WO2013009810A1 - Methods of treatment - Google Patents

Methods of treatment 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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French (fr)
Inventor
Shomir Ghosh
Mercedes Lobera
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Tempero Pharmaceuticals, Inc.
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Publication of WO2013009810A1 publication Critical patent/WO2013009810A1/en

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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.

Abstract

Disclosed is a method of treating a neurodegenerative disease or disorder by administering a compound having the formula (I): wherein X1; X2, X3, R1, R2, R3, R4, Y, A, Z, L and n are as defined herein.

Description

METHODS OF TREATMENT
BACKGROUND OF THE INVENTION
Field of the Invention
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
Background of the Invention
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
(HDACs) catalyze the deacetylation of histone and non-histone proteins and play an important role in epigenetic regulation. 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, HDAC5 and HDAC9 are highly expressed in the brain. 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
(http://bmi.epfl.ch/files/content/sites/bmi/files/shared/Abstract Gillian Bates.pdD. 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
(Kazantsev et al. Nature Reviews Drug Discovery, 2008, p. 854). Additionally, HDAC6 activity has been shown to be required for autophagic degradation of aggregated
huntingtin, suggesting a role in protecting cells from polyQ toxicity (Iwata, et al., J. Biol. Chem., 2005, p. 40282).
Based on the above evidence, 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.
SUMMARY OF THE INVENTION
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:
Figure imgf000003_0001
R1 is halo(CrC4)alkyl, wherein said halo(Ci-C4)alkyl contains at least 2 halo groups;
Y is a bond and Xi is O, N or NH, X2 is N or CH and X3 is N or NH,
or Y is -C(O)- and Xi and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and Xi is O, X2 is CH or N, and X3 is CH or N;
A is optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
wherein any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -NRARA and
-((C C4)alkyl)NRARA; Z is -C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -S02- -S02NRx-, -NRxS02-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(d-C4)alkyl-, -NRX-, or -(C C3)alkyl-NRx-; n is 0-4;
when n is 0, R2 and R3 are independently selected from H and optionally substituted (C C4)alkyl, aryl(C C4)alkyl-, and (C3-C7)cycloalkyl(C C4)alkyl-,
when n is 1-4, R2 and R3 are independently selected from H, fluoro, and optionally substituted (Ci-C4)alkyl, aryl(Ci-C4)alkyl-, and (C3-C7)cycloalkyl(Ci-C4)alkyl-, wherein, when n is 1 , R2 is F and R3 is H, then Z is -C(=0)NRx-, -NRxC(=0)NRx, -S02NRx-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(C C4)alkyl-, -NRX-, or -(C C3)alkyl-NRx-, and when n is 1-4, R2 is selected from -NRARB, -(C C4)alkyl-NRARB, -CONRARB,
-(Ci-C4)alkyl-CONRARB, -C02H, -(Ci-C4)alkyl-C02H, hydroxyl, hydroxy(C C4)alkyl-, (Ci-C3)alkoxy, and (Ci-C3)alkoxy(Ci-C4)alkyl-, and R3 is selected from H and optionally substituted (C C4)alkyl, aryl(C C4)alkyl-, and (C3-C7)cycloalkyl(C C4)alkyl-,
wherein the aryl, cycloalkyi and each of the (CrC4)alkyl moieties of said optionally substituted (C C4)alkyl, aryl(C C4)alkyl-, and (C3-C7)cycloalkyl(C C4)alkyl- of any R2 and R3 are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C4)alkyl, halo(d-C4)alkyl, (C C4)alkoxy, halo(d-C4)alkoxy, -NRARA,
-((C C4)alkyl)NRARA, and hydroxyl;
or R2 and R3 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 (Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, cyano, aryl(Ci-C4)alkyl-, (C3-C7)cycloalkyl(Ci-C4)alkyl-, -ORY, -NRYRY, -C(=0)ORY, -C(=0)NRYRY, -NRYC(=0)RY, -S02NRYRY, -NRYS02RY, -OC(=0)NRYRY, -NRYC(=0)ORY, and -NRYC(=0)NRYRY; and
L is 5-6 membered heteroaryl or phenyl which is substituted by R4 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 (Ci-C4)alkyl;
R4 is H, (Ci-C4)alkyl, halo, halo(Ci-C4)alkyl, (C C4)alkoxy,
((Ci-C4)alkyl)((CrC4)alkyl)N(Ci-C4)alkoxy, ((Ci-C4)alkyl)((Ci-C4)alkyl)N(C C4)alkyl-, (Ci-C4)haloalkoxy-, (Ci-C4)alkylamino, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyi, or optionally substituted 5-6 membered heteroaryl, wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from
(C1-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (d-C4)alkoxy, (C1-C4)alkylthio-,
halo(Ci-C4)alkoxy, hydroxyl, -NRARC and -((Ci-C4)alkyl)NRARc;
or L-R4 , taken together, form a 1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkylthio- halo(C C4)alkoxy, hydroxyl, -NRARC and -((C C4)alkyl)NRARc;
wherein each RA is independently selected from H and (CrC4)alkyl;
RB is H, (Ci-C4)alkyl, halo(Ci-C4)alkyl,
Figure imgf000005_0001
-C(=0)NH2,
Figure imgf000005_0002
-S02(Ci-C4)alkyl, or RA and RB taken together with the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (Ci-C4)alkyl;
Rc is H, (Ci-C4)alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or RA and Rc 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 (C1-C4)alkyl;
each Rx is independently selected from H, (C1-C6)alkyl, and optionally substituted
(C2-C6)alkyl, where said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((C C4)alkyl)N-; and
each RY is independently selected from H, (Ci-C4)alkyl, phenyl, and
-(CrC4)alkylphenyl;
or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
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). 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). DETAILED DESCRIPTION OF THE INVENTION
The alternative definitions for the various groups and substituent groups of Formula I provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions.
In one embodiment of the compound or salt of Formula I, R1 is a fluoro- alkyl group containing at least 2 fluoro groups (atoms). In another embodiment, R1 is a (CrC2)alkyl group containing at least 2 fluoro groups. In a specific embodiment, R1 is CHF2 or CF3; more specifically, R1 is CF3
In selected embodiments of the compound or salt of Formula I, when Y is a bond,
X-i, X2, and X3, taken together with the atoms to which they are attached, form an oxadiazolyl (X-i is O, X2 and X3 are N), oxazolyl (X-i is O, X2 is CH, X3 is N), imidazolyl (X-i is N or NH, X2 is CH, X3 is N or NH); or a triazolyl (Xi is N or NH, X2 is N, X3 is N or NH) ring moiety. In specific embodiments, when Y is a bond, X-i, X2, and X3, taken together with the atoms to which they are attached form an oxadiazolyl ring moiety.
In selected embodiments of the compound or salt of Formula I, when Y is -C(O)-, X-i, X2, and X3, taken together with the atoms to which they are attached, form an thiazolyl (X3 is S, Xi is CH and X2 is N or X3 is S, Xi is N and X2 is CH), oxazolyl (X3 is O, Xi is CH and X2 is N or X3 is O, Xi is N and X2 is CH), thienyl (X^ and X2 are CH, X3 is S) or furanyl (Xi and X2 are CH, X3 is O) ring moiety. In specific embodiments, when Y is -C(O)-, X-i, X2, and X3, taken together with the atoms to which they are attached form a thienyl, thiazolyl or oxazolyl ring moiety, more specifically a thienyl moiety.
In selected embodiments of the compound or salt of Formula I, when Y is -C(O)-, X-i, X2, and X3, taken together with the atoms to which they are attached, form a furanyl or furyl (Xi is O, X2 and X3 are CH), oxazolyl (Xi is O, X2 is CH, and X3 is N), isoxazolyl (Xi is O, X2 is N, and X3 is CH), or oxadiazolyl (Xi is O, X2 and X3 are N) ring moiety. In specific embodiments, when Y is -C(O)-, X-i, X2, and X3, taken together with the atoms to which they are attached form a furanyl (furyl) ring moiety. The invention is further directed to methods of treatment and uses of a compound of Formula (l-a):
Figure imgf000007_0001
wherein R1, R2, R3,R4, A, Z, n and L are as defined herein.
The invention is still further directed to a compound of Formula (l-b):
Figure imgf000007_0002
wherein R1, R2, R3,R4, 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):
Figure imgf000007_0003
wherein R1, R2, R3,R4, 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):
Figure imgf000007_0004
Figure imgf000008_0001
wherein R1, R2, R3,R4, 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):
Figure imgf000008_0002
In another embodiment of the compound or salt of Formula I, A is a phenyl group optionally substituted by 1-2 groups independently selected from (C1-C4)alkyl, halogen, cyano, halo(C C4)alkyl, (d-C4)alkoxy, halo(C C4)alkoxy, -NRARA and
-((CrC4)alkyl)NRARA. In further embodiments, A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and -((C C4)alkyl)NRARA, where each RA is
independently H or methyl. In specific embodiments of the compound or salt of Formula I, A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group.
In yet another embodiment of the compound or salt of Formula I, A is a
cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from (Ci-C4)alkyl, (Ci-C4)alkoxy, -NRARA and
-((CrC4)alkyl)NRARA. In further embodiments, A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NRARA and -((C C4)alkyl)NRARA, where each RA is independently H or methyl. In selected embodiments of the compound or salt of Formula I, A is a cyclopropyl, cyclopentyl or cyclohexyl group.
In another embodiment of the compound or salt of Formula I, A is naphthyl, optionally substituted by 1-2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(C C4)alkyl, (d-C4)alkoxy, halo(C C4)alkoxy, -NRARA and
-((C C4)alkyl)NRARA.
In another embodiment of the compound or salt of Formula I, A is a 4-7 membered heterocycloalkyi group optionally substituted by 1-3 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, oxo, -NRARA and -((Ci-C4)alkyl)NRARA.
In another embodiment of the compound or salt of Formula I, A is a 9-10 membered heteroaryl optionally substituted by 1 -2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, oxo, -NRARA and -((Ci-C4)alkyl)NRARA. In selected embodiments, A is isoquinolyl, indazolyl, tetrahydroisoquinolinonyl, isoindolinonyl, and indolinyl.
In further embodiments of the compound or salt of Formula I, A is a 5-6 membered heteroaryl optionally substituted by 1 -2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARA and -((CrC4)alkyl)NRARA. In still further embodiments, A is a 5-6 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl,
-NRARA and -((C1-C4)alkyl)NRARA, where each RA is independently H or methyl and the 5-6 membered heteroaryl contains 1 ring heteroatom selected form N, O and S and optionally contains 1 additional ring nitrogen atom. In selected embodiments, A is oxazolyl, pyrazolyl, or thienyl optionally substituted by a methyl group. In other selected embodiments, A is pyrazolyl or thienyl, optionally substituted by a methyl group. In specific embodiments, A is thienyl. In other specific embodiments, A is oxazolyl.
In yet other embodiments, A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 -2 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA. In further embodiments, 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, -NRARA and -((C C4)alkyl)NRARA, where each RA is
independently H or methyl. In selected embodiments of the compound or salt of Formula I, A is pyridyl or pyridyl-N-oxide. In specific embodiments, A is pyridyl.
In another embodiment of the compound or salt of Formula I, Z is -C(=0)NRx-, -NRxC(=0)NRx, or -NRxC(=0)-; particularly -C(=0)NRx- or -NRxC(=0)-. In another embodiment, Z is -S02NRx- or -NRxS02-. In another embodiment of the compound or salt of Formula I, Z is -NHCH(CF3)- or -CH(CF3)NH-. In another embodiment, Z is -CH(CF3)- or -(C1-C4)alkyl-. In another embodiment of the compound or salt of Formula I, Z is -NRX- or -(C C3)alkyl-NRx-.
For each of the above embodiments of Z, Rx, or for -NRxC(=0)NRx, each Rx, may be independently selected from H, (C1-C4)alkyl, and optionally substituted (C2-C4)alkyl, where said optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (CrC4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-. For each of the above embodiments of Z, Rx, or for -NRxC(=0)NRx, each Rx, may be independently selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N- methylaminoethyl- and dimethylaminoethyk In specific embodiments of the compound or salt of Formula I, each Rx is independently H, methyl or cyanoethyl, more specifically, Rx is H or methyl.
In particular embodiments, Z is -C(=0)NRx-, -S02-, -S02NRx-, -CH(CF3)NH-, methyl (methylenyl), ethyl (ethylenyl), -NRX-, or -(C C3)alkyl-NRx-, where each Rx is independently H, methyl or ethyl. In specific embodiments, each Rx is H. In selected embodiments of the compound or salt of Formula I, Z is -C(=0)NH-, -S02NH-,
-CH(CF3)NH-, ethyl (ethylenyl), -CH2NH-, -CH2N(CH2CH3)-, -CH(CH3)N(CH2CH3)-, or -CH(CH3)NH-. In specific embodiments, Z is -C(=0)NH- or -CH2NH-.
In another embodiment of the compound or salt of Formula I, n is 0-4; particularly
0-3. In specific embodiments, n is 1 or n is 0. In another embodiment, one of R2 and R3 is other than hydrogen. In yet another embodiment, both R2 and R3 are C1-4 alkyl (e.g., methyl). In a still further embodiment, one of R2 and R3 is H and the other of R2 and R3 is C1-4 alkyl (e.g., methyl). In a further embodiment of the compound or salt of Formula I, R2 and R3 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-C4)alkyl,
halo(Ci-C4)alkyl, halogen, cyano, aryl(Ci-C2)alkyl-, (C3-C6)cycloalkyl(Ci-C2)alkyl-, -ORYa, -NRYaRYb, -C(=0)ORYa, -C(=0)NRYaRYb, -NRYbC(=0)RYa, -S02NRYaRYb, and
-NRYbS02RYa, where RYa is selected from H, (C C4)alkyl, phenyl(C C2)alkyl- and (C3-C6)cycloalkyl(CrC2)alkyl-, and each RYb is independently selected from H and (Ci-C4)alkyl, specifically H and methyl.
In another embodiment of the compound or salt of Formula I, when n is 0, R2 and R3 are independently selected from H and optionally substituted (Ci-C4)alkyl,
phenyl(Ci-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl-.
In another embodiment, when n is 1 , R2 and R3 are independently selected from H and optionally substituted (C1-C4)alkyl, phenyl(d-C2)alkyl-, and
(C3-C6)cycloalkyl(C1-C2)alkyl-.
In another embodiment of the compound or salt of Formula I, when n is 1 , R2 is F and R3 is H, then Z is -C(=0)NH-, -NHC(=0)NH, -S02NH-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(Ci-C4)alkyl-, -NH-, or -CH2NH-; more specifically, Z is -C(=0)NH- or -CH2NH-.
In another embodiment, when n is 2-4, R2 and R3 are independently selected from H, fluoro, and optionally substituted (Ci-C4)alkyl, phenyl(Ci-C4)alkyl-, and
(C3-C6)cycloalkyl(Ci-C4)alkyk
In another embodiment of the compound or salt of Formula I, when n is 1-4, R2 is selected from amino, (Ci-C4)alkylamino, ((Ci-C3)alkyl)((Ci-C3)alkyl)amino,
amino(Ci-C4)alkyl, (Ci-C3)alkylamino(Ci-C4)alkyl,
((Ci-C3)alkyl)((Ci-C3)alkyl)amino(Ci-C4)alkyl,
(substituted(Ci-C3)alkyl)((Ci-C3)alkyl)amino(Ci-C4)alkyl (where said (substituted (Ci-C3)alkyl moiety is substituted by -C(=0)OH, -C(=0)0(C C4)alkyl, or 1-8 fluoro groups), aminocarbonyl(C1-C4)alkyl, (C1-C3)alkylaminocarbonyl(C1-C4)alkyl,
((C1-C3)alkyl)((C1-C3)alkyl)aminocarbonyl(C1-C4)alkyl, hydroxyl, hydroxy(CrC4)alkyl-, (C1-C4)alkoxy, and (C1-C4)alkoxy(C1-C4)alkyl- and R3 is selected from H and optionally substituted (C C4)alkyl, aryl(C C4)alkyl-, and (C3-C7)cycloalkyl(C C4)alkyl-. In another embodiment of the compound or salt of Formula I, when n is 1-4, R2 is selected from amino, hydroxyl, and (C1-C4)alkoxy, and R3 is selected from H and optionally substituted (Ci-C4)alkyl, phenyl(C1-C2)alkyl-, and (C3-C6)cycloalkyl(C1-C2)alkyl-. In another embodiment, n is 1-3, R2 is hydroxyl and R3 is H or methyl; more specifically, n is 1 , R2 is hydroxyl and R3 is H or methyl. In another embodiment, (for any value of n) R2 and R3 are independently selected from H and optionally substituted (CrC4)alkyl, phenyl(Ci-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl-.
In another embodiment of the compound or salt of Formula I, (for any value of n) R2 is selected from H and optionally substituted (Ci-C4)alkyl, phenyl(Ci-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl- and R3 is selected from H and methyl.
In specific embodiments of the compound or salt of Formula I (for any value of n), R2 and R3 are independently selected from H and methyl. In more specific embodiments, both R2 and R3 are H or both R2 and R3 are methyl.
In another embodiment, the aryl, phenyl, cycloalkyi and each of the (CrC4)alkyl or (Ci-C2)alkyl moieties of said optionally substituted (Ci-C4)alkyl, aryl(Ci-C4)alkyl-, phenyl (Ci-C4)alkyl- (C3-C7)cycloalkyl(Ci-C4)alkyl- and (C3-C6)cycloalkyl(C C2)alkyl- of any R2 and R3 are optionally substituted by 1 , 2 or 3 halogen (specifically fluorine) groups and/or 1 or 2 groups independently selected from cyano, (Ci-C4)alkyl, halo(C1-C4)alkyl,
(d-C4)alkoxy, halo(C C4)alkoxy, NRARA, -((C C4)alkyl)NRARA, and hydroxyl.
In another embodiment of the compound or salt of Formula I, R2 and R3 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
(Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, cyano, aryl(Ci-C2)alkyl-,
(C3-C6)cycloalkyl(CrC2)alkyl-, -ORYa, -NRYaRYb, -C(=0)ORYa, -C(=0)NRYaRYb,
-NRYbC(=0)RYa, -S02NRYaRYb, and -NRYbS02RYa, where RYa is selected from H,
(Ci-C4)alkyl phenyl(C C2)alkyl- and (C3-C6)cycloalkyl(C C2)alkyl-, and each RYb is independently selected from H and (Ci-C4)alkyl, specifically H and methyl.
In specific embodiments of the compound or salt of Formula I, R2 and R3 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-C4)alkyl, aryl(C C2)alkyl-, and (C3-C6)cycloalkyl(C1-C2)alkyl-. In selected embodiments of the compound or salt of Formula I, R2 and R3 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.
In specific embodiments, R2 and R3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1 - methyl-piperidinyl group.
In another embodiment of the compound or salt of Formula I, L is 5-6 membered heteroaryl or phenyl which is substituted by R4 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.
In another embodiment, L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano and methyl.
In selected embodiments of the compound or salt of Formula I, L is pyrazolyl, oxadiazolyl, 1 -methyl-imidazolyl, thiazolyl, thienyl, triazolyl, pyridyl, phenyl, oxazolyl or isoxazolyl, any of which is substituted by a methyl group.
In specific embodiments, L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is substituted by a methyl group.
In another embodiment of the compound or salt of Formula I, R4 is H, halogen, (Ci-C4)alkyl, halo(C C2)alkyl, (C C2)alkoxy, ((Ci-C2)alkyl)((Ci-C2)alkyl)N(Ci-C3)alkoxy-, ((Ci-C2)alkyl)((CrC2)alkyl)N(Ci-C3)alkyl-, (Ci-C2)haloalkyl, (C C3)alkylamino, optionally substituted (C3-C6)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 2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C2)alkyl, (C C2)alkoxy, halo(C C2)alkoxy, hydroxyl, -NRARC and
-((Ci-C4)alkyl)NRARc.
In a selected embodiments, R4 is H, methyl, bromo, trifluoromethyl,
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.
In a selected embodiments, of the compound or salt of Formula I R4 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.
In other embodiments of the compound or salt of Formula I, L-R4 , 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-.
In selected embodiments, L-R4 , taken together, form a 1 ,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group.
In another embodiment of the compound or salt of Formula I, each RA and Rc is independently selected from H and (Ci-C4)alkyl; specifically each RA and Rc is
independently selected from H, methyl and ethyl.
In another embodiment, each RY is independently selected from H, (C1-C4)alkyl, phenyl, and -(C1-C4)alkylphenyl; specifically each RY is independently selected from H, methyl, ethyl, phenyl, benzyl and -ethylphenyl.
As used herein, the term "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. The term "Ci-C4" refers to an alkyl containing from 1 to 4 carbon atoms.
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. For example, "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 (-CH2-phenyl).
In addition, the term "alkyl" may be used to define a divalent substituent, such as a group bonded to two other groups. In this instance, the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical. For example, "pentyl" is intended to represent a pentylene diradical -wherein the pentyl moiety is any one of a divalent straight (-CH2CH2CH2CH2CH2-) or branched (-CH2CH(CH3)CH2CH2- -CH2CH2CH(CH2CH3)-, -CH2CH2C(CH3)2-) chain 5-carbon radical.
As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "(C3-C8)cycloalkyl" refers to a non-aromatic cyclic
hydrocarbon ring having from three to eight ring carbon atoms. Exemplary
"(C3-C8)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. The term "(Ci-C4)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-C4)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
unsubstituted or substituted by one or more substituents defined herein.
Generally, in the compounds of Formula I, 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, 2- azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1 ]octyl, 8-azabicyclo[3.2.1 ]octyl, octahydro-1 H- pyrrolo[3,2-6]pyridyl group. 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. Illustrative examples of 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]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1 ]heptyl and 1 ,5,9-triazacyclododecyl.
Generally, in the compounds of Formula I, 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.
"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. This term is also intended to encompass heterocyclic groups containing nitrogen and/or sulfur where the nitrogen or sulfur heteroatoms are optionally oxidized. Illustrative examples of 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, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinzolinyl, benzothiazolyl,
benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, indolinyl, cinnolinyl, pteridinyl, isothiazolyl.
Some of the 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,
benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl.
The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo
substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH. The term "oxo" is intended to mean a keto diradical (=0), such as present on a pyrrolidin-2-one ring.
The compounds of Formula I are only those which are contemplated to be
"chemically stable" as will be appreciated by those skilled in the art.
Specifically, the ing to Formula (l-a):
Figure imgf000017_0001
wherein:
R1 is -CF3;
A is optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
wherein any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (C1-C4)alkyl, halogen, cyano, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -NRARA and
-((Ci-C4)alkyl)NRARA;
Z is -C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -S02- -S02NRx-, -NRxS02-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(Ci-C4)alkyl- -NRX-, or -(C C3)alkyl-NRx-; n is 0-4;
when n is 0, R2 and R3 are independently selected from H and optionally substituted (C C4)alkyl, aryl(C C4)alkyl-, and (C3-C7)cycloalkyl(CrC4)alkyl-,
when n is 1 -4, R2 and R3 are independently selected from H, fluoro, and optionally substituted (CrC4)alkyl, aryl(d-C4)alkyl-, and (C3-C7)cycloalkyl(CrC4)alkyl-, wherein, when n is 1 , R2 is F and R3 is H, then Z is -C(=0)NRx-, -NRxC(=0)NRx, -S02NRx-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(C C4)alkyl-, -NRX-, or -(C C3)alkyl-NRx-, and when n is 1 -4, R2 is selected from amino, hydroxyl, and (C1-C4)alkoxy, and R3 is selected from H and optionally substituted (C1-C4)alkyl, aryl(C1-C4)alkyl-, and
(C3-C7)cycloalkyl(Ci-C4)alkyl-,
wherein the aryl, cycloalkyi and each of the (CrC4)alkyl moieties of said optionally substituted (CrC4)alkyl, aryl(CrC4)alkyl-, and (C3-C7)cycloalkyl(CrC4)alkyl- of any R2 and R3 are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C4)alkyl, halo(d-C4)alkyl, (C C4)alkoxy, halo(Ci-C4)alkoxy, halogen, -NRARA, -((C C4)alkyl)NRARA, (C C4)alkoxy, hydroxyl, cyano, halo(Ci-C4)alkyl, and
halo(CrC4)alkoxy;
or R2 and R3 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 (CrC4)alkyl,
halo(C C4)alkyl, halogen, cyano, aryl(Ci-C4)alkyl-, (C3-C7)cycloalkyl(CrC4)alkyl-, -ORY, -NRYRY, -C(=0)ORY, -C(=0)NRYRY, -NRYC(=0)RY, -S02NRYRY, -NRYS02RY,
-OC(=0)NRYRY, -NRYC(=0)ORY, and -NRYC(=0)NRYRY; and
L is 5-6 membered heteroaryl or phenyl which is substituted by R4 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 (CrC4)alkyl;
R4 is H, (C C4)alkyl, halo, halo(Ci-C4)alkyl, (C C4)alkoxy,
((Ci-C4)alkyl)((CrC4)alkyl)N(Ci-C4)alkoxy, ((Ci-C4)alkyl)((Ci-C4)alkyl)N(C C4)alkyl-, (Ci-C4)haloalkoxy-, (Ci-C4)alkylamino, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyi, or optionally substituted 5-6 membered heteroaryl,
wherein said optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, (Ci-C4)alkylthio-, halo(Ci-C4)alkoxy, hydroxyl, -NRARC and -((Ci-C4)alkyl)NRARc;
or L-R4 , taken together, form a 1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, (d-C4)alkylthio-, halo(C C4)alkoxy, hydroxyl, -NRARC and -((C C4)alkyl)NRARc;
wherein each RA is independently selected from H and (C1-C4)alkyl; Rc is H, (C1-C4)alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or RA and Rc 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 Rx is independently selected from H, (CrC6)alkyl, and optionally substituted
(C2-C6)alkyl, where said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((C C4)alkyl)N-; and
each RY is independently selected from H, (Ci-C4)alkyl, phenyl, and
-(Ci-C4)alkylphenyl;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
In one embodiment of this invention, the method excludes treatment with the following compounds:
N-[(4-fluorophenyl)methyl]-4-[5-(2,2,2-trifluoroacetyl)-2-thienyl]-benzamide, N-[(4-fluorophenyl)methyl]-3-[5-(2,2,2-trifluoroacetyl)-2-thienyl]-benzamide, or a salt thereof.
Accordingly, the invention is further directed to a method of treatment or use of a compound according to Formula I, wherein:
R1 is CHF2 or CF3;
Y is a bond, Xi is O, and X2 and X3 are N, or
Y is -C(O)-, Xi and X2 are CH, and X3 is S, or
Y is -C(O)-, Xi is O, and X2 and X3 are CH;
A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and -((Ci-C4)alkyl)NRARA, or
A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NRARA and -((Ci-C4)alkyl)NRARA, 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, -NRARA and -((CrC4)alkyl)NRARA, 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,
where each RA is independently H or methyl; Z is -C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(Ci-C4)alkyl- or -(Ci-C4)alkylNRx-, where Rx is H, (C C4)alkyl, or optionally substituted (C2-C4)alkyl, where said optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (Ci-C4)alkoxy, (CrC4)alkyl)NH-, or
((Ci-C4)alkyl)((CrC4)alkyl)N-;
n is 0-3 and R2 and R3 are independently selected from H and optionally substituted (Ci-C4)alkyl, phenyl(C C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl-, or
n is 1 -3 and R2 is hydroxyl and R3 is H or methyl, or
n is 0-3 and R2 and R3 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-C4)alkyl, halo(Ci-C4)alkyl, halogen, cyano,
aryl(Ci-C2)alkyl- (C3-C6)cycloalkyl(C C2)alkyl-, -ORYa, -NRYaRYb, -C(=0)ORYa,
-C(=0)NRYaRYb, -NRYbC(=0)RYa, -S02NRYaRYb, and -NRYbS02RYa, where RYa is selected from H, (Ci-C4)alkyl phenyl(Ci-C2)alkyl- and (C3-C6)cycloalkyl(d-C2)alkyl-, and each RYb is independently selected from H and (C1-C4)alkyl;
L is 5-6 membered heteroaryl or phenyl which is substituted by R4 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; and
R4 is H, halogen, (d-C4)alkyl, halo(C C2)alkyl, (C C2)alkoxy,
((Ci-C2)alkyl)((CrC2)alkyl)N(Ci-C3)alkoxy-, ((Ci-C2)alkyl)((Ci-C2)alkyl)N(C C3)alkyl-, (Ci-C2)haloalkyl, (Ci-C3)alkylamino, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyi, or optionally substituted 5-6 membered heteroaryl, where said optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 or 2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C2)alkyl, (Ci-C2)alkoxy,
halo(Ci-C2)alkoxy, hydroxyl, -NRARC and -((Ci-C4)alkyl)NRARc;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to a method of treatment or use of a compound according to Formula I, as defined herein wherein:
n is 0-3 and R2 and R3 are independently selected from H and optionally substituted (Ci-C4)alkyl, phenyl(C C2)alkyl-, and (C3-C6)cycloalkyl(C C2)alkyl-, or
n is 1 -3 and R2 is hydroxyl and R3 is H or methyl, or
n is 0-3 and R2 and R3 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 (C1-C4)alkyl, aryl(C1-C2)alkyl-, and
(C3-C6)cycloalkyl(Ci-C2)alkyl-;
Rx is H, methyl or cyanoethyl;
L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R4 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
R4 is H, methyl, bromo, trifluoromethyl, 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;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to a method of treatment or use of a compound according to Formula I, wherein:
R1 is CHF2 or CF3;
Y is a bond, X-\ is O, and X2 and X3 are N, or
Y is -C(O)-, Xi and X2 are CH, and X3 is S, or
Y is -C(O)-, X^ is O, and X2 and X3 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;
Z is -C(=0)NH- or -CH2NH-;
n is 0 or 1 and both R2 and R3 are H or both R2 and R3 are methyl, or
n is 1 and R2 is hydroxyl and R3 is H or methyl, or
n is 0 or 1 and R2 and R3 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;
R4 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; or
L-R4 , 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:
R1 is CHF2 or CF3;
Y is a bond, Xi is O, and X2 and X3 are N;
A is an unsubstituted phenyl or pyridyl group;
Z is -C(=0)NH- or -CH2NH-;
n is 1 ;
R2 and R3 are both methyl, or
R2 is hydroxyl and R3 is methyl, or
R2 and R3 are both hydrogen, or
R2 is methyl and R3 is hydrogen, or
R2 is hydroxyl and R3 is hydrogen, or
R2 is dimethylamino and R3 is H, or
R2 is Ν,Ν-dimethylaminoethyl and R3 is H, or
R2 and R3 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;
R4 is phenyl, optionally substituted by halo (chloro or fluoro), cyano,
halo(C C2)alkyl, or (C C2)alkoxy;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
As used herein, the term "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.
The compounds of Formula I that are useful in the method of this invention (as well as methods for the preparation of such compounds) are described in WO201 1/088181 , the disclosure of which is incorporated herein by reference.
Representative compounds of Formula I include:
A/-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(4-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide, /V-(4-(1 H-imidazol-1-yl)benzyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-cyanoethyl)-/V-(pyridin-3-ylmethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)-/V-((4-(4-
(trifluoromethyl)phenyl)tetrahydro-2/-/-pyran-4-yl)methyl)benzamide ,
1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)-/V-(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzyl)methanamine,
/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
/V-((4-(4-phenylthiophen-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((1-(4-phenylthiazol-2-yl)cyclopentyl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-((4-(3-phenyl-1 H-1 ,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-
(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(2-phenylthiazol-4-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-(4-methoxyphenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(4-(4-chlorophenyl)thiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide ,
/V-(2-methyl-2-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-((1-methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(4-(4-fluorophenyl)thiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(4-cyclohexylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-(pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-(pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide, /V-((4-(4-phenylthiazol-2-yl)tetrahydro
1 ,2,4-oxadiazol-3-yl)thiophene-2-carboxamide,
/V-((4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
3-fluoro-/V-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
3-cyano-/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
3-methoxy-/\/-((4-(4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(4-(4-fluorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-((4-(4-(4-cyanophenyl)thiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)- 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzenesulfonamide,
3-ethyl-/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(3-bromophenyl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)-/V-((4-(4-(4- (trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide,
/V-(2-methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-2-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropanecarboxamide,
/V-((1-methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide, /V-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
/V-(2-(2-(4-chlorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)isonicotinamide,
/V-(2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
/V-(2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)picolinamide,
/V-(2-(dimethylamino)-2-(4-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(3-phenyl-1 H-1 ,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-((1-(4-phenylthiazol-2-yl)cyclopropyl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
3-(4-(4-f|UOrophenyl)thiazol-2-yl)-/\/-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)propanamide,
/V-(2-(2-(4-chlorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-((4-phenylthiazol-2-yl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(4-(4-fluorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
/V-(2-(4-(4-chlorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-(4-(4-chlorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
/V-((4-(3,4-dihydroisoquinolin-2(1 H)-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/\/-methyl-/\/-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide, /V-(2-(2-(4-fluorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
2,2,2-trifluoro-/\/-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-1-(3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)phenyl)ethanamine,
A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(3-(4-chlorophenyl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-methyl-2-(3-phenyl-1 H-1 ,2,4-triazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-methyl-2-(3-phenyl-1 H-1 ,2,4-triazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-5-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(3-(4-chlorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-methyl-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(3-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(5-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(3-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-methyl-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)nicotinamide, /V-(2-methyl-2-(5-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
Λ/-((4-([1 , 1 '-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
W-((4-([1 , 1 '-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-
1 ,2,4-oxadiazol-3-yl)nicotinamide,
/V-((2-(4-fluorophenyl)oxazol-4-yl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-((4-(2-(4-fluorophenyl)oxazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
/V-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methyl-/\/-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)benzyl)propan-1 -amine,
3-(3-(4-(4-phenylthiazol-2-yl)butyl)phenyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole,
/V-(2-methyl-2-(5-phenyloxazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-phenylthiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-methyl-2-(2-phenylthiazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)nicotinamide,
/V-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
2-fluoro-/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)oxazole-4-carboxamide,
Λ/-(2-(1 -methyl-2-phenyl-1 H-imidazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide, /V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
5-(5-(difluoromethyl)-1 ,2,4-oxadiazol-3-yl)-/\/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2- methylpropyl)nicotinamide,
/V-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide hydrochloride,
A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-methoxy-5-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
/V-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-((4-(2-(4-chlorophenyl)oxazol-4-yl)-1 -methylpiperidin-4-yl)methyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methyl-/\/-(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzyl)propan-1 -amine,
A/-(2-(2-(4-fluorophenyl)oxazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
W-((4-([1 , 1 '-biphenyl]-3-yl)-1 -methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)-
1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-methoxyphenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)nicotinamide,
2-chloro-/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide, A/-(2-(2-(2-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
3-(5-(2,2-difluoroacetyl)thiophen-2-yl)-/\/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2- methylpropyl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)thiazol-2-yl)benzamide,
Λ/-(2-(1 -methyl-2-phenyl-1 /-/-imidazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)furan-2-yl)benzamide,
/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(4-(4-fluorophenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
/V-(2-([1 ,1 '-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(4'-fluoro-[1 , 1 '-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-((4-(4-(3,5-difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(2-(4-(3,5-difluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-phenyloxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-phenyloxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
/V-(2-(2-(4-chlorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-(2-(4-chlorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide, /V-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
/V-(2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
W-(2-(3-phenyl-1 ,2,4-oxadiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-methyl-2-(3-phenyl-1 H-pyrazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
Λ/-((4-([1 , 1 '-biphenyl]-3-yl)-1 -methylpiperidin-4-yl)methyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(4-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)furan-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-3-yl)benzamide, and
/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2- trifluoroacetyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
and salts, particularly pharmaceutically acceptable salts, thereof.
Particular compounds of Formula I include:
N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
N-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide, N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(3-(4-Fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)nicotinamide,
N-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-3-(5-(trifluoromethyl)-
I , 2,4-oxadiazol-3-yl)benzamide,
N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)thiazol-2-yl)benzamide,
N-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
(3-(5-(4-fluorophenyl)oxazol-2-yl)piperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)phenyl)methanone,
and salts, particularly pharmaceutically acceptable salts, thereof.
As used herein, 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.
Compound names were generated using the software naming program ChemDraw
I I .0 available from CambridgeSoft Corporation., 100 CambridgePark Drive, Cambridge, MA 02140, USA (http://www.cambridgesoft.com).
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
independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula I. 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 2H, 3H, 14C, 11C, or 18F 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,
Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NIID), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA), comprising administering a therapeutically effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, in need thereof. As used herein, "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. Thus, e.g., 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 (pXC5o), efficacy (EC5o), 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. Likewise, the 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" or "treatment" 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. In addition, 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
(COMT) inhibitor, 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), neuronal intranuclear inclusion disease, Huntington's disease (such as tetrabenazine, haloperidol and clozapine, antiseizure drugs such as clonazepam and antianxiety drugs such as diazepam), and 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.
The pharmaceutical 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. Alternatively, the pharmaceutical compositions may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. 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. When prepared in unit dosage form, 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.
As used herein, "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. In addition, 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. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, 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. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
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. In addition, there are a number of 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).
The pharmaceutical 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).
In one aspect, 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. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). 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.
Pharmaceutical Compositions
Example A
Tablets are prepared using conventional methods and are formulated as follows:
Ingredient Amount per tablet
Compound 5mg
Microcrystalline cellulose 100mg
Lactose 100mg
Sodium starch glycollate 30mg
Maqnesium stearate 2ma
Total 237mg
Example B
Capsules are prepared using conventional methods and are formulated as follows
Inqredient Amount per tablet
Compound 15mg
Dried starch 178mg
Maqnesium stearate 2mq
Total 195mg
References:
US 20060269559, US Patent No. 7,521 ,044, WO2007084775
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.
"Expression of HDAC9 by T Regulatory Cells Prevents Colitis in Mice," E. F. de Zoeten, L. Wang, H. Sai, W. H. Dillmann, W. W. Hancock, Gastroenterology. 2009 Oct 28.
"Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells," L. Wang, E. F. de Zoeten, M. I. Greene and W. W. Hancock, Nature Review Drug Discovery. 8(12):969-81 , 2009 and references therein.
"HDAC7 targeting enhances FOXP3+ Treg function and induces long-term allograft survival," L. Wang, et al., Am. J. Transplant 9, S621 (2009).
"Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of 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.
"Myocyte Enhancer Factor 2 and Class II Histone Deacetylases Control a Gender-
Specific Pathway of Cardioprotection Mediated by the Estrogen Receptor," E. van Rooij, J. Fielitz, L. B. Sutherland, V. L. Thijssen, H. J. Crijns, M. J. Dimaio, J. Shelton, L. J. De Windt, J. A. Hill, E.N. Olson, Circulation Research, Jan 2010.

Claims

What is claimed is:
1. A method of treatment of a neurodegenerative disease or disorder associated with deacetylases, comprising administering, to a patient in need thereof, a compound of Formula I:
Figure imgf000038_0001
wherein:
R1 is halo(CrC4)alkyl, wherein said halo(CrC4)alkyl contains at least 2 halo atoms;
Y is a bond and Xi is O, N or NH, X2 is N or CH and X3 is N or NH,
or Y is -C(O)- and Xi and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and Xi is O, X2 is CH or N, and X3 is CH or N;
A is optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
wherein any optionally substituted cycloalkyi, phenyl, naphthyl, heterocycloalkyi, or heteroaryl is optionally substituted by 1-3 groups independently selected from
(C C4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARA and -((Ci-C4)alkyl)NRARA;
Z is -C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -S02-, -S02NRx-, -NRxS02-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(C C4)alkyl-, -NRX-, or -(C C3)alkyl-NRx-; n is 0-4;
when n is 0, R2 and R3 are independently selected from H and optionally
substituted (Ci-C4)alkyl, aryl(C C4)alkyl-, and (C3-C7)cycloalkyl(C C4)alkyl-,
when n is 1-4, R2 and R3 are independently selected from H, fluoro, and optionally substituted (Ci-C4)alkyl, aryl(Ci-C4)alkyl-, and (C3-C7)cycloalkyl(Ci-C4)alkyl-, wherein, when n is 1 , R2 is F and R3 is H, then Z is -C(=0)NRx-, -NRxC(=0)NRx, -S02NRx-,
-NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(C C4)alkyl-, -NRX-, or -(C C3)alkyl-NRx-, and when n is 1-4, R2 is selected from -NRARB, -(C C4)alkyl-NRARB, -CONRARB, -(Ci-C4)alkyl-CONRARB, -C02H, -(C C4)alkyl-C02H, hydroxyl, hydroxy(Ci-C4)alkyl-, (Ci-C3)alkoxy, and (Ci-C3)alkoxy(CrC4)alkyl-, and R3 is selected from H and optionally substituted (d-C4)alkyl, aryl(C C4)alkyl-, and (C3-C7)cycloalkyl(C C4)alkyl-,
wherein the aryl, cycloalkyi and each of the (C1-C4)alkyl moieties of said optionally substituted (C1-C4)alkyl, aryl(C1-C4)alkyl-, and (C3-C7)cycloalkyl(C1-C4)alkyl- of any R2 and R3 are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C4)alkyl, halo(C C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARA,
-((Ci-C4)alkyl)NRARA, and hydroxyl;
or R2 and R3 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 (d-C4)alkyl,
halo(CrC4)alkyl, halogen, cyano, aryl(Ci-C4)alkyl-, (C3-C7)cycloalkyl(Ci-C4)alkyl-, -ORY, -NRYRY, -C(=0)ORY, -C(=0)NRYRY, -NRYC(=0)RY, -S02NRYRY, -NRYS02RY,
-OC(=0)NRYRY, -NRYC(=0)ORY, and -N RYC(=0)N RYRY; and
L is 5-6 membered heteroaryl or phenyl which is substituted by R4 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 (CrC4)alkyl;
R4 is H, (Ci-C4)alkyl, halo, halo(C C4)alkyl, (Ci-C4)alkoxy,
((Ci-C4)alkyl)((Ci-C4)alkyl)N(CrC4)alkoxy, ((Ci-C4)alkyl)((Ci-C4)alkyl)N(C C4)alkyl-, (CrC4)haloalkoxy-, (Ci-C4)alkylamino, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyi, or optionally substituted 5-6 membered heteroaryl,
wherein said optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, (CrC4)alkylthio-, halo(Ci-C4)alkoxy, hydroxyl, -NRARC and -((C C4)alkyl)NRARc;
or L-R4 , taken together, form a 1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halogen, cyano, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C C4)alkylthio-, halo(C C4)alkoxy, hydroxyl, -NRARC and -((C C4)alkyl)NRARc;
wherein each RA is independently selected from H and (C1-C4)alkyl;
RB is H, (C C4)alkyl, halo(C C4)alkyl, -C(=0)(C C4)alkyl, -C(=0)0(d-C4)alkyl, -C(=0)NH2,
Figure imgf000039_0001
-C(=0)N((Ci-d)alkyl)((d-d)alkyl),
-S02(Ci-d)alkyl, or RA and RB taken together with the atom to which they are attached form a 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (d-d)alkyl; Rc is H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or RA and Rc 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 (Ci-C4)alkyl;
each Rx is independently selected from H, (Ci-C6)alkyl, and optionally substituted
(C2-C6)alkyl, where said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (C C4)alkyl)NH-, or ((Ci-C4)alkyl)((C C4)alkyl)N-; and
each RY is independently selected from H, (Ci-C4)alkyl, phenyl, and
-(C C4)alkylphenyl;
or a salt thereof.
2. The method according to claim 1 , wherein R1 is a fluoro-alkyl group containing at least 2 fluoro atoms.
3. The method according to claim 1 , wherein R1 is a (Ci-C2)alkyl group containing at least 2 fluoro atoms.
4. The method according to claim 1 , wherein R1 is CHF2 or CF3.
5. The method according to claim 1 , wherein R1 is CF3.
6. The method according to any one of claims 1-5, wherein when Y is a bond, Xi is O, X2 and X3 are N, or Xi is O, X2 is CH, X3 is N, or Xi is N or NH, X2 is CH, X3 is N or NH; or X, is N or NH, X2 is N, X3 is N or NH.
7. The method according to any one of claims 1-5, wherein when Y is a bond, Xi is O, X2 and X3 are N.
8. The method according to any one of claims 1-5, wherein when Y is -C(O)-, X3 is
S, X^ is CH and X2 is N, or X3 is S, X^ is N and X2 is CH, or X3 is O, X^ is CH and X2 is N, or X3 is O, Xi is N and X2 is CH, or X^ and X2 are CH, X3 is S or X^ and X2 are CH, X3 is O.
9. The method according to any one of claims 1-5, wherein when Y is -C(O)-, X3 is S, Xi is CH and X2 is N, or X3 is S, Xi is N and X2 is CH, or X3 is O, Xi is CH and X2 is N, or X3 is O, Xi is N and X2 is CH, or X^ and X2 are CH, X3 is S.
10. The method according to any one of claims 1 -5, wherein when Y is -C(O)-, Xi and X2 are CH, X3 is S.
1 1. The method according to any one of claims 1 -5, wherein when Y is -C(O)-, Xi is O, X2 and X3 are CH, or is O, X2 is CH, and X3 is N, or is O, X2 is N, and X3 is CH, or X-\ is O, X2 and X3 are N.
12. The method according to any one of claims 1 -5, wherein when Y is -C(O)-, Xi is O, X2 and X3 are CH.
13. The method according to any one of claims 1 -12, wherein A is a phenyl group optionally substituted by 1 -2 groups independently selected from (C1-C4)alkyl, halogen, cyano, halo(d-C4)alkyl, (C C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and
-((Ci-C4)alkyl)NRARA.
14. The method according to any one of claims 1 -12, wherein A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro,
trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and
-((Ci-C4)alkyl)NRARA, where each RA is independently H or methyl.
15. The method according to any one of claims 1-12, wherein A is an
unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group.
16. The method according to any one of claims 1-12, wherein A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from (C C4)alkyl, (C C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA.
17. The method according to any one of claims 1-12, wherein A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NRARA and -((Ci-C4)alkyl)NRARA, where each RA is independently H or methyl.
18. The method according to any one of claims 1 -12, wherein A is a cyclopropyl, cyclopentyl or cyclohexyl group.
19. The method according to any one of claims 1 -12, wherein A is naphthyl, optionally substituted by 1 -2 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (C C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and
-((Ci-C4)alkyl)NRARA
20. The method according to any one of claims 1 -12, wherein A is a 4-7 membered heterocycloalkyl group optionally substituted by 1-3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy,
halo(C C4)alkoxy, oxo, -NRARA and -((C C4)alkyl)NRARA.
21. The method according to any one of claims 1 -12, wherein A is a 9-10 membered heteroaryl optionally substituted by 1-2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, halo(CrC4)alkoxy, oxo, -NRARA and -((C C4)alkyl)NRARA.
22. The method according to any one of claims 1 -12, wherein A is isoquinolyl, indazolyl, tetrahydroisoquinolinonyl, isoindolinonyl, and indolinyl.
23. The method according to any one of claims 1 -12, wherein A is a 5-6 membered heteroaryl optionally substituted by 1-2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, halo(CrC4)alkoxy, -NRARA and
-((Ci-C4)alkyl)NRARA.
24. The method according to any one of claims 1 -12, wherein A is a 5-6 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl, -NRARA and -((C C4)alkyl)NRARA, where each RA is independently H or methyl and the 5-6 membered heteroaryl contains 1 ring heteroatom selected form N, O and S and optionally contains 1 additional ring nitrogen atom.
25. The method according to any one of claims 1 -12, wherein A is oxazolyl, pyrazolyl, or thienyl, optionally substituted by a methyl group.
26. The method according to any one of claims 1 -12, wherein A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 -2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARA and -((Ci-C4)alkyl)NRARA
27. The method according to any one of claims 1 -12, wherein 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, -NRARA and
-((Ci-C4)alkyl)NRARA, where each RA is independently H or methyl.
28. The method according to any one of claims 1 -12, wherein A is thienyl, oxazolyl, or pyridyl.
29. The method according to any one of claims 1 -28, wherein Z is -C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -NRxS02-, -S02NRx-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(Ci-C4)alkyl-, or -(C C3)alkylNRx-.
30. The method according to claim 29, wherein Rx, or for -NRxC(=0)NRx, each Rx, may be independently selected from H, (d-C4)alkyl, and optionally substituted (C2-C4)alkyl, where said optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (CrC4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-.
31. The method according to claim 29, wherein Rx is H, methyl or cyanoethyl.
32. The method according to claim 29, wherein Rx is H.
33. The method according to any one of claims 1 -28, wherein Z is -NHCH(CF3)-,
-CH(CF3)NH-, -CH(CF3)-, -(C C4)alkyl- or -CH2NH-.
34. The method according to any one of claims 1 -28, wherein Z is -C(=0)NH- or - CH2NH-.
35. The method according to any one of claims 1-34, wherein n is 0-3.
36. The method according to any one of claims 1-35, wherein n is 0 or 1.
37. The method according to any one of claims 1-36, wherein one of R2 and R3 is other than hydrogen.
38. The method according to any one of claims 1-36, wherein both R2 and R3 are Ci_
4alkyl.
39. The method according to any one of claims 1-36, wherein one of R2 and R3 is H and the other of R2 and R3 is C1-4 alkyl.
40. The method according to any one of claims 1-34, wherein when n is 1 -4, R2 is selected from amino, (Ci-C4)alkylamino, ((Ci-C3)alkyl)((Ci-C3)alkyl)amino, amino(Ci-C4)alkyl, (Ci-C3)alkylamino(Ci-C4)alkyl, ((Ci-C3)alkyl)((Ci-C3)alkyl)amino(Ci-C4)alkyl,
(substituted(C1-C3)alkyl)((C1-C3)alkyl)amino(C1-C4)alkyl (where said (substituted (CrC3)alkyl moiety is substituted by -C(=0)OH, -C(=0)0(C C4)alkyl, or 1-8 fluoro groups),
aminocarbonyl(C1-C4)alkyl, (C1-C3)alkylaminocarbonyl(C1-C4)alkyl,
((Ci-C3)alkyl)((Ci-C3)alkyl)aminocarbonyl(Ci-C4)alkyl, hydroxyl, hydroxy(CrC4)alkyl-,
(CrC4)alkoxy, and (Ci-C4)alkoxy(Ci-C4)alkyl- and R3 is selected from H and optionally substituted (d-C4)alkyl, aryl(C C4)alkyl- and (C3-C7)cycloalkyl(CrC4)alkyl-.
41. The method according to any one of claims 1-34, wherein when n is 1 -4, R2 is selected from amino, hydroxyl, and (Ci-C4)alkoxy, and R3 is selected from H and optionally substituted (Ci-C4)alkyl, phenyl(C C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl-.
42. The method according to any one of claims 1 -36, wherein R2 and R3 are independently selected from H and optionally substituted (Ci-C4)alkyl, phenyl(CrC2)alkyl-, and (C3-C6)cycloalkyl(CrC2)alkyl-.
43. The method according to any one of claims 1 -36, wherein R2 is selected from H and optionally substituted (Ci-C4)alkyl, phenyl(Ci-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl- and R3 is selected from H and methyl.
44. The method according to any one of claims 1 -36, wherein R2 and R3 are independently selected from H and optionally substituted (C1-C4)alkyl, phenyl(C1-C2)alkyl-, and (C3-C6)cycloalkyl(CrC2)alkyl-; wherein the phenyl, cycloalkyl and each of the (Ci-C4)alkyl or (Ci-C2)alkyl moieties of said optionally substituted (Ci-C4)alkyl, phenyl(Ci-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl- are optionally substituted by 1 , 2 or 3 halogen groups and/or 1 or 2 groups independently selected from cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (CrC4)alkoxy, halo(Ci-C4)alkoxy, NRARA, -((Ci-C4)alkyl)NRARA, and hydroxyl.
45. The method according to any one of claims 1-36, wherein both R2 and R3 are H or both R2 and R3 are methyl.
46. The method according to any one of claims 1 -34, wherein R2 is hydroxyl and
R3 is H or methyl.
47. The method according to any one of claims 1-34, wherein n is 1 , R2 is hydroxyl and R3 is H or methyl.
48. The method according to any one of claims 1 -36, wherein R2 and R3 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
(CrC4)alkyl, halo(Ci-C4)alkyl, halogen, cyano, aryl(Ci-C2)alkyl-,
(C3-C6)cycloalkyl(Ci-C2)alkyl-, -ORYa, -NRYaRYb, -C(=0)ORYa, -C(=0)NRYaRYb,
-NRYbC(=0)RYa, -S02NRYaRYb, and -NRYbS02RYa, where RYa is selected from H,
(Ci-C4)alkyl phenyl(C C2)alkyl- and (C3-C6)cycloalkyl(Ci-C2)alkyl-, and each RYb is independently selected from H and (CrC4)alkyl.
49. The method according to claim 48, wherein RY is independently selected from H, (Ci-C4)alkyl, phenyl, and -(Ci-C4)alkylphenyl.
50. The method according to claim 46, wherein each RY is independently selected from H, methyl, ethyl, phenyl, benzyl and -ethylphenyl.
51. The method according to any one of claims 1 -36, wherein R2 and R3 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-C4)alkyl, aryl(Ci-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl-.
52. The method according to any one of claims 1 -36, wherein R2 and R3 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.
53. The method according to any one of claims 1 -36, wherein R2 and R3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2- dimethyl-tetrahydropyranyl, cyclopentyl, 1 -methyl-piperidinyl group.
54. The method according to any one of claims 1 -53, wherein L is 5-6 membered heteroaryl or phenyl which is substituted by R4 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.
55. The method according to any one of claims 1 -53, wherein L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano and methyl.
56. The method according to any one of claims 1 -53, wherein L is pyrazolyl, oxadiazolyl, 1 -methyl-imidazolyl, thiazolyl, thienyl, triazolyl, pyridyl, phenyl, oxazolyl or isoxazolyl which is substituted by optionally further substituted by a methyl group.
57. The method according to any one of claims 1 -53, wherein L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl which is substituted by a methyl group.
58. The method according to any one of claims 1 -57, wherein R4 is H, halogen, (C C4)alkyl, halo(C C2)alkyl, (C C2)alkoxy, ((C1-C2)alkyl)((C1-C2)alkyl)N(C1-C3)alkoxy-, ((d-C^alkyl id-C^alky Nid^alkyl-, (C C2)haloalkyl, (C C3)alkylamino, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyi, or optionally substituted 5-6 membered heteroaryl, where said optionally substituted cycloalkyl, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 or 2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C2)alkyl, (C C2)alkoxy, halo(Ci-C2)alkoxy, hydroxyl, -NRARC and
-((Ci-C4)alkyl)NRARc.
59. The method according to any one of claims 1 -57, wherein R4 is H, methyl, bromo, trifluoromethyl, 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.
60. The method according to any one of claims 1 -57, wherein R4 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.
61. The method according to any one of claims 1 -53, wherein L-R4 , 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 morpholinylpropyk 62. The method according to any one of claims 1 -53, wherein L-R4 , taken together, form a 1 ,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group.
63. The method according to any one of claims 1-62, wherein each RA and RB is independently selected from H and (CrC4)alkyl.
64. The method according to any one of claims 1-62, wherein each RA and RB is independently selected from H, methyl and ethyl.
65. The method according to claim 1 , wherein:
R1 is CHF2 or CF3;
Y is a bond, X-\ is O, and X2 and X3 are N, or
Y is -C(O)-, Xi and X2 are CH, and X3 is S, or
Y is -C(O)-, Xi is O, and X2 and X3 are CH;
A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and -((Ci-C4)alkyl)NRARA, or A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NRARA and -((Ci-C4)alkyl)NRARA, 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, -NRARA and
-((Ci-C4)alkyl)NRARA, 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,
where each RA is independently H or methyl;
Z is -C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -NHCH(CF3)-, -CH(CF3)NH-,
-CH(CF3)-, -(C C4)alkyl-, or -(C C4)alkylNRx-, where Rx is H, (d-C4)alkyl, or optionally substituted (C2-C4)alkyl, where said optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (C1-C4)alkyl)NH-, or ((C1-C4)alkyl)((C1-C4)alkyl)N-; n is 0-3 and R2 and R3 are independently selected from H and optionally substituted (C C4)alkyl, phenyl(Ci-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl-, or
n is 1-3 and R2 is hydroxyl and R3 is H or methyl, or
n is 0-3 and R2 and R3 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 (CrC4)alkyl, halo(CrC4)alkyl, halogen, cyano, aryl(Ci-C2)alkyl-, (C3-C6)cycloalkyl(Ci-C2)alkyl-, -ORYa, -NRYaRYb, -C(=0)ORYa, -C(=0)NRYaRYb,
-NRYbC(=0)RYa, -S02NRYaRYb, and -NRYbS02RYa, where RYa is selected from H, (C C4)alkyl phenyl(Ci-C2)alkyl- and (C3-C6)cycloalkyl(CrC2)alkyl-, and each RYb is independently selected from H and (CrC4)alkyl;
L is 5-6 membered heteroaryl or phenyl which is substituted by R4 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; and
R4 is H, halogen, (C C4)alkyl, halo(C C2)alkyl, (C C2)alkoxy,
((C1-C2)alkyl)((C1-C2)alkyl)N(C1-C3)alkoxy-, ((C1-C2)alkyl)((C1-C2)alkyl)N(C1-C3)alkyl-,
(C1-C2)haloalkyl, (C1-C3)alkylamino, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyi, or optionally substituted 5-6 membered heteroaryl, where said optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 or 2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(Ci-C2)alkyl, (Ci-C2)alkoxy,
halo(Ci-C2)alkoxy, hydroxyl, -NRARC and -((C C4)alkyl)NRARc.
66. The method according to claim 65, wherein:
n is 0-3 and R2 and R3 are independently selected from H and optionally substituted (C C4)alkyl, phenyl(d-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl-, or
n is 1-3 and R2 is hydroxyl and R3 is H or methyl, or
n is 0-3 and R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyl or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyl or heterocycloalkyi group is optionally substituted by a substituent selected from (C C4)alkyl, aryl(C C2)alkyl-, and (C3-C6)cycloalkyl(C1-C2)alkyl-;
Rx is H, methyl or cyanoethyl;
L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R4 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
R4 is H, methyl, bromo, trifluoromethyl, 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.
67. The method according to claim 1 , wherein:
R1 is CHF2 or CF3;
Y is a bond, Xi is O, and X2 and X3 are N, or
Y is -C(O)-, Xi and X2 are CH, and X3 is S, or
Y is -C(O)-, Xi is O, and X2 and X3 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, cyclopropyl, cyclopentyl or cyclohexyl group;
Z is -C(=0)NH- or -CH2NH-;
n is 0 or 1 and both R2 and R3 are H or both R2 and R3 are methyl, or
n is 1 and R2 is hydroxyl and R3 is H or methyl, or
n is 0 or 1 and R2 and R3 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; R4 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; or
L-R4 , taken together, form a 1 ,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group.
68. The method according to claim 1 , wherein the compound of Formula I, or salt thereof is selected from:
A/-((4-(4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(4-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(dimethylamino)ethoxy)benzyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
Λ/-(4-(1 H-imidazol-1 -yl)benzyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-cyanoethyl)-/\/-(pyridin-3-ylmethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)-/V-((4-(4- (trifluoromethyl)phenyl)tetrahydro-2/-/-pyran-4-yl)methyl)benzamide ,
1-(4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)-/\/-(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzyl)methanamine,
A/-((4-(4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-((4-(4-phenylthiophen-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-((1 -(4-phenylthiazol-2-yl)cyclopentyl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-((4-(3-phenyl-1 H-1 ,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(2-phenylthiazol-4-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(4-(4-methoxyphenyl)thiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(4-(4-chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide , /V-(2-methyl-2-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-((1 -methyl-4-(4-phenylthiazol-2-yl)piperidin-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(4-(4-fluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(5-methyl-4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(4-cyclohexylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-(pyridin-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-(pyridin-4-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)thiophene-2-carboxamide,
/V-((4-(4-(thiophen-2-yl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
3-fluoro-/V-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
3-cyano-/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
3-methoxy-/\/-((4-(4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(4-(4-fluorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-((4-(4-(4-cyanophenyl)thiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-((4-(4-(4-fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2/-/-pyran-4- yl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzenesulfonamide, 3-ethyl-/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(3-bromophenyl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)-W-((4-(4-(4-
(trifluoromethyl)phenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzamide,
A/-(2-methyl-2-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)propyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-2-(5-(trifluorometh 1 ,2,4-oxadiazol-3-yl)cyclopropanecarboxamide,
/V-((1 -methyl-4-(2-phenylthiazol-4-yl)piperidin-4-yl)methyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
/V-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-chlorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-chlorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)isonicotinamide,
/V-(2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
/V-(2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)picolinamide,
/V-(2-(dimethylamino)-2-(4-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(3-phenyl-1 H-1 ,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-((1 -(4-phenylthiazol-2-yl)cyclopropyl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
3-(4-(4-fluorophenyl)thiazol-2-yl)-/V-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)propanamide, /V-(2-(2-(4-chlorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-((4-phenylthiazol-2-yl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(4-(4-fluorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
/V-((4-(3,4-dihydroisoquinolin-2(1 H)-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-methyl-/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2/-/-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)thiazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)thiazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
2,2,2-trifluoro-/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-1 -(3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)phenyl)ethanamine,
A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(3-(4-chlorophenyl)-1 H-1 ,2,4-triazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-methyl-2-(3-phenyl-1 H-1 ,2,4-triazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-methyl-2-(3-phenyl-1 H-1 ,2,4-triazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(3-(4-chlorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-3-(5-
(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide, A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-6-methyl-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)nicotinamide,
/V-(3-(4-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
/V-(2-(5-phenylthiazol-2-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(3-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-2-methyl-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-methyl-2-(5-phenylthiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
Λ/-((4-([1 , 1 '-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
Λ/-((4-([1 , 1 '-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-((2-(4-fluorophenyl)oxazol-4-yl)methyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-((4-(2-(4-fluorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
2- (2-(4-fluorophenyl)oxazol-4-yl)-2-methyl-/\/-(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzyl)propan-1 -amine,
3- (3-(4-(4-phenylthiazol-2-yl)butyl)phenyl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole, /V-(2-methyl-2-(5-phenyloxazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-(2-phenylthiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-(2-methyl-2-(2-phenylthiazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide, /V-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)nicotinamide,
/V-((4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
2-fluoro-/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)oxazole-4-carboxamide,
/V-(2-(1-methyl-2-phenyl-1 H-imidazol-5-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
5-(5-(difluoromethyl)-1 ,2,4-oxadiazol-3-yl)-/\/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2- methylpropyl)nicotinamide,
/V-(2-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide hydrochloride,
A/-(2-(3-(4-fluorophenyl)-1 H-1 ,2,4-triazol-5-yl)-2-methylpropyl)-5-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-2-methoxy-5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-5-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
/V-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyethyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-((4-(2-(4-chlorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methyl-/\/-(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzyl)propan-1 -amine, /V-(2-(2-(4-fluorophenyl)oxazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-((4-([1 , 1 '-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-methoxyphenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)nicotinamide,
2- chloro-/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(3-(2-(4-fluorophenyl)oxazol-4-yl)-3-hydroxypropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
/V-(2-(2-(4-cyanophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(2-(2-fluorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
3- (5-(2,2-difluoroacetyl)thiophen-2-yl)-/\/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2- methylpropyl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)thiazol-2-yl)benzamide,
/V-(2-(1-methyl-2-phenyl-1 H-imidazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)furan-2-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methoxyethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(4-(4-fluorophenyl)thiazol-2-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
/V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
/V-(2-(2-(4-fluorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
Λ/-(2-([1 , 1 '-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide, A/-(2-(4'-fluoro-[1 , 1 '-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
/V-((4-(4-(3,5-difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(4-(3,5-difluorophenyl)thiazol-2-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(2-phenyloxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-phenyloxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(2-(4-chlorophenyl)oxazol-4-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(2-(4-chlorophenyl)oxazol-4-yl)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
/V-(2-methyl-2-(2-phenyloxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
/V-(2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(3-phenyl-1 ,2,4-oxadiazol-5-yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-methyl-2-(3-phenyl-1 H-pyrazol-5-yl)propyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)propyl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)nicotinamide,
A/-(2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
/V-((4-([1 , 1 '-biphenyl]-3-yl)-1-methylpiperidin-4-yl)methyl)-5-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)nicotinamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(4-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxypropyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)furan-3-yl)benzamide,
A/-(2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-3-yl)benzamide, and /V-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-3-(5-(2,2,2- trifluoroacetyl)-1 ,2,4-oxadiazol-3-yl)benzamide.
69. The method according to claim 1 , wherein:
R1 is CHF2 or CF3;
Y is a bond, Xi is O, and X2 and X3 are N;
A is an unsubstituted phenyl or pyridyl group;
Z is -C(=0)NH- or -CH2NH-; n is 1 ;
R2 and R3 are both methyl, or
R2 is hydroxyl and R3 is methyl, or
R2 and R3 are both hydrogen, or
R2 is methyl and R3 is hydrogen, or
R2 is hydroxyl and R3 is hydrogen, or
R2 is dimethylamino and R3 is H, or
R2 is Ν,Ν-dimethylaminoethyl and R3 is H, or
R2 and R3 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;
R4 is phenyl, optionally substituted by halo (chloro or fluoro), cyano,
halo(CrC2)alkyl, or (C C2)alkoxy.
70. The method according to any one of claims 1 -69, wherein the
neurodegenerative disease or disorder associated with deacetylases is Alzheimer's disease, Parkinson's disease, or neuronal intranuclear inclusion disease.
71. The method according to any one of claims 1 -69, wherein the
neurodegenerative disease or disorder associated with deacetylases is a polyglutamine disorder, wherein the polyglutamine disorder is Huntington's disease or spinocerebellar ataxia.
72. The method according to any one of claims 1 -69, wherein the
neurodegenerative disease or disorder associated with deacetylases is Huntington's disease.
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