Hopper
John E. Macor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lucy Therapeutics Inc
Original Assignee
Lucy Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lucy Therapeutics Inc filed Critical Lucy Therapeutics Inc
Publication of WO2025038783A1 publication Critical patent/WO2025038783A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Rett syndrome is a neurological disorder caused by mutations in the X-linked gene methyl -CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator.
  • MECP2 X-linked gene methyl -CpG-binding protein 2
  • the MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which is needed for brain development and acts as one of the many biochemical switches that can regulate gene expression.
  • RTT is characterized by progressive development of motor and neurological dysfunction. Girls affected with RTT acquire speech and movement skills on a normal timeline after birth but develop symptoms between 6 months and 2 years of age. Neurological manifestations of disease include loss of speech and motor skills, stereotypic hand movements, difficulty walking, sporadic rapid respiration and apnea, and seizures. Apraxia, the inability to perform motor functions, is perhaps the most severely disabling feature of RTT, interfering with every body movement, including eye gaze and speech. Children with Rett syndrome often exhibit autistic-like behaviors in the early stages.
  • RTT Rett Syndrome Fact Sheet
  • www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Rett- Syndrome-F act- Sheet RTT was initially thought to be an entirely neurological disorder, and RTT research focused on the role of MeCP2 in the central nervous system.
  • Mecp2 mutant mouse models and RTT patients also implicate important roles for MeCP2 in peripheral systems (Kyle, Vashi and Justice, Open Biol 2018, 8(2), 170216). More than 95% of RTT patients carry a mutation in the MECP2 gene.
  • MECP2 binds to methylated DNA to regulate gene transcription through repression or activation. When MECP2 represses gene transcription, it associates with chromatin-remodeling complexes that contain Type I histone deacetylases (HDACs) (Bienvenu and Chelly, Nat Rev. Genet 2006, 7, 415-426).
  • HDACs Type I histone deacetylases
  • MECP2 may result in the upregulation of genes that would normally be repressed.
  • the severity of MECP2 mutation does not always correlate with disease severity, due at least in part to favorable patterns of X-chromosome inactivation in heterozygous females.
  • Many children diagnosed with RTT have reduced brain volume compared with healthy individuals, consistent with a smaller head circumference. Reduced brain volume is largely due to small neuronal body size and a denser packing of cells, particularly in layers III and V of the cerebral cortex, thalamus, substantia nigra, basal ganglia, amygdala, cerebellum and hippocampus. Patients also have reduced dendritic arborization, indicative of a delay in neuronal maturation.
  • mice show evidence of dysregulated neurotransmitters, neuromodulators and transporters, indicating an important role in synaptic function (Kyle, Vashi and Justice, Open Biol 2018, 8(2), 170216).
  • Mouse models that carry Mecp2 mutations and recapitulate most of the symptoms of RTT are available.
  • Mecp 2/Y male mutant mice are normal at birth and weaning, but develop symptoms that include hypo-activity, limb clasping, tremors, motor impairment and abnormal breathing as early as 4 weeks of age. Such symptoms progressively worsen, leading to their death at 6-16 weeks.
  • Adenosine is a purine nucleoside comprised of an adenine group attached to a ribose sugar by a glycosidic bond. Adenosine is present in all cells and released by certain physiological and pathophysiological stimuli. Adenosine is formed intracellularly as an intermediate during the degradation of adenosine 5'-phosphate (AMP) and S- adenosylhomocysteine, but it can be released from the cell, acting as a neurotransmitter by binding to specific receptors.
  • AMP adenosine 5'-phosphate
  • S- adenosylhomocysteine S- adenosylhomocysteine
  • adenosine may act as both a precursor and a metabolite of adenine nucleotides, and by providing the structural building block of adenosine triphosphate (ATP), it plays a central role in the basic energy transfer of all living organisms (Layland, J., Carrick, D., Lee, M., Oldroyd, K., & Berry, C. JACC. Cardiovascular Interventions 2014, 7, 581-591.)
  • ATP adenosine triphosphate
  • Adenosine exerts a variety of physiological effects by interacting with cell surface G- protein-coupled receptor subtypes, namely Al, A2A, A2B, and A3 adenosine receptors (ARs). Each receptor is encoded by a different gene.
  • Adenosine receptor selective agonists are substances that bind selectively to one or more subtypes of the adenosine receptors, thus mimicking the action of adenosine.
  • adenosine receptors are mediated intracellularly by the messenger cAMP.
  • Al AR agonists coupled preferably via Gi/o proteins
  • a decrease of the intracellular cAMP concentration is observed (preferably after direct prestimulation of adenylate cyclase by forskolin).
  • A2A and A2B AR agonists leads to an increase of cAMP concentration in the cells, and A2A and A2B AR antagonists to a decrease of the cAMP concentration in the cells.
  • adenosine As a classical neurotransmitter, adenosine is neither stored nor released and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides (Huang et al. Curr Top Med Chem 2011, 11(8), 1047-57).
  • Rett Syndrome Treatment for the disorder is symptomatic, i.e., focusing on the management of symptoms, and supportive, requiring a multidisciplinary approach.
  • medication may be used for breathing irregularities and motor difficulties, and anticonvulsant drugs may be used to control seizures.
  • occupational therapy is used to help children develop skills needed for performing self- directed activities (such as dressing, feeding, and practicing arts and crafts), while physical therapy and hydrotherapy may prolong mobility.
  • the use of a brain penetrant A1, A2B and/or dual A1/A2B AR agonists may produce a medication for treating Rett syndrome.
  • CDLK5 deficiency disorder is a developmental disease that is generally characterized by seizures appearing during infancy, and typically leads to severe intellectual disability, impaired gross and fine motor function, cortical visual impairment (Leonard H. et al., 2022 Lancet Neurol.; doi: 10.1016/S1474-4422(22)00035-7). Speech is also generally absent in individuals with CDLK5 deficiency disorder. Other common features include stereotypies (often involving the hands), sleep disruptions, gastrointestinal problems and may include breathing irregularities.
  • CDLK5 deficiency disorder The incidence of CDLK5 deficiency disorder is approximately 1 in 40,000-60,000 with ⁇ 90% of diagnosed individuals being girls.
  • CDLK5 deficiency disorder had previously been described as an atypical version of Rett syndrome but is now recognized as a separate disorder.
  • Clinical management has focused primarily on seizure management however most patients are refractory or exhibit only short term responses to treatment with seizure medications.
  • CDH8 encodes a chromodomain helicase DNA binding protein and mutations disrupting the CDH8 gene have been associated with autism spectrum disorder (ASD), leading to a specific subtype of ASD (Bernier, R. et al., 2014 Cell; doi: 10.1016/ j.cell.2014.06.017).
  • ASSD autism spectrum disorder
  • FOXG1 syndrome is a developmental disorder which is characterized by structural malformations in the brain, including underdevelopment of the corpus callosum, reduced cortical gyri and white matter deficiencies (Hou, P-S. et al., 2020 Frontiers Cell Neuro.; doi.org/10.3389/fncel.2020.00035). Individuals with FOXG1 syndrome generally exhibit microcephaly and have severe intellectual disabilities, involuntary and repetitive movements, seizures, disrupted sleep, ASD and reduced speech and language.
  • FOXG1 syndrome has been previously described as a variant of Rett syndrome, but clinicians generally consider FOXG1 syndrome as a distinct disorder. There remains a significant unmet need for therapies that could address the multiple symptoms afflicting patients with FOXG1 syndrome.
  • Heart failure is a complex cardiovascular syndrome which can involve impaired structure or function of the left ventricle and is a leading cause of cardiovascular morbidity and mortality.
  • the prevalence of HF is approximately 5.8-6.5 million patients in the U.S. and 26 million globally (Hajouli and Ludhwani, 2023 StatPearls Publishing, PMID: 31971755).
  • Heart failure involving left ventricular dysfunction is segregated into three subtypes based on left ventricular ejection fraction (EF): heart failure with reduced ejection fraction (HFrEF) with EF less than or equal to 40%; heart failure with preserved ejection fraction (HFpEF) with EF greater than or equal to 50%; and heart failure with mid-range ejection fraction (HFmrEF) between 41 to 49%.
  • EF left ventricular ejection fraction
  • HFrEF reduced ejection fraction
  • HFpEF preserved ejection fraction
  • HFmrEF mid-range ejection fraction
  • Symptoms of HFpEF, HFmrEF and HFrEF are similar and increase with physical exertion. These symptoms can include fatigue, weakness, fluid accumulation, wheezing, loss of appetite and palpitations, and can progress to tachycardia and peripheral edema.
  • HFrEF HFrEF
  • nonpharmacologic therapies such as lifestyle, diet, exercise, weight management and smoking cessation, as well as a range of pharmacologic therapeutic approaches.
  • These pharmacologic therapeutic treatments include Class IA angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, Class IB beta blockers, mineralocorticoid receptor antagonists, nitrates with hydralazine, digoxin, aspirin with statin, ivabradine, sodium-glucose cotransporter 2 inhibitors, and dobutamine or milrinone.
  • the present application provides a method of treating FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome, CDKL5 deficiency disorder (CDD) and/or one or more symptoms associated with CDD, or CHD8-related neurodevelopmental disorder (CHD8-NDD) and/or one or more symptoms associated with CHD8-NDD, chronic heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or heart failure with mid-range ejection fraction (HFmrEF) comprising administering a therapeutic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, OR 13 , and NR 2 R 3 ; R 2 and R
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1- 6 alkoxycarbonyl, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, aryl (e.g., phenyl), and optionally substituted heteroaryl.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1- 6 alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene.
  • A is selected from cyano, hydroxyl, optionally substituted C 1- 6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1- 6 alkyl, optionally substituted heterocyclyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, and optionally substituted heterocyclyl.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, - C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, - C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, aryl, and optionally substituted heteroaryl.
  • A is optionally substituted heterocyclyl
  • A is optionally substituted oxetane.
  • A is optionally substituted tetrahydrofuran.
  • Y is NR 2 R 3 and R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl.
  • Y is NH 2 .
  • Y is NMe 2 .
  • Y is NHMe.
  • Y is NR 2 R 3 and R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring.
  • Y is hydrogen.
  • Y is C 1-6 alkyl.
  • Y is C 3- 6 cycloalkyl.
  • X is S.
  • n is 1.
  • R 10 and R 11 are both hydrogen.
  • R 7 and R 8 are both hydrogen.
  • R 7 and R 8 are both C 1-6 alkyl.
  • R 7 is hydrogen and and R 8 is C 1-6 alkyl or C 1-6 haloalkyl.
  • R 9 is hydrogen.
  • R 1 is hydrogen.
  • R 1 and R 9 taken together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl ring. In ceratin such embodiments, R 1 and R 9 taken together with the atoms to which they are attached form oxetan-3-yl.
  • the present application provides a method of treating FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome, CDD and/or one or more symptoms associated with CDD, or CHD8-NDD and/or one or more symptoms associated with CHD8- NDD, chronic heart failure, HFpEF, HFrEF, or HFmrEF comprising administering a therapeutic amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206- 208, 212-230, 232-458, and pharmaceutically acceptable salts thereof.
  • the compound is selected from any one of compounds 1-10, 12-18, 20-25, 27- 37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, and 363-458, and pharmaceutically acceptable salts thereof.
  • the compound is selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is compound 360, or a pharmaceutically acceptable salt thereof. In certain embodiments of the foregoing methods, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.
  • the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.
  • the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.
  • the present application provides a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof.
  • the compound is not compound 343 (2-amino-4-(4-(2-methoxyethoxy)phenyl)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile).
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable excipient.
  • the compound is not compound 343.
  • the present application provides a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof or a pharmaceutical composition thereof for use as a medicament.
  • the compound is not compound 343.
  • the present application provides a method of treating Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising (a) a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable excipient.
  • the compound is not compound 343.
  • the present application provides a method of treating Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject, comprising administering to a subject in need thereof an effective amount of compound 360, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (a) compound 360, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient.
  • the method further comprises co-administering to the subject an additional therapeutic agent.
  • the additional therapeutic agent comprises trofinetide.
  • the present application provides use of a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising (a) a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable excipient, in the preparation of a medicament for the treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome.
  • the compound is not compound 343.
  • the present application provides use of compound 360, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (a) compound 360, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient, in the preparation of a medicament for the treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome.
  • the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism.
  • Y is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, OR 13 , and NR 2 R 3 , R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl; or R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R 1 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; R 7 and R 8 each independently is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; R 9 is hydrogen or halogen, or R 1 and R 9 taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl;
  • the present application provides a method of treating FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying) comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, OR 13 , and NR 2 R 3 , R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl; or R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R 1 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; R 7 and R 8 each independently is selected from hydrogen, C 1-6 alkyl, and C
  • the present application provides a method of treating CDKL5 deficiency disorder (CDD) and/or one or more symptoms associated with CDD (e.g., repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing) comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, OR 13 , and NR 2 R 3 , R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl; or R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optional
  • the present application provides a method of treating CHD8-related neurodevelopmental disorder (CHD8-NDD) and/or one or more symptoms associated with CHD8-NDD (e.g., generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions) comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, OR 13 , and NR 2 R 3 , R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl; or R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R 1 is selected from hydrogen, C
  • the present application provides a method of treating chronic heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HfrEF), or heart failure with mid-range ejection fraction (HfmrEF) comprising administering to a subject in need thereof a compound of formula (I) formula (I) or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, OR 13 , and NR 2 R 3 , R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl; or R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R 1 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; R 7 and R 8 each independently is selected from hydrogen
  • m is 0 and R 12 is hydrogen.
  • R 12 is hydrogen.
  • Y is NR 2 R 3 , R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring
  • X is S
  • n is 1
  • each of R 1 , R 7 , R 8 and R 9 is hydrogen, then A is not optionally substituted thiazole (e.g., substituted thiazole).
  • m is 0 and R 12 is hydrogen.
  • R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl, X is S, n is 1, and each of R 1 , R 7 , R 8 and R 9 is hydrogen, then A is not substituted pyridyl (e.g., substituted 3-pyridyl).
  • X is S, and n is 1, then A is not substituted pyridyl (e.g., substituted 3-pyridyl).
  • Y when Y is NR 2 R 3 , and R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl, then A is not substituted pyridyl (e.g., substituted 3-pyridyl).
  • A when Y is NH 2 , X is S, n is 1, and each of R 1 , R 7 , R 8 and R 9 is hydrogen, then A is not substituted 3-pyridyl.
  • Y when Y is NH 2 , X is S, and n is 1, then A is not substituted 3-pyridyl.
  • R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl
  • X is S
  • n is 1, R 7 is methyl
  • R 8 is methyl
  • each of R 1 and R 9 is hydrogen
  • A is not optionally substituted 4-pyridyl (e.g., substituted 4-pyridyl).
  • Y is NH 2
  • X is S
  • n is 1, R 7 is methyl
  • R 8 is methyl
  • each of R 1 and R 9 is hydrogen
  • A is not optionally substituted 4-pyridyl (e.g., substituted 4-pyridyl).
  • Y is NR 2 R 3 , R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring (e.g., pyrollidine)
  • X is S
  • n is 1
  • each of R 1 , R 7 , R 8 and R 9 is hydrogen
  • A is not optionally substituted aryl (e.g., optionally substituted phenyl, such as substituted phenyl).
  • Y is NR 2 R 3 , and R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring (e.g., pyrollidine)
  • A is not optionally substituted aryl (e.g., optionally substituted phenyl, such as substituted phenyl).
  • m is 0 and R 12 is hydrogen.
  • X when X is S or O, then A is not optionally substituted oxazole (e.g., substituted oxazole).
  • Y when Y is NR 2 R 3 (e.g., NH 2 ), then A is not optionally substituted oxazole (e.g., substituted oxazole).
  • A is not optionally substituted oxazole (e.g., substituted oxazole).
  • m is 0 and R 12 is hydrogen.
  • m is 0 and R 12 is hydrogen.
  • R 13 is C 1-6 alkyl, such as methyl
  • X is S
  • n is 1
  • each of R 1 , R 7 , R 8 , R 9 , R 10 and R 11 is hydrogen, then A is not substituted phenyl, substituted oxazole, imidazole, or 2-pyridyl.
  • R 13 when Y is OR 13 , R 13 is C 1-6 alkyl, such as ethyl, X is S, n is 1, and each of R 1 , R 7 , R 8 , R 9 , R 10 and R 11 is hydrogen, then A is not substituted oxazole.
  • R 13 when Y is OR 13 , R 13 is C 1-6 alkyl, such as methyl, ethyl, or sec- butyl, X is S, n is 1, and each of R 1 , R 7 , R 8 , R 9 , R 10 and R 11 is hydrogen, then A is not substituted thiazole.
  • m is 0 and R 12 is hydrogen.
  • X is O and A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1-6 alkoxycarbonyl, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, and optionally substituted thiazole.
  • X is O and A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1-6 alkoxycarbonyl, -C(O)NR 5 R 6 , - NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, aryl (e.g., phenyl), and heteroaryl (e.g., indole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, indazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, thiazole, oxazole, and pyridine).
  • aryl e.g., phenyl
  • heteroaryl e.g., indole, pyrazine, pyrimidine, pyrrolopyridine, pyrid
  • X is O and A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1- 6 alkoxycarbonyl, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, and heteroaryl (e.g., indole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, indazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, thiazole, oxazole, and pyridine).
  • heteroaryl e.g., indole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, indazole, benzofuran, benzoimidazole, benzothiazole, benzothi
  • X is O and A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1- 6 alkoxycarbonyl, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, and aryl (e.g., phenyl).
  • X is O and A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1- 6 alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)N R 5 R 6 , -N R 5 R 6 , -NR 5 C(O) C 1- 6alkyl, optionally substituted heterocyclyl, aryl, and pyridyl.
  • X is O and A is pyridyl.
  • X is O and A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1- 6 alkoxy, hydroxycarbonyl, C 1-6 alkoxycarbonyl, -C(O)N R 5 R 6 , -N R 5 R 6 , -NR 5 C(O)C1-6alkyl, optionally substituted heterocyclyl.
  • n is 0 and A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1- 6 alkoxycarbonyl, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl.
  • Y is H
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1-6 alkoxycarbonyl, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and heteroaryl (e.g., indole, oxazole, thiazole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, indazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, and pyridyl, such as oxazole, thiazole, indole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, benzofuran, benzoimidazole,
  • Y is H
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1-6 alkoxycarbonyl, -C(O)NR 5 R 6 , - NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted oxazole, optionally substituted thiazole, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene.
  • A is selected from cyano, hydroxyl, optionally substituted C 1- 6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, phenyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, phenyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole.
  • A is not substituted thiazole, such as phenyl-substituted thiazole. In certain embodiments of Formula (I), A is not optionally substituted pyridyl. In certain embodiments of Formula (I), A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, hydroxycarbonyl, C 1- 6 alkoxycarbonyl, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, aryl (e.g., phenyl), and optionally substituted heteroaryl.
  • aryl e.g., phenyl
  • A is selected from cyano, hydroxyl, optionally substituted C 1- 6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1- 6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , - NR 5 C(O)C 1-6 alkyl, and optionally substituted heterocyclyl.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl.
  • A is selected from cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, - C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)C 1-6 alkyl, optionally substituted heterocyclyl, aryl, and optionally substituted heteroaryl.
  • A is optionally substituted heterocyclyl, such as oxetane, tetrahydrofuran or tetrahydropyran.
  • A is optionally substituted oxetane, such as oxetan-3-yl.
  • A is optionally substituted tetrahydrofuran, such as tetrahydrofuran-3- yl.
  • A is optionally substituted C 1-6 alkoxy, such as methoxy or ethoxy.
  • A is optionally substituted C 1- 6 alkyl, such as methyl, trifluoromethyl, or hydroxyalkyl.
  • Y is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and NR 2 R 3 . In certain embodiments of Formula (I), Y is O.
  • Y is NR 2 R 3 and R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl, such as methyl. In certain such embodiments of Formula (I), Y is NH 2 . In certain such embodiments of Formula (I), Y is NHMe. In certain such embodiments of Formula (I), Y is Nme 2 . In certain embodiments of Formula (I), Y is NR 2 R 3 and R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring (e.g., pyrrolidine or azetidine).
  • a 4- or 5-membered heterocyclyl ring e.g., pyrrolidine or azetidine
  • the 4- or 5- membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl. In other embodiments, the 4- or 5- membered heterocyclyl ring is unsubstituted.
  • Y is hydrogen. In certain embodiments, Y is C 1-6 alkyl, such as methyl. In certain embodiments of Formula (I), Y is C 3-6 cycloalkyl, such as cyclopropyl. In certain embodiments of Formula (I), R 7 and R 8 are both hydrogen.
  • R 7 is hydrogen and and R 8 is C 1-6 alkyl, or C 1-6 haloalkyl, such as methyl or trifluoromethyl. In certain embodiments of Formula (I), R 7 and R 8 are both C 1- 6 alkyl, such as methyl.
  • R 9 is hydrogen. In certain embodiments of Formula (I), R 9 is halogen, such as F.
  • R 1 is hydrogen. In certain embodiments of Formula (I), R 1 and R 9 taken together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl ring, such as oxetane or tetrahydrofuran.
  • R 1 and R 9 taken together with the atoms to which they are attached form oxetan-3-yl. In certain embodiments of Formula (I), R 1 and R 9 taken together with the atoms to which they are attached form a 6-membered heterocyclyl ring, such as oxetane or tetrahydropyran. In certain embodiments, m is 0. In certain such embodiments, R 9 and R 8 taken together with the atoms to which they are attached form a cyclopropyl ring system. In certain embodiments, m is 1 and R 8 and R 9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system.
  • R 7 and R 8 are both hydrogen and R 1 and R 9 taken together with the atoms to which they are attached form oxetan-3-yl.
  • R 1 , R 7 , R 8 , and R 9 are each hydrogen.
  • R 10 and R 11 are both hydrogen.
  • n is 0 and A is optionally substituted heterocyclyl.
  • R 13 is C 1-6 alkyl, such as methyl.
  • X is S.
  • X is S, and n is 0.
  • X is S, and n is 1. In certain embodiments of Formula (I), X is S, and n is 2. In certain emodiments of Formula (I), X is O. In certain embodiments of Formula (I), X is O, and n is 1. In certain emodiments of Formula (I), X is a bond. In certain embodiments of Formula (I), X is a bond, and n is 0. In certain embodiments of Formula (I), X is a bond, and n is 2. In certain emodiments of Formula (I), X is NR 4 , wherein R 4 is hydrogen or C 1-6 alkyl (e.g., methyl).
  • X is NR 4 , wherein R 4 is hydrogen or C 1-6 alkyl (e.g., methyl), and n is 1. In certain embodiments of Formula (I), n is 1 or 2. In certain embodiments of Formula (I), R 1 is haloalkyl (e.g., difluoromethyl). In certain embodiments, R 1 is hydrogen. In certain embodiments of Formula (I), R 1 is C 1-6 alkyl (e.g., methyl or ethyl).
  • X is S, n is 1, R 10 and R 11 are both hydrogen, and A is optionally substituted heterocyclyl, such as oxetane (e.g., oxetan-3-yl), tetrahydrofuran (e.g., tetrahydrofuran-3-yl) or tetrahydropyran.
  • X is S, n is 1, R 10 and R 11 are both hydrogen, and A is optionally substituted oxetane, such as oxetan-3-yl.
  • X is S, n is 1, R 10 and R 11 are both hydrogen, and A is optionally substituted tetrahydrofuran, such as tetrahydrofuran-3-yl.
  • Y is NR 2 R 3 , R 2 and R 3 each independently is selected from hydrogen and C 1-6 alkyl (e.g., methyl)
  • X is S, n is 1, R 10 and R 11 are both hydrogen, and A is optionally substituted heterocyclyl, such as oxetane (e.g., oxetan-3-yl), tetrahydrofuran (e.g., tetrahydrofuran-3-yl) or tetrahydropyran.
  • Y is NH 2 . In certain such embodiments, Y is NHMe. In certain such embodiments of Formula (I), Y is Nme 2 . In certain embodiments of the foregoing, R 1 and R 9 taken together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl ring, such as oxetane or tetrahydrofuran. In certain embodiments, a compound of Formula (I) is of the following formula: , wherein A, R 1 , R 2 and R 3 are as defined herein for formula (I). In certain such embodiments, R 1 is hydrogen or methyl. In certain such embodiments, R 1 is methyl.
  • R 2 is hydrogen, C 1-3 alkyl or cyclopropyl
  • R 3 is hydrogen or C 1-3 alkyl.
  • R 2 is hydrogen, methyl, ethyl, or cyclopropyl
  • R 3 is hydrogen or methyl.
  • R 2 is hydrogen, methyl, ethyl, or cyclopropyl
  • R 3 is hydrogen.
  • A is unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted oxetanyl or unsubstituted tetrahydrofuranyl. In certain such embodiments, A is unsubstituted pyridyl, unsubstituted pyridazinyl, or unsubstituted oxetanyl.
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen, methyl, ethyl, or cyclopropyl
  • R 3 is hydrogen or methyl
  • A is unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted oxetanyl or unsubstituted tetrahydrofuranyl.
  • the compound has the absolute stereochemistry:
  • the compound is any one of compounds 387-406 or 415-418.
  • the present application provides a compound selected from any one of the following, and pharmaceutically acceptable salts thereof:
  • the present application further provides a compound selected from any one of the following, and pharmaceutically acceptable salts thereof:
  • the present application further provides a compound selected from any one of the following, and pharmaceutically acceptable salts thereof: O D O O N D D 3 D 3 O F .
  • the present application provides a compound selected from any one of 340-342 and 344-458, and pharmaceutically acceptable salts thereof:
  • alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, or oxime are substituted, they are substituted, valency permitting, with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluo
  • optically active or racemic forms Compounds of the present application containing one or multiple asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by synthesis using optically active reagents.
  • compounds of the application may be racemic.
  • a compound e.g., a compound of formula (I), or a pharmaceutically acceptable salts thereof
  • the application further contemplates the compound in its racemic form.
  • compounds of the application may be enriched in one enantiomer.
  • a compound of the application may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee.
  • the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), or a pharmaceutically acceptable salt thereof).
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. For example, a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
  • the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula (I), or a pharmaceutically acceptable salt thereof).
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • a variety of compounds in the present application may exist in particular geometric or stereoisomeric forms.
  • the present application takes into account all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this application. All tautomeric forms are encompassed in the present application. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this application, unless the stereochemistry or isomeric form is specifically indicated.
  • the present application further includes all pharmaceutically acceptable isotopically labelled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof).
  • an “isotopically” or “radio-labelled” compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a C 1-6 alkyl or a C 1-6 alkoxy are replaced with deuterium, such as d 3 -methoxy or 1,1,2,2-d 4 -3-methylbutyl).
  • isotopically labelled compounds e.g., of formula (I), or pharmaceutically acceptable salts thereof
  • the radioactive isotopes tritium, i.e. 3 H, and carbon 14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically labelled compounds e.g., of formula (I), or pharmaceutically acceptable salts thereof
  • PET Positron Emission Topography
  • Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl , 82 B r, 75 Br, 76 B r, 77 Br, 123 I, 124 I, 125 I, and 131 I.
  • the present application provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (e.g., a compound of the application, such as a compound of formula (I), or pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient.
  • Compounds of any of the above structures may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein. Uses of the compounds Compounds of the present application may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
  • the quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day.
  • dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. This, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the application.
  • the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament, e.g., for treatment of any of the disorders disclosed herein.
  • the compound is not compound 343.
  • the application relates to the use of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject.
  • the compound is not compound 343.
  • the application relates to the use of compound 360, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject.
  • the one or more symptoms associated with Rett syndrome is selected from sleep disturbances, including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming; sleep apnea; seizures, including those accompanied by an abnormal electroencephalogram (EEG); breathing disorders, including breath-holding, abnormally rapid breathing (hyperventilation), forceful exhalation of air or saliva, and swallowing air; irregular heartbeat, including problems with heart rhythm such as abnormally long pauses between heartbeats (e.g., as measured by an electrocardiogram), and other types of arrhythmia; intellectual disabilities; and autism.
  • sleep disturbances including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming
  • sleep apnea seizures, including those accompanied
  • the application relates to a method of treating or preventing Rett syndrome and/or one or more symptoms associated with Rett syndrome in a mammal, such as a human being, comprising administering to said patient a therapeutically effective amount of compound 360, or a pharmaceutically acceptable salt thereof.
  • the application relates to a method of treating or preventing Rett syndrome and/or one or more symptoms associated with Rett syndrome in a mammal, such as a human being, comprising administering to said patient a therapeutically effective amount of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the one or more symptoms associated with Rett syndrome is selected from sleep disturbances, including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming; sleep apnea; seizures, including those accompanied by an abnormal electroencephalogram (EEG); breathing disorders, including breath-holding, abnormally rapid breathing (hyperventilation), forceful exhalation of air or saliva, and swallowing air; irregular heartbeat, including problems with heart rhythm such as abnormally long pauses between heartbeats (e.g., as measured by an electrocardiogram), and other types of arrhythmia; intellectual disabilities; and autism.
  • the application relates to a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), for use as a medicament for the treatment of chronic heart failure, HFpEF, HFrEF, or HFmrEF.
  • the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146- 147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of chronic heart failure, HFpEF, HFrEF, or HFmrEF.
  • the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76- 79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212- 230, 232-359, 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of chronic heart failure, HFpEF, HFrEF, or HFmrEF.
  • the compound is not compound 343.
  • the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of chronic heart failure, HFpEF, HfrEF, or HfmrEF.
  • the compound is not compound 343.
  • the application relates to compound 360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of chronic heart failure, HfpEF, HfrEF, or HfmrEF.
  • the application relates to a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome.
  • the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.
  • the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146- 147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome.
  • the application relates to any one of compounds 1-10, 12-18, 20-25, 27- 37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome.
  • the compound is not compound 343.
  • the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome.
  • the compound is not compound 343.
  • the application relates to compound 360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome.
  • the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.
  • the application relates to a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), for use as a medicament for the treatment of CDKL5 deficiency disorder (CDD) and/or one or more symptoms associated with CDD.
  • CDD CDKL5 deficiency disorder
  • the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.
  • the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CDD and/or one or more symptoms associated with CDD.
  • the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174- 178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CDD and/or one or more symptoms associated with CDD.
  • the compound is not compound 343.
  • the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CDD and/or one or more symptoms associated with CDD.
  • the compound is not compound 343.
  • the application relates to compound 360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CDD and/or one or more symptoms associated with CDD.
  • the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.
  • the application relates to a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), for use as a medicament for the treatment of CHD8-related neurodevelopmental disorder (CHD8-NDD) and/or one or more symptoms associated with CHD8-NDD.
  • the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.
  • DD/ID developmental delay/intellectual disability
  • ASD autism spectrum disorder
  • neuropsychiatric issues neurologic problems
  • gastrointestinal and sleep dysfunctions are selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.
  • the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112- 117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD.
  • the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146- 147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD.
  • the compound is not compound 343.
  • the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD.
  • the compound is not compound 343.
  • the application relates to compound 360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CHD8- NDD and/or one or more symptoms associated with CHD8-NDD.
  • the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.
  • the application relates to a method of treating or preventing FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I).
  • the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.
  • the application relates to a method of treating or preventing of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of compound 360, or a pharmaceutically acceptable salt thereof.
  • the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.
  • the application relates to a method of treating or preventing CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I).
  • the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.
  • the application relates to a method of treating or preventing of CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1- 10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of compound 360, or a pharmaceutically acceptable salt thereof.
  • the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.
  • repetitive hand movements such as clapping, hand licking, and hand sucking
  • teeth grinding bruxism
  • disrupted sleep such as feeding difficulties
  • gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.
  • the application relates to a method of treating or preventing CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I).
  • the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.
  • the application relates to a method of treating or preventing of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61- 70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206- 208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 340-359 or 363- 458, or a pharmaceutically acceptable salt thereof.
  • the compound is not compound 343.
  • the application relates to a method of treating or preventing of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of compound 360, or a pharmaceutically acceptable salt thereof.
  • the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.
  • any one of compounds 340-360, or a pharmaceutically acceptable salt thereof, as disclosed herein is a brain penetrant.
  • any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, as disclosed herein is a brain penetrant. In certain embodiments, any one of compounds 340- 360, or a pharmaceutically acceptable salt thereof, as disclosed herein is capable of crossing the blood brain barrier. In certain embodiments, any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, as disclosed herein is capable of crossing the blood brain barrier. In certain embodiments, the compound is not compound 343.
  • the compound is useful in methods of treating or preventing Rett syndrome and/or one or more symptoms associated with Rett syndrome (e.g., sleep disturbances, including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming; sleep apnea; seizures, including those accompanied by an abnormal electroencephalogram (EEG); breathing disorders, including breath-holding, abnormally rapid breathing (hyperventilation), forceful exhalation of air or saliva, and swallowing air; irregular heartbeat, including problems with heart rhythm such as abnormally long pauses between heartbeats (e.g., as measured by an electrocardiogram), and other types of arrhythmia; intellectual disabilities; and autism), FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying), FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irrit
  • a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), as disclosed herein is not brain penetrant.
  • a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), as disclosed herein is not capable of crossing the blood brain barrier (i.e., is peripherally restricted).
  • the compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I) is useful in methods of treating or preventing chronic heart failure.
  • a pharmaceutically acceptable salt thereof e.g., any one of compounds 340-458, or a pharmaceutically acceptable salt thereof
  • the compound is not compound 343.
  • the compound is not compound 343.
  • the compound is selected from any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138- 141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, and 212- 230, and pharmaceutically acceptable salts thereof.
  • the compound is selected from any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112- 117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, and 232-339, and pharmaceutically acceptable salts thereof.
  • the compound is selected from any one of compounds 340-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is not compound 343. In certain embodiments of the methods a disclosed herein, the compound is selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, in association with at least one pharmaceutically acceptable excipient, carrier or diluent.
  • the pharmaceutical composition is for treating a disease or disorder in a patient in need thereof, such as a disease or disorder as disclosed herein.
  • the application relates to a pharmaceutical composition comprising (1) any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, (2) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (3) pharmaceutically acceptable excipients, carriers or diluents.
  • different compounds of the application may be (e.g., conjointly) administered with one or more other compounds of the application.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof such as any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458 (e.g., any one of compounds 340-458), or a pharmaceutically acceptable salt thereof, or certain combinations thereof, may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein.
  • the compound is not compound 343.
  • compounds of formula (I), or a pharmaceutically acceptable salt thereof such as any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, ISO- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 (e.g., any one of compounds 340-359 or 363-458), or a pharmaceutically acceptable salt thereof, or certain combinations thereof, may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein.
  • the compound is not compound 343.
  • compounds of the application may be used alone or conjointly administered with another type of therapeutic agent.
  • the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds).
  • the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either simultaneously, sequentially, or by separate dosing of the individual components of the treatment.
  • the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
  • conjoint administration of compounds of the application with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the application (e.g., compound of formula (I), or a pharmaceutically acceptable salt of the compound of formula (I), such as any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, ISO- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458 (e.g., any one of compounds 340-458), or a pharmaceutically acceptable salt thereof) or the one or more additional therapeutic agent(s).
  • the compound is not
  • Such conventional therapeutics may include one or more of the following categories of agents: anticonvulsants including, for example, carbamazepine, clonazepam, ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrogine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabaline, rufmamide, topiramate, valproate, vigabatrine, zonisamide and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; insomnia therapies including, for example, agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzin
  • Rett syndrome therapies including, for example, trofinetide; agents that lower blood pressure by widening blood vessels, such as angiotensinconverting enzyme (ACE) inhibitors (including, for example, captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), trandolapril (Mavik), benazepril, and moexipril) and angiotensin receptor blockers (ARBs) (including, for example, candesartan (Atacand), losartan (Cozaar), and valsartan (Diovan)); agents that improve artery opening and blood flow, reduce sodium retention and decreases strain on the heart, such as angiotensin-receptor neprilysin inhibitors (ARNIs
  • the present application provides conjoint administration of compounds of the application with trofinetide, providing improved efficacy relative to each individual administration of the compound of the application (e.g., compound of formula (I), or a pharmaceutically acceptable salt of the compound of formula (I)) or the trofinetide.
  • the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the application and the trofinetide.
  • Such combination products employ the compounds of this application within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive.
  • alkenyl groups substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined.
  • straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl.
  • a C 1 -C 6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a halogen
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CF 3 , -CN, and the like.
  • C x-y when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • C x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc.
  • C 0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • C 2-y alkenyl and “C 2-y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group.
  • substituents may occur on one or more carbons that are included or not included in one or more triple bonds.
  • substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • amide refers to a group wherein each R 30 independently represent a hydrogen or hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each R 30 independently represents a hydrogen or a hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • the term “carbamate” is art-recognized and refers to a group wherein R 29 and R 30 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R 29 and R 30 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • the term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- 1H-indene and bicyclo[4.1.0]hept-3-ene.
  • Carbocycles may be susbstituted at any one or more positions capable of bearing a hydrogen atom.
  • a “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
  • Cycloalkyl includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • a “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO 2 -R 30 , wherein R 30 represents a hydrocarbyl group.
  • carboxy refers to a group represented by the formula - CO 2 H.
  • esteer refers to a group -C(O)OR 30 wherein R 30 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group.
  • an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-.
  • Ethers may be either symmetrical or unsymmetrical.
  • Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle.
  • Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • heteroaryl and heteroaryl include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sil refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • sulfonamide is art-recognized and refers to the group represented by the general formulae wherein R 29 and R 30 independently represents hydrogen or hydrocarbyl, such as alkyl, or R 29 and R 30 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • sulfoxide is art-recognized and refers to the group -S(O)-R 30 , wherein R 30 represents a hydrocarbyl.
  • sulfonate is art-recognized and refers to the group SO 3 H, or a pharmaceutically acceptable salt thereof.
  • sulfone is art-recognized and refers to the group -S(O) 2 -R 30 , wherein R 30 represents a hydrocarbyl.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 30 or -SC(O)R 30 wherein R 30 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with asulfur.
  • urea is art-recognized and may be represented by the general formula wherein R 29 and R 30 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R 29 taken together with R 30 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis.
  • nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxylprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • Healthcare providers refers to individuals or organizations that provide healthcare services to a person, community, etc.
  • Examples of “healthcare providers” include doctors, hospitals, continuing care retirement communities, skilled nursing facilities, subacute care facilities, clinics, multispecialty clinics, freestanding ambulatory centers, home health agencies, and HMO's.
  • the present application includes prodrugs of the compounds formula (I) (such as any one of compounds 340-355), or pharmaceutically acceptable salts thereof.
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present application (e.g., a compound of formula (I) (such as any one of compounds 340-355), or pharmaceutically acceptable salts thereof).
  • a common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to yield the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • a prodrug with a nitro group on an aromatic ring could be reduced by reductase to generate the desired amino group of the corresponding active compound in vivo.
  • functional groups such as a hydroxyl, carbonate, or carboxylic acid in the parent compound are presented as an ester, which could be cleaved by esterases.
  • amine groups in the parent compounds are presented in, but not limited to, carbamate, N-alkylated or N-acylated forms (Simplicio et al, “Prodrugs for Amines,” Molecules, (2008), 13:519-547).
  • some or all of the compounds of formula (I), or pharmaceutically acceptable salts thereof, in a formulation represented above can be replaced with the corresponding suitable prodrug.
  • the present application includes metabolites of the compounds of formula (I) (such as any one of compounds 340-355), or pharmaceutically acceptable salts thereof.
  • the term “metabolite” is intended to encompass compounds that are produced by metabolism/biochemical modification of the parent compound under physiological conditions, e.g. through certain enzymatic pathway.
  • an oxidative metabolite is formed by oxidation of the parent compound during metabolism, such as the oxidation of a pyridine ring to pyridine-N-oxide.
  • an oxidative metabolite is formed by demethylation of a methoxy group to result in a hydroxyl group.
  • compositions and methods of the present application may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the application and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the application.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the application.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop).
  • routes of administration including, for example, orally (for example, drenches as in aqueous or
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the application, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present application with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the application suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the present application as an active ingredient.
  • capsules including sprinkle capsules and gelatin capsules
  • cachets pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth)
  • lyophile powders,
  • compositions or compounds may also be administered as a bolus, electuary or paste.
  • solid dosage forms for oral administration capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like)
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6)
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.
  • compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present application to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this application. Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S.
  • liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids.
  • a preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the application.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the application will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans.
  • compositions and methods of the present application includes the use of pharmaceutically acceptable salts of compounds of the application in the compositions and methods of the present application.
  • pharmaceutically acceptable salts includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, trifluoroacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzensulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, camphorsulfonic and the like.
  • the pharmaceutically acceptable salt is a hydrochloride salt. In certain embodiments, the pharmaceutically acceptable salt is a camsylate salt. In certain embodiments, contemplated salts of the compounds include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of compounds include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of compounds include, but are not limited to, Li, Na, Ca, K, Mg, Zn or other metal salts. Also included are the salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the compounds of the application can also exist as various solvates, such as with water (also known as hydrates), methanol, ethanol, dimethylformamide, diethyl ether, acetamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • the compounds of the application can also exist as various polymorphs, pseudo-polymorphs, or in amorphous state.
  • polymorph refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of the same compound.
  • pseudo-polymorphs such as hydrates, solvates, or salts of the same compound.
  • Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as x-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents.
  • crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • the application comprises a method for conducting a pharmaceutical business, by determining an appropriate formulation and dosage of a compound of the application for treating or preventing any of the diseases or conditions as described herein, conducting therapeutic profiling of identified formulations for efficacy and toxicity in animals, and providing a distribution network for selling an identified preparation as having an acceptable therapeutic profile.
  • the method further includes providing a sales group for marketing the preparation to healthcare providers.
  • the application relates to a method for conducting a pharmaceutical business by determining an appropriate formulation and dosage of a compound of the application for treating or preventing any of the disease or conditions as described herein, and licensing, to a third party, the rights for further development and sale of the formulation.
  • the following abbreviations have been used: BOC tert-butoxycarbonyl DEAD diethyl azodicarboxylate DCCI 1,3-dicyclohexyl carbodiimide DCM Dichloromethane DMA N,N-dimethylacetamide DMAP 4-dimethyl-aminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDCl 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide EEDQ 2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline EtOAc Ethyl acetate HOBT hydroxybenzotriazole MeCN aceton
  • the 2-mercaptopyridine can be reacted with an alkylating agent containing a leaving group commonly used in the art such as chloride, bromide, or mesylate in the presence of base in a solvent such as DMF to give a compound of Formula I where A is cyano, hydroxyl, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, -C(O)NR 5 R 6 , -NR 5 R 6 , - NR 5 C(O)C 1-6 alkyl, optionally substituted heterocycloalkyl, aryl, or optionally substituted heteroaryl.
  • a compound of Formula I where R 2 and R 3 are H can be further modified to give a compound of Formula I where R 2 and R 3 each independently can be C 1-6 alkyl or R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocycloalkyl ring by conversion of the amine to a chloride or bromide using a t-butyl nitrite and a copper salt in a solvent such as acetonitrile.
  • the resulting 2-halopyridine can be treated with an amine such as pyrrolidine or azetidine in a solvent such as methanol or dichloromethane to give a compound of Formula I where R 2 and R 3 are each independently C 1-6 alkyl or R 2 and R 3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocycloalkyl ring.
  • Step 3 was altered by reacting the thiolpyridine with iodopyridine in DMSO in the presence of CuI (1 eq), (2S)-pyrrolidine-2-carboxylic acid (0.4 eq) and t-BuONa (2 eq).
  • b The enantiomers were separated by SFC (Instrument: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IG (250mm ⁇ 30mm, 10um); mobile phase: [CO 2 - IPA(0.1% NH 3 H 2 O)];B%:35%, isocratic elution mode). Absolute configuration assignments require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate. Protocol 2.
  • Step 5 (R)-2-amino-4-(4-(2-(methoxy-d 3 )propoxy)phenyl)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile (405).
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Phenomenex C1875 mm ⁇ 30mm ⁇ 3 ⁇ m; mobile phase A: 10 mM NH 4 HCO 3 in water, mobile phase B: ACN; 30%-60% over 8 min, to give 2-amino-6-(1H- indol-4-ylmethylsulfanyl)-4-[4-(oxetan-3-yloxy)phenyl]pyridine-3,5-dicarbonitrile (10.1 mg, 22.27 ⁇ mol, 24.66% yield, 100% purity) as a white solid.
  • tert-butyl nitrite (1.19 g, 10.17 mmol, 1.37 mL, 5 eq)
  • CuCl 2 164.14 mg, 1.22 mmol, 0.6 eq
  • a mixture of 4-[4-(2-hydroxyethoxy)phenyl]-2-[(4-methoxyphenyl)methylthio]pyridine-3,5- dicarbonitrile (200 mg, 479.07 ⁇ mol, 1 eq) in TFA (3 mL) was stirred at 75 °C for 2 h.
  • the reaction mixture was concentrated under reduced pressure to give 4-[4-(2- hydroxyethoxy)phenyl]-2-thiopyridine-3,5-dicarbonitrile (100 mg, 336.33 ⁇ mol, 70.20% yield) as a brown oil.
  • Step 1 (2Z)-2-[[4-(2-Methoxyethoxy)phenyl]methylene]-3-oxo-butanenitrile (39B).
  • 4-(2-methoxyethoxy)benzaldehyde (1 g, 5.55 mmol, 1 eq) in EtOH (10 mL) was added L-proline (638.90 mg, 5.55 mmol, 1 eq) and 3-oxobutanenitrile (461.09 mg, 5.55 mmol, 1 eq).
  • L-proline 638.90 mg, 5.55 mmol, 1 eq
  • 3-oxobutanenitrile (461.09 mg, 5.55 mmol, 1 eq).
  • the mixture was stirred at 20 °C for 2 h.
  • Step 1 Ethyl 2-(4-bromophenoxy)-2,2-difluoroacetate (311-B).
  • 4-bro mophenol 10 g, 57.80 mmol, 1 eq
  • ethyl 2-bromo-2,2-difluoroacetate 15.25 g, 75.14 m mol, 9.65 mL, 1.3 eq
  • DMF 100 mL
  • DBU 11.44 g, 75.14 mmol, 11.33 mL, 1. 3 eq
  • Step 4 2-Amino-4-[4-(1,1-difluoro-2-hydroxy-ethoxy)phenyl]-6-sulfanyl-pyridine-3,5 -dicarbonitrile (311-E).
  • 4-(1,1-difluoro-2-hydroxy-ethoxy)benzaldehyde 27 0 mg, 1.34 mmol, 1 eq
  • 2-cyanothioacetamide 294.25 mg, 2.94 mmol, 2.2 eq
  • EtOH 5 mL
  • NMM NMM (405.28 mg, 4.01 mmol, 440.52 uL, 3 eq
  • Step 5 2-Amino-4-[4-(1,1-difluoro-2-hydroxy-ethoxy)phenyl]-6-(oxetan-3- ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (311).
  • Step 1 3-(Benzyloxy)cyclobutan-1-ol (295-B).
  • MeOH MeOH
  • NaBH 4 (1.29 g, 34.05 m mol, 1.2 eq)
  • Step 2 3-(Benzyloxy)cyclobutyl methanesulfonate (295-C).
  • TEA TEA
  • methanesulfonyl chloride 3.37 g, 29.46 mmol, 1.5 eq
  • Step 7 2-Amino-4-(4-((1r,3r)-3-hydroxycyclobutoxy)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (295) and 2-Amino-4-(4-((1s,3s)-3- hydroxycyclobutoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (296).
  • Step 1 2-Amino-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3, 5-dicarbonitrile (294-A).
  • 2-amino-6-mercapto-4-(4-(oxetan-3-yloxy)phenyl) pyridine-3,5-dicarbonitrile 1.0 g, 3.08 mmol, 1.0 eq
  • 3-(bromomethyl)oxetane 465.54 mg, 3.08 mmol, 1.0 eq)
  • DMF 5.0 mL
  • K2CO 3 852.19 mg, 6.17 mmol, 2.0 eq
  • Step 3 2-Amino-4-(4-(oxetan-3-yloxy)phenyl)-6-((tetrahydro-2H-pyran-3- yl)methoxy)pyridine-3,5-dicarbonitrile (300).
  • Step 1 2-Amino-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-di carbonitrile (312).
  • 2-amino-6-(benzylsulfinyl)-4-(4-(oxetan-3-yloxy)phenyl) pyridine-3,5-dicarbonitrile 600.0 mg, 1.39 mmol, 1.0 eq
  • DMF 5.0 mL
  • NaH 278.73 mg, 6.97 mmol, 5.0 eq
  • Step 2 2-Chloro-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-di carbonitrile (287-A).
  • 2-amino-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy) phenyl)pyridine-3,5-dicarbonitrile 200 mg, 528.57 umol, 1 eq
  • MeCN ed t-BuONO
  • ed t-BuONO 81.76 mg, 792.85 umol, 94.30 ul, 1.5 eq
  • CuCl 156.98 mg, 1.59 mmol, 3.
  • Step 3 2-(Azetidin-1-yl)-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridin e-3,5-dicarbonitrile (287).
  • the resi due was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 (150 ⁇ 40 m m, 10 um); flow rate: 25 mL/min; gradient: 25% – 65% B over 8 min; mobile phase A: 10 m M aqueous NH 4 HCO 3 , mobile phase B: acetonitrile) to give 2-(azetidin-1-yl)-6-(oxetan-3-yl methoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-dicarbonitrile (26.3 mg, 61.37 umol, 61. 04% yield, 97.6% purity) as white solid.
  • Step 4 2-Amino-4-(4-(2-(difluoromethoxy)-1,1-difluoroethoxy)phenyl)-6-((oxetan-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (289).
  • Step 5 (R)-2-amino-4-(4-(2-(methoxy-d 3 )propoxy)phenyl)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile (405).
  • Example 2 Biological activity
  • Membranes membrane extracts prepared from CHO-K1 cells expressing recombinant human Adenosine A1 receptor, thawed on ice, diluted in assay buffer and kept on ice.
  • GDP diluted in assay buffer at the optimized concentration for the specific receptor Beads: PVT-WGA (Perkin Elmer, RPNQ001), diluted in assay buffer at 50 mg/mL (0.5mg/10 ⁇ L)
  • GTP ⁇ 35 S (Perkin Elmer, NEG030X), diluted in assay buffer for a final 0.1 nM assay concentration
  • Protocol for agonist testing membranes are mixed with GDP (volume:volume). In parallel, GTP ⁇ [ 35 S] is mixed with the beads (volume:volume) just before starting the reaction.
  • cAMP HTRF assays RT room temperature
  • cAMP HTRF assay for Gs coupled receptor HEK293 cells expressing recombinant receptor grown prior to the test in media without antibiotic are detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCl, 1.25 mM MgSO 4 , 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH 2 PO 4 , 1.45 mM CaCl 2 , 0.5 g/L BSA, supplemented with 1 mM IBMX or 25 ⁇ M rolipram).
  • Dose response curves are performed in parallel with the reference compounds.
  • For agonist test (96 well): 12 ⁇ L of cells are mixed with 12 ⁇ L of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates are incubated 1 hour incubation at room temperature, and fluorescence ratios are measured according to the manufacturer specification, with the HTRF kit. Results are provided in Table 16 below. Table16: Adenosine Agonist Activity
  • Example 2.2. BCRP permeability assay Material and Methods Biological materials MDCK cell lines transfected with the BCRP gene were grown in 75 cm 2 tissue culture flasks and split (passed) two times per week to maintain desired confluence. MDCK assay plates were seeded 4 days prior to running the assay. The 24-well plates were seeded at a cell density of 0.88 ⁇ 105/well in a 400 pL apical chamber volume (2.2 ⁇ 105/mL) with 25 mL of growth medium added to the 24-well basal chamber. The plates contain an apical side (A or donor chamber) and a basolateral side (B or receiver chamber).
  • a or donor chamber apical side
  • B or receiver chamber basolateral side
  • Movement or permeability of compound is measured in both directions (A to B and B to A) for 90 minutes at 37 °C. Dosing solutions were prepared as shown in Table 17. Teriflunomide, Metoprolol and Atenolol were included as reference standards.
  • Table 17 Summary of donor solution and compound preparation Dosing solutions were added to the plate as outlined in Table 18. Table 18. Outline of how dosing solutions were added to the plate The plates were warmed to 37 °C and the transport was initiated by placing the apical plate onto the basolateral plate. The plates were incubated for 90 minutes and then separated and the concentration of compounds in the donor and receiver compartments for both A to B and B to A plates were measured by LC-MS/MS. The measurements were performed in duplicate. Lucifer yellow (LY) was included to confirm the cell monolayers had tight junctions based on TEER values.
  • LY Lucifer yellow
  • VA is the volume in the acceptor well, the Area is the surface area of the membrane and the Time is the total transport time in seconds
  • [drug] donor, 0-min and [RFU] donor, 0-min are the donor drug concentration or Lucifer Yellow count measured at 0-min
  • [drug] acceptor, 90-min and [RFU] acceptor, 90-min are the acceptor drug concentration or Lucifer Yellow count measured at 90-min
  • the Dilution Factor is the fold of dilution of the donor sample before loaded to LC- MS/MS.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present application relates to compounds of formula (I), and their pharmaceutical compositions/preparations. This application further relates to methods of treating Rett syndrome and/or one or more symptoms associated with Rett syndrome, FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome, CDKL5 deficiency disorder (CDD) and/or one or more symptoms associated with CDD, or CHD8-related neurodevelopmental disorder (CHD8-NDD) and/or one or more symptoms associated with CHD8-NDD, chronic heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or heart failure with mid-range ejection fraction (HFmrEF).

Description

ADENOSINE LIGANDS FOR THE TREATMENT OF
NEUROLOGICAL DISORDERS OR CHRONIC HEART FAILURE
CROSS REFEFRENCE TO RELATED APPLICATIONS
The benefit of priority is claimed to the United States Provisional Application Number 63/532,736, filed 15 August 2023 (15.8.2023), the entire contents of which are included herein and incorporated herein by reference in accordance with PCT Rule 20.6.
BACKGROUND
Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl -CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator. The MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which is needed for brain development and acts as one of the many biochemical switches that can regulate gene expression. Because the MECP2 gene does not function properly in individuals with Rett syndrome, insufficient amounts or structurally abnormal forms of the MeCP2 protein are produced and can cause other genes to be abnormally expressed (Rett Syndrome Fact Sheet; www.ninds.nih.gov/ Disorders/Patient- Caregiver-Education/Fact-Sheets/Rett-Syndrome-F act-Sheet). The prevalence of RTT is high (1 in 10,000 births), and it is one of the most common causes of intellectual and developmental disabilities (IDD) in females. Lifespan and disease severity vary greatly.
RTT is characterized by progressive development of motor and neurological dysfunction. Girls affected with RTT acquire speech and movement skills on a normal timeline after birth but develop symptoms between 6 months and 2 years of age. Neurological manifestations of disease include loss of speech and motor skills, stereotypic hand movements, difficulty walking, sporadic rapid respiration and apnea, and seizures. Apraxia, the inability to perform motor functions, is perhaps the most severely disabling feature of RTT, interfering with every body movement, including eye gaze and speech. Children with Rett syndrome often exhibit autistic-like behaviors in the early stages. Other symptoms may include walking on the toes, sleep problems, a wide-based gait, teeth grinding and difficulty chewing, slowed growth, seizures, cognitive disabilities, and breathing difficulties while awake such as hyperventilation, apnea (breath holding), and air swallowing (Rett Syndrome Fact Sheet; www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Rett- Syndrome-F act- Sheet) . RTT was initially thought to be an entirely neurological disorder, and RTT research focused on the role of MeCP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients also implicate important roles for MeCP2 in peripheral systems (Kyle, Vashi and Justice, Open Biol 2018, 8(2), 170216). More than 95% of RTT patients carry a mutation in the MECP2 gene. Mechanistically, MECP2 binds to methylated DNA to regulate gene transcription through repression or activation. When MECP2 represses gene transcription, it associates with chromatin-remodeling complexes that contain Type I histone deacetylases (HDACs) (Bienvenu and Chelly, Nat Rev. Genet 2006, 7, 415-426). Therefore, the elimination of MECP2 may result in the upregulation of genes that would normally be repressed. Notably, the severity of MECP2 mutation does not always correlate with disease severity, due at least in part to favorable patterns of X-chromosome inactivation in heterozygous females. Many children diagnosed with RTT have reduced brain volume compared with healthy individuals, consistent with a smaller head circumference. Reduced brain volume is largely due to small neuronal body size and a denser packing of cells, particularly in layers III and V of the cerebral cortex, thalamus, substantia nigra, basal ganglia, amygdala, cerebellum and hippocampus. Patients also have reduced dendritic arborization, indicative of a delay in neuronal maturation. Furthermore, hypopigmentation of the substantia nigra suggests a dysfunction of dopaminergic neurons. RTT patients show evidence of dysregulated neurotransmitters, neuromodulators and transporters, indicating an important role in synaptic function (Kyle, Vashi and Justice, Open Biol 2018, 8(2), 170216). Mouse models that carry Mecp2 mutations and recapitulate most of the symptoms of RTT are available. Mecp2/Y male mutant mice are normal at birth and weaning, but develop symptoms that include hypo-activity, limb clasping, tremors, motor impairment and abnormal breathing as early as 4 weeks of age. Such symptoms progressively worsen, leading to their death at 6-16 weeks. Pronounced neuronal deficits are observed in Mecp2/Y null mice, including delayed transition into mature stages, altered expression of presynaptic proteins and reduced dendritic spine density. Remarkably, re-expression of Mecp2 in mutant male and female mice after the onset of symptoms rescues neurological deficits and mice recover normal movements to live a long life (Guy et al. Science 2007, 315, 1143-1147). These findings show that RTT is not caused by a permanent abnormal development of neurons during embryogenesis; instead, MECP2 is required for the maintenance of neurons after birth. Thus, RTT may be ameliorated or even reversed by genetic or pharmacological means after the onset of symptoms, providing tremendous hope for patients and families. Unfortunately, gene therapy using MECP2 is challenging, because brain function is exquisitely sensitive to levels of MECP2: increased MECP2 causes a progressive neurological disorder that leads to death as well (Bienvenu and Chelly, Nat Rev Genet 2006, 7, 415-426).
Adenosine is a purine nucleoside comprised of an adenine group attached to a ribose sugar by a glycosidic bond. Adenosine is present in all cells and released by certain physiological and pathophysiological stimuli. Adenosine is formed intracellularly as an intermediate during the degradation of adenosine 5'-phosphate (AMP) and S- adenosylhomocysteine, but it can be released from the cell, acting as a neurotransmitter by binding to specific receptors. Thus, adenosine may act as both a precursor and a metabolite of adenine nucleotides, and by providing the structural building block of adenosine triphosphate (ATP), it plays a central role in the basic energy transfer of all living organisms (Layland, J., Carrick, D., Lee, M., Oldroyd, K., & Berry, C. JACC. Cardiovascular Interventions 2014, 7, 581-591.)
Adenosine exerts a variety of physiological effects by interacting with cell surface G- protein-coupled receptor subtypes, namely Al, A2A, A2B, and A3 adenosine receptors (ARs). Each receptor is encoded by a different gene. “Adenosine receptor selective agonists” are substances that bind selectively to one or more subtypes of the adenosine receptors, thus mimicking the action of adenosine.
The actions of these adenosine receptors are mediated intracellularly by the messenger cAMP. In the case of Al AR agonists (coupling preferably via Gi/o proteins), a decrease of the intracellular cAMP concentration is observed (preferably after direct prestimulation of adenylate cyclase by forskolin). Correspondingly, A2A and A2B AR agonists (coupling preferably via Gs proteins) leads to an increase of cAMP concentration in the cells, and A2A and A2B AR antagonists to a decrease of the cAMP concentration in the cells. As a classical neurotransmitter, adenosine is neither stored nor released and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides (Huang et al. Curr Top Med Chem 2011, 11(8), 1047-57).
Currently there is no cure for Rett Syndrome. Treatment for the disorder is symptomatic, i.e., focusing on the management of symptoms, and supportive, requiring a multidisciplinary approach. For example, medication may be used for breathing irregularities and motor difficulties, and anticonvulsant drugs may be used to control seizures. Also, occupational therapy is used to help children develop skills needed for performing self- directed activities (such as dressing, feeding, and practicing arts and crafts), while physical therapy and hydrotherapy may prolong mobility. The use of a brain penetrant A1, A2B and/or dual A1/A2B AR agonists may produce a medication for treating Rett syndrome. There is a critical need for agents and methods for treating Rett Syndrome as well as related disorders. The compounds of the present application, agonists of adenosine receptors, provide promising agents for the treatment of Rett Syndrome and its related disorders. CDLK5 deficiency disorder is a developmental disease that is generally characterized by seizures appearing during infancy, and typically leads to severe intellectual disability, impaired gross and fine motor function, cortical visual impairment (Leonard H. et al., 2022 Lancet Neurol.; doi: 10.1016/S1474-4422(22)00035-7). Speech is also generally absent in individuals with CDLK5 deficiency disorder. Other common features include stereotypies (often involving the hands), sleep disruptions, gastrointestinal problems and may include breathing irregularities. The incidence of CDLK5 deficiency disorder is approximately 1 in 40,000-60,000 with ~90% of diagnosed individuals being girls. CDLK5 deficiency disorder had previously been described as an atypical version of Rett syndrome but is now recognized as a separate disorder. Clinical management has focused primarily on seizure management however most patients are refractory or exhibit only short term responses to treatment with seizure medications. CDH8 encodes a chromodomain helicase DNA binding protein and mutations disrupting the CDH8 gene have been associated with autism spectrum disorder (ASD), leading to a specific subtype of ASD (Bernier, R. et al., 2014 Cell; doi: 10.1016/ j.cell.2014.06.017). Individuals with disruptive mutations in CDH8 commonly show macrocephaly, intellectual disabilities, sleep dysfunction and gastrointestinal problems. There is a need for therapies to address the challenges faced by patients with CDH8 mutations. FOXG1 syndrome is a developmental disorder which is characterized by structural malformations in the brain, including underdevelopment of the corpus callosum, reduced cortical gyri and white matter deficiencies (Hou, P-S. et al., 2020 Frontiers Cell Neuro.; doi.org/10.3389/fncel.2020.00035). Individuals with FOXG1 syndrome generally exhibit microcephaly and have severe intellectual disabilities, involuntary and repetitive movements, seizures, disrupted sleep, ASD and reduced speech and language. FOXG1 syndrome has been previously described as a variant of Rett syndrome, but clinicians generally consider FOXG1 syndrome as a distinct disorder. There remains a significant unmet need for therapies that could address the multiple symptoms afflicting patients with FOXG1 syndrome. Heart failure (HF) is a complex cardiovascular syndrome which can involve impaired structure or function of the left ventricle and is a leading cause of cardiovascular morbidity and mortality. The prevalence of HF is approximately 5.8-6.5 million patients in the U.S. and 26 million globally (Hajouli and Ludhwani, 2023 StatPearls Publishing, PMID: 31971755). Heart failure involving left ventricular dysfunction is segregated into three subtypes based on left ventricular ejection fraction (EF): heart failure with reduced ejection fraction (HFrEF) with EF less than or equal to 40%; heart failure with preserved ejection fraction (HFpEF) with EF greater than or equal to 50%; and heart failure with mid-range ejection fraction (HFmrEF) between 41 to 49%. Symptoms of HFpEF, HFmrEF and HFrEF are similar and increase with physical exertion. These symptoms can include fatigue, weakness, fluid accumulation, wheezing, loss of appetite and palpitations, and can progress to tachycardia and peripheral edema. Recommended treatment approaches for HFrEF include nonpharmacologic therapies such as lifestyle, diet, exercise, weight management and smoking cessation, as well as a range of pharmacologic therapeutic approaches. These pharmacologic therapeutic treatments include Class IA angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, Class IB beta blockers, mineralocorticoid receptor antagonists, nitrates with hydralazine, digoxin, aspirin with statin, ivabradine, sodium-glucose cotransporter 2 inhibitors, and dobutamine or milrinone. Disease-modifying therapies for HFpEF or HFmrEF have not been identified and therapies that have been effective for HFrEF have not shown similar benefits for HFpEF or HFmrEF. SUMMARY The present application provides a method of treating FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome, CDKL5 deficiency disorder (CDD) and/or one or more symptoms associated with CDD, or CHD8-related neurodevelopmental disorder (CHD8-NDD) and/or one or more symptoms associated with CHD8-NDD, chronic heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or heart failure with mid-range ejection fraction (HFmrEF) comprising administering a therapeutic amount of a compound of formula (I)
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, OR13, and NR2R3; R2 and R3 each independently is selected from hydrogen and C1-6alkyl; or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R1 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R7 and R8 each independently is selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; R9 is hydrogen or halogen, or R1 and R9 taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, or R9 and R8 taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 or a cyclobutyl or cyclopentyl ring system when m is 1; R10 and R11 each independently is selected from hydrogen, hydroxyl, halogen, C1-6alkyl, and C1-6 haloalkyl; R12 is hydrogen or halogen; X is selected from a bond, S, O, and NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl); R13 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5 and R6 each independently is selected from hydrogen and C1-6alkyl; m is 0 or 1, provided that when m is 1, R8 and R9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system; and n is 0, 1 or 2; provided that when Y is NH2, X is S, n is 1, R1 is hydrogen or methyl, and each of R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NH2, X is S, n is 1, R8 is methyl or CF3, and each of R1, R7 and R9 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 and R3 are both C1-6alkyl (e.g., ethyl), X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NH2, X is S, n is 1, R1 is methyl, and each of R7, R8, R9, R10, and R11 is hydrogen, then A is not 2-pyridinyl or 3- pyridinyl; when Y is NH2, X is S, n is 1, R7 is methyl, R8 is methyl, and each of R1 and R9 is hydrogen, then A is not substituted 4-pyridyl; when Y is NH2, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 3-pyridyl; when Y is hydrogen or NR2R3, R2 is hydrogen, R3 is hydrogen or C1-6alkyl, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 4-pyridyl; when Y is NH2 or pyrrolidine, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl; when Y is NH2, X is S, n is 1, R1 is hydrogen or methyl, each of R7, R8, R9, and R11 is hydrogen, and R10 is methyl, then A is not substituted phenyl; when Y is H or NH2, X is S, n is 0, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted aryl (e.g., aryl, such as phenyl); when Y is NH2, X is S or O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted phenyl, or substituted 4-pyridyl; when Y is OR13, R13 is methyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl, substituted oxazole, imidazole, or 2-pyridyl; when Y is OR13, R13 is ethyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted oxazole; when Y is OR13, R13 is methyl, ethyl, or sec-butyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted thiazole; when Y is NH2, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted oxazole, substituted phenyl, substituted 4-pyridyl, substituted thiophene, or substituted thiazole; when Y is NH2, X is S, n is 2, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not hydroxyl; when Y is NH2, X is S, n is 1, and each of R1, R7, R8, R9 , R10, R11, and R12 is hydrogen, then A is not substituted thiazolidine, substituted pyrazole, substituted imidazole, or substituted triazole; when Y is NR2R3, R2 is hydrogen, R3 is CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 is hydrogen, R3 is CH3 or CH2CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not phenyl; when Y is NH2, X is S, n is 1, R7 and R8 are both CH3, and each of R1, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring optionally substituted with hydroxyl, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is S, n is 1, R8 is CH3 or CF3, and each of R1, R7, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NR2R3, R2 is hydrogen or CH3, R3 is CH2CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is S, n is 0, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, and R12 is hydrogen, then A is not phenyl; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 5-membered heterocyclyl ring optionally substituted with hydroxyl, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, and each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted phenyl; when Y is NH2, X is O, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted phenyl; and when Y is NH2, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, R10 is CH3, each of R7, R8, R11, and R12 is hydrogen, then A is not substituted phenyl. In certain embodiments of the foregoing methods, A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1- 6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, aryl (e.g., phenyl), and optionally substituted heteroaryl. In certain embodiments of the foregoing methods, A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1- 6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene. In certain embodiments of the foregoing methods, A is selected from cyano, hydroxyl, optionally substituted C1- 6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole. In certain embodiments of the foregoing methods, A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1- 6alkyl, optionally substituted heterocyclyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene. In certain embodiments of the foregoing methods, A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, and optionally substituted heterocyclyl. In certain embodiments of the foregoing methods, A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, - C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. In certain embodiments of the foregoing methods, A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, - C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, aryl, and optionally substituted heteroaryl. In certain embodiments of the foregoing methods, A is optionally substituted heterocyclyl In certain such embodiments, A is optionally substituted oxetane. In other such embodiments, A is optionally substituted tetrahydrofuran. In certain embodiments of the foregoing methods, Y is NR2R3 and R2 and R3 each independently is selected from hydrogen and C1-6alkyl. In certain such embodiments, Y is NH2. In other such embodiments, Y is NMe2. In still further such embodiments, Y is NHMe. In certain embodiments of the foregoing methods, Y is NR2R3 and R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring. In certain embodiments of the foregoing methods, Y is hydrogen. In certain embodiments of the foregoing methods, Y is C1-6 alkyl. In certain embodiments of the foregoing methods, Y is C3- 6 cycloalkyl. In certain embodiments of the foregoing methods, X is S. In certain embodiments of the foregoing methods, n is 1. In certain embodiments of the foregoing methods, R10 and R11 are both hydrogen. In certain embodiments of the foregoing methods, R7 and R8 are both hydrogen. In certain embodiments of the foregoing methods, R7 and R8 are both C1-6alkyl. In certain embodiments of the foregoing methods, R7 is hydrogen and and R8 is C1-6alkyl or C1-6 haloalkyl. In certain embodiments of the foregoing methods, R9 is hydrogen. In certain embodiments of the foregoing methods, R1 is hydrogen. In certain embodiments of the foregoing methods, R1 and R9 taken together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl ring. In ceratin such embodiments, R1 and R9 taken together with the atoms to which they are attached form oxetan-3-yl. The present application provides a method of treating FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome, CDD and/or one or more symptoms associated with CDD, or CHD8-NDD and/or one or more symptoms associated with CHD8- NDD, chronic heart failure, HFpEF, HFrEF, or HFmrEF comprising administering a therapeutic amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206- 208, 212-230, 232-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is selected from any one of compounds 1-10, 12-18, 20-25, 27- 37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, and 363-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is compound 360, or a pharmaceutically acceptable salt thereof. In certain embodiments of the foregoing methods, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying. In certain embodiments of the foregoing methods, the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing. In certain embodiments of the foregoing methods, the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions. The present application provides a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is not compound 343 (2-amino-4-(4-(2-methoxyethoxy)phenyl)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile).
The present application provides a pharmaceutical composition comprising (a) a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable excipient. In certain embodiments, the compound is not compound 343.
The present application provides a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof or a pharmaceutical composition thereof for use as a medicament. In certain embodiments, the compound is not compound 343.
The present application provides a method of treating Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising (a) a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable excipient. In certain embodiments, the compound is not compound 343. The present application provides a method of treating Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject, comprising administering to a subject in need thereof an effective amount of compound 360, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (a) compound 360, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient. In certain embodiments, the method further comprises co-administering to the subject an additional therapeutic agent. In certain such embodiments, the additional therapeutic agent comprises trofinetide.
The present application provides use of a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising (a) a compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable excipient, in the preparation of a medicament for the treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome. In certain embodiments, the compound is not compound 343. The present application provides use of compound 360, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (a) compound 360, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient, in the preparation of a medicament for the treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome. In certain embodiments, the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism. DETAILED DESCRIPTION The present application provides a compound of formula (I)
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, OR13, and NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl; or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R1 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R7 and R8 each independently is selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; R9 is hydrogen or halogen, or R1 and R9 taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, or R9 and R8 taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 or a cyclobutyl or cyclopentyl ring system when m is 1; R10 and R11 each independently is selected from hydrogen, hydroxyl, halogen, C1-6alkyl, and C1-6 haloalkyl; R12 is hydrogen or halogen; R13 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; X is selected from a bond, S, O, and NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl); A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, - NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5 and R6 each independently is selected from hydrogen and C1-6alkyl; m is 0 or 1, provided that when m is 1, R8 and R9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system; and n is 0, 1 or 2; provided that when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R1 is hydrogen or methyl, and each of R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R8 is methyl or CF3, and each of R1, R7 and R9 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 and R3 are both C1-6alkyl (e.g., ethyl), m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R1 is methyl, and each of R7, R8, R9, R10, and R11 is hydrogen, then A is not 2-pyridinyl or 3-pyridinyl; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R7 is methyl, R8 is methyl, and each of R1 and R9 is hydrogen, then A is not substituted 4-pyridyl; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 3-pyridyl; when Y is hydrogen or NR2R3, R2 is hydrogen, R3 is hydrogen or C1-6alkyl, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 4-pyridyl; when Y is NH2 or pyrrolidine, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R1 is hydrogen or methyl, each of R7, R8, R9, and R11 is hydrogen, and R10 is methyl, then A is not substituted phenyl; when Y is H or NH2, m is 0, R12 is hydrogen, X is S, n is 0, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted aryl (e.g., aryl, such as phenyl); when Y is NH2, m is 0, R12 is hydrogen, X is S or O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted oxazole; when Y is NH2, m is 0, R12 is hydrogen, X is O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted phenyl, or substituted 4-pyridyl; when Y is OR13, R13 is methyl, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl, substituted oxazole, imidazole, or 2-pyridyl; when Y is OR13, R13 is ethyl, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted oxazole; when Y is OR13, R13 is methyl, ethyl, or sec-butyl, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted thiazole; when Y is NH2, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted oxazole, substituted phenyl, substituted 4-pyridyl, substituted thiophene, or substituted thiazole; when Y is NH2, X is S, n is 2, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not hydroxyl; when Y is NH2, X is S, n is 1, and each of R1, R7, R8, R9 , R10, R11, and R12 is hydrogen, then A is not substituted thiazolidine, substituted pyrazole, substituted imidazole, or substituted triazole; when Y is NR2R3, R2 is hydrogen, R3 is CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 is hydrogen, R3 is CH3 or CH2CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not phenyl; when Y is NH2, X is S, n is 1, R7 and R8 are both CH3, and each of R1, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring optionally substituted with hydroxyl, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is S, n is 1, R8 is CH3 or CF3, and each of R1, R7, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NR2R3, R2 is hydrogen or CH3, R3 is CH2CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is S, n is 0, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, and R12 is hydrogen, then A is not phenyl; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 5-membered heterocyclyl ring optionally substituted with hydroxyl, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5- membered heterocyclyl ring, and each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted phenyl; when Y is NH2, X is O, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted phenyl; and when Y is NH2, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, R10 is CH3, each of R7, R8, R11, and R12 is hydrogen, then A is not substituted phenyl. The present application provides a method of treating FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying) comprising administering to a subject in need thereof a compound of formula (I)
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, OR13, and NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl; or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R1 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R7 and R8 each independently is selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; R9 is hydrogen or halogen, or R1 and R9 taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, or R9 and R8 taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 or a cyclobutyl or cyclopentyl ring system when m is 1; R10 and R11 each independently is selected from hydrogen, hydroxyl, halogen, C1-6alkyl, and C1-6 haloalkyl; R12 is hydrogen or halogen; R13 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; X is selected from a bond, S, O, and NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl); A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, - NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5 and R6 each independently is selected from hydrogen and C1-6alkyl; m is 0 or 1, provided that when m is 1, R8 and R9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system; and n is 0, 1 or 2. The present application provides a method of treating CDKL5 deficiency disorder (CDD) and/or one or more symptoms associated with CDD (e.g., repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing) comprising administering to a subject in need thereof a compound of formula (I)
Figure imgf000018_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, OR13, and NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl; or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R1 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R7 and R8 each independently is selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; R9 is hydrogen or halogen, or R1 and R9 taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, or R9 and R8 taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 or a cyclobutyl or cyclopentyl ring system when m is 1; R10 and R11 each independently is selected from hydrogen, hydroxyl, halogen, C1-6alkyl, and C1-6 haloalkyl; R12 is hydrogen or halogen; R13 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; X is selected from a bond, S, O, and NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl); A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, - NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5 and R6 each independently is selected from hydrogen and C1-6alkyl; m is 0 or 1, provided that when m is 1, R8 and R9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system; and n is 0, 1 or 2. The present application provides a method of treating CHD8-related neurodevelopmental disorder (CHD8-NDD) and/or one or more symptoms associated with CHD8-NDD (e.g., generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions) comprising administering to a subject in need thereof a compound of formula (I)
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, OR13, and NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl; or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R1 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R7 and R8 each independently is selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; R9 is hydrogen or halogen, or R1 and R9 taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, or R9 and R8 taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 or a cyclobutyl or cyclopentyl ring system when m is 1; R10 and R11 each independently is selected from hydrogen, hydroxyl, halogen, C1-6alkyl, and C1-6 haloalkyl; R12 is hydrogen or halogen; R13 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; X is selected from a bond, S, O, and NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl); A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, - NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5 and R6 each independently is selected from hydrogen and C1-6alkyl; m is 0 or 1, provided that when m is 1, R8 and R9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system; and n is 0, 1 or 2. The present application provides a method of treating chronic heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HfrEF), or heart failure with mid-range ejection fraction (HfmrEF) comprising administering to a subject in need thereof a compound of formula (I) formula (I)
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, OR13, and NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl; or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R1 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R7 and R8 each independently is selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; R9 is hydrogen or halogen, or R1 and R9 taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, or R9 and R8 taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 or a cyclobutyl or cyclopentyl ring system when m is 1; R10 and R11 each independently is selected from hydrogen, hydroxyl, halogen, C1-6alkyl, and C1-6 haloalkyl; R12 is hydrogen or halogen; R13 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; X is selected from a bond, S, O, and NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl); A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, - NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5 and R6 each independently is selected from hydrogen and C1-6alkyl; m is 0 or 1, provided that when m is 1, R8 and R9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system; and n is 0, 1 or 2. In certain embodiments of the foregoing methods, when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R1 is hydrogen or methyl, and each of R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R8 is methyl or CF3, and each of R1, R7 and R9 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 and R3 are both C1-6alkyl (e.g., ethyl), m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5- membered heterocyclyl ring, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R1 is methyl, and each of R7, R8, R9, R10, and R11 is hydrogen, then A is not 2-pyridinyl or 3-pyridinyl; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R7 is methyl, R8 is methyl, and each of R1 and R9 is hydrogen, then A is not substituted 4- pyridyl; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 3-pyridyl; when Y is hydrogen or NR2R3, R2 is hydrogen, R3 is hydrogen or C1-6alkyl, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 4-pyridyl; when Y is NH2 or pyrrolidine, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl; when Y is NH2, m is 0, R12 is hydrogen, X is S, n is 1, R1 is hydrogen or methyl, each of R7, R8, R9, and R11 is hydrogen, and R10 is methyl, then A is not substituted phenyl; when Y is H or NH2, m is 0, R12 is hydrogen, X is S, n is 0, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted aryl (e.g., aryl, such as phenyl); when Y is NH2, m is 0, R12 is hydrogen, X is S or O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted oxazole; when Y is NH2, m is 0, R12 is hydrogen, X is O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted phenyl, or substituted 4-pyridyl; when Y is OR13, R13 is methyl, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl, substituted oxazole, imidazole, or 2-pyridyl; when Y is OR13, R13 is ethyl, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted oxazole; when Y is OR13, R13 is methyl, ethyl, or sec-butyl, m is 0, R12 is hydrogen, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted thiazole; when Y is NH2, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted oxazole, substituted phenyl, substituted 4-pyridyl, substituted thiophene, or substituted thiazole; when Y is NH2, X is S, n is 2, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not hydroxyl; when Y is NH2, X is S, n is 1, and each of R1, R7, R8, R9 , R10, R11, and R12 is hydrogen, then A is not substituted thiazolidine, substituted pyrazole, substituted imidazole, or substituted triazole; when Y is NR2R3, R2 is hydrogen, R3 is CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 is hydrogen, R3 is CH3 or CH2CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not phenyl; when Y is NH2, X is S, n is 1, R7 and R8 are both CH3, and each of R1, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring optionally substituted with hydroxyl, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is S, n is 1, R8 is CH3 or CF3, and each of R1, R7, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NR2R3, R2 is hydrogen or CH3, R3 is CH2CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is S, n is 0, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, and R12 is hydrogen, then A is not phenyl; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 5-membered heterocyclyl ring optionally substituted with hydroxyl, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, and each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted phenyl; when Y is NH2, X is O, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted phenyl; and/or when Y is NH2, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, R10 is CH3, each of R7, R8, R11, and R12 is hydrogen, then A is not substituted phenyl. In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, X is S, n is 1, R1 is hydrogen or methyl, and each of R7, R8 and R9 is hydrogen, then A is not substituted thiazole. In certain such embodiments, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NH2, X is S, n is 1, R1 is hydrogen or methyl, and each of R7, R8 and R9 is hydrogen, then A is not substituted thiazole. In certain such embodiments, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, X is S, n is 1, R8 is methyl, and each of R1, R7 and R9 is hydrogen, then A is not optionally substituted thiazole (e.g., substituted thiazole). In certain such embodiments, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NH2, X is S, n is 1, R8 is methyl, and each of R1, R7 and R9 is hydrogen, then A is not optionally substituted thiazole (e.g., substituted thiazole). In certain such embodiments, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted thiazole (e.g., substituted thiazole). In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5- membered heterocyclyl ring, X is S, and n is 1, then A is not optionally substituted thiazole (e.g., substituted thiazole). In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, then A is not optionally substituted thiazole (e.g., substituted thiazole). In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NH2, X is S, n is 1, R1 is methyl, and each of R7, R8 and R9 is hydrogen, then A is not optionally substituted 2-pyridinyl (e.g., 2-pyridinyl) or optionally substituted 3-pyridinyl (e.g., 3-pyridinyl). In certain embodiments, when Y is NH2, X is S, n is 1, R1 is methyl, and each of R7, R8 and R9 is hydrogen, then A is not 2-pyridinyl or 3-pyridinyl. In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, X is S, n is 1, R1 is methyl, and each of R7, R8 and R9 is hydrogen, then A is not optionally substituted 2- pyridinyl (e.g., 2-pyridinyl). In certain embodiments, when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, X is S, and n is 1, then A is not optionally substituted 2-pyridinyl (e.g., 2-pyridinyl). In certain embodiments of Formula (I), when Y is NH2, X is S, n is 1, R1 is methyl, and each of R7, R8 and R9 is hydrogen, then A is not optionally substituted 2-pyridinyl (e.g., 2-pyridinyl). In certain embodiments of Formula (I), when Y is NH2, X is S, and n is 1, then A is not optionally substituted 2-pyridinyl (e.g., 2- pyridinyl). In certain embodiments of Formula (I), when X is S, and n is 1, then A is not optionally substituted 2-pyridinyl (e.g., 2-pyridinyl). In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted pyridyl (e.g., substituted 3-pyridyl). In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, X is S, and n is 1, then A is not substituted pyridyl (e.g., substituted 3-pyridyl). In certain embodiments of Formula (I), when Y is NR2R3, and R2 and R3 each independently is selected from hydrogen and C1-6alkyl, then A is not substituted pyridyl (e.g., substituted 3-pyridyl). In certain embodiments of Formula (I), when Y is NH2, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 3-pyridyl. In certain embodiments of Formula (I), when Y is NH2, X is S, and n is 1, then A is not substituted 3-pyridyl. In certain embodiments of Formula (I), when Y is NH2, then A is not substituted 3-pyridyl. In certain embodiments of Formula (I), when Y is NH2, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted pyridyl. In certain embodiment of Formula (I) or (Ia) s, when Y is NH2, X is S, and n is 1, then A is not substituted pyridyl. In certain embodiments of Formula (I), when Y is NH2, then A is not substituted pyridyl. In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NR2R3, X is S, n is 1, R7 is methyl, R8 is methyl, and each of R1 and R9 is hydrogen, then A is not optionally substituted 4-pyridyl (e.g., substituted 4-pyridyl). In certain embodiments of Formula (I), when Y is NR2R3, X is S, n is 1, R7 is methyl, and R8 is methyl, then A is not optionally substituted 4-pyridyl (e.g., substituted 4-pyridyl). In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, X is S, n is 1, R7 is methyl, R8 is methyl, and each of R1 and R9 is hydrogen, then A is not optionally substituted 4-pyridyl (e.g., substituted 4-pyridyl). In certain embodiments, when Y is NH2, X is S, n is 1, R7 is methyl, R8 is methyl, and each of R1 and R9 is hydrogen, then A is not optionally substituted 4-pyridyl (e.g., substituted 4-pyridyl). In certain embodiments of Formula (I), when Y is NR2R3, X is S, and n is 1, then A is not substituted 4-pyridyl. In certain embodiments of Formula (I), A is not substituted 4-pyridyl. In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is hydrogen or NR2R3, R2 is hydrogen, R3 is hydrogen or C1-6alkyl, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 4-pyridyl. In certain embodiments of Formula (I), when Y is hydrogen, then A is not optionally substituted 4-pyridyl (e.g., substituted 4-pyridyl). In certain embodiments of Formula (I), when Y is hydrogen, then A is not substituted pyridyl. In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NH2, X is O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 4-pyridyl. In certain embodiments of Formula (I), when X is O, then A is not substituted 4-pyridyl. In certain embodiments of Formula (I), when X is O, then A is not substituted pyridyl. In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NH2 or pyrrolidine, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted phenyl. In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted aryl (e.g., substituted phenyl). In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted aryl (e.g., substituted phenyl). In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring (e.g., pyrollidine), X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted aryl (e.g., optionally substituted phenyl, such as substituted phenyl). In certain embodiments of Formula (I), when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring (e.g., pyrollidine), X is S, and n is 1, then A is not optionally substituted aryl (e.g., optionally substituted phenyl, such as substituted phenyl). In certain embodiments of Formula (I), when Y is NR2R3, and R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring (e.g., pyrollidine), then A is not optionally substituted aryl (e.g., optionally substituted phenyl, such as substituted phenyl). In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is H or NR2R3 (e.g., NH2), X is S, n is 0, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted aryl (e.g., aryl, such as phenyl). In certain embodiments of Formula (I), when Y is H or NR2R3 (e.g., NH2), X is S, and n is 0, then A is not optionally substituted aryl (e.g., aryl, such as phenyl). In certain embodiments, when X is S, and n is 0, then A is not optionally substituted aryl (e.g., aryl, such as phenyl). In certain embodiments of Formula (I), when n is 0, then A is not optionally substituted aryl (e.g., aryl, such as phenyl). In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NR2R3, X is S or O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted oxazole (e.g., substituted oxazole). In certain embodiments of Formula (I), when Y is NH2, X is S or O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted oxazole (e.g., substituted oxazole). In certain embodiments of Formula (I), when Y is NH2, X is S or O, and n is 1, then A is not optionally substituted oxazole (e.g., substituted oxazole). In certain embodiments of Formula (I), when X is S or O, and n is 1, then A is not optionally substituted oxazole (e.g., substituted oxazole). In certain embodiments, when X is S or O, then A is not optionally substituted oxazole (e.g., substituted oxazole). In certain embodiments of Formula (I), when Y is NR2R3 (e.g., NH2), then A is not optionally substituted oxazole (e.g., substituted oxazole). In certain embodiments of Formula (I), A is not optionally substituted oxazole (e.g., substituted oxazole). In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is NR2R3 (e.g., NH2), X is O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted phenyl. In certain embodiments of Formula (I), when Y is NR2R3 (e.g., NH2), X is O, and n is 1, then A is not substituted phenyl. In certain embodiments of Formula (I), when X is O, and n is 1, then A is not substituted phenyl. In certain embodiments of Formula (I), when X is O, then A is not substituted phenyl. In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), when Y is OR13, R13 is C1-6 alkyl, such as methyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl, substituted oxazole, imidazole, or 2-pyridyl. In certain embodiments of Formula (I), when Y is OR13, R13 is C1-6 alkyl, such as ethyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted oxazole. In certain embodiments of Formula (I), when Y is OR13, R13 is C1-6 alkyl, such as methyl, ethyl, or sec- butyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted thiazole. In certain embodiments of the foregoing, m is 0 and R12 is hydrogen. In certain embodiments of Formula (I), X is O and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, and optionally substituted thiazole. In certain embodiments of Formula (I), X is O and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, - NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, aryl (e.g., phenyl), and heteroaryl (e.g., indole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, indazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, thiazole, oxazole, and pyridine). In certain embodiments of Formula (I), X is O and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1- 6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, and heteroaryl (e.g., indole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, indazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, thiazole, oxazole, and pyridine). In certain embodiments, X is O and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1- 6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, and aryl (e.g., phenyl). In certain embodiments of Formula (I), X is O and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1- 6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)N R5R6, -N R5R6, -NR5C(O) C1- 6alkyl, optionally substituted heterocyclyl, aryl, and pyridyl. In certain embodiments of Formula (I), X is O and A is pyridyl. In certain embodiments of Formula (I), X is O and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1- 6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)N R5R6, -N R5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl. In certain embodiments of Formula (I), n is 0 and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1- 6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. In certain embodiments of Formula (I), Y is H, and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and heteroaryl (e.g., indole, oxazole, thiazole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, indazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, and pyridyl, such as oxazole, thiazole, indole, pyrazine, pyrimidine, pyrrolopyridine, pyridazine, benzofuran, benzoimidazole, benzothiazole, benzothiophene, 2-pyridyl, and 3-pyridyl). In certain embodiments of Formula (I), Y is H, and A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, - NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted oxazole, optionally substituted thiazole, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene. In certain embodiments of Formula (I), when Y is NR2R3, then A is not substituted thiazole, such as phenyl-substituted thiazole. In certain embodiments of Formula (I), when Y is NR2R3, then A is not optionally substituted pyridyl. In certain embodiments of Formula (I), when Y is NR2R3, then A is selected from cyano, hydroxyl, optionally substituted C1- 6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, phenyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole. In certain embodiments of Formula (I), when X is S, and n is 1, then A is not substituted thiazole. In certain embodiments of Formula (I), when X is S, and n is 1, then A is not optionally substituted pyridyl. In certain embodiments of Formula (I), when X is S and n is 1, then A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, phenyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole. In certain embodiments of Formula (I), A is not substituted thiazole, such as phenyl-substituted thiazole. In certain embodiments of Formula (I), A is not optionally substituted pyridyl. In certain embodiments of Formula (I), A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1- 6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, aryl (e.g., phenyl), and optionally substituted heteroaryl. In certain embodiments of Formula (I), A is selected from cyano, hydroxyl, optionally substituted C1- 6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene. In certain embodiments of Formula (I), A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole. In certain embodiments of Formula (I), A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1- 6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene. In certain embodiments of Formula (I), A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, - NR5C(O)C1-6alkyl, and optionally substituted heterocyclyl. In certain embodiments, A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. In certain embodiments of Formula (I), A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, - C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, aryl, and optionally substituted heteroaryl. In certain embodiments of Formula (I), A is optionally substituted heterocyclyl, such as oxetane, tetrahydrofuran or tetrahydropyran. In certain embodiments of Formula (I), A is optionally substituted oxetane, such as oxetan-3-yl. In certain embodiments, A is optionally substituted tetrahydrofuran, such as tetrahydrofuran-3- yl. In certain embodiments of Formula (I), A is optionally substituted C1-6alkoxy, such as methoxy or ethoxy. In certain embodiments of Formula (I), A is optionally substituted C1- 6alkyl, such as methyl, trifluoromethyl, or hydroxyalkyl. In certain embodiments of Formula (I), Y is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, and NR2R3. In certain embodiments of Formula (I), Y is O. In certain embodiments of Formula (I), Y is NR2R3 and R2 and R3 each independently is selected from hydrogen and C1-6alkyl, such as methyl. In certain such embodiments of Formula (I), Y is NH2. In certain such embodiments of Formula (I), Y is NHMe. In certain such embodiments of Formula (I), Y is Nme2. In certain embodiments of Formula (I), Y is NR2R3 and R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring (e.g., pyrrolidine or azetidine). In certain such embodiments, the 4- or 5- membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl. In other embodiments, the 4- or 5- membered heterocyclyl ring is unsubstituted. In other embodiments of Formula (I), Y is hydrogen. In certain embodiments, Y is C1-6 alkyl, such as methyl. In certain embodiments of Formula (I), Y is C3-6 cycloalkyl, such as cyclopropyl. In certain embodiments of Formula (I), R7 and R8 are both hydrogen. In certain embodiments of Formula (I), R7 is hydrogen and and R8 is C1-6alkyl, or C1-6 haloalkyl, such as methyl or trifluoromethyl. In certain embodiments of Formula (I), R7 and R8 are both C1- 6alkyl, such as methyl. In certain embodiments of Formula (I), R9 is hydrogen. In certain embodiments of Formula (I), R9 is halogen, such as F. In certain embodiments of Formula (I), R1 is hydrogen. In certain embodiments of Formula (I), R1 and R9 taken together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl ring, such as oxetane or tetrahydrofuran. In certain embodiments of Formula (I), R1 and R9 taken together with the atoms to which they are attached form oxetan-3-yl. In certain embodiments of Formula (I), R1 and R9 taken together with the atoms to which they are attached form a 6-membered heterocyclyl ring, such as oxetane or tetrahydropyran. In certain embodiments, m is 0. In certain such embodiments, R9 and R8 taken together with the atoms to which they are attached form a cyclopropyl ring system. In certain embodiments, m is 1 and R8 and R9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system. In certain embodiments of Formula (I), R7 and R8 are both hydrogen and R1 and R9 taken together with the atoms to which they are attached form oxetan-3-yl. In certain embodiments of Formula (I), R1, R7, R8, and R9 are each hydrogen. In certain embodiments of Formula (I), R10 and R11 are both hydrogen. In certain embodiments of Formula (I), n is 0 and A is optionally substituted heterocyclyl. In certain embodiments of Formula (I), R13 is C1-6 alkyl, such as methyl. In certain emodiments of Formula (I), X is S. In certain embodiments of Formula (I), X is S, and n is 0. In certain embodiments of Formula (I), X is S, and n is 1. In certain embodiments of Formula (I), X is S, and n is 2. In certain emodiments of Formula (I), X is O. In certain embodiments of Formula (I), X is O, and n is 1. In certain emodiments of Formula (I), X is a bond. In certain embodiments of Formula (I), X is a bond, and n is 0. In certain embodiments of Formula (I), X is a bond, and n is 2. In certain emodiments of Formula (I), X is NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl). In certain emodiments of Formula (I), X is NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl), and n is 1. In certain embodiments of Formula (I), n is 1 or 2. In certain embodiments of Formula (I), R1 is haloalkyl (e.g., difluoromethyl). In certain embodiments, R1 is hydrogen. In certain embodiments of Formula (I), R1 is C1-6 alkyl (e.g., methyl or ethyl). In certain embodiments of Formula (I), X is S, n is 1, R10 and R11 are both hydrogen, and A is optionally substituted heterocyclyl, such as oxetane (e.g., oxetan-3-yl), tetrahydrofuran (e.g., tetrahydrofuran-3-yl) or tetrahydropyran. In certain embodiments of Formula (I), X is S, n is 1, R10 and R11 are both hydrogen, and A is optionally substituted oxetane, such as oxetan-3-yl. In certain embodiments of Formula (I), X is S, n is 1, R10 and R11 are both hydrogen, and A is optionally substituted tetrahydrofuran, such as tetrahydrofuran-3-yl. In certain embodiments of Formula (I), Y is NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl (e.g., methyl), X is S, n is 1, R10 and R11 are both hydrogen, and A is optionally substituted heterocyclyl, such as oxetane (e.g., oxetan-3-yl), tetrahydrofuran (e.g., tetrahydrofuran-3-yl) or tetrahydropyran. In certain such embodiments of Formula (I), Y is NH2. In certain such embodiments, Y is NHMe. In certain such embodiments of Formula (I), Y is Nme2. In certain embodiments of the foregoing, R1 and R9 taken together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl ring, such as oxetane or tetrahydrofuran. In certain embodiments, a compound of Formula (I) is of the following formula:
Figure imgf000032_0001
, wherein A, R1, R2 and R3 are as defined herein for formula (I). In certain such embodiments, R1 is hydrogen or methyl. In certain such embodiments, R1 is methyl. In certain such embodiments, R2 is hydrogen, C1-3 alkyl or cyclopropyl, and R3 is hydrogen or C1-3 alkyl. In certain such embodiments, R2 is hydrogen, methyl, ethyl, or cyclopropyl, and R3 is hydrogen or methyl. In certain such embodiments, R2 is hydrogen, methyl, ethyl, or cyclopropyl, and R3 is hydrogen. In certain such embodiments, A is unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted oxetanyl or unsubstituted tetrahydrofuranyl. In certain such embodiments, A is unsubstituted pyridyl, unsubstituted pyridazinyl, or unsubstituted oxetanyl. In certain such embodiments, R1 is hydrogen or methyl; R2 is hydrogen, methyl, ethyl, or cyclopropyl; R3 is hydrogen or methyl; and A is unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted oxetanyl or unsubstituted tetrahydrofuranyl. In certain such embodiments, the compound has the absolute stereochemistry:
Figure imgf000033_0001
In certain such embodiments, the compound is any one of compounds 387-406 or 415-418. The present application provides a compound selected from any one of the following, and pharmaceutically acceptable salts thereof:
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000054_0002
The present application further provides a compound selected from any one of the following, and pharmaceutically acceptable salts thereof:
Figure imgf000054_0003
F
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
The present application further provides a compound selected from any one of the following, and pharmaceutically acceptable salts thereof:
Figure imgf000066_0002
Figure imgf000067_0001
Figure imgf000068_0001
O D
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
O
Figure imgf000072_0001
Figure imgf000073_0001
O N D D3 D3
Figure imgf000074_0001
Figure imgf000075_0001
O F
Figure imgf000076_0001
Figure imgf000077_0001
. In certain embodiments, the present application provides a compound selected from any one of 340-342 and 344-458, and pharmaceutically acceptable salts thereof: In certain embodiments wherein alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, or oxime are substituted, they are substituted, valency permitting, with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluoromethoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino, acylaminoalkyl, such as perfluoro acylaminoalkyl (e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroaryloxyalkyl, heterocyclylaminoalkyl, heterocyclylaminoalkoxy, amido, amidoalkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, including perfluoroacyl (e.g., C(O)CF3)), carbonylalkyl (such as carboxyalkyl, alkoxycarbonylalkyl, formylalkyl, or acylalkyl, including perfluoroacylalkyl (e.g., -alkylC(O)CF3)), carbamate, carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone, sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl, alkylthio, thiocarbonyl (such as thioester, thioacetate, or thioformate), phosphoryl, phosphate, phosphonate or phosphinate. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and/or variables are permissible only if such combinations result in chemically stable compounds. As used in this application, the term "optionally substituted" means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted.
Compounds of the present application containing one or multiple asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by synthesis using optically active reagents.
In certain embodiments, compounds of the application may be racemic. For example, in embodiments of the application wherein a compound (e.g., a compound of formula (I), or a pharmaceutically acceptable salts thereof) is disclosed herein as a particular enantiomer, the application further contemplates the compound in its racemic form. In certain embodiments, compounds of the application may be enriched in one enantiomer. For example, a compound of the application may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee.
In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), or a pharmaceutically acceptable salt thereof). An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
In certain embodiments, compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. For example, a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula (I), or a pharmaceutically acceptable salt thereof). A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent. A variety of compounds in the present application may exist in particular geometric or stereoisomeric forms. The present application takes into account all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this application. All tautomeric forms are encompassed in the present application. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this application, unless the stereochemistry or isomeric form is specifically indicated. The present application further includes all pharmaceutically acceptable isotopically labelled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof). An "isotopically" or "radio-labelled" compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in certain embodiments, in compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof), hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a C1-6 alkyl or a C1-6 alkoxy are replaced with deuterium, such as d3-methoxy or 1,1,2,2-d4-3-methylbutyl). Certain isotopically labelled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof), in the application, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon 14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O, and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labelled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed. Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C,14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl , 82B r, 75Br, 76B r, 77Br, 123I, 124I, 125I, and 131I. In certain embodiments, the present application provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (e.g., a compound of the application, such as a compound of formula (I), or pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient. Compounds of any of the above structures may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein. Uses of the compounds Compounds of the present application may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient. The quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng/kg of body weight to 100 mg/kg of body weight per day. For instance, dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. This, the skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions and to be administered in methods of the application. In certain embodiments, the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament, e.g., for treatment of any of the disorders disclosed herein. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to the use of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to the use of compound 360, or a pharmaceutically acceptable salt thereof, in the
Figure imgf000081_0001
manufacture of a medicament for treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject. In certain such embodiments, the one or more symptoms associated with Rett syndrome is selected from sleep disturbances, including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming; sleep apnea; seizures, including those accompanied by an abnormal electroencephalogram (EEG); breathing disorders, including breath-holding, abnormally rapid breathing (hyperventilation), forceful exhalation of air or saliva, and swallowing air; irregular heartbeat, including problems with heart rhythm such as abnormally long pauses between heartbeats (e.g., as measured by an electrocardiogram), and other types of arrhythmia; intellectual disabilities; and autism. In certain embodiments, the application relates to a method of treating or preventing Rett syndrome and/or one or more symptoms associated with Rett syndrome in a mammal, such as a human being, comprising administering to said patient a therapeutically effective amount of compound 360, or a pharmaceutically acceptable salt thereof. In certain embodiments, the application relates to a method of treating or preventing Rett syndrome and/or one or more symptoms associated with Rett syndrome in a mammal, such as a human being, comprising administering to said patient a therapeutically effective amount of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain such embodiments, the one or more symptoms associated with Rett syndrome is selected from sleep disturbances, including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming; sleep apnea; seizures, including those accompanied by an abnormal electroencephalogram (EEG); breathing disorders, including breath-holding, abnormally rapid breathing (hyperventilation), forceful exhalation of air or saliva, and swallowing air; irregular heartbeat, including problems with heart rhythm such as abnormally long pauses between heartbeats (e.g., as measured by an electrocardiogram), and other types of arrhythmia; intellectual disabilities; and autism.In certain embodiments, the application relates to a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), for use as a medicament for the treatment of chronic heart failure, HFpEF, HFrEF, or HFmrEF. In certain embodiments, the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146- 147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of chronic heart failure, HFpEF, HFrEF, or HFmrEF. In certain embodiments, the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76- 79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212- 230, 232-359, 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of chronic heart failure, HFpEF, HFrEF, or HFmrEF. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of chronic heart failure, HFpEF, HfrEF, or HfmrEF. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to compound 360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of chronic heart failure, HfpEF, HfrEF, or HfmrEF. In certain embodiments, the application relates to a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome. In certain such embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying. In certain embodiments, the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146- 147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome. In certain embodiments, the application relates to any one of compounds 1-10, 12-18, 20-25, 27- 37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to compound 360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome. In certain embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying. In certain embodiments, the application relates to a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), for use as a medicament for the treatment of CDKL5 deficiency disorder (CDD) and/or one or more symptoms associated with CDD. In certain such embodiments, the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing. In certain embodiments, the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CDD and/or one or more symptoms associated with CDD. In certain embodiments, the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174- 178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CDD and/or one or more symptoms associated with CDD. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CDD and/or one or more symptoms associated with CDD. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to compound 360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CDD and/or one or more symptoms associated with CDD. In certain embodiments, the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing. In certain embodiments, the application relates to a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), for use as a medicament for the treatment of CHD8-related neurodevelopmental disorder (CHD8-NDD) and/or one or more symptoms associated with CHD8-NDD. In certain such embodiments, the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions. In certain embodiments, the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112- 117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD. In certain embodiments, the application relates to any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146- 147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to compound 360, or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of CHD8- NDD and/or one or more symptoms associated with CHD8-NDD. In certain embodiments, the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions. In certain embodiments, the application relates to a method of treating or preventing FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I). In certain such embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying. In certain embodiments, the application relates to a method of treating or preventing of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of compound 360, or a pharmaceutically acceptable salt thereof. In certain embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.
In certain embodiments, the application relates to a method of treating or preventing CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I). In certain such embodiments, the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing. In certain embodiments, the application relates to a method of treating or preventing of CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1- 10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of CDD and/or one or more symptoms associated with CDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of compound 360, or a pharmaceutically acceptable salt thereof. In certain embodiments, the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.
In certain embodiments, the application relates to a method of treating or preventing CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I). In certain such embodiments, the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions. In certain embodiments, the application relates to a method of treating or preventing of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61- 70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206- 208, 212-230, 232-359, 363-458 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of any one of compounds 340-359 or 363- 458, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a method of treating or preventing of CHD8-NDD and/or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, comprising administering to said mammal a therapeutically effective amount of compound 360, or a pharmaceutically acceptable salt thereof. In certain embodiments, the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions. In certain embodiments, any one of compounds 340-360, or a pharmaceutically acceptable salt thereof, as disclosed herein is a brain penetrant. In certain embodiments, any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, as disclosed herein is a brain penetrant. In certain embodiments, any one of compounds 340- 360, or a pharmaceutically acceptable salt thereof, as disclosed herein is capable of crossing the blood brain barrier. In certain embodiments, any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, as disclosed herein is capable of crossing the blood brain barrier. In certain embodiments, the compound is not compound 343. In certain such embodiments, the compound is useful in methods of treating or preventing Rett syndrome and/or one or more symptoms associated with Rett syndrome (e.g., sleep disturbances, including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming; sleep apnea; seizures, including those accompanied by an abnormal electroencephalogram (EEG); breathing disorders, including breath-holding, abnormally rapid breathing (hyperventilation), forceful exhalation of air or saliva, and swallowing air; irregular heartbeat, including problems with heart rhythm such as abnormally long pauses between heartbeats (e.g., as measured by an electrocardiogram), and other types of arrhythmia; intellectual disabilities; and autism), FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying), FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying), or CHD8-related neurodevelopmental disorder (CHD8-NDD) and/or one or more symptoms associated with CHD8-NDD (e.g., generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions). In certain embodiments, a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), as disclosed herein is not brain penetrant. In certain embodiments, a compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), as disclosed herein is not capable of crossing the blood brain barrier (i.e., is peripherally restricted). In certain such embodiments, the compound according to formula (I), or a pharmaceutically acceptable salt of the compound according to formula (I), is useful in methods of treating or preventing chronic heart failure. In certain embodiments, any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174- 178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, or a pharmaceutically acceptable salt thereof (e.g., any one of compounds 340-458, or a pharmaceutically acceptable salt thereof), is useful in methods of treating or preventing chronic heart failure, HFpEF, HFrEF, or HFmrEF. In certain embodiments, the compound is not compound 343. In certain embodiments, any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212- 230, 232-359, 363-458, or a pharmaceutically acceptable salt thereof (e.g., any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof), is useful in methods of treating or preventing chronic heart failure, HFpEF, HFrEF, or HFmrEF. In certain embodiments, the compound is not compound 343. In certain embodiments of the methods a disclosed herein, the compound is selected from any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138- 141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, and 212- 230, and pharmaceutically acceptable salts thereof. In certain embodiments of the methods a disclosed herein, the compound is selected from any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112- 117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, and 232-339, and pharmaceutically acceptable salts thereof. In certain embodiments of the methods a disclosed herein, the compound is selected from any one of compounds 340-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is not compound 343. In certain embodiments of the methods a disclosed herein, the compound is selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is not compound 343. In certain embodiments, the application relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, in association with at least one pharmaceutically acceptable excipient, carrier or diluent. In certain such embodiments, the pharmaceutical composition is for treating a disease or disorder in a patient in need thereof, such as a disease or disorder as disclosed herein. In certain embodiments, the application relates to a pharmaceutical composition comprising (1) any one of compounds 340-359 or 363-458, or a pharmaceutically acceptable salt thereof, (2) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (3) pharmaceutically acceptable excipients, carriers or diluents. In the treatment of any of the disorders disclosed herein, different compounds of the application may be (e.g., conjointly) administered with one or more other compounds of the application. Moreover, compounds of formula (I), or a pharmaceutically acceptable salt thereof, such as any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93-96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150-152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458 (e.g., any one of compounds 340-458), or a pharmaceutically acceptable salt thereof, or certain combinations thereof, may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein. In certain embodiments, the compound is not compound 343. In certain embodiments, compounds of formula (I), or a pharmaceutically acceptable salt thereof, such as any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, ISO- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, 363-458 (e.g., any one of compounds 340-359 or 363-458), or a pharmaceutically acceptable salt thereof, or certain combinations thereof, may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein. In certain embodiments, the compound is not compound 343.
In certain embodiments, compounds of the application may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either simultaneously, sequentially, or by separate dosing of the individual components of the treatment. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
In certain embodiments, conjoint administration of compounds of the application with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the application (e.g., compound of formula (I), or a pharmaceutically acceptable salt of the compound of formula (I), such as any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, ISO- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458 (e.g., any one of compounds 340-458), or a pharmaceutically acceptable salt thereof) or the one or more additional therapeutic agent(s). In certain embodiments, the compound is not compound 343. In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the application and the one or more additional therapeutic agent(s).
Such conventional therapeutics may include one or more of the following categories of agents: anticonvulsants including, for example, carbamazepine, clonazepam, ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrogine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabaline, rufmamide, topiramate, valproate, vigabatrine, zonisamide and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; insomnia therapies including, for example, agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ramelteon, roletamide, triclofos, secobarbital, zaleplon, zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;
Rett syndrome therapies including, for example, trofinetide; agents that lower blood pressure by widening blood vessels, such as angiotensinconverting enzyme (ACE) inhibitors (including, for example, captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), trandolapril (Mavik), benazepril, and moexipril) and angiotensin receptor blockers (ARBs) (including, for example, candesartan (Atacand), losartan (Cozaar), and valsartan (Diovan)); agents that improve artery opening and blood flow, reduce sodium retention and decreases strain on the heart, such as angiotensin-receptor neprilysin inhibitors (ARNIs) (e.g., a drug combination of a neprilysin inhibitor and an ARB) including, for example, sacubitril/valsartan (Entresto); agents that reduce heart rate, such as 1(f) channel blockers including, for example, ivabradine (Corlanor); beta-adrenergic blocking agents (“beta blockers”) including, for example, acebutolol, atenolol (Tenormin), betaxolol (Bisoprolol), carvedilol (Coreg), carvedilol phosphate (Coreg CR), labetalol (Trandate), metoprolol succinate (Toprol XL and Kapspargo Sprinkle), metoprolol tartrate (Lopressor), nadolol (Corgard), nebivolol (Bystolic), pindolol (Visken), and propranolol (Inderal, Inderal LA, and InnoPran XL); agents that improve blood glucose control and decrease body weight and blood pressure, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors including, for example, empagliflozin (Jardiance), and dapagliflozin (Farxiga); aldosterone antagonists including, for example, spironolactone (Aldactone), and eplerenone (Inspra); vasodilators including, for example, hydralazine and nitrates (e.g., nitroglycerin or isosorbide dinitrate) and combinations thereof; diuretics including, for example, furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), chlorothiazide (Diuril), amiloride (Midamor Chlorthalidone, Hygroton), hydrochlorothiazide or HCTZ (Esidrix, Hydrodiuril), indapamide (Lozol), metolazone (Zaroxolyn), and triamterene (Dyrenium); anticoagulants; cholesterol-lowering drugs (e.g., statins); digoxin; calcium channel blockers (CCBs); potassium; and oxygen therapy.
In certain emodiments of methods of the invention for the treatment of Rett syndrome, the present application provides conjoint administration of compounds of the application with trofinetide, providing improved efficacy relative to each individual administration of the compound of the application (e.g., compound of formula (I), or a pharmaceutically acceptable salt of the compound of formula (I)) or the trofinetide. In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the application and the trofinetide.
Such combination products employ the compounds of this application within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and/or the dosage described in the publication reference.
Definitions
The definitions set forth in this application are intended to clarify terms used throughout this application.
The term "herein" means the entire application. The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-. The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-. The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term “alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group. Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CF3, -CN, and the like. The term “Cx-y” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. C0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C2-yalkenyl” and “C2-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group. The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-. The term “alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. The term “amide”, as used herein, refers to a group
Figure imgf000096_0001
wherein each R30 independently represent a hydrogen or hydrocarbyl group, or two R30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
Figure imgf000096_0002
wherein each R30 independently represents a hydrogen or a hydrocarbyl group, or two R30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group. The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group. The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7- membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term “carbamate” is art-recognized and refers to a group
Figure imgf000096_0003
wherein R29 and R30 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R29 and R30 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. The terms “carbocycle”, and “carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- 1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be susbstituted at any one or more positions capable of bearing a hydrogen atom. A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group. The term “carbonate” is art-recognized and refers to a group -OCO2-R30, wherein R30 represents a hydrocarbyl group. The term “carboxy”, as used herein, refers to a group represented by the formula - CO2H. The term “ester”, as used herein, refers to a group -C(O)OR30 wherein R30 represents a hydrocarbyl group. The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl. The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo. The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group. The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent. The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur. The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group. The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof. The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group. The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7. The term “silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this application, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof. The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae
Figure imgf000100_0001
wherein R29 and R30 independently represents hydrogen or hydrocarbyl, such as alkyl, or R29 and R30 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “sulfoxide” is art-recognized and refers to the group -S(O)-R30, wherein R30 represents a hydrocarbyl. The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof. The term “sulfone” is art-recognized and refers to the group -S(O)2-R30, wherein R30 represents a hydrocarbyl. The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group. The term “thioester”, as used herein, refers to a group -C(O)SR30 or -SC(O)R30 wherein R30 represents a hydrocarbyl. The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with asulfur. The term “urea” is art-recognized and may be represented by the general formula
Figure imgf000101_0001
wherein R29 and R30 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R29 taken together with R30 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure. “Protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
The term "healthcare providers" refers to individuals or organizations that provide healthcare services to a person, community, etc. Examples of "healthcare providers" include doctors, hospitals, continuing care retirement communities, skilled nursing facilities, subacute care facilities, clinics, multispecialty clinics, freestanding ambulatory centers, home health agencies, and HMO's.
The present application includes prodrugs of the compounds formula (I) (such as any one of compounds 340-355), or pharmaceutically acceptable salts thereof. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present application (e.g., a compound of formula (I) (such as any one of compounds 340-355), or pharmaceutically acceptable salts thereof). A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to yield the desired molecule. In certain embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, a prodrug with a nitro group on an aromatic ring could be reduced by reductase to generate the desired amino group of the corresponding active compound in vivo. In another example, functional groups such as a hydroxyl, carbonate, or carboxylic acid in the parent compound are presented as an ester, which could be cleaved by esterases. Additionally, amine groups in the parent compounds are presented in, but not limited to, carbamate, N-alkylated or N-acylated forms (Simplicio et al, “Prodrugs for Amines,” Molecules, (2008), 13:519-547). In certain embodiments, some or all of the compounds of formula (I), or pharmaceutically acceptable salts thereof, in a formulation represented above can be replaced with the corresponding suitable prodrug.
The present application includes metabolites of the compounds of formula (I) (such as any one of compounds 340-355), or pharmaceutically acceptable salts thereof. The term “metabolite” is intended to encompass compounds that are produced by metabolism/biochemical modification of the parent compound under physiological conditions, e.g. through certain enzymatic pathway. For example, an oxidative metabolite is formed by oxidation of the parent compound during metabolism, such as the oxidation of a pyridine ring to pyridine-N-oxide. In another example, an oxidative metabolite is formed by demethylation of a methoxy group to result in a hydroxyl group.
Pharmaceutical Compositions
The compositions and methods of the present application may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the application and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.
A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the application. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the application. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the application, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present application with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations of the application suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the present application as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste. To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.
Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.
Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing controlled delivery of a compound of the present application to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this application. Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No.6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant). The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the application include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
For use in the methods of this application, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the application. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
In general, a suitable daily dose of an active compound used in the compositions and methods of the application will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present application, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
The patient receiving this treatment is any animal in need, including primates, in particular humans.
This application includes the use of pharmaceutically acceptable salts of compounds of the application in the compositions and methods of the present application. The term “pharmaceutically acceptable salts” includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, such as an amine, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, trifluoroacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzensulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, camphorsulfonic and the like. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In certain embodiments, the pharmaceutically acceptable salt is a camsylate salt. In certain embodiments, contemplated salts of the compounds include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of compounds include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of compounds include, but are not limited to, Li, Na, Ca, K, Mg, Zn or other metal salts. Also included are the salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. The compounds of the application, including their pharmaceutically acceptable salts, can also exist as various solvates, such as with water (also known as hydrates), methanol, ethanol, dimethylformamide, diethyl ether, acetamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. The compounds of the application, including their pharmaceutically acceptable salts, can also exist as various polymorphs, pseudo-polymorphs, or in amorphous state. As used herein, the term “polymorph” refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of the same compound. Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as x-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents. Thus, crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
In certain embodiments, the application comprises a method for conducting a pharmaceutical business, by determining an appropriate formulation and dosage of a compound of the application for treating or preventing any of the diseases or conditions as described herein, conducting therapeutic profiling of identified formulations for efficacy and toxicity in animals, and providing a distribution network for selling an identified preparation as having an acceptable therapeutic profile. In certain embodiments, the method further includes providing a sales group for marketing the preparation to healthcare providers.
In certain embodiments, the application relates to a method for conducting a pharmaceutical business by determining an appropriate formulation and dosage of a compound of the application for treating or preventing any of the disease or conditions as described herein, and licensing, to a third party, the rights for further development and sale of the formulation.
Examples
Example 1: Synthetic Protocols
Below follows a number of non-limiting examples of compounds of the application. Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room temperature (about 18 °C to about 25 °C) under nitrogen atmosphere. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure. The course of a reaction was followed by thin layer chromatography (TLC), high-pressure liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC-MS), and reaction times are given for illustration only. The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). Silica gel chromatography was performed on silica gel 60 (230-400 mesh). Chromatography columns available for use in the separation/purification of the enantiomers/diastereoisomers provided herein include, but are not limited to, Waters Xbridge Prep OBD®, Waters Xbridge BEH®, Kromasil®, Phenomenex Luna®, etc. The structure and purity of all final products was assured by at least one of the following analytical methods: nuclear magnetic resonance (NMR) and LC-MS. NMR spectra was recorded on a Bruker 400 MHz NMR Spectrometer using the indicated solvent. Chemical shift (δ) is given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J) are expressed in hertz (Hz), and conventional abbreviations used for signal shape are: s = singlet; d = doublet; t = triplet; m = multiplet; br = broad; etc. The following abbreviations have been used: BOC tert-butoxycarbonyl DEAD diethyl azodicarboxylate DCCI 1,3-dicyclohexyl carbodiimide DCM Dichloromethane DMA N,N-dimethylacetamide DMAP 4-dimethyl-aminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDCl 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide EEDQ 2-ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline EtOAc Ethyl acetate HOBT hydroxybenzotriazole MeCN acetonitrile mCPBA m-chloroperoxybenzoic acid NMM N-methylmorpholine NMMO N-methylmorpholine-N-oxide PE Petroleum ether TBAF tetra-n-butylammonium fluoride TFA trifluoroacetic acid THF tetrahydrofuran TMEDA Ν,Ν,Ν',Ν'-tetramethylethylenediamine TMSI trimethylsilyliodide TPAP tetrapropylammonium perruthenate General synthetic methods for the preparation of the compounds of the present invention The general synthetic routes to prepare diversely substituted amino-3,5- dicyanopyridine derivatives are depicted in the schemes below. Compounds were synthesized starting from the suitable commercially available 4-hydroxybenzaldehyde properly alkylated, followed by a one-pot cyclization with cyanothioacetamide in the presence of a base such as triethylamine or piperidine. Upon treatment with alkylating agents, the thiolate gave new 2- (alkylthio)pyridines (Scheme 1). (Matrosova, S. V.; Zav'yalova, V. K.; Litvinov, V. P.; Sharanin, Yu. A. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1991), (7), 1643-6.) Scheme 1
Figure imgf000115_0001
Preparation of 6-amino-3,5-dicyanopyridines diversely substituted on C-6 with mono- or dialkylamino groups may then be carried out by reaction with t-butyl nitrite and a copper salt in a solvent such as acetonitrile, followed by nucleophilic substitution of the halogen by a mono- or dialkyl-substituted amine (Scheme 2). Scheme 2
Figure imgf000116_0001
Preparation of Compounds of Formula I: Compounds of formula I
Figure imgf000116_0002
i.e., compounds of Formula I where X is S
Figure imgf000116_0003
and R2 and R3 are H
Figure imgf000116_0004
are prepared by treatment of a phenol with an alkylating agent such as 1-bromo-2- methoxyethane or 1-bromo-hydroxyethane and a base such as K2CO3 in a solvent such as DMF or acetonitrile to give an intermediate aldehyde.
Figure imgf000117_0001
The aromatic aldehyde can be condensed with 2-cyanothioacetamide in the presence of a base such as N-methylmorpholine or K2CO3 in a solvent such as ethanol to give a 4-aryl-2- mercaptopyridine.
Figure imgf000117_0002
The 2-mercaptopyridine can be reacted with an alkylating agent containing a leaving group commonly used in the art such as chloride, bromide, or mesylate in the presence of base in a solvent such as DMF to give a compound of Formula I where A is cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, - NR5C(O)C1-6alkyl, optionally substituted heterocycloalkyl, aryl, or optionally substituted heteroaryl.
Figure imgf000117_0003
A compound of Formula I where R2 and R3 are H can be further modified to give a compound of Formula I where R2 and R3 each independently can be C1-6alkyl or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocycloalkyl ring by conversion of the amine to a chloride or bromide using a t-butyl nitrite and a copper salt in a solvent such as acetonitrile. The resulting 2-halopyridine can be treated with an amine such as pyrrolidine or azetidine in a solvent such as methanol or dichloromethane to give a compound of Formula I where R2 and R3 are each independently C1-6alkyl or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocycloalkyl ring.
Figure imgf000118_0001
Protocol 1.2-Amino-4-[4-(2-hydroxy-propoxy)phenyl]-6-(3- pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (56) and 2-(azetidin-1-yl)-4-[4-(2- hydroxypropoxy)phenyl]-6-(3-pyridylmethylsulfanyl)-pyridine-3,5-dicarbonitrile (53)
Figure imgf000118_0002
Step 1: Preparation of 4-(2-hydroxypropoxy)benzaldehyde (53-B). A mixture of 4- hydroxybenzaldehyde (4 g, 32.75 mmol, 1 eq), 1-bromopropan-2-ol (5.01 g, 36.03 mmol, 3.27 mL, 1.1 eq), K22CO3 (9.05 g, 65.51 mmol, 2 eq) in DMF (1 mL) was stirred at 90 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EtOAc = 20:1 to 2:1) to give 4-(2-hydroxypropoxy)benzaldehyde (2.8 g, 15.54 mmol, 47.44% yield) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ = 1.18 (d, J = 6.0 Hz, 3H), 3.89 - 3.97 (m, 2 H), 4.00-4.04 (m, 1H), 7.14 (m, J = 8.8 Hz, 2H), 7.84 - 7.89 (m, 2H), 9.86 - 9.89 (m, 1H). [M+H] = 180.9 Step 2. Preparation of 2-amino-4-[4-(2-hydroxypropoxy)phenyl]-6-sulfanyl-pyridine- 3,5-dicarbonitrile (53-D). A mixture of 4-(2-hydroxypropoxy)benzaldehyde (1 g, 5.55 mmol, 1 eq) , 2-cyanothioacetamide (1.22 g, 12.21 mmol, 2.2 eq), NMM (1.18 g, 11.65 mmol, 1.28 mL, 2.1 eq) in EtOH (10 mL) was stirred at 80 °C for 12 h. To the reaction mixture was added H2O (15 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-amino-4-[4-(2-hydroxypropoxy)phenyl]-6-sulfanyl-pyridine-3,5- dicarbonitrile (800 mg, 2.45 mmol, 44.17% yield) as a white solid. [M-H] = 324.9. Step 3. Preparation of 2-amino-4-[4-(2-hydroxypropoxy)phenyl]-6-(3- pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (56). A mixture of 2-amino-4- [4 - (2- hydroxypropoxy)phenyl] - 6-sulfanyl - pyridine-3,5 - dicarbonitrile (53-D, 750 mg, 2.30 mmol, 1 eq) , 3-(chloromethyl)pyridine (322.47 mg, 2.53 mmol, 1.1 eq) , K2CO3 (635.19 mg, 4.60 mmol, 2 eq) in DMF (10 mL) was stirred at 60 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 mm × 40 mm × 10 µm; mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 25%-55% over 8 min, to give 2-amino-4-[4-(2-hydroxypropoxy)phenyl]-6-(3- pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (540 mg, 1.23 mmol, 53.42% yield, 94.9% purity) as white solid.1H-NMR (400 MHz, DMSO-d6) δ = 1.13 (d, J = 6.4 Hz, 3H), 3.79 - 3.88 (m, 2H) 3.90 - 4.00 (m, 1H) 4.43 - 4.49 (m, 2 H) 4.91 (d, J = 4.8 Hz, 1H) 7.05 (d, J = 8.4 Hz, 2H) 7.31 (dd, J = 7.6, 5.2 Hz, 1 H) 7.47 (s, 2H) 7.91 (br d, J = 7.6 Hz, 1H) 8.42 (br d, J = 4.4 Hz, 1H), 8.79 (br d, J = 1.6 Hz, 1H). [M+H] = 418.0 Step 4. Preparation of 2-chloro-4-[4-(2-hydroxypropoxy)phenyl]-6-(3- pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (53-E). A mixture of 2-amino-4-[4-(2- hydroxypropoxy)phenyl]-6-(3-pyridylmethylsulfanyl)-pyridine-3,5-dicarbonitrile (56, 520 mg, 1.25 mmol, 1 eq), tert-butyl nitrite (192.66 mg, 1.87 mmol, 222.22 µL, 1.5 eq), CuCl2 (334.94 mg, 2.49 mmol, 2 eq) in ACN (6 mL) was stirred at 60 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give 2- chloro-4-[4-(2-hydroxypropoxy)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine-3,5- dicarbonitrile (500 mg, 1.14 mmol, 91.88% yield) as a black solid. [M+H] = 437.1. Step 5. Preparation of 2-(azetidin-1-yl)-4-[4-(2-hydroxypropoxy)phenyl]-6-(3- pyridylmethylsulfanyl)-pyridine-3,5-dicarbonitrile (53). A mixture of 2-chloro-4-[4-(2- hydroxypropoxy)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (250 mg, 572.20 µmol, 1 eq) , azetidine (326.69 mg, 5.72 mmol, 386.16 µL 10 eq) in MeOH (3 mL) was stirred at 15 °C for 0.5 h. The reaction mixture was filtered, and filtrate was collected. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10µm mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 25%- 55% over 8 min, to give 2-(azetidin-1-yl)-4-[4-(2-hydroxypropoxy)phenyl]-6-(3- pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (119.2 mg, 260.52 µmol, 45.53% yield, 100% purity) as white solid.1H-NMR (400 MHz, DMSO-d6) δ = 9.11 - 8.78 (br s, 2 H), 7.86 (br s, 1H), 7.44 (br s, 3H), 7.10 (br s, 2H), 4.92 (br s, 1H), 4.55 (br s, 6H), 3.98 - 3.89 (br s, 3H), 2.18 - 2.44 (m, 2H), 1.17 (br s, 3H). [M+H]=161.9 Table 1: Compounds were synthesized in a similar manner as described for compounds 56 and 53, but with different starting materials.
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000152_0002
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
a. Step 3 was altered by reacting the thiolpyridine with iodopyridine in DMSO in the presence of CuI (1 eq), (2S)-pyrrolidine-2-carboxylic acid (0.4 eq) and t-BuONa (2 eq). b. The enantiomers were separated by SFC (Instrument: Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK IG (250mm × 30mm, 10um); mobile phase: [CO2- IPA(0.1% NH3H2O)];B%:35%, isocratic elution mode). Absolute configuration assignments require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate. Protocol 2. Synthesis of (R)-4-(4-(2-(methoxy-d3)propoxy)phenyl)-2-(methylamino)-6- ((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (391) and (R)-2-amino-4-(4-(2- (methoxy-d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (405)
Figure imgf000172_0001
Step 1: R-2-(methoxy-d3)propoxy]methylbenzene (391-B). To a solution of (R)-1- (benzyloxy)propan-2-ol (30 g, 180.49 mmol, 1 eq) in THF (500 mL) was added NaH (10.83 g, 270.73 mmol, 60% purity, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 0.5 hr. Then iodomethane-d3 was added (31.40 g, 216.59 mmol, 13.48 mL, 1.2 eq) at 0°C. The mixture was stirred at 25°C for 3 hrs under N2. TLC (PE: EtOAc = 5:1) indicated 391-A was consumed completely and one major new spot was detected. The reaction mixture was quenched by addition sat.aq. NH4Cl 300 mL at 0°C, and then extracted with EtOAc 900 mL (300 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE: EtOAc = 1:0 to 5:1) to give R-2-(methoxy-d3)propoxy]methylbenzene (391-B) (45 g, 171.89 mmol, 95.23% yield, 70% purity) as a yellow oil. Step 2: R-2-(methoxy-d3)propan-1-ol (391-C). To a solution of R-2-(methoxy- d3)propoxy]methylbenzene (30 g, 163.70 mmol, 1 eq) in THF (300 mL) was added Pd/C (17 g, 15.97 mmol, 10% purity, 9.76e-2 eq). The mixture was stirred at 25°C for 12 hrs under H2 (40 Psi). TLC (PE: EtOAc =1:1) indicated 391-B was consumed completely and one major new spot was detected. The suspension was filtered through a pad of silica gel and the pad was washed with THF (150 mL×3), the filtrate was concentrated under reduced pressure to give R-2-(methoxy-d3)propan-1-ol (18 g, crude) as a white solid. Steps 3 and 4: (R)-4-(2-(methoxy-d3)propoxy)benzaldehyde (391-D). To a solution of (R)-2- (methoxy-d3)propan-1-ol (1.0 eq) in THF at 0 °C was added TEA (1.1 eq.) followed by the slow addition of Ms2O (1.1 eq). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by addition of water and extracted with CHCl3 and the organic fraction dried over Na2SO4 and concentrated. The crude (R)-2-(methoxy-d3)propyl methanesulfonate was used directly in the next step. To a solution of 4-hydroxybenaldehyde (1.1 eq) in DMF and Cs2CO3 (1.2 eq) was added (R)- 2-(methoxy-d3)propyl methanesulfonate (1.0 eq). The reaction was warmed to 100 °C and stirred for 12 hr, then quenched by the addition of water. The mixture was extracted with CHCl3 and the combined organic fractions were washed with water, 5% HCl solution, brine and dried over Na2SO4. The crude (R)-4-(2-(methoxy-d3)propoxy)benzaldehyde was estimated to be 90% pure by LCMS and used as such in Step 5. Step 5: (R)-2-amino-4-(4-(2-(methoxy-d3)propoxy)phenyl)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile (405). To a solution of (R)-2-amino-6-mercapto-4- (4-(2-(methoxy-d3)propoxy)phenyl)pyridine-3,5-dicarbonitrile (500 mg, 1.46 mmol, 1 eq) and 2-(chloromethyl)pyridine;hydrochloride (358.23 mg, 2.18 mmol, 1.5 eq) in DMF (3 mL) was added K2CO3 (402.44 mg, 2.91 mmol, 2 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was diluted with H2O 10 mL, then was filtered and the filter cake was concentrated under reduced pressure to give (R)-2-amino-4-(4-(2-(methoxy- d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (470 mg, crude) as a white solid. ESI [M+H] = 435.3. Step 6: (R)-2-chloro-4-(4-(2-(methoxy-d3)propoxy)phenyl)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile (391-F). To a solution of (R)-2-amino-4-(4-(2- (methoxy-d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (470 mg, 1.08 mmol, 1 eq) in ACN (3 mL) was added t-BuONO (479.61 mg, 4.65 mmol, 553.19 μL, 4.3 eq) and CuCl2 (479.91 mg, 3.57 mmol, 3.3 eq). The mixture was stirred at 60°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give (R)-2-chloro-4- (4-(2-(methoxy-d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (400 mg, crude) as a white solid. ESI [M+H] = 454.1. Step 7: (R)-4-(4-(2-(methoxy-d3)propoxy)phenyl)-2-(methylamino)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile (391). To a solution of (R)-2-chloro-4-(4-(2- (methoxy-d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (100 mg, 220.28 μmol, 1 eq) and methanamine;hydrochloride (22.31 mg, 330.43 μmol, 1.5 eq) in ACN (1 mL) was added K2CO3 (152.22 mg, 1.10 mmol, 5 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (150 × 40 mm, 10 mm); flow rate: 25 mL/min; gradient: 35% – 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give (R)-4-(4-(2-(methoxy-d3)propoxy)phenyl)-2- (methylamino)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (42.2 mg, 93.61 μmol, 42.49% yield, 99.5% purity) as a white solid. ESI [M+H] = 449.2.1H NMR (400 MHz, CD3OD) δ = 8.50 (d, J = 4.4 Hz, 1H), 7.82 (dt, J = 7.6, 2.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.33 (dd, J = 6.8, 5.2 Hz, 1H), 7.14 - 7.05 (m, 2H), 4.71 (s, 2H), 4.07 - 3.98 (m, 2H), 3.85 - 3.71 (m, 1H), 3.00 (s, 3H), 1.28 (d, J = 6.4 Hz, 3H). Table 2: Compounds synthesized in a similar manner as compound 391, but with different starting materials.
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Protocol 2. 2-Amino-6-(1H-indol-4-ylmethylsulfanyl)-4-[4-(oxetan-3- yloxy)phenyl]pyridine-3,5-dicarbonitrile (22)
Figure imgf000183_0001
Step 1. tert-Butyl 4-(chloromethyl)indole-1-carboxylate (22-B) To a mixture of tert- butyl 4-(hydroxymethyl)indole-1-carboxylate (180 mg, 727.89 µmol, 1 eq) in CHCl3 (2.5 mL) was added SOCl2 (173.19 mg, 1.46 mmol, 105.61 µL, 2 eq) at 0°C, the mixture was stirred at 65 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give tert-butyl 4-(chloromethyl)indole-1-carboxylate (180 mg, crude) as brown solid. [M+H] = 265.7 Step 2. tert-Butyl 4-[[6-amino-3,5-dicyano-4-[4-(oxetan-3-yloxy)phenyl]-2-pyridyl]- sulfanylmethyl]indole-1-carboxylate (22-C). To a mixture of 2-amino-4-[4-(oxetan-3- yloxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (150 mg, 462.45 µmol, 1 eq) and tert- butyl 4-(chloromethyl)indole-1-carboxylate (122.89 mg, 462.45 µmol, 1 eq) in DMF (2 mL) was added K2CO3 (191.74 mg, 1.39 mmol, 3 eq) at 25°C, the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition saturated aqueous NaCl (20 mL), and then extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE:EtOAc = 1:1) to give tert-butyl 4-[[6-amino-3,5-dicyano-4-[4- (oxetan-3-yloxy)phenyl]-2-pyridyl]sulfanylmethyl]indole-1-carboxylate (70 mg, 126.44 µmol, 27.34% yield) as brown solid. [M+H] = 554.3 Step 3. 2-Amino-6-(1H-indol-4-ylmethylsulfanyl)-4-[4-(oxetan-3-yloxy)phenyl]- pyridine-3,5-dicarbonitrile (22). A mixture of tert-butyl 4-[[6-amino-3,5-dicyano-4-[4- (oxetan-3-yloxy)phenyl]-2-pyridyl]-sulfanylmethyl]indole-1-carboxylate (50 mg, 90.31 µmol, 1 eq) in DCM (3 mL) and TFA (0.1 mL) was stirred at 25 °C for 72 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C1875 mm×30mm×3 µm; mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 30%-60% over 8 min, to give 2-amino-6-(1H- indol-4-ylmethylsulfanyl)-4-[4-(oxetan-3-yloxy)phenyl]pyridine-3,5-dicarbonitrile (10.1 mg, 22.27 µmol, 24.66% yield, 100% purity) as a white solid. 1H-NMR (400 MHz, CDCl3) δ = 1.71-1.82 (m, 1H), 2.14-2.27 (m, 1 H), 2.67 (dt, J=13.2, 6.8 Hz, 1H), 3.41 (dd, J=7.2, 2.0 Hz, 2H), 3.63 (dd, J=8.8, 5.6 Hz, 1H), 3.81 (q, J=7.6 Hz, 1H), 3.89-3.97 (m, 2 H), 4.76-4.90 (m, 2H), 5.02 (br t, J=6.8 Hz, 2H), 5.30 (quin, J=5.6 Hz, 1H), 6.89 (br d, J=8.4 Hz, 2H), 7.53 (br d, J = 8.4 Hz, 2H), 8.78 (s, 1H). [M+H] = 454.2.
Table 2: Compounds synthesized in a similar manner as compound 22, but with different starting materials.
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0002
Protocol 3. 2-(Azetidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(oxetan-3- ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (63)
Figure imgf000187_0001
Step 1.2-Amino-4-[4-(2-hydroxyethoxy)phenyl]-6-[(4-methoxyphenyl)methyl- sulfanyl]pyridine-3,5-dicarbonitrile (63-B). A mixture of 2-amino-4-[4-(2- hydroxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (63-A, 500 mg, 60 mmol, 1 eq) , 1-(chloromethyl)-4-methoxy-benzene (300.84 mg, 1.92 mmol, 261.60 µL, 1.2 eq) , K2CO3 (442.48 mg, 3.20 mmol, 2 eq) in DMF (5 mL) was stirred at 45 °C for 2 h. To the reaction mixture was added H2O (8 mL) and the reaction mixture was filtered, and the filter cake was collected to give 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-[(4-methoxy- phenyl)methylsulfanyl]pyridine-3,5-dicarbonitrile (420 mg, 971.11 µmol, 60.66% yield) as a brown solid. ESI [M+H] = 433.1. Step 2.2-Chloro-4-[4-(2-hydroxyethoxy)phenyl]-6-[(4-methoxyphenyl)methyl- sulfanyl]pyridine-3,5-dicarbonitrile (63-C). A mixture of 2-amino-4-[4-(2- hydroxyethoxy)phenyl]-6-[(4-methoxyphenyl)methylsulfanyl]-pyridine-3,5-dicarbonitrile (300 mg, 693.65 µmol, 1 eq) , tert-butyl nitrite (143.06 mg, 1.39 mmol, 165.00 µL, 2 eq) , CuCl2 (186.52 mg, 1.39 mmol, 2 eq) in ACN (4 mL) was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 2-chloro-4-[4-(2- hydroxyethoxy)phenyl]-6-[(4-methoxyphenyl)methylsulfanyl]pyridine-3,5-dicarbonitrile (250 mg, 553.19 µmol, 79.75% yield) as a green solid. ESI [M+H] = 452.1. Step 3. 2-(Azetidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]-6-[(4-methoxyphenyl)- methylsulfanyl]pyridine-3,5-dicarbonitrile (63-D). A mixture of 2-chloro-4-[4-(2- hydroxyethoxy)phenyl]-6-[(4-methoxyphenyl)methylsulfanyl]-pyridine-3,5-dicarbonitrile (250 mg, 553.19 µmol, 1 eq) , azetidine (63.17 mg, 1.11 mmol, 74.67 µL, 2 eq), in MeOH (3 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was collected. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 mm×40 mm×10 µm; mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 45%-75% over 8 min, to give 2-(azetidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]-6-[(4- methoxyphenyl)-methylsulfanyl]pyridine-3,5-dicarbonitrile (150 mg, 317.42 µmol, 57.38% yield) as a white solid. ESI [M+H] = 473.2. Step 4. 2-(Azetidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5- dicarbonitrile (63-E). A mixture of 2-(azetidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]-6-[(4- methoxyphenyl)-methyl-sulfanyl]pyridine-3,5-dicarbonitrile (120 mg, 253.94 µmol, 1 eq) in TFA (3 mL) at 75 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 2-(azetidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5- dicarbonitrile (80 mg, 227.01 µmol, 89.40% yield) as a yellow solid. ESI [M+H] = 353.2. Step 5. 2-(Azetidin-1-yl)-4-[4-(2-hydroxyethoxy)phenyl]-6-(oxetan-3- ylmethylsulfanyl)-pyridine-3,5-dicarbonitrile (63). A mixture of 2-(azetidin-1-yl)-4-[4-(2- hydroxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (70 mg, 198.63 µmol, 1 eq) , 3-(bromomethyl)oxetane (32.99 mg, 218.50 µmol, 1.1 eq) , K2CO3 (54.90 mg, 397.27 µmol, 2 eq) in DMF (1 mL) was stirred at 45 °C for 2 h. The reaction mixture was filtered, and filtrate was collected. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBDC18150 mm×40 mm×10 µm; mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 25%-55% over 8 min, to give 2-(azetidin-1-yl)-4-[4-(2- hydroxyethoxy)phenyl]-6-(oxetan-3-ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (0.7 mg, 1.66 µmol, 0.83% yield, 100% purity) as white solid.1H-NMR (400 MHz, DMSO-d6) δ = 7.43 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.82 - 5.03 (m, 1H), 4.75 - 5.09 (m, 2H), 4.63 (dd, J = 7.6, 6.4 Hz, 6H), 4.28 - 4.37 (m, 2H), 4.05 (t, J = 4.8 Hz, 2H), 3.72 (t, J = 4.4 Hz, 2H), 3.52 (d, J = 7.2 Hz, 1H), 2.29 - 2.42 (m, 2H). Table 3: Compounds synthesized in a similar manner as compound 63, but with different starting materials.
Figure imgf000189_0001
Figure imgf000190_0001
Protocol 4. 4-[4-(2-hydroxyethoxy)phenyl]-2-(oxetan-3-ylmethythio)pyridine-3,5- dicarbonitrile (61)
Figure imgf000191_0001
Step 1.4-(4-(2-Hydroxyethoxy)phenyl)-2-((4-methoxybenzyl)thio)pyridine-3,5- dicarbonitrile (61-B). A mixture of 2-amino-4-[4-(2-hydroxyethoxy)phenyl]-6-[(4- methoxyphenyl)methyl-thio]pyridine-3,5-dicarbonitrile (0.88 g, 2.03 mmol, 1 eq), tert-butyl nitrite (1.19 g, 10.17 mmol, 1.37 mL, 5 eq), CuCl2 (164.14 mg, 1.22 mmol, 0.6 eq) in MeCN (10 mL) was stirred at 60 °C for 48 h. The reaction mixture was filtered, and the filtrate was collected. The residue was purified by prep-HPLC (column: Kromasil C18 (250 mm×50 mm×10 µm); mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 50%-75% over 10 min, to give 4-[4-(2-hydroxyethoxy)phenyl]-2-[(4-methoxyphenyl)- methylthio]pyridine-3,5-dicarbonitrile (220 mg, 526.97 µmol, 25.90% yield) as a white solid. ESI [M+H] = 418.1. Step 2.4-[4-(2-Hydroxyethoxy)phenyl]-2-thiopyridine-3,5-dicarbonitrile (61-C). A mixture of 4-[4-(2-hydroxyethoxy)phenyl]-2-[(4-methoxyphenyl)methylthio]pyridine-3,5- dicarbonitrile (200 mg, 479.07 µmol, 1 eq) in TFA (3 mL) was stirred at 75 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 4-[4-(2- hydroxyethoxy)phenyl]-2-thiopyridine-3,5-dicarbonitrile (100 mg, 336.33 µmol, 70.20% yield) as a brown oil. ESI [M+H] = 296.0. Step 3. 4-[4-(2-Hydroxyethoxy)phenyl]-2-(oxetan-3-ylmethylthio)pyridine-3,5- dicarbonitrile (61). A mixture of 4-[4-(2-hydroxyethoxy)phenyl]-2-thiopyridine-3,5- dicarbonitrile (100 mg, 336.33 µmol, 1 eq), 3-(bromomethyl)oxetane (60.94 mg, 403.59 µmol, 1.2 eq), K2CO3 (92.96 mg, 672.65 µmol, 2 eq) in DMF (2 mL) was stirred at 45 °C for 1 h. The reaction mixture was filtered, and the filtrate was collected. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 mm×40mm×10 µm; mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 25%-55% over 8 min, to give 4-[4-(2-hydroxyethoxy)phenyl]-2-(oxetan-3-ylmethylsulfanyl)pyridine-3,5- dicarbonitrile (53.8 mg, 146.43 µmol, 43.54% yield, 100% purity) as white solid. 1H-NMR (400 MHz, DMSO-d6) δ = 9.11 (d, J = 0.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 4.91 (t, J = 5.2 Hz, 1H), 4.61 - 4.68 (m, 2H), 4.34 (t, J = 6.4 Hz, 2H), 4.04 - 4.11 (m, 2H), 3.58 - 3.80 (m, 4H), 3.32 - 3.37 (m, 1H). ESI [M+H] = 368.0 Table 4: Compounds synthesized in a similar manner as compound 61, but with different starting materials.
Figure imgf000192_0001
Protocol 5. 4-[4-(2-Methoxyethoxy)phenyl]-2-(3-pyridylmethylthio)-pyridine-3,5- dicarbonitrile (83)
Figure imgf000193_0001
A mixture of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-(3-pyridylmethylthio)pyridine-3,5- dicarbonitrile (200 mg, 479.06 µmol, 1 eq), t-BuONO (395.20 mg, 3.83 mmol, 455.83 µL, 8 eq) in THF (5 mL) was stirred at 50 °C for 12 h under N2 atmosphere. The reaction mixture was filtered, and the filtrate was collected. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150 mm×40 mm×10 µm; mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 30%-55% over 8 min, to give 4-[4-(2- methoxyethoxy)phenyl]-2-(3-pyridylmethyl-thio)pyridine-3,5-dicarbonitrile (147.5 mg, 340.83 µmol, 71.15% yield, 93.0% purity) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ = 9.22 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.49 (dd, J=4.8, 1.2 Hz, 1H), 7.91 (dt, J=7.6, 1.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.39 (dd, J=7.8, 4.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 2H), 4.68 (s, 2H), 4.22 Protocol 6. 2-Cyclopropyl-4-[4-(2-hydroxyethoxy)phenyl]-6-(3-pyridylmethylsulfanyl)- pyridine-3,5-dicarbonitrile (45)
Figure imgf000193_0002
Step 1.2-Cyclopropyl-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5- dicarbonitrile (45-B). A mixture of 4-(2-hydroxyethoxy)benzaldehyde (300 mg, 1.81 mmol, 1 eq), 3-cyclopropyl-3-oxo-propanenitrile (197.01 mg, 1.81 mmol, 1 eq) and 2- cyanothioacetamide (180.79 mg, 1.81 mmol, 1 eq) and NMM (456.53 mg, 4.51 mmol, 496.22 µL, 2.5 eq) in EtOH (5 mL) was degassed at 80 °C for 2 h. The reaction mixture was added H2O (20 mL) at 0°C, and then extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2- cyclopropyl-4-[4-(2-hydroxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (350 mg, crude) as a yellow oil. [M+H] = 338.0. Step 2.2-Cyclopropyl-4-[4-(2-hydroxyethoxy)phenyl]-6-(3-pyridylmethyl- sulfanyl)pyridine-3,5-dicarbonitrile (45). A mixture of 2-cyclopropyl-4-[4-(2- hydroxyethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (350 mg, 1.04 mmol, 1 eq), 3- (chloromethyl)pyridine (198.51 mg, 1.56 mmol, 1.5 eq) and K2CO3 (286.74 mg, 2.07 mmol, 2 eq) in DMF (3 mL) was stirred at 45 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by HPLC using a column Phenomenex Gemini-NX 80 mm × 40 mm × 3 µm; mobile phase A: 10 mM NH4HCO3 in water, mobile phase B: ACN; 30%-55% over 8 min, to give 2-cyclopropyl-4-[4-(2- hydroxyethoxy)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (56.9 mg, 129.20 µmol, 12.45% yield, 97.3% purity) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ = 8.60 (s, 1H) 8.45 (d, J=4.8 Hz, 1H) 7.79 (d, J=7.6 Hz, 1H) 7.55 (d, J=8.4 Hz, 2H) 7.35 (dd, J=7.6, 4.8 Hz, 1H) 7.36-7.08 (m, 1H) 7.12 (d, J=8.8 Hz, 1H) 4.91 (t, J=5.2 Hz, 1H) 4.55 (s, 2H) 4.06 (t, J=4.8 Hz, 2H) 3.72 (q, J=4.8 Hz, 2H) 2.44-2.40 (m, 1H) 1.28-1.20 (m, 2H) 1.16-1.08 (m, 2H). [M+H] = 429.1. Table 5: Compounds synthesized in a similar manner as described for compound 45, but with different starting materials.
Figure imgf000194_0001
Figure imgf000195_0001
Protocol 7. 2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-methyl-pyridine-3,5- dicarbonitrile (39)
Figure imgf000196_0001
Step 1: (2Z)-2-[[4-(2-Methoxyethoxy)phenyl]methylene]-3-oxo-butanenitrile (39B). To a solution of 4-(2-methoxyethoxy)benzaldehyde (1 g, 5.55 mmol, 1 eq) in EtOH (10 mL) was added L-proline (638.90 mg, 5.55 mmol, 1 eq) and 3-oxobutanenitrile (461.09 mg, 5.55 mmol, 1 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered, and the filtrate was collected to give (2Z)-2-[[4-(2-methoxyethoxy)phenyl]methylene]-3-oxo- butanenitrile (800 mg, crude) as a white oil. [M+H] = 246.1 Step 2: 4-[4-(2-Methoxyethoxy)phenyl]-2-methyl-6-sulfanyl-pyridine-3,5- dicarbonitrile (39-C). To a solution of (2E)-2-[[4-(2-methoxyethoxy)phenyl]methylene]-3- oxo-butanenitrile (700 mg, 2.85 mmol, 1 eq) in EtOH (10 mL) was added NMM (577.34 mg, 5.71 mmol, 627.54 µL, 2 eq) and 2-cyanothioacetamide (285.80 mg, 2.85 mmol, 1 eq). The mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, and the solid was collected to give 4-[4-(2-methoxyethoxy)phenyl]-2-methyl-6-sulfanyl-pyridine-3,5- dicarbonitrile (450 mg, crude) as white oil. ESI [M+H] = 326.1 Step 3: 2-Benzylsulfanyl-4-[4-(2-methoxyethoxy)phenyl]-6-methyl-pyridine-3,5- dicarbonitrile (39-D). To a solution of 4-[4-(2-methoxyethoxy)phenyl]-2-methyl-6-sulfanyl- pyridine-3,5-dicarbonitrile (50 mg, 153.66 µmol, 1 eq) in DMF (1 mL) was added K2CO3 (42.47 mg, 307.33 µmol, 2 eq) and bromomethylbenzene (26.28 mg, 153.66 µmol, 18.25 µL, 1 eq). The mixture was stirred at 45 °C for 2 h. The reaction mixture was poured into 10 mL of H2O and extracted with EtOAc (3×10 mL). The combined organic phase was extracted with H2O (3×10 mL), then dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give 2-benzylsulfanyl-4-[4-(2-methoxyethoxy)phenyl]-6-methyl-pyridine-3,5- dicarbonitrile (50 mg, crude) as a white oil. ESI [M+H] = 416.1. Step 4: 2-Benzylsulfonyl-4-[4-(2-methoxyethoxy)phenyl]-6-methyl-pyridine-3,5- dicarbonitrile (39-E). To a solution of 2-benzylsulfanyl-4-[4-(2-methoxyethoxy)phenyl]-6- methyl-pyridine-3,5-dicarbonitrile (50 mg, 120.34 µmol, 1 eq) in THF (2 mL) and DMF (1 mL) was added m-CPBA (73.29 mg, 361.01 µmol, 85% purity, 3 eq). The mixture was stirred at 20 °C for 12h. The reaction mixture was quenched by addition of saturated aqueous Na2SO3 (5 mL) at 0°C, and then extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2- benzylsulfonyl-4-[4-(2-methoxyethoxy)phenyl]-6-methyl-pyridine-3,5-dicarbonitrile (50 mg, crude) as a white oil. ESI [M+H] = 448.1. Step 5: 2-Amino-4-[4-(2-methoxyethoxy)phenyl]-6-methyl-pyridine-3,5-dicarbonitrile (39). To a solution of 2-benzylsulfonyl-4-[4-(2-methoxyethoxy)phenyl]-6-methyl-pyridine- 3,5-dicarbonitrile (20 mg, 44.69 µmol, 1 eq) in DMF (2 mL) was added NH3 in water (5.59 mg, 44.69 µmol, 6.15 µL, 28% purity, 1 eq). The mixture was stirred at 20 °C for 4 h. The reaction mixture was filtered, and the filtrate was collected. The crude was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 75 mm × 30 mm × 3 µm; mobile phase A: 0.05% NH3 + 10 mM NH4HCO3 in water, mobile phase B: ACN; 20%-45% over 8 min, to give 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-methyl-pyridine-3,5-dicarbonitrile (1.9 mg, 5.92 µmol, 13.25% yield, 96.08% purity) as a white solid. 1H-NMR (400 MHz, CDCl3) δ = 7.52 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 5.72 (s, 2H), 4.22 (t, J=9.6, 4.8 Hz, 2H), 3.81 (t, J=9.6, 4.8 Hz, 2H), 3.49 (s, 3H), 2.70 (m, 3H). [M+H] = 309.1 Protocol 8.2-Amino-4-[4-(1,1-difluoro-2-hydroxy-ethoxy)phenyl]-6-(oxetan-3- ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (311)
Figure imgf000198_0001
Step 1: Ethyl 2-(4-bromophenoxy)-2,2-difluoroacetate (311-B). To a mixture of 4-bro mophenol (10 g, 57.80 mmol, 1 eq) and ethyl 2-bromo-2,2-difluoroacetate (15.25 g, 75.14 m mol, 9.65 mL, 1.3 eq) in DMF (100 mL) was added DBU (11.44 g, 75.14 mmol, 11.33 mL, 1. 3 eq) and the mixture was stirred at 70°C for 12 hrs under N2. The reaction mixture was filter ed. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate =10/1 to 1/1,plate1), based on TLC (Plate 1: Petroleum ether : Ethyl acetate=3:1) to give ethy l 2-(4-bromophenoxy)-2,2-difluoroacetate (7 g, 23.72 mmol, 41.04% yield) as brown oil. [M +H]=294.1.1H-NMR (400 MHz, CD3OD) δ ppm 7.46 - 7.36 (m, 2H), 7.04 (d, J = 8.8 Hz, 2H ), 4.32 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H) Step 2: 2-(4-Bromophenoxy)-2,2-difluoro-ethanol (311-C). To a mixture of LiAlH4 (1. 67 g, 44.06 mmol, 2 eq) in THF (3 mL) was added ethyl 2-(4-bromophenoxy)-2,2-difluoroac etate (6.5 g, 22.03 mmol, 1 eq) and the mixture was stirred at 0°C for 1 hr under N2. The react ion mixture was quenched by addition Na2SO4.10H2O 3g at 0 °C, and then diluted with THF 50 mL. The mixture was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ethe r/Ethyl acetate=10/1 to 1/1,plate1), based on TLC (Plate 1: Petroleum ether : Ethyl acetate=8: 1) to give 2-(4-bromophenoxy)-2,2-difluoroethanol (3.9 g, 15.41 mmol, 69.97% yield) as Bro wn oil. [M+H]=252.8. Step 3: 4-(1,1-Difluoro-2-hydroxy-ethoxy)benzaldehyde (311-D). To a mixture of 2-(4 -bromophenoxy)-2,2-difluoroethanol (1.5 g, 5.93 mmol, 1 eq) in THF (50 mL) was added n- BuLi (2.5 M, 7.11 mL, 3 eq) at -78°C for 0.5 hr , then was added DMF (866.58 mg, 11.86 m mol, 912.19 uL, 2 eq), the mixture was stirred at 20°C for 1.5 hrs under N2. The reaction mixt ure was diluted with sat.aq NH4Cl 50 mL and extracted with EtOAc (15 mL × 3). The combi ned organic layers were washed with sat.aq.NaCl (10 mL),dried over Na2SO4, filtered and co ncentrated under reduced pressure to give a residue. The residue was purified by column chro matography (SiO2, Petroleum ether/Ethyl acetate=50/1 to 1/1,plate1), based on TLC (Plate 1: Petroleum ether : Ethyl acetate=8:1) to give 4-(1,1-difluoro-2-hydroxy-ethoxy)benzaldehyde (300 mg, 1.48 mmol, 25.03% yield) as Brown oil. [M+H]=203.0. Step 4: 2-Amino-4-[4-(1,1-difluoro-2-hydroxy-ethoxy)phenyl]-6-sulfanyl-pyridine-3,5 -dicarbonitrile (311-E). To a mixture of 4-(1,1-difluoro-2-hydroxy-ethoxy)benzaldehyde (27 0 mg, 1.34 mmol, 1 eq) and 2-cyanothioacetamide (294.25 mg, 2.94 mmol, 2.2 eq) in EtOH ( 5 mL) was added NMM (405.28 mg, 4.01 mmol, 440.52 uL, 3 eq), the mixture was stirred at 60°C for 2 hrs. The reaction mixture was diluted with H2O10 mL and extracted with EtOAc ( 15 mL × 3). The combined organic layers were washed with sat.aq.NaCl (10 mL),dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. to give 2-amino-4 -[4-(1,1-difluoro-2-hydroxy-ethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (300 mg, c rude) as Brown oil. [M+H]=349.2. Step 5: 2-Amino-4-[4-(1,1-difluoro-2-hydroxy-ethoxy)phenyl]-6-(oxetan-3- ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (311). To a solution of 2-amino-4-[4-(1,1- difluoro-2-hydroxy-ethoxy)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (120 mg, 344.50 umol, 1 eq) and 3-(bromomethyl)oxetane (104.04 mg, 689.01 umol, 2 eq) in DMF (1 mL) was added K2CO3 (142.84 mg, 1.03 mmol, 3 eq) ,the mixture was stirred at 20°C for 0.5 hr.The reaction mixture was filtered. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (75 × 30 mm, 3 mm); flow rate: 25 mL/min; gradient: 25% – 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-amino-4-[4-(1,1-difluoro-2-hydroxy-ethoxy)phenyl]-6-(oxetan-3- ylmethylsulfanyl)pyridine-3,5-dicarbonitrile (38.7 mg, 92.49 umol, 26.85% yield, 100% purity) as a brown oil.1H NMR (400 MHz, CD3OD) δ = 7.58 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.83 (d, J = 7.6 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.96 (t, J = 9.6 Hz, 2H), 3.65 (d, J = 7.6 Hz, 2H), 3.51 - 3.40 (m, 1H). [M+H]=419.2 Table 6: Compounds synthesized in a similar manner as described for compound 311.
Figure imgf000200_0001
Protocol 9.2-Amino-4-(4-((1r,3r)-3-hydroxycyclobutoxy)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (295) and 2-Amino-4-(4-((1s,3s)-3- hydroxycyclobutoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (296)
Figure imgf000201_0001
Step 1: 3-(Benzyloxy)cyclobutan-1-ol (295-B). To a mixture of 3-(benzyloxy)cyclobut an-1-one (5.0 g, 28.38 mmol, 1.0 eq) in MeOH (60.0 mL) was added NaBH4 (1.29 g, 34.05 m mol, 1.2 eq) at 0°C and the mixture was stirred at 20°C for 1.5 hrs. TLC (Petroleum ether:Eth yl acetate = 1:1) showed the reaction was completed and then quenched by addition of saturat ed aqueous NH4Cl (100 mL) at 0°C and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrate d. The residue was purified by preparative TLC (SiO2, Petroleum ether:Ethyl acetate = 1:1) to give 3-(benzyloxy)cyclobutan-1-ol (3.6 g, 20.20 mmol, 71% yield) as yellow oil.1H NMR (4 00 MHz, CD3OD) δ ppm 7.39 - 7.26 (m, 5H), 4.49 - 4.37 (m, 2H), 3.91 -3.79 (m, 1H), 3.71 - 3.57 (m, 1H), 2.78 - 2.55 (m, 2H), 2.00 - 1.78 (m, 2H). Step 2: 3-(Benzyloxy)cyclobutyl methanesulfonate (295-C). To a mixture of 3-(benzyl oxy)cyclobutan-1-ol (3.5 g, 19.64 mmol, 1.0 eq) in DCM (50.0 mL) was added TEA (5.96 g, 58.91 mmol, 8.20 mL, 3.0 eq) and methanesulfonyl chloride (3.37 g, 29.46 mmol, 1.5 eq) at 0 °C and the mixture was stirred at 25°C for 1 hr. Then the mixture was quenched by addition o f saturated aqueous Na2CO3 (100 mL) at 0°C and extracted with EtOAc (100 mL × 3). The c ombined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and co ncentrated. The residue was purified by preparative TLC (SiO2, Petroleum ether:Ethyl acetate = 1:1) to give 3-(benzyloxy)cyclobutyl methanesulfonate (4.5 g, 17.56 mmol, 89.40% yield) as yellow oil. Step 3: 4-(3-(Benzyloxy)cyclobutoxy)benzaldehyde (295-D). To a mixture of 3-(benzy loxy)cyclobutyl methanesulfonate (4.5 g, 17.56 mmol, 1.0 eq) and 4-hydroxybenzaldehyde (2 .14 g, 17.56 mmol, 1.0 eq) in DMF (25.0 mL) was added Cs2CO3 (11.44 g, 35.11 mmol, 2 eq ) at 25°C, the mixture was stirred at 100°C for 5 hrs. Then the mixture was filtered and the fil trate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether:Ethyl acetate = 3:1) to give 4-(3-(benzyloxy)cyclobu toxy)benzaldehyde (2.5 g, 8.85 mmol, 50.44% yield) as yellow oil. [M+H]=283.1 Step 4: 3-(4-(Hydroxymethyl)phenoxy)cyclobutan-1-ol (295-E). To a mixture of 4-(3-( benzyloxy)cyclobutoxy)benzaldehyde (1.0 g, 3.54 mmol, 1.0 eq) in MeCN (15.0 mL) was ad ded NaI (1.59 g, 10.63 mmol, 3 eq) and TMSCl (1.15 g, 10.63 mmol, 3 eq) at 25°C and the m ixture was stirred at 60°C for 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether:Ethyl acetate = 1:1) to give 3-(4-(hydroxymethyl)phenoxy)cyclobutan-1-ol ( 400.0 mg, 2.06 mmol, 58.15% yield) as yellow solid. [M+H]=193.1.1H NMR (400 MHz, C D3OD) δ ppm 9.86 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.87 - 6.76 (m, 2H), 5.34 (s, 1H), 4.91 - 4.80 (m, 1H), 4.59 - 4.45 (m, 1H), 2.53 - 2.33 (m, 4H) Step 5: 4-(3-Hydroxycyclobutoxy)benzaldehyde (295-F). To a mixture of 3-(4-(hydro xymethyl)phenoxy)cyclobutan-1-ol (350.0 mg, 1.80 mmol, 1.0 eq) in THF (15.0 mL) was ad ded MnO2 (234.99 mg, 2.70 mmol, 1.5 eq) at 25°C and the mixture was stirred at 60°C for 1 hr. Then the mixture was filtered and the filtrate was concentrated under reduced pressure to give 4-(3-hydroxycyclobutoxy)benzaldehyde (300.0 mg, crude) as yellow solid.1H NMR (40 0 MHz, CD3OD) δ ppm 9.85 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 5.03 - 4.96 (m, 1H), 4.54 (t, J = 6.4 Hz, 1H), 2.55 - 2.41 (m, 4H). Step 6: 2-Amino-4-(4-(3-hydroxycyclobutoxy)phenyl)-6-mercaptopyridine-3,5- dicarbonitrile (295-G). To a mixture of 4-(3-hydroxycyclobutoxy)benzaldehyde (300.0 mg, 1.56 mmol, 1.0 eq) and 2-cyanoethanethioamide (390.75 mg, 3.90 mmol, 2.5 eq) in EtOH (5.0 mL) was added NMM (394.67 mg, 3.90 mmol, 2.5 eq) at 25°C and the mixture was stirred at 25°C for 12 hrs. Then the mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-amino-4-(4-(3-hydroxycyclobutoxy)phenyl)-6- mercaptopyridine-3,5-dicarbonitrile (230.0 mg, 679.70 umol, crude) as yellow solid. [M+H]=339.1 Step 7: 2-Amino-4-(4-((1r,3r)-3-hydroxycyclobutoxy)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (295) and 2-Amino-4-(4-((1s,3s)-3- hydroxycyclobutoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (296). To a mixture of 2-amino-4-(4-(3-hydroxycyclobutoxy)phenyl)-6-mercaptopyridine-3,5- dicarbonitrile (220.0 mg, 650.15 umol, 1.0 eq) and 3-(chloromethyl)pyridine (95.98 mg, 585.14 umol, 0.9 eq) in DMF (4.0 mL) was added K2CO3 (179.71 mg, 1.30 mmol, 2 eq) at 25°C and the mixture was stirred at 80°C for 2 hrs The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 column (100 × 30 mm, 10 um); flow rate: 25 mL/min; gradient: 20% – 50% B over 10 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give the product as a mixture of stereoisomers. The mixture was further separated by SFC (Instrument: Waters UPCC with PDA； Column: DAICEL CHIRALPAK IG (250mm*30mm,10um); Mobile phase A: CO2 B: 0.1%IPA in EtOH, ; Gradient: B%=45% isocratic elution mode; Flow rate: CO2 (4.2 mg/min), B(3.4 mL/min); Wavelength:220 nm; Column temperature: 35ºC； System back pressure: 2000 Psi) to give 2-amino-4-(4-((1r,3r)-3-hydroxycyclobutoxy)phenyl)-6-((pyridin- 3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (47.9 mg, 105.34 umol, 16.20% yield, 94.45% purity, free), 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 7.95 (dt, J = 7.6, 1.6 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.35 (dd, J = 7.6, 4.8 Hz, 1H), 6.98 - 6.93 (m, 2H), 5.20 (d, J = 5.2 Hz, 1H), 4.90 (t, J = 5.2 Hz, 1H), 4.50 (s, 2H), 4.43 - 4.34 (m, 1H), 2.34 (t, J = 5.6 Hz, 4H), [M+H]=430.2, and 2-amino-4-(4-((1s,3s)-3- hydroxycyclobutoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (8.7 mg, 20.07 umol, 3.09% yield, 99.07% purity), 1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 4.4, 1.2 Hz, 1H), 7.96 (dt, J = 7.2 Hz, 1H), 7.46(d, J = 8.8 Hz, 2H), 7.36 (dd, J = 7.2, 4.8 Hz, 1H), 7.03 - 6.96 (m, 2H), 5.25 (d, J = 6.4 Hz, 1H), 4.50 (s, J = 5.2 Hz, 1H), 4.50 (s, 2H), 4.43 - 4.34 (m, 1H), 2.34 (t, J = 5.6 Hz, 4H). [M+H]=430.2 Table 7: Compounds synthesized in a similar manner as described for compounds 295 and 296.
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Protocol 10.2-Methoxy-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan-3- yloxy)phenyl)pyridine-3,5-dicarbonitrile (294)
Figure imgf000206_0001
Step 1: 2-Amino-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3, 5-dicarbonitrile (294-A). To a mixture of 2-amino-6-mercapto-4-(4-(oxetan-3-yloxy)phenyl) pyridine-3,5-dicarbonitrile (1.0 g, 3.08 mmol, 1.0 eq) and 3-(bromomethyl)oxetane (465.54 mg, 3.08 mmol, 1.0 eq) in DMF (5.0 mL) was added K2CO3 (852.19 mg, 6.17 mmol, 2.0 eq) at 25°C and the recation mixture was stirred at 25°C for 1 hr. The reaction mixture was filtere d and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Ethyl acetate : Petroleum ether = 1:0 to 1: 2 ) to give 2-amino-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-di carbonitrile (550.0 mg, 1.39 mmol, 45.23% yield) as brown solid. [M+H] = 395.1 Step 2: 2-Chloro-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3, 5-dicarbonitrile (294-B). To a mixture of 2-amino-4-[4-(oxetan-3-yloxy)phenyl]-6-(3-pyridyl methylsulfanyl)pyridine-3,5-dicarbonitrile (250 mg, 633.80 umol, 1.0 eq) in MeCN (3.0 mL) was added t-BuONO (98.04 mg, 950.70 umol, 113.08 ul, 1.5 eq) and CuCl (125.49 mg, 1.27 Mmol, 2.0 eq) at 25°C, the recation mixture was stirred at 60°C for 1 hr under N2 atmosphere . The reaction mixture was filtered and the filtrate was concentrated under reduced pressure t o give a residue. The residue was purified by preparative TLC (Petroleum ether : Ethyl acetat e = 0:1) to give 2-chloro-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3 ,5-dicarbonitrile (120.0 mg, crude) as green solid. [M+H] = 414.1 Step 3: 2-Methoxy-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan-3-yloxy)phenyl)pyridine- 3,5-dicarbonitrile (294). To a mixture of 2-chloro-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan- 3-yloxy)phenyl)pyridine-3,5-dicarbonitrile (35.0 mg, 84.57 umol, 1.0 eq) in MeOH (1.0 mL) was added NaOMe (5.48 mg, 101.48 umol, 1.2 eq) at 25°C, the recation mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 (100 × 30 mm, 10 um); flow rate: 25 mL/min; gradient: 40% – 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-methoxy-6-((oxetan-3-ylmethyl)thio)-4-(4-(oxetan-3- yloxy)phenyl)pyridine-3,5-dicarbonitrile (7.2 mg, 17.58 umol, 20.79% yield) as white solid. [M+H] = 410.2.1H-NMR (400 MHz, DMSO-d6) δ ppm 7.57 (d, 2H), 7.02 (d, 2H), 5.40 (t, 1H), 4.97 (t, 2H), 4.69 (dd, 2H), 4.61 (dd, 2H), 4.39 (t, 2H), 4.15 (s, 3H), 3.70 (d, 2H), 3.48 - 3.39 (m, 1H). Table 8: Compounds synthesized in a similar manner as described for compound 294.
Figure imgf000207_0001
Figure imgf000208_0002
Protocol 11.2-Amino-4-(4-(oxetan-3-yloxy)phenyl)-6-((tetrahydro-2H-pyran-3- yl)methoxy)pyridine-3,5-dicarbonitrile (300)
Figure imgf000208_0001
Step 1: 2-Amino-6-(benzylthio)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5- dicarbonitrile (300-A). To a mixture of 2-amino-6-mercapto-4-(4-(oxetan-3- yloxy)phenyl)pyridine-3,5-dicarbonitrile (2 g, 6.17 mmol, 1 eq) and (bromomethyl)benzene (1.05 g, 6.17 mmol, 732.37 uL, 1.00 eq) in DMF (15 mL) was added K2CO3 (1.70 g, 12.33 mmol, 2 eq) at 25°C, the mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure, then diluted with H2O 30 mL and extracted with EtOAc 90 mL(30 mL×3).The combined organic layers were washed with brine (30 mL×2), dried over Na2SO4,filtered and concentrated under reduced pressure to 2-amino-6- (benzylthio)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-dicarbonitrile (3.8 g, crude) as white oil. [M+H]=415.1. Step 2: 2-Amino-6-(benzylsulfinyl)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5- dicarbonitrile (300-B). To a mixture of 2-amino-6-(benzylthio)-4-(4-(oxetan-3- yloxy)phenyl)pyridine-3,5-dicarbonitrile (3.8 g, 9.17 mmol, 1 eq) in DCM (20 mL) was added m-CPBA (1.12 g, 5.50 mmol, 85% purity, 0.6 eq) at 0°C and the mixture was stirred at 25°C for 5 hrs. The reaction mixture was quenched by addition saturated aqueous Na2SO3 (30 mL) at 0°C, and then extracted with DCM (30 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:0 to 0:1) to give 2-amino-6-(benzylsulfinyl)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5- dicarbonitrile (600 mg, 1.39 mmol, 15.20% yield) as yellow solid.1H-NMR (400 MHz, DMSO-d6) δ = 7.50 (d, J = 8.4 Hz, 2H), 7.44 - 7.37 (m, 3H), 7.25 (dd, J = 6.4, 2.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 5.45 (t, J = 5.2 Hz, 1H), 5.03 (t, J = 6.8 Hz, 2H), 4.66 (dd, J = 7.2, 5.2 Hz, 2H), 4.46 (s, 2H). [M+H]=431.1. Step 3: 2-Amino-4-(4-(oxetan-3-yloxy)phenyl)-6-((tetrahydro-2H-pyran-3- yl)methoxy)pyridine-3,5-dicarbonitrile (300). To a mixture of (tetrahydro-2H-pyran-3- yl)methanol (26.98 mg, 232.30 umol, 1 eq) in THF (2 mL) was added NaH (37.16 mg, 929.20 umol, 60% purity, 4 eq) at 0°C. The mixture was stirred at 25°C for 1 hr, then 2- amino-6-(benzylsulfinyl)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-dicarbonitrile (100 mg, 232.30 umol, 1 eq) was added to the mixture reaction at 0°C, the mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue, and the filter cake was quenched by addition saturated aqueous H2O (2 mL) at 0°C. The residue was purified by preparative HPLC (column: Phenomenex C18 column (75 × 30 mm, 3 um); flow rate: 25 mL/min; gradient: 20% – 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-amino-4-(4-(oxetan-3-yloxy)phenyl)-6- ((tetrahydro-2H-pyran-3-yl)methoxy)pyridine-3,5-dicarbonitrile (19.6 mg, 48.22 umol, 20.76% yield, 100.0% purity) as yellow solid.1H-NMR (400 MHz, DMSO-d6) δ ppm 8.21 - 7.69 (m, 2 H), 7.50 (d, J = 8.8 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 5.44 - 5.33 (m, 1 H), 4.97 (t, J = 6.8 Hz, 2 H), 4.61 (dd, J = 7.2, 5.2 Hz, 2 H), 4.34 - 4.17 (m, 2 H), 3.93 - 3.67 (m, 2 H), 3.40 - 3.35 (m, 1 H), 3.28 (dd, J = 11.2, 9.2 Hz, 1 H), 2.12 - 1.96 (m, 1 H), 1.90 - 1.77 (m, 1 H), 1.69 - 1.46 (m, 2 H), 1.45 - 1.33 (m, 1 H). [M+H] = 407.2 Table 9: Compounds synthesized in a similar manner as described for compound 300.
Figure imgf000210_0001
Protocol 12. 2-(azetidin-l-yl)-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3- yloxy)phenyl)pyridine-3,5-dicarbonitrile (287)
Figure imgf000211_0001
Step 1: 2-Amino-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-di carbonitrile (312). To a mixture of 2-amino-6-(benzylsulfinyl)-4-(4-(oxetan-3-yloxy)phenyl) pyridine-3,5-dicarbonitrile (600.0 mg, 1.39 mmol, 1.0 eq) in DMF (5.0 mL) was added NaH ( 278.73 mg, 6.97 mmol, 5.0 eq) at 0°C and the reaction mixture was stirred at 20 °C for 1 hr. Then oxetan-3-ylmethanol (122.80 mg, 1.39 mmol, 1.0 eq) was added to the mixture reaction at 0°C , the reaction mixture was stirred at 20 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched by addition saturated aqueous H2O (10 mL) at 0°C, and then extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na2SO4, filtered and c oncentrated under reduced pressure to give a residue. The residue was purified by column chr omatography on silica gel (Petroleum ether : Ethyl acetate =1:0 to 0:1) to give 2-amino-6-(ox etan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-dicarbonitrile (260.0 mg, 687.1 4 umol, 49.30% yield) as yellow solid. 1H NMR (400 MHz, CD3OD) δ = 7.54 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.41 (t, J = 5.2 Hz, 1H) , 5.09 (t, J = 6.8 Hz, 2H), 4.91 - 4.87 ( m, 2H) , 4.77 (dd, J = 7.2, 5.2 Hz, 2H), 4.72 (d, J = 6.4 Hz, 2H), 4.63 (t, J = 6.0 Hz, 2 H), 3.5 9 - 3.49(m, 1H). [M+H]=379.4. Step 2: 2-Chloro-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-di carbonitrile (287-A). To a mixture of 2-amino-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy) phenyl)pyridine-3,5-dicarbonitrile (200 mg, 528.57 umol, 1 eq) in MeCN (10.0 mL) was add ed t-BuONO (81.76 mg, 792.85 umol, 94.30 ul, 1.5 eq) and CuCl (156.98 mg, 1.59 mmol, 3. 0 eq) at 25 °C and the reaction mixture was stirred at 60 °C for 5 hrs under N2 atmosphere. T he reaction mixture was filtered and the filtrate was concentrated under reduced pressure to gi ve a residue. The residue was purified by preparative TLC (Petroleum ether : Ethyl acetate = 0:1) to give 2-chloro-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-di carbonitrile (120.0 mg, crude) as brown solid. [M+H] = 398.2. Step 3: 2-(Azetidin-1-yl)-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridin e-3,5-dicarbonitrile (287). To a mixture of 2-chloro-6-(oxetan-3-ylmethoxy)-4-(4-(oxetan-3- yloxy)phenyl)pyridine-3,5-dicarbonitrile (40.0 mg, 100.55 umol, 1.0 eq) in THF (1.0 mL) wa s added TEA (30.52 mg, 301.65 umol, 41.99 uL, 3 eq) and azetidine (17.22 mg, 184.09 umol, 1.83 eq) at 25°C and the reaction mixture was stirred at 25°C for 1 hr. The reaction mixture w as filtered and the filtrate was concentrated under reduced pressure to give a residue. The resi due was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 (150 × 40 m m, 10 um); flow rate: 25 mL/min; gradient: 25% – 65% B over 8 min; mobile phase A: 10 m M aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-(azetidin-1-yl)-6-(oxetan-3-yl methoxy)-4-(4-(oxetan-3-yloxy)phenyl)pyridine-3,5-dicarbonitrile (26.3 mg, 61.37 umol, 61. 04% yield, 97.6% purity) as white solid.1H-NMR (400 MHz, CD3OD) δ ppm 7.48 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.46 - 5.33 (m, 1 H), 5.13 - 5.01 (m, 2H), 4.93 - 4.88 (m, 2 H), 4.87 - 4.84 (m, 1H), 4.80 - 4.72 (m, 2H), 4.71 - 4.66 (m, 2H), 4.64 - 4.58 (m, 2H), 4.57 - 4.44 (m, 3H), 3.57 - 3.47 (m, 1H), 2.53 - 2.41 (m, 2H). [M+H] = 419.2. Table 10: Compounds synthesized in a similar manner as described for compound 287.
Figure imgf000212_0001
Figure imgf000213_0002
Protocol 13.2-(Azetidin-1-yl)-4-(4-(1,1-difluoro-2-hydroxyethoxy)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (259)
Figure imgf000213_0001
Step 1: 2-Chloro-4-(4-(1,1-difluoro-2-hydroxyethoxy)phenyl)-6-((pyridin-3-ylmethyl)t hio)pyridine-3,5-dicarbonitrile (259-A). To the mixture of 2-amino-4-[4-(1,1-difluoro-2-hydr oxy-ethoxy)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (210 mg, 477.88 umol, 1 eq) in ACN (5 mL) was added tert-butyl nitrite (49.28 mg, 477.88 umol, 56.84 uL, 1 eq) and CuCl (47.31 mg, 477.88 umol, 11.43 uL, 1 eq), the mixture was stirred at 60°C for 1 hr under N2. The reaction mixture was filtered and concentrated to give 2-chloro-4-(4-(1,1-dif luoro-2-hydroxyethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (200 mg, crude) as yellow solid. [M+H]=459.9 Step 2: 2-(Azetidin-1-yl)-4-(4-(1,1-difluoro-2-hydroxyethoxy)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (259). To a solution of 2-chloro-4-[4-(1,1-difluoro- 2-hydroxy-ethoxy)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (200 mg, 435.86 μmol, 1 eq) in THF (3 mL) was added TEA (132.31 mg, 1.31 mmol, 182.00 μL, 3 eq) and azetidine.hydrochloride (163.11 mg, 1.74 mmol, 4 eq). The mixture was stirred at 25 °C for1 hr . The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC(Phenomenex Luna C18 column (75 × 30mm , 3 um); flow rate: 25 mL/min; gradient: 15% – 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-(azetidin-1-yl)-4-(4-(1,1-difluoro-2- hydroxyethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (26.6 mg, 50.46 μmol, 11.58% yield, 99.7% purity, FA) as yellow solid. 1H NMR (400 MHz, DMSO) δ = 8.65 (d, J = 1.6 Hz, 1H), 8.47 (d, J = 3.6 Hz, 1H), 7.84 (br d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.43 - 7.34 (m, 3H), 5.94 (t, J = 6.8 Hz, 1H), 4.54 (s, 2H), 4.43 (br d, J = 1.2 Hz, 4H), 3.88 (dt, J = 10.0, 6.8 Hz, 2H), 3.34 (br s, 1H), 2.41 - 2.30 (m, 2H). [M+H]=480.5. Table 11: Compounds synthesized in a similar manner as described for compound 259.
Figure imgf000214_0001
Figure imgf000215_0001
Protocol 14.2-Amino-4-(4-(2-(difluoromethoxy)-1,1-difluoroethoxy)phenyl)-6-((oxetan- 3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (289)
Figure imgf000216_0001
Step 1: 1-Bromo-4-(2-(difluoromethoxy)-1,1-difluoroethoxy)benzene (289-A). To a mixture of 2-(4-bromophenoxy)-2,2-difluoroethan-1-ol (2 g, 7.90 mmol, 1 eq) and KOH (2.00 g, 35.57 mmol, 4.5 eq) in Tol. (20 mL) and H2O (6 mL) was stirred at 20°C for 10 mins, then (bromodifluoromethyl)trimethylsilane (3.21 g, 15.81 mmol, 2 eq) was added to the mixture reaction at -78°C, the mixture was stirred at 60°C for 2 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (SiO2, Petroleum ether : Ethyl acetate = 1:0 to 1:1) to give 1-bromo-4-(2-(difluoromethoxy)-1,1- difluoroethoxy)benzene (780 mg, 2.57 mmol, 32.56% yield) as yellow oil. Step 2: 1-(2-(Difluoromethoxy)-1,1-difluoroethoxy)-4-vinylbenzene (289-B). To a mixture of 1-bromo-4-(2-(difluoromethoxy)-1,1-difluoroethoxy)benzene (750 mg, 2.47 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (457.39 mg, 2.97 mmol, 503.74 uL, 1.2 eq) in EtOH (3 mL) and H2O (0.3 mL) was added 4-ditert-butylphosphanyl- N,N-dimethyl-aniline;dichloropalladium (175.24 mg, 247.49 umol, 175.24 uL, 0.1 eq) and KOAc (485.78 mg, 4.95 mmol, 2 eq) at 25°C, the reaction mixture was stirred at 80°C for 2 hrs under the N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prepartive TLC (SiO2, Petroleum ether : Ethyl acetate = 5:1) to give 1-(2-(difluoromethoxy)-1,1- difluoroethoxy)-4-vinylbenzene (320 mg, 1.28 mmol, 51.68% yield) as white solid.1H-NMR (400 MHz, CD3OD) δ ppm 7.39 - 7.31 (m, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.64 (dd, J = 10.4, 7.2 Hz, 1H), 6.60 - 6.26 (m, 1H), 5.66 (dd, J = 17.6, 0.63 Hz, 1H), 5.21 - 5.07 (m, 1H), 4.21 (t, J = 8.8 Hz, 2H). Step 3: 4-(2-(Difluoromethoxy)-1,1-difluoroethoxy)benzaldehyde (289-C). To a mixture of 1-(2-(difluoromethoxy)-1,1-difluoroethoxy)-4-vinylbenzene (300 mg, 1.20 mmol, 1 eq) in ACN (2 mL) and H2O (2 mL) was added K2OsO4.2H2O (44.18 mg, 119.91 umol, 0.1 eq) at 0°C and the reaction mixture was stirred at 25°C for 0.5hr, then NaIO4 (1.03 g, 4.80 mmol, 265.78 uL, 4 eq) was added to the reaction mixture and the reaction mixture was stirred at 25°C for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prepartive TLC (SiO2, Petroleum ether : Ethyl acetate = 5:1) to give 4-(2-(difluoromethoxy)-1,1- difluoroethoxy)benzaldehyde (155 mg, 614.68 umol, 51.26% yield) as white solid.1H-NMR (400 MHz, CD3OD) δ ppm 10.01 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.97 - 6.33 (m, 1H), 4.42 (t, J = 8.8 Hz, 2H). Step 3: 2-Amino-4-(4-(2-(difluoromethoxy)-1,1-difluoroethoxy)phenyl)-6- mercaptopyridine-3,5-dicarbonitrile (289-D). To a mixture of 4-(2-(difluoromethoxy)-1,1- difluoroethoxy)benzaldehyde (140 mg, 555.20 umol, 1 eq) and 2-cyanoethanethioamide (111.20 mg, 1.11 mmol, 2 eq) in EtOH (4 mL) was added NMM (112.31 mg, 1.11 mmol, 122.08 uL, 2 eq) at 25°C and the reaction mixture was stirred at 25°C for 24 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 column (75 × 30 mm, 3 um); flow rate: 25 mL/min; gradient: 20% – 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-amino-4-(4-(2- (difluoromethoxy)-1,1-difluoroethoxy)phenyl)-6-mercaptopyridine-3,5-dicarbonitrile (70 mg, 175.73 umol, 31.65% yield) as brown solid. [M-H] = 397.1. Step 4: 2-Amino-4-(4-(2-(difluoromethoxy)-1,1-difluoroethoxy)phenyl)-6-((oxetan-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (289). To a mixture of 2-amino-4-(4-(2- (difluoromethoxy)-1,1-difluoroethoxy)phenyl)-6-mercaptopyridine-3,5-dicarbonitrile (35 mg, 87.87 umol, 1 eq) and 3-(bromomethyl)oxetane (15.92 mg, 105.44 umol, 1.2 eq) in DMF (1.5 mL) was added K2CO3 (24.29 mg, 175.73 umol, 2 eq) and the mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 column (100 × 30 mm, 10 um); flow rate: 25 mL/min; gradient: 35% – 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-amino-4-(4-(2-(difluoromethoxy)-1,1-difluoroethoxy)phenyl)-6- ((oxetan-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (14.7 mg, 31.38 umol, 35.72% yield) as yellow solid. [M+H] = 469.1.1H-NMR (400 MHz, CD3OD) δ ppm 7.60 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.61 (t, J = 73.6 Hz, 1H), 4.84 (dd, J = 7.6, 6.4 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 4.40 (t, J = 8.8 Hz, 2H), 3.65 (d, J = 7.6 Hz, 2H), 3.53 - 3.39 (m, 1H). Protocol 15.2-(3-Fluoroazetidin-1-yl)-4-(4-(2-methoxyethoxy)phenyl)-6-((pyrimidin-4- ylmethyl)thio)pyridine-3,5-dicarbonitrile (334)
Figure imgf000218_0001
Step 1: 2-Chloro-6-(3-fluoroazetidin-1-yl)-4-(4-(2-methoxyethoxy)phenyl)pyridine- 3,5-dicarbonitrile (334-B). To a solution of 2-amino-6-(3-fluoroazetidin-1-yl)-4-(4-(2- methoxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (250 mg, 680.50 μmol, 1 eq) in ACN (5 mL) was added tert-butyl nitrite (140.35 mg, 1.36 mmol, 161.88 μL, 2 eq) and CuCl (134.74 mg, 1.36 mmol, 32.55 μL, 2 eq). The mixture was stirred at 60°C for 1 hr under N2, then filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 3:1 to 1:1) to give 2-chloro-6-(3-fluoroazetidin-1-yl)-4-(4-(2- methoxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (160 mg, 413.64 μmol, 60.79% yield) as a yellow oil. [M+H] = 387.2 Step 2: 2-(3-Fluoroazetidin-1-yl)-6-mercapto-4-(4-(2-methoxyethoxy)phenyl)pyridine- 3,5-dicarbonitrile (334-C). To a solution of 2-chloro-6-(3-fluoroazetidin-1-yl)-4-(4-(2- methoxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (160 mg, 413.64 μmol, 1 eq) in DMF (2 mL) was added potassium ethanethioate (94.48 mg, 827.29 μmol, 2 eq) at 0°C. The mixture was warmed to 25 °C and stirred for 2 hrs. The reaction mixture was added to the sat.aq. NaClO, then the reaction mixture was partitioned between EtOAc (10 mL) and H2O (5 mL), the water phase was extracted with EtOAc (15 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated to give 2-(3-fluoroazetidin-1-yl)-6-mercapto-4- (4-(2-methoxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (150 mg, crude) as a black solid. [M+H] = 385.1 Step 3: 2-(3-Fluoroazetidin-1-yl)-4-(4-(2-methoxyethoxy)phenyl)-6-((pyrimidin-4- ylmethyl)thio)pyridine-3,5-dicarbonitrile (334). To a solution of 2-(3-fluoroazetidin-1-yl)-6- mercapto-4-(4-(2-methoxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (150 mg, 390.19 μmol, 1 eq) in DMF (2 mL) was added K2CO3 (107.85 mg, 780.38 μmol, 2 eq) and 4- (chloromethyl)pyrimidine (50.16 mg, 390.19 μmol, 1 eq). The mixture was stirred at 25°C for 0.5 hr, then filtered. The residue was purified by preparative HPLC (Waters Xbridge BEH C18(100 × 30 mm, 10 um ); flow rate: 25 mL/min; gradient: 25% – 60% B over 8 min; mobile phase A:10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-(3-fluoroazetidin-1-yl)-4-(4-(2-methoxyethoxy)phenyl)-6-((pyrimidin-4- ylmethyl)thio)pyridine-3,5-dicarbonitrile (37.0 mg, 76.87 μmol, 19.70% yield, 99.0% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 9.14 (d, J = 1.2 Hz, 1H), 8.77 (d, J = 5.2 Hz, 1H), 7.66 (d, J = 4.2 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 5.56 - 5.36 (m, 1H), 4.70 - 4.57 (m, 4H), 4.41 - 4.27 (m, 2H), 4.20 - 4.16 (m, 2H), 3.70 - 3.67 (m, 2H), 3.32 (s, 3H) [M+H] = 477.0. Protocol 16. Synthesis of (R)-4-(4-(2-(methoxy-d3)propoxy)phenyl)-2-(methylamino)-6- ((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (391) and (R)-2-amino-4-(4-(2- (methoxy-d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (405)
Figure imgf000220_0001
Step 1: R-2-(methoxy-d3)propoxy]methylbenzene (391-B). To a solution of (R)-1- (benzyloxy)propan-2-ol (30 g, 180.49 mmol, 1 eq) in THF (500 mL) was added NaH (10.83 g, 270.73 mmol, 60% purity, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 0.5 hr. Then iodomethane-d3 was added (31.40 g, 216.59 mmol, 13.48 mL, 1.2 eq) at 0°C. The mixture was stirred at 25°C for 3 hrs under N2. TLC (PE: EtOAc = 5:1) indicated 391-A was consumed completely and one major new spot was detected. The reaction mixture was quenched by addition sat.aq. NH4Cl 300 mL at 0°C, and then extracted with EtOAc 900 mL (300 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE: EtOAc = 1:0 to 5:1) to give R-2-(methoxy-d3)propoxy]methylbenzene (391-B) (45 g, 171.89 mmol, 95.23% yield, 70% purity) as a yellow oil. Step 2: R-2-(methoxy-d3)propan-1-ol (391-C). To a solution of R-2-(methoxy- d3)propoxy]methylbenzene (30 g, 163.70 mmol, 1 eq) in THF (300 mL) was added Pd/C (17 g, 15.97 mmol, 10% purity, 9.76e-2 eq). The mixture was stirred at 25°C for 12 hrs under H2 (40 Psi). TLC (PE: EtOAc =1:1) indicated 391-B was consumed completely and one major new spot was detected. The suspension was filtered through a pad of silica gel and the pad was washed with THF (150 mL×3), the filtrate was concentrated under reduced pressure to give R-2-(methoxy-d3)propan-1-ol (18 g, crude) as a white solid. Steps 3 and 4: (R)-4-(2-(methoxy-d3)propoxy)benzaldehyde (391-D). To a solution of (R)-2- (methoxy-d3)propan-1-ol (1.0 eq) in THF at 0 °C was added TEA (1.1 eq.) followed by the slow addition of Ms2O (1.1 eq). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by addition of water and extracted with CHCl3 and the organic fraction dried over Na2SO4 and concentrated. The crude (R)-2-(methoxy-d3)propyl methanesulfonate was used directly in the next step. To a solution of 4-hydroxybenaldehyde (1.1 eq) in DMF and Cs2CO3 (1.2 eq) was added (R)- 2-(methoxy-d3)propyl methanesulfonate (1.0 eq). The reaction was warmed to 100 °C and stirred for 12 hr, then quenched by the addition of water. The mixture was extracted with CHCl3 and the combined organic fractions were washed with water, 5% HCl solution, brine and dried over Na2SO4. The crude (R)-4-(2-(methoxy-d3)propoxy)benzaldehyde was estimated to be 90% pure by LCMS and used as such in Step 5. Step 5: (R)-2-amino-4-(4-(2-(methoxy-d3)propoxy)phenyl)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile (405). To a solution of (R)-2-amino-6-mercapto-4- (4-(2-(methoxy-d3)propoxy)phenyl)pyridine-3,5-dicarbonitrile (500 mg, 1.46 mmol, 1 eq) and 2-(chloromethyl)pyridine;hydrochloride (358.23 mg, 2.18 mmol, 1.5 eq) in DMF (3 mL) was added K2CO3 (402.44 mg, 2.91 mmol, 2 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was diluted with H2O 10 mL, then was filtered and the filter cake was concentrated under reduced pressure to give (R)-2-amino-4-(4-(2-(methoxy- d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (470 mg, crude) as a white solid. ESI [M+H] = 435.3. Step 6: (R)-2-chloro-4-(4-(2-(methoxy-d3)propoxy)phenyl)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile (391-F). To a solution of (R)-2-amino-4-(4-(2- (methoxy-d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (470 mg, 1.08 mmol, 1 eq) in ACN (3 mL) was added t-BuONO (479.61 mg, 4.65 mmol, 553.19 μL, 4.3 eq) and CuCl2 (479.91 mg, 3.57 mmol, 3.3 eq). The mixture was stirred at 60°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give (R)-2-chloro-4- (4-(2-(methoxy-d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (400 mg, crude) as a white solid. ESI [M+H] = 454.1. Step 7: (R)-4-(4-(2-(methoxy-d3)propoxy)phenyl)-2-(methylamino)-6-((pyridin-2- ylmethyl)thio)pyridine-3,5-dicarbonitrile (391). To a solution of (R)-2-chloro-4-(4-(2- (methoxy-d3)propoxy)phenyl)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (100 mg, 220.28 μmol, 1 eq) and methanamine;hydrochloride (22.31 mg, 330.43 μmol, 1.5 eq) in ACN (1 mL) was added K2CO3 (152.22 mg, 1.10 mmol, 5 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (150 × 40 mm, 10 mm); flow rate: 25 mL/min; gradient: 35% – 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give (R)-4-(4-(2-(methoxy-d3)propoxy)phenyl)-2- (methylamino)-6-((pyridin-2-ylmethyl)thio)pyridine-3,5-dicarbonitrile (42.2 mg, 93.61 μmol, 42.49% yield, 99.5% purity) as a white solid. ESI [M+H] = 449.2.1H NMR (400 MHz, CD3OD) δ = 8.50 (d, J = 4.4 Hz, 1H), 7.82 (dt, J = 7.6, 2.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.33 (dd, J = 6.8, 5.2 Hz, 1H), 7.14 - 7.05 (m, 2H), 4.71 (s, 2H), 4.07 - 3.98 (m, 2H), 3.85 - 3.71 (m, 1H), 3.00 (s, 3H), 1.28 (d, J = 6.4 Hz, 3H). Table 12: Compounds synthesized in a similar manner as compound 391, but with different starting materials.
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Example 2: Biological activity Example 2.1. Adenosine Agonist Activity Material and Methods: Biological materials SPA 35S-GTPγS experiments were conducted with Epics Therapeutics membrane preparations. cAMP HTRF assays were conducted with recombinant cell lines. Receptor accession numbers and cellular backgrounds are shown in Table 13. Table 13. Cell lines used for in vitro assays
Figure imgf000230_0002
Conditions for the GTPγS scintillation proximity assay are shown in Table14. Table14. GTPγS scintillation proximity assay (96 w)
Figure imgf000231_0001
RT = room temperature Assay buffer: 20 mM HEPES pH 7.4; 100 mM NaCl, 10 µg/mL saponin, MgCl2 at optimized concentration for the specific receptor. Membranes: membrane extracts prepared from CHO-K1 cells expressing recombinant human Adenosine A1 receptor, thawed on ice, diluted in assay buffer and kept on ice. GDP: diluted in assay buffer at the optimized concentration for the specific receptor Beads: PVT-WGA (Perkin Elmer, RPNQ001), diluted in assay buffer at 50 mg/mL (0.5mg/10 µL) GTPγ35S: (Perkin Elmer, NEG030X), diluted in assay buffer for a final 0.1 nM assay concentration Protocol for agonist testing: membranes are mixed with GDP (volume:volume). In parallel, GTPγ[35S] is mixed with the beads (volume:volume) just before starting the reaction. The following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 µL of test or reference ligand, 25 µL of the membranes:GDP mix, and 25 µL of the GTPγ[35S]:beads mix. The plates are covered with a top seal, mixed on an orbital shaker for 2 min, and then incubated for 1 hour at room temperature. Then the plates are centrifuged for 10 min at 2000 rpm, incubated at room temperature and counted for 30 sec/well with a PerkinElmer TopCountTM reader. Conditions for the GTPγS scintillation proximity assay are shown in Table15. Table15. cAMP HTRF assays
Figure imgf000231_0002
RT = room temperature cAMP HTRF assay for Gs coupled receptor: HEK293 cells expressing recombinant receptor grown prior to the test in media without antibiotic are detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g/L BSA, supplemented with 1 mM IBMX or 25 µM rolipram). Dose response curves are performed in parallel with the reference compounds. For agonist test (96 well): 12 µL of cells are mixed with 12 µL of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates are incubated 1 hour incubation at room temperature, and fluorescence ratios are measured according to the manufacturer specification, with the HTRF kit. Results are provided in Table 16 below. Table16: Adenosine Agonist Activity
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Example 2.2. BCRP permeability assay Material and Methods: Biological materials MDCK cell lines transfected with the BCRP gene were grown in 75 cm2 tissue culture flasks and split (passed) two times per week to maintain desired confluence. MDCK assay plates were seeded 4 days prior to running the assay. The 24-well plates were seeded at a cell density of 0.88×105/well in a 400 pL apical chamber volume (2.2×105/mL) with 25 mL of growth medium added to the 24-well basal chamber. The plates contain an apical side (A or donor chamber) and a basolateral side (B or receiver chamber). Movement or permeability of compound is measured in both directions (A to B and B to A) for 90 minutes at 37 °C. Dosing solutions were prepared as shown in Table 17. Teriflunomide, Metoprolol and Atenolol were included as reference standards.
Table 17. Summary of donor solution and compound preparation
Figure imgf000240_0001
Dosing solutions were added to the plate as outlined in Table 18. Table 18. Outline of how dosing solutions were added to the plate
Figure imgf000241_0001
The plates were warmed to 37 °C and the transport was initiated by placing the apical plate onto the basolateral plate. The plates were incubated for 90 minutes and then separated and the concentration of compounds in the donor and receiver compartments for both A to B and B to A plates were measured by LC-MS/MS. The measurements were performed in duplicate. Lucifer yellow (LY) was included to confirm the cell monolayers had tight junctions based on TEER values. The permeability calculations are as follows: Transepithelial electrical resistance (TEER) = (Resistance sample – Resistance blank) × Effective Membrane Area Drug permeability: Papp = (VA/(Area × Time)) × ([drug]accepter, 90-min/(([drug]donor, 0-min) × Dilution Factor) where: VA is the volume in the acceptor well, the Area is the surface area of the membrane and the Time is the total transport time in seconds; [drug]donor, 0-min and [RFU]donor, 0-min are the donor drug concentration or Lucifer Yellow count measured at 0-min; [drug]acceptor, 90-min and [RFU]acceptor, 90-min are the acceptor drug concentration or Lucifer Yellow count measured at 90-min; and the Dilution Factor is the fold of dilution of the donor sample before loaded to LC- MS/MS. Permeability Papp A to B values of < 3 x 10-6 cm/sec are low, values between 3 and 10 x 10-6 cm/sec are moderate, and values > 10 x 10-6 cm/sec are considered high. Efflux ratios > 10-fold are considered high and could significantly limit brain penetration, values between 3 and 10 are moderate and could limit brain penetration, and values < 3 are low and would be consistent with good brain penetration. Results are provided in Table 19. Table 19: BCRP Permeability and efflux ratio data
Figure imgf000242_0001
Figure imgf000243_0001
Incorporation by Reference
All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
Equivalents
While specific embodiments of the subject application have been discussed, the above specification is illustrative and not restrictive. Many variations of the subject of the application will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the application should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMS 1. A method of treating FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome, CDKL5 deficiency disorder (CDD) and/or one or more symptoms associated with CDD, or CHD8-related neurodevelopmental disorder (CHD8- NDD) and/or one or more symptoms associated with CHD8-NDD, chronic heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or heart failure with mid-range ejection fraction (HFmrEF) comprising administering a therapeutic amount of a compound of formula (I)
Figure imgf000244_0001
or a pharmaceutically acceptable salt thereof, wherein: Y is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, OR13, and NR2R3, R2 and R3 each independently is selected from hydrogen and C1-6alkyl; or R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4- or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R1 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; R7 and R8 each independently is selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; R9 is hydrogen or halogen, or R1 and R9 taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, or R9 and R8 taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 or a cyclobutyl or cyclopentyl ring system when m is 1; R10 and R11 each independently is selected from hydrogen, hydroxyl, halogen, C1-6alkyl, and C1-6 haloalkyl; R12 is hydrogen or halogen; X is selected from a bond, S, O, and NR4, wherein R4 is hydrogen or C1-6alkyl (e.g., methyl); R13 is selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, - NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5 and R6 each independently is selected from hydrogen and C1-6alkyl; m is 0 or 1, provided that when m is 1, R8 and R9 are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system; and n is 0, 1 or 2; provided that when Y is NH2, X is S, n is 1, R1 is hydrogen or methyl, and each of R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NH2, X is S, n is 1, R8 is methyl or CF3, and each of R1, R7 and R9 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 and R3 are both C1-6alkyl (e.g., ethyl), X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted thiazole; when Y is NH2, X is S, n is 1, R1 is methyl, and each of R7, R8, R9, R10, and R11 is hydrogen, then A is not 2-pyridinyl or 3-pyridinyl; when Y is NH2, X is S, n is 1, R7 is methyl, R8 is methyl, and each of R1 and R9 is hydrogen, then A is not substituted 4-pyridyl; when Y is NH2, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 3-pyridyl; when Y is hydrogen or NR2R3, R2 is hydrogen, R3 is hydrogen or C1-6alkyl, X is S, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted 4-pyridyl; when Y is NH2 or pyrrolidine, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl; when Y is NH2, X is S, n is 1, R1 is hydrogen or methyl, each of R7, R8, R9, and R11 is hydrogen, and R10 is methyl, then A is not substituted phenyl; when Y is H or NH2, X is S, n is 0, and each of R1, R7, R8 and R9 is hydrogen, then A is not optionally substituted aryl (e.g., aryl, such as phenyl); when Y is NH2, X is S or O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is O, n is 1, and each of R1, R7, R8 and R9 is hydrogen, then A is not substituted phenyl, or substituted 4-pyridyl; when Y is OR13, R13 is methyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted phenyl, substituted oxazole, imidazole, or 2- pyridyl; when Y is OR13, R13 is ethyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted oxazole; when Y is OR13, R13 is methyl, ethyl, or sec-butyl, X is S, n is 1, and each of R1, R7, R8, R9, R10 and R11 is hydrogen, then A is not substituted thiazole; when Y is NH2, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted oxazole, substituted phenyl, substituted 4-pyridyl, substituted thiophene, or substituted thiazole; when Y is NH2, X is S, n is 2, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not hydroxyl; when Y is NH2, X is S, n is 1, and each of R1, R7, R8, R9 , R10, R11, and R12 is hydrogen, then A is not substituted thiazolidine, substituted pyrazole, substituted imidazole, or substituted triazole; when Y is NR2R3, R2 is hydrogen, R3 is CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted thiazole; when Y is NR2R3, R2 is hydrogen, R3 is CH3 or CH2CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not phenyl; when Y is NH2, X is S, n is 1, R7 and R8 are both CH3, and each of R1, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring optionally substituted with hydroxyl, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is S, n is 1, R8 is CH3 or CF3, and each of R1, R7, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NR2R3, R2 is hydrogen or CH3, R3 is CH2CH3, X is S, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12 is hydrogen, then A is not substituted oxazole; when Y is NH2, X is S, n is 0, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, and R12 is hydrogen, then A is not phenyl; when Y is NR2R3, R2 and R3 taken together with the nitrogen to which they are attached form a 5-membered heterocyclyl ring optionally substituted with hydroxyl, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5- membered heterocyclyl ring, and each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted phenyl; when Y is NH2, X is O, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, each of R7, R8, R10, R11, and R12 is hydrogen, then A is not substituted phenyl; and when Y is NH2, X is S, n is 1, R1 and R9 taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring, R10 is CH3, each of R7, R8, R11, and R12 is hydrogen, then A is not substituted phenyl.
2. The method of claim 1, wherein A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1- 6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, aryl (e.g., phenyl), and optionally substituted heteroaryl.
3. The method of claim 1, wherein A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1- 6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene.
4. The method of claim 1, wherein A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1- 6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, optionally substituted benzothiophene, oxazole, and thiazole.
5. The method of claim 1, wherein A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1- 6alkyl, optionally substituted heterocyclyl, optionally substituted indole, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrrolopyridine, optionally substituted pyridazine, optionally substituted indazole, optionally substituted benzofuran, optionally substituted benzoimidazole, optionally substituted benzothiazole, and optionally substituted benzothiophene.
6. The method of claim 1, wherein A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1- 6alkyl, and optionally substituted heterocyclyl.
7. The method of claim 1, wherein A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6 alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1- 6alkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl.
8. The method of claim 1, wherein A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1- 6alkyl, optionally substituted heterocyclyl, aryl, and optionally substituted heteroaryl.
9. The method of claim 1, wherein A is optionally substituted heterocyclyl
10. The method of claim 9, wherein A is optionally substituted oxetane.
11. The method of claim 9, wherein A is optionally substituted tetrahydrofuran.
12. The method of any preceding claim, wherein Y is NR2R3 and R2 and R3 each independently is selected from hydrogen and C1-6alkyl.
13. The method of claim 12, wherein Y is NH2.
14. The method of claim 12, wherein Y is NMe2.
15. The method of claim 12, wherein Y is NHMe.
16. The method of any one of claims 1-11, wherein Y is NR2R3 and R2 and R3 taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring.
17. The method of any one of claims 1-11, wherein Y is hydrogen.
18. The method of any one of claims 1-11, wherein Y is C1-6 alkyl.
19. The method of any one of claims 1-11, wherein Y is C3-6 cycloalkyl.
20. The method of any preceding claim, wherein X is S.
21. The method of any preceding claim, wherein n is 1.
22. The method of any preceding claim, wherein R10 and R11 are both hydrogen. 23. The method of any preceding claim, wherein R7 and R8 are both hydrogen.
23. The method of any one of claims 1-22, wherein R7 and R8 are both C1-6alkyl.
24. The method of any one of claims 1-22, wherein R7 is hydrogen and and R8 is C1-6alkyl or C1-6 haloalkyl.
25. The method of any preceding claim, wherein R9 is hydrogen.
26. The method of any preceding claim, wherein R1 is hydrogen.
27. The method of any one of claims 1-24, wherein R1 and R9 taken together with the atoms to which they are attached form a 4- or 5-membered heterocyclyl ring
28. The method of claim 27, wherein R1 and R9 taken together with the atoms to which they are attached form oxetan-3-yl.
29. A method of treating FOXG1 syndrome and/or one or more symptoms associated with FOXG1 syndrome, CDD and/or one or more symptoms associated with CDD, or CHD8- NDD and/or one or more symptoms associated with CHD8-NDD, chronic heart failure, HFpEF, HFrEF, or HFmrEF comprising administering a therapeutic amount of any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-458, and pharmaceutically acceptable salts thereof.
30. The method of claim 29, wherein the compound is selected from any one of compounds 1-10, 12-18, 20-25, 27-37, 39, 40, 44-53, 56, 61-70, 74, 76-79, 83, 84, 89, 90, 93- 96, 104, 106, 107, 110, 112-117, 119-123, 125, 127-129, 132, 136, 138-141, 146-147, 150- 152, 159-162, 172, 174-178, 183, 191-195, 197, 198, 206-208, 212-230, 232-359, and 363- 458, and pharmaceutically acceptable salts thereof.
31. The method of claim 29, wherein the compound is selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof.
32. The method of claim 29, wherein the compound is compound 360, or a pharmaceutically acceptable salt thereof.
33. The method of any one of claims 1-32, wherein the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.
34. The method of any one of claims 1-32, wherein the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.
35. The method of any one of claims 1-32, wherein the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.
36. A compound selected from any one of compounds 340-359 and 363-458, and pharmaceutically acceptable salts thereof.
37. A pharmaceutical composition comprising (a) a compound of claim 36; and (b) a pharmaceutically acceptable excipient.
38. A compound of claim 36 or a pharmaceutical composition of claim 37 for use as a medicament.
39. A method of treating Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of claim 36 or a pharmaceutical composition of claim 37.
40. A method of treating Rett syndrome and/or one or more symptoms associated with Rett syndrome in a subject, comprising administering to a subject in need thereof an effective amount of compound 360, or a pharmaceutically acceptable
Figure imgf000251_0001
salt thereof, or a pharmaceutical composition comprising (a) compound 360, and (b) a pharmaceutically acceptable excipient.
41. The method of claim 39 or 40, comprising co-administering to the subject an additional therapeutic agent.
42. The method of claim 41, wherein the additional therapeutic agent comprises trofinetide.
43. The method of any one of claims 39-42, wherein the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism.
44. Use of a compound of claim 36 or a pharmaceutical composition of claim 37, in the preparation of a medicament for the treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome.
45. Use of compound 360, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising (a) compound 360, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable excipient, in the preparation of a medicament for the treatment of Rett syndrome and/or one or more symptoms associated with Rett syndrome.
46. The use of claim 44 or 45, wherein the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism.
PCT/US2024/042362 2023-08-15 2024-08-14 Adenosine ligands for the treatment of neurological disorders or chronic heart failure Pending WO2025038783A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363532736P 2023-08-15 2023-08-15
US63/532,736 2023-08-15

Publications (1)

Publication Number Publication Date
WO2025038783A1 true WO2025038783A1 (en) 2025-02-20

Family

ID=94633135

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/042362 Pending WO2025038783A1 (en) 2023-08-15 2024-08-14 Adenosine ligands for the treatment of neurological disorders or chronic heart failure

Country Status (1)

Country Link
WO (1) WO2025038783A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025214474A1 (en) * 2024-04-11 2025-10-16 Shaoxing City Youluofei Pharmaceutical Co., Ltd. Adenosine receptor selective ligands

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160130230A1 (en) * 2010-06-30 2016-05-12 Bayer Intellectual Property Gmbh Substituted dicyanopyridines and use thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160130230A1 (en) * 2010-06-30 2016-05-12 Bayer Intellectual Property Gmbh Substituted dicyanopyridines and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Pyridine", 18 July 2018, INTECH, ISBN: 978-1-78923-423-7, article HAMADA YOSHIO: "Role of Pyridines in Medicinal Chemistry and Design of BACE1 Inhibitors Possessing a Pyridine Scaffold", XP055884259, DOI: 10.5772/intechopen.74719 *
JUNG JUYOUNG, LEE YOONSUK, MOON AN-NA, ANN JIHYAE, JEONG JIN JU, DO NAYEON, LEE JEEWOO: "Discovery of Novel Dual Adenosine A2A and A1 Receptor Antagonists with 1H-Pyrazolo[3,4-d]pyrimidin-6-amine Core Scaffold as Anti-Parkinson’s Disease Agents", PHARMACEUTICALS, M D P I AG, CH, vol. 15, no. 8, CH , pages 922, XP093282462, ISSN: 1424-8247, DOI: 10.3390/ph15080922 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025214474A1 (en) * 2024-04-11 2025-10-16 Shaoxing City Youluofei Pharmaceutical Co., Ltd. Adenosine receptor selective ligands

Similar Documents

Publication Publication Date Title
US20240261288A1 (en) Combination of a 3-(imidazol-4-yl)-4-(amino)-benzenesulfonamide tead inhibitor with an egfr inhibitor and/or mek inhibitor for use in the treatment of lung cancer
CN110740993B (en) Deuterated pyridone amides and prodrugs thereof as sodium channel modulators
JP7007302B2 (en) Inhibitor of Menin-MLL Interaction
CN104352492B (en) Extend enzyme inhibitor using arylsulfonyl derivatives as the long chain fatty acids of active ingredient
DE60202452T2 (en) PYRIDAZINONAL DOSE REDUCTASE INHIBITORS
JP6404332B2 (en) Novel 3- (1H-pyrazol-4-yl) -1H-pyrrolo [2,3-c] pyridine derivatives as NIK inhibitors
JP4124805B1 (en) Substituted triazole derivatives as oxytocin antagonists
JP2020500207A (en) Calpain modulators and their therapeutic use
US20130296351A1 (en) 2-Thiopyrimidinones
US9624199B2 (en) Substituted bipiperidinyl derivatives
CN104520291A (en) Compounds and compositions for modulating egfr activity
JP2023554282A (en) SUBSTITUTED PIPERIDINO COMPOUNDS AND RELATED TREATMENT METHODS
CN109153672B (en) TRPV4 antagonists
KR20150082633A (en) Novel Orally Bioavailable Breathing Control Modulating Compounds, and Methods of Using Same
TW200815412A (en) A pharmaceutical combination comprising 3-or 4-monosubstituted phenol and thiophenol derivatives
JP2008531679A (en) 1,2,4-Triazole derivatives and their use as oxytocin antagonists
JP2006508055A (en) Oxytocin inhibitor
TW202003472A (en) Calpain modulators and therapeutic uses thereof
PH12014502743B1 (en) Carbamate/urea derivatives
KR20240158230A (en) Deuterium-enriched piperidinyl-methyl-purine amines and related compounds and their use in the treatment of diseases and conditions
EP4479399A1 (en) Adenosine ligands for the treatment of neurological disorders
WO2025038783A1 (en) Adenosine ligands for the treatment of neurological disorders or chronic heart failure
JP5243596B2 (en) 3-Trifluoromethyl-pyrazine-2-carboxylic acid amide derivatives as HDL-cholesterol raising agents
JP2008501775A (en) Substituted triazole derivatives as oxytocin antagonists
JP2008533193A (en) Substituted triazole derivatives as oxytocin antagonists

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24854897

Country of ref document: EP

Kind code of ref document: A1