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WO2013009827A1 - Méthodes de traitement - Google Patents

Méthodes de traitement 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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WO
WIPO (PCT)
Prior art keywords
alkyl
phenyl
optionally substituted
trifluoromethyl
independently selected
Prior art date
Application number
PCT/US2012/046198
Other languages
English (en)
Inventor
Shomir Ghosh
Mercedes Lobera
Original Assignee
Tempero Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tempero Pharmaceuticals, Inc. filed Critical Tempero Pharmaceuticals, Inc.
Publication of WO2013009827A1 publication Critical patent/WO2013009827A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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 or sparfloxacin
    • 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.

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Abstract

La présente invention a pour objet une méthode de traitement d'une maladie ou d'un trouble neurodégénératif ou d'un lymphome B par l'administration d'un composé ayant la formule : dans laquelle X1 ; X2, X3, R1, R2, Y, Q, X, B et L sont tels que définis ici, et ses méthodes de fabrication et d'utilisation.
PCT/US2012/046198 2011-07-13 2012-07-11 Méthodes de traitement WO2013009827A1 (fr)

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