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WO2024158698A1 - Novel f-atpase hydrolase inhibitors - Google Patents

Novel f-atpase hydrolase inhibitors Download PDF

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Publication number
WO2024158698A1
WO2024158698A1 PCT/US2024/012416 US2024012416W WO2024158698A1 WO 2024158698 A1 WO2024158698 A1 WO 2024158698A1 US 2024012416 W US2024012416 W US 2024012416W WO 2024158698 A1 WO2024158698 A1 WO 2024158698A1
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Prior art keywords
alkyl
compound
cycloalkyl
heterocyclyl
pharmaceutically acceptable
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PCT/US2024/012416
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French (fr)
Inventor
Stepan Vyskocil
Allen T. Hopper
Dario Doller
Amy Ripka
Guiying Li
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Lucy Therapeutics Inc
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Lucy Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • Mitochondria are essential organelles to all eukaryotic cells. They possess a highly dynamic double membrane-bound structure, containing their own circular, double stranded mitochondrial DNA (mtDNA), distinct from nuclear DNA. Mitochondria generate ATP and meet most of the cell’s energy requirements via an oxidative phosphorylation (OXPHOS) pathway. This is carried out by five protein complexes (complexes I-V).
  • ETC IM-localized electron transport chain
  • F1F0-ATPase (also known as F-ATPase, complex V, F1F0-ATP synthase and F1F0 ATP hydrolase) is a multi-component, membrane-associated protein complex that catalyzes the phosphorylation of ADP to ATP at the expense of a proton motive force generated by an electron transport chain during oxidative phosphorylation and acts as the powerhouse of the cell.
  • ATP synthases arepresent in all living organisms, and are located in the membranes of mitochondria, bacteria, and chloroplast thylakoids as well as on the surfaces of various cell types (e.g., endothelial cells, keratinocytes and adipocytes).
  • F1F0-ATP synthase is reversible and operates in the reverse direction, hydrolyzing ATP and pumping protons in the opposite direction under certain conditions, depending on the concentrations and nature of the substrate and product present, as well as the pmf and the voltage across inner mitochondrial membrane.
  • the broad role of mitochondria in health and disease is supported by the mitochondrial dysfunction association with a number of human disorders, such as idiopathic neurodegenerative disorders, mitochondrial diseases including neuropathies, epilepsies, cardiomyopathies, and neurodegenerative disorders, cardiomyopathies, metabolic syndrome, cancer, and obesity.
  • mitochondrial abnormalities increase with aging and in age-related diseases.
  • AD Alzheimer's disease
  • PD PD
  • ALS ALS
  • FRDA FRDA
  • cancer cancer
  • diabetes aging may play a role in these diseases.
  • ROS mitochondria-generated reactive oxygen species
  • A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , -OC(O)R 9 , - C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido,
  • the compound is a compound of formula (Ia), (Ia), or a pharmaceutically acceptable salt thereof.
  • the compound is a compound of formula (Ib), (Ib), or a pharmaceutically acceptable salt thereof.
  • the present application provides a compound of formula (II), (II), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , -OC(O)R 9 , - C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alk
  • the compound is a compound of formula (IIa), (IIa), or a pharmaceutically acceptable salt thereof.
  • each Y is C(R 6 ).
  • o is 1.
  • R 4 is selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy.
  • R 4 is halogen.
  • R 4 is F.
  • o is 0.
  • R 1 is hydrogen.
  • each of R 2 and R 3 is hydrogen.
  • X is selected from CH 2 and O. In certain embodiments, X is CH 2 , n is 1, m is 0, and q is 1.
  • R 5 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl, may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • R 5 is aryl optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl.
  • R 5 is alkyl substituted with 1-3 substituents independently selected from halogen.
  • R 5 is CF3.
  • A is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • A is selected from cyclopentyl or phenyl, wherein the cyclopentyl or phenyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl,
  • A is phenyl. In certain embodiments, A is cyclopentane.
  • R 6 is is selected from hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino,
  • R 6 is hydrogen.
  • the present application provides a compound selected from any one of compounds 1-224, 226-232, 235-244, 246-249, 251, and 253-264, and pharmaceutically acceptable salts thereof.
  • the compound is compound 78, or a pharmaceutically acceptable salt thereof.
  • the compound is compound 135, or a pharmaceutically acceptable salt thereof.
  • the compound is compound 264, or a pharmaceutically acceptable salt thereof.
  • the compound is compound 263, or a pharmaceutically acceptable salt thereof.
  • the compound is compound 256, or a pharmaceutically acceptable salt thereof.
  • the compound is compound 217, or a pharmaceutically acceptable salt thereof.
  • the compound is compound 251, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 178, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 240, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 175, or a pharmaceutically acceptable salt thereof.
  • the present application provides a pharmaceutical composition comprising (a) a compound as disclosed herein; and (b) a pharmaceutically acceptable excipient. The present application provides a compound or pharmaceutical composition as disclosed herein for use as a medicament. The present application provides a method of treating a neurodegenerative disorder in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound or pharmaceutical composition as disclosed herein.
  • the neurodegenerative disorder is selected from Parkinson’s disease; Huntington’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis (ALS); Rett syndrome; multiple systems atrophy (MSA); Charcot Marie Tooth; Friedreich’s Ataxia; spinal cerebellar atrophy (SCA); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), age- related macular degeneration (AMD), and traumatic brain injury (TBI).
  • the present application provides a method of treating a cardiovascular disorder, ischemia, or acute coronary syndromes in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound or pharmaceutical composition as disclosed herein.
  • the present application provides a method of treating cancer or inhibiting tumor growth from a cancer in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound or pharmaceutical composition as disclosed herein.
  • the cancer is selected from cancer of the lung, prostate, colon, breast, ovaries and bone.
  • the present application provides a method of treating Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound or a pharmaceutical composition as disclosed herein.
  • the present application provides use of a compound or a pharmaceutical composition as disclosed herein, in the preparation of a medicament for the treatment of Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease.
  • A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , - OC(O)R 9 , -C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino
  • A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , - OC(O)R 9 , -C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine
  • A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , - OC(O)R 9 , -C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido,
  • A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , - OC(O)R 9 , -C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido,
  • the present application further provides a compound of formula (II), (II), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , - OC(O)R 9 , -C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amid
  • the present application further provides a compound of formula (II), (II), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , - OC(O)R 9 , -C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amid
  • A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR 9 , - OC(O)R 9 , -C(O)N(R 9 ) 2 , -N(R 9 )C(O)R 9 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amid
  • Z is SO 2 .
  • each occurrence of Y is C(R 6 ).
  • three occurrences of Y are C(R 6 ).
  • two occurrences of Y are C(R 6 ).
  • one occurrence of Y is N.
  • R 6 independently for each occurrence, is selected from hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl,
  • R 6 is selected from cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine
  • each occurrence of R 6 is hydrogen.
  • one occurrence of R 6 is alkyl, such as methyl, and all other occurrences of R 6 are hydrogen.
  • one occurrence of R 6 is cycloalkyl, such as cyclopropyl, and all other occurrences of R 6 are hydrogen.
  • R 6 is selected from hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, am
  • R 6 is hydrogen. In certain embodiments of the compound of formula Ia, Ib, or IIa, or a pharmaceutically acceptable salt thereof, one occurrence of R 6 is alkyl, such as methyl, and all other occurrences of R 6 are hydrogen. In certain embodiments of the compound of formula Ia, Ib, or IIa, or a pharmaceutically acceptable salt thereof, one occurrence of R 6 is cycloalkyl, such as cyclopropyl, and all other occurrences of R 6 are hydrogen. In certain embodiments of the compound of formula I, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, o is 0.
  • o is 1. In certain embodiments of the compound of formula I, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, o is 2. In certain embodiments of the compound of formula I, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, o is 3. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R 4 , independently for each occurrence, is selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy. In certain such embodiments, R 4 is halogen, such as F.
  • o is 1, and R 4 is selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy. .
  • R 4 is halogen, such as F.
  • R 1 is hydrogen.
  • R 1 is alkyl, such as methyl.
  • each of R 2 and R 3 is hydrogen. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, each of R 2 and R 3 is alkyl, such as methyl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, and R 3 is alkyl, such as methyl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, and R 3 is alkyl, such as methyl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R 2 is hydrogen, and R 3 is acyl.
  • R 2 is selected from hydrogen and NR 3 and one ortho-positioned occurrence of R 4 , together with the carbon atoms to which they are attached, form a heterocyclic ring, such as piperidine (i.e., a piperidine fused to the pyridine ring system, together forming a tetrahydronaphthyridine).
  • a heterocyclic ring such as piperidine (i.e., a piperidine fused to the pyridine ring system, together forming a tetrahydronaphthyridine).
  • R 2 is absent, and NR 3 and one ortho-positioned occurrence of R 4 , together with the carbon atoms to which they are attached, form a heteroaromatic ring, such as pyrrole, thiazole, or imidazole (i.e., a pyrrole, thiazole, or imidazole fused to the pyridine ring system, together forming a pyrrolopyridine, thiazolopyridine, or imidazopyridine, respectively).
  • a heteroaromatic ring such as pyrrole, thiazole, or imidazole (i.e., a pyrrole, thiazole, or imidazole fused to the pyridine ring system, together forming a pyrrolopyridine, thiazolopyridine, or imidazopyridine, respectively).
  • NR 3 and one ortho-positioned occurrence of R 4 together with the carbon atoms to which they are attached, form a heteroaromatic ring and R 2 is absent or, valence permitting, is selected from H and alkyl (e.g., NR 2 R 3 and one ortho-positioned occurrence of R 4 , together with the carbon atoms to which they are attached, form a pyrrole, thiazole, or imidazole), wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkyl
  • the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen and alkyl, such as lower alkyl.
  • X is selected from C(R 7 ) 2 , alkenyl, alkynyl, O, S, and NR 8 .
  • X is selected from CH 2 , O, S, and NH, such as CH 2 and O.
  • q is 1 and X is CH 2 . In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, q is 1 and X is O. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, q is 1, n is 0, m is 0, and X is CH 2 (i.e., L is -CH 2 -).
  • q is 1, n is 1, R 7 for each occurrence is hydrogen, m is 0, and X is CH 2 (i.e., L is -CH 2 CH 2 -).
  • q is 1, n is 1, R 7 for each occurrence is hydrogen, m is 0, and X is O (i.e., L is -CH 2 O-).
  • each of n, q, and m is 0 (i.e., L is absent or a bond).
  • R 7 for each occurrence is hydrogen.
  • R 8 is selected from hydrogen and alkyl (e.g., hydrogen).
  • R 5 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl, may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, ary
  • R 5 is aryl optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl (e.g., R 5 is phenyl or phenyl substituted with alkyl, such as t- butylphenyl).
  • R 5 is alkyl optionally substituted with 1- 3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl (e.g., R 5 is haloalkyl, such as CF3).
  • A is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • A is selected from cycloalkyl (e.g., cyclopentyl) optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl e.g., cyclopentyl
  • substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as
  • A is selected from aryl (e.g., phenyl) optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • aryl e.g., phenyl
  • substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl
  • A is cyclopentane. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is cyclopropane. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is bicyclo[1.1.1]pentane. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is phenyl. The present application provides a compound selected from any one of
  • the compound is selected from any one of compounds 1-162, and pharmaceutically acceptable salts thereof.
  • 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.
  • substituents 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.
  • 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.
  • compounds of the application may be racemic.
  • a compound e.g., a compound of formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt 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), (Ia), (Ib), (II), or (IIb), 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.
  • compounds of the application may be enriched in one or more diastereomer.
  • 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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).
  • 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), (Ia), (Ib), (II), or (IIb), or pharmaceutically acceptable salts thereof
  • 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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.
  • 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. The skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions to be administered in methods of the application.
  • the application relates to a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), for use as a medicament, e.g., for treatment of any of the disorders disclosed herein.
  • the application relates to a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), for use as a medicament.
  • the application relates to the use of an effective amount of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), in the manufacture of a medicament for treatment of a neurodegenerative disorder in a subject.
  • the neurodegenerative disorder is selected from Parkinson’s disease; Huntington’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis (ALS); Rett syndrome; multiple systems atrophy (MSA); Charcot Marie Tooth; Friedreich’s Ataxia; spinal cerebellar atrophy (SCA); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), age-related macular degeneration (AMD), and traumatic brain injury (TBI).
  • Parkinson’s disease Huntington’s disease
  • Alzheimer’s disease Alzheimer’s disease
  • ALS amyotrophic lateral sclerosis
  • MSA multiple systems atrophy
  • MSA Charcot Marie Tooth
  • Friedreich’s Ataxia spinal cerebellar atrophy
  • MELAS syndrome mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
  • AMD age-related macular degeneration
  • TBI traumatic brain injury
  • the present application provides a method of treating a cardiovascular disorder, ischemia (e.g., ischemia resulting from vascular occlusion, cerebral infarction, stroke and related cerebral vascular diseases e.g., cerebrovascular accident and transient ischemic attack), or acute coronary syndromes (e.g., myocardial infarction, coronary artery disease, unstable angina, and non-Q wave MI) in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb).
  • ischemia e.g., ischemia resulting from vascular occlusion, cerebral infarction, stroke and related cerebral vascular diseases e.g., cerebrovascular accident and transient ischemic attack
  • acute coronary syndromes e.g.
  • the present application provides a method of treating cancer or inhibiting tumor growth from a cancer in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb).
  • the cancer is selected from cancer of the lung, prostate, colon, breast, ovaries and bone.
  • the present application provides a method of treating Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb).
  • the present application provides use of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), in the preparation of a medicament for the treatment of Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease.
  • the compound is selected from any one of compounds 1-162, and pharmaceutically acceptable salts thereof.
  • the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), inhibits F-ATPase hydrolase activity more than the compound inhibits F-ATPase synthase activity.
  • the ratio of the IC50 of F-ATPase synthase activity to the IC50 of F-ATPase hydrolase activity is greater than or equal to 4, greater than or equal to 5, greater than or equal to 6, greater than or equal to 7, greater than or equal to 8, greater than or equal to 9, or greater than or equal to 10.
  • the application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), 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
  • a pharmaceutical composition comprising (1) a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound of formula (I), (Ia), (Ib), (II), or (IIb), (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), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound of formula (I), (Ia), (Ib), (II), or (IIb), or certain combinations thereof may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein.
  • 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), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound of formula (I), (Ia), (Ib), (II), or (IIb)) or the one or more additional therapeutic agent(s).
  • 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: cardiovascular drugs, immunosuppressants, narcolepsy treatments, potassium channel openers, calcium channel blockers, sodium hydrogen exchanger inhibitors, anti-arrhythmic agents, thrombin inhibitors, platelet aggregation inhibitors or anti-platelet agents, fibrinogen antatagonists, diuretics, anti-hypertensive agents, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti-diabetic agents, anti- depressants, anti-inflammatory agents (steroidal and non- steroidal), anti-oxidant agents, antipsychotics (e.g., typical or atypical antipsychotics), angiogenesis modulators, anti-osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-coagulants, anti-obesity agents, anti-anxiety agents, anti- proliferative agents, anti-tumor agents, anti-ulcer and
  • the compound of the application may be administered with one or more of the following: other F-ATPase inhibitors such as efrapeptin, oligomycin, autovertin B, and azide; anti-arrhythmic agents including Class I agents (such as propafenone); Class II agents (propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K+ channel openers such as I Ach inhibitors, and I Kur inhibitors; alpha- or beta- adrenergic blockers (such as propranolol, nadolol and LJY]NMRSVS$& V
  • other F-ATPase inhibitors such as efrapeptin, oligomycin, autovertin B, and azide
  • anti-arrhythmic agents including Class I agents (such as propafenone); Class II agents (propranolol); Class III agents
  • metformin glucosidase inhibitors (e.g. acarbose); insulins (including insulin secretagogues or insulin sensitizers); meglitinides (e.g. repaglinide); sulfonylureas (e.g., glimepiride, glyburide and glipizide); biguanide/glyburide combinations (e.g., glucovance), thiozolidinediones (e.g.
  • TNF-alpha converting enzyme TACE
  • Interleukin-1 converting enzyme ICE
  • Interleukin-1 receptor antagonists angiogenesis modulators such as endostatin
  • anti-oxidant agents and/or lipid peroxidation inhibitors such as probucol, BO- 653, Vitamin A, Vitamin E, AGI-1067
  • antipsychotic agents including atypical antipsychotics such as risperidone, quetiapine, olanzapine, ziprasidone, paliperidone, aripiprazole and clozapine, or typical antipsychotics such as chlorpromazine, flupenthixol, afluphenazine, haloperidol, loxapine, perphenazine, pimozide, trifluoperazine, thiothixene and zuclopenthixol; anti-platelet agents such as GPII-b/GPIIIa blockers, (e.g., abciximab, eptif
  • squalene synthetase inhibitors include fibrates; bile acid sequestrants (such as questran); ACATI inhibitors; ACAT2 inhibitors; dual ACAT1/2 inhibitors; MTP inhibitors; cholesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414); PPAR- delta agonists; PPAR-alpha agonists; dual PPAR-alpha/delta agonists; LXR-alpha agonists; LXR-beta agonists; LXR dual alpha/beta agonists; mineralocorticoid receptor antagonists such as spironolactone and eplirinone; microsomal triglyceride transport protein inhibitors; narcolepsy medications such as modafinil and armodafinil; phosphodiesterase (PDE) inhibitors including dipyridamole, cilostazol, or
  • 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.
  • the term “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.
  • 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-trifluoroethyl, etc.
  • C0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • 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.
  • 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 or 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.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds, as described herein.
  • 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.
  • 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 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 as used herein, 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. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8, 1971-1996, John Wiley & Sons, NY.
  • 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.
  • hydroxyl protecting 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.
  • 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.
  • prodrugs examples 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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 (Simpl ⁇ cio et al, “Prodrugs for Amines,” Molecules, (2008), 13:519- 547).
  • some or all of the compounds of formula (I), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), or pharmaceutically acceptable salts thereof.
  • 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.
  • Scheme A General scheme for preparation of Intermediate vi. An exemplary method of preparing Intermediate vi is shown in Scheme A.
  • diamine i is condensed with keto ester ii at elevated temperature, for example 135 oC, in a suitable solvent, such as toluene (Method A).
  • a suitable solvent such as toluene (Method A).
  • the resulting product iii is then subjected to reductive hydrolytic conditions with a suitable acid, for example TFA, reducing agent, such as triethylsilane in an appropriate solvent, such as TFA at room temperature (Method B) to afford compound of formula iv.
  • Cyclization to lactam v is then carried out using suitable hydrolytic conditions, for example NaOH in aqueous methanol at room temperature (Method C).
  • Reduction to diazepane vi is accomplished using a suitable reducing agent, for example LAH in an appropriate solvent, such as THF at room temperature.
  • a suitable reducing agent for example LAH in an appropriate solvent, such as THF at room temperature.
  • reduction can be also run using BH3.Me2S in a suitable solvent, such as toluene at elevated temperature, for example 100 oC (Method D).
  • Scheme B General scheme for preparation of Intermediate x. An exemplary method of preparing Intermediate x is shown in Scheme B. In this scheme, substituted anthranilic acid vii is converted to acid chloride under suitable conditions, such as oxalyl chloride and DMF in an appropriate solvent, for example DCM (Method E).
  • amide viii is then treated with suitably protected crotylamine under appropriate conditions, such as TEA/DCM to afford amide viii.
  • This reaction may be conducted at room temperature or under cooling, for example at 0 oC.
  • Protecting group (“PG”) may include Bn, PMB or another suitable alternative.
  • Amide viii is then transformed using diacyliodobenzene-driven palladium catalyzed cyclization under suitable conditions, for example Pd(OAc) 2 , sodium acetate, tetrabutylammonium hydrogen sulfate to lactam ix.
  • the reaction may be conducted in a suitable solvent, such as DCE at elevated temperature, for example reflux (Method G).
  • Nitrile function in xii is then reduced using a suitable reagent, such as Raney-Ni and hydrogen at room temperature under conditions that allow subsequent cyclization of the formed amine to produce lactam xiii.
  • the reaction may be conducted in presence of a suitable base, for example TEA, a suitable solvent, such as aqueous MeOH at room temperature (Method I).
  • a suitable base for example TEA
  • a suitable solvent such as aqueous MeOH at room temperature
  • diazepane vi is converted to sulfonamide xv using appropriate alkyl or aryl sulfonylation reagent, for example sulfonyl anhydride or sulfonyl chloride.
  • the reaction may be conducted using a suitable base, for example DIEA in a suitable solvent, such as DCM (Method J).
  • the reaction may be conducted under cooling conditions, for example -78 oC with slow warming to 0 oC in appropriate cases.
  • Intermediates x or xiv may also be used as starting points for this synthetic sequence.
  • Compound xv is then treated with 4-bromopicolinyl chloride or 5- bromopicolinyl chloride under conditions of Method F described above to afford amide xvi(a) or xvi(b), respectively.
  • Amide function in xvi(a) or xvi(b) is then reduced using suitable reagents, for example sodium borohydride and BF3.Et2O to afford xvii(a) or xvii(b).
  • suitable reagents for example sodium borohydride and BF3.Et2O
  • the reaction may be conducted in THF or another suitable solvent, with initial cooling and subsequent temperature elevation, for example to 60 oC (Method K).
  • Compound xvii(a) or xvii(b) is then subjected to aryl amination conditions, for example using Pd(OAc) 2 / XANTPHOS in presence of a suitable base, such as Cs 2 CO 3 to afford compound of formula I(c) or II(c).
  • a suitable base such as Cs 2 CO 3
  • the reaction may be conducted in dioxane or another suitable solvent, at elevated temperature, for example 80 oC (Method L).
  • amidation using a suitable reagent for example t- butyl carbamate can be used for preparation of unsubstituted pyridine amines.
  • Initial transformation may be run under the conditions of Method L to afford protected amines, for example bearing Boc group.
  • the protecting group can be then deprotected using well-known organic chemistry transformations, for example TFA in DCM at room temperature for Boc group removal.
  • Racemic compounds of formula I(c) or II(c) can be subsequently separated into individual enantiomers using suitable chiral separation method, for example chiral SFC.
  • Scheme E Alternative method for preparation of compounds of formulae I(c) and II(c) An alternative method of preparing compounds of formulae I(c) and II(c) is shown in Scheme E.
  • compounds xv are treated with bromo substituted benzaldehyde under suitable reducing conditions, such as triethylsilane and TFA, in an appropriate solvent, such as DCM (Method M).
  • Resulting products xvii are then converted to I(c) or II(c) as shown in Scheme D.
  • Scheme F Alternative method for preparation of Intermediate v. An alternative method of preparing intermediates of formulae v is shown in Scheme F.
  • bromobenzonitriles xviii are treated with amino acids ixx under suitable Pd catalytic conditions, for example SPhos Pd G3 in a presence of a suitable base, such as cesium carbonate in an appropriate solvent, for example toluene at elevated temperature to afford compouds of formula xx (Method N).
  • a suitable base such as cesium carbonate in an appropriate solvent, for example toluene at elevated temperature
  • Scheme G Alternative method for preparation of Intermediate v. An alternative method of preparing intermediates of formulae v is shown in Scheme G.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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 eth
  • 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)
  • 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.
  • 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, corn, 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, such
  • 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.
  • compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device.
  • 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.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms 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.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • 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 rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
  • 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.
  • biocompatible polymers including hydrogels
  • 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.
  • terapéuticaally 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.
  • 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.
  • 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.
  • 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.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric,
  • 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, 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.
  • 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
  • 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.
  • Example 1 Synthetic Protocols Below follows synthetic protocols for a number of non-limiting examples of compounds of the application.
  • Table 1 Abbreviation list Protocol 1: 5-Fluoro-2-((2-(4-fluorophenethyl)-6-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (1)
  • Step 1 5-(4-fluorophenyl)-3-oxo-2-(tributyl-l5-phosphaneylidene)pentanenitrile (1-B).
  • Ozone (1.47 g, 30.65 mmol, 1 eq) was bubbled into a solution of 5-(4-fluorophenyl)-3-oxo-2-(tributyl- phosphanylidene)pentanenitrile (12 g, 30.65 mmol, 1 eq) in DCM (100 mL) and MeOH (50 mL) at -78°C for 3 hrs. After excess O3 was purged by O2, mixture was concentrated.
  • Step 6 2-(4-Fluorophenethyl)-6-(trifluoromethyl)-2, 3, 4, 5 -tetrahydro- 1H- benzo[e] [1 ,4]diazepine (1-G).
  • 2-[2-(4-fluorophenyl)ethyl]-6- (trifluoromethyl)-l,2,4,5-tetrahydro-l,4-benzodiazepin-3-one 450 mg, 1.28 mmol, 1 eq
  • THF 5 mL
  • LAH 1 M, 3 eq
  • the reaction mixture was quenched by addition Na 2 SO 4 .
  • Step 7 2-(4-Fluorophenethyl)-6-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-lH-benzo[e] [l,4]diazepine (1-H).
  • Step 8 (4-Bromo-5-fluoropyridin-2-yl)(2-(4-fluorophenethyl)-6-(trifluoromethyl)- 4-((trifluoromethyl)sulfonyl)-2, 3,4,5-tetrahydro-lH-benzo[e] [ 1,4] diazepin- 1- yl)methanone (l-I).
  • TP& ./(/0 hTVS& +(/ eq) in dioxane (1 mL) was added MRJLN[V_ ⁇ WJSSJMR ⁇ T #02+(32 hP& -(*. hTVS& *(+ eq) and Pd(OAc)2 #-(/, TP& 0(*2 hTVS& 0.2 eq) and Cs2CO3 #+3(13 TP& 0*(1/ hTVS& , eq).
  • Step 11 5-Fluoro-2-((2-(4-fluorophenethyl)-6-(trifluoromethyl)-4-
  • Protocol 2 (2R)-2-(2-Phenylethyl)-1-(1,2,3,4-tetrahydro-1,6-naphthyridin-7- ylmethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepine (8)
  • Step 1 (2R)-2-(2-Phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (8-B) and (2S)-2-(2-Phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (8-C).
  • ESI [M+H] 253.17.
  • Step 5 (R)-2-Phenethyl-1-((1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)methyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (8).
  • Protocol 3 (R)-2-((6-(2-(Dimethylamino)ethoxy)-2-phenethyl-4-((trifluoromethyl)- sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)pyridin-4-amine (15)
  • Step 1 (R)-1-((4-Bromopyridin-2-yl)methyl)-2-phenethyl-4-((trifluoromethyl)- sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (15-B).
  • Step 4 Tert-butyl (R)-(2-((l-((4-aminopyridin-2-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2, 3,4,5-tetrahydro-lH-benzo[e] [l,4]diazepin-6- yl)oxy)ethyl)carbamate (15-E).
  • HCHO (17.72 mg, 218.34 umol, 4 eq) was added to the mixture.
  • the mixture was stirred at 25 °C for 0.5 hr.
  • NaBH iCN (5.15 mg, 81.88 umol, 1.5 eq) was added to the mixture.
  • Step 2 a. tert-butyl(2-iodoethoxy) dimethylsilane was used in Step 2, the formed TBS protecting group was removed using TFA in DCM at room temperature. b.1-iodo-2-methoxy-ethane was used in Step 2.
  • Protocol 4 1-(1-((4-Amino-5-fluoropyridin-2-yl)methyl)-6-chloro-2-(2- cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,2,2- trifluoroethan-1-one (29)
  • Step 1 synthesis of tert-butyl 6-chloro-2-(2-cyclopentylethyl)-1,2,3,5-tetrahydro- 4H-benzo[e][1,4]diazepine-4-carboxylate (29-B).
  • step 5 by coupling 2-(4-(trifluoromethyl)phenyl)acetic acid with 1-((4- bromopyridin-2-yl)methyl)-2-(2-cyclopentylethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine using HOBT, DMAP, EDCI in DIEA and DMF to give intermediate 1-(1-((4-bromopyridin-2-yl)methyl)-2-(2-cyclopentylethyl)-1,2,3,5- tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethan-1-one b
  • the 4-(trifluoromethyl)phenyl)methanone functionality was introduced in step 5 by coupling 2-(4-(trifluoromethyl)phenyl)acetic acid with 1-((4- bromopyridin-2-
  • Protocol 5 (S)-2-((2-(2-Cyclopentylethyl)-6-(pyridin-2-yl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (40)
  • Step 1 (S)-1-((4-Chloropyridin-2-yl)methyl)-2-(2-cyclopentylethyl)-6-(pyridin-2- yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (40B).
  • Table 5 Compounds prepared according to procedure analogous to preparation of Compound 40 in Protocol 5 a. CuCN in NMP was used in Step 1 at 140oC for 12 hours. b. Boronic acid coupling was done with catalyst XPhos Pd G2/K3PO4 in dioxane/H2O
  • Protocol 6 (S)-2-((2-(2-Cyclopentylethyl)-6-methyl-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (61)
  • Step 1 (S)-2-(2-Cyclopentylethyl)-6-methyl-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (61- B).
  • Step 4 2-((Cyclopentyloxy)methyl)-1,2,4,5-tetrahydro-3H- benzo[e][1,4]diazepin-3-one (84-E).
  • ethyl N-(2- (aminomethyl)phenyl)-O-cyclopentylserinate (84-D, 1.9 g, 6.20 mmol, 1 eq, crude from step 3)
  • MeOH 10 mL
  • H 2 O 5 mL
  • ESI [M+H] 247.3.
  • the residue was purified by prep-HPLC (The residue was purified by preparative HPLC (Phenomenex Luna C18 column (80 ⁇ 30 mm, 3 mm); flow rate: 25 mL/min; gradient: 35% – 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) and the residue was re-purified by prep-HPLC (The residue was purified by preparative HPLC (Phenomenex Luna C18 column (75 ⁇ 30 mm, 3 mm); flow rate: 25 mL/min; gradient: 30% – 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give N,N-dimethyl-2-[[(2S)-2-(2-phenylethyl)-4- (trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepin-1-yl]methyl]pyridin-4- amine
  • Step 1 synthesis of 2-bromo-6-cyclopropylbenzonitrile (172-B).
  • cyclopropylboronic acid 10.46 g, 121.79 mmol, 1.5 eq
  • dioxane 300 mL
  • H2O 10 mL
  • cyclopentyl(diphenyl)phosphane was added in dioxane (300 mL) and H2O (10 mL) was added cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (5.94 g, 8.12 mmol, 0.1 eq) and K2CO3 (22.44 g, 162.38 mmol, 2 eq).
  • Steps 7-8 were carried out according to procedures in Protocol 1, Steps 10-11 to afford the title compound 172.
  • Step 1 (S)-(2-(methylthio)thiazolo[5,4-c]pyridin-6-yl)(2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methanone (231-B).
  • reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc 90 mL (30 mL ⁇ 3). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Steps 3-4 were carried out according to procedures in Protocol 1, Steps 10-11.
  • Step 5 (S)-1-((2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)methyl)-2-phenethyl- 4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (183) and (R)-1-((2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (184).
  • Protocol 14 (R)-5-fluoro-2-((2-(4-fluorophenyl)-6-methyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine and (S)-5-fluoro-2-((2-(4-fluorophenyl)-6-methyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (203 and 202).
  • Step 1 Ethyl 2-bromo-2-(4-fluorophenyl)acetate (202-B). To a mixture of ethyl 2-(4-fluorophenyl)acetate (202-A, 11 g, 60.38 mmol, 1 eq) in CHCl3 (400 mL) was added AIBN (991.42 mg, 6.04 mmol, 0.1 eq) and NBS (10.75 g, 60.38 mmol, 1 eq). The mixture was stirred at 60°C for 3 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • AIBN 991.42 mg, 6.04 mmol, 0.1 eq
  • NBS 10.75 g, 60.38 mmol, 1 eq
  • Example 2 F-ATPase Synthase and Hydrolase Assay The assay was adapted from Rogers et al., 2011, PLoS ONE (buffers and mitochondrial analysis), and Divakaruni et al., 2018, Cell Metabolism (Supplemental Figure 3) for ATP hydrolysis measurements.
  • a Seahorse XF cartridge (from the Extracellular Flux Assay Kit) was hydrated by soaking fluorophores in 200 ⁇ L of manufacturer supplied XF calibrant per well, according to the manufacturer’s instructions. The cartridge was left calibrating at room temperature overnight. On the day of the assay, 25 ⁇ L of rotenone and antimycin A (1 ⁇ M final concentration) were added to port A (subtracted out as background) and 25 ⁇ L ATP (30 mM final concentration) and FCCP (1.5 ⁇ M final concentration) to ports B and C (to initiate ATP hydrolysis).
  • Rates of ATP hydrolysis in ECAR were converted to pmol H+/min by determining the buffer capacity of the medium.
  • Data for compounds of the present application is provided in Table 11.
  • Table 11 Rodent Hydrolase and Synthase Data Compo UCLA - UCLA - UCLA - UCLA - UCLA - UCLA - und # mouse mouse mouse RAT RAT RAT C57BL/6 C57BL/6 C57BL/6 Sprague Sprague Sprague isolated isolated isolated isolated Dawley Dawley Dawley heart heart heart isolated isolated isolated isolated mitochon mitochon mitochon heart heart heart dria F- dria F- dria F- mitochon mitochon mitochon ATPase ATPase ATPase dria F- dria F- IC50 IC50 IC50 ATPase ATPase ATPase ATPase ATPase dria F- dria F-
  • the assay measured NADH oxidation in the presence of pyruvate kinase and lactate dehydrogenase as a readout of hydrolase activity.
  • a 5x dilution plate was prepared prior to the assay.
  • the dilution plate contained Oligomycin A (positive control) and test compounds at 7-concentrations starting at 50 ⁇ M and going down by 3-fold serial dilutions. All dilutions were made in mitochondrial complex V activity assay buffer.
  • Two tubes were labeled for reaction mixes. Tube 1 contained 4.9 mL of complex V activity assay buffer, 100 ⁇ L bovine heart mitochondria (5 mg/mL) and 10 ⁇ L rotenone (1 mM).
  • Tube 2 contained 3.810 mL of mitochondrial complex V enzyme mix, 120 ⁇ L ATP reagent and 120 ⁇ L NADH. In a clear 96 well plate 50 ⁇ L of tube 1 mix, 20 ⁇ L of compounds and finally 30 ⁇ L of tube 2 mix were added. The absorbance was immediately read at 340 nm wavelength and continued for the duration of the 60 minute incubation at 54 seconds intervals at 25 °C. Hydrolase activity was calculated by plotting the absorbance data (y-axis) over time (x-axis).
  • hydrolase activity was plotted as a function of test compound concentration. Data for compounds of the present application is provided in Table 12.
  • Table 12 Bovine Hydrolase Data Compound # Complex V Hydrolase assay_Bovine Heart Mitochondria: Average IC50 1 0.205 2 > 10.0 6 > 10.0 7 0.0401 9 1.15 10 0.314 11 1.19 12 0.084 13 0.503 14 3.11 15 > 10.0 16 > 10.0 17 6.91 18 > 10.0 19 0.853 20 > 10.0 21 > 10.0 22 1.21 23 > 10.0 24 > 10.0 25 > 10.0 26 1.46 27 > 10.0 28 0.726 29 0.238 30 8.45 31 7.79 32 0.586 33 > 10.0 34 7.8 35 0.178 36 2.5 37 0.145 38 7.8 39 > 10.0 40 0.492 41 > 10.0 42 8.12 43 2.72 44 0.111 45 1.16 46 > 10.0 47 0.133 48 1.07 49 1.65 50 5.51 51 0.324 52 0.045 53 9.39 54 6.84 55 8.36 56 1.82 57 0.195 58 6.09 59 3.73 60 0.121 61 1.22 62 > 10.0 63 > 10.0 64 8.04 65 > 10.0 66 0.0
  • Compound 2 or 55 was used as a positive control compound for the assay.
  • the dilution plate was made by performing sequential 1 ⁇ 2 log dilutions by sequentially taking 10uL of 30mM stock compound and place it into 20uL of DMSO. Mixed well by pipetting 8-10 times then transferring 10uL from the 10mM stock into 20uL of DMSO to get 3mM final. From this point on continued making 3-fold dilutions by taking 20uL DMSO, adding 10uL of previous concentration of control compound; continued making 3-fold dilutions (keeping final volume 30uL within each well) until you got to row B (then stopped). Each dilution was pipetted 8-10 times prior to moving to the next well.
  • reagents provided in the kit were thawed. Mixed 10 mL of the Mitochondrial Complex V Activity Assay buffer at room temperature (RT) by vortexing well. Kept the Mitochondrial Complex V enzyme mix (4ml) on ice. Isolated mitochondria from Human HEK293 cells were used in place of the kit’s bovine heart mitochondria reagent. The mitochondria were kept on ice until addition to assay buffer. Reconstituted the Mitochondrial Complex V NADH reagent with 120uL of ultrapure water on ice. Reconstituted the Mitochondrial Complex V ATP reagent with 120uL ultrapure water on ice. Kept the plate that was supplied with kit at room temperature (RT).
  • Performing the Assay Made the compound dilution plate using a 96-well deep well plate (0.5mL volume) using 1 ⁇ 2 log concentrations. Started by adding 250uL of Complex V Activity Assay buffer in each well. Mixed the stock compounds in the PCR plate by pipetting up and down 8-10 times and transferring 1.25uL of compound stock from the PCR plate to the deep well plate (containing the 250uL Complex V Activity Assay buffer). Mixed diluted compounds by pipetting up and down 10 times, making sure that a good volume of mixing was performed (using P-200 multichannel). The compound dilution plate was now ready for the experiment. Labeled two 15 mL conical tubes as A and B.
  • Tube A total volume 5ml added a) 4,900uL of Complex V activity assay buffer; b) X uL of isolated mitochondria from Human HEK293 cells (concentration of mitochondria used varied based on purity of mitochondrial preparation); c) 10uL of Rotenone (1mM stock), Note: made 1mM rotenone stock using a fresh aliquot of 20mM ROT stock each time.
  • Tube B total volume 4.050ml
  • Reaction Set Up For each assay condition (all done at RT): Transferred 50uL of the content of tube A to each well of the plate supplied by the kit using a multichannel pipette. Added 20uL of positive control or test compounds from the deep-well compound dilution plate. Mixed gently by pipetting up and down, avoided creating bubbles. If there were bubbles, spun the plate down briefly prior to proceeding with the assay. Using a multichannel pipette, added 30uL of the contents of tube B (which had been placed in a reservoir) to each well to start the reaction. Made sure to begin by adding first to row A and moving down the rows as quickly as possible to avoid variation in start time.

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Abstract

The present application relates to compounds of formulae (I), (la), (lb), (II), or (Ila) and pharmaceutical compositions/preparations thereof which are F-ATPase hydrolase inhibitors. This application further relates to methods of treating neurodegenerative disorders such as Parkinson's disease.

Description

NOVEL F-ATPASE HYDROLASE INHIBITORS Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No.63/440,621, filed January 23, 2023, which application is hereby incorporated by reference in its entirety. Background Mitochondria are essential organelles to all eukaryotic cells. They possess a highly dynamic double membrane-bound structure, containing their own circular, double stranded mitochondrial DNA (mtDNA), distinct from nuclear DNA. Mitochondria generate ATP and meet most of the cell’s energy requirements via an oxidative phosphorylation (OXPHOS) pathway. This is carried out by five protein complexes (complexes I-V). During oxidative phosphorylation, an electrochemical gradient is produced across the inner membrane of the mitochondria, which drives the synthesis of ATP. Enzymes in the tricarboxylic acid cycle generate electron carriers (NADH and FADH2), which donate electrons to the IM-localized electron transport chain (ETC). The ETC consists of four proteins (Complex I–IV), which through sequential redox reactions undergo conformational changes to pump protons from the matrix into the IMS. The proton gradient generated by complexes I, III, and IV is released through the rotary turbine-like ATP synthase machine or complex V, which drives phosphorylation of ADP to ATP. F1F0-ATPase (also known as F-ATPase, complex V, F1F0-ATP synthase and F1F0 ATP hydrolase) is a multi-component, membrane-associated protein complex that catalyzes the phosphorylation of ADP to ATP at the expense of a proton motive force generated by an electron transport chain during oxidative phosphorylation and acts as the powerhouse of the cell. ATP synthases arepresent in all living organisms, and are located in the membranes of mitochondria, bacteria, and chloroplast thylakoids as well as on the surfaces of various cell types (e.g., endothelial cells, keratinocytes and adipocytes). F1F0-ATP synthase is reversible and operates in the reverse direction, hydrolyzing ATP and pumping protons in the opposite direction under certain conditions, depending on the concentrations and nature of the substrate and product present, as well as the pmf and the voltage across inner mitochondrial membrane. The broad role of mitochondria in health and disease is supported by the mitochondrial dysfunction association with a number of human disorders, such as idiopathic neurodegenerative disorders, mitochondrial diseases including neuropathies, epilepsies, cardiomyopathies, and neurodegenerative disorders, cardiomyopathies, metabolic syndrome, cancer, and obesity. In addition, a growing body of evidence suggests that mitochondrial abnormalities increase with aging and in age-related diseases. Based on several cellular, molecular, and animal model studies of Alzheimer's disease (AD), PD, ALS, FRDA, cancer, and diabetes, aging may play a role in these diseases. For example, age-dependent, mitochondria-generated reactive oxygen species (ROS) have been identified as important factors for disease progression, particularly in late-onset diseases, in which genetic mutations are not causal factors (Reddy PH. CNS Spectr.2009, 14, 8-13). Summary of Application The present application provides a compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, -OC(O)R9, - C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8; Y, independently for each occurrence, is selected from C(R6) and N; Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6, independently for each occurrence, is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, - SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl; R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1.
In certain embodiments, the compound is a compound of formula (Ia), (Ia), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula (Ib), (Ib), or a pharmaceutically acceptable salt thereof. The present application provides a compound of formula (II), (II), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, -OC(O)R9, - C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8; Y, independently for each occurrence, is selected from C(R6) and N; Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6, independently for each occurrence, is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, - SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl; R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1. In certain embodiments, the compound is a compound of formula (IIa), (IIa), or a pharmaceutically acceptable salt thereof. In certain embodiments, each Y is C(R6). In certain embodiments, o is 1. In certain embodiments, R4 is selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy. In certain embodiments, R4 is halogen. In certain embodiments, R4 is F. In certain embodiments, o is 0. In certain embodiments, R1 is hydrogen. In certain embodiments, each of R2 and R3 is hydrogen. In certain embodiments, X is selected from CH2 and O. In certain embodiments, X is CH2, n is 1, m is 0, and q is 1. In certain embodiments, R5 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl, may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments, R5 is aryl optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl. In certain embodiments, R5 is alkyl substituted with 1-3 substituents independently selected from halogen. In certain embodiments, R5 is CF3. In certain embodiments, A is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments, A is selected from cyclopentyl or phenyl, wherein the cyclopentyl or phenyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments, A is phenyl. In certain embodiments, A is cyclopentane. In certain embodiments, R6 is is selected from hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments, R6 is hydrogen. The present application provides a compound selected from any one of compounds 1-224, 226-232, 235-244, 246-249, 251, and 253-264, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound is compound 78, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 135, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 264, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 263, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 256, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 217, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 251, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 178, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 240, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound 175, or a pharmaceutically acceptable salt thereof. The present application provides a pharmaceutical composition comprising (a) a compound as disclosed herein; and (b) a pharmaceutically acceptable excipient. The present application provides a compound or pharmaceutical composition as disclosed herein for use as a medicament. The present application provides a method of treating a neurodegenerative disorder in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound or pharmaceutical composition as disclosed herein. In certain embodiments, the neurodegenerative disorder is selected from Parkinson’s disease; Huntington’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis (ALS); Rett syndrome; multiple systems atrophy (MSA); Charcot Marie Tooth; Friedreich’s Ataxia; spinal cerebellar atrophy (SCA); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), age- related macular degeneration (AMD), and traumatic brain injury (TBI). The present application provides a method of treating a cardiovascular disorder, ischemia, or acute coronary syndromes in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound or pharmaceutical composition as disclosed herein. The present application provides a method of treating cancer or inhibiting tumor growth from a cancer in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound or pharmaceutical composition as disclosed herein. In certain embodiments, the cancer is selected from cancer of the lung, prostate, colon, breast, ovaries and bone. The present application provides a method of treating Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound or a pharmaceutical composition as disclosed herein. The present application provides use of a compound or a pharmaceutical composition as disclosed herein, in the preparation of a medicament for the treatment of Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease. Detailed Description of the Application The present application provides a compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, and NR8 (e.g., CH2, O, S, and NH); Y, independently for each occurrence, is selected from C(R6) and N; Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, and C(O)alkyl, wherein alkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, and C(O)alkyl, wherein alkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6, independently for each occurrence, is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, - C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, - SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl (e.g., hydrogen and alkyl); R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1. The present application provides a compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8 (e.g., CH2, O, S, and NH); Y, independently for each occurrence, is selected from C(R6) and N; Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6, independently for each occurrence, is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, - C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, - SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl (e.g., hydrogen and alkyl); R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1. The present application provides a compound of formula (Ia), (Ia), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8 (e.g., CH2, O, S, and NH); Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, - N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6 is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, -OC(O)R9, - C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl (e.g., hydrogen and alkyl); R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; and q is 0 or 1. The present application provides a compound of formula (Ib), (Ib), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8 (e.g., CH2, O, S, and NH); Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4, independently for each occurrence, is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, - C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, - C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6 is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, -OC(O)R9, - C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl (e.g., hydrogen and alkyl); R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1. The present application further provides a compound of formula (II), (II), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, and NR8 (e.g., CH2, O, S, and NH); Y, independently for each occurrence, is selected from C(R6) and N; Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, and C(O)alkyl, wherein alkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, and C(O)alkyl, wherein alkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6, independently for each occurrence, is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, - C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, - SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl (e.g., hydrogen and alkyl); R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1. The present application further provides a compound of formula (II), (II), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8 (e.g., CH2, O, S, and NH); Y, independently for each occurrence, is selected from C(R6) and N; Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6, independently for each occurrence, is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, - C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, - SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl (e.g., hydrogen and alkyl); R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1. The present application provides a compound of formula (IIa), (IIa), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8 (e.g., CH2, O, S, and NH); Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6 is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, -OC(O)R9, - C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), cycloalkenyl, heterocyclyl, heterocyclylalkyl (e.g., oxetanylmethyl), heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl (e.g., hydrogen and alkyl); R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, Z is SO2. In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, each occurrence of Y is C(R6). In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, three occurrences of Y are C(R6). In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, two occurrences of Y are C(R6). In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, one occurrence of Y is N. In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, two occurrences of Y are N. In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, R6, independently for each occurrence, is selected from hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, one occurrence of R6 is selected from cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, and all other occurrences of R6 are hydrogen. In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, each occurrence of R6 is hydrogen. In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, one occurrence of R6 is alkyl, such as methyl, and all other occurrences of R6 are hydrogen. In certain embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, one occurrence of R6 is cycloalkyl, such as cyclopropyl, and all other occurrences of R6 are hydrogen. In certain embodiments of the compound of formula Ia, Ib, or IIa, or a pharmaceutically acceptable salt thereof, R6 is selected from hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments of the compound of formula Ia, Ib, or IIa, or a pharmaceutically acceptable salt thereof, R6 is hydrogen. In certain embodiments of the compound of formula Ia, Ib, or IIa, or a pharmaceutically acceptable salt thereof, one occurrence of R6 is alkyl, such as methyl, and all other occurrences of R6 are hydrogen. In certain embodiments of the compound of formula Ia, Ib, or IIa, or a pharmaceutically acceptable salt thereof, one occurrence of R6 is cycloalkyl, such as cyclopropyl, and all other occurrences of R6 are hydrogen. In certain embodiments of the compound of formula I, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, o is 0. In certain embodiments of the compound of formula I, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, o is 1. In certain embodiments of the compound of formula I, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, o is 2. In certain embodiments of the compound of formula I, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, o is 3. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R4, independently for each occurrence, is selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy. In certain such embodiments, R4 is halogen, such as F. In certain embodiments of the compound of formula I, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, o is 1, and R4 is selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy. . In certain such embodiments, R4 is halogen, such as F. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is hydrogen. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R1 is alkyl, such as methyl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, each of R2 and R3 is hydrogen. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, each of R2 and R3 is alkyl, such as methyl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R2 is hydrogen, and R3 is alkyl, such as methyl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R2 is hydrogen, and R3 is acyl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R2 is selected from hydrogen and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring, such as piperidine (i.e., a piperidine fused to the pyridine ring system, together forming a tetrahydronaphthyridine). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R2 is absent, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring, such as pyrrole, thiazole, or imidazole (i.e., a pyrrole, thiazole, or imidazole fused to the pyridine ring system, together forming a pyrrolopyridine, thiazolopyridine, or imidazopyridine, respectively). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl (e.g., NR2R3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a pyrrole, thiazole, or imidazole), wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain such embodiments, the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen and alkyl, such as lower alkyl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, X is selected from C(R7)2, alkenyl, alkynyl, O, S, and NR8. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, X is selected from CH2, O, S, and NH, such as CH2 and O. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, q is 1 and X is CH2. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, q is 1 and X is O. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, q is 1, n is 0, m is 0, and X is CH2 (i.e., L is -CH2-). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, q is 1, n is 1, R7 for each occurrence is hydrogen, m is 0, and X is CH2 (i.e., L is -CH2CH2-). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, q is 1, n is 1, R7 for each occurrence is hydrogen, m is 0, and X is O (i.e., L is -CH2O-). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, each of n, q, and m is 0 (i.e., L is absent or a bond). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R7 for each occurrence is hydrogen. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R8 is selected from hydrogen and alkyl (e.g., hydrogen). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R5 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl, may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R5 is aryl optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl (e.g., R5 is phenyl or phenyl substituted with alkyl, such as t- butylphenyl). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, R5 is alkyl optionally substituted with 1- 3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl (e.g., R5 is haloalkyl, such as CF3). In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is selected from cycloalkyl (e.g., cyclopentyl) optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is selected from aryl (e.g., phenyl) optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is cyclopentane. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is cyclopropane. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is bicyclo[1.1.1]pentane. In certain embodiments of the compound of formula I, Ia, Ib, II, or IIa, or a pharmaceutically acceptable salt thereof, A is phenyl. The present application provides a compound selected from any one of
Figure imgf000038_0001
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Figure imgf000041_0001
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Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
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Figure imgf000051_0001
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Figure imgf000053_0001
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Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
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(262), (263), and (264), and pharmaceutically acceptable salts thereof. Indication of “*” in the numbering of the foregoing compounds designates known absolute configuration. Absolute configuration assignments of the remaining analogs require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate. In certain embodiments, the compound is selected from any one of compounds 1-162, and pharmaceutically acceptable salts thereof. 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), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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. The skilled artisan can readily determine the amount of compound and optional additives, vehicles, and/or carrier in compositions to be administered in methods of the application. In certain embodiments, the application relates to a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), for use as a medicament, e.g., for treatment of any of the disorders disclosed herein. In certain embodiments, the application relates to a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), for use as a medicament. In certain embodiments, the application relates to the use of an effective amount of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), in the manufacture of a medicament for treatment of a neurodegenerative disorder in a subject. In certain embodiments, the neurodegenerative disorder is selected from Parkinson’s disease; Huntington’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis (ALS); Rett syndrome; multiple systems atrophy (MSA); Charcot Marie Tooth; Friedreich’s Ataxia; spinal cerebellar atrophy (SCA); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), age-related macular degeneration (AMD), and traumatic brain injury (TBI). The present application provides a method of treating a cardiovascular disorder, ischemia (e.g., ischemia resulting from vascular occlusion, cerebral infarction, stroke and related cerebral vascular diseases e.g., cerebrovascular accident and transient ischemic attack), or acute coronary syndromes (e.g., myocardial infarction, coronary artery disease, unstable angina, and non-Q wave MI) in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb). The present application provides a method of treating cancer or inhibiting tumor growth from a cancer in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb). In certain embodiment, the cancer is selected from cancer of the lung, prostate, colon, breast, ovaries and bone. The present application provides a method of treating Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb). The present application provides use of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), in the preparation of a medicament for the treatment of Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease. In certain embodiments of the methods a disclosed herein, the compound is selected from any one of compounds 1-162, and pharmaceutically acceptable salts thereof. In certain embodiments, the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to (I), (Ia), (Ib), (II), or (IIb), inhibits F-ATPase hydrolase activity and does not inhibits F- ATPase synthase activity (i.e., the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to (I), (Ia), (Ib), (II), or (IIb), selectively inhibits F-ATPase hydrolase activity relative to F- ATPase synthase activity. In certain embodiments, the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), inhibits F-ATPase hydrolase activity more than the compound inhibits F-ATPase synthase activity. In certain such embodiments, the ratio of the IC50 of F-ATPase synthase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), to the IC50 of F-ATPase hydrolase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), is greater than or equal to 3, such as greater than 3. In certain embodiments, the ratio of the IC50 of F-ATPase synthase activity to the IC50 of F-ATPase hydrolase activity is greater than or equal to 4, greater than or equal to 5, greater than or equal to 6, greater than or equal to 7, greater than or equal to 8, greater than or equal to 9, or greater than or equal to 10. In certain such embodiments, the ratio of the IC50 of F-ATPase synthase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), to the IC50 of F-ATPase hydrolase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), is greater than or equal to 100, 90, 80, 70, 60, 50, 40, 30, 20, or 10. In certain such embodiments, the ratio of the IC50 of F- ATPase synthase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), to the IC50 of F-ATPase hydrolase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), is greater than or equal to 100. In certain such embodiments, the ratio of the IC50 of F-ATPase synthase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), to the IC50 of F-ATPase hydrolase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), is greater than or equal to 30. In certain such embodiments, the ratio of the IC50 of F-ATPase synthase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), to the IC50 of F-ATPase hydrolase activity for the compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), is greater than or equal to 10, such as greater than 10. In certain embodiments, the application relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound according to formula (I), (Ia), (Ib), (II), or (IIb), 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) a compound according to formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound of formula (I), (Ia), (Ib), (II), or (IIb), (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), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound of formula (I), (Ia), (Ib), (II), or (IIb), 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, 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), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound of formula (I), (Ia), (Ib), (II), or (IIb)) or the one or more additional therapeutic agent(s). 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: cardiovascular drugs, immunosuppressants, narcolepsy treatments, potassium channel openers, calcium channel blockers, sodium hydrogen exchanger inhibitors, anti-arrhythmic agents, thrombin inhibitors, platelet aggregation inhibitors or anti-platelet agents, fibrinogen antatagonists, diuretics, anti-hypertensive agents, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, cholesterol/lipid lowering agents and lipid profile therapies, anti-diabetic agents, anti- depressants, anti-inflammatory agents (steroidal and non- steroidal), anti-oxidant agents, antipsychotics (e.g., typical or atypical antipsychotics), angiogenesis modulators, anti-osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-coagulants, anti-obesity agents, anti-anxiety agents, anti- proliferative agents, anti-tumor agents, anti-ulcer and gastroesophageal reflux disease agents, growth hormone and/or growth hormone secretagogues, thyroid mimetics (including thyroid receptor antagonist), anti-infective agents, anti-viral agents, anti- bacterial agents, and anti-fungal agents. In certain embodiments, the compound of the application (e.g., compound of formula (I), (Ia), (Ib), (II), or (IIb), or a pharmaceutically acceptable salt of the compound of formula (I), (Ia), (Ib), (II), or (IIb)) may be administered with one or more of the following: other F-ATPase inhibitors such as efrapeptin, oligomycin, autovertin B, and azide; anti-arrhythmic agents including Class I agents (such as propafenone); Class II agents (propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K+ channel openers such as IAch inhibitors, and IKur inhibitors; alpha- or beta- adrenergic blockers (such as propranolol, nadolol and LJY]NMRSVS$& VY g'JMYNUNYPRL JPVURZ[Z Z\LQ JZ JSK\[NYVS& [NYK\[JSRUN& OVYTV[NYVS& salmeterol, bitolterol, pilbuterol, and/or fenoterol; angiotensin-E receptor antagonists (e.g., irbesartan, losartan or valsartan); anticholinergics such as ipratropium bromide; anti-diabetic agents such as biguanides (e.g. metformin); glucosidase inhibitors (e.g. acarbose); insulins (including insulin secretagogues or insulin sensitizers); meglitinides (e.g. repaglinide); sulfonylureas (e.g., glimepiride, glyburide and glipizide); biguanide/glyburide combinations (e.g., glucovance), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2), glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors; anti-depressant or anti-anxiety agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), noradrenaline and specific serotonergic antidepressants (NASSAs), tricyclic antidepressants (TCAs), serotonin antagonists and reuptake inhibitors (SARIs), and monoamine oxidase inhibitors (MAOIs), such as nefazodone, sertraline, diazepam, lorazepam, buspirone, hydroxyzine pamoate, fluoxetine, citalopram, escitalopram, paroxetine, bupropion, duloxetine, venlafaxine, mirtazapine, amitriptyline, clomipramine, dosulepin, imipramine, lofepramine and nortriptyline, trazodone, tranylcypromine, phenelzine and isocarboxazid; anti-hypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, lisinopril, zofenopril, ramipril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril), vasopeptidase inhibitors, i.e., dual 68:)f:C RUQRKR[VYZ #N(P(& VTJWJ[YRSJ[ JUM PNTVWJ[YRSJ[$& 6F'+ YNLNW[VY JU[JPVURZ[Z (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, J[YZNU[JU$49\JS :F)6== JU[JPVURZ[4 UN\[YJS NUMVWNW[RMJZN #f:C$ RUQRKR[VYZ4 anti-inflammatory agents such as cromolyn, nedocromil, theophylline, zileuton, zafirlukast,_monteleukast and/or pranleukast or cortiocosteroids including, beclomethasone, triamcinolone, budesonide, fluticasone, flunisolide or dexamethasone; prednisone; dexamethasone; enbrel; protien tyrosine kinase (PTK) RUQRKR[VYZ4 L`LSVV_`PNUJZN RUQRKR[VYZ #RULS\MRUP fE6=9Z& JUM 8BG'+ JUM)VY 8BG', inhibitors); aspirin; or indomethacin; lipoxygenase inhibitors; chemokine receptor modulators (including CCR1, CCR2, CCR3, CXCR2 receptor antagonists); secretory and cytosolic phospholipase A2 inhibitors; VLA4 antagonists; cytokine modulators (e.g. TNF-alpha converting enzyme (TACE) inhibitors, Interleukin-1 converting enzyme (ICE) inhibitors, Interleukin-1 receptor antagonists); angiogenesis modulators such as endostatin; anti-oxidant agents and/or lipid peroxidation inhibitors such as probucol, BO- 653, Vitamin A, Vitamin E, AGI-1067; antipsychotic agents including atypical antipsychotics such as risperidone, quetiapine, olanzapine, ziprasidone, paliperidone, aripiprazole and clozapine, or typical antipsychotics such as chlorpromazine, flupenthixol, afluphenazine, haloperidol, loxapine, perphenazine, pimozide, trifluoperazine, thiothixene and zuclopenthixol; anti-platelet agents such as GPII-b/GPIIIa blockers, (e.g., abciximab, eptifibatide, tirofiban); P2Y12 antagonists (e.g., clopidogrel, ticlopidine, CS-747); or thromboxane receptor antagonists (e.g., ifetroban); anti-osteoporosis agents including alendronate and raloxifene; anti-obesity agents including orlistat and aP2 inhibitors; anti-proliferative agents including cyclosporin A, paclitaxel, FK 506, and adriamycin; anti-ulcer and gastroesophageal reflux disease agents including famotidine, ranitidine, and omeprazole; sodium hydrogen exchanger-1 (NHE-1) inhibitors such as cariporide; calcium channel blocking agents such as verapamil, nifedipine, diltiazem, amlodipine and mybefradil; cardiac glycosides such as digitalis and ouabain; diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, pojythiazide, musolimine, bumetanide, triamtrenene, amiloride; hormone replacement therapies including estrogen (e.g., congugated estrogens) and estradiol; immunosuppressants including cyclosporine, everolimus, and tacrolimus; lipid profile modulators including HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin, ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACATI inhibitors; ACAT2 inhibitors; dual ACAT1/2 inhibitors; MTP inhibitors; cholesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414); PPAR- delta agonists; PPAR-alpha agonists; dual PPAR-alpha/delta agonists; LXR-alpha agonists; LXR-beta agonists; LXR dual alpha/beta agonists; mineralocorticoid receptor antagonists such as spironolactone and eplirinone; microsomal triglyceride transport protein inhibitors; narcolepsy medications such as modafinil and armodafinil; phosphodiesterase (PDE) inhibitors including dipyridamole, cilostazol, or sildenafil, or PDE inhibitors in combination with aspirin, ifetroban, picotamide, ketanserin, clopidogrel, and/or thromboxane receptor antagonists or thromboxane A synthetase inhibitors (such as picotamide); serotonin-2-receptor antagonists (such as ketanserin), fibrinogen receptor antagonists; thrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, prourokinase, tenecteplase (TNK), lanoteplase (nPA), anisolated streptokinase plasminogen activator complex (ASPAC), factor Vila inhibitors, factor Xa inhibitors, thrombin inhibitors (such as hirudin and argatroban), animal salivary gland plasminogen JL[R]J[VYZ& C6='+ RUQRKR[VYZ Z\LQ JZ GD'--* JUM F'020& JUM RUQRKR[VYZ VO d',' JU[RWSJZTRU Z\LQ JZ JU[R'd',' JU[RWSJZTRU JU[RKVM`& WYVZ[JL`LSRU TRTN[RLZ4 JUM anticancer strategies, including radiation, and chemotherapies, including paclitaxel, adriamycin, epithilones, cisplatin, and carboplatin. 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. 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-trifluoroethyl, 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 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 or 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 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. The permissible substituents can be one or more and the same or different for appropriate organic compounds, as described herein. 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. 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 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 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 hydroxyl protecting 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), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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 (Simplício et al, “Prodrugs for Amines,” Molecules, (2008), 13:519- 547). In certain embodiments, some or all of the compounds of formula (I), (Ia), (Ib), (II), or (IIb), 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), (Ia), (Ib), (II), or (IIb), 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. Prepartion of Compounds of Formulae I and II Compounds of the present application may be prepared using synthetic protocols illustrated below in Schemes A-D. Scheme A: General scheme for preparation of Intermediate vi.
Figure imgf000088_0001
An exemplary method of preparing Intermediate vi is shown in Scheme A. In this scheme, diamine i is condensed with keto ester ii at elevated temperature, for example 135 ºC, in a suitable solvent, such as toluene (Method A). The resulting product iii is then subjected to reductive hydrolytic conditions with a suitable acid, for example TFA, reducing agent, such as triethylsilane in an appropriate solvent, such as TFA at room temperature (Method B) to afford compound of formula iv. Cyclization to lactam v is then carried out using suitable hydrolytic conditions, for example NaOH in aqueous methanol at room temperature (Method C). Reduction to diazepane vi is accomplished using a suitable reducing agent, for example LAH in an appropriate solvent, such as THF at room temperature. Alternatively, reduction can be also run using BH3.Me2S in a suitable solvent, such as toluene at elevated temperature, for example 100 ºC (Method D). Scheme B: General scheme for preparation of Intermediate x.
Figure imgf000089_0001
An exemplary method of preparing Intermediate x is shown in Scheme B. In this scheme, substituted anthranilic acid vii is converted to acid chloride under suitable conditions, such as oxalyl chloride and DMF in an appropriate solvent, for example DCM (Method E). Acyl chloride is then treated with suitably protected crotylamine under appropriate conditions, such as TEA/DCM to afford amide viii. This reaction may be conducted at room temperature or under cooling, for example at 0 ºC. Protecting group (“PG”) may include Bn, PMB or another suitable alternative. Amide viii is then transformed using diacyliodobenzene-driven palladium catalyzed cyclization under suitable conditions, for example Pd(OAc)2, sodium acetate, tetrabutylammonium hydrogen sulfate to lactam ix. The reaction may be conducted in a suitable solvent, such as DCE at elevated temperature, for example reflux (Method G). Deprotections are then accomplished using well-known organic chemistry transformations, for example Pd-catalyzed hydrogenation for debenzylation, and HBr/acetic acid for tosyl removal. Formed lactam ix is then transformed to diazepane x using Method D described above. Scheme C: General scheme for preparation of Intermediate xiv.
Figure imgf000090_0001
An exemplary method of preparing Intermediate xiv is shown in Scheme C. In this scheme, aziridine xi is treated with an alcohol A-OH under Lewis acid conditions, such as BF3.Et2O in a suitable solvent, for example chloroform (Method H) to afford ring opening product xii. This transformation may be conducted while cooling, for example 0ºC, following slow warming to room temperature. Nitrile function in xii is then reduced using a suitable reagent, such as Raney-Ni and hydrogen at room temperature under conditions that allow subsequent cyclization of the formed amine to produce lactam xiii. The reaction may be conducted in presence of a suitable base, for example TEA, a suitable solvent, such as aqueous MeOH at room temperature (Method I). The latter compound is then transformed to diazepane xiv using Method D described above. Scheme D: General scheme for preparation of compound of formula I(c) and II(c).
Figure imgf000090_0002
An exemplary method of preparing compounds of formulae I(c) and II(c) is shown in Scheme D. In this scheme, diazepane vi is converted to sulfonamide xv using appropriate alkyl or aryl sulfonylation reagent, for example sulfonyl anhydride or sulfonyl chloride. The reaction may be conducted using a suitable base, for example DIEA in a suitable solvent, such as DCM (Method J). The reaction may be conducted under cooling conditions, for example -78 ºC with slow warming to 0 ºC in appropriate cases. Intermediates x or xiv may also be used as starting points for this synthetic sequence. Compound xv is then treated with 4-bromopicolinyl chloride or 5- bromopicolinyl chloride under conditions of Method F described above to afford amide xvi(a) or xvi(b), respectively. Amide function in xvi(a) or xvi(b) is then reduced using suitable reagents, for example sodium borohydride and BF3.Et2O to afford xvii(a) or xvii(b). The reaction may be conducted in THF or another suitable solvent, with initial cooling and subsequent temperature elevation, for example to 60 ºC (Method K). Compound xvii(a) or xvii(b)is then subjected to aryl amination conditions, for example using Pd(OAc)2 / XANTPHOS in presence of a suitable base, such as Cs2CO3 to afford compound of formula I(c) or II(c). The reaction may be conducted in dioxane or another suitable solvent, at elevated temperature, for example 80 ºC (Method L). Alternatively, amidation using a suitable reagent, for example t- butyl carbamate can be used for preparation of unsubstituted pyridine amines. Initial transformation may be run under the conditions of Method L to afford protected amines, for example bearing Boc group. The protecting group can be then deprotected using well-known organic chemistry transformations, for example TFA in DCM at room temperature for Boc group removal. Racemic compounds of formula I(c) or II(c) can be subsequently separated into individual enantiomers using suitable chiral separation method, for example chiral SFC.
Scheme E: Alternative method for preparation of compounds of formulae I(c) and II(c)
Figure imgf000092_0001
An alternative method of preparing compounds of formulae I(c) and II(c) is shown in Scheme E. In this scheme, compounds xv are treated with bromo substituted benzaldehyde under suitable reducing conditions, such as triethylsilane and TFA, in an appropriate solvent, such as DCM (Method M). Resulting products xvii are then converted to I(c) or II(c) as shown in Scheme D. Scheme F: Alternative method for preparation of Intermediate v.
Figure imgf000092_0002
An alternative method of preparing intermediates of formulae v is shown in Scheme F. In this scheme, bromobenzonitriles xviii are treated with amino acids ixx under suitable Pd catalytic conditions, for example SPhos Pd G3 in a presence of a suitable base, such as cesium carbonate in an appropriate solvent, for example toluene at elevated temperature to afford compouds of formula xx (Method N). Compounds xxare then cyclized to v using suitable hydrogenation conditions, for example Ra-Ni in presence of a suitable base, such as TEA in an appropriate solvent, for example MeOH/water mixture to afford compounds of Formulae v (Method O). Scheme G: Alternative method for preparation of Intermediate v.
Figure imgf000092_0003
An alternative method of preparing intermediates of formulae v is shown in Scheme G. In this scheme, aminobenzonitriles xxi are treated with halogenated acids xxii under presence of a suitable base, for example DIEA at elevated temperature to afford compounds of formulae xxiii (Method P). The subsequent step is carried out as described in Scheme F. 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, corn, 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 synthetic protocols for a number of non-limiting examples of compounds of the application. Table 1: Abbreviation list
Figure imgf000105_0001
Figure imgf000106_0002
Protocol 1: 5-Fluoro-2-((2-(4-fluorophenethyl)-6-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (1)
Figure imgf000106_0001
Step 1: 5-(4-fluorophenyl)-3-oxo-2-(tributyl-l5-phosphaneylidene)pentanenitrile (1-B). A mixture of 3-(4-fluorophenyl)propanoic acid (15 g, 89.20 mmol, 1 eq) and 2- (tributyl-phosphanylidene)acetonitrile (10.76 g, 44.60 mmol, 0.5 eq) in DCM (100 mL) was added EDCI (17.10 g, 89.20 mmol, 1 eq) and DMAP (1.09 g, 8.92 mmol, 0.1 eq) was stirred at 25°C for 1 hr. The mixture was concentrated and the residue was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 10:1 to 1:1) to give 5-(4-fluorophenyl)-3-oxo-2-(tributyl-l5-phosphaneylidene)pentanenitrile 1-B (12 g, 30.65 mmol, 34.36% yield) as yellow solid. ESI [M+H] = 392.3 Step 2: Methyl 4-(4-fluorophenyl)-2-oxobutanoate (1-C). Ozone (1.47 g, 30.65 mmol, 1 eq) was bubbled into a solution of 5-(4-fluorophenyl)-3-oxo-2-(tributyl- phosphanylidene)pentanenitrile (12 g, 30.65 mmol, 1 eq) in DCM (100 mL) and MeOH (50 mL) at -78°C for 3 hrs. After excess O3 was purged by O2, mixture was concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 100:1 to 1:1) to give methyl 4-(4-fluorophenyl)-2- oxobutanoate (1-C, 4 g, 19.03 mmol, 62.1% yield) as a white solid. ESI [M+H] = 211.2 Step 3: Methyl 2-(4-fluorophenethyl)-5-(trifluoromethyl)-1,2,3,4- tetrahydroquinazoline-2-carboxylate (1-D). To the mixture of methyl 4-(4- fluorophenyl)-2-oxo-butanoate (4 g, 19.03 mmol, 1 eq) and 2-(aminomethyl)-3- (trifluoromethyl)aniline (3.62 g, 19.03 mmol, 1 eq) in toluene (100 mL). The mixture was stirred at 135°C for 2 hrs, concentrated and the residue was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 100:1 to 10:1) to give methyl 2-(4-fluorophenethyl)-5-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-2- carboxylate (1-D, 1.8 g, 4.71 mmol, 24.74% yield) as a yellow solid. ESI [M+H] = 383.1 Step 4: Methyl 2-((2-(aminomethyl)-3-(trifluoromethyl)phenyl)amino)-4-(4- fluorophenyl)butanoate (1-E). To the mixture of methyl 2-[2-(4-fluorophenyl)ethyl]-5- (trifluoromethyl)-3,4-dihydro-1H-quinazoline-2-carboxylate (1.7 g, 4.45 mmol, 1 eq) in DCM (30 mL) and TFA (15 mL) was added Et3SiH (1.03 g, 8.89 mmol, 2 eq) at 0°C. The mixture was stirred at 25°C for 1 hr, the filtrate was concentrated under reduced pressure to give methyl 2-((2-(aminomethyl)-3-(trifluoromethyl)phenyl)amino)-4-(4- fluorophenyl)butanoate (1-E, 1.5 g, crude) as a yellow solid. ESI [M+H] = 385.2 Step 5: 2-(4-fluorophenethyl)-6-(trifluoromethyl)-l,2,4,5-tetrahydro-3H- benzo[e] [1 ,4] diazepin-3-one (1-F). To the mixture of methyl 2-((2-(aminomethyl)-3- (trifluoromethyl)phenyl)amino)-4-(4-fluorophenyl)butanoate (1.5 g, 3.90 mmol, 1 eq) in MeOH (3 mL) and H2O (1.5 mL) was added NaOH (468.27 mg, 11.71 mmol, 3 eq). The reaction mixture was filtered and the filtrate cake was concentrated under reduced pressure to give 2-(4-fluorophenethyl)-6-(trifluoromethyl)- 1,2,4, 5-tetrahydro-3H- benzo[e][l,4]diazepin-3-one (1-F, 450 mg, crude) as a white solid. ESI [M+H] = 353.2
Step 6: 2-(4-Fluorophenethyl)-6-(trifluoromethyl)-2, 3, 4, 5 -tetrahydro- 1H- benzo[e] [1 ,4]diazepine (1-G). To a mixture of 2-[2-(4-fluorophenyl)ethyl]-6- (trifluoromethyl)-l,2,4,5-tetrahydro-l,4-benzodiazepin-3-one (450 mg, 1.28 mmol, 1 eq) in THF (5 mL) was added LAH (1 M, 3 eq) at 0°C ,the mixture was stirred at 40°C for 1 hr. The reaction mixture was quenched by addition Na2SO4. lO H2O (1 g) slowly at 0°C under N2, stirred at 25°C for 30 min. and concentrated in vacuum to give 2-(4- fluorophenethyl)-6-(trifluoromethyl)-2,3,4,5-tetrahydro-lH-benzo[e][l,4]diazepine (1-G, 350 mg, crude) as a yellow solid. ESI [M+H] = 339.2
Step 7: 2-(4-Fluorophenethyl)-6-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-lH-benzo[e] [l,4]diazepine (1-H). To a mixture of 2-[2-(4- fhiorophenyl)ethyl]-6-(trifluoromethyl)-2,3,4,5-tetrahydro-lH-l,4-benzodiazepine (220 mg, 650.23 pmol, 1 eq) and trifluoromethylsulfonyl trifluoromethanesulfonate (238.5 mg, 845.30 pmol, 1.3 eq) in DCM (5 mL) was added DIEA (252.11 mg, 1.95 mmol, 3 eq) at -78°C, the mixture was stirred at -78°C for 1 hr under N2, then concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 100:1 to 5: 1) to give 2-(4-fluorophenethyl)-6- (trifhioromethyl)-4-((trifhioromethyl)sulfonyl)-2,3,4,5-tetrahydro-lH- benzo[e][l,4]diazepine (1-H, 180 mg, 382.65 pmol, 58.85% yield) as a yellow solid. ESI [M+H] - 471.1
Step 8: (4-Bromo-5-fluoropyridin-2-yl)(2-(4-fluorophenethyl)-6-(trifluoromethyl)- 4-((trifluoromethyl)sulfonyl)-2, 3,4,5-tetrahydro-lH-benzo[e] [ 1,4] diazepin- 1- yl)methanone (l-I). To a mixture of 2-(4-fluorophenethyl)-6-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2, 3, 4, 5 -tetrahydro- 1 H-bcnzo[c] [1 ,4]diazepine (130 mg, 276.36 pmol, 1 eq) in DCM (5 mL) was added TEA (83.89 mg, 829.08 pmol, 3 eq) and 4-bromo-5-fluoropicolinoyl chloride (329.48 mg, 1.38 mmol, 5 eq.) at 0°C. The mixture was stirred at 40°C for 1 hr, then filtered and concentrated. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate =5:1) to give (4-bromo-5- fluoropyridin-2-yl)(2-(4-fluorophenethyl)-6-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methanone (1-I, 70 mg, 104.11 umol, 37.67% yield) as a yellow solid. ESI [M+H] =674.2 Step 9: 1-((4-Bromo-5-fluoropyridin-2-yl)methyl)-2-(4-fluorophenethyl)-6- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (1-J). To a mixture of (4-bromo-5-fluoropyridin-2-yl)(2-(4- fluorophenethyl)-6-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-1-yl)methanone #0* TP& 23(,- hTVS& + eq) in THF (3 mL) was added BF3.Et2O (202.64 mg, 1.43 mmol, 16 eq). The mixture was stirred for 6 minutes while continued addition of NaBH4 #,1(*+ TP& 1+-(22 hTVS& 2 NX$ J[ * b8( FQN mixture was stirred at 60°C for 1 hr, quenched with saturated aqueous NH4Cl (8 mL), then extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE:EtOAc =3:1 )to give 1-((4-bromo-5-fluoropyridin-2-yl)methyl)-2-(4- fluorophenethyl)-6-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-bcnzo[c][l ,4]diazepine (1-J, 20 mg, 30.38 pmol, 34.04% yield) as a yellow solid. ESI [M+H] = 660.3 Step 10: Tert-butyl (5-fluoro-2-((2-(4-fluorophenethyl)-6-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-yl)carbamate (1-K). To a mixture of 1-((4-bromo-5-fluoropyridin- 2-yl)methyl)-2-(4-fluorophenethyl)-6-(trifluoromethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H'KNUaVHNIH+&.IMRJaNWRUN #,* TP& -*(-2 hTVS& + eq) and tert-butyl carbamate #/(-. TP& ./(/0 hTVS& +(/ eq) in dioxane (1 mL) was added MRJLN[V_`WJSSJMR\T #02+(32 hP& -(*. hTVS& *(+ eq) and Pd(OAc)2 #-(/, TP& 0(*2 hTVS& 0.2 eq) and Cs2CO3 #+3(13 TP& 0*(1/ hTVS& , eq). The mixture was stirred at 80°C for 1 hr under N2, then filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (5-fluoro-2-((2-(4-fluorophenethyl)-6-(trifluoromethyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-yl)carbamate (1-K, 15 mg, crude) as a yellow solid. ESI [M+H] = 695.3
Step 11: 5-Fluoro-2-((2-(4-fluorophenethyl)-6-(trifluoromethyl)-4-
((trifluoromethyl)sulfonyl)-2, 3 ,4,5-tetrahydro-lH-benzo [e] [1 ,4] diazepin- 1 - yl)methyl)pyridin-4-amine (1). A mixture of tert-butyl A-[5-fluoro-2-[[2-[2-(4- fluorophenyl)ethyl]-6-(trifluoromethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro-2//- l,4-benzodiazepin-l-yl]methyl]-4-pyridyl] carbamate (15 mg, 21.59 pmol, 1 eq) in TFA (0.5 mL) and DCM (1 mL) was stirred at 20°C for 1 hr. The residue was purified by preparative HPLC (Phenomenex Luna Cl 8 column (100 x 40 mm, 5 um); flow rate: 50 mL/min; gradient: 25% -65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 5-fluoro-2-((2-(4-fluorophenethyl)-6- (trifluoromethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-lH- benzo[e][l,4]diazepin-l-yl)methyl)pyridin-4-amine (1, 4.9 mg, 7.57 pmol, 35.07% yield, 99.0% purity, FA salt) as a yellow solid. ESI [M+H] = 595.2. *H-NMR (400 MHz, DMSO-d6) 5 = 8.04 (br s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.50 (br t, J = 8.0 Hz, 1H), 7.41 (d, .7- 7.6 Hz, 1H), 7.11 - 7.02 (m, 4H), 6.82 (d, J- 7.6 Hz, 1H), 6.46 - 6.08 (m, 2H), 5.05 (br d, J= 14.8 Hz, 1H), 4.72 - 4.61 (m, 1H), 4.54 - 4.45 (m, 1H), 4.43 - 4.34 (m, 1H), 3.89 - 3.70 (m, 1H), 3.55 - 3.45 (m, 2H), 2.60 - 2.52 (m, 2H), 1.63 (br dd, J= 11.2, 2.0 Hz, 1H), 1.39 - 1.26 (m, 1H).
Protocol 2: (2R)-2-(2-Phenylethyl)-1-(1,2,3,4-tetrahydro-1,6-naphthyridin-7- ylmethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepine (8)
Figure imgf000111_0001
Step 1: (2R)-2-(2-Phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (8-B) and (2S)-2-(2-Phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (8-C). Racemic 8-A was separated by SFC (Instrument: Waters SFC80 preparative SFC; Column: DAICEL CHIRALCEL OJ (250mm*50mm,10um); Mobile phase A: CO2 and B: 0.1% IPA in NH3H2O; Gradient: B% = 20% isocratic elution mode; Flow rate: A(2.9 g/min), B(3.4 mL/min); Wavelength: 220 nm; Column temperature: 35°C; System back pressure: 2000 PSI) to generate two enantiomers. Peak 1 (Rt=1.656 min) was assigned as (2R)-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H- 1,4-benzodiazepine (8-B) (3.2 g, 12.68 mmol, 32.00% yield) using VCD analysis. ESI [M+H] = 253.17. Peak 2 (Rt=2.133 min) was assigned as (2S)-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H- 1,4-benzodiazepine (8-C) (3.4 g, 12.68 mmol, 34.00% yield) using VCD analysis. ESI [M+H] = 253.17 Steps 2-4 were carried out in a similar manner as Steps 7-9 in Protocol 1 above. Step 5: (R)-2-Phenethyl-1-((1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)methyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (8). To a mixture of benzyl 7-[[(2R)-2-(2-phenylethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro- 2H- 1 ,4-benzodiazepin- 1 -yl] methyl ] -3 ,4-dihydro-2H - 1 ,6-naphthyridine- 1 -carboxylate (40 mg, 60.17 pmol, 1 eq) in EtOAc (2 mL) was added Pd/C (64.04 mg, 60.17 pmol, 10%, 1 eq) and the mixture was stirred at 20°C for 0.5 hr under H2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and was purified by preparative HPLC (Phenomenex LunaC18 column (100x40 mm, 5um); flow rate: 25 mL/min; gradient: 25% -65% B over 8 min; mobile phase A: H2O(0.2%FA), mobile phase B: acetonitrile) to give (2R )-2-(2-phenylethyl)-l-(l,2,3,4-tetrahydro-l,6- naphthyridin-7-ylmethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro-2H-l,4- benzodiazepine (8, 14 mg, 24.00 pmol, 40% yield, FA salt). ESI [M+H] = 531.1. 1H- NMR (400 MHz, DMSO-d 6) δ = 8.22 (s, 1H), 7.77 (s, 1H), 7.80 - 7.73 (m, 1H), 7.30 - 7.19 (m, 5H), 7.15 - 7.10 (m, 1H), 7.03 - 6.94 (m, 3H), 6.86 (br s, 1H), 6.58 (s, 1H), 4.70 (br d, J= 14.4 Hz, 1H), 4.51 (br d, J= 14.4 Hz, 2H), 4.26 (d, J= 14.8 Hz, 1H), 3.88 (br d, J = 13.2 Hz, 1H), 3.50 (br d, J= 13.2 Hz, 1H), 3.38 (br t, J= 6.4 Hz, 1H), 3.22 (br s, 2H), 2.61 - 2.54 (m, 3H), 2.49 - 2.44 (m, 1H), 1.80 - 1.72 (m, 2H), 1.41 (td, J = 6.4, 12.4 Hz, 1H), 1.24 - 1.12 (m, 1H) .
Compounds in table 2 were prepared according to procedures analogous to preparation of Compounds 1 and 8 shown above in Protocols 1 and 2, using intermediates specified in the table.
Table 2: Compounds prepared according to procedures analogous to preparation of
Compounds 1 and 8 in Protocols 1 and 2
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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
a Cyclopropyl was installed to the central core by treatment with potassium cyclopropyltetrafluoroborate under Pd(OAc)2 / bis(1-adamantyl)-butyl-phosphane catalysis with cesium carbonate in toluene/water mixture at 80ºC for 12 hours. b. Reacted the 4-bromo-5-fluoropyridine under aryl nucleophilic substitution conditions as in Protocol 1 step 10, with methanimidamide in DMA and K2CO3 as base. c. Reacted the 4-bromopyridine in a similar manner as in Protocol 1 step 10, but replaced tert-butyl carbamate with acetamide. d. Acyl chloride prepared in situ using POCl3/Pyridine/DCM in Step 8, Protocol 1 e. N-alkylation was performed using alkyl iodide (or bromide) and NaH (or Cs2CO3) after Step 10, Protocol 1 f. Conversion of Br to COOH group was accomplished by treatment with oxalic acid, XantPhos/Pd(OAc)2 in DIEA/EtOAc/DMF mixture after Step 9, Protocol 1. g. Alkyl amine was coupled with aryl halide after Step 9 using Pd(OAc)2 / BINAP / tBuONa in dioxane (*) Known absolute configuration. Absolute configuration assignments of the remaining analogs require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate. Protocol 3: (R)-2-((6-(2-(Dimethylamino)ethoxy)-2-phenethyl-4-((trifluoromethyl)- sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)pyridin-4-amine (15)
Figure imgf000164_0001
Step 1: (R)-1-((4-Bromopyridin-2-yl)methyl)-2-phenethyl-4-((trifluoromethyl)- sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (15-B). To a solution of (R)-1-((4-bromopyridin-2-yl)methyl)-6-methoxy-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (15-A, prepared according to procedures in Protocols 1 and 2 above, 500 mg, 855.51 umol, 1 eq) in DCM (2.5 mL) was added BBr3 (2.5 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was added to sat.aq. NaHCO3 ( 10 mL) slowly and stirred at 0°C for 0.5 hr under N2, and then extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give (R)-1-((4-bromopyridin-2-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ol (15-B, 400 mg, crude) as a white solid. ESI [M+H] = 571.9 Step 2: Tert-butyl (R)-(2-((1-((4-bromopyridin-2-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6- yl)oxy)ethyl)carbamate (15-C). To a solution of (R)-1-((4-bromopyridin-2-yl)methyl)- 2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-6-ol (40 mg, 70.12 umol, 1 eq, crude from Step 9) in DMF (1 mL) was added K2CO3 (19.38 mg, 140.25 umol, 2 eq), tert-butyl (2- bromoethyl)carbamate (18.86 mg, 84.15 umol, 1.2 eq) and KI (23.28 mg, 140.25 umol, 2 eq). The mixture was stirred at 40°C for 12 hr, then filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 3:1) to give tert-butyl (R)-(2-((1-((4- bromopyridin-2-yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-6-yl)oxy)ethyl)carbamate (15-C, 50 mg, 70.07 umol, 99.92% yield) as a white solid. ESI [M+H] = 713.2 Step 3: Tert-butyl (R)-(2-((6-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-phenethyl- 4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-yl)carbamate (15-D). To a solution of tert-butyl (R)-(2-((1-((4- bromopyridin-2-yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-6-yl)oxy)ethyl)carbamate (45 mg, 63.06 umol, 1 eq) in dioxane (2 mL) was added Xantphos (7.30 mg, 12.61 umol, 0.2 eq), tert-butyl carbamate (8.86 mg, 75.67 umol, 1.2 eq), Cs2CO3 (41.09 mg, 126.12 umol, 2 eq) and Pd(OAc)2 (1.42 mg, 6.31 umol, 0.1 eq). The mixture was stirred at 80°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 prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 1:1) to give tert-butyl (R)-(2-((6-(2-((tert-butoxycarbonyl)amino)ethoxy)-2- phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin- l-yl)methyl)pyridin-4-yl)carbamate (15-D, 45 mg, 60.01 umol, 95.17% yield) as a brown oil. ESI [M+H] = 750.2
Step 4: Tert-butyl (R)-(2-((l-((4-aminopyridin-2-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2, 3,4,5-tetrahydro-lH-benzo[e] [l,4]diazepin-6- yl)oxy)ethyl)carbamate (15-E). To a solution of tert-butyl (/?)-(2-((6-(2-((tcrt- butoxycarbonyl)amino)ethoxy)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2, 3,4,5- tetrahydro- 1 H-bcnzo[c] [ 1 ,4]diazepin- 1 -yl)methyl)pyridin-4-yl)carbamate (45 mg, 60.01 umol, 1 eq) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 25°C for 0.5 hr, then concentrated under reduced pressure to give tert-butyl (R)-(2- ((l-((4-aminopyridin-2-yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][l,4]diazepin-6-yl)oxy)ethyl)carbamate (15-E, 30 mg, crude) as a yellow oil. ESI [M+H] = 550.3
Step 5: (R)-2-((6-(2-(Dimethylamino)ethoxy)-2-phenethyl-4-
((trifluoromethyl)sulfonyl)-2, 3 ,4,5-tetrahydro-lH-benzo [e] [1 ,4] diazepin- 1 - yl)methyl)pyridin-4-amine (15). A solution of tert-butyl (R)-(2-((l-((4-aminopyridin-2- yl)methyl)-2-phenethyl-4-((trifluoromethy l)sulfonyl)-2, 3, 4, 5 -tetrahydro- 1H- benzo[e][l,4]diazepin-6-yl)oxy)ethyl)carbamate (30 mg, 54.58 umol, 1 eq) in MeOH (2 mL) was adjusted to pH > 10 with DIEA (21.16 mg, 163.75 umol, 3 eq) and then to pH = 4 - 5 with AcOH (9.83 mg, 163.75 umol, 3 eq). Then HCHO (17.72 mg, 218.34 umol, 4 eq) was added to the mixture. The mixture was stirred at 25 °C for 0.5 hr. Then NaBH iCN (5.15 mg, 81.88 umol, 1.5 eq) was added to the mixture. The mixture was stirred at 25 °C for 0.5 hr, concentrated under reduced pressure and the residue was purified by preparative HPLC (Phenomenex Luna C18 (75 x 30 mm, 3 mm); flow rate: 50 mL/min; gradient: 15% - 35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give (R)-2-((6-(2-(dimethylamino)ethoxy)-2- phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][l,4]diazepin- 1 -yl)methyl)pyridin-4-amine (15, 17.6 mg, 28.13 pmol, 51.54% yield, FA salt) as a white solid. ESI [M+H] = 578. 1. 'H-NMR (400 MHz, CD3OD) 5 = 8.47 (br s, 2H), 7.96 (br d, J= 6.4 Hz, 1H), 7.32 (t, J= 8.4 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.20 - 7. 15 (m, 1H), 7.10 (d, J= 7.2 Hz, 2H), 6.89 (dd, J= 8.4, 12.4 Hz, 2H), 6.75 - 6.69 (m, 2H), 5.54 (br d, J= 14.4 Hz, 1H), 4.72 (br d, J = 15.2 Hz, 2H), 4.46 - 4.40 (m, 1H), 4.34 (br d, J= 15.2 Hz, 3H), 3.99 (br d, J = 13.2 Hz, 1H), 3.55 - 3.49 (m, 2H), 3.27 - 3.21 (m, 1H), 2.93 (s, 6H), 2.75 - 2.68 (m, 1H), 2.54 (ddd, J = 13.6, 9.6, 7.2 Hz, 1H), 1.58 (br d, J = 6.4 Hz, 1H), 1.41 - 1.32 (m, 1H) Compounds in table 3 were prepared according to procedure analogous to preparation of Compound 15 shown above in Protocol 3. Absolute configuration assignments require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate. Table 3: Compounds prepared according to procedure analogous to preparation of Compound 15 in Protocol 3
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0002
a. tert-butyl(2-iodoethoxy) dimethylsilane was used in Step 2, the formed TBS protecting group was removed using TFA in DCM at room temperature. b.1-iodo-2-methoxy-ethane was used in Step 2. Protocol 4: 1-(1-((4-Amino-5-fluoropyridin-2-yl)methyl)-6-chloro-2-(2- cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,2,2- trifluoroethan-1-one (29)
Figure imgf000179_0001
Step 1: synthesis of tert-butyl 6-chloro-2-(2-cyclopentylethyl)-1,2,3,5-tetrahydro- 4H-benzo[e][1,4]diazepine-4-carboxylate (29-B). To a mixture of 6-chloro-2-(2- cyclopentylethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (29-A, 530 mg, 1.90 mmol, 1 eq) in MeOH (50 mL) was added di-tert-butyl dicarbonate (207.43 mg, 950.44 umol, 0.5 eq). The mixture was stirred at 20 °C for 0.5 hr, then filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE:EtOAc = 100:1 to 20:1) to give tert-butyl 6- chloro-2-(2-cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4- carboxylate (29-B, 500 mg, 1.32 mmol, 69.41% yield) as a yellow solid. ESI [M+H] = 379.3 Step 2: Tert-butyl 1-(4-bromo-5-fluoropicolinoyl)-6-chloro-2-(2- cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate (29- C). Procedure was carried according to Step 8 in Protocol 1. ESI [M-56H] = 526.2 Step 3: synthesis of tert-butyl 1-((4-bromo-5-fluoropyridin-2-yl)methyl)-6-chloro- 2-(2-cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate (29-D). Procedure was carried according to Step 9 in Protocol 1. ESI [M+H] = 566.0 Step 4: 1-((4-Bromo-5-fluoropyridin-2-yl)methyl)-6-chloro-2-(2- cyclopentylethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (29-E). To a solution of tert-butyl 1-((4-bromo-5-fluoropyridin-2-yl)methyl)-6-chloro-2-(2- cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate (70 mg, 123.47 umol, 1 eq) in DCM (1 mL) was added TFA (0.3 mL). The mixture was stirred at 20 °C for 0.5 hr, then concentrated under reduced pressure to give 1-[(4- bromo-5-fluoro-2-pyridyl)methyl]-6-chloro-2-(2-cyclopentylethyl)-2,3,4,5- tetrahydro-1,4-benzodiazepine (29-E, 50 mg, crude) as a yellow oil. ESI [M+H] = 466.3 Step 5: 1-(1-((4-Bromo-5-fluoropyridin-2-yl)methyl)-6-chloro-2-(2- cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,2,2- trifluoroethan-1-one (29-F). To a solution of 1-((4-bromo-5-fluoropyridin-2- yl)methyl)-6-chloro-2-(2-cyclopentylethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (40 mg, 85.69 umol, 1 eq) in DCM (1 mL) was added DIEA (16.61 mg, 128.53 umol, 1.5 eq) and 2,2,2-trifluoroacetic anhydride (53.99 mg, 25.06 umol, 3 eq). The mixture was stirred at 0°C for 0.5 hr under N2, then the residue was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 3:1) to give 1-(1-((4- bromo-5-fluoropyridin-2-yl)methyl)-6-chloro-2-(2-cyclopentylethyl)-1,2,3,5- tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,2,2-trifluoroethan-1-one (29-F, 30 mg, 53.30 umol, 62.21% yield) as a yellow oil. ESI [M+H] = 562.1 Step 6: Tert-butyl (2-((6-chloro-2-(2-cyclopentylethyl)-4-(2,2,2-trifluoroacetyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-5-fluoropyridin-4- yl)carbamate (29-G). Procedure was carried according to Step 10 in Protocol 1. ESI [M+H] = 600.1 Step 7: 1-(1-((4-Amino-5-fluoropyridin-2-yl)methyl)-6-chloro-2-(2- cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2,2,2- trifluoroethan-1-one (29). Procedure was carried according to Step 11 in Protocol 1. ESI [M+H] = 545.4. 1H-NMR (400 MHz, DMSO-d6$ e 52(.2 ' 2(.+ #T& +<$& 1(,1 (q, J = 8.3 Hz, 1H), 7.19 - 7.05 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 5.50 - 5.13 (m, 1H), 4.88 - 4.66 (m, 1H), 4.58 - 4.38 (m, 2H), 3.66 - 3.52 (m, 2H), 3.26 (br s, 1H), 1.64 - 1.39 (m, 7H), 1.32 - 1.15 (m, 3H), 1.13 - 0.76 (m, 3H). Compounds in table 4 were prepared according to procedure analogous to preparation of Compound 29 shown above in Protocol 4. Table 4: Compounds prepared according to procedure analogous to preparation of Compound 29 in Protocol 4 Compound #, Structure Analytical data ESI [M+H] = 479.3. 1H-NMR (400 MHz, 35 (*) DMSO-d6$ e 52(*, ' 1(3. #T& +<$ 1(+0 ' 1(*0 #T& O 1H) 6.98 (br d, J = 7.2 Hz, 1H) 6.84 (br d, J = 6.8 F3C Hz, 2H) 5.84 (br s, 2H) 5.18 (br d, J = 13.8 Hz, N 1H) 4.46 (br d, J = 14.4 Hz, 1H) 4.33 - 4.24 (m, N NH2 2H) 3.75 - 3.43 (m, 2H) 3.37 (br s, 1H) 2.49 (br s, 3H) 1.66 - 1.58 (m, 2H) 1.56 - 1.48 (m, 3H) 1.46 N F - 1.38 (m, 2H) 1.26 (br d, J = 6.0 Hz, 3H) 1.04 - 0.85 (m, 3H)
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
aPrepared similarly, but the 2-(4-(trifluoromethyl)phenyl)ethan-1-one functionality was introduced in step 5 by coupling 2-(4-(trifluoromethyl)phenyl)acetic acid with 1-((4- bromopyridin-2-yl)methyl)-2-(2-cyclopentylethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine using HOBT, DMAP, EDCI in DIEA and DMF to give intermediate 1-(1-((4-bromopyridin-2-yl)methyl)-2-(2-cyclopentylethyl)-1,2,3,5- tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethan-1-one bPrepared similarly, but the 4-(trifluoromethyl)phenyl)methanone functionality was introduced in step 5 by coupling 4-(trifluoromethyl)benzoyl chloride with 1-((4- bromopyridin-2-yl)methyl)-2-(2-cyclopentylethyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine in TEA and DCM to give intermediate (1-((4-bromopyridin-2- yl)methyl)-2-(2-cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4- yl)(4-(trifluoromethyl)phenyl)methanone. cPrepared similarly, but the trifluoroethane-1-one functionality was introduced in step 5 by coupling 1-((4-bromopyridin-2-yl)methyl)-2-(2-cyclopentylethyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine with 3,3,3-trifluoropropanoic acid using HATU as coupling reagent to give intermediate 1-(1-((4-bromopyridin-2-yl)methyl)-2-(2- cyclopentylethyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl)-3,3,3- trifluoropropan-1-one. (*) Known absolute configuration. Absolute configuration assignments of the remaining analogs require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate.
Protocol 5: (S)-2-((2-(2-Cyclopentylethyl)-6-(pyridin-2-yl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (40)
Figure imgf000193_0001
Step 1: (S)-1-((4-Chloropyridin-2-yl)methyl)-2-(2-cyclopentylethyl)-6-(pyridin-2- yl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (40B). To a solution of 40-A (130 mg, 223.80 umol, 1 eq, absolute configuration assignment requires further analysis to confirm the preliminary designation provided, as one of ordinary skill will readily appreciate) in dioxane (2 mL) was added Catacxium A-Pd- G3 (16.30 mg, 22.38 umol, 0.1 eq) and 2-(tributylstannyl)pyridine (98.87 mg, 268.55 umol, 1.2 eq). The mixture was stirred at 110°C for 3 hrs under N2.The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (Petroleum ether : Ethyl acetate= 3:1) to give 40-B (60 mg, 103.61 umol, 46.30% yield) was obtained as a yellow oil. ESI [M+H] = 579.0 Steps 2 and 3: (S)-2-((2-(2-Cyclopentylethyl)-6-(pyridin-2-yl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (40) Steps 2 and 3 were carried according to procedures in Steps 10, 11 in Protocol 1. ESI [M+H] = 560.2. 1H-NMR (400 MHz, DMSO-d6$ e 52(0. ' 2(/3 #T& + <$& 1(3- ' 7.88 (m, 2 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.41 - 7.33 (m, 2 H), 7.30 - 7.26 (m, 1 H), 7.06 (d, J = 7.2 Hz, 1 H), 6.73 (d, J = 1.2 Hz, 1 H), 6.35 (dd, J = 5.6, 2.0 Hz, 1 H), 5.97 (s, 2 H), 5.48 (br d, J = 14.0 Hz, 1 H), 4.55 - 4.43 (m, 2 H), 4.36 - 4.29 (m, 1 H), 3.64 (br d, J = 12.0 Hz, 2 H), 3.42 - 3.41 (m, 1 H), 1.63 - 1.48 (m, 5 H), 1.42 - 1.42 (m, 1 H), 1.45 - 1.38 (m, 1 H), 1.29 (br s, 1 H), 1.27 - 1.21 (m, 2 H), 1.03 - 0.95 (m, 2 H), 0.93 (br dd, J = 7.2, 3.6 Hz, 1 H) Compounds in table 5 were prepared according to procedure analogous to preparation of Compound 40 shown above in Protocol 5. Absolute configuration require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate. Table 5: Compounds prepared according to procedure analogous to preparation of Compound 40 in Protocol 5
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
a. CuCN in NMP was used in Step 1 at 140ºC for 12 hours. b. Boronic acid coupling was done with catalyst XPhos Pd G2/K3PO4 in dioxane/H2O
Protocol 6: (S)-2-((2-(2-Cyclopentylethyl)-6-methyl-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (61)
Figure imgf000198_0001
Step 1: (S)-2-(2-Cyclopentylethyl)-6-methyl-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (61- B). To a solution of 61-A (200 mg, 773.99 umol, 1 eq, absolute configuration determined using X-ray crystallography analysis) in DCM (5 mL) was added TEA (156.64 mg, 1.55 mmol, 215.46 uL, 2 eq) and 4-(trifluoromethyl)benzenesulfonyl chloride (227.20 mg, 928.79 umol, 1.2 eq) 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, which was purified by prep-TLC (SiO2, Petroleum ether:Ethyl acetate = 5:1) to give (S)-2-(2-cyclopentylethyl)-6-methyl-4-((4-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (61-B, 350 mg, 750.17 umol, 96.92% yield) as a yellow solid. ESI [M+H] = 467.3 Steps 2 - 5: (S)-2-((2-(2-Cyclopentylethyl)-6-methyl-4-((4- (trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (61). Steps 2 – 5 were carried according to procedures analogous to those shown in Protocol 1, Steps 8-11 to provide the title compound 61. ESI [M+H] = 573.2.1H-NMR (400 MHz, DMSO-d6$ e 5 +,(2+ #Z& +<$ 2(+0 ' 2(*3 #T& 2 H) 8.09 -8.03 (m, 2 H) 8.03 - 7.82 (m, 3 H) 7.14 - 7.07 (m, 1 H) 6.94 (d, J = 8.0 Hz, 1 H) 6.8 (d, J = 7.6 Hz, 1 H) 6.80 (d, J = 2.0 Hz, 1 H) 6.62 (dd, J = 6.8, 2.4 Hz, 1 H) 4.86 (br d, J = 14.0 Hz, 1 H) 4.69 (d, J = 15.6 Hz, 1 H) 4.36 (d, J = 15.6 Hz, 1 H) 3.92 (br d, J = 14.4 Hz, 1 H) 3.72 (br d, J = 12.0 Hz, 1 H) 3.17 (br d, J = 2.4 Hz, 1 H) 3.00 - 2.91 (m, 1 H) 2.46 (s, 3 H) 1.62 - 1.46 (m, 5 H) 1.45 - 1.35 (m, 2 H) 1.29 - 1.10 (m, 3 H) 1.02 - 0.83 (m, 3 H) Compounds in table 6 were prepared according to procedure analogous to preparation of Compound 61 shown above in Protocol 6. Table 6: Compounds prepared according to procedure analogous to preparation of Compound 61 in Protocol 6
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
(*) Known absolute configuration.
Protocol 7. (S)-2-((2-((Syclopentyloxy)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)pyridin-4-amine (84)
Figure imgf000202_0001
Step 1: Ethyl 1-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)aziridine-2- carboxylate (84-B). To a mixture of tert-butyl (2-aminobenzyl)carbamate (84-A, 75 g, 337.41 mmol, 1 eq) in EtOH (500 mL), was added TEA (68.28 g, 674.82 mmol, 93.93 mL, 2 eq) and ethyl 2,3-dibromopropanoate (87.70 g, 337.41 mmol, 49.27 mL, 1 eq) at 25°C, the reaction mixture was stirred at 80°C for 12 hrs under the N2, then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE : Ethyl acetate = 1:0 to 5:1) to give ethyl 1-(2-(((tert- butoxycarbonyl)amino)methyl)phenyl)aziridine-2-carboxylate (84-B, 90 g, 196.64 mmol, 58.3% yield, 70% purity) as a brown oil. ESI [M+H] = 321.2 Step 2: Ethyl N-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)-O- cyclopentylserinate (84-C). To a solution of BF3.Et2O (19.93 g, 140.46 mmol, 17.33 mL, 3 eq) in CHCl3 (200 mL) was added ethyl 1-(2-(((tert- butoxycarbonyl)amino)methyl)phenyl)aziridine-2-carboxylate (84-B, 15 g, 46.82 mmol, 1 eq) and cyclopentanol (32.26 g, 374.55 mmol, 33.99 mL, 8 eq) at 0°C. The mixture was stirred at 25°C for 1 hr, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (250 × 150 mm, 10 um); flow rate: 500 mL/min; gradient: 55% – 95% B over 20 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give ethyl N-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)-O-cyclopentylserinate (84- C, 1.9 g, 4.20 mmol, 9.75% yield, FA salt) as a brown oil. ESI [M+H] = 407.3 Step 3: Ethyl N-(2-(aminomethyl)phenyl)-O-cyclopentylserinate (84-D). A mixture of ethyl N-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)-O- cyclopentylserinate (84-C, 1.9 g, 4.92 mmol, 1 eq) in EtOAc (10 mL) and HCl/EtOAc (10 mL) was stirred at 25°C for 1 hr and concentrated under reduced pressure to give (84-D, 2 g, crude) as a brown oil. ESI [M+H] = 307.2. Step 4: 2-((Cyclopentyloxy)methyl)-1,2,4,5-tetrahydro-3H- benzo[e][1,4]diazepin-3-one (84-E). To a mixture of ethyl N-(2- (aminomethyl)phenyl)-O-cyclopentylserinate (84-D, 1.9 g, 6.20 mmol, 1 eq, crude from step 3) in MeOH (10 mL) and H2O (5 mL) was added NaOH (248 mg, 6.20 mmol, 1 eq) at 25°C. The reaction mixture was stirred at 25°C for 1 hr, filtered and the filtrate was concentrated under reduced pressure to give 2-((cyclopentyloxy)methyl)-1,2,4,5- tetrahydro-3H-benzo[e][1,4]diazepin-3-one (84-E, 1.5 g, crude) as a brown oil, ESI [M+H] = 261.3. Step 5: 2-((Cyclopentyloxy)methyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (84-F). To a mixture of 2-((cyclopentyloxy)methyl)-1,2,4,5- tetrahydro-3H-benzo[e][1,4]diazepin-3-one (84-E, 900 mg, 3.46 mmol, 1 eq, crude from step 4) in THF (20 mL) was added LiAlH4 (656.07 mg, 17.29 mmol, 5 eq) at 25°C, the reaction mixture was stirred at 25°C for 2 hr under the N2, then quenched by slow addition of Na2SO4·10H2O (2 g) at 0oC under N2 and stirred at 25oC for 30 mins. The resultling mixture was filtered, dried over MgSO4, and concentrated in vacuo to give 2-((cyclopentyloxy)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (84-F, 800 mg, crude) as a white solid. Step 6: (R)-2-((Cyclopentyloxy)methyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (84-G) and (S)-2-((cyclopentyloxy)methyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepine (84-H). Racemic 84-F was separated by SFC (Instrument: Waters UPCC with PDA; Column: ChiralPak IH (250mm × 30mm,10um); Mobile phase A: CO2 and B: 0.1% NH3H2O in EtOH; Gradient: B% = 25% isocratic elution mode; Flow rate: CO2 (64.6 g/min), B (3.4 mL/min); Wavelength: 220 nm; Column temperature: 35°C; System back pressure: 2000 Psi) to generate two enantiomers. Peak 1 (Rt=1.243 min) was assigned as (R)-2-((cyclopentyloxy)methyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (84-G, 370 mg, 1.35 mmol, 39.1% yield, 90% purity). ESI [M+H] = 247.3. Peak 2 (Rt=1.510 min) was assigned as (S)-2-((cyclopentyloxy)methyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (84-H, 460 mg, 1.68 mmol, 48.6% yield, 90% purity) using X-ray crystallography analysis. ESI [M+H] = 247.3. Step 7: (S)-2-((Cyclopentyloxy)methyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (84-I). Intermediate 84-H (220 mg, 893.05 umol, 1 eq) and trifluoromethanesulfonic anhydride (2.07 g, 9.41 mmol, 5 eq) were combined as described in Protocol 1 for intermediate 1-H to provide 84-I (180 mg, 475 umol, 53.2% yield), ESI [M+H] = 379.3. Step 8: (S)-(4-Bromopyridin-2-yl)(2-((cyclopentyloxy)methyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methanone (84-J) was synthesized as described in Protocol 1 by coupling intermediate 84-I (170 mg, 449.25 umol, 1 eq) with 4-bromopicolinoyl chloride (99 mg, 449 umol, 1 eq) to give (84-J, 180 mg, 320 umol, 71.2% yield), ESI [M+H] = 562.2. Step 9: (S)-1-((4-Bromopyridin-2-yl)methyl)-2-((cyclopentyloxy)methyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (84-K) was prepared in a similar fashion as described in Protocol 1. Intermediate 84-J (180 mg, 320 umol, 1 eq) was reduced using NaBH4 (121 mg, 3.20 mmol, 10 eq) to give (84-K, 130 mg, 237 umol, 74% yield), ESI [M+H] = 550.1. Step 10: tert-Butyl (S)-(2-((2-((cyclopentyloxy)methyl)-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-yl)carbamate (84-L) was prepared as described in Protocol 1 by coupling 84-K (130 mg, 237 umol, 1 eq) with tert-butyl carbamate (33 mg, 284 umol, 1.2 eq), to give 84-L (20 mg, 34 umol, 14.4% yield), ESI [M+H] = 585.3. Step 11: (S)-2-((2-((Cyclopentyloxy)methyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)pyridin-4-amine (84) was prepared as described in Protocol 1 to give 84 (5.1 mg, 9.61 umol, 28.1% yield, 100% purity, FA salt), ESI [M+H] = 485.1.1H-NMR (400 MHz, CD3B9$ e 51(30 #M& > 50(2 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.13 - 7.07 (m, 1H), 6.91 (s, 1H), 6.68 (br d, J = 6.4 Hz, 1H), 4.86 (br d, J = 15.6 Hz, 1H), 4.79 - 4.72 (m, 1H), 4.70 - 4.57 (m, 2H), 3.96 (br d, J = 12.8 Hz, 1H), 3.63 (br s, 1H), 3.58 - 3.48 (m, 2H), 3.26 - 3.18 (m, 1H), 3.16 - 3.06 (m, 1H), 1.77 - 1.40 (m, 8H). Compounds in table 7 were prepared according to procedure analogous to preparation of Compound 84 shown above in Protocol 7. Table 7: Compounds prepared according to procedure analogous to preparation of Compound 84 in Protocol 7
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
a. Prepared from 84-G or 84-H using methods in Protocol 4 (*) Known absolute configuration. Absolute configuration assignments of the remaining analogs require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate.
Protocol 8. (S)-N,N-dimethyl-2-((2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)pyridin-4-amine (145) Step 1: synthesis of (S)-N,N-dimethyl-2-((2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (145) To a solution of 2-[[(2S)-2-(2-phenylethyl)-4- (trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepin-1-yl]methyl]pyridin-4- amine 146 (20 mg, 40.77 umol, 1 eq, absolute configuration of synthetic precursor determined using VCD analysis as shown in Protocol 2) in DMF (1 mL) at 0°C was added NaH (4.89 mg, 122 umol, 60% purity, 3 eq). The mixture was stirred at 25°C for 20 min, cooled to at 0°C and CH3I (17.3 mg, 122 umol, 3 eq) was added. The mixture was stirred at 25°C for 1 hr under N2, added to H2O (5 ml), partitioned between EtOAc (5 mL) and H2O (5 mL), the water phase was extracted with EtOAc (5 mL*3). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (The residue was purified by preparative HPLC (Phenomenex Luna C18 column (80 × 30 mm, 3 mm); flow rate: 25 mL/min; gradient: 35% – 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) and the residue was re-purified by prep-HPLC (The residue was purified by preparative HPLC (Phenomenex Luna C18 column (75× 30 mm, 3 mm); flow rate: 25 mL/min; gradient: 30% – 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give N,N-dimethyl-2-[[(2S)-2-(2-phenylethyl)-4- (trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepin-1-yl]methyl]pyridin-4- amine 145 (2.6 mg, 4.60 umol, 11.29% yield, 100.000% purity, FA) was obtained as yellow solid, ESI [M+H] =519.2. 1H-NMR (400 MHz, CD3B9$ e WWT 2(/0 #KY Z& +<$ 8.02 (d, J = 6.4 Hz, 1H) 7.29 - 7.35 (m, 2H) 7.20 - 7.27 (m, 3H) 7.16 (d, J = 7.2 Hz, 1H) 7.11 (d, J = 7.2 Hz, 2H) 7.03 - 7.08 (m, 1H) 6.71 - 6.76 (m, 2H) 4.63 - 4.77 (m, 3H) 4.35 (d, J=14.4 Hz, 1H) 3.94 (br d, J = 13.2 Hz, 1H) 3.46 (br d, J = 13.2 Hz, 1H) 3.25 (td, J = 5.6, 2.4Hz, 1H) 3.14 (s, 6H) 2.68 - 2.77 (m, 1H) 2.55 (ddd, J = 13.6, 9.2, 7.2 Hz, 1H) 1.53 - 1.63 (m, 1H) 1.36 (br dd, J = 9.2, 4.8 Hz, 1H). Protocol 9. 2-((2-(2-Cyclopentylethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-N,6-dimethylpyridin-4-amine (153) Step 1: tert-Butyl (2-((2-(2-cyclopentylethyl)-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-6-methylpyridin-4- yl)(methyl)carbamate (153-B) To a solution of 153-A (100 mg, 168 umol, 1 eq) in DMF (1 mL) was added NaH (20.11 mg, 502.76 umol, 60% purity, 3 eq) at 0°C. The mixture was stirred at 25°C for 20 min under N2 and CH3I (47.57 mg, 335.18 umol, 2 eq) was added to the solution at 0°C. The mixture was stirred at 25°C for 1 hr under N2, concentrated, diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3), dried over Na2SO4, filtered and concentrated to give 153-B (100 mg, crude) as a yellow oil, ESI [M+H] = 611.4. Step 2: 2-((2-(2-cyclopentylethyl)-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)methyl)-N,6-dimethylpyridin-4-amine (153) Using the same procedure for the synthesis of compound 1, to give 153 (75.5 mg, 136 umol, 82.8% yield, 100% purity, FA salt), ESI [M+H] = 511.2. 1H-NMR (400 MHz, DMSO-d6$ e 5 +,(13 #KY MM& > 5 /(0& ,(2 <a& + <$& 2(,1 #KY M& > 5.(* <a& + <$& 7.35 - 7.24 (m, 2 H), 7.17 (br d, J = 8.0 Hz, 1 H), 7.05 (t, J = 7.60 Hz, 1 H), 6.79 (s, 1 H), 6.58 (br s, 1 H), 4.77 - 4.56 (m, 3 H), 4.43 (br d, J = 15.6 Hz, 1 H), 3.74 (br d, J = 13.2 Hz, 1 H), 3.52 (br d, J = 13.6 Hz, 1 H), 3.34 (br t, J = 6.4 Hz, 1 H), 2.88 (d, J = 4.8 Hz, 3 H), 2.46 (br s, 3 H), 1.68 - 1.56 (m, 3 H), 1.56 - 1.49 (m, 2 H), 1.48 - 1.40 (m, 2 H), 1.37 - 1.19 (m, 3 H), 1.10 – 0.99 (m, 2 H), 0.97 - 0.87 (m, 1 H). The compounds in table 8 were prepared in a similar manner as described in Protocol 8 for compound 145 or Protocol 9 for compound 153. Table 8: Compounds prepared in a similar manner as described in Protocol 8 for compound 145 or Protocol 9 for compound 153
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0002
(*) Known absolute configuration. Absolute configuration assignments of the remaining analogs require further analysis to confirm the preliminary designations provided, as one of ordinary skill will readily appreciate. Protocol 10.2-((2-(bicyclo[1.1.1]pentan-1-yl)-6-cyclopropyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (169)
Figure imgf000212_0001
Step 1. 2-(bicyclo[1.1.1]pentan-1-yl)-1-((4-bromopyridin-2-yl)methyl)-6- cyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (169-B). To a solution of 2-(bicyclo[1.1.1]pentan-1-yl)-6- cyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (169-A& +** TP& ,/2(12 hTVS& + eq) and 4- KYVTVWRLVSRUJSMNQ`MN #+..(.* TP& 110(-. hTVS& - eq) in DCE (2 mL) and TFA (2 mL) was added Et3ER< #3*(,1 TP& 110(-. hTVS& +,.(** h?& - eq). The mixture was stirred at 100°C for 1 hr. The reaction mixture was added to the sat.aq. NaHCO3 (5 mL), then the reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL), the water phase was extracted with EtOAc (10 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE : EtOAc = 3 : 1) to give 2-(bicyclo[1.1.1]pentan-1-yl)-1-((4- bromopyridin-2-yl)methyl)-6-cyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5- tetrahydro-1H-benzo[e][1,4]diazepine (169-B& +.* TP& ,/+(0* hTVS& 31(,-" `RNSM$ JZ yellow oil. ESI [M+H] = 556.0 Steps 2-3 were carried out according to procedures in Protocol 1, Steps 10-11 to afford the title compound 169. ESI [M+H] = 493.2 1H NMR (400 MHz, CD3B9$ e 5 7.95 (d, J = 7.2 Hz, 1H), 7.27 – 7.19 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.95 – 6.87 (m, 2H), 6.73 (dd, J = 7.2, 2.4 Hz, 1H), 5.62 (br d, J = 14.4 Hz, 1H), 4.91 (s, 1H), 4.55 – 4.46 (m, 2H), 3.97 (br d, J = 8.4 Hz, 1H), 3.48 (dd, J = 13.2, 2.4 Hz, 1H), 3.32 (br s, 1H), 2.40 – 2.27 (m, 2H), 1.75 (dd, J = 9.2, 1.2 Hz, 3H), 1.44 (br d, J = 9.2 Hz, 3H), 1.09 – 0.87 (m, 3H), 0.43 – 0.27 (m, 1H). Protocol 11.2-((2,6-dicyclopropyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-1-yl)methyl)pyridin-4-amine (172).
Step 1: synthesis of 2-bromo-6-cyclopropylbenzonitrile (172-B). To a solution of 2-bromo-6-iodo-benzonitrile (172-A, 25 g, 81.19 mmol, 1 eq), cyclopropylboronic acid (10.46 g, 121.79 mmol, 1.5 eq) in dioxane (300 mL) and H2O (10 mL) was added cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (5.94 g, 8.12 mmol, 0.1 eq) and K2CO3 (22.44 g, 162.38 mmol, 2 eq). The mixture was stirred at 80°C for 12 hrs under N2. The reaction mixture was filtered and concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography on silica gel (PE:EtOAc=1:0 to 0:1) to give 2-bromo-6-cyclopropyl-benzonitrile (172-B, 22 g, crude) as a yellow solid. ESI [M+H] = 221.6. 1H NMR (400 MHz, CD3B9$ e 51(/0 (dd, J = 8.0, 0.8 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 2.34 - 2.21 (m, 1H), 1.23 - 1.16 (m, 2H), 0.90 - 0.83 (m, 2H) Step 2: synthesis ofmethyl 2-((2-cyano-3-cyclopropylphenyl)amino)-2- cyclopropylacetate (172-C). To a solution of 2-bromo-6-cyclopropyl-benzonitrile (172-B, 9 g, 40.53 mmol, 1 eq) and methyl 2-amino-2-cyclopropyl-acetate; hydrochloride (8.05 g, 48.63 mmol, 1.2 eq) in Tol. (1 mL) was added dicyclohexyl- [2-(2,6-dimethoxyphenyl)phenyl]phosphane;methanesulfonate;(2- phenylanilino)palladium(1+) (1.58 g, 2.03 mmol, 0.05 eq) and Cs2CO3 (26.41 g, 81.05 mmol, 2 eq). The mixture was stirred at 90 °C for 12 hrs. The residue was purified by column chromatography (SiO2, PE : EtOAc =1:0 to 0:1) to give methyl 2- ((2-cyano-3-cyclopropylphenyl)amino)-2-cyclopropylacetate (172-C, 2 g, 7.40 mmol, 18.26% yield) as white solid. ESI [M+H] = 271.4 Step 3: synthesis of 2,6-dicyclopropyl-1,2,4,5-tetrahydro-3H- benzo[e][1,4]diazepin-3-one (172-D. To a solution of methyl 2-(2-cyano-3- cyclopropyl-anilino)-2-cyclopropyl-acetate (172-C, 1.9 g, 7.03 mmol, 1 eq) in MeOH (40 mL) and H2O (4 mL) was added Ni (1.24 g, 21.09 mmol, 3 eq) and TEA (711.21 TP& 1(*- TTVS& 312(,2 h?& + eq) . The suspension was degassed and purged with H2 for 3 times. The mixture was stirred at 25 °C for 6 hrs under H2 (7.03 mmol, 1.00 eq). The suspension was filtered through a pad of silica gel and filter cake was washed with MeOH (10 mL×3), the filtrate was concentrated under reduced pressure to give a residue. And the filter cake was collected and handled safely. The residue was purified by column chromatography (SiO2, PE : EtOAc = 1:0 to 0:1) to give 2,6- dicyclopropyl-1,2,4,5-tetrahydro-3H-benzo[e][1,4]diazepin-3-one (172-D, 1.1 g, 4.54 mmol, 64.59% yield) as white solid. ESI [M+H] = 243.3. Steps 4-5 were carried out according to procedures in Protocol 1, Steps 6-7. Step 6 was carried out using procedure in Protocol 10, Step 1. Steps 7-8 were carried out according to procedures in Protocol 1, Steps 10-11 to afford the title compound 172. ESI [M+H] = 467.1 1H NMR (400 MHz, CD3B9$ e 51(3. #M& J = 6.8 Hz, 1H), 7.33 - 7.20 (m, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.99 - 6.86 (m, 2H), 6.70 (dd, J = 6.8, 2.4 Hz, 1H), 5.62 - 5.41 (m, 1H), 4.83 (br d, J = 15.6 Hz, 1H), 4.68 - 4.51 (m, 3H), 3.68 - 3.53 (m, 1H), 2.61 (br dd, J = 8.8, 4.4 Hz, 1H), 2.40 - 2.08 (m, 1H), 1.11 - 0.93 (m, 2H), 0.86 (br s, 1H), 0.72 - 0.37 (m, 5H), 0.25 - 0.08 (m, 1H). Table 9: Compounds prepared in a similar manner as described in Protocol 11 for compound 172.
Figure imgf000215_0001
Figure imgf000216_0001
Protocol 12. (S)-6-((2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-1-yl)methyl)thiazolo[5,4-c]pyridine (231).
Step 1. (S)-(2-(methylthio)thiazolo[5,4-c]pyridin-6-yl)(2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methanone (231-B). To a mixture of (S)-2-phenethyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (231-A& ++* TP& ,20(+/ hTVS& + eq) JUM F:6 #20(21 TP& 2/2(./ hTVS& ++3(.3 h?& - eq) in DCM (10 mL) was dropwsie ,'#TN[Q`S[QRV$[QRJaVSVH/&.'LIW`YRMRUN'0'LJYKVU`S LQSVYRMN #,+*(*2 TP& 2/2(./ hTVS& 3 eq) at 0°C, then the reaction mixture was stirred at 25°C for 1hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE : EtOAc = 1 : 1 ) to give (S)-(2-(methylthio)thiazolo[5,4- c]pyridin-6-yl)(2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-1-yl)methanone (231-B& 1* TP& ++2(++ hTVS& .+(,2" `RNSM$ JZ white solid. ESI [M+H] =593.1. Step 2. (S)-(1,2-dihydrothiazolo[5,4-c]pyridin-6-yl)(2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methanone (231-C). To a mixture of (S)-(2-(methylthio)thiazolo[5,4-c]pyridin-6- yl)(2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-1-yl)methanone (231-B& 1* TP& ++2(++ hTVS& + eq) and BF3.Et2B #,02(,+ TP& +(23 TTVS& ,-,(., h?& +0 eq) in THF (3 mL) was added NaBH4 (0.14 g, 3.70 mmol, 31.33 eq) at 0°C, then the reaction mixture was stirred at 25°C for 0.5 hr. Then the reaction mixture was quenched with sat.aq. NH4Cl (5 mL) slowly and stirred at 0°C for 0.5 hr under N2, then extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give (S)-(1,2-dihydrothiazolo[5,4-c]pyridin-6-yl)(2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methanone (231-C, 60 mg, crude) as white solid and used directly into the next step without further purification. ESI [M+H] =535.2. Step 3. (S)-6-((2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro- 1H-benzo[e][1,4]diazepin-1-yl)methyl)thiazolo[5,4-c]pyridine (231). To a mixture of 6-[[(2S)-2-(2-phenylethyl)-4-(trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4- KNUaVMRJaNWRU'+'`SITN[Q`SI'+&,'MRQ`MYV[QRJaVSVH/&.'LIW`YRMRUN #// TP& +*,(22 hTVS& 1 eq) in THF (3 mL) was added MnO2 #,0(2- TP& -*2(0- hTVS& - eq) at 25°C, then the reaction mixture was stirred at 80°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 prep-HPLC (Phenomenex Gemini C18 column (100 × 30 mm, 3 um); flow rate: 25 mL/min; gradient: 25% – 65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 6-[[(2S)-2-(2-phenylethyl)-4- (trifluoromethylsulfonyl)-3,5-dihydro-2H-1,4-benzodiazepin-1- `SITN[Q`SI[QRJaVSVH/&.' LIW`YRMRUN #+1(/ TP& ,2(1- hTVS& ,1(3-" `RNSM& 3/(**" purity, FA salt) as white solid. Absolute configuration was determined arbitrarily. ESI [M+H] =533.1.1H NMR (400 MHz, CD3B9$ e53(/1 ' 3(.3 #T& +<$& 3(,3 #Z& 1H), 8.04 (s, 1H), 7.30 - 7.25 (m, 3H), 7.25 - 7.20 (m, 2H), 7.17 - 7.11 (m, 1H), 7.09 (d, J = 7.2 Hz, 2H), 7.02 (td, J = 7.2, 1.6 Hz, 1H), 4.97 - 4.92 (m, 2H), 4.80 - 4.72 (m, 1H), 4.66 - 4.59 (m, 2H), 3.91 (br d, J = 13.6 Hz, 1H), 3.51 - 3.45 (m, 1H), 2.76 - 2.66(m, 1H), 2.56 (ddd, J = 13.6, 9.6, 6.8 Hz, 1H), 1.74 - 1.53 (m, 1H), 1.40 - 1.28 (m, 1H). Protocol 13. (S)-1-((2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine and (R)-1- ((2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine ( 183 and 184)
Step 1.5-bromo-N-(4-methoxybenzyl)-2-((2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)218yridine-4-amine (183-B). To a solution of 1-((5-bromo-4-chloropyridin- 2-yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (183-A, 900 mg, 1.53 mmol, 1 eq) in DIEA (3.95 g, 30.57 mmol, 5.32 mL, 20 eq) was added (4-methoxyphenyl)methanamine (4.19 g, 30.57 mmol, 3.97 mL, 20 eq). The mixture was stirred at 135°C for 24 hrs. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc 90 mL (30 mL×3). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:0 to 1:1) to give 5-bromo-N-(4-methoxybenzyl)-2-((2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (183-B, 02* TP& 320(+* hTVS& 0.(/," `RNSM$ JZ `NSSV^ solid. ESI [M+H] = 689.2 Step 2.1-((1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-c]pyridin-6- yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (183-C). To a solution of 5-bromo-N-(4-methoxybenzyl)-2- ((2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepin-1-yl)methyl)pyridin-4-amine (183-B, ,-* TP& ---(/- hTVS& 1 eq) and acetamide (197.01 mg, 3.34 mmol, 10 eq) in dioxane (5 mL) was JMMNM 7YN[[CQVZ #-/(2+ TP& 00(1+ hTVS& *(, eq) and BrettPhos Pd G3 (30.23 mg, --(-/ hTVS& *(+ eq) and Cs2CO3 #,+1(-. TP& 001(*1 hTVS& , eq). The mixture was stirred at 80°C for 36 hrs under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (EtOAc : MeOH = 10 : 1) to give 1-((1-(4-methoxybenzyl)-2-methyl- 1H-imidazo[4,5-c]pyridin-6-yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)- 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (183-C& +/* TP& ,-*(21 hTVS& 03(,," yield) as yellow solid. ESI [M+H] = 650.2 Steps 3-4 were carried out according to procedures in Protocol 1, Steps 10-11. Step 5: (S)-1-((2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)methyl)-2-phenethyl- 4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (183) and (R)-1-((2-methyl-1H-imidazo[4,5-c]pyridin-6-yl)methyl)-2-phenethyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (184). A mixture of 1-((1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-c]pyridin-6- yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- benzo[e][1,4]diazepine (184-C, +.* TP& ,+/(.2 hTVS& + eq) in TFA (2 mL) was stirred at 80°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (DCM:MeOH = 10 : 1) to give crude product. The crude product was separated by SFC (Instrument: Waters SFC150AP Preparative SFC System; Column: DAICEL CHIRALCEL OZ 250 × 25 mm I.D.10um; Mobile phase A: CO2 and B: 0.1% NH3H2O in MeOH; Gradient: B% = 25% isocratic elution mode; Flow rate:CO2(50 g/min) and B (150 g/min); Wavelength: 220&254nm; Column temperature: 40°C; System back pressure: 100 bar) to generate two enantiomers. Then the Peak 1 (Rt =1.603) was purified by preparative HPLC (Phenomenex Gemini-NX C18 (75× 30 mm, 3mm); flow rate: 25 mL/min; gradient: 15% – 60% B over 8 min; mobile phase A: 0.05% aqueous NH3H2O + 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give (S)-1-((2-methyl-1H-imidazo[4,5-c]pyridin-6- yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- KNUaVHNIH+&.IMRJaNWRUN #-*(- TP& /0(33 hTVS& ,0(./" `RNSM& 33(0" W\YR[`$ JZ ^QR[N solid. ESI [M+H] = 530.2 1H NMR (400 MHz, CD3B9$ e 52(1* #Z& +<$& 1(./ #KY Z& 1H), 7.32 - 7.13 (m, 6H), 7.08 (d, J = 7.2 Hz, 2H), 7.04 - 6.97 (m, 1H), 4.82 - 4.71 (m, 2H), 4.62 - 4.57 (m, 1H), 4.49 (d, J = 14.4 Hz, 1H), 3.88 (br d, J = 13.6 Hz, 1H), 3.38 (br s, 1H), 3.30 (br dd, J = 5.2, 2.8 Hz, 1H), 2.69 (dt, J = 9.2, 5.2 Hz, 1H), 2.63 (s, 3H), 2.53 (ddd, J = 13.6, 9.6, 7.2 Hz, 1H), 1.58 (dt, J = 14.4, 6.4 Hz, 1H), 1.40 - 1.30 (m, 1H). Peak 2 (Rt = 1.827) was purified by preparative HPLC (Waters Xbridge Prep OBD C18 (150 × 40 mm, 10mm); flow rate: 60 mL/min; gradient: 40% – 60% B over 8 min; mobile phase A: 0.05% aqueous NH3H2O + 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give (R)-1-((2-methyl-1H-imidazo[4,5-c]pyridin-6- yl)methyl)-2-phenethyl-4-((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H- KNUaVHNIH+&.IMRJaNWRUN #,3(* TP& /.(10 hTVS& ,/(.+" `RNSM& +**(*" W\YR[`$ JZ ^QR[N solid. ESI [M+H] = 530.2 1H NMR (400 MHz, CD3B9$ e 52(11 #Z& +<$& 1(/, #KY Z& 1H), 7.39 - 7.19 (m, 6H), 7.14 (d, J = 7.2 Hz, 2H), 7.10 - 7.05 (m, 1H), 4.89 - 4.76 (m, 2H), 4.70 - 4.62 (m, 1H), 4.56 (d, J = 14.0 Hz, 1H), 3.94 (br d, J = 13.6 Hz, 1H), 3.45 (br s, 1H), 3.30 (br dd, J = 5.2, 2.8 Hz, 1H), 2.75 (td, J = 9.2, 4.4 Hz, 1H), 2.70 (s, 3H), 2.60 (ddd, J = 13.6, 9.6, 7.2 Hz, 1H), 1.72 - 1.58 (m, 1H), 1.48 - 1.36 (m, 1H). Absolute configurations were assigned arbitrarily. Protocol 14. (R)-5-fluoro-2-((2-(4-fluorophenyl)-6-methyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine and (S)-5-fluoro-2-((2-(4-fluorophenyl)-6-methyl-4- ((trifluoromethyl)sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1- yl)methyl)pyridin-4-amine (203 and 202).
Step 1. Ethyl 2-bromo-2-(4-fluorophenyl)acetate (202-B). To a mixture of ethyl 2-(4-fluorophenyl)acetate (202-A, 11 g, 60.38 mmol, 1 eq) in CHCl3 (400 mL) was added AIBN (991.42 mg, 6.04 mmol, 0.1 eq) and NBS (10.75 g, 60.38 mmol, 1 eq). The mixture was stirred at 60°C for 3 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE:EtOAc = 3 : 1) to give ethyl 2-bromo-2-(4- fluorophenyl)acetate (202-B, 14.5 g, 55.54 mmol, 91.98% yield) as black oil.1H NMR (400 MHz, CDCl3$ e 51(/+ ' 1(.. #T& ,<$& 1(*, ' 0(3/ #T& ,<$& /(,. #Z& +<$& 4.24 - 4.10 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H). Step 2. Ethyl 2-((2-cyano-3-methylphenyl)amino)-2-(4-fluorophenyl)acetate (202-C). A mixture of ethyl 2-bromo-2-(4-fluorophenyl)acetate (202-B, 14 g, 53.62 mmol, 1 eq) and 2-amino-6-methyl-benzonitrile (7.09 g, 53.62 mmol, 1 eq), DIEA (27.72 g, 214.49 mmol, 37.36 mL, 4 eq) was stirred at 60°C for 12 hrs. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE:EtOAc = 5 : 1) to give ethyl 2- ((2-cyano-3-methylphenyl)amino)-2-(4-fluorophenyl)acetate (202-C, 10.6 g, 33.94 mmol, 63.29% yield) as white solid. ESI [M+H] = 313.1. Step 3.2-(4-fluorophenyl)-6-methyl-1,2,4,5-tetrahydro-3H- benzo[e][1,4]diazepin-3-one (202-D). A mixture of ethyl 2-((2-cyano-3- methylphenyl)amino)-2-(4-fluorophenyl)acetate (202-C, 10.3 g, 32.98 mmol, 1 eq) in MeOH (200 mL), H2O (20 mL) and was added Ni (1.94 g, 32.98 mmol, 1 eq), TEA (3.34 g, 32.98 mmol, 4.59 mL, 1 eq). The mixture was stirred at 25°C for 12 hrs under H2 (15 Psi). The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue to give 2-(4-fluorophenyl)-6-methyl-1,2,4,5- tetrahydro-3H-benzo[e][1,4]diazepin-3-one (202-D, 8.5 g, crude). ESI [M+H] = 271.2. Steps 4-9 were carried out according to procedures in Protocol 1, Steps 6-11 to afford the title compounds. Compound 203. ESI [M+H] = 513.0 1H NMR (400 MHz, DMSO-d6$ e 52(+. #Z& +<$& 1(3/ #M& J = 3.2 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.28 - 7.16 (m, 3H), 6.96 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.12 (br s, 2H), 5.02 - 4.75 (m, 2H), 4.64 - 4.44 (m, 1H), 4.20 - 4.08 (m, 1H), 4.06 - 3.92 (m, 1H), 3.66 - 3.52 (m, 1H), 3.51 - 3.41 (m, 1H), 2.37 (s, 3H). Compound 202. ESI [M+H] = 513.0 1H NMR (400 MHz, DMSO- d6$ e 52(+. #Z& +<$& 1(3/ #M& J = 3.2 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.28 - 7.16 (m, 3H), 6.96 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.12 (br s, 2H), 5.02 - 4.75 (m, 2H), 4.64 - 4.44 (m, 1H), 4.20 - 4.08 (m, 1H), 4.06 - 3.92 (m, 1H), 3.66 - 3.52 (m, 1H), 3.51 - 3.41 (m, 1H), 2.37 (s, 3H). Absolute configurations were assigned arbitrarily. Table 10: Compounds prepared in a similar manner as described in Protocol 14 for compound 202.
Figure imgf000223_0001
Figure imgf000224_0001
(d, J = 8.0 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 5.12 - 4.94 (m, 2H), 4.45 (br s, 1H), 4.12 (s, 2H), 3.63 - 3.54 (m, 1H), 3.53 - 3.43 (m, 1H), 2.42 (s, 3H). ESI [M+H] =521.2 1H NMR (400 MHz, DMSO-d6$ e 52(+- (s, 1H), 7.96 (d, J = 3.2 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.35 - 7.30 (m, 3H), 7.21 (t, J = 215 a 7.6 Hz, 1H), 6.87 (br d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.24 (br s, 2H), 5.21 (br d, J = 11.6 Hz, 1H), 5.08 (br d, J = 11.6 Hz, 1H), 4.52 (br s, 1H), 4.12 - 4.07 (m, 1H), 4.03 - 3.96 (m, 1H), 3.51 (br s, 2H), 2.04 - 1.96 (m, 1H), 0.94 (br d, J = 8.4 Hz, 2H), 0.70 - 0.62 (m, 2H). ESI [M+H] =521.2 1H NMR (400 MHz, DMSO-d6$ e 52(+0 214 a (s, 1H), 7.92 (d, J = 3.2 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.35 - 7.30 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H), 6.87 (br d, J = 8.0 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.05 (br d, J = 3.2 Hz, 2H), 5.21 (br d, J = 11.6 Hz, 1H), 5.13 - 5.04 (m, 1H), 4.52 (br s, 1H), 4.11 - 4.06 (m, 1H), 4.02 - 3.95 (m, 1H), 3.57 - 3.49 (m, 2H), 2.04 - 1.97 (m, 1H), 0.94 (dd, J = 8.4, 1.2 Hz, 2H), 0.70 - 0.63 (m, 2H). a Cyclopropyl was installed after Step 2 by treatment with potassium cyclopropyltetrafluoroborate under Pd(OAc)2 / bis(1-adamantyl)-butyl-phosphane catalysis with cesium carbonate in toluene/water mixture at 80ºC for 12 hours. Example 2: F-ATPase Synthase and Hydrolase Assay The assay was adapted from Rogers et al., 2011, PLoS ONE (buffers and mitochondrial analysis), and Divakaruni et al., 2018, Cell Metabolism (Supplemental Figure 3) for ATP hydrolysis measurements. One day prior to the assay, a Seahorse XF cartridge (from the Extracellular Flux Assay Kit) was hydrated by soaking fluorophores in 200µL of manufacturer supplied XF calibrant per well, according to the manufacturer’s instructions. The cartridge was left calibrating at room temperature overnight. On the day of the assay, 25 µL of rotenone and antimycin A (1 µM final concentration) were added to port A (subtracted out as background) and 25 µL ATP (30 mM final concentration) and FCCP (1.5 µM final concentration) to ports B and C (to initiate ATP hydrolysis). Compounds to be injected were prepared in Mitochondrial Assay Solution (MAS) containing 70 mM sucrose, 220 mM mannitol, 10 mM KH2PO4, 5 mM MgCl2, 2 mM HEPES and 1 mM EGTA, pH 7.2. Next, Seahorse cartridge was placed in 37 °C non-CO2 incubator. Freshly isolated rodent mitochondria were diluted to appropriate concentration in MAS medium and kept on ice. Mitochondria were loaded into the seahorse plate on ice (leaving 4 wells for MAS, for background subtraction). The Seahorse plate with mitochondria was spun down at 2000g for 20 min in a pre-cooled 4 °C centrifuge. Then 120 µL of compound or vehicle solution was added to each well and incubated at 37 °C for 20 minutes. The compound and vehicle solutions were prepared by diluting to the desired concentrations in Base Assay Media, which was MAS containing pyruvate (5 mM), malate (1 mM), fatty-acid free BSA (0.04%), and ADP (2 mM). The plate was then placed in the XF96 Extracellular Flux Analyzer (Seahorse Bioscience) to initiate the assay. Rates of ATP synthesis were calculated in response to 5 mM pyruvate, 1 mM malate, and 2 mM ADP. Rates of ATP hydrolysis in ECAR (mpH/min) were converted to pmol H+/min by determining the buffer capacity of the medium. Data for compounds of the present application is provided in Table 11. Table 11: Rodent Hydrolase and Synthase Data Compo UCLA - UCLA - UCLA - UCLA - UCLA - UCLA - und # mouse mouse mouse RAT RAT RAT C57BL/6 C57BL/6 C57BL/6 Sprague Sprague Sprague isolated isolated isolated Dawley Dawley Dawley heart heart heart isolated isolated isolated mitochon mitochon mitochon heart heart heart dria F- dria F- dria F- mitochon mitochon mitochon ATPase ATPase ATPase dria F- dria F- dria F- IC50 IC50 IC50 ATPase ATPase ATPase Synthase Hydrolas Hydrolas IC50 IC50 IC50 activity: e activity: e activity: Synthase Hydrolas Hydrolas Average Average S/H activity: e activity: e activity: IC50 IC50 IC50 IC50 S/H (uM) (uM) (uM) (uM) 19 > 10.0 > 10.0 <=> 1.00 29 1.62 < 0.0300 > 54.1 35 1.99 < 0.0300 > 66.2 37 2 0.786 2.54 44 2.36 0.58 4.07 47 2.35 0.762 3.08 57 2.26 0.556 4.06 67 0.516 0.05 10.3 69 0.345 0.146 2.37 78 0.984 0.0378 26 82 > 10.0 0.172 > 58.2 84 > 10.0 > 10.0 <=> 1.00 86 > 10.0 > 10.0 <=> 1.00 87 > 10.0 > 10.0 <=> 1.00 88 4.67 3 1.56 89 > 10.0 > 10.0 <=> 1.00 91 > 10.0 4.63 > 2.16 92 2.98 1.57 1.9 93 2.77 0.873 3.18 94 > 10.0 > 10.0 <=> 1.00 95 > 10.0 > 10.0 <=> 1.00 96 9.35 6.18 1.51 97 7.63 9.79 0.779 98 > 10.0 > 10.0 <=> 1.00 99 6.28 4.65 1.35 100 1.77 1.27 1.4 102 > 10.0 2.71 > 3.69 108 > 10.0 8.26 > 1.21 110 9.66 6.33 1.52 115 5.9 > 10.0 < 0.590 119 > 10.0 > 10.0 <=> 1.00 120 > 10.0 > 10.0 <=> 1.00 121 > 10.0 2.18 > 4.58 3.99 0.707 5.64 122 9.32 3.42 2.72 5.96 1.38 4.31 123 > 10.0 5.69 > 1.76 5.11 1.46 3.51 124 > 10.0 > 10.0 <=> 1.00 125 4.1 1.83 2.25 127 > 10.0 > 10.0 <=> 1.00 128 > 10.0 7.71 > 1.30 4.79 1.63 2.95 130 > 10.0 2.85 > 3.51 131 3.52 1.82 1.94 6.71 1.28 5.23 132 8.71 > 10.0 < 0.871 133 3.63 1.34 2.71 2.85 0.998 2.85 135 9.77 3.66 2.67 4.13 0.72 5.74 136 > 10.0 > 10.0 <=> 1.00 137 > 10.0 2.19 > 4.56 139 14.4 > 30.0 < 0.479 140 4.85 2.57 1.89 141 2.96 1.43 2.08 2.78 0.511 5.43 146 3.82 4.75 0.804 7.89 6.44 1.23 147 29.6 > 30.0 < 0.988 152 11.3 28.8 0.39 157 8.5 > 10.0 < 0.850 158 > 10.0 6.88 > 1.45 160 9.47 6.78 1.4 162 7.5 7.7 0.974 Example 3: Bovine Hydrolase Assay The bovine hydrolase assay was performed using MitoCheck Complex V Activity Assay Kit (cat# 701000). The assay measured NADH oxidation in the presence of pyruvate kinase and lactate dehydrogenase as a readout of hydrolase activity. Prior to the assay, a 5x dilution plate was prepared. The dilution plate contained Oligomycin A (positive control) and test compounds at 7-concentrations starting at 50 µM and going down by 3-fold serial dilutions. All dilutions were made in mitochondrial complex V activity assay buffer. Two tubes were labeled for reaction mixes. Tube 1 contained 4.9 mL of complex V activity assay buffer, 100 µL bovine heart mitochondria (5 mg/mL) and 10 µL rotenone (1 mM). Tube 2 contained 3.810 mL of mitochondrial complex V enzyme mix, 120 µL ATP reagent and 120 µL NADH. In a clear 96 well plate 50 µL of tube 1 mix, 20 µL of compounds and finally 30 µL of tube 2 mix were added. The absorbance was immediately read at 340 nm wavelength and continued for the duration of the 60 minute incubation at 54 seconds intervals at 25 °C. Hydrolase activity was calculated by plotting the absorbance data (y-axis) over time (x-axis). The reaction rate was measured by calculating the slope of the linear phase of the curve (initial 15-30 min.) and the percentage activity by using the equation: #7(1/,&2) &'3+5+37 (%) = 8$)&'3+/. $&3) /* "/-0/4.( $)&'3+/. $&3) /* %)"+',) 96100 To determine IC50 value for each compound, hydrolase activity was plotted as a function of test compound concentration. Data for compounds of the present application is provided in Table 12. Table 12: Bovine Hydrolase Data Compound # Complex V Hydrolase assay_Bovine Heart Mitochondria: Average IC50 1 0.205 2 > 10.0 6 > 10.0 7 0.0401 9 1.15 10 0.314 11 1.19 12 0.084 13 0.503 14 3.11 15 > 10.0 16 > 10.0 17 6.91 18 > 10.0 19 0.853 20 > 10.0 21 > 10.0 22 1.21 23 > 10.0 24 > 10.0 25 > 10.0 26 1.46 27 > 10.0 28 0.726 29 0.238 30 8.45 31 7.79 32 0.586 33 > 10.0 34 7.8 35 0.178 36 2.5 37 0.145 38 7.8 39 > 10.0 40 0.492 41 > 10.0 42 8.12 43 2.72 44 0.111 45 1.16 46 > 10.0 47 0.133 48 1.07 49 1.65 50 5.51 51 0.324 52 0.045 53 9.39 54 6.84 55 8.36 56 1.82 57 0.195 58 6.09 59 3.73 60 0.121 61 1.22 62 > 10.0 63 > 10.0 64 8.04 65 > 10.0 66 0.033 67 0.0184 68 > 10.0 76 1.09 77 1.11 78 0.0453 79 0.672 80 0.325 81 1.02 84 1.82 85 1.41 86 1.61 87 > 10.0 88 0.103 89 1.9 90 7.91 91 1.04 92 0.0492 93 0.0193 94 0.0792 96 > 10.0 97 1.18 98 2.57 99 0.411 100 0.044 101 > 10.0 102 0.0733 103 > 10.0 104 > 10.0 105 0.541 106 > 10.0 107 > 10.0 108 0.4 109 0.874 110 0.376 111 1.34 112 1.23 113 7.68 114 > 10.0 115 0.316 116 1.81 117 0.828 118 1.42 119 > 10.0 120 0.413 121 0.167 122 0.227 123 0.368 124 3.35 125 0.0948 126 > 10.0 127 > 10.0 128 0.271 129 > 10.0 130 0.237 131 0.273 132 1.49 133 0.194 134 1.23 135 0.19 136 1.93 137 0.221 138 1.25 141 0.0559 142 1.05 143 1.07 144 > 10.0 145 7.15 146 0.408 147 6.35 148 9.13 149 7.19 162 0.793 232 > 10.0 258 0.357 259 1.19 260 0.332 261 0.72 262 0.533 263 0.188 264 0.25 223 0.416 224 0.18 226 0.073 227 1.38 228 2.17 229 0.060 230 0.13 231 >10.0 Example 4: Complex V Hydrolase assay (human) Compounds were made as DMSO stock at 30mM. Compound 2 or 55 was used as a positive control compound for the assay. The dilution plate was made by performing sequential ½ log dilutions by sequentially taking 10uL of 30mM stock compound and place it into 20uL of DMSO. Mixed well by pipetting 8-10 times then transferring 10uL from the 10mM stock into 20uL of DMSO to get 3mM final. From this point on continued making 3-fold dilutions by taking 20uL DMSO, adding 10uL of previous concentration of control compound; continued making 3-fold dilutions (keeping final volume 30uL within each well) until you got to row B (then stopped). Each dilution was pipetted 8-10 times prior to moving to the next well. Preparing the reagents: reagents provided in the kit were thawed. Mixed 10 mL of the Mitochondrial Complex V Activity Assay buffer at room temperature (RT) by vortexing well. Kept the Mitochondrial Complex V enzyme mix (4ml) on ice. Isolated mitochondria from Human HEK293 cells were used in place of the kit’s bovine heart mitochondria reagent. The mitochondria were kept on ice until addition to assay buffer. Reconstituted the Mitochondrial Complex V NADH reagent with 120uL of ultrapure water on ice. Reconstituted the Mitochondrial Complex V ATP reagent with 120uL ultrapure water on ice. Kept the plate that was supplied with kit at room temperature (RT). Performing the Assay: Made the compound dilution plate using a 96-well deep well plate (0.5mL volume) using ½ log concentrations. Started by adding 250uL of Complex V Activity Assay buffer in each well. Mixed the stock compounds in the PCR plate by pipetting up and down 8-10 times and transferring 1.25uL of compound stock from the PCR plate to the deep well plate (containing the 250uL Complex V Activity Assay buffer). Mixed diluted compounds by pipetting up and down 10 times, making sure that a good volume of mixing was performed (using P-200 multichannel). The compound dilution plate was now ready for the experiment. Labeled two 15 mL conical tubes as A and B. In Tube A (total volume 5ml) added a) 4,900uL of Complex V activity assay buffer; b) X uL of isolated mitochondria from Human HEK293 cells (concentration of mitochondria used varied based on purity of mitochondrial preparation); c) 10uL of Rotenone (1mM stock), Note: made 1mM rotenone stock using a fresh aliquot of 20mM ROT stock each time. Tube B (total volume 4.050ml) added a) 3,810uL of Mitochondrial Complex V enzyme mix; b) 120uL of Complex V ATP reagent; and c) Complex V NADH reagent (120uL). Made sure that both tubes A and B were kept on ice until ready to run the assay. Reaction Set Up: For each assay condition (all done at RT): Transferred 50uL of the content of tube A to each well of the plate supplied by the kit using a multichannel pipette. Added 20uL of positive control or test compounds from the deep-well compound dilution plate. Mixed gently by pipetting up and down, avoided creating bubbles. If there were bubbles, spun the plate down briefly prior to proceeding with the assay. Using a multichannel pipette, added 30uL of the contents of tube B (which had been placed in a reservoir) to each well to start the reaction. Made sure to begin by adding first to row A and moving down the rows as quickly as possible to avoid variation in start time. When dispensing the solution from tube B, pipetted up and down 3x to mix the reaction. Changed tips with every row. Immediately placed the plate into the plate reader and measured absorbance at 340nm (54 sec intervals for 60 min) at 25°C. Data analysis: Exported the data as an EXCEL file following the run and plotted the time-dependent reaction as absorbance (Y-axis) vs time (X-axis). To determine the reaction rate, calculated the slope for the linear portion of the curve (should capture 15- 30 minutes of total reaction time). Determined the % activity relative to the vehicle control (DMSO) using the following formula: Complex V Activity (%) = [Rate of Sample wells / Rate of Vehicle Control] x 100 Data for compounds of the present application is provided in Table 13. Table 13: Human Hydrolase Data Compound # Human Hydrolase IC50 (NADH Oxidation): Average IC50 (uM) 163 1.32 164 0.653 165 1.77 166 >10.0 167 1.15 168 >10.0 169 1.94 170 5.2 171 1.27 235 0.555 236 2.3 172 2.71 237 1.2 238 > 10.0 173 0.592 239 > 10.0 174 0.043 175 <0.010 176 0.134 177 3.86 240 0.797 178 0.255 179 >10.0 241 > 10.0 180 >10.0 242 > 10.0 181 4.87 243 > 10.0 182 0.569 183 1.17 184 5.49 185 >10.0 244 > 10.0 186 0.445 187 >10.0 188 0.908 189 1.3 190 >10.0 191 0.26 192 > 10.0 193 >10.0 246 0.971 194 1.75 195 3.03 196 >10.0 197 >10.0 198 >10.0 199 9.35 200 7.02 201 1.7 247 3.5 248 1.37 249 1.56 202 2.09 203 0.118 204 >10.0 205 >10.0 206 1.68 207 >10.0 208 0.69 209 >10.0 210 >10.0 211 0.132 212 >10.0 213 1.5 251 0.62 214 >10.0 215 0.161 216 >10.0 217 0.224 218 >10.0 219 >10.0 220 4.29 253 1.95 254 0.769 255 1.73 221 1.38 222 >10.0 256 0.343 257 0.928 258 0.589 260 0.541 263 0.295 264 0.796 223 4.64 224 0.658 226 0.155 229 0.091 230 0.133 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 compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8; Y, independently for each occurrence, is selected from C(R6) and N; Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6, independently for each occurrence, is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, - C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, - SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl; R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1.
2. The compound of claim 1, wherein the compound is a compound of formula (Ia), (Ia), or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, wherein the compound is a compound of formula (Ib), (Ib), or a pharmaceutically acceptable salt thereof.
4. A compound of formula (II), (II), or a pharmaceutically acceptable salt thereof, wherein: A is selected from hydrogen, cyano, alkyl, alkenyl, alkynyl, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; L is –(C(R7)2)nXq(C(R7)2)m-; X is selected from C(R7)2, alkenyl, alkynyl, O, S, S(O), S(O)2, and NR8; Y, independently for each occurrence, is selected from C(R6) and N; Z is selected from SO2 and C(O); R1 is selected from hydrogen, alkyl, and haloalkyl; R2 and R3 each independently is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, or R2 and R3 taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring; or R2 is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, and C(O)alkyl, wherein alkyl, cycloalkyl, or heterocycloalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, oxo, carbonyl, amino, alkylamino, dialkylamino, cycloalkyl, and heterocyclyl, and NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heterocyclic ring; or NR3 and one ortho-positioned occurrence of R4, together with the carbon atoms to which they are attached, form a heteroaromatic ring and R2 is absent or, valence permitting, is selected from H and alkyl, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R4 independently for each occurrence is selected from halogen, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, -C(O)R9, -C(O)OR9, - OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, -SC(O)R9, -C(O)SR9, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, or heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R6, independently for each occurrence, is selected from hydrogen, halogen, cyano, nitro, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, - C(O)R9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -N(R9)C(O)R9, -S(O)2R9, - SC(O)R9, -C(O)SR9, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocycloalkenyl, aryl, and heteroaryl, wherein any occurrence of alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, alkylthio, amino, carboxyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocycloalkenyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R7, independently for each occurrence, is selected from hydrogen, halogen, alkyl, haloalkyl, and cycloalkyl; R8 is selected from hydrogen, alkyl, and cycloalkyl; R9, independently for each occurrence, is selected from hydrogen, alkyl, cycloalkyl, and heterocyclyl, wherein any occurrence of alkyl, cycloalkyl, and heterocyclyl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; and q is 0 or 1.
5. The compound of claim 4, wherein the compound is a compound of formula (IIa), (IIa), or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein each Y is C(R6).
7. The compound of any of claims 1 or 3-6, or a pharmaceutically acceptable salt thereof, wherein o is 1.
8. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy.
9. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R4 is halogen.
10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R4 is F.
11. The compound of any of claims 1 or 3-6, or a pharmaceutically acceptable salt thereof, wherein o is 0.
12. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.
13. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein each of R2 and R3 is hydrogen.
14. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein X is selected from CH2 and O.
15. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein X is CH2, n is 1, m is 0, and q is 1.
16. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, or heteroaryl, may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
17. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R5 is aryl optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl, cycloalkyl, and heterocyclyl.
18. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R5 is alkyl substituted with 1-3 substituents independently selected from halogen.
19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R5 is CF3.
20. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein A is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein A is selected from cyclopentyl or phenyl, wherein the cyclopentyl or phenyl may be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein A is phenyl.
23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein A is cyclopentane.
24. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R6 is is selected from hydrogen, cyano, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy, acetamidealkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein any occurrence of cycloalkyl, heterocyclyl, aryl, or heteroaryl may independently be optionally substituted with 1-3 substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), amino, alkylamino, dialkylamino, amido, amidine, imine, nitro, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.
26. A compound selected from any one of compounds 1-224, 226-232, 235-244, 246-249, 251, and 253-264, and pharmaceutically acceptable salts thereof.
27. The compound of claim 26, wherein the compound is compound 78, (78), or a pharmaceutically acceptable salt thereof.
28. The compound of claim 26, wherein the compound is compound 135, (135), or a pharmaceutically acceptable salt thereof.
29. The compound of claim 26, wherein the compound is compound 264, (264), or a pharmaceutically acceptable salt thereof.
30. The compound of claim 26, wherein the compound is compound 263, (263), or a pharmaceutically acceptable salt thereof.
31. The compound of claim 26, wherein the compound is compound 256, (256), or a pharmaceutically acceptable salt thereof.
32. The compound of claim 26, wherein the compound is compound 217, (217), or a pharmaceutically acceptable salt thereof.
33. The compound of claim 26, wherein the compound is compound 251, (251), or a pharmaceutically acceptable salt thereof.
34. The compound of claim 26, wherein the compound is compound 178, (178), or a pharmaceutically acceptable salt thereof.
35. The compound of claim 26, wherein the compound is compound 240, (240), or a pharmaceutically acceptable salt thereof.
36. The compound of claim 26, wherein the compound is compound 175, (175), or a pharmaceutically acceptable salt thereof.
37. A pharmaceutical composition comprising (a) a compound of any preceding claim; and (b) a pharmaceutically acceptable excipient.
38. A compound of any one of claims 1-36 or a pharmaceutical composition of claim 37 for use as a medicament.
39. A method of treating a neurodegenerative disorder in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1-36 or a pharmaceutical composition of claim 37.
40. The method of claim 39, wherein the neurodegenerative disorder is selected from Parkinson’s disease; Huntington’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis (ALS); Rett syndrome; multiple systems atrophy (MSA); Charcot Marie Tooth; Friedreich’s Ataxia; spinal cerebellar atrophy (SCA); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), age- related macular degeneration (AMD), and traumatic brain injury (TBI).
41. A method of treating a cardiovascular disorder, ischemia, or acute coronary syndromes in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1-36 or a pharmaceutical composition of claim 37.
42. A method of treating cancer or inhibiting tumor growth from a cancer in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1-36 or a pharmaceutical composition of claim 37.
43. The method of claim 42, wherein the cancer is selected from cancer of the lung, prostate, colon, breast, ovaries and bone.
44. A method of treating Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1- 36 or a pharmaceutical composition of claim 37.
45. Use of a compound of any one of claims 1-36 or a pharmaceutical composition of claim 37, in the preparation of a medicament for the treatment of Parkinson’s disease and/or one or more symptoms associated with Parkinson’s disease.
PCT/US2024/012416 2023-01-23 2024-01-22 Novel f-atpase hydrolase inhibitors Ceased WO2024158698A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001081322A1 (en) * 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
EP1329450A1 (en) * 2000-09-27 2003-07-23 Ajinomoto Co., Inc. Benzodiazepine derivative
WO2006049984A2 (en) * 2004-10-28 2006-05-11 Janssen Pharmaceutica, N.V. Novel [1,4]benzodiazepines as vasopressin v2 receptor antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001081322A1 (en) * 2000-04-21 2001-11-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
EP1329450A1 (en) * 2000-09-27 2003-07-23 Ajinomoto Co., Inc. Benzodiazepine derivative
WO2006049984A2 (en) * 2004-10-28 2006-05-11 Janssen Pharmaceutica, N.V. Novel [1,4]benzodiazepines as vasopressin v2 receptor antagonists

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