WO2013009827A1 - Methods of treatment - Google Patents

Methods of treatment Download PDF

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Publication number
WO2013009827A1
WO2013009827A1 PCT/US2012/046198 US2012046198W WO2013009827A1 WO 2013009827 A1 WO2013009827 A1 WO 2013009827A1 US 2012046198 W US2012046198 W US 2012046198W WO 2013009827 A1 WO2013009827 A1 WO 2013009827A1
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Prior art keywords
alkyl
phenyl
optionally substituted
trifluoromethyl
independently selected
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PCT/US2012/046198
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French (fr)
Inventor
Shomir Ghosh
Mercedes Lobera
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Tempero Pharmaceuticals, Inc.
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Publication of WO2013009827A1 publication Critical patent/WO2013009827A1/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
    • A61K31/435—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
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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 neurodegenerative diseases and 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
  • neurodegenerative diseases or disorders particularly neurodegenerative diseases and 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
  • the present invention also relates to a method of treating a B-cell lymphoma, particularly B-cell lymphomas associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma), by administering to a patient in need thereof a compound that inhibits HDAC activity.
  • B-cell lymphoma particularly B-cell lymphomas associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphom
  • 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.
  • 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.
  • SCA1 spinocerebellar ataxia type 1
  • 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).
  • HDAC9 is a class lla histone deacetylase highly expressed in human B cells. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell tumours and HDAC9 is highly overexpressed in cells derived from patients with non- Hodgkin's lymphoma
  • HDAC4 and HDAC9 have booth been reported to be overexpressed in CD19+ cells from patients with Waldenstrom Macroglobulinemia (Sun et al., Clinical Lymphoma, Myeloma & Leukemia, 201 1 , p. 152)
  • Class lla HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) have been reported to associate with Bcl-6, a transcription factor implicated in the pathogenesis of B-cell malignancies (Lemercier et al, Journal of Biological Chemistry, 2002, p. 22045, and Petrie et al, Journal of Biological Chemistry, 2003, p. 16059). Due to these interactions class lla HDACs have been suggested to modulate the transcriptional repression of BCL6 and participate in its role in B-cell activation and differentiation, inflammation, and cell-cycle regulation (Verdin et al. TRENDS in Genetics, 2003, p. 286) .
  • HDAC6 a class lib HDAC
  • HDAC6 a class lib HDAC
  • the invention is directed to a method of treatment of a neurodegenerative disease or disorder and is further directed to a method of treatment of B-cell lymphoma, wherein each of said methods comprise administering, to a patient in need of treatment of a
  • R 1 is fluoro(CrC 4 )alkyl containing at least 2 fluoro atoms
  • 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;
  • Q is A-Z or E, wherein:
  • A is optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
  • membered heterocycloalkyi 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, -NR A R B and
  • X is NR x or a bond
  • B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2
  • heteroatoms independently selected from N, O and S, wherein said phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, aryl(C C 4 )alkyl-, (C3-C 7 )cycloalkyl(C C 4 )alkyl-, — OR Y , -(C C 4 )OR Y , -NR Y R Y ,
  • L is a bond or (CrC 4 )alkyl
  • any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C 3 -C 6 )cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C 4 )alkyl, halo(CrC 4 )alkyl, halogen, cyano, nitro, (CrC 4 )alkoxy, (CrC 4 )alkylthio-,halo(Ci-C 4 )alkoxy,
  • each R A and R B are independently selected from H, (CrC 4 )alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or R A and R B taken together with the atom or atoms through 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, or optionally substituted (C 2 -C 6 )alkyl, wherein 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)((Ci-C 4 )alkyl)N-; and
  • each R Y is independently selected from H, (CrC 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, 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).
  • NMD neuronal intranuclear inclusion disease
  • SCA spinocerebellar ataxia
  • the invention is still 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 B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
  • a B-cell lymphoma particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphoc
  • the invention is 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, wherein the neurodegenerative disease or disorder is as defined above.
  • 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 B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
  • a B-cell lymphoma particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B
  • R 1 is a (Ci-C 2 )alkyl group containing at least 2 fluoro atoms (groups).
  • R 1 is CHF 2 or CF 3 ; more specifically, R 1 is CF 3
  • 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, X ⁇ is CH and X 2 is N or X 3 is S, X ⁇ is N and X 2 is CH), oxazolyl (X 3 is O, X ⁇ is CH and X 2 is N or X 3 is O, X ⁇ 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 (X- ⁇ 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.
  • the invention is still further directed methods of treatment and uses of a compound of Formula (l-b):
  • R 1 , R 2 , R 3 ,R 4 , A, Z, n and L are as defined herein.
  • the invention is further directed methods of treatment and uses of a compound Formula (l-c), (l-d), o -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- -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):
  • R 1 , R 2 , R 3 ,R 4 , A, n and L are as defined herein.
  • the invention is directed methods of treatment and uses of a compound according to Formula l-A:
  • R 1 is fluoro(C 1 -C 4 )alkyl containing at least 2 fluoro atoms
  • 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 heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
  • optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (CrC 4 )alkoxy, halo(CrC 4 )alkoxy, -NR A R B and
  • X is NR x or a bond
  • B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S,
  • phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, aryl(C C 4 )alkyl-, (C 3 -C 7 )cycloalkyl(C C 4 )alkyl-, — OR Y , -(C C 4 )OR Y , -NR Y R Y ,
  • L is a bond or (CrC 4 )alkyl
  • any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C 3 -C 6 )cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C 4 )alkyl, halo(CrC 4 )alkyl, halogen, cyano, nitro, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio-,halo(C 1 -C 4 )alkoxy,
  • each R A and R B are independently selected from H, (CrC 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or R A and R B taken together with the atom or atoms through 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, or optionally substituted (C 2 -C 6 )alkyl, wherein 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)((Ci-C 4 )alkyl)N-; and
  • each R Y is independently selected from H, (CrC 4 )alkyl, phenyl, and
  • the invention is directed methods of treatment and uses of a compound according to
  • R 1 is fluoro(CrC 4 )alkyl containing at least 2 fluoro atoms
  • 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;
  • X is NR x or a bond
  • B is a phenyl, pyridyl or 4-10 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, aryl(C C 4 )alkyl-, (C3-C 7 )cycloalkyl(C C 4 )alkyl-, — OR Y , -(C C 4 )OR Y , -NR Y R Y ,
  • L is a bond or (CrC 4 )alkyl
  • any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C 3 -C 6 )cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C 4 )alkyl, halo(CrC 4 )alkyl, halogen, cyano, nitro, (CrC 4 )alkoxy, (CrC 4 )alkylthio-,halo(Ci-C 4 )alkoxy,
  • each R A and R B are independently selected from H, (CrC 4 )alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or R A and R B taken together with the atom or atoms through 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, or optionally substituted (C 2 -C 6 )alkyl, wherein 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)((Ci-C 4 )alkyl)N-; and
  • each R Y is independently selected from H, (CrC 4 )alkyl, phenyl, and
  • the invention is directed methods of treatment and uses of a compound according to Formula l-C:
  • R 1 is fluoro(CrC 4 )alkyl containing at least 2 fluoro atoms
  • 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 X ⁇ and X 2 are CH or N, X 3 is O or S,
  • Y is -C(O)- and X ⁇ is O, X 2 is CH or N, and X 3 is CH or N;
  • heteroaryl )-S0 2 - -(5-6 membered heteroaryl)-CH(CF 3 )-, -(5-6 membered
  • L is a bond or is (C 1 -C 4 )alkyl
  • any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C 3 -C 6 )cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C 4 )alkyl, halo(CrC 4 )alkyl, halogen, cyano, nitro, (CrC 4 )alkoxy, (CrC 4 )alkylthio-,halo(Ci-C 4 )alkoxy, ((C 1 -C4)alkyl)((C 1 -C 4 )alkyl)N(C 2 -C 4 )alkoxy, hydroxyl, -NR A R B , ((d-C 4 )alkyl)NR A R B , and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group
  • each R A and R B are independently selected from H, (Ci-C )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or R A and R B taken together with the atom or atoms through which they are attached form an optionally substituted 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, S; is an optionally substituted 4-10 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S, where said 4-10 membered heterocyclic ring is optionally substituted by 1 or 2 groups independently selected from (Ci-C )alkyl, halo(Ci-C )alkyl, halogen, cyano, aryl(Ci-C )alkyl-,
  • R 1 is -CF 3 ;
  • Y is a bond and Xi is O, N or NH, X 2 is N or CH and X 3 is N or NH,
  • phenyl, pyridyl, isoquinolyl, indazolyl, or (C 3 -C 6 )cycloalkyl is optionally substituted by chloro, fluoro, cyano, methoxy, methyl, or trifluoromethyl;
  • L is a bond, methylene, ethylene or propylene;
  • benzimidazolyl, or benzimidazolonyl moiety is optionally substituted with 1 or 2 groups independently selected from (d-C 4 )alkyl, halo(CrC 4 )alkyl, halogen, cyano, nitro,
  • R A and R B are independently selected from H and (Ci-C 4 )alkyl or R A and
  • A is a phenyl or pyridyl group optionally substituted by 1-2 groups independently selected from (CrC 4 )alkyl, halogen, cyano, halo(C C 4 )alkyl, (Ci-C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and
  • A is a phenyl or pyridyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A R B and -((C C 4 )alkyl)NR A R B , where each R A and R B is independently selected from H and methyl.
  • A is an unsubstituted phenyl or pyridyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group. In specific embodiments of a compound or salt of Formula l-A, A is an unsubstituted phenyl group.
  • A is naphthyl, optionally substituted by 1-2 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(C C 4 )alkyl, (Ci-C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R B and
  • A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from (CrC 4 )alkyl, (Ci-C 4 )alkoxy, -NR A R B 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 B and -((C C 4 )alkyl)NR A R B , where each R A and R B is independently selected from H and methyl.
  • A is a 5-6 membered heteroaryl or a 9-10 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 AB and
  • 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 B and -((C C 4 )alkyl)NR A R B , where each R A and R B is independently selected from H and 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.
  • A is a 4-7 membered heterocycloalkyl group optionally substituted by 1-3 groups independently selected from (CrC 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (CrC 4 )alkoxy,
  • Z is -S0 2 -.
  • Z is -CH(CF 3 )- or -(CrC 4 )alkyl-.
  • E is -((Ci-C 5 )alkyl)S0 2 - or
  • E is -CH(CF 3 )- or -((Ci-C 4 )alkyl)CH(CF 3 )-.
  • X is NR x or a bond, where each R x is independently selected from H, (d-C 4 )alkyl, or optionally substituted (C 2 -C 4 )alkyl, where the optionally substituted (C 2 -C 4 )alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC 4 )alkoxy, (CrC 4 )alkyl)NH-, or
  • each R x is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and dimethylaminoethyl-. In specific embodiments, each R x is H.
  • B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 or 2 groups independently selected from (Ci-C 2 )alkyl, halo(Ci-C 2 )alkyl, halogen, cyano, aryl(Ci-C 3 )alkyl-,
  • each R Y is as defined above, and more particularly, where each R Y is independently selected from H and methyl.
  • B is a phenyl, pyridyl or 4-8 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted as defined above.
  • B is a 4, 5, 6 or 7 membered heterocycloalkyi containing 1 or 2 nitrogen atoms, optionally substituted by 1 or 2 groups independently selected from (d-C 2 )alkyl, halo(d-C 2 )alkyl, halogen, cyano, aryl(d-d)alkyl-,
  • the bonding arrangement of X-B-L is such that X and L are attached to different ring atoms, that is X and L are not attached to the same ring atom of B.
  • L is a bond or (d-C 3 )alkyl (that is, a (Ci-C 3 )alkylene linker), specifically, L is a bond or is methyl (methylene), ethyl (ethylene) or propyl (propylene).
  • R 2 is (CrC 4 )alkyl, -NR A R B ,
  • each R A and R B are independently selected from H, (Ci-C 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or R A and R B taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S.
  • R 2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyl, (C 3 -C 6 )cycloalkyl, phenyl,
  • any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyl, (C 3 -C 6 )cycloalkyl, or phenyl groups is optionally substituted by 1 or 2 groups independently selected from (d-C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, nitro, (CrC 4 )alkoxy, (C 1 -C 4 )alkylthio-, halo(CrC 4 )alkoxy,
  • each R A and R B are independently selected from H, (Ci-C 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or R A and R B taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S.
  • benzimidazolonyl tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl,
  • thienopyrimidinyl benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyk
  • 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.
  • C 1 -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 (-CH2CH2CH2CH2CH2-) or branched (-CH2CH(CH3)CH 2 CH2- -CH2CH 2 CH(CH 2 CH3)-, -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.
  • exemplary "(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, 2- azabicyclo[
  • 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
  • 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), 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, quin
  • heteroaryl groups present in the compounds of this invention 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, thiadiazolyl, thiazolyl, triazolyl, and tetrazolyl or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • heteroaryl groups present in the compounds of this invention 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,
  • halogen and halo represent chloro, fluoro, bromo or iodo substituents.
  • the invention is further directed to the use of a compound of Formula I, wherein:
  • A is a phenyl or pyridyl group optionally substituted by 1 -2 groups independently selected from (CrC 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (d-C 4 )alkoxy,
  • X is NR x or a bond, where R x is independently selected from H, (CrC 4 )alkyl, or optionally substituted (C 2 -C 4 )alkyl, where the optionally substituted (C 2 -C 4 )alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC 4 )alkoxy, (Ci-C 4 )alkyl)NH-, or ((Ci-C 4 )alkyl)((CrC 4 )alkyl)N-;
  • B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 or 2 groups independently selected from (C 1 -C 2 )alkyl, halo(C 1 -C 2 )alkyl, halogen, cyano, aryl(C 1 -C 3 )alkyl-,
  • L is a bond or (C C 3 )alkyl
  • R 2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C 3 -C 6 )cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C 3 -C 6 )cycloalkyl), or -C(0)-phenyl,
  • any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C 3 -C 6 )cycloalkyl, or phenyl groups is optionally substituted by 1 or 2 groups independently selected from (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, halogen, cyano, nitro, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio-, halo(C 1 -C 4 )alkoxy,
  • each R A and R B are independently selected from H, (CrC 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or R A and R B taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
  • the invention is further directed to the use of a compound of Formula I, wherein:
  • A is a phenyl or pyridyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A R B and -((C 1 -C 4 )alkyl)NR A R B , where each R A and R B is independently selected from H and methyl;
  • X is NR x or a bond, where R x is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
  • L is a bond or (CrC 3 )alkyl
  • 2,3-dihydro-1 ,4-benzodioxinyl benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyl-;
  • the invention is further directed to the use of a compound of Formula I, wherein:
  • A is an unsubstituted phenyl or pyridyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group;
  • X is NR x or a bond, where R x is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
  • L is a bond or (d-C 3 )alkyl
  • 2,3-dihydro-1 ,4-benzodioxinyl benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyl-;
  • the invention is further directed to the use of a compound of Formula I, wherein:
  • A is an unsubstituted phenyl or pyridyl group
  • X is NR X or a bond, where R x is H;
  • L is a bond or is methyl (methylene), ethyl (ethylene) or propyl (propylene);
  • benzimidazolonyl or indolinyl, where the phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, and benzimidazolonyl are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, 4- fluoro-phenyl, and morpholinylpropyl-;
  • the invention is further directed to the use of a compound of Formula I, wherein:
  • A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from (d-C 4 )alkyl, (CrC 4 )alkoxy, -NR A R B and
  • X is NR x or a bond, where R x is independently selected from H, (CrC 4 )alkyl, or optionally substituted (C 2 -C 4 )alkyl, where the optionally substituted (C 2 -C 4 )alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC 4 )alkoxy, (Ci-C 4 )alkyl)NH-, or ((Ci-C 4 )alkyl)((CrC 4 )alkyl)N-;
  • B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 or 2 groups independently selected from (Ci-C 2 )alkyl, halo(CrC 2 )alkyl, halogen, cyano, aryl(Ci-C 3 )alkyl-,
  • L is a bond or (d-C 3 )alkyl
  • R 2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C 3 -C 6 )cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C 3 -C 6 )cycloalkyl), or -C(0)-phenyl,
  • any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C 3 -C 6 )cycloalkyl, or phenyl groups is optionally substituted by 1 or 2 groups independently selected from (d-d)alkyl, halo(d-C 4 )alkyl, halogen, cyano, nitro, (d-d)alkoxy, (d-d)alkylthio-, halo(d-C 4 )alkoxy, ((C 1 -C4)alkyl)((C 1 -C 4 )alkyl)N(C 2 -C 4 )alkoxy, hydroxyl, -NR A R B , -((C C 4 )alkyl)NR A R B , and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups
  • each R A and R B are independently selected from H, (Ci-C )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or R A and R B taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
  • 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 B and -((CrC )alkyl)NR A R B , where each R A and R B is independently selected from H and methyl;
  • X is NR x or a bond, where R x is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
  • L is a bond or (d-C 3 )alkyl
  • 2,3-dihydro-1 ,4-benzodioxinyl benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyl-;
  • X is NR x or a bond, where R x is independently selected from H, (C 1 -C 4 )alkyl, or optionally substituted (C 2 -C 4 )alkyl, where the optionally substituted (C 2 -C 4 )alkyl is optionally substituted by hydroxyl, cyano, amino, (Ci-C 4 )alkoxy, (Ci-C 4 )alkyl)NH-, or ((Ci-C 4 )alkyl)((CrC 4 )alkyl)N-;
  • L is a bond or (d-C 3 )alkyl
  • 2,3-dihydro-1 ,4-benzodioxinyl benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyl-;
  • X is NR x or a bond, where R x is H;
  • L is a bond or is methyl (methylene), ethyl (ethylene) or propyl (propylene);
  • benzimidazolonyl or indolinyl, where the phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, and benzimidazolonyl are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, fluoro-phenyl, and morpholinylpropyl-;
  • Q is A-Z or E, wherein;
  • X is a bond
  • B is 1 ,4-diazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl, optionally substituted by 1 or 2 methyl groups;
  • L is a bond or is methyl (methylene);
  • R 2 is phenyl, pyridyl, pyrimidinyl, thiazolyl, or oxazolyl, where the phenyl, pyridyl, pyrimidinyl, thiazolyl, or oxazolyl is unsubstituted or is substituted by a group selected from methyl, cyano, phenyl or 4-fluorophenyl;
  • the term "compound(s) of Formula I" means a compound of Formula (I) (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable 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, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), 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 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, solvates, including hydrate
  • 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, Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), 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.
  • 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 present invention is directed to a method of treating a B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, 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 directed to a method of treatment of Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma), 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.
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • diffuse large B-cell lymphoma follicular lymphoma
  • immunoblastic large cell lymphoma precursor B-lymphoblastic lymphoma
  • mantle cell lymphoma mantle cell lymphoma
  • patient refers to a mammal, specifically, a human.
  • 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 50 ), efficacy (EC 50 ), 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.
  • the particular compound e.g., the potency (pXC 50 ), efficacy (EC 50 ), and the biological half-life of the particular compound
  • disease condition and its severity e.g., the identity 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 or “treatment” is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is associated with, that is caused or mediated by, HDAC.
  • deacetylases that may be treated using the method of this invention include Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA).
  • B-cell lymphomas associated with deacetylases examples include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
  • this invention is directed to inhibitors of HDAC and their use to stop or reduce the growth of neoplastic cells, e.g., cancer cells and tumor cells.
  • 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 of a neurodegenerative disease or disorder 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.
  • NMDA glutamate
  • 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.
  • Treatment of a B-cell lymphoma 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: antibodies (such as rituxumab, alone or in combination with
  • cyclophosphamide chemotherapeutic regimens
  • proteasome inhibitors such as bortezomib
  • HDAC inhibitors such as vorinostat, romidepsin, valproic acid, panobinostat, mocetinostat, givinostat, belinostat and entinostat
  • mTOR inhibitors such as
  • temsirolimus deforolimus, everolimus,and rapamycin
  • DNA methyltransferase inhibitors DNA methyltransferase inhibitors
  • acetyl transferase enhancers DNA methyltransferase inhibitors
  • proteasome or HSP90 inhibitors 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 B cell lymphomas.
  • the pharmaceutical compositions useful in the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of Formula I 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.
  • 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. In addition, 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
  • 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 or a B- lymphoma by administering a compound having the formula: wherein X1; X2, X3, R1, R2, Y, Q, X, B and L are as defined herein, and methods of making and using the same.

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 neurodegenerative diseases and 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
The present invention also relates to a method of treating a B-cell lymphoma, particularly B-cell lymphomas associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma), 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).
HDAC9 is a class lla histone deacetylase highly expressed in human B cells. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell tumours and HDAC9 is highly overexpressed in cells derived from patients with non- Hodgkin's lymphoma
(http://icr.ac.uk/research/team leaders/Zelent Arthur/Zelent Arthur Rl/index.shtml). HDAC4 and HDAC9 have booth been reported to be overexpressed in CD19+ cells from patients with Waldenstrom Macroglobulinemia (Sun et al., Clinical Lymphoma, Myeloma & Leukemia, 201 1 , p. 152)
Class lla HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) have been reported to associate with Bcl-6, a transcription factor implicated in the pathogenesis of B-cell malignancies (Lemercier et al, Journal of Biological Chemistry, 2002, p. 22045, and Petrie et al, Journal of Biological Chemistry, 2003, p. 16059). Due to these interactions class lla HDACs have been suggested to modulate the transcriptional repression of BCL6 and participate in its role in B-cell activation and differentiation, inflammation, and cell-cycle regulation (Verdin et al. TRENDS in Genetics, 2003, p. 286) .
HDAC6, a class lib HDAC, has been reported to play an important role in aggresomal protein degradation, making it a target for the treatment of B cell malignancies (Simms-Waldrip et al., Molecular Genetics and Metabolism, 2008, p. 283) 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 and in the treatment of B-cell malignancies 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 and is further directed to a method of treatment of B-cell lymphoma, wherein each of said methods comprise administering, to a patient in need of treatment of a
neurodegenerative disease or disorder or in need of treatment of a B-cell
lymphoma, respectively, a compound of Formula I:
Figure imgf000004_0001
wherein:
R1 is fluoro(CrC4)alkyl containing at least 2 fluoro 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;
Q is A-Z or E, wherein:
A is optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
wherein said optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7
membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB; and
Z is -C(=0)-, -S02-, -NRxC(=0)-, -CH(CF3)-, -(C C4)alkyl-; and
E is -((d-C6)alkyl)C(=0)-, -((C C6)alkyl)S02-, -((C1-C6)alkyl)NRxC(=0)-,
-CH(CF3)-, -((CrQ alky CI-KCF,)-;
X is NRx or a bond;
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2
heteroatoms independently selected from N, O and S, wherein said phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, aryl(C C4)alkyl-, (C3-C7)cycloalkyl(C C4)alkyl-, — ORY, -(C C4)ORY, -NRYRY,
-(Ci-C4)NRYRY, -C(=0)ORY, -(C C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY,
Figure imgf000005_0001
-S02NRYRY, -(Ci-C4)S02NRYRY, -NRYS02RY, -(Ci-C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY,
Figure imgf000005_0002
wherein when B is heterocycloalkyi, X and L are attached to different ring atoms;
L is a bond or (CrC4)alkyl;
R2 is (Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-,halo(Ci-C4)alkoxy,
((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((d-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl 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, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through 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, or optionally substituted (C2-C6)alkyl, wherein said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-; and
each RY is independently selected from H, (CrC4)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, 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).
The invention is still 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 B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
The invention is 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, wherein the neurodegenerative disease or disorder is as defined above.
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 B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma). 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 the definition of the compound of Formula I, or a salt thereof, includes any combination of these group and substituent group definitions.
In one embodiment of the compound or salt of Formula I, R1 is a (Ci-C2)alkyl group containing at least 2 fluoro atoms (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 (Xi is O, X2 and X3 are N), oxazolyl (Xi is O, X2 is CH, X3 is N), imidazolyl (Xi 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, X^ is CH and X2 is N or X3 is S, X^ is N and X2 is CH), oxazolyl (X3 is O, X^ is CH and X2 is N or X3 is O, X^ 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 (X-\ 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 imgf000008_0001
wherein R1, R2, R3,R4, A, Z, n and L are as defined herein.
The invention is still further directed methods of treatment and uses of a compound of Formula (l-b):
Figure imgf000008_0002
wherein R1, R2, R3,R4, A, Z, n and L are as defined herein.
The invention is further directed methods of treatment and uses of a compound Formula (l-c), (l-d), o -e):
Figure imgf000008_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- -g), (l-h), (l-i), or (l-j):
Figure imgf000008_0004
Figure imgf000009_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 imgf000009_0002
wherein R1 , R2, R3,R4, A, n and L are as defined herein.
In another embodiment, the invention is directed methods of treatment and uses of a compound according to Formula l-A:
Figure imgf000010_0001
wherein:
R1 is fluoro(C1-C4)alkyl containing at least 2 fluoro 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 said optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, halo(CrC4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB;
Z is -C(=0)-, -SO2-, -NRxC(=0)-, -CH(CF3)-, -(C C4)alkyl-;
X is NRx or a bond;
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S,
wherein said phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, aryl(C C4)alkyl-, (C3-C7)cycloalkyl(C C4)alkyl-, — ORY, -(C C4)ORY, -NRYRY,
-(C C4)NRYRY, -C(=0)ORY, -(C C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY,
Figure imgf000010_0002
-S02NRYRY, -(Ci-C4)S02NRYRY, -NRYS02RY, -(Ci-C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY,
Figure imgf000010_0003
wherein when B is heterocycloalkyi, X and L are attached to different ring atoms;
L is a bond or (CrC4)alkyl;
R2 is (Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro, (C1-C4)alkoxy, (C1-C4)alkylthio-,halo(C1-C4)alkoxy,
((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((d-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through 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, or optionally substituted (C2-C6)alkyl, wherein said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-; and
each RY is independently selected from H, (CrC4)alkyl, phenyl, and
-(C1-C4)alkylphenyl;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
In another embodiment, the invention is directed methods of treatment and uses of a compound according
Figure imgf000011_0001
R1 is fluoro(CrC4)alkyl containing at least 2 fluoro 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;
E is -((CrC6)alkyl)C(=0)-, -((Ci-C6)alkyl)S02-, -((C C6)alkyl)NRxC(=0)-,
-CH(CF3)-, -((Ci-C6)alkyl)CH(CF3)-;
X is NRx or a bond,
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, aryl(C C4)alkyl-, (C3-C7)cycloalkyl(C C4)alkyl-, — ORY, -(C C4)ORY, -NRYRY,
-(Ci-C4)NRYRY, -C(=0)ORY, -(C C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY,
Figure imgf000012_0001
-S02NRYRY, -(Ci-C4)S02NRYRY, -NRYS02RY, -(Ci-C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY,
Figure imgf000012_0002
wherein when B is heterocycloalkyi, X and L are attached to different ring atoms;
L is a bond or (CrC4)alkyl;
R2 is (Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-,halo(Ci-C4)alkoxy,
((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((d-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl 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, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through 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, or optionally substituted (C2-C6)alkyl, wherein said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-; and
each RY is independently selected from H, (CrC4)alkyl, phenyl, and
-(CrC4)alkylphenyl;
or a salt, particularly a pharmaceutically acceptable salt, thereof. In another embodiment, the invention is directed methods of treatment and uses of a compound according to Formula l-C:
Figure imgf000013_0001
wherein:
R1 is fluoro(CrC4)alkyl containing at least 2 fluoro 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 X^ and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and X^ is O, X2 is CH or N, and X3 is CH or N;
Q is -CH(CF3)-, ,-phenyl-C(=0)-, -phenyl-S(02)-, -phenyl-CH(CF3)-,
-phenyl-(C1-C4)alkyl-, -(5-6 membered heteroaryl)-C(=0)-, -(5-6 membered
heteroaryl )-S02-, -(5-6 membered heteroaryl)-CH(CF3)-, -(5-6 membered
heteroaryl)-(CrC4)alkyl-, -(9-10 membered heteroaryl) -C(=0)-, -(9-10 membered heteroaryl) -S02-, -(9-10 membered heteroaryl)-CH(CF3)-, -(9-10 membered
heteroaryl)-(C C4)alkyl-, -(C3-C6)cycloalkyl-C(=0)-, -(C3-C6)cycloalkyl-S02-,
-(C3-C6)cycloalkyl-CH(CF3)-„ -(C3-C6)cycloalkyl-(C C4)alkyl-, -(C C6)alkyl-C(=0)-,
-(CrC6)alkyl-S02-, -(C C6)alkyl-CH(CF3)-, naphthyl-C(=0)-, - naphthyl -S(02)-, - naphthyl -CH(CF3)-, - naphthyl -(C C4)alkyl-, -(4-7 membered heterocycloalkyl)-C(=0)-, -(4-7 membered heterocycloalkyl)-S02-, -(4-7 membered heterocycloalkyl)-CH(CF3)-, -(4-7 membered heterocycloalkyl)-(CrC4)alkyl; wherein any (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl moiety is optionally substituted by 1 , 2 or 3 groups independently selected from
(Ci-C4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARB and -((Ci-C4)alkyl)NRARB;
L is a bond or is (C1-C4)alkyl;
R2 is (d-C4)alkyl, -NRARB, -(C C4)alkyl-NRARB, -NRAC(=0)RB, -C(=0)-NRARB,
5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or
-C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-,halo(Ci-C4)alkoxy, ((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((d-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C )alkyl, halogen, cyano, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (Ci-C )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through which they are attached form an optionally substituted 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, S;
Figure imgf000014_0001
is an optionally substituted 4-10 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S, where said 4-10 membered heterocyclic ring is optionally substituted by 1 or 2 groups independently selected from (Ci-C )alkyl, halo(Ci-C )alkyl, halogen, cyano, aryl(Ci-C )alkyl-,
(C3-C7)cycloalkyl(C C4)alkyl-, — ORY, -(C C4)ORY, -NRYRY, -(C C4)NRYRY, - C(=0)ORY, -(d-C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY, -(C C4)NRYC(=0)RY, -S02NRYRY, -(C C4)S02NRYRY, -NRYS02RY, -(C C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY, -(d-C4)NRYC(=0)ORY, -NRYC(=0)NRYRY, and -(d-C4)NRYC(=0)NRYRY, where each Ry is independently selected from H and (d-d)alkyl, phenyl, and -(d-d)alkylphenyl;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
Another embodiment of this invention is directed to a method of treatment and use of a compound of Formula l-C wherein
R1 is -CF3;
Y is a bond and Xi is O, N or NH, X2 is N or CH and X3 is N or NH,
Q is -phenyl-C(=0)-, -phenyl-S02-, -phenyl-CH(CF3)-, -pyridyl-C(=0)-,
-pyridyl-S02-, -pyridyl-CH(CF3)-, -isoquinolyl-C(=0)-, -isoquinolyl-S02-,
-isoquinolyl-CH(CF3)-, -indazolyl-C(=0)-, -indazolyl-S02-, -indazolyl-CH(CF3)-,
-(C3-C6)cycloalkyl-C(=0)-, -(C3-C6)cycloalkyl-S02-, -(C3-C6)cycloalkyl-CH(CF3)-,
Figure imgf000014_0002
-(d-C8)alkyl-S02-, or -(d-C8)alkyl-CH(CF3)-,
wherein said phenyl, pyridyl, isoquinolyl, indazolyl, or (C3-C6)cycloalkyl is optionally substituted by chloro, fluoro, cyano, methoxy, methyl, or trifluoromethyl;
L is a bond, methylene, ethylene or propylene; R2 is -C(=0)NH2, morpholinyl, -CO-morpholinyl, dimethylamino-, diethylamino-, butylaminocarbonyl-, -CO-pyrrolidinyl, -CO-indolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
benzimidazolyl, benzimidazolonyl, or indolinyl,
where any morpholinyl, pyrrolidinyl, indolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
benzimidazolyl, or benzimidazolonyl moiety is optionally substituted with 1 or 2 groups independently selected from (d-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro,
(Ci-C4)alkoxy, (CrC4)alkylthio-, halo(CrC4)alkoxy,
((CrC4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, NRARB, ((C C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy;
wherein RA and RB are independently selected from H and (Ci-C4)alkyl or RA and
RB taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
Figure imgf000015_0001
is an optionally substituted 5 or 6-membered heterocyclic ring, optionally containing one additional nitrogen ring atom, where said 5 or 6-membered heterocyclic ring is optionally substituted by 1 or 2 groups independently selected from (CrC2)alkyl, halo(CrC2)alkyl, cyano, -ORy, -(C C2)ORy, -NRyRy, -(Ci-C2)NRyRy, -C(=0)ORy, -
Figure imgf000015_0002
where each Ry is
independently selected from H and methyl;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
In embodiments of compounds of Formula l-A, A is a phenyl or pyridyl group optionally substituted by 1-2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(C C4)alkyl, (Ci-C4)alkoxy, halo(C C4)alkoxy, -NRARA and
-((CrC4)alkyl)NRARA. In further embodiments, A is a phenyl or pyridyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARB and -((C C4)alkyl)NRARB, where each RA and RB is independently selected from H and methyl. In further embodiments of the compound or salt of Formula l-A, A is an unsubstituted phenyl or pyridyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group. In specific embodiments of a compound or salt of Formula l-A, A is an unsubstituted phenyl group.
In another embodiment of a compound or salt of Formulas I and l-A, A is naphthyl, optionally substituted by 1-2 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(C C4)alkyl, (Ci-C4)alkoxy, halo(C C4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB.
In yet another embodiment of compounds or salts of Formulas I and l-A, A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from (CrC4)alkyl, (Ci-C4)alkoxy, -NRARB and
-((CrC4)alkyl)NRARB. 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, -NRARB and -((C C4)alkyl)NRARB, where each RA and RB is independently selected from H and methyl.
In further embodiments, A is a 5-6 membered heteroaryl or a 9-10 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, -NRARAB and
-((CrC4)alkyl)NRARB. In still further embodiments, A is a 5-6 membered heteroaryl or a 9-10 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl, -NRARB and -((C C4)alkyl)NRARB, where each RA and RB is independently selected from H and 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 another embodiment of compounds or salts of Formulas I and l-A, 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(Ci-C4)alkoxy, -NRARB and -((C C4)alkyl)NRARB.
In another embodiment of compounds or salts of Formulas I and l-A of this invention, Z is -C(=0)- or -NRxC(=0)-, particularly -C(=0)-. In another embodiment of this invention, Z is -S02-. In another embodiment of this invention, Z is -CH(CF3)- or -(CrC4)alkyl-. In selected embodiments Z is -NHC(=0)-. In specific embodiments Z is - C(=0)-.
In an embodiment of compounds of Formulas I and l-B, , E is -((CrC5)alkyl)C(=0)- or -((C C5)alkyl)NRxC(=0)-. In an embodiment, E is -((C C4)alkyl)C(=0)- or
-((C C4)alkyl)NRxC(=0)-. In another embodiment, E is -((Ci-C5)alkyl)S02- or
-((Ci-C4)alkyl)S02-. In another embodiment, E is -CH(CF3)- or -((Ci-C4)alkyl)CH(CF3)-. In other embodiments, E is -propyl-C(=0)- or -pentyl-C(=0)-; more specifically, E is -CH2CH2CH2C(=0)- or -CH2CH2C(CH3)2C(=0)-.
Further, in embodiments of the compounds or salts of Formulas I, l-A and l-B, X is NRx or a bond, where each Rx is independently selected from H, (d-C4)alkyl, or optionally substituted (C2-C4)alkyl, where the optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC4)alkoxy, (CrC4)alkyl)NH-, or
((Ci-C4)alkyl)((Ci-C4)alkyl)N-. In another embodiment, each Rx is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and dimethylaminoethyl-. In specific embodiments, each Rx is H.
Accordingly, in specific embodiments of the compounds useful in the method of this invention, the moiety Z-X is -C(=0)- or -C(=0)NH- and the moiety E-X is
-((CrC5)alkyl)C(=0)- or -((Ci-C5)alkyl)C(=0)NH-.
In another embodiment, B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 or 2 groups independently selected from (Ci-C2)alkyl, halo(Ci-C2)alkyl, halogen, cyano, aryl(Ci-C3)alkyl-,
(C3-C6)cycloalkyl(Ci-C3)alkyl-, -ORY, -(C C2)ORY, -NRYRY, -(C C2)NRYRY, - C(=0)ORY, -(d-C2)C(=0)ORY, -C(=0)NRYRY, -(C C2)C(=0)NRYRY, -NRYC(=0)RY, -(C C2)NRYC(=0)RY, -S02NRYRY, -(C C2)S02NRYRY, -NRYS02RY, -(C C2)NRYS02RY, -OC(=0)NRYRY, -(C C2)OC(=0)NRYRY, -NRYC(=0)ORY, -(d-C2)NRYC(=0)ORY,
-NRYC(=0)NRYRY, and -(d-C2)NRYC(=0)NRYRY, where each RY is as defined above, and more particularly, where each RY is independently selected from H and methyl.
In another embodiment, B is a phenyl, pyridyl or 4-8 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted as defined above.
In other embodiments, B is a 4, 5, 6 or 7 membered heterocycloalkyi containing 1 or 2 nitrogen atoms, optionally substituted by 1 or 2 groups independently selected from (d-C2)alkyl, halo(d-C2)alkyl, halogen, cyano, aryl(d-d)alkyl-,
(C3-C6)cycloalkyl(d-C3)alkyl-, — ORY, -(d-C2)ORY, -NRYRY, -(C C2)NRYRY,
-C(=0)ORY, -(d-C2)C(=0)ORY, -C(=0)NRYRY, and -(C C2)C(=0)NRYRY, where each RY is independently selected from H and methyl.
In selected embodiments, B is 1 ,4-diazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl, optionally substituted by 1 or 2 groups independently selected from methyl, -CH2OH and -C(=0)OH. In specific embodiments, B is 1 ,4-diazepanyl, piperazinyl or piperidinyl, optionally substituted by 1 or 2 groups independently selected from methyl and -C(=0)OH. In all cases where B is heterocycloalkyl, the bonding arrangement of X-B-L is such that X and L are attached to different ring atoms, that is X and L are not attached to the same ring atom of B.
In another embodiment of this invention, L is a bond or (d-C3)alkyl (that is, a (Ci-C3)alkylene linker), specifically, L is a bond or is methyl (methylene), ethyl (ethylene) or propyl (propylene).
In another embodiment of this invention, R2 is (CrC4)alkyl, -NRARB,
-NRAC(=0)RB, -C(=0)-NRARB, where each RA and RB are independently selected from H, (Ci-C4)alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S.
In another embodiment of this invention, R2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyl, (C3-C6)cycloalkyl, phenyl,
-C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyl), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyl, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 or 2 groups independently selected from (d-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (C1-C4)alkylthio-, halo(CrC4)alkoxy,
((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, -((C C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (Ci-C4)alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S.
In selected embodiments, R2 is -N(CH2CH3)2, -C(=0)NH2,
-C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo- isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl,
benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl,
thienopyrimidinyl , benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyk
In specific embodiments, R2 is -N(CH2CH3)2, -C(=0)NH2,
-C(=0)NH(CH2CH2CH2CI-l3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo- isothiazolyl, benzimidazolyl, benzimidazolonyl, or indolinyl, where the phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, and benzimidazolonyl are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, fluoro-phenyl, and morpholinylpropyk 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 "C1-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 this invention, 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 this invention, 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. 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), 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, cinnolinyl, pteridinyl, isothiazolyl.
Some of the heteroaryl groups present in the compounds of this invention 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, thiadiazolyl, thiazolyl, triazolyl, and tetrazolyl or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
Some of the heteroaryl groups present in the compounds of this invention 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 compounds of Formula I are only those which are contemplated to be
"chemically stable" as will be appreciated by those skilled in the art.
The invention is further directed to the use of a compound of Formula I, wherein:
A is a phenyl or pyridyl group optionally substituted by 1 -2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (d-C4)alkoxy,
halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
Z is -C(=0)- or -NRxC(=0)-;
X is NRx or a bond, where Rx is independently selected from H, (CrC4)alkyl, or optionally substituted (C2-C4)alkyl, where the optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((CrC4)alkyl)N-;
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 or 2 groups independently selected from (C1-C2)alkyl, halo(C1-C2)alkyl, halogen, cyano, aryl(C1-C3)alkyl-,
(C3-C6)cycloalkyl(C1-C3)alkyl-, — ORY, -(C C2)ORY, -NRYRY, -(C C2)NRYRY, -
C(=0)ORY, -(d-C2)C(=0)ORY, -C(=0)NRYRY, -(C C2)C(=0)NRYRY, -NRYC(=0)RY,
Figure imgf000022_0001
-S02NRYRY, -(C C2)S02NRYRY, -NRYS02RY, -(C C2)NRYS02RY, -OC(=0)NRYRY,
Figure imgf000022_0002
-NRYC(=0)NRYRY, and -(C C2)NRYC(=0)NRYRY;
L is a bond or (C C3)alkyl;
R2 is (Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, where each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
or R2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 or 2 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, nitro, (C1-C4)alkoxy, (C1-C4)alkylthio-, halo(C1-C4)alkoxy,
((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, -((C C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to the use of a compound of Formula I, wherein:
A is a phenyl or pyridyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARB and -((C1-C4)alkyl)NRARB, where each RA and RB is independently selected from H and methyl;
Z is -C(=0)- or -NRxC(=0)-;
X is NRx or a bond, where Rx is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
dimethylaminoethyl-;
B is a 4, 5, 6 or 7 membered heterocycloalkyl containing 1 or 2 nitrogen atoms, optionally substituted by 1 or 2 groups independently selected from (CrC2)alkyl, halo(C C2)alkyl, halogen, cyano, aryl(Ci-C3)alkyl-, (C3-C6)cycloalkyl(Ci-C3)alkyl-, -ORY, -(Ci-C2)ORY, -NRYRY, -(Ci-C2)NRYRY, -C(=0)ORY, -(C C2)C(=0)ORY, -C(=0)NRYRY, and
Figure imgf000023_0001
where each RY is independently selected from H and methyl;
L is a bond or (CrC3)alkyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl,
-C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyl-;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to the use of a compound of Formula I, wherein:
A is an unsubstituted phenyl or pyridyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group;
Z is -C(=0)- or -NRxC(=0)-;
X is NRx or a bond, where Rx is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
dimethylaminoethyl-;
B is 1 ,4-diazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl, optionally substituted by 1 or 2 groups independently selected from methyl, -CH2OH and -C(=0)OH;
L is a bond or (d-C3)alkyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl,
-C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyl-;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to the use of a compound of Formula I, wherein:
A is an unsubstituted phenyl or pyridyl group;
Z is -C(=0)-;
X is NRX or a bond, where Rx is H;
B is 1 ,4-diazepanyl, piperazinyl or piperidinyl, optionally substituted by 1 or 2 groups independently selected from methyl and -C(=0)OH;
L is a bond or is methyl (methylene), ethyl (ethylene) or propyl (propylene);
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl, benzimidazolyl,
benzimidazolonyl, or indolinyl, where the phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, and benzimidazolonyl are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, 4- fluoro-phenyl, and morpholinylpropyl-;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to the use of a compound of Formula I, wherein:
A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from (d-C4)alkyl, (CrC4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB;
Z is -C(=0)-;
X is NRx or a bond, where Rx is independently selected from H, (CrC4)alkyl, or optionally substituted (C2-C4)alkyl, where the optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((CrC4)alkyl)N-;
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 or 2 groups independently selected from (Ci-C2)alkyl, halo(CrC2)alkyl, halogen, cyano, aryl(Ci-C3)alkyl-,
(C3-C6)cycloalkyl(C1-C3)alkyl-, — ORY, -(C C2)ORY, -NRYRY, -(C C2)NRYRY, - C(=0)ORY, -(d-C2)C(=0)ORY, -C(=0)NRYRY, -(C C2)C(=0)NRYRY, -NRYC(=0)RY, -(C C2)NRYC(=0)RY, -S02NRYRY, -(C C2)S02NRYRY, -NRYS02RY, -(C C2)NRYS02RY, -OC(=0)NRYRY, -(C C2)OC(=0)NRYRY, -NRYC(=0)ORY, -(d-d)NRYC(=0)ORY, -NRYC(=0)NRYRY, and -(C C2)NRYC(=0)NRYRY;
L is a bond or (d-C3)alkyl;
R2 is (d-d)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, where each RA and RB are independently selected from H, (d-d)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
or R2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 or 2 groups independently selected from (d-d)alkyl, halo(d-C4)alkyl, halogen, cyano, nitro, (d-d)alkoxy, (d-d)alkylthio-, halo(d-C4)alkoxy, ((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, -((C C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups independently selected from (Ci-C )alkyl, halogen, cyano, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (Ci-C )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to the use of a compound of Formula I, wherein: A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NRARB and -((CrC )alkyl)NRARB, where each RA and RB is independently selected from H and methyl;
Z is -C(=0)- or -NRxC(=0)-;
X is NRx or a bond, where Rx is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
dimethylaminoethyl-;
B is 1 ,4-diazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl, optionally substituted by 1 or 2 groups independently selected from methyl, -CH2OH and -C(=0)OH;
L is a bond or (d-C3)alkyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl,
-C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyl-;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to the use of a compound of Formula I, wherein: E is -((C C5)alkyl)C(=0)- or -((C C5)alkyl)NRxC(=0)-;
X is NRx or a bond, where Rx is independently selected from H, (C1-C4)alkyl, or optionally substituted (C2-C4)alkyl, where the optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (Ci-C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((CrC4)alkyl)N-;
B is a 4, 5, 6 or 7 membered heterocycloalkyl containing 1 or 2 nitrogen atoms, optionally substituted by 1 or 2 groups independently selected from (CrC2)alkyl, halo(C C2)alkyl, halogen, cyano, aryl(Ci-C3)alkyl-, (C3-C6)cycloalkyl(Ci-C3)alkyl-, -ORY, -(Ci-C2)ORY, -NRYRY, -(Ci-C2)NRYRY, -C(=0)ORY, -(C C2)C(=0)ORY, -C(=0)NRYRY, and -(CrC2)C(=0)NRYRY, where each RY is independently selected from H and methyl;
L is a bond or (d-C3)alkyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl, and morpholinylpropyl-;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to the use of a compound of Formula I, wherein: E is -propyl-C(=0)- or -pentyl-C(=0)-;
X is NRx or a bond, where Rx is H;
B is 1 ,4-diazepanyl, piperazinyl or piperidinyl, optionally substituted by 1 or 2 groups independently selected from methyl and -C(=0)OH;
L is a bond or is methyl (methylene), ethyl (ethylene) or propyl (propylene);
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl, benzimidazolyl,
benzimidazolonyl, or indolinyl, where the phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, and benzimidazolonyl are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, fluoro-phenyl, and morpholinylpropyl-;
or a salt, particularly a pharmaceutically acceptable salt, thereof. The invention is still further directed to the use of a compound of Formula I, wherein:
Q is A-Z or E, wherein;
A is phenyl and Z is -C(=0)- or E is -CH2CH2C(CH3)2-C(=0)-;
X is a bond;
B is 1 ,4-diazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl, optionally substituted by 1 or 2 methyl groups;
L is a bond or is methyl (methylene);
R2 is phenyl, pyridyl, pyrimidinyl, thiazolyl, or oxazolyl, where the phenyl, pyridyl, pyrimidinyl, thiazolyl, or oxazolyl is unsubstituted or is substituted by a group selected from methyl, cyano, phenyl or 4-fluorophenyl;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
As used herein, the term "compound(s) of Formula I " means a compound of Formula (I) (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable 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, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
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 1/088192, the disclosure of which is incorporated herein by reference.
Representative compounds of Formula I include:
(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)phenyl)(4-(5-(trifluoromethyl)pyridin-2- yl)-1 ,4-diazepan-1-yl)methanone,
(4-(3,4-dimethylphenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(3,4-dichlorophenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(pyrazin-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperidine-2-carboxamide, (4-(2-morpholinoethyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone, (4-(3-(dimethylamino)propyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
2-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 -yl)benzonitrile,
(4-(2,4-dimethoxyphenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
1-morpholino-2-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)ethanone,
(4-phenethylpiperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
/V-butyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazine-1 - carboxamide,
(4-(pyridin-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
1-(pyrrolidin-1 -yl)-2-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazin-1-yl)ethanone,
(4-benzylpiperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(benzo[d][1 ,3]dioxol-5-ylmethyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
3-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1-yl)pyrazine-2- carbonitrile,
(4-(pyridin-4-ylmethyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(3-(diethylamino)propyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(1 /-/-indole-6-carbonyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-picolinoylpiperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(thieno[3,2-Q0pyrimidin-4-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)phenyl)methanone,
(4-(4-nitrobenzyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(pyridin-4-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone, 6-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile,
(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)phenyl)(4-(3-(trifluoromethyl)pyridin-2- yl)piperazin-1 -yl)methanone,
(4-(2-chlorophenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(3-fluorophenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(3-(methylthio)phenyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(4-chlorobenzyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(2-methoxybenzyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone„
(4-(4-methoxyphenyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
4-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1-yl)-1 H- benzo[c ]imidazol-2(3H)-one,
/V-(4-((/V-methylacetamido)methyl)phenyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
Λ/-(4-((1 H-1 ,2,4-triazol-1 -yl)methyl)phenyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
(3-benzylpiperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
4-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 -yl)benzonitrile, 6-(2-methyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile,
6-(3-methyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile,
6-(3,5-dimethyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
methyl 4-(5-cyanopyridin-2-yl)-1 -(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazine-2-carboxylate, 4-(5-cyanopyridin-2-yl)-1 -(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazine-2-carboxylic acid,
6-(2,6-dimethyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
1-(3-morpholinopropyl)-3-(1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperidin-4-yl)-1 H-benzo[c/]imidazol-2(3H)-one,
1-(1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperidin-4-yl)-1 /-/- benzo[c ]imidazol-2(3H)-one,
6-((3-methyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)methyl)nicotinonitrile,
6-((3-methyl-4-(4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanoyl)piperazin-1- yl)methyl)nicotinonitrile,
1-(4-phenylthiazol-2-yl)-/V-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)pyrrolidine-3-carboxamide,
6-(1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)azetidin-3-yl)nicotinonitrile, 6-(1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperidin-4- yl)nicotinonitrile,
/V-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
1-(5-cyanopyridin-2-yl)-/\/-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)pyrrolidine-3-carboxamide ,
6-(3-methyl-4-(4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanoyl)piperazin-1 - yl)nicotinonitrile,
6-(2,2-dimethyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
/V-(1-(5-cyanopyridin-2-yl)piperidin-3-yl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
6-(3,3-dimethyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
6-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)-1 ,4-diazepan-1- yl)nicotinonitrile,
1-(5-cyanopyridin-2-yl)-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazine-2-carboxylic acid,
(4-methyl-3-(4-phenylthiazol-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone, 6-(3-methyl-4-(3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
6-(4-(3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoyl)piperazin-1-yl)nicotinonitrile, 6-(4-(2,2-dimethyl-4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanoyl)-3- methylpiperazin-1 -yl)nicotinonitrile,
(4-(5-methoxypyridin-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(3-(4-(4-f|UOrophenyl)thiazol-2-yl)piperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
6-(3-methyl-4-(4-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)butanoyl)piperazin-1- yl)nicotinonitrile,
(4-(2,3-dihydro-1 H-inden-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)phenyl)methanone,
(4-(1 /-/-benzo[c ]imidazol-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)phenyl)methanone,
(3-(5-(4-fluorophenyl)oxazol-2-yl)piperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
(4-(3-methoxyphenyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(pyrimidin-5-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
2- (4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile
(4-(4-phenylpyrimidin-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(2-fluorophenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(2-methoxyphenyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(pyridin-3-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
3- fluoro-4-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)benzonitrile,
(4-(pyrimidin-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone, (4-([1 , 1 '-biphenyl]-3-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(3-((4-(4-f|UOrophenyl)thiazol-2-yl)methyl)azetidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
(4-(4-methylthiazol-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(benzo[c/]oxazol-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-((2-(4-fluorophenyl)thiazol-4-yl)methyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)phenyl)methanone,
(4-((2-(4-fluorophenyl)oxazol-4-yl)methyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)phenyl)methanone,
(2-phenylthiazol-4-yl)(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazin-1-yl)methanone,
((1 S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)phenyl)methanone,
or a salt, particularly a pharmaceutically acceptable salt, thereof.
Particular compounds of Formula I include:
(3-((4-(4-fluorophenyl)thiazol-2-yl)methyl)azetidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
6-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)-1 ,4-diazepan-1 - yl)nicotinonitrile,
(4-methyl-3-(4-phenylthiazol-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
(4-(pyrimidin-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
6-((3-methyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)methyl)nicotinonitrile,
6-(4-(2,2-dimethyl-4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanoyl)-3- methylpiperazin-1 -yl)nicotinonitrile,
6-(4-(3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoyl)piperazin-1-yl)nicotinonitrile,
(4-(4-methylthiazol-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(3-(5-(4-fluorophenyl)oxazol-2-yl)piperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone, (3-(4-(4-f|UOrophenyl)thiazol-2-yl)piperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
6-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile,
or a salt, particularly a pharmaceutical salt 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
1 1 .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.
In one embodiment, 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 (NMD), 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. In another embodiment, the present invention is directed to a method of treating a B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, which comprises administering to a patient in need thereof, a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof. More specifically, this invention is directed to a method of treatment of Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma), 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 (pXC50), efficacy (EC50), 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 associated with, that is caused or mediated by, HDAC.
Examples of neurodegenerative diseases or disorders associated with
deacetylases that may be treated using the method of this invention include Alzheimer's disease, Parkinson's disease, neuronal intranuclear inclusion disease (NMD), and polyglutamine disorders, such as Huntington's disease and spinocerebellar ataxia (SCA). Examples of B-cell lymphomas associated with deacetylases that may be treated using the method of this invention include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
In another embodiment, this invention is directed to inhibitors of HDAC and their use to stop or reduce the growth of neoplastic cells, e.g., cancer cells and tumor cells.
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 of a neurodegenerative disease or disorder 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.
Treatment of a B-cell lymphoma 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: antibodies (such as rituxumab, alone or in combination with
cyclophosphamide), chemotherapeutic regimens, proteasome inhibitors (such as bortezomib), HDAC inhibitors (such as vorinostat, romidepsin, valproic acid, panobinostat, mocetinostat, givinostat, belinostat and entinostat), mTOR inhibitors (such as
temsirolimus, deforolimus, everolimus,and rapamycin), DNA methyltransferase inhibitors, acetyl transferase enhancers, proteasome or HSP90 inhibitors, 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 B cell lymphomas. The pharmaceutical compositions useful in the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of Formula I 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:
Inqredient Amount per tablet
Compound 5mg
Microcrystalline cellulose 100mg
Lactose 100mg
Sodium starch glycollate 30mg
Maqnesium stearate 2mq
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 1/088192
"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

pi WO 2013/009827 PCT/US2012/046198 What is claimed is: 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 imgf000042_0001
wherein:
R1 is fluoro(CrC4)alkyl containing at least 2 fluoro atoms;
Y is a bond and X^ is O, N or NH, X2 is N or CH and X3 is N or NH,
or Y is -C(O)- and X^ and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and X^ is O, X2 is CH or N, and X3 is CH or N;
Q is A-Z or E, wherein:
A is optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocydoalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
wherein said optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7
membered heterocydoalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB; and
Z is -C(=0)-, -SO2-, -NRxC(=0)-, -CH(CF3)-, -(C C4)alkyl-; and
E is
Figure imgf000042_0002
-((C C6)alkyl)S02-,
-CH(CF3)-, -((Ci-C6)alkyl)CH(CF3)-;
X is NRx or a bond;
B is a phenyl, pyridyl or 4-10 membered heterocydoalkyi containing 1 or 2
heteroatoms independently selected from N, O and S,
wherein said phenyl, pyridyl or heterocydoalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, aryl(C C4)alkyl-, (C3-C7)cycloalkyl(C1-C4)alkyl-, — ORY, -(C C4)ORY, -NRYRY,
-(C C4)NRYRY, -C(=0)ORY, -(C C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY, -(C C4)NRYC(=0)RY, -S02NRYRY, -(d-C4)S02NRYRY, -NRYS02RY, -(Ci-C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY,
Figure imgf000042_0003
-NRYC(=0)NRYRY, and -(C C4)NRYC(=0)NRYRY, pi IR4RQR
WO 2013/009827 PCT/US2012/046198 wherein when B is heterocycloalkyi, X and L are attached to different ring atoms; L is a bond or (C1-C4)alkyl;
R2 is (d-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-,halo(Ci-C4)alkoxy,
((CrC4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((Ci-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through 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, or optionally substituted (C2-C6)alkyl, wherein said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-; and
each RY is independently selected from H, (CrC4)alkyl, phenyl, and
-(CrC4)alkylphenyl;
or a salt thereof.
pi IR4RQR
WO 2013/009827 PCT/US2012/046198
2. A method of treatment of a B-cell lymphoma associated with deacetylases comprising administering, to a patient in need thereof, a compound of Formula I:
Figure imgf000044_0001
wherein:
R1 is fluoro(C1-C4)alkyl containing at least 2 fluoro atoms;
Y is a bond and X^ 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;
Q is A-Z or E, wherein:
A is optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocydoalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
wherein said optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocydoalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, halo(CrC4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB; and
Z is -C(=0)-, -SO2-, -NRxC(=0)-, -CH(CF3)-, -(C C4)alkyl-; and
E is
Figure imgf000044_0002
-((C C6)alkyl)S02-,
-CH(CF3)-, -((Ci-C6)alkyl)CH(CF3)-;
X is NRx or a bond;
B is a phenyl, pyridyl or 4-10 membered heterocydoalkyi containing 1 or 2 heteroatoms independently selected from N, O and S,
wherein said phenyl, pyridyl or heterocydoalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, aryl(Ci-C4)alkyl-, (C3-C7)cycloalkyl(Ci-C4)alkyl-, -ORY, -(C C4)ORY, -NRYRY,
-(Ci-C4)NRYRY, -C(=0)ORY, -(C C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY,
Figure imgf000044_0003
-S02NRYRY, -(Ci-C4)S02NRYRY, -NRYS02RY, -(Ci-C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY,
Figure imgf000044_0004
wherein when B is heterocydoalkyi, X and L are attached to different ring atoms;
L is a bond or (CrC4)alkyl; pi IR4RQR
WO 2013/009827 PCT/US2012/046198
R2 is (Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-,halo(Ci-C4)alkoxy,
((CrC4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((Ci-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through 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, (C1-C6)alkyl, or optionally substituted
(C2-C6)alkyl, wherein said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-; and
each RY is independently selected from H, (CrC4)alkyl, phenyl, and
-(C C4)alkylphenyl;
or a salt thereof.
3. The method according to claim 1 or claim 2, wherein the compound of Formula I has Formula l-A:
Figure imgf000045_0001
wherein:
R1 is fluoro(CrC4)alkyl containing at least 2 fluoro atoms;
Y is a bond and Xi is O, N or NH, X2 is N or CH and X3 is N or NH, pi IR4RQR
WO 2013/009827 PCT/US2012/046198 or Y is -C(O)- and X^ and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and X^ 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 said optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, halo(CrC4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB;
Z is -C(=0)-, -SO2-, -NRxC(=0)-, -CH(CF3)-, -(C C4)alkyl-;
X is NRx or a bond;
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S,
wherein said phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, aryl(Ci-C4)alkyl- (C3-C7)cycloalkyl(C C4)alkyl-, -ORY, -(C C4)ORY, -NRYRY,
-(Ci-C4)NRYRY, -C(=0)ORY, -(C C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY, -(C C4)NRYC(=0)RY, -S02NRYRY, -(d-C4)S02NRYRY, -NRYS02RY, -(C C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY,
-(C C4)NRYC(=0)ORY, -NRYC(=0)NRYRY, and -(C C4)NRYC(=0)NRYRY,
wherein when B is heterocycloalkyi, X and L are attached to different ring atoms;
L is a bond or (d-C4)alkyl;
R2 is (Ci-d)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halo(Ci-C4)alkyl, halogen, cyano, nitro, (Ci-C4)alkoxy, (Ci-C4)alkylthio-,halo(Ci-C4)alkoxy,
((Ci-C4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((Ci-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (d-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein: pi IR4RQR
WO 2013/009827 PCT/US2012/046198 each RA and RB are independently selected from H, (C1-C4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through 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, or optionally substituted (C2-C6)alkyl, wherein 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.
4. The method according to claim 1 or claim 2, wherein the compound of Formula I has Formula l-B:
Figure imgf000047_0001
R1 is fluoro(CrC4)alkyl containing at least 2 fluoro 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 X^ and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and X^ is O, X2 is CH or N, and X3 is CH or N;
E is -((d-C6)alkyl)C(=0)-, -((C C6)alkyl)S02-, -((C1-C6)alkyl)NRxC(=0)-,
-CH(CF3)-, -((CrC6)alkyl)CH(CF3)-;
X is NRx or a bond,
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S,
wherein said phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or
3 groups independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, halogen, cyano, aryl(Ci-C4)alkyl- (C3-C7)cycloalkyl(C C4)alkyl-, -ORY, -(C C4)ORY, -NRYRY,
-(Ci-C4)NRYRY, -C(=0)ORY, -(C C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY,
Figure imgf000047_0002
-S02NRYRY, -(Ci-C4)S02NRYRY, -NRYS02RY, -(Ci-C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY,
Figure imgf000047_0003
wherein when B is heterocycloalkyi, X and L are attached to different ring atoms;
L is a bond or (Ci-C4)alkyl; pi IR4RQR
WO 2013/009827 PCT/US2012/046198
R2 is (Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-,halo(Ci-C4)alkoxy,
((CrC4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((Ci-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through 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, (C1-C6)alkyl, or optionally substituted
(C2-C6)alkyl, wherein said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-; and
each RY is independently selected from H, (CrC4)alkyl, phenyl, and
-(C C4)alkylphenyl.
pi IR4RQR
WO 2013/009827 PCT/US2012/046198
5. The method according to claim 1 or claim 2, wherein the compound of Formula I has Formula l-C:
Figure imgf000049_0001
wherein:
R1 is fluoro(CrC4)alkyl containing at least 2 fluoro 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 X^ and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and X^ is O, X2 is CH or N, and X3 is CH or N;
Q is -CH(CF3)-, ,-phenyl-C(=0)-, -phenyl-S(02)-, -phenyl-CH(CF3)-,
-phenyl-(Ci-C4)alkyl-, -(5-6 membered heteroaryl)-C(=0)-, -(5-6 membered
heteroaryl )-S02-, -(5-6 membered heteroaryl)-CH(CF3)-, -(5-6 membered
heteroaryl)-(CrC4)alkyl-, -(9-10 membered heteroaryl) -C(=0)-, -(9-10 membered heteroaryl) -S02-, -(9-10 membered heteroaryl)-CH(CF3)-, -(9-10 membered
heteroaryl)-(C C4)alkyl-, -(C3-C6)cycloalkyl-C(=0)-, -(C3-C6)cycloalkyl-S02-,
-(C3-C6)cycloalkyl-CH(CF3)-„ -(C3-C6)cycloalkyl-(CrC4)alkyl-, -(C C6)alkyl-C(=0)-,
-(CrC6)alkyl-S02-, -(C C6)alkyl-CH(CF3)-, naphthyl-C(=0)-, - naphthyl -S(02)-, - naphthyl -CH(CF3)-, - naphthyl -(C C4)alkyl-, -(4-7 membered heterocycloalkyl)-C(=0)-, -(4-7 membered heterocycloalkyl)-S02-, -(4-7 membered heterocycloalkyl)-CH(CF3)-, -(4-7 membered heterocycloalkyl)-(d-C4)alkyl; wherein any (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl moiety is optionally substituted by 1 , 2 or 3 groups independently selected from
(Ci-C4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARB and -((Ci-C4)alkyl)NRARB;
L is a bond or is (C1-C4)alkyl;
R2 is (d-C4)alkyl, -NRARB, -(C C4)alkyl-NRARB, -NRAC(=0)RB, -C(=0)-NRARB,
5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or
-C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-,halo(Ci-C4)alkoxy, pi IR4RQR
WO 2013/009827 PCT/US2012/046198
((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((d-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C )alkyl, halogen, cyano, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (Ci-C )alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through which they are attached form an optionally substituted 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, S;
Figure imgf000050_0001
is an optionally substituted 4-10 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S, where said 4-10 membered heterocyclic ring is optionally substituted by 1 or 2 groups independently selected from (Ci-C )alkyl, halo(Ci-C )alkyl, halogen, cyano, aryl(Ci-C )alkyl-,
(C3-C7)cycloalkyl(C C4)alkyl-, — ORY, -(C C4)ORY, -NRYRY, -(C C4)NRYRY, - C(=0)ORY, -(d-C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY, -(C C4)NRYC(=0)RY, -S02NRYRY, -(C C4)S02NRYRY, -NRYS02RY, -(C C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY, -(d-C4)NRYC(=0)ORY, -NRYC(=0)NRYRY, and -(d-d)NRYC(=0)NRYRY, where each Ry is independently selected from H and (d-d)alkyl, phenyl, and -(d-d)alkylphenyl.
6. The method according to claim 5, wherein:
R1 is -CF3;
Y is a bond and Xi is O, N or NH, X2 is N or CH and X3 is N or NH,
Q is -phenyl-C(=0)-, -phenyl-S02-, -phenyl-CH(CF3)-, -pyridyl-C(=0)-,
-pyridyl-S02-, -pyridyl-CH(CF3)-, -isoquinolyl-C(=0)-, -isoquinolyl-S02-,
-isoquinolyl-CH(CF3)-, -indazolyl-C(=0)-, -indazolyl-S02-, -indazolyl-CH(CF3)-,
-(C3-C6)cycloalkyl-C(=0)-, -(C3-C6)cycloalkyl-S02-, -(d-C6)cycloalkyl-CH(CF3)-,
-(d-C8)alkyl-C(=0)-, -(C C8)alkyl-S02-, or -(d-C8)alkyl-CH(CF3)-,
wherein said phenyl, pyridyl, isoquinolyl, indazolyl, or (C3-C6)cycloalkyl is optionally substituted by chloro, fluoro, cyano, methoxy, methyl, or trifluoromethyl;
L is a bond, methylene, ethylene or propylene; pi
WO 2013/009827 PCT/US2012/046198
R2 is -C(=0)NH2, morpholinyl, -CO-morpholinyl, dimethylamino-, diethylamino-, butylaminocarbonyl-, -CO-pyrrolidinyl, -CO-indolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
benzimidazolyl, benzimidazolonyl, or indolinyl,
where any morpholinyl, pyrrolidinyl, indolyl, phenyl, pyridyl pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
benzimidazolyl, or benzimidazolonyl moiety is optionally substituted with 1 or 2 groups independently selected from (d-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, nitro,
(Ci-C4)alkoxy, (CrC4)alkylthio-, halo(CrC4)alkoxy,
((CrC4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, NRARB, ((C C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, and halo(Ci-C4)alkoxy;
wherein RA and RB are independently selected from H and (Ci-C4)alkyl or RA and
RB taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
Figure imgf000051_0001
is an optionally substituted 5 or 6-membered heterocyclic ring, optionally containing one additional nitrogen ring atom, where said 5 or 6-membered heterocyclic ring is optionally substituted by 1 or 2 groups independently selected from (CrC2)alkyl, halo(CrC2)alkyl, cyano, -ORy, -(C C2)ORy, -NRyRy, -(Ci-C2)NRyRy, -C(=0)ORy, -
Figure imgf000051_0002
where each Ry is independently selected from H and methyl.
7. The method according to any one of claims 1 -5, wherein R1 is CHF2 or CF3.
8. The method according to any one of claims 1 -5, wherein R1 is CF3.
9. The method according to any one of claims 1 -5 and 7-8, 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 X1 is N or NH, X2 is N, X3 is N or NH. pi
WO 2013/009827 PCT/US2012/046198
10. The method according to any one of claims 1 -5 and 7-8, wherein when Y is a bond, Xi is O, X2 and X3 are N.
1 1 . The method according to any one of claims 1 -5 and 7-8, 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 Xi and X2 are CH, X3 is S or Xi and X2 are CH, X3 is O.
12. The method according to any one of claims 1 -5 and 7-8, 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 Xi and X2 are CH, X3 is S.
13. The method according to any one of claims 1 -5 and 7-8, wherein when Y is -C(O)-, Xi and X2 are CH, X3 is S.
14. The method according to any one of claims 1 -5 and 7-8, wherein when Y is -C(O)-, Xi is O, X2 and X3 are CH, or Xi is O, X2 is CH, and X3 is N, or Xi is O, X2 is N, and X3 is CH, or X-i is O, X2 and X3 are N.
15. The method according to any one of claims 1 -5 and 7-8, wherein when Y is
-C(O)-, Xi is O, X2 and X3 are CH.
16. The method according to any one of claims 1 -3 or 7-15, wherein A is a phenyl or pyridyl 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.
17. The method according to 1 -3 or 7-15, wherein A is a phenyl or pyridyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARB and -((Ci-C4)alkyl)NRARB, where each RA and RB is independently selected from H and methyl.
18. The method according to any one of claims 1 -3 or 7-15, wherein A is an unsubstituted phenyl or pyridyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group. pi IR4RQR
WO 2013/009827 PCT/US2012/046198
19. The method according to any one of claims 1-3 or 7-15, wherein A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from (C1-C4)alkyl, (C1-C4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB.
20. The method according to any one of claims 1-3 or 7-15, wherein A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NRARB and -((CrC4)alkyl)NRARB, where each RA and RB is independently selected from H and methyl.
21 . The method according to any one of claims 1-3 or 7-15, wherein A is a 5-6 membered heteroaryl or a 9-10 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl, -NRARB and -((Ci-C4)alkyl)NRARB, where each RA and RB is independently selected from H and 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.
22. The method according to any one of claims 16-21 , Z is -C(=0)- or
-NHC(=0)-.
23. The method according to any one of claims 1 , 2, 4 or 7-15, wherein E is -((CrC5)alkyl)C(=0)-,
Figure imgf000053_0001
or
Figure imgf000053_0002
24. The method according to claim 23, wherein E is -propyl-C(=0)- or -pentyl-
C(=0)-.
25. The method according to any one of claims 1 -4 or 7-24, wherein each Rx is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and dimethylaminoethyk
26. The method according to claim 25, wherein each Rx is H.
27. The method according to any one of claims 1-4 or 7-26, wherein B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally pi IR4RQR
WO 2013/009827 PCT/US2012/046198 substituted by 1 or 2 groups independently selected from (C1-C2)alkyl, halo(C1-C2)alkyl, halogen, cyano, aryl(Ci-C3)alkyl-, (C3-C6)cycloalkyl(C1-C3)alkyl-, -ORY, -(C C2)ORY, -NRYRY, -(d-C2)NRYRY, -C(=0)ORY, -(d-C2)C(=0)ORY, -C(=0)NRYRY,
Figure imgf000054_0001
-S02NRYRY,
-(Ci-C2)S02NRYRY, -NRYS02RY, -(Ci-C2)NRYS02RY, -OC(=0)NRYRY,
-NRYC(=0)NRYRY, and
Figure imgf000054_0002
28. The method according to any one of claims 1 -4 or 7-26, wherein B is a 4, 5, 6 or 7 membered heterocycloalkyi containing 1 or 2 nitrogen atoms, optionally substituted by
1 or 2 groups independently selected from (Ci-C2)alkyl, halo(Ci-C2)alkyl, halogen, cyano, aryl(Ci-C3)alkyl- (C3-C6)cycloalkyl(Ci-C3)alkyl-, -ORY, -(C C2)ORY, -NRYRY,
-(Ci-C2)NRYRY, -C(=0)ORY, -(C C2)C(=0)ORY, -C(=0)NRYRY, and
Figure imgf000054_0003
where each RY is independently selected from H and methyl.
29. The method according to any one of claims 1-4 or 7-26, wherein B is
1 ,4-diazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl, optionally substituted by 1 or 2 groups independently selected from methyl, -CH2OH and -C(=0)OH.
30. The method according to any one of claims 1-4 or 7-26, wherein B is
1 ,4-diazepanyl, piperazinyl or piperidinyl, optionally substituted by 1 or 2 groups independently selected from methyl and -C(=0)OH.
31 . The method according to any one of claims 1-4 or 7-26, wherein where B is heterocycloalkyi, in the bonding arrangement of X-B-L, X and L are not attached to the same ring atom of B.
32. The method according to any one of claims 1-4 or 7-31 , wherein L is a bond or (Ci-C3)alkyl,
33. The method according to any one of claims 1-4 or 7-32, wherein R2 is
(Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, where each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S. pi
WO 2013/009827 PCT/US2012/046198
34. The method according to any one of claims 1-4 or 7-32, wherein R2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyl, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyl), -C(0)-((C3-C6)cycloalkyl), or
-C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyl, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 or 2 groups independently selected from (d-C4)alkyl, halo(Ci-C4)alkyl, halogen, cyano, nitro, (Ci-C4)alkoxy, (Ci-C4)alkylthio-, halo(Ci-C4)alkoxy,
((CrC4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, -((C C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (Ci-C4)alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S.
35. The method according to any one of claims 1-4 or 7-32, wherein R2 is
-N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl,
-C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl and morpholinylpropyk
36. The method according to any one of claims 1-4 or 7-32, wherein R2 is
-N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, pi IR4RQR
WO 2013/009827 PCT/US2012/046198
-C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, benzimidazolyl, benzimidazolonyl, or indolinyl, where the phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, and benzimidazolonyl are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, fluorophenyl and morpholinylpropyk
37. The method according to claim 1 or claim 2, wherein
A is a phenyl or pyridyl group optionally substituted by 1 -2 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy,
halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
Z is -C(=0)- or -NRxC(=0)-;
X is NRx or a bond, where Rx is independently selected from H, (CrC4)alkyl, or optionally substituted (C2-C4)alkyl, where the optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((CrC4)alkyl)N-;
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 or 2 groups independently selected from (C1-C2)alkyl, halo(C1-C2)alkyl, halogen, cyano, aryl(C1-C3)alkyl-,
(C3-C6)cycloalkyl(C1-C3)alkyl-, — ORY, -(C C2)ORY, -NRYRY, -(C C2)NRYRY,
-C(=0)ORY,
Figure imgf000056_0001
-NRYC(=0)RY,
Figure imgf000056_0002
-S02NRYRY, -(C C2)S02NRYRY, -NRYS02RY, -(C C2)NRYS02RY, -OC(=0)NRYRY,
Figure imgf000056_0003
-NRYC(=0)NRYRY, and -(C C2)NRYC(=0)NRYRY;
L is a bond or (CrC3)alkyl;
R2 is (Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, where each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
or R2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl, pi IR4RQR
WO 2013/009827 PCT/US2012/046198 wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyl, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 or 2 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-, halo(CrC4)alkoxy,
((CrC4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, -((C C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S.
38. The method according to claim 1 or claim 2, wherein
A is a phenyl or pyridyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARB and -((d-C4)alkyl)NRARB, where each RA and RB is independently selected from
H and methyl;
Z is -C(=0)- or -NRxC(=0)-;
X is NRx or a bond, where Rx is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
dimethylaminoethyl-;
B is a 4, 5, 6 or 7 membered heterocycloalkyl containing 1 or 2 nitrogen atoms, optionally substituted by 1 or 2 groups independently selected from (CrC2)alkyl, halo(CrC2)alkyl, halogen, cyano, aryl(Ci-C3)alkyl- (C3-C6)cycloalkyl(Ci-C3)alkyl-, -ORY, -(Ci-C2)ORY, -NRYRY, -(Ci-C2)NRYRY, -C(=0)ORY, -(C C2)C(=0)ORY, -C(=0)NRYRY, and -(CrC2)C(=0)NRYRY, where each RY is independently selected from H and methyl;
L is a bond or (Ci-C3)alkyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, pi
WO 2013/009827 PCT/US2012/046198 oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl and morpholinylpropyk
39. The method according to claim 1 or claim 2, wherein
A is an unsubstituted phenyl or pyridyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group;
Z is -C(=0)- or -NRxC(=0)-;
X is NRx or a bond, where Rx is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
dimethylaminoethyl-;
B is 1 ,4-diazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl, optionally substituted by 1 or 2 groups independently selected from methyl, -CH2OH and -C(=0)OH;
L is a bond or (d-C3)alkyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl and morpholinylpropyk
40. The method according to claim 1 or claim 2, wherein
A is an unsubstituted phenyl or pyridyl group;
Z is -C(=0)-;
X is NRX or a bond, where Rx is H;
B is 1 ,4-diazepanyl, piperazinyl or piperidinyl, optionally substituted by 1 or 2 groups independently selected from methyl and -C(=0)OH;
L is a bond or is methyl, ethyl or propyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, pi IR4RQR
WO 2013/009827 PCT/US2012/046198
1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, benzimidazolyl, benzimidazolonyl, or indolinyl, where the phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, and benzimidazolonyl are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, fluoro- phenyl and morpholinylpropyk
41 . The method according to claim 1 or claim 2, wherein
A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from (d-C4)alkyl, (CrC4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB;
Z is -C(=0)-;
X is NRx or a bond, where Rx is independently selected from H, (CrC4)alkyl, or optionally substituted (C2-C4)alkyl, where the optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((CrC4)alkyl)N-;
B is a phenyl, pyridyl or 4-10 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 or 2 groups independently selected from (C1-C2)alkyl, halo(C1-C2)alkyl, halogen, cyano, aryl(C1-C3)alkyl-,
(C3-C6)cycloalkyl(C1-C3)alkyl-, — ORY, -(C C2)ORY, -NRYRY, -(C C2)NRYRY, -
C(=0)ORY, -(d-C2)C(=0)ORY, -C(=0)NRYRY, -(C C2)C(=0)NRYRY, -NRYC(=0)RY,
Figure imgf000059_0001
-S02NRYRY, -(C C2)S02NRYRY, -NRYS02RY, -(C C2)NRYS02RY, -OC(=0)NRYRY,
Figure imgf000059_0002
-NRYC(=0)NRYRY, and -(C C2)NRYC(=0)NRYRY;
L is a bond or (C C3)alkyl;
R2 is (Ci-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, where each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyi, and 5-6 membered heteroaryl, or RA and RB taken together with the nitrogen atom to which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
or R2 is 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl,
wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted pi
WO 2013/009827 PCT/US2012/046198 by 1 or 2 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, nitro, (C1-C4)alkoxy, (C1-C4)alkylthio-, halo(C1-C4)alkoxy,
((C1-C4)alkyl)((C1-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, -((C C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 or 2 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through which they are attached form an optionally substituted 4-6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S.
42. The method according to claim 1 or claim 2, wherein
A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NRARB and -((C1-C4)alkyl)NRARB, where each RA and RB is independently selected from H and methyl;
Z is -C(=0)- or -NRxC(=0)-;
X is NRx or a bond, where Rx is selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N-methylaminoethyl- and
dimethylaminoethyl-;
B is 1 ,4-diazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, or azetidinyl, optionally substituted by 1 or 2 groups independently selected from methyl, -CH2OH and -C(=0)OH;
L is a bond or (C C3)alkyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl and morpholinylpropyk pi
WO 2013/009827 PCT/US2012/046198
43. The method according to claim 1 or claim 2, wherein
E is -((d-C4)alkyl)C(=0)- or -((C1-C4)alkyl)NRxC(=0)-,;
X is NRx or a bond, where Rx is independently selected from H, (C1-C4)alkyl, or optionally substituted (C2-C4)alkyl, where the optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (Ci-C4)alkoxy, (Ci-C4)alkyl)NH-, or ((Ci-C4)alkyl)((CrC4)alkyl)N-;
B is a 4, 5, 6 or 7 membered heterocycloalkyl containing 1 or 2 nitrogen atoms, optionally substituted by 1 or 2 groups independently selected from (CrC2)alkyl, halo(C C2)alkyl, halogen, cyano, aryl(Ci-C3)alkyl-, (C3-C6)cycloalkyl(Ci-C3)alkyl-, -ORY, -(Ci-C2)ORY, -NRYRY, -(C C2)NRYRY, -C(=0)ORY, -(C C2)C(=0)ORY, -C(=0)NRYRY, and
Figure imgf000061_0001
where each RY is independently selected from H and methyl;
L is a bond or (CrC3)alkyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl, -C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl, where the pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, 1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl,
2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl moieties are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, phenyl, fluoro-phenyl and morpholinylpropyk
44. The method according to claim 1 or claim 2, wherein
E is -propyl-C(=0)-;
X is NRX or a bond, where Rx is H;
B is 1 ,4-diazepanyl, piperazinyl or piperidinyl, optionally substituted by 1 or 2 groups independently selected from methyl and -C(=0)OH;
L is a bond or is methyl, ethyl or propyl;
R2 is -N(CH2CH3)2, -C(=0)NH2, -C(=0)NH(CH2CH2CH2CH3), -C(=0)morpholinyl,
-C(=0)pyrrolidinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl,
1 ,3-benzodioxolyl, thienopyrimidinyl, benzo-isothiazolyl, benzimidazolyl, benzimidazolonyl, or indolinyl, where the phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, oxazolyl, and benzimidazolonyl are optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, methylthio-, nitro, fluoro- phenyl and morpholinylpropyk pi IR4RQR
WO 2013/009827 PCT/US2012/046198
45. The method according to claim 1 or claim 2, wherein the compound of Formula I has the formula:
Figure imgf000062_0001
wherein:
R1 is -CF3;
Q is A-Z or E, wherein:
A is optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
wherein said optionally substituted (C3-C6)cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyi, 5-6 membered heteroaryl, or 9-10 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (d-C4)alkoxy, halo(CrC4)alkoxy, -NRARB and
-((Ci-C4)alkyl)NRARB; and
Z is -C(=0)-, -SO2-, -NRxC(=0)-, -CH(CF3)-, -(C C4)alkyl-; and
E is
Figure imgf000062_0002
-((C C6)alkyl)S02-,
-CH(CF3)-, -((Ci-C6)alkyl)CH(CF3)-;
X is NRx or a bond;
B is a phenyl, pyridyl or 4-8 membered heterocycloalkyi containing 1 or 2 heteroatoms independently selected from N, O and S,
wherein said phenyl, pyridyl or heterocycloalkyi is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C4)alkyl, halo(CrC4)alkyl, halogen, cyano, aryl(Ci-C4)alkyl-, (C3-C7)cycloalkyl(C C4)alkyl-, -ORY, -(C C4)ORY, -NRYRY,
-(Ci-C4)NRYRY, -C(=0)ORY, -(C C4)C(=0)ORY, -C(=0)NRYRY, -(C C4)C(=0)NRYRY, -NRYC(=0)RY,
Figure imgf000062_0003
-S02NRYRY, -(Ci-C4)S02NRYRY, -NRYS02RY, -(C C4)NRYS02RY, -OC(=0)NRYRY, -(C C4)OC(=0)NRYRY, -NRYC(=0)ORY,
-(C C4)NRYC(=0)ORY, -NRYC(=0)NRYRY, and -(C C4)NRYC(=0)NRYRY,
wherein when B is heterocycloalkyi, X and L are attached to different ring atoms; L is a bond or (C C4)alkyl;
R2 is (d-C4)alkyl, -NRARB, -NRAC(=0)RB, -C(=0)-NRARB, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyi, (C3-C6)cycloalkyl, phenyl, -C(0)-(5-6 membered heteroaryl), -C(O)-(9-10 membered heteroaryl), -C(0)-(3-7 membered heterocycloalkyi), -C(0)-((C3-C6)cycloalkyl), or -C(0)-phenyl, pi IR4RQR
WO 2013/009827 PCT/US2012/046198 wherein any of said 5-6 membered heteroaryl, 9-10 membered heteroaryl, 3-7 membered heterocycloalkyl, (C3-C6)cycloalkyl, or phenyl groups is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, halogen, cyano, nitro, (CrC4)alkoxy, (CrC4)alkylthio-,halo(Ci-C4)alkoxy,
((CrC4)alkyl)((Ci-C4)alkyl)N(C2-C4)alkoxy, hydroxyl, -NRARB, ((Ci-C4)alkyl)NRARB, and an optionally substituted 5-6 membered heteroaryl or phenyl group, wherein said optionally substituted heteroaryl or phenyl group is optionally substituted by 1 , 2 or 3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARB and -((C C4)alkyl)NRARB;
and wherein:
each RA and RB are independently selected from H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl, or RA and RB taken together with the atom or atoms through 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, or optionally substituted (C2-C6)alkyl, wherein said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (d-C alkoxy, (C1-C4)alkyl)NH-, or ((C1-C4)alkyl)((C1-C4)alkyl)N-; and
each RY is independently selected from H, (C1-C4)alkyl, phenyl, and
-(C1-C4)alkylphenyl.
46. The method according to claim 1 or claim 2, wherein the compound of
Formula I is selected from:
(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)phenyl)(4-(5-(trifluoromethyl)pyridin-2- yl)-1 ,4-diazepan-1-yl)methanone,
(4-(3,4-dimethylphenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(3,4-dichlorophenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(pyrazin-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperidine-2-carboxamide,
(4-(2-morpholinoethyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone, pi
WO 2013/009827 PCT/US2012/046198
(4-(3-(dimethylamino)propyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
2-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 -yl)benzonitrile,
(4-(2,4-dimethoxyphenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
1-morpholino-2-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)ethanone,
(4-phenethylpiperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
/V-butyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazine-1 - carboxamide,
(4-(pyridin-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
1-(pyrrolidin-1 -yl)-2-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazin-1-yl)ethanone,
(4-benzylpiperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(benzo[d][1 ,3]dioxol-5-ylmethyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
3-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1-yl)pyrazine-2- carbonitrile,
(4-(pyridin-4-ylmethyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(3-(diethylamino)propyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(1 /-/-indole-6-carbonyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-picolinoylpiperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(thieno[3,2-Q0pyrimidin-4-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)phenyl)methanone,
(4-(4-nitrobenzyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(pyridin-4-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone, pi
WO 2013/009827 PCT/US2012/046198
6-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile,
(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)phenyl)(4-(3-(trifluoromethyl)pyridin-2- yl)piperazin-1 -yl)methanone,
(4-(2-chlorophenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(3-fluorophenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(3-(methylthio)phenyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(4-chlorobenzyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(2-methoxybenzyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone„
(4-(4-methoxyphenyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
4-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1-yl)-1 H- benzo[c ]imidazol-2(3H)-one,
/V-(4-((/V-methylacetamido)methyl)phenyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
Λ/-(4-((1 H-1 ,2,4-triazol-1 -yl)methyl)phenyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
(3-benzylpiperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
4-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 -yl)benzonitrile, 6-(2-methyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile,
6-(3-methyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile,
6-(3,5-dimethyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
methyl 4-(5-cyanopyridin-2-yl)-1 -(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazine-2-carboxylate, pi
WO 2013/009827 PCT/US2012/046198
4-(5-cyanopyridin-2-yl)-1 -(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazine-2-carboxylic acid,
6-(2,6-dimethyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
1-(3-morpholinopropyl)-3-(1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperidin-4-yl)-1 H-benzo[c/]imidazol-2(3H)-one,
1-(1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperidin-4-yl)-1 /-/- benzo[c ]imidazol-2(3H)-one,
6-((3-methyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)methyl)nicotinonitrile,
6-((3-methyl-4-(4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanoyl)piperazin-1- yl)methyl)nicotinonitrile,
1-(4-phenylthiazol-2-yl)-/V-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)pyrrolidine-3-carboxamide,
6-(1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)azetidin-3-yl)nicotinonitrile, 6-(1-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperidin-4- yl)nicotinonitrile,
/V-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
1-(5-cyanopyridin-2-yl)-/\/-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)pyrrolidine-3-carboxamide ,
6-(3-methyl-4-(4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanoyl)piperazin-1 - yl)nicotinonitrile,
6-(2,2-dimethyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
/V-(1-(5-cyanopyridin-2-yl)piperidin-3-yl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
6-(3,3-dimethyl-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
6-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)-1 ,4-diazepan-1- yl)nicotinonitrile,
1-(5-cyanopyridin-2-yl)-4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazine-2-carboxylic acid,
(4-methyl-3-(4-phenylthiazol-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone, pi
WO 2013/009827 PCT/US2012/046198
6-(3-methyl-4-(3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoyl)piperazin-1 - yl)nicotinonitrile,
6-(4-(3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoyl)piperazin-1-yl)nicotinonitrile, 6-(4-(2,2-dimethyl-4-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)butanoyl)-3- methylpiperazin-1 -yl)nicotinonitrile,
(4-(5-methoxypyridin-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(3-(4-(4-f|UOrophenyl)thiazol-2-yl)piperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
6-(3-methyl-4-(4-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)butanoyl)piperazin-1- yl)nicotinonitrile,
(4-(2,3-dihydro-1 H-inden-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)phenyl)methanone,
(4-(1 /-/-benzo[c ]imidazol-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)phenyl)methanone,
(3-(5-(4-fluorophenyl)oxazol-2-yl)piperidin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)phenyl)methanone,
(4-(3-methoxyphenyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(pyrimidin-5-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
2- (4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1- yl)nicotinonitrile
(4-(4-phenylpyrimidin-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(2-fluorophenyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(2-methoxyphenyl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(pyridin-3-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
3- fluoro-4-(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoyl)piperazin-1 - yl)benzonitrile,
(4-(pyrimidin-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone, pi IR4RQR
WO 2013/009827 PCT/US2012/046198
(4-([1 , 1 '-biphenyl]-3-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(3-((4-(4-f|UOrophenyl)thiazol-2-yl)methyl)azetidin-1-yl)(3-(5-(trifluorometh oxadiazol-3-yl)phenyl)methanone,
(4-(4-methylthiazol-2-yl)piperazin-1-yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-(benzo[(^oxazol-2-yl)piperazin-1 -yl)(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)phenyl)methanone,
(4-((2-(4-fluorophenyl)thiazol-4-yl)methyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)phenyl)methanone,
(4-((2-(4-fluorophenyl)oxazol-4-yl)methyl)piperazin-1 -yl)(3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)phenyl)methanone,
(2-phenylthiazol-4-yl)(4-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoyl)piperazin-1-yl)methanone, and
((1 S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)phenyl)methanone,
or a pharmaceutically acceptable salt thereof.
47. The method according to any one of claims 1 or 3-46, wherein the neurodegenerative disease or disorder associated with deacetylases is Alzheimer's disease, Parkinson's disease, or neuronal intranuclear inclusion disease.
48. The method according to any one of claims 1 or 3-46, wherein the neurodegenerative disease or disorder associated with deacetylases is a polyglutamine disorder, wherein the polyglutamine disorder is Huntington's disease or spinocerebellar ataxia.
49. The method according to any one of claims 1 or 3-46, wherein the neurodegenerative disease or disorder associated with deacetylases is Huntington's disease.
50. The method according to any one of claims 2-46, wherein the B-cell lymphoma is Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma or Waldenstrom Macroglobulinemia.
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CN104262238A (en) * 2014-08-29 2015-01-07 西安交通大学 Aromatic heterocyclic biphenyl Bcr-Abl inhibitors as well as preparation method and application thereof
CN104262245A (en) * 2014-08-29 2015-01-07 西安交通大学 6-phenylpyridine-2-amine Bcr-Abl inhibitors as well as preparation method and application thereof
CN104262246A (en) * 2014-08-29 2015-01-07 西安交通大学 5-phenylnicotinamide Bcr-Abl inhibitors as well as preparation method and application thereof
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