WO2024015055A1 - Dérivés de pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk-1 et le traitement du cancer - Google Patents

Dérivés de pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk-1 et le traitement du cancer Download PDF

Info

Publication number
WO2024015055A1
WO2024015055A1 PCT/US2022/036956 US2022036956W WO2024015055A1 WO 2024015055 A1 WO2024015055 A1 WO 2024015055A1 US 2022036956 W US2022036956 W US 2022036956W WO 2024015055 A1 WO2024015055 A1 WO 2024015055A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
cancer
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/US2022/036956
Other languages
English (en)
Inventor
Martin Maguire
Marc Vidal
Maroua KHALIFA
Eric Campeau
Original Assignee
Thryv Therapeutics Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thryv Therapeutics Inc. filed Critical Thryv Therapeutics Inc.
Priority to PCT/US2022/036956 priority Critical patent/WO2024015055A1/fr
Priority to PCT/CA2023/050681 priority patent/WO2024011307A1/fr
Publication of WO2024015055A1 publication Critical patent/WO2024015055A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast

Definitions

  • the technical field relates to pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide derivatives and pharmaceutical compositions that inhibit SGK-1 , and more particularly relates to pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide derivatives and pharmaceutical compositions for the treatment of heart conditions treatable by SGK-1 inhibition such as Long QT syndrome, and for the treatment of cancer.
  • Serine/threonine-protein kinase (also known as serum/glucocorticoid-regulated kinase 1) is a protein kinase that plays a role in a cell's response to stress. SGK-1 activates certain potassium, sodium, and chloride channels. For instance, SGK-1 is known to regulate the myo-inositol transporter during osmotic stress.
  • SGK-1 inhibitor for the treatment of heart conditions such as LOTS, and/or for the treatment of cancer.
  • a compound of Formula VII: or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, is provided, wherein:
  • Y 1 is H or F; Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; W 1 is selected from the group consisting of H and halogen; and R 35 is H or methyl.
  • Figure 1 is a graph and a Dose-response matrix showing synergistic combination of Compound 79 with AKT inhibitor Ipatasertib
  • Figure 2 is a graph and a Dose-response matrix showing synergistic combination of Compound 79 with AKT inhibitor Capivasertib
  • Figure 3 is a graph and a Dose-response matrix showing synergistic combination of Compound 79 with AKT inhibitor MK-2206
  • Figure 4 is a Western blot showing inhibition of NDRG1 phosphorylation in PBMCs by Compound 79
  • Figure 5 is a series of Western blots showing inhibition of NDRG1 phosphorylation in ex- vivo treated blood by Compound 84
  • Figure 6 is a series of Western blots showing NDRG1 is a direct target of SGK1 phosphorylation.
  • the present description relates to compounds of Formula I, or pharmaceutically acceptable salts thereof.
  • the compounds of Formula I and their pharmaceutically acceptable salts are pharmacologically active compounds that modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase isoform 1 (SGK-1).
  • the compounds of Formula I or their pharmaceutically acceptable salts can be suitable for the treatment of conditions in which SGK-1 activity is inappropriate. Non-limiting examples of such conditions can include Long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, stent failure, cancer and epilepsy.
  • an alkyl group can have 1 to 20 carbon atoms (i.e, C 1 -C 20 alkyl), 1 to 8 carbon atoms (i.e., C 1 -C 8 alkyl), or 1 to 4 carbon atoms (i.e., C 1 -C 4 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1- propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, —CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH 3 )3), 1-pentyl (n-pentyl, —CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (—CH(CH(CH)CH
  • Alkoxy means a group having the formula —O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e., C 1 -C 12 alkoxy), or 1 to 4 carbon atoms (i.e., C 1 -C 4 alkoxy).
  • alkoxy groups include, but are not limited to, methoxy (—O—CH 3 or —OMe), ethoxy (—OCH 2 CH 3 or —OEt), t-butoxy (—O—C(CH 3 ) 3 or -OtBu), and the like.
  • “Haloalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom.
  • the alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C 1 -C 12 haloalkyl), or 1 to 4 carbon atoms (i.e., C 1 -C 4 haloalkyl).
  • suitable haloalkyl groups include, but are not limited to, —CF 3 , —CHF 2 , —CFH 2 , —CH 2 CF 3 , and the like.
  • Cycloalkyl means a mono or bicyclic carbocyclic ring functional group including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl.
  • the cycloalkyl can have 3 to 12 carbon atoms (i.e., C 3 -C 12 cycloalkyl), 3 to 7 carbon atoms (i.e., C 3 -C 7 cycloalkyl) or 3 to 6 carbon atoms (i.e., C 3 -C 6 cycloalkyl).
  • the term “(C 3 -C 7 )cycloalkyl” refers to a cycloalkyl group containing from 3 to 8 carbons.
  • (C 3 -C 7 )cycloalkyl encompasses a monocyclic cycloalkyl group containing from 3 to 7 carbons and a bicyclic cycloalkyl group containing from 6 to 7 carbons.
  • Alkenyl is a hydrocarbon containing primary, secondary or tertiary carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond.
  • an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkenyl), 2 to 12 carbon atoms (i.e., C 2 -C 12 alkenyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl).
  • suitable alkenyl groups include, but are not limited to, ethylene, vinyl (—CH ⁇ CH 2 ), allyl (— CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C5H7), and 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ).
  • Alkynyl is a hydrocarbon containing primary, secondary or tertiary carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.
  • an alkynyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkynyl), 2 to 12 carbon atoms (i.e., C 2 - C 12 alkynyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic (—C ⁇ CH), propargyl (—CH 2 C ⁇ CH), and the like.
  • Alkylene refers to a saturated, branched or straight hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • alkylene radicals include, but are not limited to, methylene (—CH 2 —), 1,1-ethylene (—CH(CH 3 )—), 1,2-ethylene (—CH 2 CH 2 —), 1,1-propylene (—CH(CH 2 CH 3 )—), 1,2- propylene (—CH 2 CH(CH 3 )—), 1,3-propylene (—CH 2 CH 2 CH 2 —), 1,4-butylene (—CH 2 CH 2 CH 2 CH 2 —), and the like.
  • Alkenylene refers to an unsaturated, branched or straight hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (—CH ⁇ CH—).
  • Alkynylene refers to an unsaturated, branched or straight hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • alkynylene radicals include, but are not limited to, acetylene (—C ⁇ C—), propargyl (— CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ C—).
  • Aryl means a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • “Arylene” refers to an aryl as defined above having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent aryl.
  • Typical arylene radicals include, but are not limited to, phenylene, such as 1,4- phenylene.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group can comprise 6 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • “Arylalkenyl” refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also an sp2 carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein.
  • the arylalkenyl group can comprise 6 to 20 carbon atoms, e.g., the alkenyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • “Arylalkynyl” refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also an sp carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein.
  • the arylalkynyl group can comprise 6 to 20 carbon atoms, e.g., the alkynyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • the “halogen” refers to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group, as defined herein, that is substituted with at least one halogen.
  • haloalkyl groups examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n- butyl, and t-butyl substituted independently with one or more halogens, for example, fluoro, chloro, bromo, and iodo.
  • haloalkyl should be interpreted to include such substituents as perfluoroalkyl groups such as —CF 3 .
  • substituted in reference to alkyl, aryl, arylalkyl, carbocyclyl, heterocyclyl, and other groups used herein, for example, “substituted alkyl”, “substituted cycloalkyl”, “substituted aryl”, “substituted arylalkyl”, “substituted heterocyclyl”, and “substituted carbocyclyl” means a group, alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Typical substituents include, but are not limited to, —X, —R, —O—, ⁇ O, —OR, —SR, —S—, —NR 2 , —N(+)R 3 , ⁇ NR, —CX 3 , —CRX 2 , —CR 2 X, —CN, —OCN, —SCN, —N ⁇ C ⁇ O, —NCS, —NO, —NO 2 , ⁇ N 2 , —N 3 , —NRC( ⁇ O)R, —NRC( ⁇ O)OR, —NRC( ⁇ O)NRR, —C( ⁇ O)NRR, —C( ⁇ O)NRR, —C( ⁇ O)OR, —OC( ⁇ O)NRR, —OC( ⁇ O)OR, —C( ⁇ O)R, —S( ⁇ O) 2 OR, —S( ⁇ O) 2 R, —OS( ⁇ O) 2 OR, —S
  • Divalent groups may also be similarly substituted.
  • moieties such as “alkyl”, “aryl”, “heterocyclyl”, etc. when substituted with one or more substituents, they could alternatively be referred to as “alkylene”, “arylene”, “heterocyclylene”, etc. moieties (i.e., indicating that at least one of the hydrogen atoms of the parent “alkyl”, “aryl”, “heterocyclyl” moieties has been replaced with the indicated substituent(s)).
  • alkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH 3 , etc.), an amine (e.g., —NHCH 3 , —N(CH 3 ) 2 , and the like), or a thioalkyl group (e.g., —SCH 3 ).
  • a heteroatom e.g., O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH 3 , etc.), an amine (e.g., —NHCH 3 , —N(CH 3 ) 2 , and the like), or a thioalkyl group (e.g., —SCH 3 ).
  • heteroalkyl groups are, respectively, an alkyl ether (e.g., —CH 2 CH 2 —O—CH 3 , etc.), an alkyl amine (e.g., — CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , and the like), or a thioalkyl ether (e.g., —CH 2 —S—CH 3 ).
  • an alkyl ether e.g., —CH 2 CH 2 —O—CH 3 , etc.
  • alkyl amine e.g., — CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , and the like
  • thioalkyl ether e.g., —CH 2 —S—CH 3
  • the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., —CH 2 CH 2 — OH), an aminoalkyl group (e.g., —CH 2 NH 2 ), or an alkyl thiol group (e.g., —CH 2 CH 2 —SH).
  • a heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • a C 1 -C 6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.
  • Heterocycle or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
  • heterocycle includes a “carbocycle” as defined herein, wherein one or more (e.g.1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, P or S).
  • heteroatom e.g. O, N, P or S.
  • heterocycle or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings).
  • Heterocycles includes aromatic and non- aromatic mono-, bi-, and poly-cyclic rings, whether fused, bridged, or spiro.
  • heterocycle encompasses, but is not limited to “heteroaryl.”
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, azetidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofur
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4- thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3- pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Heterocyclylene refers to a heterocyclyl, as defined herein, derived by replacing a hydrogen atom from a carbon atom or heteroatom of a heterocyclyl, with an open valence.
  • heteroarylene refers to an aromatic heterocyclylene.
  • Heterocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety).
  • Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CH 2 —, 2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry.
  • heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon- heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkyl group comprises 2 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises 1 to 14 carbon atoms.
  • heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and the like, 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, and the like.
  • heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and the like
  • 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridin
  • Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also a sp2 carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkenylene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkenyl group comprises 2 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group comprises 1 to 6 carbon atoms and the heterocyclyl moiety comprises 1 to 14 carbon atoms.
  • “Heteroaryl” refers to a monovalent aromatic heterocyclyl having at least one heteroatom in the ring.
  • Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
  • suitable heteroaryl rings include all of those listed in the definition of “heterocyclyl”, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, and the like.
  • Carbocycle or “carbocyclyl” refers to a saturated, partially unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo (4,5), (5,5), (5,6) or (6,6) system, or 9 or 10 ring atoms arranged as a bicyclo (5,6) or (6,6) system.
  • Carbocycles includes aromatic and non-aromatic mono-, bi-, and poly-cyclic rings, whether fused, bridged, or spiro.
  • monocyclic carbocycles include the cycloalkyls group such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl or aryl groups such as phenyl, and the like.
  • Carbocycle encompasses but is not limited to “aryl”, “phenyl” and “biphenyl.”
  • Carbocyclylene refers to a carbocyclyl or carbocycle as defined above having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent carbocyclyl. Typical carbocyclylene radicals include, but are not limited to, phenylene.
  • Carbocyclylene encompasses but is not limited to “arylene.”
  • Carbocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a carbocyclyl radical as defined above.
  • Typical carbocyclylalkyl groups include, but are not limited to the arylalkyl groups such as benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2- naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl or the cycloalkylalkyl groups such as cyclopropylmethyl, cyclobutylethyl, cyclohexylmethyl and the like.
  • the arylalkyl group can comprise 6 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • the cycloalkylalkyl group can comprise 4 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the cycloalkyl group is 3 to 14 carbon atoms.
  • “Arylheteroalkyl” refers to a heteroalkyl as defined herein, in which a hydrogen atom, which may be attached either to a carbon atom or a heteroatom, has been replaced with an aryl group as defined herein.
  • the aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety.
  • an arylheteroalkyl group can have the general formulae -alkylene-O-aryl, -alkylene-O-alkylene-aryl, - alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, and the like.
  • any of the alkylene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.
  • “Heteroarylalkyl” refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein.
  • heteroaryl alkyl examples include —CH 2 -pyridinyl, —CH 2 -pyrrolyl, —CH 2 -oxazolyl, —CH 2 -indolyl, — CH 2 -isoindolyl, —CH 2 -purinyl, —CH 2 -furanyl, —CH 2 -thienyl, —CH 2 -benzofuranyl, —CH 2 - benzothiophenyl, —CH 2 -carbazolyl, —CH 2 -imidazolyl, —CH 2 -thiazolyl, —CH 2 -isoxazolyl, —CH 2 -pyrazolyl, —CH 2 -isothiazolyl, —CH 2 -quinolyl, —CH 2 -isoquinolyl, —CH 2 -pyridazyl, —CH 2 -pyrimidyl, —CH 2 -pyrimi
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
  • substituents and other moieties of the compounds of the present description should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition.
  • Some compounds of the present description and their pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs.
  • crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • the crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism).
  • crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures.
  • the pseudopolymorphs of some of the compounds of the present description may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). It is understood that all polymorphs and pseudopolymorphs of the compounds described herein and their pharmaceutically acceptable salts are included within the scope of the present description.
  • an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less. Additives, including solvents, may be used to create amorphous forms the compounds of the present description.
  • Certain of the compounds described herein contain one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present description includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the present description are the individual isomers of the compounds described herein, as well as any wholly or partially equilibrated mixtures thereof.
  • the compounds of the present description and their pharmaceutically acceptable salts also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • the compounds of the present description may exist in solvated, for example hydrated, as well as unsolvated forms.
  • the salts of the compounds of the present description are pharmaceutically acceptable salts. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of the present description.
  • Suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N′-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt.
  • inorganic acid addition salts such as chlor
  • the salts may be in some cases hydrates or ethanol solvates.
  • the definitions and substituents for various genus and subgenus of the present compounds are described and illustrated herein. It should be understood by one skilled in the art that any combination of the definitions and substituents described above should not result in an inoperable species or compound. “Inoperable species or compounds” means compound structures that violates relevant scientific principles (such as, for example, a carbon atom connecting to more than four covalent bonds) or compounds too unstable to permit isolation and formulation into pharmaceutically acceptable dosage forms.
  • Pharmaceutical compositions The compounds of the present description can be formulated with conventional carriers and excipients, which will be selected in accordance with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986), herein incorporated by reference in its entirety. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11 but is ordinarily about 7 to 10. While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations.
  • the formulations of the invention both for veterinary and for human use, comprise at least one active ingredient, together with one or more acceptable carriers and optionally other therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), herein incorporated by reference in its entirety. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient.
  • compositions according to the present description include one or more compounds together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, microcrystalline cellulose, starch,
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth herein, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally- occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • the amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • compositions comprising one or more compounds of the present description formulated for sustained or controlled release.
  • the effective dose of an active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active disease or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
  • the effective dose can be expected to be from about 0.0001 to about 10 mg/kg body weight per day, typically from about 0.001 to about 1 mg/kg body weight per day, more typically from about 0.01 to about 1 mg/kg body weight per day, even more typically from about 0.05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from about 0.05 mg to about 100 mg, or between about 0.1 mg and about 25 mg, or between about 0.4 mg and about 4 mg, and may take the form of single or multiple doses.
  • the present description relates to compounds or pharmaceutically acceptable salts thereof, for the treatment various conditions treatable by inhibiting SGK-1.
  • the condition can be Long QT syndrome (LQTS), such as genetic LQTS or acquired LQTS, or other cardiovascular diseases (e.g., dilated cardiomyopathy - genetic or acquired) that are treatable by inhibiting SGK-1.
  • LQTS Long QT syndrome
  • cardiovascular diseases e.g., dilated cardiomyopathy - genetic or acquired
  • SGK- 1 inhibition in vivo has a protective effect and can alleviate symptoms associated with LQTS; can reduce and alleviate symptoms associated with heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, genetic or acquired dilated cardiomyopathy, hypertrophic cardiomyopathy, and stent failure.
  • Long QT syndrome can be genetic (e.g. caused by a mutation in the KCNQ1 gene, the KCNH2 gene, or the SCN5a gene).
  • Long QT syndrome is not associated with a genetic mutation and is acquired as a result of exposure to an external stimulus.
  • acquired Long QT syndrome can be a side effect of drugs such as erythromycin or haloperidol.
  • Acquired Long QT syndrome is also associated with other heart conditions such as myocardial ischemia.
  • the present description also relates to compounds or pharmaceutically acceptable salts thereof, for the treatment of other conditions related to SGK-1 mediated mechanisms, such as cancer, Parkinson’s disease and Lafora disease.
  • the present description provides compounds or pharmaceutically acceptable salts thereof for treating cancer or another proliferative disorder.
  • the terms “inhibition of cancer”, “inhibition of cancer cell proliferation”, and “inhibition of cancer invasion and metastasis” refer to the inhibition, or decrease in the rate, of the growth, division, maturation, viability, or ability to invade and colonize other organs and tissues of cancer cells, and/or causing the death of cancer cells, individually or in aggregate with other cancer cells, by cytotoxicity, nutrient depletion, induction of differentiation or apoptosis, or recognition by the immune system in order to elicit an immune response to the cancer cells.
  • tissues containing cancerous cells whose proliferation can be inhibited by a compound, salt or composition thereof described herein and against which the methods described herein are useful include but are not limited to breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, bone, and stomach.
  • the cancer treated by a provided compound, salt or composition thereof is a melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer or colorectal cancer.
  • the cancer treated by a provided compound, salt or composition thereof is prostate cancer, colorectal cancer or breast cancer (e.g., resistant breast cancer).
  • the compounds of the present description can be used to treat cancer by inhibiting signaling of the AKT/PI3K/mTOR pathway in patients whose tumors have activation of this pathway through mutations in PIK3CA, AKT1, and/or PTEN for example.
  • the compounds of the present description can be used in combination with compounds that inhibit AKT/PI3K/mTOR signaling to treat cancer in patients whose tumors have activation of this pathway through mutations in PIK3CA, AKT1, and/or PTEN for example.
  • Non-limiting examples of AKT/PI3K/mTOR inhibitors include NVP-BEZ235 (BEZ235, Dactolisib), GDC-0084 (RG7666), GDC-0980 (Apitolisib, RG7422), LY3023414, PF-05212384 (Gedatolisib, PKI-587), PQR309 (Bimiralisib), P7170, SF-1126, Copanlisib (BAY 80–6946), Buparlisib (BKM120 NVP-BKM120), IPI-145 (Duvelisib), RP6530 (Tenalisib), GDC-0032 (Taselisib), KA2237, BYL719 (Alpelisib), CAL- 101 (GS-1101, Idelalisib), GSK2636771, INCB050465 (Parsaclisib), Serabelisib (INK- 1117,MLN-1117,
  • the compounds of the present description can be used to treat inflammatory and fibrotic diseases that can include fatty liver diseases, endometriosis, types 1 or 2 diabetes mellitus, inflammatory bowel disease, asthma, rheumatoid arthritis, obesity, systemic sclerosis, sclerodermatous graft vs. host disease, nephrogenic systemic fibrosis, as well as organ-specific fibrosis, including radiation-induced fibrosis, and auto- immune diseases.
  • inflammatory and fibrotic diseases can include fatty liver diseases, endometriosis, types 1 or 2 diabetes mellitus, inflammatory bowel disease, asthma, rheumatoid arthritis, obesity, systemic sclerosis, sclerodermatous graft vs. host disease, nephrogenic systemic fibrosis, as well as organ-specific fibrosis, including radiation-induced fibrosis, and auto- immune diseases.
  • Serine/threonine-protein kinase (also known as serum/glucocorticoid-regulated kinase 1) is a protein kinase that plays a role in a cell's response to stress. In vivo, SGK- 1 activates certain potassium, sodium, and chloride channels. For instance, the protein is known to regulate the myo-inositol transporter during osmotic stress.
  • HbF fetal hemoglobin
  • the compounds of the present description can be used for the treatment of a ⁇ -hemoglobinopathy. In some embodiments, the compounds of the present description can be used for the treatment of sickle cell disease. In some embodiments, the compounds of the present description can be used for the treatment of prostate cancer. In other embodiments, the compounds of the present description can be used for the treatment of epilepsy.
  • Inhibitors of SGK-1 The compounds of the present description and their pharmaceutically acceptable salts thereof are pharmacologically active compounds that modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase isoform 1 (SGK-1).
  • the compounds of the present description or their pharmaceutically acceptable salts can be suitable for the treatment of conditions in which SGK-1 activity is inappropriate.
  • Non- limiting examples of such conditions can include Long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, stent failure, prostate cancer and epilepsy.
  • Other non- limiting examples of such conditions include ⁇ -hemoglobinopathies, such as sickle cell disease.
  • compounds of Formula I, or pharmaceutically acceptable salts thereof are provided.
  • Z is selected from the group consisting of a direct bond, -O-, -S-, - CH(R 9 )- and -N(R 10 )-, wherein R 9 and R 10 are independently of one another selected from the group consisting of H and (C 1 -C 4 )-alkyl.
  • Z is selected from the group consisting of a direct bond, -O-, -S-, -CH 2 - and -NH-.
  • Z is a direct bond.
  • Z is selected from the group consisting of -O- and - NH-.
  • R 3 is selected from the group consisting of H, (C 1 -C 8 )-alkyl, R 30 and (C 1 -C 4 )-alkyl-R 30 , wherein (C 1 -C 8 )-alkyl is unsubstituted or substituted by one or more identical or different substituents R 31 .
  • R 30 is a 3-membered to 12-membered, monocyclic or bicyclic, saturated, partially unsaturated or aromatic, cyclic group which comprises 0, 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by one or more identical or different substituents R 32 .
  • R 31 is selected from the group consisting of halogen, -OH, -CF 3 , -O-(C 1 -C 4 )-alkyl, -N(R 33 )-R 34 and -CN.
  • R 33 and R 34 are independently of one another selected from the group consisting of H, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl, wherein (C 1 -C 4 )-alkyl and (C 3 - C 7 )-cycloalkyl are unsubstituted or substituted by one or more identical or different substituents R 50 , wherein R 50 is selected from the group consisting of halogen, -OH, -O- (C 1 -C 4 )-alkyl, -CF 3 and -CN.
  • R 37 , R 38 , R 39 , R 40 , R 41 , R 42 and R 43 are independently of one another selected from the group consisting of H and (C 1 -C 4 )-alkyl.
  • R 3 is selected from the group consisting of H, -CH 2 OH,
  • Z is a direct bond and R 3 is selected from the group consisting of H, -CH 2 OH and -CH 3 .
  • Z is selected from the group consisting of - O- and -NH- and R 3 is selected from the group consisting of:
  • R 1 is selected from the group consisting of H, -N(R 11 )R 12 , -N(R 13 )- C(O)-R 14 , -NR 13 -S(O) 2 -R 15 , -NR 13 -C(O)-NH-R 16 , -(C 1 -C 4 )-alkyl, –(C 1 -C 4 )-alkyl-OR 17 and – (C 1 -C 4 )-alkyl-N(R 18 )R 19 , wherein R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are independently of one another selected from the group consisting of H and (C 1 -C 4 )-alkyl.
  • R 1 is selected from the group consisting of -(C 1 -C 4 )-alkyl, and – (C 1 -C 4 )-alkyl-N(R 18 )R 19 . In some embodiments, R 1 is selected from the group consisting of -CH 3 , -CH 2 N(CH 3 ) 2 and -CH 2 -CH 2 -N(CH 3 ) 2 .
  • Y is selected from the group consisting of carbocyclylene and heterocyclylene, which is unsubstituted or substituted by one or more identical or different substituents R 5 , wherein R 5 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, -O-( C 1 -C 4 )-alkyl and -CN.
  • R 5 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, -O-( C 1 -C 4 )-alkyl and -CN.
  • Y is selected from the group consisting of arylene and heteroarylene, which is unsubstituted or substituted by one or more identical or different substituents R 5 .
  • Y is selected from the group consisting of: It is understood that when two symmetrical Y groups are listed, such as and , , it is meant that both options: or are included.
  • A is selected from the group of a direct bond or -CH 2 -. When A is a direct bond, -Y- is directly linked to the nitrogen of the sulfonamide group.
  • R 2 is selected from the group consisting of (C 1 -C 4 )-alkyl, (C 3 -C 7 )- cycloalkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, phenyl and a 5-membered or 6-membered monocyclic, saturated, partially unsaturated or aromatic, heterocyclic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom or a ring nitrogen atom, wherein R 2 is unsubstituted or substituted by one or more identical or different substituents R 20 , wherein R 20 is selected from the group consisting of halogen, -CF 3 , (C 1 -C 4 )-alkyl, -OR 21 , -N(R 22 )R 23 , (C 1 -C 4 )-alkyl-OR 24
  • R 2 is selected from the group consisting of (C 1 -C 4 )-alkyl, (C 3 - C 7 )-cycloalkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl, phenyl and a 5-membered or 6-membered monocyclic, saturated, partially unsaturated or aromatic, heterocyclic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom or a ring nitrogen atom, wherein R 2 is unsubstituted or substituted by one or more identical or different substituents R 20 , wherein R 20 is selected from the group consisting of halogen,
  • R 1 is H, -N(R 11 )R 12 , -N(R 13 )-C(O)-R 14 , -NR 13 -S(O) 2 -R 15 , -NR 13 -C(O)-NH-R 16 , -(C 1 -C 4 )-alkyl or –(C 1 -C 4 )-alkyl-OR 17
  • R 2 is selected from the group consisting of (C 1 -C 4 )-alkyl, (C 3 -C 7 )- cycloalkyl, (C 2 -C 4 )-alkenyl, (C 2 -C 4 )-alkynyl and a 5-membered or 6-membered monocyclic, saturated or partially unsaturated, heterocyclic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring
  • R 2 is selected from the group consisting of: , In some embodiments, Y is 1,4-phenylene and R 2 is selected from the group consisting of: -CH 3 , In some embodiments, the compound of Formula I is selected from the group consisting of:
  • the compound of Formula I is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • compounds of Formula II, or pharmaceutically acceptable salts thereof are provided: wherein: Z is selected from the group consisting of O, CH 2 , S and NH; R 1 is selected from the group consisting of H, and -(C 1 -C 4 )-alkyl; R 3 is selected from the group consisting of -(CH 2 ) p -N(R 33 )R 34 ; p is 1, 2, 3 or 4; R 2 is selected from the group consisting of a 5-membered or 6-membered monocyclic, aromatic or heteroaromatic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein R 2 is unsubstituted or substituted by one or more identical or different substituents R 20 ; R 20 is selected from the group consisting of halogen, -CF
  • Z is NH. In other embodiments, Z is O. In some embodiments, R 1 is methyl. In some embodiments, p is 2, 3 or 4. In some embodiments, R 2 is selected from the group consisting of: In some embodiments, R 33 is methyl. In some embodiments, R 34 is methyl. In some embodiments, R 3 is selected from the group consisting of: In some embodiments, the compound of Formula II is selected from the group consisting of:
  • Z is selected from the group consisting of a direct bond, O, S, CH(R 9 ) and N(R 10 );
  • R 1 is selected from the group consisting of H, -N(R 11 )R 12 , -N(R 13 )-C(O)-R 14 , -NR 13 -S(O) 2 -R 15 , -NR 13 -C(O)-NH-R 16 , -(C 1 -C 4 )-alkyl, –(C 1 -C 4 )-alkyl-OR 17 and –(C 1 -C 4 )-alkyl-N(R 18 )R 19 ;
  • R 3 is selected from the group consisting of H, (C 1 -C 8 )-alkyl, R 30 and (C 1 -C 4 )-alkyl- R 30 , wherein (C 1 -C
  • R 1 is selected from the group consisting of -(C 1 -C 4 )-alkyl, and – (C 1 -C 4 )-alkyl-N(R 18 )R 19 .
  • R 1 is selected from the group consisting of -CH 3 , -CH 2 N(CH 3 ) 2 and -CH 2 -CH 2 -N(CH 3 ) 2 .
  • Z is selected from the group consisting of -O- and -NH-.
  • R 3 is selected from the group consisting of: In some embodiments, Z is a direct bond.
  • R 3 is selected from the group consisting of H, -CH 2 OH and -CH 3 .
  • R 2 is selected from the group consisting of:
  • the compound of Formula II is selected from the group consisting of:
  • a compound of Formula III is provided: or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of O, CH 2 , S and NH; R 1 is selected from the group consisting of H, and -(C 1 -C 4 )-alkyl; R 3 is selected from the group consisting of –(CH 2 ) p -N(R 33 )R 34 , wherein zero, one or two hydrogen atoms of the group –(CH 2 ) p - are independently replaced with F; p is 1, 2, 3 or 4; R 2 is selected from the group consisting of a 5-membered or 6-membered monocyclic, aromatic or heteroaromatic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein R 2 is unsubstituted or substituted by one or more identical or different substituents R 20 ; R 20 is selected from the group consisting of halogen
  • Z is NH. In other embodiments, Z is O. In some embodiments, R 1 is methyl. In some embodiments, p is 2, 3 or 4. In some embodiments, R 2 is wherein Z 1 and Z 2 are independently from one another selected from the group consisting of Cl, F, -OMe and - CN, and Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN.
  • W 1 is F or Cl
  • W 2 is H
  • W 3 is H and W 4 is H.
  • W 1 is F
  • W 2 is H
  • W 3 is H and W 4 is H.
  • W 1 is Cl
  • W 2 is H
  • W 3 is H and W 4 is H.
  • a compound of Formula III is provided: or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of O and NH; R 1 is selected from the group consisting of H and (C 1 -C 4 )-alkyl; R 3 is selected from the group consisting of –(CH 2 ) p -N(R 33 )R 34 ; p is 2, 3 or 4; R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN; R 33 and R 34 are independently of one another a (C 1 -C 4 )-
  • R 1 is methyl.
  • R 3 is selected from the group consisting of: and In some embodiments, R 3 is In some embodiments, R 2 is selected from the group consisting of: In some embodiments, R 2 is In some embodiments, W 1 , W 2 , W 3 and W 4 are each H; W 1 is F, W 2 , W 3 and W 4 are each H; or W 1 and W 2 are each F, W 3 and W 4 are each H. In some embodiments, W 1 is F, W 2 , W 3 and W 4 are each H. In some embodiments, Z is NH. In some embodiments, there is provided a compound selected from the group consisting of: , or a pharmaceutically acceptable sale thereof.
  • a compound of Formula III is provided: or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of O, and NH; R 1 is selected from the group consisting of H, and -(C 1 -C 4 )-alkyl; R 3 is a nitrogen-bearing heterocycle selected from the group consisting of , wherein zero, one or two hydrogens on the -CH 2 - groups of the nitrogen-bearing heterocycle is replaced with halogen, -OH, -CN, -CF3 or (C 1 -C 4 )-alkyl; R 35 is H or (C 1 -C 4 )-alkyl which is unsubstituted or substituted by one or more identical or different substituents R 50 ; and R 50 is selected from the group consisting of halogen, -OH, -O-(C 1 -C 4 )- alkyl, CF 3 , and -CN; R 2 is Z 1 and Z 2 are independently from one another
  • Z is O.
  • R 2 is selected from the group consisting of In some embodiments, R 2 is selected from the group consisting of: , In some embodiments, R 1 is methyl. In some embodiments, R 3 is In some embodiments, R 35 is methyl or isopropyl. In some embodiments, W 2 is H.
  • a compound of Formula III is provided: or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of O, and NH; R 1 is selected from the group consisting of H, and -(C 1 -C 4 )-alkyl; R 3 is a nitrogen-bearing heterocycle selected from the group consisting of , wherein zero, one or two hydrogens on any of the -CH 2 - groups of the nitrogen-bearing heterocycle is replaced with halogen, -OH, -CN, -CF3 or (C 1 -C 4 )-alkyl; R 35 is H or (C 1 -C 4 )-alkyl which is unsubstituted or substituted by one or more identical or different substituents R 50 ; and R 50 is selected from the group consisting of halogen, -OH, -O-(C 1 -C 4 )- alkyl, CF 3 , and -CN; R 2 is Z 1 and Z 2 are independently from
  • R 2 is is selected from the group consisting of: , , , , , In some embodiments, R 2 is: In some embodiments, there is provided a compound selected from the group consisting of: , or a pharmaceutically acceptable sale thereof.
  • a compound of Formula III is provided: or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of O, and NH; R 1 is selected from the group consisting of H, and -(C 1 -C 4 )-alkyl; R 3 is a nitrogen-bearing heterocycle selected from the group consisting of and , wherein zero, one or two hydrogens on any of the -CH 2 - groups of the nitrogen-bearing heterocycle is replaced with halogen, -OH, -CN, -CF3 or (C 1 -C 4 )-alkyl; R 35 is H or (C 1 -C 4 )-alkyl which is unsubstituted or substituted by one or more identical or different substituents R 50 ; and R 50 is selected from the group consisting of halogen, -OH, -O-(C 1 -C 4 )- alkyl, CF 3 , and -CN; R 2 is Z 1 and Z 2 are independently
  • Z is O.
  • R 1 is methyl.
  • R 3 is In some embodiments, R 35 is methyl or isopropyl.
  • W 1 is H, F, Cl or OMe; W 2 is H or F; W 3 is H; and W 4 is H.
  • W 1 is F, W 2 is H, W 3 is H and W 4 is H.
  • W 1 is Cl, W 2 is H, W 3 is H and W 4 is H.
  • R 2 is selected from the group consisting of: , , , , , , , in some embodiments, R 2 is In some embodiments, there is provided a compound selected from the group consisting of: or a pharmaceutically acceptable sale thereof. In yet another aspect, a compound of Formula IV is provided:
  • Z is selected from the group consisting of O and NH;
  • R 3 is selected from the group consisting of: –(CH 2 ) p -N(R 33 )R 34 , , p is 2, 3 or 4;
  • R 33 and R 34 are independently from one another a (C 1 -C 4 )-alkyl which is unsubstituted or substituted by one or more identical or different substituents R 50 ;
  • R 35 is H or a (C 1 -C 4 )-alkyl which is unsubstituted or substituted by one or more identical or different substituents R 50 ;
  • R 50 is selected from the group consisting of halogen, -OR 27 , -O-(C 1 -C 4 )-alkyl, -CF 3 , and -CN;
  • R 35 is methyl or isopropyl. In some embodiments, R 3 is . In some embodiments, R 35 is H. In some embodiments, Z-R 3 is selected from the group consisting of , In some embodiments, Z-R 3 is selected from the group consisting of and . In some embodiments, Z-R 3 is selected from the group consisting of In some embodiments, Z-R 3 is In some embodiments, W 1 is F. In other embodiments, W 1 is Cl. In some embodiments, R 2 is . Z 1 and Z 2 can be independently from one another selected from the group consisting of Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe.
  • R 2 is o In some embodiments, R 2 is In some embodiments, R 2 is .
  • Z 3 can be selected from the group consisting of H, Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe, or from the group consisting of H, -CH 3 , -CF 3 , -OCH(CH 3 ) 2 and -OMe, or from the group consisting of -CH 3 , -OCH(CH 3 ) 2 and - OMe.
  • the compound of Formula IV is a compound of Formula IVa: , or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of: , , , , ; W 1 is selected from the group consisting of Cl and F; and R 27 is selected from the group consisting of: H, , , , ,
  • the compound of Formula IV is a compound of Formula IVb: or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of: and W 1 is selected from the group consisting of Cl and F.
  • the compound of Formula IV is a compound of Formula IVc:
  • the compound of Formula IV is a compound of Formula IVd: , or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of: and W 1 is selected from the group consisting of Cl and F.
  • the compound of Formula IV is selected from the group consisting of Compounds 28, 38, 78, 79, 84, 85, 99, 100, 101, 102, 103,104, 105, 107, 106, 108, 109, 110, 111, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 155, 156, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173 and 174, as numbered in Table A hereinbelow, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula IV is provided: or a pharmaceutically acceptable salt thereof, wherein: Z-R 3 is selected from the group consisting of: , and R 27 is selected from the group consisting of: H, R 2 is selected from the group consisting of and W 1 is selected from the group consisting of Cl and F. In some embodiments, W 1 is Cl. In other embodiments, W 1 is F. In some embodiments, R 2 is In some embodiments, R 27 is H.
  • W 1 is F. In some embodiments, W 1 is Cl.. In some embodiments, R 2 is . Z 1 and Z 2 can be independently from one another selected from the group consisting of Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe.
  • R 2 is o In some embodiments, R 2 is In some embodiments, R 2 is .Z 3 can be selected from the group consisting of H, Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe, or from the group consisting of H, -CH 3 , - CF 3 , -OCH(CH 3 ) 2 and -OMe, or from the group consisting of -CH 3 , -OCH(CH 3 ) 2 and - OMe.
  • the compound of Formula V is a compound of Formula Va: , or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of: W 1 is selected from the group consisting of H, Cl and F; and R 27 is selected from the group consisting of: H, In some embodiments, the compound of Formula V is a compound of Formula Vb: or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of: , , , and W 1 is selected from the group consisting of H, Cl and F.
  • the compound of Formula V is selected from the group consisting of Compounds 9, 20, 22, 24, 27, 30, 38, 45, 72, 73, 78, 84, 85, 99, 100, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 150, 151, 152 and 153, as numbered in Table A hereinbelow, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula Vb is provided: or a pharmaceutically acceptable salt thereof, wherein: R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN; and W 1 is selected from the group consisting of H and halogen. In some embodiments, W 1 is F. In other embodiments, W 1 is Cl.
  • R 2 is .
  • Z 1 and Z 2 can be independently from one another selected from the group consisting of Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe.
  • R 2 is In some embodiments, R 2 is .
  • Z 3 can be selected from the group consisting of H, Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe, or from the group consisting of H, -CH 3 , - CF 3 , -OCH(CH 3 ) 2 and -OMe, or from the group consisting of -CH 3 , -OCH(CH 3 ) 2 and - OMe.
  • the compound of Formula Vb is selected from the group consisting of Compounds 9, 38, 45, 84, 85 and 111, as numbered in Table A hereinbelow, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula Vb is selected from the group consisting of Compounds 24, 27, 30, 73, 100, 103, 104, 105, 106, 107, 108, 109, 110, 113 and 112, as numbered in Table A hereinbelow, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula VI or a pharmaceutically acceptable salt thereof, wherein: Y 1 is H or F; q is 0 or 1; R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN; W 1 is selected from the group consisting of H and halogen; R 35 is H or a (C 1 -C 4 )-alkyl which is unsubstituted or substituted by one or more identical or different substituents R 50 ; R 50 is selected from the group consisting of halogen, -OR 27 , -O-
  • Y 1 is H.
  • the compound of Formula VI is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • the compound of Formula VI is a compound of Formula VIa: or a pharmaceutically acceptable salt thereof.
  • q 1.
  • W 1 is F.
  • W 1 is Cl.
  • R 2 is .
  • Z 1 and Z 2 can be independently from one another selected from the group consisting of Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe.
  • R 2 is In some embodiments, R 2 is .
  • Z 3 can be selected from the group consisting of H, Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe, or from the group consisting of H, -CH 3 , - CF 3 , -OCH(CH 3 ) 2 and -OMe, or from the group consisting of -CH 3 , -OCH(CH 3 ) 2 and - OMe.
  • R 35 is H or a (C 1 -C 4 )-alkyl a (C 1 -C 4 )-alkyl which is unsubstituted. In some embodiments, R 35 is H.
  • the compound of Formula VI is a compound of Formula VIa: , or a pharmaceutically acceptable salt thereof, wherein: R 2 is selected from the group consisting of: and W 1 is selected from the group consisting of H, Cl and F.
  • the compound of Formula VI is selected from the group consisting of Compounds 29, 41, 42, 44, 46, 47, 49, 50, 53, 54, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 69, 70, 71, 92, 155 and 156, as numbered in Table A hereinbelow, or a pharmaceutically acceptable salt thereof.
  • the compound of Formula VI is preferably not a compound of Formula VIa in racemic form: or a pharmaceutically acceptable salt thereof, wherein: Y 2 is H or F; and R 52 is selected from the group consisting of:
  • a compound of Formula Vb or a pharmaceutically acceptable salt thereof, wherein: R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN; and W 1 is selected from the group consisting of H and halogen. 2. The compound of embodiment 1, wherein W 1 is F. 3.
  • a compound of Formula V: or a pharmaceutically acceptable salt thereof, wherein: R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN; W 1 is selected from the group consisting of H and halogen; R 33 is -CH 3 or –(CH 2 )–(CH 2 )–OR 27 ; and R 27 is selected from the group consisting of H, -C( O)-(C 1 -C 4 )alkyl, a natural amino acid bound by the ⁇ -carboxyl group, and -P
  • a compound of Formula VI: or a pharmaceutically acceptable salt thereof wherein: Y 1 is H or F; q is 0 or 1; R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN; W 1 is selected from the group consisting of H and halogen; R 35 is H or a (C 1 -C 4 )-alkyl which is unsubstituted or substituted by one or more identical or different substituents R 50 ; R 50 is selected from the group consisting of halogen, -OR 27 ,
  • the compound of embodiment 72, wherein Z 1 and Z 2 are independently from one another selected from the group consisting of Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe. 74.
  • the compound of embodiment 76, wherein Z 3 is selected from the group consisting of H, Cl, F, -CH 3 , -CN, -OCH(CH 3 ) 2 and -OMe. 78.
  • R 2 is selected from the group consisting of: , , , W 1 is selected from the group consisting of Cl and F; and R 27 is selected from the group consisting of: H, 81.
  • R 2 is selected from the group consisting of: W 1 is selected from the group consisting of Cl and F; and R 35 is selected from the group consisting of methyl and isopropyl.
  • a compound of Formula II or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of O, CH 2 , S and NH; R 1 is selected from the group consisting of H, and -(C 1 -C 4 )-alkyl; R 3 is selected from the group consisting of -(CH 2 ) p -N(R 33 )R 34 ; p is 1, 2, 3 or 4; R 2 is selected from the group consisting of a 5-membered or 6-membered monocyclic, aromatic or heteroaromatic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein R 2 is unsubstituted or substituted by one or more identical or different substituents R 20 ; R 20 is selected from the group consisting of halogen, -CF 3 , (C 1 -C 4 )-alkyl, -OR 21 , -N(R 22 )R 23 , (C 1 -C 4 )
  • a compound of Formula II: or a pharmaceutically acceptable salt thereof wherein: Z is selected from the group consisting of a direct bond, O, S, CH(R 9 ) and N(R 10 ); R 1 is selected from the group consisting of H, -N(R 11 )R 12 , -N(R 13 )-C(O)-R 14 , -NR 13 -S(O) 2 -R 15 , -NR 13 -C(O)-NH-R 16 , -(C 1 -C 4 )-alkyl, –(C 1 -C 4 )-alkyl-OR 17 and –(C 1 -C 4 )-alkyl-N(R 18 )R 19 ; R 3 is selected from the group consisting of H, (C 1 -C 8 )-alkyl, R 30 and (C 1 -C 4 )-alkyl- R 30 , wherein (C 1 -C 8 )
  • a compound of Formula II: or a pharmaceutically acceptable salt thereof wherein: Z is selected from the group consisting of O, CH 2 , S and NH; R 1 is selected from the group consisting of H, and -(C 1 -C 4 )-alkyl; R 3 is selected from the group consisting of -(CH 2 ) p -N(R 33 )R 34 ; p is 1, 2, 3 or 4; R 2 is a 6-membered monocyclic, heteroaromatic group which comprises 1 or 2 nitrogen atoms, wherein R 2 is unsubstituted or substituted by one or more identical or different substituents R 20 ; R 20 is selected from the group consisting of halogen, -CF 3 , (C 1 -C 4 )-alkyl, -OR 21 , -N(R 22 )R 23 , (C 1 -C 4 )-alkyl-OR 24 , (C 1 -C 4 )
  • R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; and Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN.
  • R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; and Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF
  • a compound of Formula III or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of O and NH; R 1 is selected from the group consisting of H and (C 1 -C 4 )-alkyl; R 3 is –(CH 2 ) p -N(R 33 )R 34 ; p is 2, 3 or 4; R 2 is Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; Z 3 is selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 and -CN; R 33 and R 34 are independently of one another a (C 1 -C 4 )-alkyl; and W 1 , W 2 , W 3
  • a compound of Formula III or a pharmaceutically acceptable salt thereof, wherein: Z is selected from the group consisting of O, and NH; R 1 is selected from the group consisting of H, and -(C 1 -C 4 )-alkyl; R 3 is a nitrogen-bearing heterocycle selected from the group consisting of wherein zero, one or two hydrogens on any of the -CH 2 - groups of the nitrogen-bearing heterocycle is replaced with halogen, -OH, -CN, -CF3 or (C 1 -C 4 )-alkyl; R 35 is H or (C 1 -C 4 )-alkyl which is unsubstituted or substituted by one or more identical or different substituents R 50 ; and R 50 is selected from the group consisting of halogen, -OH, -O-(C 1 -C 4 )- alkyl, CF 3 , and -CN; R 2 is Z 1 and Z2 are independently from one another selected from the group consisting of
  • R 2 is selected from the group consisting of: , , , , , 174.
  • cancer affects tissues comprising cancerous cells in at least one of the breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, bone, and stomach. 179.
  • embodiment 177 wherein the cancer is a melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer or colorectal cancer.
  • the cancer is prostate cancer, colorectal cancer or breast cancer.
  • 181. The use of any one of embodiments 177 to 180, wherein the compound or pharmaceutically acceptable salt thereof is used in combination with at least one inhibitor of AKT/PI3K/mTOR. 182.
  • embodiment 181 wherein the at least one inhibitor of AKT/PI3K/mTOR is selected from the group consisting of NVP-BEZ235 (BEZ235, Dactolisib), GDC-0084 (RG7666), GDC-0980 (Apitolisib, RG7422), LY3023414, PF-05212384 (Gedatolisib, PKI- 587), PQR309 (Bimiralisib), P7170, SF-1126, Copanlisib (BAY 80–6946), Buparlisib (BKM120 NVP-BKM120), IPI-145 (Duvelisib), RP6530 (Tenalisib), GDC-0032 (Taselisib), KA2237, BYL719 (Alpelisib), CAL-101 (GS-1101, Idelalisib), GSK2636771, INCB050465 (Parsaclisib), Serabelis
  • embodiment 181 wherein the at least one inhibitor of AKT/PI3K/mTOR is selected from the group consisting of capivasertib, ipatasertib and MK-2206.
  • 184 Use of the compound of any one of embodiments 1 to 174, or a pharmaceutically acceptable salt thereof, for the treatment of Parkinson’s disease or Lafora disease.
  • 185 Use of the compound of any one of embodiments 1 to 174, or a pharmaceutically acceptable salt thereof, for the treatment of epilepsy.
  • a cardiovascular disease selected from the group consisting of Long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure.
  • cancer affects tissues comprising cancerous cells in at least one of the breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, bone, and stomach.
  • embodiment 193 wherein the cancer is a melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer or colorectal cancer.
  • embodiment 191 wherein the cancer is prostate cancer, colorectal cancer or breast cancer.
  • the compound or pharmaceutically acceptable salt thereof is used in combination with at least one inhibitor of AKT/PI3K/mTOR.
  • embodiment 195 wherein the at least one inhibitor of AKT/PI3K/mTOR is selected from the group consisting of NVP-BEZ235 (BEZ235, Dactolisib), GDC-0084 (RG7666), GDC-0980 (Apitolisib, RG7422), LY3023414, PF-05212384 (Gedatolisib, PKI- 587), PQR309 (Bimiralisib), P7170, SF-1126, Copanlisib (BAY 80–6946), Buparlisib (BKM120 NVP-BKM120), IPI-145 (Duvelisib), RP6530 (Tenalisib), GDC-0032 (Taselisib), KA2237, BYL719 (Alpelisib), CAL-101 (GS-1101, Idelalisib), GSK2636771, INCB050465 (Parsaclisib), Serabel
  • embodiment 195 wherein the at least one inhibitor of AKT/PI3K/mTOR is selected from the group consisting of capivasertib, ipatasertib and MK-2206.
  • embodiment 195 wherein the at least one inhibitor of AKT/PI3K/mTOR is selected from the group consisting of capivasertib, ipatasertib and MK-2206.
  • a cardiovascular disease selected from the group consisting of Long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure.
  • a method for the treatment of cancer comprising administering to a subject a therapeutically effective amount of the compound as defined in any one of embodiments 1 to 174, or a pharmaceutically acceptable salt thereof.
  • cancer affects tissues comprising cancerous cells in at least one of the breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, bone, and stomach.
  • cancer is a melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer or colorectal cancer.
  • the at least one inhibitor of AKT/PI3K/mTOR is selected from the group consisting of NVP-BEZ235 (BEZ235, Dactolisib), GDC-0084 (RG7666), GDC-0980 (Apitolisib, RG7422), LY3023414, PF- 05212384 (Gedatolisib, PKI-587), PQR309 (Bimiralisib), P7170, SF-1126, Copanlisib (BAY 80-6946), Buparlisib (BKM120 NVP-BKM120), IPI-145 (Duvelisib), RP6530 (Tenalisib), GDC-0032 (Taselisib), KA2237, BYL
  • a method for the treatment of epilepsy comprising administering to a subject a therapeutically effective amount of a compound as defined in any one of embodiments 1 to 174, or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of a cardiovascular disease comprising administering to a subject a therapeutically effective amount of a compound as defined in any one of embodiments 1 to 174, or a pharmaceutically acceptable salt thereof, the cardiovascular disease being selected from the group consisting of Long QT syndrome, heart failure, arrhythmia, ischemic injury, ischemic infarction, cardiac fibrosis, vascular proliferation, restenosis, dilated cardiomyopathy, and stent failure.
  • a method for the treatment of Long QT syndrome comprising administering to a subject a therapeutically effective amount of a compound as defined in any one of embodiments 1 to 174, or a pharmaceutically acceptable salt thereof. 214. The method of embodiment 193, wherein the Long QT syndrome is genetic Long QT syndrome. 215. The method of embodiment 193, wherein The Long QT syndrome is acquired Long QT syndrome. 216.
  • a compound of Formula VII: or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer wherein: Y 1 is H or F; Z 1 and Z 2 are independently from one another selected from the group consisting of halogen, (C 1 -C 4 )alkyl, -OH, -O-(C 1 -C 4 )alkyl, -CF 3 , and -CN; W 1 is selected from the group consisting of H and halogen; and R 35 is H or methyl. 217.
  • the compound of embodiment 216 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer wherein Y 1 is H. 218.
  • the compound of embodiment 216 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer which is a compound of Formula VIIa: wherein: Z 1 is F or Cl; Z 2 is F; and W 1 is H, Cl or F. 227.
  • the compound of any one of embodiments 216 to 245, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer wherein the cancer affects tissues comprising cancerous cells in at least one of the breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, intestine, endometrium, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, bone, and stomach. 247.
  • the compound of any one of embodiments 216 to 245, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer wherein the cancer is a melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, colon cancer or colorectal cancer. 248.
  • a pharmaceutical composition, for use in the treatment of cancer comprising the compound of any one of embodiments 216 to 242, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 250.
  • composition of embodiment 250 for use in the treatment of cancer, wherein the at least one inhibitor of AKT/PI3K/mTOR is selected from the group consisting of capivasertib, ipatasertib and MK-2206.
  • a method for the treatment of cancer comprising administering to a subject in need thereof the compound of any one of embodiments 216 to 242, or a pharmaceutically acceptable salt thereof.
  • the chemical shift ⁇ (in ppm), the number of hydrogen atoms (H), the coupling constant J (in Hz) and the multiplicity (s: singlet, d: doublet, dd: double doublet, t: triplet, dt: double triplet, m: multiplet; br: broad) of the peaks are given.
  • the MS characterization the mass number (m/z) of the peak of the molecular ion (M) or of a related ion such as the ion [M+1], i.e. the protonated molecular ion [M+H)] or the ion [M- 1], which was formed depending on the ionization method used, is given.
  • the ionization method was electrospray ionization (ES+ or ES-).
  • Compound 1 N-(4-(4-((1-isopropylpiperidin-4-yl)oxy)-3-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)phenyl)ethenesulfonamide i) 4,6-dichloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine
  • 4,6-Dichloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 5.29 mmol, 1.00 equiv.) was dissolved in THF (13.3 ml, 0.4 M) in a reaction vessel containing a magnetic stirring bar, followed by addition of 3,4-dihydro-2H-pyran (2.42 ml, 26.5 mmol, 5.00 equiv.) and
  • reaction mixture was cooled on an ice-bath and quenched with 1M aqueous Sodium hydroxide solution (formation of yellow solution).
  • the organic phase was separated and the aqueous phase acidified with 2M aqueous hydrochloric acid (formation of a white precipitate) and extracted three times with ethyl acetate.
  • the combined organic phases were washed with brine and dried over sodium sulfate and evaporated to afford the crude product. Purification by flash chromatography on silica gel using a mixture of ethyl acetate and hexanes as the eluent afforded the desired product as a white solid (234 mg, 33% yield).
  • the resulting mixture was stirred for overnight at room temperature under air atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred for overnight at 60 oC under air atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting solution was stirred for 40 hours at 100 oC in an oil bath.
  • the reaction mixture was cooled with a water bath.
  • the resulting solution and E08786-007 were diluted with 20 mL of water.
  • the resulting mixture was washed with 2 x20 ml of DCM.
  • the resulting mixture was concentrated.
  • the residue was applied onto a C18 gel with H2O (0.5% NH4HCO3)/ACN (90:10 to 10:90) in 45 minutes.
  • the collected fractions were combined and concentrated.
  • the resulting solution was stirred for 3 hr at 100 oC.
  • the resulting solution was extracted with 3x50 mL of ethyl acetate dried in an oven under reduced pressure and concentrated.
  • the crude product was purified by Flash-Prep-HPLC with the following conditions: Column, silica gel C18 (210 g); mobile phaseA:Water-10 mM NH 4 HCO 3 , mobile phaseB:Acetonitrile; Flow rate:50 mL/min; Gradient:55 B to 60 B; 254 nm;.
  • the solution was concentrated.
  • the solid was washed with CH 3 CN (3 mLx2). The solid was collected by filtration.
  • the resulting solution was stirred for 20 min at room temperature. Then added NaH (59.10 mg, 2.463 mmol, 5 equiv.) at 0 oC. The resulting solution was stirred for 2 hr at room temperature. The reaction was then quenched by the addition of water. The resulting solution was extracted with 2x50 mL of ethyl acetate dried over anhydrous sodium sulfate and concentrated. The resulting mixture was washed with EtOAc. The solids were collected by filtration.
  • the reaction mixture was cooled to ambient temperature and filtered.
  • the filtrate was purified by prep-HPLC with the following condition: Column: YMC-Actus Triart C18, 30 mm X 150 mm, 5um; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate:60 mL/min; Gradient:20% B to 50% B in 7 min; 254 nm; RT:5.12.
  • reaction mixture was purged with nitrogen 3 times and stirred at 100 oC for 12 hours under nitrogen.
  • the reaction was cooled to the room temperature and neutralized with saturated aqueous 1 N HCl to pH 7 ⁇ 8 and washed by DCM (3*100 mL).
  • the combined organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to provide the crude. Then the crude purified by HPLC chromatography to provide the desired product (350.0 mg, 90% purity, off-white solid).
  • reaction mixture was purged with nitrogen 3 times and stirred at 100 oC for 18 h under nitrogen.
  • the reaction was cooled to the room temperature and neutralized with saturated aqueous 1 N HCl to pH 7 ⁇ 8 and washed by DCM (3*5 mL).
  • the combined organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to provide the crude.
  • the crude purified by reversed-phase chromatography(10 mmol/L NH 4 HCO 3 /ACN) to provide the desired product (75 mg, 50% purity, off-white solid).
  • the reaction mixture was purged with nitrogen 3 times and stirred at 100 °C for 16 hours under nitrogen.
  • the reaction was cooled to the room temperature and neutralized with aqueous 1 N HCl to pH 7 ⁇ 8 and washed by DCM (3*20 mL).
  • the combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to provide the crude.
  • the crude purified by reversed-phase chromatography (C18 column; mobile phase, MeCN in water, 10% to 36% gradient in 18 min; detector, UV 254 nm) to provide the desired product (130 mg, 48% purity, light brown solid).
  • the reaction mixture was purged with nitrogen 3 times and stirred at 100 °C for 16 hours under nitrogen.
  • the reaction was cooled to the room temperature and neutralized with saturated aqueous 1 N HCl to pH 7 ⁇ 8 and washed by DCM (3*20 mL).
  • the combined organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to provide the crude.
  • the reaction mixture was purged with nitrogen 3 times and stirred at 100 °C for 16 hours under nitrogen.
  • the reaction was cooled to the room temperature and neutralized with aqueous 1 N HCl to pH 7 ⁇ 8 and washed by DCM (3*20 mL).
  • the combined organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to provide the crude.
  • the mixture was allowed to cool down to room temperature.
  • the resulting mixture was concentrated under vacuum.
  • the sloid was purified by flash with the following conditions (Column, C18 (40 g); mobile phase A: Water- 10 mM NH4HCO3, mobile phase B: Acetonitrile; Flow rate:40 mL/min; Gradient 60 B to 65 B; 254 nm).
  • the resulting mixture was concentrated under reduced pressure.
  • the solid was purified by flash with the following conditions (Column, C18 (80 g); mobile phase A:Water-10 mM NH4HCO3, mobile phase B: Acetonitrile; Flow rate:50 mL/min; Gradient 65 B to 72 B; 254 nm).
  • the solid was purified by flash Prep-HPLC with the following conditions (Column, C18 spherical 20- 35 um 100A (40 g); mobile phase A: Water-10 mM NH 4 HCO 3 , mobile phase B: Acetonitrile; Flow rate:35 mL/min; Gradient: 56 B to 67 B; 254 nm) to afford (3S,4R)-4-( ⁇ 6-chloro-3- methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl ⁇ oxy)-1-(2,2-difluoroethyl)-3-fluoropiperidine (20 mg, 31.42%) as a white solid.
  • the resulting mixture was concentrated under reduced pressure.
  • the solid was purified by flash Prep-HPLC with the following conditions (Column, C18 spherical 20- 35 um 100A (40 g); mobile phase A: Water-10 mM NH4HCO3, mobile phase B: Acetonitrile; Flow rate:35 mL/min; Gradient: 60 B to 68 B; 254 nm). The resulting mixture was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30x150 mm, 5 ⁇ m; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 55% B in 7 min, 55% B; Wave Length: 254 nm; RT1(min): 6.58;) to afford 5-chloro-N-[4-(4- ⁇ [(3S,4R)-1-(2,2-difluoroethyl)-3-fluoropiperidin-4-yl]oxy ⁇ -3- methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl]-2-fluorobenzenesulfonamide; trifluoroacetic acid (8.6 mg, 13.71%) as an off-white solid.
  • the resulting mixture was concentrated under reduced pressure.
  • the solid was purified by flash Prep-HPLC with the following conditions (Column, C18 spherical 20-35 um 100A (80 g); mobile phase A: Water-10 mM NH 4 HCO 3 , mobile phase B: Acetonitrile; Flow rate:40 mL/min; Gradient: 40 B to 51 B; 254 nm). The resulting mixture was concentrated under reduced pressure.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30x150 mm, 5 ⁇ m; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 43% B in 7 min, 43% B; Wave Length: 254 nm; RT1(min): 4.93) to afford 5-chloro-2-fluoro-N-[4-(4- ⁇ [(3S,4R)-3-fluoro-1- (2H3)methylpiperidin-4-yl]oxy ⁇ -3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6- yl)phenyl]benzenesulfonamide; trifluoroacetic acid (21.4 mg, 7.79%) as an off-white solid.
  • the resulting solution was stirred for overnight at 90 °C in an oil bath.
  • the reaction mixture was cooled to room temperature.
  • the resulting mixture was concentrated.
  • the resulting solution was diluted with 50 mL of DCM.
  • the resulting mixture was washed with 2 x30 ml of brine and 1 x30 mL of water.
  • the mixture was dried over anhydrous sodium sulfate.
  • the residue was applied onto a silica gel column with dichloromethane/methanol (100:0 to 10:90). The collected fractions were combined and concentrated.
  • the residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, can in water, 10% to 50% gradient in 30 min; detector, UV 254 nm, 40ml/min.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 ⁇ m; Mobile Phase A: Water(0.05%TFA ), Mobile Phase canACN; Flow rate: 60 mL/min; Gradient: 27% B to 47% B in 7 min, 47% B; Wave Length: 254 nm; RT1(min): 4; Number Of Runs: 0) to afford 2- ⁇ [2-( ⁇ 6-[4-(5-chloro-2-fluorobenzenesulfonamido)phenyl]-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4-yl ⁇ amino)ethyl](methyl)amin
  • the resulting mixture was concentrated under reduced pressure.
  • the solid was purified by flash Prep-HPLC with the following conditions (Column, C18 spherical 20-35 um 100A (800 g); mobile phase A: Water-10 mM NH 4 HCO 3 , mobile phase B: Acetonitrile; Flow rate:40 mL/min; Gradient 50 B to 58 B; 254 nm). The resulting mixture was concentrated under reduced pressure.
  • Biological Activity ⁇ SGK1 assay The ability of the synthesized compounds to inhibit SGK-1 was assessed in an enzymatic assay by determining their effect on the ability of the isolated SGK1 enzyme to catalyze the transfer of the phosphate from ATP to serine/threonine residues in a labeled substrate peptide and in cellular assay by using the NanoBRET target engagement assay kit.
  • Enzymatic activity assay The compounds were tested for SGK-1 activity by measuring the ability of the compound to inhibit the transfer of phosphate from ATP by the isolated enzyme to serine/threonine residues in a fluorescein labeled substrate peptide, FLPeptide 6 (PerkinElmer, Waltham, USA, Cat. No: 760350).
  • the enzymatic reaction was initiated by addition of 15 ⁇ L of solution 1 containing (in mM) 10 MgCl2, 0.010 % Brij-35, 2 DTT, 0.05 % BSA, 1 EGTA, 50 HEPE (pH7.5) and 0.665 nM SGK to 5 ⁇ L of solution 2 containing 10 MgCl2, 0.010 % of Brij-35, 2 DTT, 0.05 %BSA, 1 EGTA, 50 HEPES (pH7.5), 6 ⁇ M of FLPeptide and 80 ⁇ M of ATP. After incubating the plate at room temperature for 90 min, 75 ⁇ L of stopping buffer (containing 0.5 M EDTA) is added to terminate the reaction.
  • stopping buffer containing 0.5 M EDTA
  • HEK293 cells that were cultured in Dulbecco modified Eagle medium (DMEM), was transfected with 9 ug/mL Carrier DNA and 1 ug/mL SGK1-NanoLuc fusion vector and mix liplid:DNA complex with 1:20 (v:v) cell suspension. Transfected cells were seeded at 2000 cells/100 ⁇ L/well in 96-well plate and incubated overnight.
  • DMEM Dulbecco modified Eagle medium
  • Solubility Buffer for preparing FeSSIF buffer was prepared by dissolving 4.040 g of NaOH, 8.650 g of glacial acetic acid and 11.874 g of NaCl in about 900 mL ultrapure water and the pH of the solution was adjusted to 5.0 with 1 N NaOH or 1 N HCl. Then the solution was diluted with ultrapure water to 1000 mL at room temperature. 11.200 g of FaSSIF, FeSSIF & FaSSGF Powder was added to about 500 mL of buffer. Stir until the powder was completely dissolved. Then the solution was diluted with the buffer to 1000 mL at room temperature. Ready to use within 48 hours at room temperature and 24 hours at 37°C.
  • Solubility values of the test compound and control compound were calculated as follows: Any value of the compounds that was not within the specified limits was rejected and the experiment was repeated. Table C. Solubility of the compound ⁇ Kinase Selectivity The following compounds were profiled against a 50-kinase Mixed panel at 10 ⁇ M using the KinaseSeekerTM assay.
  • Assay Design KinaseSeeker is a homogeneous competition binding assay where the displacement of an active site dependent probe by an inhibitor is measured by a change in luminescence signal. Luminescence readout translates into a highly sensitive and robust assay with low background and minimal interference from test compounds. Assay Method 10 mM stock of the compound was diluted in DMSO to a concentration of 250 ⁇ M. Prior to initiating a profiling campaign, the compound was evaluated for false positive against split-luciferase. The compound was then screened in duplicate against each of the kinases.
  • each Cfluc-Kinase was translated along with Fos- Nfluc using a cell-free system (cell lysate) at 30 °C for 90 min.24 ⁇ L aliquot of this lysate containing either 1 ⁇ L of DMSO (for no inhibitor control) or compound solution in DMSO (10 ⁇ M final concentration) was incubated for 2 hours at room temperature in presence of a kinase specific probe.80 ⁇ L of luciferin assay reagent was added to each solution and luminescence was immediately measured on a luminometer.
  • Profiling data for all kinases was plotted as % inhibition vs. kinases profiled. A heat map representing the effect of compounds on kinases was also generated. Table D. Kinase Selectivity of the compounds
  • ⁇ hERG Cell lines and cell culture hERG stably expressed HEK 293 cell line (Cat# K1236) was purchased from Invitrogen. The cells are cultured in 85% DMEM, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM HEPES, 100 U/mL Penicillin-Streptomycin and 5 ⁇ g/mL Blasticidin and 400 ⁇ g/mL Geneticin. Cells are split using TrypLETM Express about three times a week, and maintained between ⁇ 40% to ⁇ 80% confluence.
  • Solution preparations Extracellular solution (in mM): 132 NaCl, 4 KCl, 3 CaCl 2 , 0.5 MgCl 2 , 11.1 glucose, and 10 HEPES (pH adjusted to 7.35 with NaOH).
  • Intercellular solution in mM: 140 KCl, 2 MgCl 2 , 10 EGTA, 10 HEPES and 5 MgATP (pH adjusted to 7.35 with KOH)
  • Working solution preparation for test compound Test compounds were initially prepared in DMSO with final concentration of 10 mM as stock solution according to SOP- ADMET-MAN-007. Then stock solution of each compound was serial-diluted by ratio of 1:3 with DMSO to prepare additional 3 intermediate solutions including 3.33, 1.11 and 0.37 mM.
  • hERG assay Before hERG assay, the working solutions were prepared by dilution of 10, 3.33, 1.11- and 0.37-mM intermediate solutions in 1000 folds using extracellular solution, so that the final concentration of working solution was 10, 3.33, 1.11 and 0.37 mM, while 30 ⁇ M working solution was prepared by 333.333-folds dilution of 10 mM DMSO stock. The final DMSO concentration in working solutions was maintained in range of 0.1-0.3% (v/v). hERG current in presence of 5 doses including 30, 10, 3.33, 1.11 and 0.37 ⁇ M, was measured for IC50 determination. Data analysis Percent current inhibition was calculated using the following equation.
  • the dose response curve of test compounds was plotted with %inhibition against the concentration of test compounds using Graphpad Prism 8.0, and fit the data to a sigmoid dose-response curve with a variable slope.
  • Table E. hERG values of the compounds ⁇ Determination of the efficacy of SGK1 inhibitors on LQT3 by studying its effect on the action potential duration (APD) of LQT-patient derived cardiomyocytes (iPSC-CMs) SGK1 inhibition is suggested to decrease the APD of cardiomyocytes that exhibits the phenotype of LQT3 patients. Incubation with SGK1 inhibitors reduces the APD of the cardiomyocytes which can be investigated by imaging of cells using FluoVolt dye.
  • iPSCs Stem cells derived from LQT-3 patients (iPSCs) were cultured in mTeSRTM1 media (STEMCELL Tech., 85851) in 6-cm dishes pre-coated with Geltrex (Life Technology, A1413302) and incubated at 37oC and 5% CO 2 . At 85% confluence, iPSCs were disaggregated with ReLeSRTM (STEMCELL Tech., 05872), passaged into 24-well plates, and allowed to grow for 3-4 days to create a monolayer. The differentiation strategy used has been reported previously.
  • the culture medium was changed to RPMI 1640 GlutaMAXTM plus 25mM HEPES supplemented with B27-minus Insulin (Gibco, A18956-01) containing CHIR99021 (TOCRIS, 4423, 6 ⁇ M as working concentration) from days 0 to 2.
  • B27-minus Insulin Gibco, A18956-01
  • CHIR99021 TOCRIS, 4423, 6 ⁇ M as working concentration
  • medium was changed to RPMI-B27-minus insulin containing IWP2 (TOCRIS, 3533, 5 ⁇ M as working concentration) and incubated until day 4.
  • the medium was changed back to normal RPMI GlutaMAXTM-B27-minus insulin and cells were maintained in this media until beating cardiomyocytes appeared, typically around day 10 or day 12.
  • iPSC-CMs were maintained in cardiomyocyte maintenance medium (DMEM, No phenol red, 2% charcoal stripped FBS). Cardiomyocyte differentiation and maintenance are done in a 24 well format. Prior to each experiment iPSC-CMs need to be re-plated onto a 35mm dish and allowed to stabilize for 1 week. Following stabilization of iPSC-CMs in a glass bottom 35 mm dish for 1 week, compounds are applied. Experiment design of APD measurement: iPSC-CMs are maintained in DMEM plus 2% FBS until replating. 3x10 5 cells are plated into each 35 mm glass dish in DMEM plus 20% FBS and maintained in DMEM plus 2% for 1 week for CM stabilization.
  • DMEM cardiomyocyte maintenance medium
  • Either DMSO, Mex (10uM), SGK1 Inhibitor Compound (3uM), or SGK1 Inhibitor Compound (30uM) in DMEM plus 2% FBS are added to the plated cells.
  • the media with the drug is washed out of the first set of 4 plates and replaced with a Tyrode solution containing the FluoVolt dye.
  • Live imaging is taken of approximately 10-12 randomly selected “flashing” cells (see live imaging methods section). Cells are paced at 1 Hz.
  • the raw data from live cell imaging is exported to Excel software (Microsoft, Redmond, WA) and then analyzed with an “in-lab” developed Excel-based program.
  • the loading of the FluoVolt dye in the experiments is performed as follows: Before starting, pre-warm 6.5mL Tyrode’s solution to 37°C.Aspirate medium and rinse cells with 1mL Tyrode. Add 1.25 ⁇ L PowerLoad and 0.125 ⁇ L FluoVolt to 0.5mL Tyrode’s and add to the center of the 35mm dish glass inset. Incubate 20min at 37°C. Rinse cells 3 times with 1mL Tyrode’s. Add 2mL Tyrode’s. Image cells within 2h, using GFP filter.
  • Live cell imaging for action potential duration (APD) measurement iPSC-CMs were cultured on 35mm glass bottom dishes (MatTek, P35G-1.5-10-C) that was pre-coated with fibronectin solution at 10 ⁇ g/ml (Thermofisher, 3016015) at 37oC, 5% CO 2 .
  • fibronectin solution 10 ⁇ g/ml (Thermofisher, 3016015) at 37oC, 5% CO 2 .
  • cells were incubated at 37oC, 5% CO2 for 20 minutes in Tyrode solution containing a fluorescent voltage sensitive dye, FluoVolt (ThermoFisher, Cat#F10488, working concentration of 5 uM) and Pluronic ® F-127 (Thremofisher, P3000MP, working concentration of 0.05%). They were then washed three times in fresh Tyrode solution.
  • the test compound Following the administration of the test compound, 30 uL of blood was collected from each mouse at 0.25, 0.5, 1, 2, 4, 8, 24 h post dosing to measure the concentration of test samples in the plasma.
  • the collected blood sample is dissolved in heparin to prevent the coagulation of blood, following which it is centrifuged at 4000 g for 5 minutes. After centrifugation, the separated plasma will be stored in freezer at 75 ⁇ 15°C.
  • a LC-MS/MS system is used to measure the concentration of the test sample in plasma.
  • WinNonlin (Phoenix TM , version 6.1) will be used for the pharmacokinetic calculations and from the plasma concentration versus time data C max , T max , T 1/2 , AUC inf , AUC last , the number of points for regression are calculated.
  • ⁇ IV (2 mg/kg, 5 mL/kg)
  • the test compound Following the administration of the test compound, 30 uL of blood was collected from each mouse at 0.25, 0.5, 1, 2, 4, 8, 24 h post dosing to measure the concentration of test samples in the plasma.
  • the collected blood sample is dissolved in heparin to prevent the coagulation of blood, following which it is centrifuged at 4000 g for 5 minutes. After centrifugation, the separated plasma will be stored in freezer at 75 ⁇ 15°C.
  • a LC-MS/MS system is used to measure the concentration of the test sample in plasma.
  • WinNonlin (Phoenix TM , version 6.1) will be used for the pharmacokinetic calculations and from the plasma concentration versus time data C max , T max , T 1/2 , AUC inf , AUC last , the number of points for regression are calculated.
  • Table G Mouse Pharmacokinetic data
  • Protocol for PK study in SD rat via ora/IV administration All experimental procedures have been conducted in accordance to German Animal Protection Law, as well as according to international animal welfare legislation and rules.
  • ⁇ PO (30 mg/kg, 10 mL/kg) dosing Three male SD rat (6-8 weeks, 200-300 g) were used for this study. Each mouse was given 30 mg/kg of the tested drug by oral route PO. The test compound was dissolved in 0.5% HEC, 0.4% Tween 80 in saline for oral PK. Following the administration of the test compound, 200 uL of blood was collected from each rat at 0.25, 0.5, 1, 2, 4, 8, 24 h post dosing to measure the concentration of test samples in the plasma.
  • the collected blood sample is dissolved in heparin to prevent the coagulation of blood, following which it is centrifuged at 4000 g for 5 minutes. After centrifugation, the separated plasma will be stored in freezer at 75 ⁇ 15°C. A LC-MS/MS system is used to measure the concentration of the test sample in plasma. WinNonlin (Phoenix TM , version 6.1) will be used for the pharmacokinetic calculations and from the plasma concentration versus time data C max , T max , T 1/2 , AUC inf , AUC last , the number of points for regression are calculated.
  • ⁇ IV (2 mg/kg, 5 mL/kg) Dosing Six male SD rat (6-8 weeks, 200-300 g) were used for this study. Each mouse was given 2 mg/kg of the tested drug by IV route PO. The test compound was dissolved 5% NMP, 5% solutol in “20% SBE in PBS (pH 7.4)”. Following the administration of the test compound, 200 uL of blood was collected from each rat at 0.25, 0.5, 1, 2, 4, 8, 24 h post dosing to measure the concentration of test samples in the plasma. For the processing of collected blood samples, the collected blood sample is dissolved in heparin to prevent the coagulation of blood, following which it is centrifuged at 4000 g for 5 minutes.
  • CYP3A4/5 inhibition 1 ⁇ L of specific drug substrate (Midazolam: 1 mM) was added at the final concentration of 5 ⁇ M to the above solution.
  • 1 ⁇ L of specific drug substrate 1 ⁇ L was added at the final concentration of 50 ⁇ M to the above solution. The mixture was pre-warmed at 37°C for 5 min. The reaction was started by the addition of 20 ⁇ L of 10 mM NADPH solution at the final concentration of 1 mM and carried out at 37°C.
  • the reaction was stopped by addition of 400 ⁇ L of cold quench solution (methanol containing internal standards (IS: 100 nM alprazolam, 500 nM labetalol and 2 ⁇ M ketoprofen)) at the designated time points (Phenacetin: 20 min; Bupropion: 20 min; Tolbutamide: 20 min; Dextromethorphan: 20 min; Midazolam: 5 min; Testosterone: 10 min). Samples were vortexed for 5 minutes and centrifuged at 3220 g for 40 minutes at 4°C. And then 100 ⁇ L of the supernatant was transferred to a new 96-well plate with 100 ⁇ L water for LC-MS/MS analysis. All experiments were performed in duplicate.
  • cold quench solution methanol containing internal standards (IS: 100 nM alprazolam, 500 nM labetalol and 2 ⁇ M ketoprofen)
  • Safety Margin can be obtained by calculating hERG / IC 50 , using the values IC 50 (Whole cell) and hERG (IC 50 , nM) from tables B and E, respectively. A higher safety margin is desired.
  • the safety margins of several compounds of the present application were compared with each other and with the safety margin of example compounds disclosed in patent application Pub No. WO 2014/140065, which is hereby incorporated by reference in its entirety. Some safety margin values are shown at Table K.
  • the safety margin of several compounds of the following Formula is shown at Table K, to evaluate the effect of the Z-R 3 group on the safety margin.
  • R 2 group generally has an effect on activity and kinase selectivity.
  • JIMT-1 cells (Creative Bioarray catalogue number CSC-C0592) were grown in Dulbecco′s Modified Eagle′s Medium - high glucose, (DMEM, Sigma catalogue number D6429-500ml) containing 10% heat-inactivated fetal bovine serum (VWR catalogue number 97068-085) and penicillin/streptomycin (Corning, catalogue number 30-002-CL) and prophylactic plasmocin (InvivoGen, catalogue number ant-mpp) as per the cell line manufacturer’s instructions.
  • DMEM Dulbecco′s Modified Eagle′s Medium - high glucose, (DMEM, Sigma catalogue number D6429-500ml) containing 10% heat-inactivated fetal bovine serum (VWR catalogue number 97068-085) and penicillin/streptomycin (Corning, catalogue number 30-002-CL) and prophylactic plasmocin (InvivoGen, catalogue number ant-mpp) as per the cell line manufacturer’s instructions.
  • Cell treatment Culture media was removed from the 96 well cell plate by aspiration and 100 ⁇ L of the drug combination dilutions was added to the cell plate, in triplicate for each treatment (written in simplicate in Table O below for easier read). A total of two 96-well plates were needed for each combination, as outlined below. Plates containing the cells with compounds were incubated at 37oC, 5%CO2 for 3 days. The compound dilution plate was stored at -20oC to re-use at Day 4 to re-treat the cells for an additional four days (total of 7 day incubation). Table O.
  • the Bliss synergy scores for combinations of Compound 79 with several AKT inhibitors are shown at: - Figure 1 (combination of Compound 79 with Ipatasertib) – Bliss synergy score of 26; - Figure 2 (combination of Compound 79 with Capivasertib) – Bliss synergy score of 26; and - Figure 3 (combination of Compound 79 with MK-2206 (allosteric)) – Bliss synergy score of 18.
  • PBMCs peripheral blood mononuclear cells
  • the 6-well plates were then put on ice, and the PBMC suspension was transferred in a separate 15 mL centrifuge tube for each treatment. Each well of the 6-well plate was rinsed with 2 ml of cold 1X PBS, and added to the corresponding 15 mL centrifuge tube.
  • PBMCs peripheral blood mononuclear cells
  • the gels were run at 120V for 90 min, and transferred on Hybond 0.45 PVDF membrane (Cytiva catalogue number 10600029) in 10X Tris/Glycine Transfer buffer (Biorad catalogue number 1610734) at 400mA for 1.5 hours at 4oC. Membranes were rinsed in TBST buffer (1X TBS +0.1%Tween 20 (Fisher catalogue number 0777-1L)), and blocked for 1 hour with 5% BSA (Sigma catalogue number 10735086001) in TBST at RT.
  • the membranes were then incubated overnight with primary antibodies (anti pNDRG1, Cell Signaling catalogue number 5482S at 1:1000 dilution, anti-NDRG1, Cell signaling catalogue number 5196S at 1:1000 dilution, and anti-vinculin, Cell Signaling catalogue number 13901S at 1: 5000 dilution in 1% BSA in TBST.
  • the membranes were washed three times 15minutes in TBST at room temperature, and incubated with anti-Rabbit HRP Antibody (Cell Signaling, 7074P2) at 1:5,000 dilution for pNDRG1 and NDRG1, and 1:50,000 dilution for vinculin in 1% BSA in TBST for 1 hour at room temperature.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des composés de formule I : et des sels pharmaceutiquement acceptables de ceux-ci sont fournis en tant qu'inhibiteurs de SGK-1, par exemple pour le traitement d'états tels que le syndrome du QT Long, l'insuffisance cardiaque, l'arythmie, une lésion ischémique, un infarctus ischémique, une fibrose cardiaque, une prolifération vasculaire, une resténose, une cardiomyopathie dilatée, un défaut d'endoprothèse, un cancer, la maladie de Parkinson et une maladie de Lafora.
PCT/US2022/036956 2022-07-13 2022-07-13 Dérivés de pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk-1 et le traitement du cancer WO2024015055A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2022/036956 WO2024015055A1 (fr) 2022-07-13 2022-07-13 Dérivés de pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk-1 et le traitement du cancer
PCT/CA2023/050681 WO2024011307A1 (fr) 2022-07-13 2023-05-17 Dérivés de pyrazolo [3,4-d] pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk -1 et le traitement du cancer

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2022/036956 WO2024015055A1 (fr) 2022-07-13 2022-07-13 Dérivés de pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk-1 et le traitement du cancer

Publications (1)

Publication Number Publication Date
WO2024015055A1 true WO2024015055A1 (fr) 2024-01-18

Family

ID=89535091

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2022/036956 WO2024015055A1 (fr) 2022-07-13 2022-07-13 Dérivés de pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk-1 et le traitement du cancer
PCT/CA2023/050681 WO2024011307A1 (fr) 2022-07-13 2023-05-17 Dérivés de pyrazolo [3,4-d] pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk -1 et le traitement du cancer

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/CA2023/050681 WO2024011307A1 (fr) 2022-07-13 2023-05-17 Dérivés de pyrazolo [3,4-d] pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk -1 et le traitement du cancer

Country Status (1)

Country Link
WO (2) WO2024015055A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008086854A1 (fr) * 2007-01-18 2008-07-24 Merck Patent Gmbh Dérivés de 5-( [1, 3, 4] oxadiazole-2-yl)-ih-indazole et 5-( [1, 3, 4] thiadiazole-2-yl)-ih-indazole comme inhibiteurs de la sgk pour le traitement de diabètes
WO2013041502A1 (fr) * 2011-09-19 2013-03-28 Sanofi N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phényl]-sulfonamides et leur utilisation comme produits pharmaceutiques
WO2014140065A1 (fr) * 2013-03-13 2014-09-18 Sanofi N-(4-(azaindazol-6-yl)phényl)sulfonamides et leur utilisation comme produits pharmaceutiques

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2023008219A (es) * 2021-01-13 2023-08-24 Thryv Therapeutics Inc Derivados de pirazolo[3,4-d]pirimidin-6-il-sulfonamida para la inhibición de la serina/treonina proteina cinasa (sgk-1).

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008086854A1 (fr) * 2007-01-18 2008-07-24 Merck Patent Gmbh Dérivés de 5-( [1, 3, 4] oxadiazole-2-yl)-ih-indazole et 5-( [1, 3, 4] thiadiazole-2-yl)-ih-indazole comme inhibiteurs de la sgk pour le traitement de diabètes
WO2013041502A1 (fr) * 2011-09-19 2013-03-28 Sanofi N-[4-(1h-pyrazolo[3,4-b]pyrazin-6-yl)-phényl]-sulfonamides et leur utilisation comme produits pharmaceutiques
WO2014140065A1 (fr) * 2013-03-13 2014-09-18 Sanofi N-(4-(azaindazol-6-yl)phényl)sulfonamides et leur utilisation comme produits pharmaceutiques
US9718825B2 (en) * 2013-03-13 2017-08-01 Sanofi N-(4-(azaindazol-6-yl)-phenyl)-sulfonamides and their use as pharmaceuticals

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BAILLACHE DANIEL J., UNCITI-BROCETA ASIER: "Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4- d ]pyrimidine scaffold", MEDCHEMCOMM, vol. 11, no. 10, 21 October 2020 (2020-10-21), United Kingdom , pages 1112 - 1135, XP093049379, ISSN: 2040-2503, DOI: 10.1039/D0MD00227E *
DATABASE PUBCHEM COMPOUND 23 January 2019 (2019-01-23), ANONYMOUS : "US9718825, Example 296", XP093132317, retrieved from PUBCHEM Database accession no. 136213277 *

Also Published As

Publication number Publication date
WO2024011307A1 (fr) 2024-01-18

Similar Documents

Publication Publication Date Title
JP6577537B2 (ja) Ａｔｒキナーゼのインヒビターとして有用なピラジン誘導体
AU2018200536B2 (en) Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors
JP6140170B2 (ja) 過増殖性疾患の処置におけるｂｕｂ１キナーゼ阻害剤として使用するための置換ベンジルインダゾール類
RU2537945C2 (ru) Триазиновые, пиримидиновые и пиридиновые аналоги и их применение в качестве терапевтических агентов и диагностических проб
WO2019037678A1 (fr) Dérivé de pyrazolo[3,4-d]pyrimidin-3-one, composition pharmaceutique et utilisation associée
AU2012284540B2 (en) TRPV4 antagonists
EP2935271A1 (fr) Utilisation de nouveaux imidazoles substitués comme inhibiteurs de la caséine kinase 1 /
KR20140117651A (ko) 이소퀴놀린 및 나프티리딘 유도체
EP4277905A1 (fr) Dérivés de pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide pour l'inhibition de la sgk-1
AU2018200460A1 (en) Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors
JP7282743B2 (ja) 複素環化合物
WO2024015055A1 (fr) Dérivés de pyrazolo[3,4-d]pyrimidin-6-yl-sulfonamide pour l'inhibition de sgk-1 et le traitement du cancer
CN117062817A (zh) 用于抑制sgk-1的吡唑并[3,4-d]嘧啶-6-基-磺酰胺衍生物

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: 22951320

Country of ref document: EP

Kind code of ref document: A1