WO2013009810A1 - Méthodes de traitement - Google Patents

Méthodes de traitement Download PDF

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Publication number
WO2013009810A1
WO2013009810A1 PCT/US2012/046170 US2012046170W WO2013009810A1 WO 2013009810 A1 WO2013009810 A1 WO 2013009810A1 US 2012046170 W US2012046170 W US 2012046170W WO 2013009810 A1 WO2013009810 A1 WO 2013009810A1
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Prior art keywords
alkyl
trifluoromethyl
oxadiazol
methyl
benzamide
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PCT/US2012/046170
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English (en)
Inventor
Shomir Ghosh
Mercedes Lobera
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Tempero Pharmaceuticals, Inc.
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Publication of WO2013009810A1 publication Critical patent/WO2013009810A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a method of treating neurodegenerative diseases or disorders, particularly, a neurodegenerative disease or disorder associated with deacetylases, such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA), among others, by administering to a patient in need thereof a compound that inhibits HDAC activity
  • a neurodegenerative disease or disorder associated with deacetylases such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA), among others, by administering to a patient in need thereof a compound that inhibits HDAC activity
  • Chromatin organization involves DNA wound around histone octamers that form nucleosomes.
  • Core histones with N-terminal tails extending from compact nucleosomal core particles can be acetylated or deacetylated at epsilon lysine residues affecting histone-DNA and histone-non-histone protein interactions.
  • Histone deacetylases Histone deacetylases
  • HDACs catalyze the deacetylation of histone and non-histone proteins and play an important role in epigenetic regulation.
  • HDACs There are currently 18 known HDACs that are organized into three classes: class I HDACs (HDAC1 , HDAC2, HDAC3, HDAC8 and HDAC1 1 ) are mainly localized to the nucleus; class II HDACs (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10), which shuttle between the nucleus and the cytoplasm; and class III HDACs (SIRT1-7), whose cellular localization includes various organelles.
  • Class II HDACs are further characterized as class lla HDACs and class lib HDACs.
  • HDAC4 has been linked to a variety of neurodegenerative disorders: it is a downstream target of Parkin (associating it to Parkinson's disease), it's is a major component of intranuclear inclusions produced in NIIND. HDAC4 also contains a conserved glutamine rich domain, such domain has been observed to increase susceptibility to amyloid formation associated with Alzheimer's disease (Majdzadeh et al. Front. Biosci., 2009, p. 1072). Heterozygotes of HDAC4 knockouts crossed to R6/2 mice (Huntington's disease model) led to improved motor/behavior and reduced aggregation
  • HDAC4 and HDAC5 localization are regulated by neuronal activity, and HDAC5 nuclear import is increased in diseased neurons of Huntington's disease patients.
  • HDAC7 another class lla HDAC, has been implicated in regulating ataxin-7 turnover in a SCA-7 model (Mookerjee S et al., J Neurosci., 2009, p. 15134).
  • HDAC6 a class lib HDAC, is expressed in most neurons and most abundantly in cerebellar Purkinje cells, the degeneration of this type of neurons is observed in patients with spinocerebellar ataxia type 1 (SCA1 ) or SCA7. HDAC6 is involved in regulating microtubule dynamics and protein degradation and a defect in microtubule-based transport may contribute to the neuronal toxicity observed in Huntington's disease
  • a small molecule selective inhibitor of HDAC activity (more specifically, an inhibitor of HDAC4 and/or HDAC5 and/or HDAC6 and/or HDAC7 and/or HDAC8 and/or HDAC9 activity) is expected to be beneficial in the treatment of neurodegenerative diseases by targeting one or several of the above enzymes.
  • the invention is directed to a method of treatment of a neurodegenerative disease or disorder comprising administering, to a patient in need thereof, a compound of Formula I:
  • R 1 is halo(CrC 4 )alkyl, wherein said halo(Ci-C 4 )alkyl contains at least 2 halo groups;
  • Y is a bond and Xi is O, N or NH, X 2 is N or CH and X 3 is N or NH,
  • Y is -C(O)- and Xi and X 2 are CH or N, X 3 is O or S,
  • Y is -C(O)- and Xi is O, X 2 is CH or N, and X 3 is CH or N;
  • A is optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
  • any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, -NR A R A and
  • R 2 and R 3 are independently selected from H and optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C C 4 )alkyl-,
  • R 3 is selected from H and optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C C 4 )alkyl-,
  • aryl, cycloalkyi and each of the (CrC 4 )alkyl moieties of said optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C C 4 )alkyl- of any R 2 and R 3 are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C 4 )alkyl, halo(d-C 4 )alkyl, (C C 4 )alkoxy, halo(d-C 4 )alkoxy, -NR A R A ,
  • L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted,
  • L when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (Ci-C 4 )alkyl;
  • R 4 is H, (Ci-C 4 )alkyl, halo, halo(Ci-C 4 )alkyl, (C C 4 )alkoxy,
  • each R A is independently selected from H and (CrC 4 )alkyl
  • R B is H, (Ci-C 4 )alkyl, halo(Ci-C 4 )alkyl,
  • R c is H, (Ci-C 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or R A and R c taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C 1 -C 4 )alkyl;
  • each R x is independently selected from H, (C 1 -C 6 )alkyl, and optionally substituted
  • (C 2 -C 6 )alkyl where said optionally substituted (C 2 -C 6 )alkyl is optionally substituted by hydroxyl, cyano, amino, (C C 4 )alkoxy, (Ci-C 4 )alkyl)NH-, or ((Ci-C 4 )alkyl)((C C 4 )alkyl)N-; and
  • each R Y is independently selected from H, (Ci-C 4 )alkyl, phenyl, and
  • the invention is further directed to the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt, thereof in therapy, particularly the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to treat a neurodegenerative disease or disorder associated with deacetylases, such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA).
  • a neurodegenerative disease or disorder associated with deacetylases such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA).
  • the invention is still further directed to the manufacture of a medicament containing a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy, particularly for use to treat a neurodegenerative disease or disorder associated with deacetylases, such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA).
  • a neurodegenerative disease or disorder associated with deacetylases such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA).
  • R 1 is a fluoro- alkyl group containing at least 2 fluoro groups (atoms). In another embodiment, R 1 is a (CrC 2 )alkyl group containing at least 2 fluoro groups. In a specific embodiment, R 1 is CHF 2 or CF 3 ; more specifically, R 1 is CF 3
  • X-i, X 2 , and X 3 taken together with the atoms to which they are attached, form an oxadiazolyl (X-i is O, X 2 and X 3 are N), oxazolyl (X-i is O, X 2 is CH, X 3 is N), imidazolyl (X-i is N or NH, X 2 is CH, X 3 is N or NH); or a triazolyl (Xi is N or NH, X 2 is N, X 3 is N or NH) ring moiety.
  • Y is a bond
  • X-i, X 2 , and X 3 taken together with the atoms to which they are attached form an oxadiazolyl ring moiety.
  • Y is -C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached, form an thiazolyl (X 3 is S, Xi is CH and X 2 is N or X 3 is S, Xi is N and X 2 is CH), oxazolyl (X 3 is O, Xi is CH and X 2 is N or X 3 is O, Xi is N and X 2 is CH), thienyl (X ⁇ and X 2 are CH, X 3 is S) or furanyl (Xi and X 2 are CH, X 3 is O) ring moiety.
  • Y is -C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached form a thienyl, thiazolyl or oxazolyl ring moiety, more specifically a thienyl moiety.
  • Y is -C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached, form a furanyl or furyl (Xi is O, X 2 and X 3 are CH), oxazolyl (Xi is O, X 2 is CH, and X 3 is N), isoxazolyl (Xi is O, X 2 is N, and X 3 is CH), or oxadiazolyl (Xi is O, X 2 and X 3 are N) ring moiety.
  • R 1 , R 2 , R 3 ,R 4 , A, Z, n and L are as defined herein.
  • R 1 , R 2 , R 3 ,R 4 , A, Z, n and L are as defined herein.
  • the invention is further directed to methods of treatment and uses of a compound of Formula (l-c), (l-d) -e):
  • R 1 , R 2 , R 3 ,R 4 , A, Z, n and L are as defined herein.
  • the invention is still further directed to methods of treatment and uses of a compound of Formula (l-f), (l-g), (l-h), (l-i) or (l-j):
  • R 1 , R 2 , R 3 ,R 4 , A, Z, n and L are as defined herein.
  • the invention is still further directed to methods of treatment and uses of a compound of Formula (l-k), (l-l), (l-m), or (l-n):
  • A is a phenyl group optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C C 4 )alkyl, (d-C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and
  • A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A R A and -((C C 4 )alkyl)NR A R A , where each R A is
  • A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group.
  • A is a
  • cyclopropyl, cyclopentyl or cyclohexyl group optionally substituted by 1-2 groups independently selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, -NR A R A and
  • A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NR A R A and -((C C 4 )alkyl)NR A R A , where each R A is independently H or methyl.
  • A is a cyclopropyl, cyclopentyl or cyclohexyl group.
  • A is naphthyl, optionally substituted by 1-2 groups independently selected from (CrC 4 )alkyl, halogen, cyano, halo(C C 4 )alkyl, (d-C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and
  • A is a 4-7 membered heterocycloalkyi group optionally substituted by 1-3 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, oxo, -NR A R A and -((Ci-C 4 )alkyl)NR A R A .
  • A is a 9-10 membered heteroaryl optionally substituted by 1 -2 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, oxo, -NR A R A and -((Ci-C 4 )alkyl)NR A R A .
  • A is isoquinolyl, indazolyl, tetrahydroisoquinolinonyl, isoindolinonyl, and indolinyl.
  • A is a 5-6 membered heteroaryl optionally substituted by 1 -2 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(C C 4 )alkyl, (C C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and -((CrC 4 )alkyl)NR A R A .
  • A is a 5-6 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl,
  • A is oxazolyl, pyrazolyl, or thienyl optionally substituted by a methyl group.
  • A is pyrazolyl or thienyl, optionally substituted by a methyl group.
  • A is thienyl.
  • A is oxazolyl.
  • A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 -2 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (C C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and -((C C 4 )alkyl)NR A R A .
  • A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A R A and -((C C 4 )alkyl)NR A R A , where each R A is
  • A is pyridyl or pyridyl-N-oxide. In specific embodiments, A is pyridyl.
  • Z is -S0 2 NR x - or -NR x S0 2 -.
  • Z is -NHCH(CF 3 )- or -CH(CF 3 )NH-.
  • Z is -CH(CF 3 )- or -(C 1 -C 4 )alkyl-.
  • Z is -NR X - or -(C C 3 )alkyl-NR x -.
  • each R x may be independently selected from H, (C 1 -C 4 )alkyl, and optionally substituted (C 2 -C 4 )alkyl, where said optionally substituted (C 2 -C 4 )alkyl is optionally substituted by hydroxyl, cyano, amino, (C C 4 )alkoxy, (CrC 4 )alkyl)NH-, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)N-.
  • each R x may be independently selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N- methylaminoethyl- and dimethylaminoethyk
  • each R x is independently H, methyl or cyanoethyl, more specifically, R x is H or methyl.
  • n is 0-4; particularly
  • n is 1 or n is 0.
  • one of R 2 and R 3 is other than hydrogen.
  • both R 2 and R 3 are C 1-4 alkyl (e.g., methyl).
  • one of R 2 and R 3 is H and the other of R 2 and R 3 is C 1-4 alkyl (e.g., methyl).
  • R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (Ci-C 4 )alkyl,
  • R Ya is selected from H, (C C 4 )alkyl, phenyl(C C 2 )alkyl- and (C 3 -C 6 )cycloalkyl(CrC 2 )alkyl-, and each R Yb is independently selected from H and (Ci-C 4 )alkyl, specifically H and methyl.
  • R 2 and R 3 are independently selected from H and optionally substituted (Ci-C 4 )alkyl
  • R 2 and R 3 are independently selected from H and optionally substituted (C 1 -C 4 )alkyl, phenyl(d-C 2 )alkyl-, and
  • R 2 and R 3 are independently selected from H, fluoro, and optionally substituted (Ci-C 4 )alkyl, phenyl(Ci-C 4 )alkyl-, and
  • R 2 is selected from amino, (Ci-C 4 )alkylamino, ((Ci-C 3 )alkyl)((Ci-C 3 )alkyl)amino,
  • R 3 is selected from H and optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl-, and (C 3 -C7)cycloalkyl(C C 4 )alkyl-.
  • n when n is 1-4, R 2 is selected from amino, hydroxyl, and (C 1 -C 4 )alkoxy, and R 3 is selected from H and optionally substituted (Ci-C 4 )alkyl, phenyl(C 1 -C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C 1 -C 2 )alkyl-.
  • n is 1-3
  • R 2 is hydroxyl and R 3 is H or methyl; more specifically, n is 1 , R 2 is hydroxyl and R 3 is H or methyl.
  • R 2 and R 3 are independently selected from H and optionally substituted (CrC 4 )alkyl, phenyl(Ci-C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl-.
  • R 2 is selected from H and optionally substituted (Ci-C 4 )alkyl, phenyl(Ci-C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl- and R 3 is selected from H and methyl.
  • R 2 and R 3 are independently selected from H and methyl. In more specific embodiments, both R 2 and R 3 are H or both R 2 and R 3 are methyl.
  • the aryl, phenyl, cycloalkyi and each of the (CrC 4 )alkyl or (Ci-C 2 )alkyl moieties of said optionally substituted (Ci-C 4 )alkyl, aryl(Ci-C 4 )alkyl-, phenyl (Ci-C 4 )alkyl- (C 3 -C 7 )cycloalkyl(Ci-C 4 )alkyl- and (C 3 -C 6 )cycloalkyl(C C 2 )alkyl- of any R 2 and R 3 are optionally substituted by 1 , 2 or 3 halogen (specifically fluorine) groups and/or 1 or 2 groups independently selected from cyano, (Ci-C 4 )alkyl, halo(C 1 -C 4 )alkyl,
  • R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyl group is optionally substituted by a substituent selected from
  • each R Yb is independently selected from H and (Ci-C 4 )alkyl, specifically H and methyl.
  • R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyi or heterocycloalkyl group is optionally substituted by a substituent selected from (Ci-C 4 )alkyl, aryl(C C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C 1 -C 2 )alkyl-.
  • R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2- dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl, cyclopropyl, cyclohexyl, 1- ethyl-piperidinyyl, tetrahydrofuranyl, piperidinyl, 1-methyl-pyrrolidinyl, 1-benzyl-pyrrolidinyl, 1-cyclopropylmethyl-pyrrolidinyl, oxetanyl, azetidinyl, 1-methyl-azetidinyl, 1-benzyl- azetidinyl, or 1-cyclopropylmethyl-azetidinyl group.
  • R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1 - methyl-piperidinyl group.
  • L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and methyl.
  • L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano and methyl.
  • L is pyrazolyl, oxadiazolyl, 1 -methyl-imidazolyl, thiazolyl, thienyl, triazolyl, pyridyl, phenyl, oxazolyl or isoxazolyl, any of which is substituted by a methyl group.
  • L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is substituted by a methyl group.
  • R 4 is H, halogen, (Ci-C 4 )alkyl, halo(C C 2 )alkyl, (C C 2 )alkoxy, ((Ci-C 2 )alkyl)((Ci-C 2 )alkyl)N(Ci-C 3 )alkoxy-, ((Ci-C 2 )alkyl)((CrC 2 )alkyl)N(Ci-C 3 )alkyl-, (Ci-C 2 )haloalkyl, (C C 3 )alkylamino, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl, where said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 or
  • R 4 is H, methyl, bromo, trifluoromethyl
  • pyridyl dimethylaminoethoxy-, dimethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyl, or phenyl, where the pyridyl, cyclohexyl, piperidinyl, piperizinyl, imidazolyl, thienyl, or phenyl are optionally substituted by 1 -2 substituents independently selected from methyl, chloro, bromo, fluoro, trifluoromethyl, methoxy, and cyano.
  • R 4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, phenyl, 4-chlorophenyl, 2-bromophenyl-,4- fluorophenyl, 4-cyanophenyl, 3-trifluoromethylphenyl, 4-methoxyphenyl, cyclohexyl, imidazolyl, thienyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.
  • L-R 4 taken together, form a 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
  • 2,3-dihydro-1 ,4-benzodioxinyl benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl group, optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, phenyl, and morpholinylpropyl-.
  • L-R 4 taken together, form a 1 ,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group.
  • each R A and R c is independently selected from H and (Ci-C 4 )alkyl; specifically each R A and R c is
  • each R Y is independently selected from H, (C 1 -C 4 )alkyl, phenyl, and -(C 1 -C 4 )alkylphenyl; specifically each R Y is independently selected from H, methyl, ethyl, phenyl, benzyl and -ethylphenyl.
  • alkyl represents a saturated, straight or branched hydrocarbon moiety, which may be unsubstituted or substituted by one, or more of the substituents defined herein.
  • exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, f-butyl, n-pentyl, iso-pentyl (3- methyl-butyl), neo-pentyl (2,2-dimethylpropyl), etc.
  • Ci-C 4 refers to an alkyl containing from 1 to 4 carbon atoms.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as “haloalkyl” or “cycloalkyl-alkyl” or “arylalkyl”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • arylalkyl is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by the bonding arrangement present in a benzyl group (-CH 2 -phenyl).
  • alkyl may be used to define a divalent substituent, such as a group bonded to two other groups.
  • alkyl is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • pentyl is intended to represent a pentylene diradical -wherein the pentyl moiety is any one of a divalent straight (-CH 2 CH 2 CH 2 CH 2 -) or branched (-CH 2 CH(CH 3 )CH 2 CH 2 - -CH 2 CH 2 CH(CH 2 CH 3 )-, -CH 2 CH 2 C(CH 3 ) 2 -) chain 5-carbon radical.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring.
  • (C 3 -C 8 )cycloalkyl refers to a non-aromatic cyclic
  • hydrocarbon ring having from three to eight ring carbon atoms.
  • (C 3 -C 8 )cycloalkyl groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkoxy refers to a group containing an alkyl radical attached through an oxygen linking atom.
  • (Ci-C 4 )alkoxy refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary "(d-C 4 )alkoxy” groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy.
  • Aryl represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be
  • aryl is phenyl
  • Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
  • Heterocycloalkyl represents a group or moiety comprising a stable, non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • the heterocycloalkyl may be attached by any atom of the monocyclic or bicyclic radical which results in the creation of a stable structure.
  • This term encompasses bicyclic heterocycloalkyl moieties where the rings are joined at two atoms per ring, as exemplified by the bonding arrangement in 2,5-diazabicyclo[2.2.1 ]heptyl, 2- azabicyclo[2.2.1 ]heptyl, 2-oxa-5-azabicyclo[2.2.1 ]heptyl, 7-oxa-2-azabicyclo[2.2.1 ]heptyl, 2-thia-5-azabicyclo[2.2.1 ]heptyl,7-azabicyclo[2.2.1 ]heptyl, 2,6- diazatricyclo[3.3.1 .13,7]decyl, 2-azatricyclo[3.3.1 .13,7]decyl, 2,4,9- triazatricyclo[3.3.1 .13,7]decyl, 8-azabicyclo[3.2.1 ]octyl, 2,5-diazabicyclo[2.2.2]octyl,
  • This term specifically excludes bicyclic heterocycloalkyl moieties where the rings are joined at a single atom per ring (spiro), as exemplified by the bonding arrangement in a 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl group.
  • heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]non
  • heterocycloalkyi groups are
  • 5-membered and/or 6-membered heterocycloalkyi groups such as pyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl or pyrazolinyl, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, tetrahydro-2H-1 ,4-thiazinyl, 1 ,4-dioxanyl, 1 ,3-oxathianyl, and 1 ,3-dithianyl.
  • pyrrolidyl or pyrrolidinyl
  • tetrahydrofuryl or tetrahydrofuranyl
  • Heteroaryl represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyi ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, isobenzofuryl, 2,3- dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl,
  • benzimidazolyl tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, indolinyl, cinnolinyl, pteridinyl, isothiazolyl.
  • heteroaryl groups present in the compounds of Formula I are 5-6 membered monocyclic heteroaryl groups.
  • Selected 5-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2 or 3 additional nitrogen ring atoms.
  • Selected 6-membered heteroaryl groups contain 1 , 2, 3 or 4 nitrogen ring heteroatoms.
  • Selected 5- or 6-membered heteroaryl groups include thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, and tetrazolyl or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and thiadiazolyl.
  • Some of the heteroaryl groups present in the compounds of Formula I are 9-10 membered bicyclic heteroaryl groups.
  • Selected 9-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2 or 3 additional nitrogen ring atoms.
  • Selected 10-membered heteroaryl groups contain one nitrogen, oxygen or sulfur ring heteroatom, and optionally contain 1 , 2, 3 or 4 additional nitrogen ring atoms.
  • Selected 9-10 membered heteroaryl groups include benzo[b]thienyl, isobenzofuryl, 2,3-dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinzolinyl,
  • Haldroxy or “hydroxyl” is intended to mean the radical -OH.
  • R 1 is -CF 3 ;
  • A is optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
  • any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, -NR A R A and
  • R 2 and R 3 are independently selected from H and optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(CrC 4 )alkyl-,
  • aryl, cycloalkyi and each of the (CrC 4 )alkyl moieties of said optionally substituted (CrC 4 )alkyl, aryl(CrC 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(CrC 4 )alkyl- of any R 2 and R 3 are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C 4 )alkyl, halo(d-C 4 )alkyl, (C C 4 )alkoxy, halo(Ci-C 4 )alkoxy, halogen, -NR A R A , -((C C 4 )alkyl)NR A R A , (C C 4 )alkoxy, hydroxyl, cyano, halo(Ci-C 4 )alkyl, and
  • R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 or 2 heteroatoms independently selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by 1 , 2 or 3 substituents independently selected from (CrC 4 )alkyl,
  • L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted,
  • L when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (CrC 4 )alkyl;
  • R 4 is H, (C C 4 )alkyl, halo, halo(Ci-C 4 )alkyl, (C C 4 )alkoxy,
  • optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (CrC 4 )alkoxy, (Ci-C 4 )alkylthio-, halo(Ci-C 4 )alkoxy, hydroxyl, -NR A R C and -((Ci-C 4 )alkyl)NR A R c ;
  • each R A is independently selected from H and (C 1 -C 4 )alkyl;
  • R c is H, (C 1 -C 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or R A and R c taken together with the atom to which they are attached form an optionally substituted 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
  • each R x is independently selected from H, (CrC 6 )alkyl, and optionally substituted
  • (C 2 -C 6 )alkyl where said optionally substituted (C 2 -C 6 )alkyl is optionally substituted by hydroxyl, cyano, amino, (C C 4 )alkoxy, (Ci-C 4 )alkyl)NH-, or ((Ci-C 4 )alkyl)((C C 4 )alkyl)N-; and
  • each R Y is independently selected from H, (Ci-C 4 )alkyl, phenyl, and
  • the method excludes treatment with the following compounds:
  • the invention is further directed to a method of treatment or use of a compound according to Formula I, wherein:
  • R 1 is CHF 2 or CF 3 ;
  • Y is a bond, Xi is O, and X 2 and X 3 are N, or
  • Y is -C(O)-, Xi and X 2 are CH, and X 3 is S, or
  • Y is -C(O)-, Xi is O, and X 2 and X 3 are CH;
  • A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A R A and -((Ci-C 4 )alkyl)NR A R A , or
  • A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NR A R A and -((Ci-C 4 )alkyl)NR A R A , or
  • A is a 5-6 membered heteroaryl or a 9-10 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl, -NR A R A and -((CrC 4 )alkyl)NR A R A , where the 5-6 membered heteroaryl or 9-10 membered heteroaryl contains 1 ring heteroatom selected form N, O and S and optionally contains 1 additional ring nitrogen atom,
  • each R A is independently H or methyl;
  • n 0-3 and R 2 and R 3 are independently selected from H and optionally substituted (Ci-C 4 )alkyl, phenyl(C C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl-, or
  • n 1 -3 and R 2 is hydroxyl and R 3 is H or methyl, or
  • n is 0-3 and R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (Ci-C 4 )alkyl, halo(Ci-C 4 )alkyl, halogen, cyano,
  • R Ya is selected from H, (Ci-C 4 )alkyl phenyl(Ci-C 2 )alkyl- and (C 3 -C 6 )cycloalkyl(d-C 2 )alkyl-, and each R Yb is independently selected from H and (C 1 -C 4 )alkyl;
  • L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and methyl;
  • R 4 is H, halogen, (d-C 4 )alkyl, halo(C C 2 )alkyl, (C C 2 )alkoxy,
  • the invention is further directed to a method of treatment or use of a compound according to Formula I, as defined herein wherein:
  • n 0-3 and R 2 and R 3 are independently selected from H and optionally substituted (Ci-C 4 )alkyl, phenyl(C C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C C 2 )alkyl-, or
  • n 1 -3 and R2 is hydroxyl and R 3 is H or methyl, or
  • n is 0-3 and R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by a substituent selected from (C 1 -C 4 )alkyl, aryl(C 1 -C 2 )alkyl-, and
  • R x is H, methyl or cyanoethyl
  • L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano and methyl; and
  • R 4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-,
  • the invention is further directed to a method of treatment or use of a compound according to Formula I, wherein:
  • R 1 is CHF 2 or CF 3 ;
  • Y is a bond
  • X- ⁇ is O
  • X 2 and X 3 are N
  • Y is -C(O)-, Xi and X 2 are CH, and X 3 is S, or
  • Y is -C(O)-, X ⁇ is O, and X 2 and X 3 are CH;
  • A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group, or a thienyl, pyridyl, cydopropyl, cyclopentyl or cyclohexyl group;
  • n 0 or 1 and both R 2 and R 3 are H or both R 2 and R 3 are methyl, or
  • n 1 and R 2 is hydroxyl and R 3 is H or methyl, or
  • n 0 or 1 and R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1 -methyl-piperidinyl group;
  • L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is optionally substituted by a methyl group;
  • R 4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, phenyl, 4-chlorophenyl,
  • L-R 4 taken together, form a 1 ,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group; or a salt, particularly a pharmaceutically acceptable salt, thereof.
  • the invention is more specifically directed to a method of treatment or use of a compound according to Formula I, wherein:
  • R 1 is CHF 2 or CF 3 ;
  • Y is a bond, Xi is O, and X 2 and X 3 are N;
  • A is an unsubstituted phenyl or pyridyl group
  • n 1 ;
  • R 2 and R 3 are both methyl, or
  • R 2 is hydroxyl and R 3 is methyl, or
  • R 2 and R 3 are both hydrogen, or
  • R 2 is methyl and R 3 is hydrogen, or
  • R 2 is hydroxyl and R 3 is hydrogen, or
  • R 2 is dimethylamino and R 3 is H, or
  • R 2 is ⁇ , ⁇ -dimethylaminoethyl and R 3 is H, or
  • R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, or a 1-methyl-piperidinyl group;
  • L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is optionally substituted by a methyl group;
  • R 4 is phenyl, optionally substituted by halo (chloro or fluoro), cyano,
  • optionally substituted means unsubstituted groups or rings (e.g., cycloalkyi, heterocycle, and heteroaryl rings) and groups or rings substituted with one or more specified substituents.
  • Representative compounds of Formula I include:
  • Particular compounds of Formula I include:
  • the term "compound(s) of Formula I" means a compound of Formula I, including any stereoisomer thereof (e.g., including any enantiomer or diastereomer of a compound recited above), in any form, for example, any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof), any solvate form (particularly a hydrate thereof (including mono-, di- and hemi- hydrates and including any hydrate of a salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms of any of the above)), and mixtures of various forms.
  • any salt or non-salt form e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof
  • any solvate form particularly a hydrate thereof (including mono-, di- and
  • the invention also includes the use of various deuterated forms of the compounds of Formula I.
  • Each available hydrogen atom attached to a carbon atom may be
  • the invention further includes the use of various radio-labelled or other isotopically enriched forms of the compounds of Formula I, such as compounds that contain a 2 H, 3 H, 14 C, 11 C, or 18 F atom. Similarly, a person of ordinary skill in the art will know how to synthesize such radio- labelled or isotopically enriched forms of the compounds of Formula I.
  • the present invention is directed to a method of treating an HDAC-mediated neurodegenerative disease or disorder which comprises administering to a patient in need thereof, a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
  • This invention is also directed to a method of treatment of a neurodegenerative disease or disorder associated with deacetylases, such as,
  • patient refers to a mammal, specifically, a human.
  • a therapeutically "effective amount” is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to inhibit the activity of HDAC such that a disease condition which is mediated by that activity is reduced, alleviated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC 5 o), efficacy (EC 5 o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is a neurodegenerative disease or disorder associated with deacetylases, such as, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NIID), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA).
  • the methods of treatment for mitigation of a disease condition include the use of the compounds in Formula I in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease.
  • the compounds of Formula I may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • the compounds of Formula I may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of Formula I depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of Formula I depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Treatment may be achieved using the compounds of Formula I as a monotherapy, or in dual or multiple combination therapy, such as in combination with other agents, for example, in combination with one or more of the following agents: DNA methyltransferase inhibitors, acetyl transferase enhancers, proteasome or HSP90 inhibitors, , and drugs that are currently used for the treatment of Alzheimer's disease (such as a cholinesterase inhibitor (galantamine, rivastigmine, donepezil, or tacrine, or memantine), Parkinson's disease (such as levodopa, alone or combined with carbidopa or combined with benserazide, a dopamine agonist, such as pramipexole, ropinirole, or apomorphine , a MAO B inhibitor, such as selegiline or rasagiline, or a Catechol O-methyltransferase
  • DNA methyltransferase inhibitors such as a cholinesterase inhibitor (galant
  • tolcapone such as tolcapone.
  • entacapone alone or combined with carbidopa and levodopa or an anticholinergic, such as benztropine or trihexyphenidy, or a glutamate (NMDA) blocking drug, such as amantadine
  • NMDA glutamate
  • amantadine neuronal intranuclear inclusion disease
  • Huntington's disease such as tetrabenazine, haloperidol and clozapine
  • antiseizure drugs such as clonazepam and antianxiety drugs such as diazepam
  • spinocerebellar ataxia which are administered in effective amounts as is known in the art.
  • the compounds of Formula I will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect, the invention is directed to the administration of a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically-acceptable excipient to treat a neurodegenerative disease, disorder or condition.
  • compositions useful in the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions may be prepared and packaged in unit dosage form.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof.
  • the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of Formula I.
  • the pharmaceutical compositions typically contain one compound of Formula I. However, in certain embodiments, the pharmaceutical compositions may contain more than one compound of Formula I. In addition, the pharmaceutical compositions may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a material, composition or vehicle involved in giving form or consistency to the composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of Formula I when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically-acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • the compounds of Formula I and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of Formula I once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants,
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions useful in the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to the use of a solid oral dosage form , such as a tablet or capsule, comprising an effective amount of a compound of Formula I and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • Tablets are prepared using conventional methods and are formulated as follows:
  • Capsules are prepared using conventional methods and are formulated as follows
  • WO201 1/088181 "Deacetylase inhibition promotes the generation and function of regulatory T cells," R.Tao, E. F. de Zoeten, E. O " zkaynak, C. Chen, L. Wang, P. M. Porrett, B. Li, L. A. Turka, E. N. Olson, M. I. Greene, A. D. Wells, W. W. Hancock, Nature Medicine, 13 (1 1 ), 2007.
  • HDAC7 targeting enhances FOXP3+ Treg function and induces long-term allograft survival L. Wang, et al., Am. J. Transplant 9, S621 (2009).
  • HDAC-MEF2 complexes A. Nebbioso, F. Manzo, M. Miceli, M. Conte, L. Manente, A. Baldi, A. De Luca, D. Rotili, S. Valente, A. Mai, A. Usiello, H. Gronemeyer, L. Altucci, EMBO reports 10 (7) , 776-782, 2009. and references therein.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention a pour objet une méthode de traitement d'une maladie ou d'un trouble neurodégénératif par l'administration d'un composé ayant la formule (I) : dans laquelle X1 ; X2, X3, R1, R2, R3, R4, Y, A, Z, L et n sont tels que définis ici.
PCT/US2012/046170 2011-07-13 2012-07-11 Méthodes de traitement WO2013009810A1 (fr)

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016031815A1 (fr) * 2014-08-26 2016-03-03 武田薬品工業株式会社 Composé hétérocyclique
WO2016065583A1 (fr) * 2014-10-30 2016-05-06 Merck Sharp & Dohme Corp. Antagonistes du récepteur d'orexine à base d'oxazole
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10047073B2 (en) 2015-05-07 2018-08-14 Chdi Foundation, Inc Histone deacetylase inhibitors and compositions and methods of use thereof
US10053434B2 (en) 2015-05-07 2018-08-21 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10183937B2 (en) * 2014-12-09 2019-01-22 Bayer Aktiengesellschaft 1,3-thiazol-2-yl substituted benzamides
US10308643B2 (en) 2015-07-17 2019-06-04 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10357484B2 (en) 2015-07-17 2019-07-23 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10406146B2 (en) 2015-08-25 2019-09-10 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10435399B2 (en) 2017-07-31 2019-10-08 Takeda Pharmaceutical Company Limited HDAC6 inhibitory heterocyclic compound
US10472354B2 (en) 2014-12-09 2019-11-12 Bayer Aktiengesellschaft 1,3-thiazol-2-yl substituted benzamides
US10501425B2 (en) 2015-10-02 2019-12-10 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
WO2020032071A1 (fr) * 2018-08-08 2020-02-13 日本農薬株式会社 Composé oxadiazoline ou sels de celui-ci, bactéricide agricole ou horticole contenant ledit composé, et procédé d'utilisation associé
US10640497B2 (en) 2015-12-02 2020-05-05 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10798941B2 (en) 2016-01-08 2020-10-13 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10899724B2 (en) 2015-10-02 2021-01-26 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11083196B2 (en) 2016-03-24 2021-08-10 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
CN114846012A (zh) * 2019-09-27 2022-08-02 武田药品工业株式会社 可用作hdac6抑制剂的2-异吲哚-1,3,4-噁二唑衍生物
CN115463215A (zh) * 2022-07-26 2022-12-13 苏州大学 Hdac9及其抑制剂的新用途
US11897871B1 (en) 2021-06-14 2024-02-13 Scorpion Therapeutics, Inc. Methods for treating cancer
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US11974572B2 (en) 2017-03-31 2024-05-07 Sygenta Participations Ag Fungicidal compositions

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018045A1 (fr) * 1999-09-08 2001-03-15 Sloan-Kettering Institute For Cancer Research Structure cristalline d'une deacetylase et ses inhibiteurs
US20050256153A1 (en) * 2004-05-17 2005-11-17 Dhanoa Dale S Thienopyridinone compounds and methods of treatment
US20090048228A1 (en) * 2004-12-10 2009-02-19 Barbara Attenni Heterocycle Derivatives As Histone Deacetylase (Hdac) Inhibitors
US20100197723A1 (en) * 2008-12-03 2010-08-05 Shomir Ghosh Bicyclic compounds and methods of making and using same
US20110117073A1 (en) * 2009-09-16 2011-05-19 Avila Therapeutics, Inc. Protein Kinase Conjugates and Inhibitors
WO2011088187A1 (fr) * 2010-01-13 2011-07-21 Tempero Pharmaceuticals, Inc. Composés et procédés

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018045A1 (fr) * 1999-09-08 2001-03-15 Sloan-Kettering Institute For Cancer Research Structure cristalline d'une deacetylase et ses inhibiteurs
US20050256153A1 (en) * 2004-05-17 2005-11-17 Dhanoa Dale S Thienopyridinone compounds and methods of treatment
US20090048228A1 (en) * 2004-12-10 2009-02-19 Barbara Attenni Heterocycle Derivatives As Histone Deacetylase (Hdac) Inhibitors
US20100197723A1 (en) * 2008-12-03 2010-08-05 Shomir Ghosh Bicyclic compounds and methods of making and using same
US20110117073A1 (en) * 2009-09-16 2011-05-19 Avila Therapeutics, Inc. Protein Kinase Conjugates and Inhibitors
WO2011088187A1 (fr) * 2010-01-13 2011-07-21 Tempero Pharmaceuticals, Inc. Composés et procédés

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US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
USRE47193E1 (en) 2013-10-14 2019-01-08 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
JPWO2016031815A1 (ja) * 2014-08-26 2017-06-15 武田薬品工業株式会社 複素環化合物
WO2016031815A1 (fr) * 2014-08-26 2016-03-03 武田薬品工業株式会社 Composé hétérocyclique
US10081624B2 (en) 2014-08-26 2018-09-25 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10435398B2 (en) 2014-10-30 2019-10-08 Merck Sharp & Dohme Corp. Oxazole orexin receptor antagonists
WO2016065583A1 (fr) * 2014-10-30 2016-05-06 Merck Sharp & Dohme Corp. Antagonistes du récepteur d'orexine à base d'oxazole
US11142523B2 (en) 2014-12-09 2021-10-12 Bayer Aktiengesellschaft 1,3-thiazol-2-yl substituted benzamides
US10183937B2 (en) * 2014-12-09 2019-01-22 Bayer Aktiengesellschaft 1,3-thiazol-2-yl substituted benzamides
US10472354B2 (en) 2014-12-09 2019-11-12 Bayer Aktiengesellschaft 1,3-thiazol-2-yl substituted benzamides
US10053434B2 (en) 2015-05-07 2018-08-21 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
US10047073B2 (en) 2015-05-07 2018-08-14 Chdi Foundation, Inc Histone deacetylase inhibitors and compositions and methods of use thereof
US10357484B2 (en) 2015-07-17 2019-07-23 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10308643B2 (en) 2015-07-17 2019-06-04 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10406146B2 (en) 2015-08-25 2019-09-10 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11180462B2 (en) 2015-10-02 2021-11-23 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10501425B2 (en) 2015-10-02 2019-12-10 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10899724B2 (en) 2015-10-02 2021-01-26 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11066375B2 (en) 2015-10-02 2021-07-20 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10640497B2 (en) 2015-12-02 2020-05-05 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11259524B2 (en) 2016-01-08 2022-03-01 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10798941B2 (en) 2016-01-08 2020-10-13 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11083196B2 (en) 2016-03-24 2021-08-10 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US11974572B2 (en) 2017-03-31 2024-05-07 Sygenta Participations Ag Fungicidal compositions
US10435399B2 (en) 2017-07-31 2019-10-08 Takeda Pharmaceutical Company Limited HDAC6 inhibitory heterocyclic compound
JP7407114B2 (ja) 2018-08-08 2023-12-28 日本農薬株式会社 オキサジアゾリン化合物又はその塩類及び該化合物を含有する農園芸用殺菌剤並びにその使用方法
WO2020032071A1 (fr) * 2018-08-08 2020-02-13 日本農薬株式会社 Composé oxadiazoline ou sels de celui-ci, bactéricide agricole ou horticole contenant ledit composé, et procédé d'utilisation associé
JPWO2020032071A1 (ja) * 2018-08-08 2021-08-26 日本農薬株式会社 オキサジアゾリン化合物又はその塩類及び該化合物を含有する農園芸用殺菌剤並びにその使用方法
US12010995B2 (en) 2018-08-08 2024-06-18 Nihon Nohyaku Co., Ltd. Oxadiazoline compounds or salts thereof, agrohorticultural fungicides containing the compounds, and methods of using the same
CN114846012A (zh) * 2019-09-27 2022-08-02 武田药品工业株式会社 可用作hdac6抑制剂的2-异吲哚-1,3,4-噁二唑衍生物
US11453661B2 (en) 2019-09-27 2022-09-27 Takeda Pharmaceutical Company Limited Heterocyclic compound
CN114846012B (zh) * 2019-09-27 2024-01-26 武田药品工业株式会社 可用作hdac6抑制剂的2-异吲哚-1,3,4-噁二唑衍生物
US11958845B2 (en) 2019-09-27 2024-04-16 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11897871B1 (en) 2021-06-14 2024-02-13 Scorpion Therapeutics, Inc. Methods for treating cancer
CN115463215A (zh) * 2022-07-26 2022-12-13 苏州大学 Hdac9及其抑制剂的新用途

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