WO2014036268A2 - Dérivés d'indole en tant qu'activateurs de la protéine sumo - Google Patents

Dérivés d'indole en tant qu'activateurs de la protéine sumo Download PDF

Info

Publication number
WO2014036268A2
WO2014036268A2 PCT/US2013/057302 US2013057302W WO2014036268A2 WO 2014036268 A2 WO2014036268 A2 WO 2014036268A2 US 2013057302 W US2013057302 W US 2013057302W WO 2014036268 A2 WO2014036268 A2 WO 2014036268A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkylamino
ethyl
hydrogen
triazol
Prior art date
Application number
PCT/US2013/057302
Other languages
English (en)
Other versions
WO2014036268A3 (fr
Inventor
Russell Dahl
Ah Young Lee
Changwon KHO
Roger J. Hajjar
Original Assignee
Mount Sinai School Of Medicine
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mount Sinai School Of Medicine filed Critical Mount Sinai School Of Medicine
Publication of WO2014036268A2 publication Critical patent/WO2014036268A2/fr
Publication of WO2014036268A3 publication Critical patent/WO2014036268A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application relates to SUMO activators, which can enhance SUMOylation of SERCA2a, which are useful in the treatment of heart failure, cardiovascular diseases, cancer, neurodegenerative disorders, viral infection, bacterial infection, liver disease, inflammation, and other diseases.
  • Heart failure remains a leading cause of death in Western countries and the development of new therapeutic agents for HF has been challenged.
  • the calcium-transporting ATPase ATP2A2 (SERCA2a) is ATPase responsible for Ca 2+ reuptake during excitation-contraction coupling.
  • a characteristic of heart failure is impaired Ca 2+ uptake resulting from decreased expression and reduced activity of SERCA2a.
  • restoration of SERCA2a expression by gene transfer can be effective in improving cardiac function in animal models and heart-failure patients.
  • SERCA2a small ubiquitin-like modifier type 1 (SUMOl)-mediated unique post-translational modification (PTM), named SUMOylation (Kho C, Lee A, Jeong D, Oh JG, Chaanine AH, Kizana E, Park WJ, Hajjar RJ, "SUMO 1 -dependent modulation of SERCA2a in heart failure", Nature 2011 Sep 7;477(7366):601-5).
  • SERCA2a is SUMOylated by SUMOl at two specific sites Lysine 480 and 585. The levels of SUMO l and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts.
  • SUMOl restitution by adeno-associated- virus-mediated gene delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Since it has been shown that SUMOl enhances the stability and the ATPase activity of SERCA2a, its decrease causes further dysfunction of SERCA2a and further worsening of dysfunction. Further, gain of function experiments by transgenesis and gene therapy showed that SUMO 1 gene therapy rescues contractile function and improves mortality in models of heart failure.
  • Huntington's disease a Huntington's disease
  • Parkinson's disease Dorval, V., Fraser, RE. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and a-synuclein. J. Biol. Chem. (2006) 281, 9919-9924
  • Alzheimer's disease Zhang, Y.Q. and Sarge, K.D. SUMOylation of amyloid precursor protein negatively regulates ⁇ aggregate levels. (2008) Biochem. Biophys. Res. Commun.
  • ALS amyotrophic lateral sclerosis
  • the present application provides, inter alia, a method of treating heart failure, cardiac hypertrophy, myocarditis, myocardial infarction, ischemia, cardiac arrhythmias, vascular rhexis, cardiac arrhythmia, valvulopathy, diastolic dysfunction, hypertension, cancer, neurodegenerative disorders, viral infection, bacterial infection, liver disease, or inflammation in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
  • Ar is aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R la groups;
  • Z is O, S, NR A , or CH 2 ;
  • R A is H or Ci_ 4 alkyl
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 are each independently selected from hydrogen, halo, CN, nitro, hydroxy, Ci- 6 alkyl, alkoxy, Ci_6 haloalkoxy, amino, Ci-6 alkylamino, di-Ci- 4 -alkylamino, carboxy, carbamyl, Ci-6 alkylcarbamyl, di(Ci_ 4 alkyl)carbamyl, Ci_6 alkylcarbonyl, Ci_6 alkoxycarbonyl, Ci_6 alkylcarbonyloxy, Ci_6 alkylsulfonyl, Ci_6 alkylcarbonylamino, Ci_6
  • Ci_ 6 alkylaminosulfonyl aminosulfonylamino, Ci_6 alkylaminosulfonylamino, and di-Ci_ 4 alkylaminosulfonylamino; wherein said C h alky!, Ci_ 6 haloalkyl, Ci- 6 alkoxy, Ci_6 haloalkoxy, Ci_6 alkylamino, di-Ci_ 4 -alkylamino, Ci_6 alkylcarbamyl, di(Ci_ 4 alkyl)carbamyl, and Ci-6 alkylcarbonyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, hydroxy, C1-3 alkoxy, amino, C1-3 alkylamino, and di-Ci_3_alkylamino;
  • R 6 is selected from hydrogen, Ci_ 4 alkyl, and Ci_ 4 haloalkyl; each R la is independently selected from halo, CN, nitro, hydroxy, Ci_6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, Ci_6 heteroaryl, Ci- 6 alkoxy, Ci ⁇ haloalkoxy, amino, Ci_6 alkylamino, di-Ci-4- alkylamino, carboxy, carbamyl, Ci_6 alkylcarbamyl, di(Ci_4 alkyl)carbamyl, Ci_6 alkylcarbonyl, Ci_6 alkoxycarbonyl, Ci_6 alkylcarbonyloxy, Ci_6 alkylsulfonyl, Ci_6 alkylcarbonylamino, Ci_6 alkylsulfonylamino,
  • n 1, 2, 3, 4, 5, 6, 7, or 8.
  • the heart failure is selected from congestive heart failure (CHF), chronic heart failure, and ischemic heart failure.
  • CHF congestive heart failure
  • chronic heart failure chronic heart failure
  • ischemic heart failure ischemic heart failure
  • Ar is monocyclic 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3, or 4 independently selected R la groups. In some embodiments, Ar is monocyclic 5-6 membered heteroaryl.
  • Ar can be
  • R 7 , R 8 , R 9 , and R 10 are each hydrogen.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen. In some embodiments, at least four of R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen. In some embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, CN, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and Ci-6 haloalkoxy. In some embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, and Ci_6 alkoxy. In some embodiments, R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, CI, and methoxy.
  • R 6 is methyl
  • n is 1, 2, 3, or 4.
  • n can be 2.
  • Z is O.
  • the compound is a compound of Formula la:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, CN, hydroxy, Ci- 6 alkyl, Ci ⁇ haloalkyl, Ci- 6 alkoxy, and C e haloalkoxy; R 7 , R 8 , R 9 , and R 10 are each hydrogen; and R 6 is C 1-4 alkyl.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, and C e alkoxy; R 7 , R 8 , R 9 , and R 10 are each hydrogen; and R 6 is C 1-4 alkyl.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, and Ci_6 alkoxy; R 7 , R 8 , R 9 , and R 10 are each hydrogen; and R 6 is methyl.
  • Non-limiting examples of compounds of Formula I include:
  • the compound of Formula I is selected from the group consisting of:
  • the method further comprises administering to the patient an adeno-associated vector (AAV) comprising SERCA2a.
  • AAV adeno-associated vector
  • the present application further provides a method of activating SUMO l, comprising contacting comprising contacting a cell with a compound, salt, or composition described herein, in an amount effective to activate SUMO 1.
  • the present application further provides a compound or salt as described herein for use in any of the methods described herein.
  • the present application further provides use of a compound or salt as described herein for manufacture of a medicament for use in any of the method described herein.
  • the present application further provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present application further provides a compound, which is selected from:
  • FIG. 1 depicts intracellular fluorescence measurements for DMSO control versus Examples 1-3 in HEK-293 cells expressing YFP-SUMOl and pcDNA3.0- SERCA2a.
  • FIG. 2 depicts immunoblotting from cells treated with Examples 1-3 or DMSO.
  • FIG. 3 depicts effects of Examples 1-3 on the mechanical properties of the ARVMs from measurements using a video-based edge detection system (lonOptix).
  • FIG. 4 depicts SERCA2a SUMOylation profiling in the same set of ARVMs.
  • the present application provides, inter alia, a method of treating heart failure, cardiac hypertrophy, myocarditis, myocardial infarction, ischemia, cardiac arrhythmias, vascular rhexis, cardiac arrhythmia, valvulopathy, diastolic dysfunction, hypertension, cancer, neurodegenerative disorders, viral infection, bacterial infection, liver disease, or inflammation in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
  • Ar is aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R la groups;
  • Z is O, S, NR A , or CH 2 ;
  • R A is H or Ci_ 4 alkyl
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 are each independently selected from hydrogen, halo, CN, nitro, hydroxy, Ci_ 6 alkyl, alkoxy, Ci_6 haloalkoxy, amino, Ci-6 alkylamino, di-Ci- 4 -alkylamino, carboxy, carbamyl, Ci-6 alkylcarbamyl, di(Ci_ 4 alkyl)carbamyl, Ci_6 alkylcarbonyl, Ci_6 alkoxycarbonyl, Ci_6 alkylcarbonyloxy, Ci_6 alkylsulfonyl, Ci_6 alkylcarbonylamino, Ci_6
  • Ci_6 alkylaminosulfonyl aminosulfonylamino, Ci_6 alkylaminosulfonylamino, and di-Ci_ 4 alkylaminosulfonylamino; wherein said C h alky!, Ci ⁇ haloalkyl, Ci- 6 alkoxy, Ci_6 haloalkoxy, Ci_6 alkylamino, di-Ci_ 4 -alkylamino, Ci_6 alkylcarbamyl, di(Ci_ 4 alkyl)carbamyl, and Ci-6 alkylcarbonyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, CN, hydroxy, C 1-3 alkoxy, amino, C 1-3 alkylamino, and di-Ci- 3 -alkylamino;
  • R 6 is selected from hydrogen, C 1-4 alkyl, and Ci ⁇ haloalkyl
  • each R la is independently selected from halo, CN, nitro, hydroxy, Ci_6 alkyl, Ci_ 6 haloalkyl, C2-6 alkenyl, C2- 6 alkynyl, C 3 _7 cycloalkyl, C2-6 heterocycloalkyl, phenyl, Ci ⁇ heteroaryl, C e alkoxy, Ci ⁇ haloalkoxy, amino, C e alkylamino, di-C 1-4 - alkylamino, carboxy, carbamyl, Ci_6 alkylcarbamyl, di(C 1-4 alkyl)carbamyl, Ci_6 alkylcarbonyl, C e alkoxycarbonyl, C e alkylcarbonyloxy, C e alkylsulfonyl, Ci_6 alkylcarbonylamino, Ci-6 alkylsulfonylamino, aminosulfonyl, Ci-6 alkylaminosulfonyl, di-C
  • n 1, 2, 3, 4, 5, 6, 7, or 8.
  • the heart failure is selected from congestive heart failure (CHF), chronic heart failure, and ischemic heart failure.
  • CHF congestive heart failure
  • chronic heart failure chronic heart failure
  • ischemic heart failure ischemic heart failure
  • Cancers include, but are not limited to, solid tumors such as breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, and other tumors of tissue organs and cancers of the blood cells, such as lymphomas and leukemias, including acute myelogenous leukemia, chronic lymphocytic leukemia, T cell lymphocytic leukemia, and B cell lymphomas.
  • lymphomas and leukemias including acute myelogenous leukemia, chronic lymphocytic leukemia, T cell lymphocytic leukemia, and B cell lymphomas.
  • Neurodegenerative disorders include, but are not limited to Huntington's disease, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • Inflammatory disorders include, but are not limited to, transplant rejection, including skin graft rejection; chronic inflammatory disorders of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung disorders such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory disorders of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disorders of the gums, including gingivitis and periodontitis;
  • tuberculosis leprosy
  • inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory disorders of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune disorders, immune-complex vasculitis, systemic lupus and erythematodes; systemic lupus erythematosus (SLE); and inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease hypercholesterolemia, atherosclerosis; as well as various other diseases with significant inflammatory components, including preeclampsia; chronic liver failure,
  • a systemic inflammation of the body exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent used in cancer chemotherapy.
  • Viral infections include but are not limited to, infections by a hepatitis virus (e.g., hepatitis B or C), human immunodeficiency virus (HIV), rhinovirus, herpes- zoster virus (VZV), herpes simplex virus (e.g., HSV-1 or HSV-2), cytomegalovirus (CMV), vaccinia virus, influenza virus, encephalitis virus, hantavirus, arbovirus, West Nile virus, human papilloma virus (HPV), Epstein-Ban virus, and respiratory syncytial virus.
  • a hepatitis virus e.g., hepatitis B or C
  • HSV-1 or HSV-2 herpes- zoster virus
  • CMV herpes simplex virus
  • vaccinia virus influenza virus, encephalitis virus, hantavirus, arbovirus, West Nile virus, human papilloma virus (HPV), Epstein-Ban virus
  • Liver diseases include, but are not limited to liver cirrhosis, alcoholic liver cirrhosis, fatty liver, toxipathic liver diseases, and acute and chronic hepatitis.
  • Ar is monocyclic 5-6 membered heteroaryl, which is optionally substituted by 1, 2, 3, or 4 independently selected R la groups.
  • Ar is monocyclic 5-6 membered heteroaryl.
  • Ar is .
  • R 7 , R 8 , R 9 , and R 10 are each hydrogen.
  • At least three of R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen.
  • At least four of R 1 , R 2 , R 3 , R 4 , and R 5 are hydi
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, CN, hydroxy, Ci- 6 alkyl, Ci ⁇ haloalkyl, Ci- 6 alkoxy, and C e haloalkoxy.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, and Ci_6 alkoxy.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, CI, and methoxy.
  • R 6 is methyl. In some embodiments, R 6 is hydrogen.
  • R 2 is selected from Ci_6 alkyl and Ci_6 alkoxy. In some embodiments, R 2 is methyl. In some embodiments, R 2 is methoxy.
  • R 3 is selected from halo and Ci_6 alkoxy. In some embodiments, R 3 is chloro. In some embodiments, R 3 is methoxy.
  • R 4 is Ci_6 alkyl. In some embodiments, R 4 is ethyl.
  • R 2 is methyl and R 4 is ethyl.
  • n 1, 2, 3, or 4.
  • n is 2.
  • Z is O.
  • the compound is a compound having Formula la:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, CN, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and Ci-6haloalkoxy;
  • R 7 , R 8 , R 9 , and R 10 are each hydrogen
  • R 6 is Ci_ 4 alkyl.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, and Ci_6 alkoxy;
  • R 7 , R 8 , R 9 , and R 10 are each hydrogen
  • R 6 is Ci- 4 alkyl.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, and Ci_6 alkoxy;
  • R 7 , R 8 , R 9 , and R 10 are each hydrogen
  • R 6 is methyl
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, halo, and Ci_6 alkoxy;
  • R 6 , R 7 , R 8 , R 9 , and R 10 are each hydrogen.
  • the compound is selected from:
  • the compounds described herein can activate SUMOl. Accordingly, the present application further provides a method of activating SUMO 1 , comprising contacting comprising contacting a cell with a compound, salt, or composition described herein, in an amount effective to activate SUMO 1. The contacting can be done in vivo or in vitro. In further embodiments, the compounds of the present application can be used to activate SUMOl in an individual in need of the activation by administering a compound, salt, or composition described herein, in an amount effective to activate SUMOl.
  • the present application further provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present application further provides a compound, which is selected from: N-(( 1 -(2 -(3 -methoxyphenoxy)ethyl)-2-methyl- 1 H-indol-3 -yl)methylene)-4H- 1,2,4- triazol-4-amine; and
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci_ 6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C 4 alkyl, C5 alkyl, and Ce alkyl.
  • the phrase "optionally substituted” means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency.
  • C n _ m alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbon atoms.
  • the alkyl group contains 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, w-pentyl, 2-methyl-l -butyl, 3-pentyl, w-hexyl, 1,2,2- trimethylpropyl, and the like.
  • C n m alkenyl refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, w-propenyl, isopropenyl, w-butenyl, sec-butenyl, and the like.
  • C n _ m alkynyP' refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • C n m alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n- propoxy and isopropoxy), t-butoxy, and the like.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • amino refers to a group of formula -NH2.
  • C n - m alkylamino refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • di-C n - m -alkylamino refers to a group of formula - N(alkyl) 2 , wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.
  • C n - m alkoxycarbonyl refers to a group of formula -C(0)0-alkyl, wherein the alkyl group has n to m carbon atoms.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • C n _ m alkylcarbonyl refers to a group of formula -C(0)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • C n m alkylsulfonyl refers to a group of formula -S(0)2-alkyl, wherein the alkyl group has n to m carbon atoms.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • C n m alkylcarbonyloxy refers to a group of formula -OC(0)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • C n m alkylcarbonylamino refers to a group of formula -NHC(0)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • C n m alkylcarbamyl refers to a group of formula -C(0)-NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • di(C n - m -alkyl)carbamyl refers to a group of formula -C(0)N(alkyl) 2 , wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.
  • C1-4 alkylsulfonylamino refers to a group of formula -NHS(0)2-alkyl, wherein said alkyl has 1 to 4 carbon atoms.
  • aminosulfonyl refers to a group of formula - S(0) 2 NH 2 .
  • C1-4 alkylaminosulfonyl refers to a group of formula -S(0)2NH(alkyl), wherein said alkyl has 1 to 4 carbon atoms.
  • di-Ci-4 alkylaminosulfonyl refers to a group of formula -S(0)2N(alkyl)2, wherein each alkyl independently has 1 to 4 carbon atoms.
  • aminosulfonylamino refers to a group of formula - HS(0)2 H2, wherein said alkyl has 1 to 4 carbon atoms.
  • C1-4 alkylaminosulfonylamino refers to a group of formula -NHS(0)2NH(alkyl), wherein said alkyl has 1 to 4 carbon atoms.
  • di-Ci-4 alkylaminosulfonylamino refers to a group of formula -NHS(0)2N(alkyl)2, wherein each alkyl independently has 1 to 4 carbon atoms.
  • halo or “halogen”, employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo.
  • C n - m haloalkyl refers to an C n - m alkyl group having up to ⁇ 2(n to m)+l ⁇ halogen atoms which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • Example haloalkyl groups include CF 3 , C2F5, CHF 2 , CCI 3 , CHCI2, C2CI5, and the like.
  • the haloalkyl group is a fluoroalkyl group.
  • C n - m haloalkoxy refers to a group of formula -O-haloalkyl having n to m carbon atoms.
  • An example haloalkoxy group is OCF 3 .
  • the haloalkoxy group is fluorinated only.
  • the alkyl group has 1 to 6 or 1 to 4 carbon atoms.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, or 7 ring-forming carbons (C3-7). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido.
  • Cycloalkyl groups also include cycloalkylidenes.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring- forming atom of the fused aromatic ring.
  • heteroaryl refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen.
  • the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • any ring- forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl is a five-membered or six-membereted heteroaryl ring.
  • a five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3- triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl.
  • a six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • a "bicyclic C9-10 heteroaryl” is bicyclic fused heteroaryl having 9 to 10 ring members.
  • heterocycloalkyl refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles.
  • Example heterocycloalkyl groups include pyrrolidin-2-one, l,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like.
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(0)2, etc.).
  • the heterocycloalkyl group can be attached through a ring- forming carbon atom or a ring-forming heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the heterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen or sulfur and having one or more oxidized ring members.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present application can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • the term, "compound,” as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
  • Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.
  • the compounds of the present application, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compounds of the present application.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the present application, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present application also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present application include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • ACN acetonitrile
  • a compound of the present application or a
  • the additional agent can be a therapeutic agent that is art-recognized as being useful to treat the disease or condition being treated by the compound of the present application.
  • the additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition (e.g., an agent that affects the viscosity of the composition).
  • the combination therapy contemplated by the invention includes, for example, administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, and additional agent(s) in a single pharmaceutical formulation as well as administration of a compound of the present application, or a
  • co-administration shall mean the administration of at least two agents to a subject so as to provide the beneficial effects of the combination of both agents.
  • the agents may be administered simultaneously or sequentially over a period of time.
  • the additional therapeutic agent can be any therapeutic agent useful for the treatment of the disease states of the methods described herein.
  • the additional therapeutic agent can be administered simultaneously or sequentially.
  • the method further comprises administering to the patient a viral expression vector comprising SERCA2a.
  • the method further comprises administering to the patient an adeno-associated vector (AAV) comprising SERCA2a.
  • AAV adeno-associated vector
  • vectors useful in the present methods include, but are not limited to those described in US 2011/0256101, which is incorporated herein by reference in its entirety.
  • SERCA2 is incorporated into a viral vector to mediate transfer to a cell.
  • a retrovirus bovine papilloma virus, an adenovirus vector, a lentiviral vector, a vaccinia virus, a polyoma virus, or an infective virus may be used.
  • nonviral methods which include, but are not limited to, direct delivery of DNA such as by perfusion, naked DNA trans fection, liposome mediated transfection, encapsulation, and receptor-mediated endocytosis may be employed. These techniques are well known to those of skill in the art, and the particulars thereof do not lie at the crux of the present invention and thus need not be exhaustively detailed herein.
  • a viral vector is used for the transduction of pulmonary cells to deliver a therapeutically significant polynucleotide to a cell.
  • the virus may gain access to the interior of the cell by a specific means such as receptor-mediated endocytosis, or by non-specific means such as pinocytosis
  • compositions When employed as pharmaceuticals, the compounds of the present application can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration routes include, but are not limited, to pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, the compound of the present application or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients).
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • the compounds of the present application may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the present application can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include:
  • compositions of the present application can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • compositions of the present application contain from about 5 to about 50 mg of the active ingredient.
  • the compositions of the present application contain from about 5 to about 50 mg of the active ingredient.
  • One having ordinary skill in the art will appreciate that this embodies compositions containing about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient.
  • compositions of the present application contain from about 50 to about 500 mg of the active ingredient.
  • compositions of the present application contain from about 500 to about 1000 mg of the active ingredient.
  • compositions containing about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present application.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present application.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present application.
  • the tablets or pills of the present application can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present application can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of
  • compositions described above can be sterilized by conventional sterilization techniques, or may be sterile filtered.
  • Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 1 1, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of
  • the therapeutic dosage of a compound of the present application can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the present application in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the present application can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the reactions for preparing compounds of the present application can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., l H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid
  • LCMS chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1 ,2-diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • the synthesis of the compounds of Formula (I) may be performed according to the following synthetic sequence:
  • the synthesis of the compounds of Formula (I) may include the following steps: formation of an imine, and alkylation of the indole nitrogen.
  • formation of an imine may involve an aldehyde and an amine.
  • the amine may be a primary amine.
  • the alkylation of the indole nitrogen may involve use of an alkyl bromide.
  • kits useful for example, in the treatment or prevention of any of the disease states described herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • Example 1 N-((l-(2-(3-methoxyphenoxy)ethyl)-2-methyl-lH-indol-3- yl)methylene)-4H-l,2,4-triazol-4-amine.
  • 2-Methylindole-3-carboxaldehyde (237 mg, 1.50 mmol) is dissolved in dimethylformamide (DMF) containing 1% acetic acid (AcOH).
  • AcOH 1% acetic acid
  • 4-amino-l,2,4-triazole 126 mg, 1.50 mmol. After stirring for 2.5 h, the mixture is diluted with water and extracted with 2 volumes (40 mL) of ethyl acetate (EtOAc).
  • Example 2 N-((l-(2-(4-chlorophenoxy)ethyl)-2-methyl-lH-indol-3- yl)methylene)-4H-l,2,4-triazol-4-amine.
  • 2-Methylindole-3-carboxaldehyde (237 mg, 1.50 mmol) is dissolved in dimethylformamide (DMF) containing 1% acetic acid (AcOH).
  • AcOH acetic acid
  • 4-amino-l,2,4-triazole 126 mg, 1.50 mmol. After stirring for 2.5 h, the mixture is diluted with water and extracted with 2 volumes (40 mL) of ethyl acetate (EtOAc).
  • Example 3 can be obtained from ChemBridge (catalog number 6372149).
  • Example 4 3-(2-(4H-l,2,4-triazol-4-yl)vinyl)-l-(2-(3-methoxyphenoxy)ethyl)-lH- indole
  • Example 4 can be obtained from ChemBridge Corp.
  • Example 5 can be obtained from ChemBridge Corp.
  • IP immunoprecipitation
  • SUMO 1 Cell Signaling Technology Inc., catalog no. 4930
  • HRP horseradish peroxidase
  • anti-rabbit anti-rabbit
  • the plasmid DNA was amplified in the Escherichia coli strain DH5a and extracted by using a commercial purification kit (Qiagen, catalog no. 12263). Purified plasmid was resuspended in sterile TE buffer (10 mM Tris-HCI and 1 mM EDTA, pH 7.6). Only the preparation highest purity (A260/A28O 1.8) was used for transfection. 1 ⁇ g of each plasmid was used for transfection.
  • HEK-293 cells (American Type Culture Collection, catalog no. CRL-1873) were grown at 37°C and under a 5% CO 2 humidified atmosphere in Dulbecco's modified Eagle's medium (DMEM, Cellgro, catalog no.
  • HEK- 293 cells were seeded at a density of 3-5 x 10 5 cells per 60 mm culture dish in DMEM. The cells were transiently transfected using Lipofectamine 2000 (Invitrogen, catalog no. 1 1668) with indicated expression plasmids. After 24 hours, the cells were treated with either small molecules or dimethyl sulfoxide (DMSO, Sigma-Aldrich, catalog no. D2650).
  • DMSO dimethyl sulfoxide
  • ARVMs Calcium-tolerant adult rat ventricular myocytes
  • DMEM without L-glutamine supplemented with 10 mmolll HEPES, 3.7 mg/ml NaHC03, 1 mg/ml glucose, 0.1 1 mg/ml sodium pyruvate, 2 mg/ml bovine serum albumin, 2 mmol/1 L-camitine, 5 mmol/1 creatine, 5 mmol/1 taurine, 1% penicillin-streptomycin,and 1% gentamycin. Following isolation, cells were allowed to settle for 1 hour. Cultures were incubated at 37°C, in an atmosphere of 5% CO2- 95% air. Fresh medium was added
  • HEK-293 cells expressing YFP-SUMOI and pcDNA3.0-SERCA2a were incubated with either 10 ⁇ DMSO or 10 ⁇ small molecules for 24 hours at 37°C. Fluorescent signals were monitored by fluorescence microscopy. HA-tagged Ubc9 expressing cells were served as a positive control.
  • MyoCam® system (lonOptix, Milton, MA).
  • cells were placed in a Warner chamber mounted on the stage of an inverted microscope (Olympus, IX-70) and superfused (1 ml/min at 30°C) with a buffer containing 131 mM NaCl, 4 mM KC1, ImM CaCh, ImM MgCh, 10 mM glucose, and 10 mM HEPES, pH 7.4.
  • ARVMs were field stimulated with suprathreshold voltage and at a frequency of 0.5 Hz.
  • the ARVMs being studied was displayed on the computer monitor using an lonOptix MyoCam camera.
  • SoftEdge software (lonOptix) was used to capture changes in cell length during shortening and re-lengthening.
  • ARVMs were placed in a chamber on an Olympus IX-70 inverted microscope and
  • Fluorescence emissions were detected between 480 and 520 nm by a photomultiplier tube after first illuminating cells at 360 nm
  • Equal amounts of protein from either small molecule treated or DMSO treated cells or immunoprecipitates were resolved by 7.5% SDS-PAGE and transferred to nitrocellulose membranes (Bio-Rad, catalog no. 162-0112). The membranes were blocked for 1 hour at room temperature with 5% non-fat milk (Cell Signaling
  • TBST 10 mM Tris-HCI, 150 mM NaCI, and 0.05% tween-20, pH 8.0.
  • the blots were incubated with specific primary antibodies at 4°C for overnight.
  • the blots were then washed five times for 10 minutes each with TBST and incubated for 1 hour with HRP-conjugated secondary antibodies in TBST with 5% non-fat milk.
  • HRP-conjugated secondary antibodies in TBST with 5% non-fat milk.
  • the protein bands were visualized with enhanced chemiluminescence (Pierce Biotechnology Inc., catalog no.32132) and exposed to x-ray film (Denville Scientific Inc., catalog no. E3012).
  • GAPDH expression provided an internal control.
  • the HEK-293 cells were rinsed twice with phosphate-buffered saline (PBS, Cellgro, catalog no. 21-040-CM) and lysed in 1% Nonidet P-40 lysis buffer (Boston Bioproducts, catalog no. BP-119) with 10 mM N- ethylmaleimide (NEM, Sigma- Aldrich, catalog no. N3876) and phosphatase inhibitor cocktail (Complete Mini Tablet, Roche Applied Science, catalog no.
  • PBS phosphate-buffered saline
  • NAM N- ethylmaleimide
  • N3876 phosphatase inhibitor cocktail
  • Example A Induction of YFP-SUMOl accumulation and SERCA2A
  • Example compounds The ability of the Example compounds to SUMOylate SERCA2a was examined using an in vitro system in HEK 293 cells where both SERCA2a and SUMO 1 are expressed.
  • the cellular permeability and potential activity of the Example compounds was examined by tracking of the YFP-SUMOl.
  • HEK-293 cells expressing YFP-SUMOl and pcDNA3.0-SERCA2a were treated with either 10 ⁇ DMSO or 10 ⁇ indicated Examples 1-3 for 24 hrs. Fluorescent signals were monitored by fluorescence
  • FIG. 1 scale bars, 10 ⁇ .
  • the SERCA2a SUMOylation profiling was then analyzed by using the same cells (FIG. 2, WCL, whole cell lysates; S-SERCA2a, SUMOylated SERCA2a).
  • Example B Effect of Examples 1-3 on intracellular calcium decay, cell contractility and SERCA2a SUMOylation in isolated adult cardiomyocytes
  • Table 1 illustrates some embodiments of the disclosure and their
  • the compounds shown were all soluble up to 10 mM and demonstrated no toxic behavior.
  • the examples showed activity on YFP accumulation, SERCA2a SUMOylation, and demonstrated better contractility on cardiac myocytes than controls.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des activateurs de la protéine SUMO, qui peuvent améliorer la sumoylation du gène SERCA2a, qui sont utiles dans le traitement de l'insuffisance cardiaque, des maladies cardio-vasculaires, du cancer, des troubles neurodégénératifs, des infections virales, des infections bactériennes, des maladies du foie, des inflammations et d'autres maladies.
PCT/US2013/057302 2012-08-29 2013-08-29 Dérivés d'indole en tant qu'activateurs de la protéine sumo WO2014036268A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201261694657P 2012-08-29 2012-08-29
US61/694,657 2012-08-29

Publications (2)

Publication Number Publication Date
WO2014036268A2 true WO2014036268A2 (fr) 2014-03-06
WO2014036268A3 WO2014036268A3 (fr) 2015-07-16

Family

ID=50184635

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2013/057302 WO2014036268A2 (fr) 2012-08-29 2013-08-29 Dérivés d'indole en tant qu'activateurs de la protéine sumo

Country Status (1)

Country Link
WO (1) WO2014036268A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITUA20161992A1 (it) * 2016-03-24 2017-09-24 Plico Biotech Inc Sumo e suoi utilizzi
WO2019058318A1 (fr) * 2017-09-22 2019-03-28 Plico Biotech Inc. Formulations pour l'administration de sumo2/3

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9904933D0 (en) * 1999-03-04 1999-04-28 Glaxo Group Ltd Compounds
GB0400895D0 (en) * 2004-01-15 2004-02-18 Smithkline Beecham Corp Chemical compounds
EP2300460A1 (fr) * 2008-05-28 2011-03-30 Wyeth LLC Composés de 1h-indole 3 substitués, leur utilisation en tant qu'inhibiteurs de 3mtor kinase et p13 kinase, et leurs synthèses

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITUA20161992A1 (it) * 2016-03-24 2017-09-24 Plico Biotech Inc Sumo e suoi utilizzi
WO2017163203A1 (fr) * 2016-03-24 2017-09-28 Plico Biotech Inc. Protéine sumo et ses utilisations
WO2019058318A1 (fr) * 2017-09-22 2019-03-28 Plico Biotech Inc. Formulations pour l'administration de sumo2/3

Also Published As

Publication number Publication date
WO2014036268A3 (fr) 2015-07-16

Similar Documents

Publication Publication Date Title
US10968221B2 (en) Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
ES2928714T3 (es) Compuestos para mejorar el empalme del ARNm
US10501453B2 (en) Benzothiazole or benzoxazole compounds as SUMO activators
CN113677346A (zh) 周期蛋白依赖性激酶7(cdk7)的抑制剂
CN107001378B (zh) 吡咯并嘧啶化合物
EP3983384B1 (fr) Dérivés de n-(phényl)-indole-3-sulfonamide et composés similares en tant que modulateurs du gpr17 pour le traitement de troubles du snc tels que sclérose en plaques
EP3473626B1 (fr) Cristal de pyrrolopyrimidine pour la préparation d'un inhibiteur jak
JP7128345B2 (ja) ジアリール大員環化合物、医薬組成物及びその用途
WO2012136111A1 (fr) Composé phénylproponiate, son procédé de préparation et ses applications médicales
WO2014059314A1 (fr) Traitement du cancer du cerveau à l'aide d'agélastatine a (aa) et d'analogues de celle-ci
WO2021033729A1 (fr) Sel et forme cristalline d'un composé ayant une activité agoniste vis-à-vis du récepteur s1p5
WO2021150695A1 (fr) Sulfonamides de tétrahydrobenzoazépines n-substituées contraintes utilisés en tant qu'agents anticancéreux et neuroprotecteurs
WO2021160012A1 (fr) Composé à petites molécules capable de dégrader de manière spécifique la protéine tau et son utilisation
WO2021129841A1 (fr) Composé utilisé comme inhibiteur de kinase ret et son application
WO2014036268A2 (fr) Dérivés d'indole en tant qu'activateurs de la protéine sumo
WO2021078227A1 (fr) Dérivé d'hétéroaryle fusionné, son procédé de préparation et son utilisation en médecine
JP2017516829A (ja) ピリドピリミジンジオン誘導体
WO2022237825A1 (fr) Dérivé d'azaaryle ayant une activité inhibitrice de l'egfr, son procédé de préparation et son utilisation
WO2021150697A1 (fr) Dérivés de 3-tricyclyl-pipéridines n-substituées utilisés en tant qu'agents anticancéreux et neuroprotecteurs
CN104203922A (zh) 螺乙内酰脲化合物及其作为选择性雄激素受体调节剂的用途
US20200270240A1 (en) Benzothiazole and pyridothiazole compounds as sumo activators
WO2023145873A1 (fr) Analogue de lysophosphatidylsérine, et composition pharmaceutique contenant un analogue de lysophosphatidylsérine pour le traitement ou la prévention de la fibrose
WO2021150700A1 (fr) Dérivés de 3-tricyclyl-pipéridines n-substituées utilisés en tant qu'agents anticancéreux et neuroprotecteurs
WO2024084364A1 (fr) Composés pour le traitement du cancer
WO2022161447A1 (fr) Composé dicarboxamide, son procédé de préparation et son utilisation pharmaceutique

Legal Events

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

Ref document number: 13832235

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13832235

Country of ref document: EP

Kind code of ref document: A2