WO2013066831A1 - Compounds and methods - Google Patents

Compounds and methods Download PDF

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Publication number
WO2013066831A1
WO2013066831A1 PCT/US2012/062505 US2012062505W WO2013066831A1 WO 2013066831 A1 WO2013066831 A1 WO 2013066831A1 US 2012062505 W US2012062505 W US 2012062505W WO 2013066831 A1 WO2013066831 A1 WO 2013066831A1
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alkyl
amino
alkoxy
alkylamino
hydroxy
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PCT/US2012/062505
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French (fr)
Inventor
Shomir Ghosh
Mercedes Lobera
Denise Teotico POHLHAUS
Ryan Paul Trump
Cunyu Zhang
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Glaxosmithkline Llc
Tempero Pharmaceuticals, Inc.
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Publication of WO2013066831A1 publication Critical patent/WO2013066831A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds that inhibit histone deacetylase
  • HDAC HDAC enzymes
  • preparation of these compounds the preparation of these compounds, the use of these compounds in the treatment of diseases or conditions ameliorated by inhibition of HDAC activity and pharmaceutical compositions comprising these compounds.
  • 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.
  • HDAC1 HDAC1 , HDAC2, HDAC3, HDAC8 and HDAC1 1
  • HDAC4 HDAC5
  • HDAC6, HDAC7, HDAC9 and HDAC10 which shuttle between the nucleus and the cytoplasm
  • SIRT1-7 class III HDACs
  • Class II HDACs are further characterized as class lla HDACs and class lib HDACs.
  • HDAC9 is a class lla histone deacetylase highly expressed in human Tregs.
  • HDAC9 deficiency 1 ) increases Foxp3 expression (and other Treg markers), 2) increases Foxp3 and histone 3 acetylation, 3) increases Foxp3 DNA binding, 4) increases Treg numbers, 5) increases suppressive activity in vitro and in vivo, and 6) ameliorates murine colitis.
  • Tregs which are deficient in HDAC9 induce permanent tolerance of fully mismatched cardiac allografts.
  • HDAC9 inhibitors maybe useful for treatment of diseases and disorders associated with abnormal cell proliferation, differentiation and survival, e.g. breast and prostate tumors.
  • HDAC7 a class lla histone deacetylase
  • HDAC7 enhances Treg suppression in vitro and in vivo.
  • HDAC7 enhances FOXP3+ Treg function and induces long-term allograft survival.
  • HDAC6 inhibition in vivo decreased severity of colitis in the dextran sodium sulphate-induced colitis model and the
  • CD4 + CD62Lhigh adoptive transfer model of colitis In addition, inhibition of HDAC6 with a subtherapeutic dose of rapamycin led to prolonged cardiac allograft survival.
  • an orally available small molecule selective inhibitor of Class II HDAC activity (more specifically HDAC9 or HDAC7 or HDAC6) is expected to modulate autoimmune diseases through expansion and enhancement of Treg activity.
  • HDAC4 and 5 impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes and maybe potentially useful for the treatment of muscle and heart diseases including cardiac hypertrophy and heart failure. Also, inhibition of Class II HDAC activity represents a novel approach for disrupting or intervening in cell cycle regulation.
  • HDAC9 is also highly expressed in human B cells. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell tumors 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 both 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 Ma 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
  • HDAC4 a small molecule selective inhibitor of HDAC4, HDAC5, HDAC6, HDAC7, HDAC8 and/or HDAC9 is expected to be beneficial in the treatment of B-cell malignancies by targeting one or several of the above enzymes
  • HDAC4 has been linked to a variety of neurodegenerative disorders: it is a downstream target of Parkin (associating it to Parkinson's disease); it 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).
  • HDAC4 and HDAC5 localization are regulated by neuronal activity, and HDAC5 nuclear import is increased in diseased neurons of Huntington's disease patients.
  • HDAC7 has been implicated in regulating ataxin-7 turnover in a SCA-7 model (Mookerjee S et al., J Neurosci., 2009, p. 15134).
  • HDAC6 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).
  • HDAC4 or HDAC5 or HDAC6 or HDAC7or HDAC9 is expected to be beneficial in the treatment of neurodegenerative diseases.
  • Class II HDAC inhibitors have therapeutic potential in the study and/or treatment of the various diseases or conditions described herein.
  • HDAC inhibitors Many of the known small-molecule HDAC inhibitors, however, inhibit all HDAC isoforms. It would be advantageous to identify HDAC inhibitors that inhibited one or more, but not all HDAC isoforms.
  • Ar is an optionally substituted aryl (arylene) or 5-6 membered, monocyclic or 9-10 membered, bicyclic heteroaryl (heteroarylene), wherein said optionally substituted aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of (CrC 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, -NR A R A and -((C C 4 )alkyl)NR A R A ;
  • each R A is independently selected from the group consisting of H and (Ci-C 4 )alkyl
  • each n is independently 0, 1 or 2;
  • k O, 1 or 2;
  • each R x is independently selected from the group consisting of (CrC 4 )alkyl, halo(Ci-C 4 )alkyl, oxo, -NR A R A , -((Ci-C 4 )alkyl)OR A , and -((C C 4 )alkyl)NR A R A , or two R x taken together with the atoms through which they are attached form a 3-7 membered saturated ring, optionally containing 1 or 2 heteroatoms each independently selected from N and O;
  • n 0, 1 or 2;
  • X is N or CH, wherein when X is N, Z is S0 2 , CO, C0 2 , CONR Za , or a direct bond and when X is CH, Z is NR Za S0 2 , NR Za CO, NR Zb , O, or NR Za C0 2 , wherein R Za is H or
  • (d-C 6 )alkyl and R Zb is H, (C C 6 )alkyl, or -CO(C C 4 )alkyl;
  • R is H or a (C 1 -C 8 )alkyl, halo(CrC 4 )alkyl, aryl, heteroaryl, heterocycloalkyl, aryl(C 1 -C 6 )alkyl-, aryl(C 2 -C 6 )alkenyl-, heteroaryl(C 1 -C 6 )alkyl- or
  • any of said aryl, heteroaryl, or heterocycloalkyl (that is the aryl, heteroaryl or heterocycloalkyl group or the aryl, heteroaryl or heterocycloalkyl moiety of the aryl(CrC 6 )alkyl-, aryl(Ci-C 6 )alkenyl-, heteroaryl(Ci-C 6 )alkyl- or
  • heterocycloalkyl(Ci-C 6 )alkyl-) is substituted by Q 2 and by 1 , 2 or 3 Q 1 substituents,
  • heterocycloalkyl(Ci-C 6 )alkyl- group is optionally substituted by cyano, halo(Ci-C 2 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, amino, (Ci-C 4 )alkylamino-,
  • any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(C 1 -C 4 )alkyl- group) is a 5-6 membered or 9-10 membered heteroaryl, wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom,
  • any of said heterocycloalkyl (that is the heterocycloalkyl group or the heterocycloalkyl moiety of the heterocycloalkyl(Ci-C 4 alkyl- group) is a 5-6 membered heterocycloalkyl and contains a nitrogen, oxygen or sulfur ring atom,
  • R Y is hydrogen, (C C 6 )alkyl, (Ci-C 6 )alkoxy(C 2 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl,
  • each Q 1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl,
  • heteroaryl ((Ci-C 6 )alkyl)amino-,(5-6 membered heterocycloalkyl)((Ci-C 6 )alkyl)amino-, hydroxy(C 2 -C 6 )alkylamino, (hydroxy(C 2 -C 6 )alkyl)((Ci-C 6 )alkyl)amino,
  • heteroaryl ((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkyl, (5-6 membered heterocycloalkyl)amino(C 1 -C 6 )alkyl-, (5-6 membered
  • heterocycloalkyl ((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkyl-, ((C 1 -C 6 )alkyl)amino(C2-C 6 )alkoxy, ((C 1 -C 6 )alkyl)((C 1 -C 6 )alkyl)amino(C 2 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl,
  • heterocycloalkyl ((Ci-C6)alkyl)amino(C2-C 6 )alkylamino(Ci-C 6 )alkyl, (5-6 membered heteroaryl)(hydroxy(C2-C6)alkyl)amino(C2-C 6 )alkylamino-, (5-6 membered
  • heteroaryl (hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(C 1 -C 6 )alkyl, (5-6 membered heterocycloalkyl)(hydroxy(C2-C 6 )alkyl)amino(C2-C 6 )alkylamino-, (5-6 membered heterocycloalkyl)(hydroxy(C 2 -C6)alkyl))amino(C2-C6)alkylamino(C 1 -C 6 )alkyl,
  • heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl, and wherein any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (C 1 -C 6 )alkyl, aryl, halo(C 1 -C 6 )alkyl, (Ci-C 6 )alkoxy, aryloxy, halo(CrC 6 )alkoxy, hydroxy(Ci-C)alkyl-, hydroxy(C 2 -C 4 )alkoxy, (Ci-C 4 )alkoxy(C 2 -C 4 )alkoxy, amino(C 2 -C 4 )alkoxy,
  • Q 1 is a divalent (C 3 -C 6 )alkyl or -0(C 2 -C 4 )alkoxy (that is -0(C 2 -C 4 )alkyl-0-) moiety;
  • Q 2 is hydrogen, halogen, cyano, (CrC 6 )alkyl, halo(CrC 6 )alkyl, (CrC 6 )alkoxy, halo(CrC 6 )alkoxy, amino, (Ci-C 6 )alkylamino-, ((Ci-C 6 )alkyl)((Ci-C 6 )alkyl)amino-, phenylamino-, (phenyl)((Ci-C 6 )alkyl)amino-, aminocarbonyl, (d-C 6 )alkylaminocarbonyl, ((Ci-C 6 )alkyl)((Ci-C 6 )alkyl)aminocarbonyl, aminosulfonyl, (Ci-C 6 )alkylaminosulfonyl, ((Ci-C 6 )alkyl)((Ci-C 6 )alkyl)aminosulfon
  • Q 2 is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(Ci-C 6 )alkyl-, aryl(C C 6 )alkyl-, -S0 2 N(Ci-C 6 )alkyl(Ci-C 6 )alkyl or -COCHR YA R YB , or where R YA and R YB are each independently selected from the group consisting of hydrogen, amino, (CrC 6 )alkyl, and amino(Ci-C 6 )alkyl-;
  • the invention is further directed to a method of treating a subject having a disease or disorder mediated by inhibition of a HDAC comprising administering the compound of Formula I, or a salt thereof, or a pharmaceutical composition comprising the compound of Formula I, or a salt thereof, to the subject.
  • This invention is also directed to a compound of Formula (I) wherein:
  • Ar is an optionally substituted aryl (arylene) or 5-6 membered, monocyclic or 9-10 membered, bicyclic heteroaryl (heteroarylene), wherein said optionally substituted aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of (Ci-C )alkyl, halogen, cyano, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C 4 )alkoxy, -NR A R A and -((C C 4 )alkyl)NR A R A ; wherein each R A is independently selected from the group consisting of H and (d-C 4 )alkyl;
  • each n is independently 0, 1 or 2;
  • k 0, 1 or 2;
  • each R x is independently selected from the group consisting of (CrC 4 )alkyl, halo(CrC 4 )alkyl, oxo, -NR A R A , -((Ci-C 4 )alkyl)OR A , and -((C C 4 )alkyl)NR A R A , or two R x taken together with the atoms through which they are attached form a 3-7 membered saturated ring, optionally containing 1 or 2 heteroatoms each independently selected from N and O;
  • n 0, 1 or 2 and X is N or CH, wherein
  • Z is NR Za S0 2 , NR Za CO, NR Zb , O, or NR Za C0 2 ,
  • R is H or a (CrC 8 )alkyl, halo(CrC 4 )alkyl, aryl, heteroaryl, heterocycloalkyl, aryl(C 1 -C 6 )alkyl-, aryl(C 2 -C 6 )alkenyl-, heteroaryl(C 1 -C 6 )alkyl- or
  • any of said aryl, heteroaryl, or heterocycloalkyl (that is the aryl, heteroaryl or heterocycloalkyl group or the aryl, heteroaryl or heterocycloalkyl moiety of the aryl(CrC 6 )alkyl-, aryl(C 2 -C 6 )alkenyl-, heteroaryl(Ci-C 6 )alkyl- or
  • heterocycloalkyl(Ci-C 6 )alkyl-) is substituted by Q 2 and by 1 , 2 or 3 Q 1 substituents,
  • heterocycloalkyl(Ci-C 6 )alkyl- group is optionally substituted by cyano, halo(Ci-C 2 )alkyl, (Ci-C 4 )alkoxy, halo(CrC 4 )alkoxy, amino, (Ci-C 4 )alkylamino-,
  • any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(Ci-C 4 )alkyl- group) is a 5-6 membered or 9-10 membered heteroaryl, wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom,
  • any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(CrC 4 alkyl- group) is a 5-6 membered heterocycloalkyi and contains a nitrogen, oxygen or sulfur ring atom,
  • R Y is hydrogen, (C C 6 )alkyl, (Ci-C 6 )alkoxy(C 2 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(Ci-C 6 )alkyl-, aryl(C C 6 )alkyl-, -S0 2 N(Ci-C 6 )alkyl(Ci-C 6 )alkyl or -COCHR YA R YB , where R YA and R YB are each independently selected from the group consisting of hydrogen, amino, (CrC 6 )alkyl, and amino(Ci-C 6 )alkyl-,
  • R Y and Q 1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O and S or an oxide thereof (e.g., SO or S0 2 );
  • each Q 1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (CrC 6 )alkyl, halo(CrC 6 )alkyl, cyano(CrC 6 )alkyl, (Ci-C 6 )alkoxy, halo(C C 6 )alkoxy, (Ci-C 6 )alkoxy(C 2 -C 6 )alkyl-, (Ci-C 6 )alkoxy(C 2 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkyl-, hydroxy(C 2 -C 6 )alkoxy, amino, (C 1 -C 6 )alkylamino-,
  • heteroaryl ((C 1 -C 6 )alkyl)amino-,(5-6 membered heterocycloalkyl)((C 1 -C 6 )alkyl)amino-, hydroxy(C 2 -C 6 )alkylamino, (hydroxy(C 2 -C 6 )alkyl)((Ci-C 6 )alkyl)amino,
  • heterocycloalkyl ((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkyl-, ((C 1 -C 6 )alkyl)amino(C 2 -C 6 )alkoxy, ((C 1 -C 6 )alkyl)((C 1 -C 6 )alkyl)amino(C 2 -C 6 )alkoxy, (C C 6 )alkylcarbonyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
  • heterocycloalkyl ((Ci-C6)alkyl)amino(C2-C 6 )alkylamino(Ci-C 6 )alkyl, (5-6 membered heteroaryl)(hydroxy(C2-C 6 )alkyl)amino(C2-C 6 )alkylamino-, (5-6 membered
  • heteroaryl (hydroxy(C2-C 6 )alkyl))amino(C2-C6)alkylamino(Ci-C 6 )alkyl, (5-6 membered heterocycloalkyl)(hydroxy(C2-C 6 )alkyl)amino(C2-C 6 )alkylamino-, (5-6 membered heterocycloalkyl)(hydroxy(C 2 -C6)alkyl))amino(C2-C6)alkylamino(C 1 -C 6 )alkyl,
  • heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl
  • any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (C 1 -C 6 )alkyl, aryl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, aryloxy, halo(C 1 -C 6 )alkoxy, hydroxy(C 1 -C)alkyl-, hydroxy(C 2 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkoxy, amino(C 2 -C 4 )alkoxy,
  • Q 1 is a divalent (C 3 -C 6 )alkyl or -0(C 2 -C 4 )alkoxy (that is -0(C 2 -C 4 )alkyl-0-) moiety;
  • Q 2 is hydrogen, halogen, cyano, (CrC 6 )alkyl, halo(CrC 6 )alkyl, (d-C 6 )alkoxy, halo(CrC 6 )alkoxy, amino, (Ci-C 6 )alkylamino-, ((Ci-C 6 )alkyl)((Ci-C 6 )alkyl)amino-, phenylamino-, (phenyl)((Ci-C 6 )alkyl)amino-, aminocarbonyl, (Ci-C 6 )alkylaminocarbonyl, ((Ci-C 6 )alkyl)((Ci-C 6 )alkyl)aminocarbonyl, aminosulfonyl, (Ci-C 6 )alkylaminosulfonyl, ((Ci-C 6 )alkyl)((Ci-C 6 )alkyl)aminosulf
  • Q 2 is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl-, aryl(C C 6 )alkyl-, -S0 2 N(C 1 -C 6 )alkyl(C 1 -C 6 )alkyl or -COCHR YA R YB , or where R YA and R YB are each independently selected from the group consisting of hydrogen, amino, (C 1 -C 6 )alkyl, and amino(C 1 -C 6 )alkyl-;
  • the invention is further directed to a pharmaceutical composition comprising a compound of the invention.
  • the invention is still further directed to methods of inhibiting HDAC enzymes and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
  • alkyl represents a saturated, straight or branched hydrocarbon moiety.
  • alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, f-butyl, n-pentyl, iso-pentyl (3-methyl- butyl), neo-pentyl (2,2-dimethylpropyl), etc.
  • (Ci-C 4 )alkyl refers to an alkyl containing from 1 to 4 carbon atoms.
  • alkenyl represents an unsaturated, straight or branched hydrocarbon moiety.
  • exemplary alkenyls include, but are not limited to ethylene, n- propylene, isopropylene, n-butylene, n-butyldiene, etc.
  • C 2 -C 4 alkenyl refers to an alkyl containing from 2 to 4 carbon atoms and one or two double bonds.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring.
  • (C 3 -C 8 )cycloalkyl refers to a non-aromatic cyclic
  • hydrocarbon ring having from three to eight ring carbon atoms.
  • (C 3 -C 8 )cycloalkyl groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkoxy refers to a group containing an alkyl radical attached through an oxygen linking atom.
  • (Ci-C 4 )alkoxy refers to a straight- or branched-chain
  • hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • exemplary "(C 1 -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, monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms and to which may be fused one or more cycloalkyl rings.
  • aryl is phenyl
  • Heterocyclic groups may be heteroaryl or heterocycloalkyi groups.
  • Heterocycloalkyi represents a group or moiety comprising a stable, non-aromatic, 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.
  • the heterocycloalkyi 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 heterocycloalkyi 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-azabicy
  • This term specifically excludes bicyclic heterocycloalkyi 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 ]octy
  • heterocycloalkyi groups are
  • 5-membered and/or 6-membered heterocycloalkyi groups such as pyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl or pyrazolinyl, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, tetrahydro-2H-1 ,4-thiazinyl, 1 ,4-dioxanyl, 1 ,3-oxathianyl, and 1 ,3-dithianyl.
  • pyrrolidyl or pyrrolidinyl
  • tetrahydrofuryl or tetrahydrofuranyl
  • Heteroaryl represents a group or moiety comprising an aromatic monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. 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. This term is also intended to encompass heterocyclic groups containing nitrogen and/or sulfur where the nitrogen or sulfur heteroatoms are optionally oxidized.
  • heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, isobenzofuryl, 2,3- dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalaziny
  • benzimidazolyl tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, indolinyl, cinnolinyl, pteridinyl, isothiazolyl.
  • 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, thiazolyl, triazolyl, and tetrazolyl or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and thiadiazolyl.
  • 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,
  • alkyl When any of the terms defined herein, for, example "alkyl,” is used in combination with other substituent groups, such as “haloalkyl” or “cycloalkyl-alkyl” or “arylalkyl”, the term is intended to encompass a divalent radical.
  • arylalkyl is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical (an alkylene or alkylenyl moiety )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, aryl, cycloalkyl, heteroaryl, etc. may be used to define a divalent substituent, such as a group bonded to two other groups. In this instance, such terms are intended to encompass divalent moieties.
  • pentyl may be used to represent a pentylenyl diradical -wherein the pentyl moiety is any one of a divalent straight (e.g. -CH2CH2CH2CH2CH2-) or branched (e.g. -CH2CH(CH3)CH 2 CH2-, -CH2CH 2 CH(CH 2 CH3)-, -CH 2 CH 2 C(CH 3 )2-) chain 5-carbon radical.
  • Haldroxy or “hydroxyl” is intended to mean the radical -OH.
  • Ar is on optionally substituted phenyl (phenylene) or
  • 6-membered heteroaryl (heteroarylene) group wherein said 6-membered heteroaryl contains 1 , 2 or 3 nitrogen atoms, and said optionally substituted phenyl or heteroaryl is optionally substituted by a group selected from the group consisting of (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, -NR A R A and
  • each R A is independently selected from the group consisting of H and (C 1 -C 4 )alkyl.
  • Ar is optionally substituted phenyl, pyridyl or pyrimidinyl.
  • Ar is unsubstituted phenyl or pyridyl.
  • each n is 1 .
  • one n is 0 and the other n is 1 or is 2.
  • each n is 0.
  • one n is 1 and the other n is 2.
  • the total number of ring atoms in this heterocycloalkyl ring is 4-7, more specifically 5-6.
  • the total number of ring atoms in this heterocycloalkyl ring is 6, such that each n is 1 or one n is 0 and the other n is 2.
  • k is 0.
  • R x is (C C 2 )alkyl, halo(C C 2 )alkyl, -NR A R A , -((C C 2 )alkyl)OR A , or -((CrC 2 )alkyl)NR A R A , wherein each R A is independently selected from the group consisting of H and (CrC 2 )alkyl, specifically H or methyl.
  • k is 2 and two R x taken together with the atoms through which they are attached form a 3-6 membered ring, that is, two R x taken together are a bond or a -CH 2 -, -CH 2 CH 2 -,
  • two R x taken together with the atoms through which they are attached form a 3-5 membered ring, thereby forming a bicydic ring moiety between the Ar and the (CH 2 ) m moieties in Formula (I).
  • a 3-azabicyclo[3.1.0]hexanyl or 2,5- diazabicyclo[2.2.1]heptanyl ring moiety is formed when k is 2 and two R x taken together with the atoms through which they are attached form a 3-5 membered ring (that is, the two R x taken together are a bond or -CH 2 -).
  • X is CH, m is 0, 1 or 2, and Z is NR Za S0 2 , NR Za CO, NR Zb , O, or NR Za C0 2 .
  • X is CH, m is 0 or 1 , and Z is NR Za S0 2 , NR Za CO, NR Zb , O, or NR Za C0 2 .
  • X is CH, m is 0 or 1 , and Z is NR Za CO, NR Zb or NR Za C0 2 .
  • R Za is H or (C C 3 )alkyl.
  • R Za is H or methyl.
  • R Za is H.
  • R Zb is H. In other embodiments, R Za and R Zb are each H. In selected embodiments, R Zb is (CrC 3 )alkyl ( specifically, methyl, ethyl, n-propyl or isopropyl) or -CO(Ci-C 2 )alkyl (specifically, -CO(CH 3 )).
  • X is N, m is 0, and Z is S0 2 or a direct bond. In other selected embodiments of the compounds of this invention, X is N, m is 1 or 2 and Z is S0 2 , CO, C0 2 , or a direct bond.
  • X is N, m is 0 or 1 and Z is S0 2 , CO, C0 2 , CONH, or a direct bond.
  • R is H or a (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, aryl, heteroaryl, heterocycloalkyi, aryl(C 1 -C 4 )alkyl-, aryl(C 2 -C 4 )alkenyl-, heteroaryl(C 1 -C 4 )alkyl- or heterocycloalkyl(C 1 -C 4 )alkyl- group, wherein:
  • aryl(C 2 -C 6 )alkenyl-, heteroaryl(Ci-C 4 )alkyl- or heterocycloalkyl(d-C 4 )alkyl- group is optionally substituted by (Ci-C 4 )alkoxy, amino, (Ci-C 4 )alkylamino-,
  • any of said aryl (that is, the aryl group or the aryl moiety of the aryl(Ci-C 4 )alkyl- or aryl(C 2 -C 4 )alkenyl- group) is a phenyl or naphthyl group substituted by 1-3 Q 1 groups and Q 2 ,
  • any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(Ci-C 4 )alkyl- group) is a 5-6 membered heteroaryl or 9-10 membered heteroaryl group substituted by 1 -2 Q 1 and Q 2 , wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom, and any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(C 1 -C 4 alkyl- group) is a 5-6 membered heterocycloalkyi substituted by Q 2 and by 1 or 2 Q 1 substituents and contains a nitrogen, oxygen or sulfur ring atom;
  • R Y is hydrogen, (C C 6 )alkyl, (Ci-C 6 )alkoxy(C 2 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(Ci-C 6 )alkyl-, aryl(C C 6 )alkyl-, -S0 2 N(Ci-C 6 )alkyl(Ci-C 6 )alkyl or -COCH R YA R YB , where R YA and R YB are each independently selected from the group consisting of hydrogen, amino, (CrC 6 )alkyl, and amino(Ci-C 6 )alkyl-,
  • R Y and Q 1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, SO and S0 2 .
  • R is H or a (Ci-C 4 )alkyl, halo(CrC 4 )alkyl, aryl, heteroaryl, heterocycloalkyi, aryl(Ci-C 4 )alkyl-, aryl(C 2 -C 4 )alkenyl-, heteroaryl(Ci-C 4 )alkyl- or heterocycloalkyl(Ci-C 4 )alkyl- group, wherein:
  • aryl(C 2 -C 6 )alkenyl-, heteroaryl(Ci-C 4 )alkyl- or heterocycloalkyl(CrC 4 )alkyl- group is optionally substituted by (C 1 -C 4 )alkoxy, amino, (C 1 -C 4 )alkylamino-, ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)amino-, hydroxy, hydroxy(C 2 -C 4 )alkylamino-, amino(C 2 -C 4 )alkylamino-, ((C 1 -C 4 )alkyl)amino(C 2 -C 4 )alkylamino-,
  • any of said aryl (that is, the aryl group or the aryl moiety of the aryl(Ci-C )alkyl- or aryl(C 2 -C )alkenyl- group) is phenyl substituted by 1-3 Q 1 groups (Q 2 is H) or naphthyl substituted by 1 -2 Q 1 groups and Q 2 ,
  • any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(Ci-C )alkyl- group) is a 5-6 membered heteroaryl substituted by 1-2 Q 1 groups (Q 2 is H) or a 9-10 membered heteroaryl substituted by 1 -2 Q 1 and Q 2 , wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom,
  • any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(Ci-C alkyl- group) is a 5-6 membered heterocycloalkyi substituted by 1-2 Q 1 groups (Q 2 is H) and contains a nitrogen, oxygen or sulfur ring atom,
  • R Y is hydrogen, (C C 4 )alkyl, (C C 4 )alkoxy(C 2 -C 4 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3- C 6 )cycloalkyl-(C 1 -C 4 )alkyl-, aryl(C C 4 )alkyl-, -S0 2 N(C 1 -C 4 )alkyl(C 1 -C 4 )alkyl or
  • R YA and R YB are each independently selected from the group consisting of hydrogen, amino, (CrC )alkyl, and amino(C-i-C )alkyl-,
  • R Y and Q 1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, SO and S0 2 .
  • R is (CrC )alkyl, halo(CrC )alkyl, aryl, heteroaryl, heterocycloalkyi, aryl(Ci-C )alkyl-, heteroaryl(Ci-C )alkyl- or heterocycloalkyl(Ci-C )alkyl- group, wherein:
  • any of said aryl that is, the aryl group or the aryl moiety of the aryl(Ci-C )alkyl- group
  • any of said heteroaryl that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(Ci-C )alkyl- group
  • any of said heteroaryl is a 5-6 membered heteroaryl substituted by Q 1 or a 9-10 membered heteroaryl substituted by Q 1 and Q 2
  • any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom
  • any of said heterocycloalkyi that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(C 1 -C 4 )alkyl- group
  • any of said heterocycloalkyi that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(C 1 -C 4 )al
  • R Y is hydrogen, (C C 4 )alkyl, (Ci-C 4 )alkoxy(C 2 -C 4 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(Ci-C 4 )alkyl-, aryl(C C 4 )alkyl-, -S0 2 N(Ci-C 4 )alkyl(Ci-C 4 )alkyl or
  • R YA and R YB are each independently selected from the group consisting of hydrogen, amino, (CrC 4 )alkyl, and amino(Ci-C 4 )alkyl-,
  • R Y and Q 1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, SO and S0 2 .
  • R is (CrC 4 )alkyl, halo(CrC 4 )alkyl, aryl, heteroaryl, heterocyclkoalkyl, aryl(Ci-C 4 )alkyl-, heteroaryl(d-C 4 )alkyl- or heterocycloalkyl(CrC 4 )alkyl- group, wherein:
  • any of said aryl (that is, the aryl group or the aryl moiety of the aryl(Ci-C 4 )alkyl- group) is phenyl substituted by Q 1 or naphthyl substituted by Q 1 and Q 2 ,
  • any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(C 1 -C 4 )alkyl- group) is a 5-membered heteroaryl selected furyl (furanyl), thienyl, and pyrrolyl substituted by R Y , wherein any of said 5-membered heteroaryl is substituted by Q 1 ,
  • heteroaryl is a 9-10 membered heteroaryl selected from the group consisting of quinolyl, indolyl substituted by R Y , benzofuranyl, and benzothienyl, wherein said any of 9-10 memebered heteroaryl is substituted by Q 1 and Q 2 ,
  • any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(Ci-C 4 )alkyl- group) is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, and pyrrolidinyl substituted by R Y , wherein any of said heterocycloalkyi is substituted by Q 1 .
  • R is H. In another embodiment, R is (CrC 4 )alkyl,
  • heteroaryl(Ci-C 2 )alkyl- or heterocycloalkyl(CrC 2 )alkyl- group wherein:
  • any of said aryl is phenyl substituted by 1-2 Q 1 (Q 2 is H) or naphthyl substituted by
  • any of said heteroaryl is a 5-membered heteroaryl selected from the group consisting of furyl (furanyl), thienyl, and pyrrolyl substituted by R Y , wherein any of said 5- membered heteroaryl is substituted by Q 1 , or any of said heteroaryl is a 9-10 membered heteroaryl selected from the group consisting of quinolyl, indolyl substituted by R Y , benzofuranyl, and benzothienyl, and wherein any of said 9-10 membered heteroaryl is substituted by Q 2 ,
  • any of said heterocycloalkyl is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, and pyrrolidinyl substituted by R Y , and wherein any of said heterocycloalkyl is substituted by Q 1 .
  • R is aryl or aryl(Ci-C 2 )alkyl-, wherein any of said aryl is phenyl substituted by Q 1 or naphthyl substituted by Q 2 .
  • each Q 1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, trihalo(Ci-C 6 )alkyl, trihalo(CrC 6 )alkoxy, (Ci-C 6 )alkyl, (d-C 6 )alkyl substituted with aryl or (C 3 -Ci 0 )cycloalkyl, (CrC 6 )alkoxy, (Ci-C 6 )alkoxy(C 2 -C 6 )alkoxy, (CrC 6 )alkylcarbonyl, (CrC 6 )alkoxycarbonyl,
  • (Ci-C 6 )alkylsulfonyl cyano(CrC 6 )alkyl, hydroxy(CrC 6 )alkyl, hydroxy(C 2 -C 6 )alkoxy, hydroxy(C 2 -C 6 )alkylamino, amino(C 2 -C 6 )alkoxy, aminocarbonyl,
  • (Ci-C 6 )alkylaminocarbonyl di((Ci-C 6 )alkyl)aminocarbonyl, di(hydroxy(C 2 -C 6 )alkyl)amino, (aryl)((Ci-C 6 )alkyl)amino, di((Ci-C 6 )alkyl)amino(C 2 -C 6 )alkoxy,
  • each Q 1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, trihalo(CrC 6 )alkyl,
  • each Q 1 is independently hydrogen, halogen, hydroxy, amino, nitro, trihalo(Ci-C 6 )alkyl, trihalo(CrC 6 )alkoxy, (Ci-C 6 )alkyl, (CrC 6 )alkoxy,
  • each Q 1 is independently hydrogen, halogen, nitro, trihalo(Ci-C 6 )alkyl, trihalo(C C 6 )alkoxy, (Ci-C 6 )alkyl, (C C 6 )alkoxy, (C C 6 )alkylsulfonyl, (aryl)((Ci-C 6 )alkyl)amino, aminocarbonyl, (Ci-C 4 )alkylaminocarbonyl,
  • each Q 1 is independently hydrogen, thienyl, thienyl substituted with di((Ci-C 6 )alkyl)amino(Ci-C 6 )alkyl, or (Ci-C 6 )alkylpiperazinyl(CrC 6 )alkyl, furanyl, phenyl, phenyl substituted with one substituent selected from the group consisting of di((Ci-C 4 )alkyl)amino(C 2 -C 4 )alkoxy, di((Ci-C 4 )alkyl)amino,
  • each Q 1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (CrC 6 )alkyl, halo(CrC 6 )alkyl,
  • any of said aryl is phenyl or naphthyl
  • any of said heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl and any of said
  • heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl
  • any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (Ci-C 6 )alkyl, halo(CrC 6 )alkyl,
  • each Q 1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, (C 1 -C 4 )alkyl, halo(Ci-C 3 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 2 )alkoxy, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkyl-, hydroxy(C 1 -C 4 )alkyl-, amino,
  • Q 1 is phenyl or a 5-6 membered monocyclic heteroaryl, wherein said phenyl or heteroaryl is optionally substituted by 1-2 substituents each independently selected from the group consisting of halogen, cyano, (Ci-C )alkyl, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C )alkoxy, 5-6 membered heterocycloalkyl- (Ci-C )alkyl-, 5-6 membered heterocycloalkyl-(Ci-C )alkoxy, amino, (Ci-C )alkylamino-, ((Ci-C )alkyl)((Ci-C )alkyl)amino-, aminocarbonyl, (Ci-C )alkylaminocarbonyl,
  • Q 1 is a 9-10 membered, bicyclic heteroaryl, optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, cyano, (Ci-C )alkyl, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C )alkoxy, oxo, amino, (Ci-C )alkylamino-, ((Ci-C )alkyl)((Ci-C )alkyl)amino-, aminocarbonyl,
  • (Ci-C )alkylaminocarbonyl ((Ci-C )alkyl)( (Ci-C )alkyl)aminocarbonyl, amino(Ci-C )alkyl-, (Ci-C 4 )alkylamino(Ci-C 4 )alkyl-, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino(C C 4 )alkyl-,
  • Q 1 is a divalent -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -,
  • R Y and Q 1 taken together are a divalent -CH 2 CH 2 -, -CH2CH2CH2-,
  • Q 1 is selected from the group consisting of hydrogen, thienyl, thienyl substituted with ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C 4 )alkyl, or (Ci-C 4 )alkylpiperazinyl(Ci-C 4 )alkyl, furanyl, phenyl, and phenyl substituted with one substituent selected from the group consisting of
  • Q 1 is hydrogen, halogen, hydroxy, amino, nitro, halo(CrC 6 )alkyl, halo(Ci-C 6 )alkoxy, (C C 6 )alkyl, (C C 6 )alkoxy, (Ci-C 6 )alkylcarbonyl, (Ci-C 6 )alkoxycarbonyl, hydroxy(CrC 6 )alkyl, aryloxy, ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)amino, cyano, thienyl, furanyl, furanyl substituted with hydroxy(C 1 -C 6 )alkyl-, benzofuranyl, imidazolyl, oxazolyl, oxazolyl substituted with aryl and/or (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyltriazolyl, tetrazol
  • each Q 1 is H.
  • R is phenyl substituted by two Q 1 groups, wherein one Q 1 group is
  • Q 2 is hydrogen, halogen, cyano, (Ci-C 4 )alkyl
  • Q 2 is hydrogen, halogen, cyano, (CrC)alkyl, halo(Ci-C )alkyl, (Ci-C)alkoxy, halo(Ci-C )alkoxy, amino, (Ci-C )alkylamino-,
  • Q 2 is hydrogen, halogen, cyano, (Ci-C)alkyl,
  • Q 2 is a divalent -OCH 2 0- or -OCH 2 CH 2 0- moiety.
  • Q 2 is hydrogen, halogen, (Ci-C 2 )alkyl, -CF 3 , (Ci-C 2 )alkoxy or
  • R is indolyl, optionally substituted by Q 2 .
  • the invention is further directed to a compound according to Formula (l-a):
  • a 1 and A 2 are each independently selected from the group consisting of CH and N; each n is independently 0, 1 or 2;
  • n 0, 1 or 2 and X is N or CH, wherein
  • Z is NHS0 2 , NHCO, NH, O, or NHC0 2 ,
  • R is (CrC 4 )alkyl, halo(Ci-C 4 )alkyl, or a group selected from the group consisting
  • Y is O, S or NR Y ,
  • R Y is hydrogen, (d-C 6 )alkyl, (Ci-C 6 )alkoxy(C2-C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-(Ci-C 6 )alkyl-, aryl(C C 6 )alkyl-, -S0 2 N(Ci-C 6 )alkyl(Ci-C 6 )alkyl or -COCHR YA R YB , or where R YA and R YB are each independently selected from the group consisting of hydrogen, amino, (CrC 6 )alkyl, and amino(Ci-C 6 )alkyl-; or when Y is NR Y (that is, R is indolyl) and Q 2 is in the 7 position of the indolyl, then Q 2 and R Y taken together with the atoms through which they are attached to form a 5 or 6 member
  • R Y is hydrogen, (d-C 6 )alkyl, (Ci-C 6 )alkoxyC 2 - 6 alkyl-, C 3-6 cycloalkyl, C 3 - 6 cycloalkyl-Ci -3 alkyl-, phenyl-Ci -3 alkyl-, or (Ci-C 6 )alkylcarbonyk
  • R Y is hydrogen., (CrC 5 )alkyl, (Ci-C 3 )alkoxyC 2 - 4 alkyl-, C 3-6 cycloalkyl, C 3 - 6 cycloalkyl-Ci- 2 alkyl-, or benzyl.
  • R Y is H or methyl.
  • R is selected from the group consisting of:
  • Y is O, S or NR Y , wherein R Y Q 1 and Q 2 are as defined herein and Q 2 may be substituted on either ring of the illustrated bicyclic group.
  • the invention is directed to a compound according to Formula (l-b):
  • a 1 is N and A 2 is CH or N;
  • n 0, 1 or 2 and X is CH or N, wherein:
  • Z is NHS0 2 , NHCO, NH, O, or NHC0 2 ,
  • R' is phenyl, naphthyl, furyl (furanyl), thienyl, quinolyl, indolyl substituted by R Y , benzofuranyl, or benzothienyl, substituted by Q 1 or Q 2 as defined/illustrated herein.
  • the invention is directed to a compound according to Formula l-c) or (l-d):
  • a 1 is N and A 2 is CH or N;
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • the invention is directed to a compound according to any one of Formula (l-e):
  • a 1 is N and A 2 is CH or N;
  • n 0 or 1 ;
  • Z is S0 2 , CO, C0 2 , CONH, or a direct bond
  • p is 0 or 1 ;
  • R QA is hydrogen, halogen, cyano, (Ci-C 4 )alkyl, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(CrC 4 )alkoxy, 5-6 membered heterocycloalkyl-(Ci-C 4 )alkyl-, 5-6 membered heterocycloalkyl-(Ci-C 4 )alkoxy, amino, (Ci-C 4 )alkylamino-,
  • R QB is hydrogen, halogen, cyano, (C 1 -C 4 )alkyl, halo(CrC 4 )alkyl, (d-C 4 )alkoxy, or halo(C 1 -C 4 )alkoxy.
  • R QB is hydrogen.
  • the terms "compound(s) of the invention” or “compound(s) of this invention” mean 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 salt, particularly a
  • 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, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • non-solid forms e.g., liquid or semi-solid forms
  • solid forms e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemi- hydrates)
  • mixtures of various forms e.g., including hydrate forms (e.g., mono-, di- and hemi- hydrates)
  • optionally substituted means unsubstituted groups or rings (e.g., cycloalkyl, heterocycle, and heteroaryl rings) and groups or rings substituted with one or more specified substituents.
  • the compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula I containing one or more chiral centers may be used as racemic mixtures, scalemic mixtures, or as diaseteromerically or enantiomerically pure materials.
  • Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer- specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compound or salt including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof.
  • the compound or salt, or solvates (particularly, hydrates) thereof may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs.”
  • polymorphs typically known as “polymorphs.”
  • the disclosed compound, or solvates (particularly, hydrates) thereof also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state.
  • Polymorphs therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
  • Formula I are preferably pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse,
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Typically, a salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like, or with a pyranosidyl acid, such as glucuronic acid or galacturonic acid, or with an alpha-hydroxy acid, such as citric acid or tartaric acid, or with an amino acid, such as aspartic acid or glutamic acid, or with an aromatic acid, such as benzoic acid or cinnamic acid, or with a sulfonic acid, such as
  • Suitable addition salts are formed from acids which form non-toxic salts and examples include acetate, p-aminobenzoate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, dihydrochloride, hydrofumarate, hydrogen phosphate, hydroiodide, hydromaleate, hydrosuccinate, hydroxyn
  • exemplary acid addition salts include pyrosulfate, sulfite, bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suberate, sebacate, butyne-1 ,4-dioate, hexyne-1 ,6-dioate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutrate, lactate, ⁇ -hydroxybutyrate, mandelate, and sulfonates, such as xylenesulfonate, propanesulfonate, naphthalene-1 -sulfonate and naphthalene-2-sulfonate.
  • an inventive basic compound is isolated as a salt
  • the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as N-methyl-D-glucamine, diethylamine, isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as glycine and arginine
  • ammonia such as glycine and arginine
  • primary, secondary, and tertiary amines such as N-methyl-D-glucamine, diethylamine, isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine
  • Certain of the compounds of this invention may form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety).
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.
  • Compounds of the invention having both a basic and acidic moiety may be in the form of zwitterions, acid-addition salt of the basic moiety or base salts of the acidic moiety.
  • This invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of this invention, e.g., a hydrochloride salt, into another
  • a pharmaceutically acceptable salt of a compound of this invention e.g., a sulfate salt.
  • solvates of the compounds of Formula I, or salts thereof that are in crystalline form may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as
  • Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
  • the invention includes all such solvates.
  • the compounds of Formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • the compounds of this invention may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist. The synthesis provided in these Schemes are applicable for producing compounds of the invention having a variety of different substituent groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of Formula I, they are illustrative of processes that may be used to make the compounds of the invention.
  • Specific compounds of this invention are the compounds of Examples 1 -33, including salts, particularly pharmaceutically acceptable salts, thereof.
  • ChemDraw 1 1.0 available from CambridgeSoft Corporation., 100 Cambridge Park Drive, Cambridge, MA 02140, USA (http://www.cambridgesoft.com).
  • the compounds of Formula I can be prepared according to the methods outlined below.
  • the invention also includes various deuterated forms of the compounds of Formula I.
  • Each available hydrogen atom attached to a carbon atom may be
  • deuterated alkyl groups e.g., /V-(deutero-methyl) amines
  • deuterated alkyl groups may be prepared by conventional techniques (see for example: methyl-c/3-amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).
  • Employing such compounds will allow for the preparation of compounds of Formula I in which various hydrogen atoms of the N- methyl groups are replaced with a deuterium atom.
  • the present invention is directed to a method of inhibiting an HDAC which comprises contacting the acetylase with 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 inhibiting HDAC comprising contacting a cell with an effective amount of 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 an HDAC-mediated disease or disorder 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.
  • 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 5 o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by HDAC.
  • the methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease.
  • this invention is directed to a method of treating, ameliorating, or preventing an autoimmune disorder, an immunological disease, an inflammatory disorder, transplant/graft rejection (e.g., allograft), lymphopenia, or graft-versus-host disease (GvHD) in a patient, specifically in a human, comprising administering to the patient a compound of this invention, in an amount sufficient to increase the level and/or activity of a Treg cell or a population of Treg cells in the patient, thereby treating, ameliorating, or preventing the autoimmune disorder, inflammatory disorder,
  • transplant/graft rejection e.g., allograft
  • lymphopenia e.g., allograft
  • GvHD graft-versus-host disease
  • transplant/graft rejection transplant/graft rejection, lymphopenia, or GvHD in the patient.
  • diseases and conditions that may be treated by the compounds of this invention include but not limited to type II diabetes mellitus, coronary artery disease, alopecia, allergies and allergic reactions, and sepsis/toxic shock.
  • Exemplary autoimmune disorders include, but are not limited to, multiple sclerosis, juvenile idiopathic arthritis, psoriatic arthritis, hepatitis C virus-associated mixed cryoglobulinemia, polymyositis, dermatomyositis, polyglandular syndrome type II, autoimmune liver disease, Kawasaki disease, myasthenia gravis, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX (syndrome)), type I diabetes, psoriasis, hypothyroidism, hemolytic anemia, autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED), thrombocytopenia, spondyloarthritis, Sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, eczema, gastritis, or thyroiditis.
  • the inflammatory bowel disease IBD
  • autoimmune diseases include osteoarthritis, systemic sclerosis, sarcoidosis, insulin dependent diabetes mellitus (IDDM, type I diabetes), reactive arthritis, scleroderma, vasculitis, Wegener's granulomatosis, Hashimoto's disease, scleroderma, oophoritis, Lupus (SLE), Grave's disease, asthma, cryoglobulinemia, primary biliary sclerosis, pemphigus vulgaris, hemolytic anemia and pernicious anemia.
  • IDDM insulin dependent diabetes mellitus
  • SLE oophoritis
  • Grave's disease asthma, cryoglobulinemia, primary biliary sclerosis, pemphigus vulgaris, hemolytic anemia and pernicious anemia.
  • transplant/graft rejection e.g., allograft
  • lymphopenia e.g., lymphopenia
  • graft- versus-host disease e.g., graft- versus-host disease
  • transplant/graft rejection e.g., allograft
  • lymphopenia e.g., lymphopenia
  • graft- versus-host disease e.g., graft- versus-host disease
  • transplant/graft rejection e.g., allograft
  • lymphopenia e.g., lymphopenia
  • GvHD graft- versus-host disease
  • this 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)
  • diseases and conditions include but are not limited to cystic fibrosis, osteoporosis, obesity, epilepsy, depression, thalassemia, sickle cell anemia, amyotrophic lateral sclerosis (ALS) and hyperalgesia, cardiac disease (e.g., stroke, hypertension, atherothrombotic diseases, atherosclerosis or limitation of infarct size in acute coronary syndrome), diseases or disorders involving muscular atrophy, gentamicin-induced hearing loss, drug resistance (e.g., drug resistance in osteosarcoma and colon cancer cells), infectious diseases, and immune deficiency/immunocompromised patients.
  • cystic fibrosis e.g., osteoporosis
  • obesity e.g., epilepsy, depression, thalassemia, sickle cell anemia, amyotrophic lateral sclerosis (ALS) and hyperalgesia
  • cardiac disease e.g., stroke, hypertension, atherothrombotic diseases, atherosclerosis or limitation
  • infectious diseases relate to various pathogen infections such as viral, fungal, bacterial, mycoplasm, and infections by unicellular and multicellular eukaryotic organisms.
  • pathogens include but are not limited to HIV, HSV, HPV, Hepatitis A, B and C viruses, influenza, denge, zostrella, rubella, RSV, rotavirus, gram positive, gram negative, streptococcus, tetanus, staphalococcus, tuberculosis, listeria, and malaria.
  • the compounds of the invention may be employed alone or in combination with standard anti-cancer regimens for neoplastic cell, e.g., tumor cell and cancer cell, treatments.
  • 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.
  • carcinoma e.g., adenocarcinoma
  • heptaocellular carcinoma e.g., sarcoma
  • myeloma e.g., multiple myeloma
  • treating bone disease in multiple myeloma leukemia, childhood acute lymphoblastic leukemia and lymphoma (e.g., cutaneous cell lymphoma)
  • mixed types of cancers such as adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma, and teratocarcinoma.
  • breast or prostate cancers or tumors are treated using the HDAC inhibitors of this invention.
  • Other cancers that may be treated using the compounds of this invention include, but are not limited to, bladder cancer, breast cancer, prostate cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, endometrial cancer, pancreatic cancer, cervical cancer, ovarian cancer; head and neck cancer, and melanoma.
  • the present invention is further 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.
  • B-cell lymphomas associated with deacetylases 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
  • 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
  • follicular lymphoma immunoblastic large cell lymphoma
  • precursor B-lymphoblastic lymphoma precursor B-lymphoblastic lymphoma
  • mantle cell lymphoma mantle cell lymphoma
  • the compounds of the invention 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 the invention 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 the invention 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 the invention 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 HDAC-mediated disease conditions may be achieved using the compounds of this invention 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 one or more immunosuppressants that do not activate the T suppressor cells including but are not limited to corticosteroids, rapamycin, Azathioprine, Mycophenolate, Cyclosporine, Mercaptopurine (6-MP), basiliximab, daclizumab, sirolimus, tacrolimus, Muromonab-CD3, cyclophosphamide, and
  • methotrexate which are administered in effective amounts as is known in the art.
  • the compounds of the invention 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 pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., 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 this invention.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention 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 the invention 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 the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention 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 of 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
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention 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.
  • ferf-Butyl ((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)carbamate: A mixture of ferf-butyl (piperidin-4-ylmethyl)carbamate (0.323 g, 1.505 mmol), 3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (0.1878 g, 0.752 mmol), and / ' -Pr 2 NEt (0.329 ml_, 1.881 mmol) in DCM (10 ml.) was stirred at rt overnight.
  • the DCM was removed under reduced pressure. 7 ml of anhydrous DMF was added. The mixture was heated at 70 °C for 4 h, cooled, and partitioned between 50% EtOAc in hexanes and water. The organic phase was separated, and the aqueous was further extracted with 50% EtOAc in hexanes twice. The combined organic phases were washed with water and brine, dried over MgS0 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% - 40% EtOAc in hexanes) to afford the title compound as a white solid (0.21 g, 63%).
  • 2-Chloropyrimidine-5-carbonitrile Prepared from 2-aminopyrimidine-5-carbonitrile according to the method reported in the patent WO2010009183 (Authored by D. A.
  • ferf-Butyl ((1 -(5-cyanopyrimidin-2-yl)piperidin-4-yl)methyl)carbamate The mixture of 2-chloropyrimidine-5-carbonitrile (0.90 g, 5.74 mmol), ferf-butyl (piperidin-4- ylmethyl)carbamate (1.818 g, 8.48 mmol), and / ' -Pr 2 NEt (2.506 mL, 14.35 mmol) in anhydrous NMP (10 mL) was heated at 70 °C for 5 h, cooled to rt, and partitioned between 50% EtOAc/hexanes and water.
  • ferf-Butyl ((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methyl)carbamate: 50% Hydroxylamine in water (1 .255 mL, 20.48 mmol) was added to a solution of ferf-butyl ((1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)methyl)carbamate (1.3 g, 4.10 mmol) in THF. The resulting mixture was heated at 60 °C with stirring overnight. The solvent was removed under reduced pressure. The residue was washed with water, dried in air flow, and dissolved in dry THF (20ml).
  • a -((1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methyl)acetamide Acetyl chloride (4.24 ⁇ _, 0.060 mmol) was added to a solution of (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine, trifluoroacetic acid salt (22 mg, 0.050 mmol) and / ' -Pr 2 NEt (0.026 mL, 0.149 mmol) in DCM (3 mL) .
  • ferf-Butyl (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)carbamate The mixture of ferf-butyl piperidin-4-ylcarbamate (0.332 g, 1 .659 mmol), 3- (6-chloropyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (0.207 g, 0.829 mmol), and / ' - Pr 2 NEt (0.362 mL, 2.073 mmol) in NMP (5 mL) was heated at 70 °C for 4 h, cooled, and partitioned between EtOAc and water.
  • ferf-Butyl 4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperazine-1 - carboxylate A procedure similar to the one used in the synthesis of ferf-butyl (1-(5-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)carbamate (example 20) but using ferf-butyl piperazine-1 -carboxylate was used to prepare the title compound as a white solid.
  • ferf-Butyl 4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperazine-1 - carboxylate A mixture of ferf-butyl piperazine-1 -carboxylate (0.417 g, 2.239 mmol), 3- (2-chloropyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (0.2805 g, 1 .1 19 mmol), and / ' - Pr 2 NEt (0.391 mL, 2.239 mmol) in NMP (6.5 mL) was heated at 70 °C for 4 h, cooled, and poured into water (15 ml).
  • Phenyl(4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperazin-1 - yl)methanone A procedure similar to the one used in the synthesis of 3-(2-(4- (naphthalen-2-ylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (example 30) but using benzoyl chloride was used to prepare the title compound as a white solid.
  • ferf-Butyl (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)carbamate A procedure similar to the one used in the synthesis of ferf-butyl 4-(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (example 27) but using ferf-butyl piperidin-4-ylcarbamate was used to prepare the title compound as an off-white solid.
  • ferf-Butyl 4-(((2-cyano-5-(3,6,6-tri methyl -4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 - yl)phenyl)amino)methyl)piperidine-1 -carboxylate A mixture of 2-bromo-4-(3,6,6- trimethyl-4-oxo-4,5,6,7-tetrahydro-1 /-/-indazol-1 -yl)benzonitrile (0.358 g, 1 mmol), ferf- butyl 4-(aminomethyl)piperidine-1-carboxylate (0.321 g, 1.500 mmol), and PdCI 2 (dppf)- CH 2 CI 2 adduct (0.163 g, 0.200 mmol) in toluene (15 ml.) was degassed by vacuum- nitrogen back-filling cycles.
  • ferf-Butyl 4-(((2 -carbamoyl -5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazoM - yl)phenyl)amino)methyl)piperidine-1 -carboxylate A mixture of ferf-butyl 4-(((2-cyano- 5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 - yl)phenyl)amino)methyl)piperidine-1-carboxylate (0.22 g, 0.447 mmol), sodium hydroxide (aq.
  • ferf-Butyl 4-((5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2- yl)amino)piperidine-1 -carboxylate A mixture of ferf-butyl 4-aminopiperidine-1 - carboxylate (320 mg, 1.600 mmol), 3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole (200 mg, 0.8 mmol), and / ' -Pr 2 NEt (0.349 mL, 2.000 mmol) in DMF (7 mL) was heated at 70 °C for 4 h, cooled, and partitioned between 50% EtOAc in hexanes and water.
  • ferf-Butyl 4-((5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)amino)piperidine-1 -carboxylate A mixture of ferf-butyl 4-aminopiperidine-1 - carboxylate (0.401 g, 2.000 mmol), 3-(2-chloropyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole (0.251 g, 1 mmol), and / ' -Pr 2 NEt (0.437 ml_, 2.500 mmol) in NMP (5 ml.) was heated at 75 °C overnight, cooled, and partitioned between EtOAc and water.
  • trifluoroacetic acid salt A procedure similar to the one used in the synthesis of (1 -(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methanamine,
  • Tablets are prepared using conventional methods and are formulated as follows:
  • Capsules are prepared using conventional methods and are formulated as follows
  • HDAC9 Histone Deacetylase 9
  • Novel histone deacetylase 9 (HDAC9) inhibitors were characterized in an in vitro biochemical functional assay.
  • the assay measures the increased fluorescent signal due to deacetylation, by HDAC9, of a fluorogenic substrate.
  • the commercial available substrate is Class lla HDAC-specific and contains an acetylated lysine residue and would releases the fluorescent signal upon trypsin cleavage after deacetylation.
  • test compounds diluted to various concentrations in 100% DMSO are first dispensed into 384-well assay plates.
  • Recombinant HDAC9 isoform 4 (purchased from BPS Bioscience) in complete assay buffer (50 mM Tris-HCI, pH 8.0, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCI 2 , 0.05% BSA & 0.005% Tween 20) were then added to each well (5uL/well) using Multidrop Combi (Thermo Scientific), followed by 5 uL/well substrate (purchased from BPS Bioscience, 4.5 uM final).
  • the compounds of Examples 1-33 exhibited a plC 5 o between 5.0 and 9.0 e.g., for example, the compound of Example 6 inhibited HDAC9 in the above method with a mean pICso of >6.
  • 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

Disclosed are compounds having the formula I, wherein Ar, n, Rx, k, X, m, Z and R are as defined herein, and methods of making and using the same.

Description

COMPOUNDS AND METHODS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to compounds that inhibit histone deacetylase
(HDAC) enzymes, the preparation of these compounds, the use of these compounds in the treatment of diseases or conditions ameliorated by inhibition of HDAC activity and pharmaceutical compositions comprising these compounds. 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.
HDAC9 is a class lla histone deacetylase highly expressed in human Tregs. HDAC9 deficiency: 1 ) increases Foxp3 expression (and other Treg markers), 2) increases Foxp3 and histone 3 acetylation, 3) increases Foxp3 DNA binding, 4) increases Treg numbers, 5) increases suppressive activity in vitro and in vivo, and 6) ameliorates murine colitis. Tregs which are deficient in HDAC9 induce permanent tolerance of fully mismatched cardiac allografts. In addition, HDAC9 inhibitors maybe useful for treatment of diseases and disorders associated with abnormal cell proliferation, differentiation and survival, e.g. breast and prostate tumors.
Preliminary data shows that targeting HDAC7, a class lla histone deacetylase, enhances Treg suppression in vitro and in vivo. HDAC7 enhances FOXP3+ Treg function and induces long-term allograft survival.
Inhibition of HDAC6, a class lib HDAC, has been shown to increase Treg suppressive function in vitro along with increased expression of FOXP3 protein and Treg associated genes including CTLA, IL-10, TNR18. HDAC6 inhibition in vivo decreased severity of colitis in the dextran sodium sulphate-induced colitis model and the
CD4+CD62Lhigh adoptive transfer model of colitis. In addition, inhibition of HDAC6 with a subtherapeutic dose of rapamycin led to prolonged cardiac allograft survival.
Thus, an orally available small molecule selective inhibitor of Class II HDAC activity (more specifically HDAC9 or HDAC7 or HDAC6) is expected to modulate autoimmune diseases through expansion and enhancement of Treg activity.
Inhibition of other Class II HDAC's for example HDAC4 and 5 impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes and maybe potentially useful for the treatment of muscle and heart diseases including cardiac hypertrophy and heart failure. Also, inhibition of Class II HDAC activity represents a novel approach for disrupting or intervening in cell cycle regulation.
HDAC9 is also highly expressed in human B cells. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell tumors 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 both 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 Ma 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)
Accordingly, a small molecule selective inhibitor of HDAC4, HDAC5, HDAC6, HDAC7, HDAC8 and/or HDAC9 is expected to be beneficial in the treatment of B-cell malignancies by targeting one or several of the above enzymes
HDAC4, HDAC5 and HDAC9 are also 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 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 has been implicated in regulating ataxin-7 turnover in a SCA-7 model (Mookerjee S et al., J Neurosci., 2009, p. 15134).
HDAC6 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).
Accordingly, a small molecule selective inhibitor of HDAC activity (more
specifically HDAC4 or HDAC5 or HDAC6 or HDAC7or HDAC9) is expected to be beneficial in the treatment of neurodegenerative diseases.
Class II HDAC inhibitors have therapeutic potential in the study and/or treatment of the various diseases or conditions described herein.
Many of the known small-molecule HDAC inhibitors, however, inhibit all HDAC isoforms. It would be advantageous to identify HDAC inhibitors that inhibited one or more, but not all HDAC isoforms.
SUMMARY OF THE INVENTION
One embodiment of this invention is directed to a method of inhibiting HDAC prising contacting a cell with an effective amount of a compound according to Formula I
Figure imgf000004_0001
wherein:
Ar is an optionally substituted aryl (arylene) or 5-6 membered, monocyclic or 9-10 membered, bicyclic heteroaryl (heteroarylene), wherein said optionally substituted aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of (CrC4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
wherein each RA is independently selected from the group consisting of H and (Ci-C4)alkyl;
each n is independently 0, 1 or 2;
k is O, 1 or 2;
each Rx is independently selected from the group consisting of (CrC4)alkyl, halo(Ci-C4)alkyl, oxo, -NRARA, -((Ci-C4)alkyl)ORA, and -((C C4)alkyl)NRARA, or two Rx taken together with the atoms through which they are attached form a 3-7 membered saturated ring, optionally containing 1 or 2 heteroatoms each independently selected from N and O;
m is 0, 1 or 2;
X is N or CH, wherein when X is N, Z is S02, CO, C02, CONRZa, or a direct bond and when X is CH, Z is NRZaS02, NRZaCO, NRZb, O, or NRZaC02, wherein RZa is H or
(d-C6)alkyl and RZb is H, (C C6)alkyl, or -CO(C C4)alkyl; and
R is H or a (C1-C8)alkyl, halo(CrC4)alkyl, aryl, heteroaryl, heterocycloalkyl, aryl(C1-C6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(C1-C6)alkyl- or
heterocycloalkyl(Ci-C6)alkyl- group,
wherein any of said aryl, heteroaryl, or heterocycloalkyl, (that is the aryl, heteroaryl or heterocycloalkyl group or the aryl, heteroaryl or heterocycloalkyl moiety of the aryl(CrC6)alkyl-, aryl(Ci-C6)alkenyl-, heteroaryl(Ci-C6)alkyl- or
heterocycloalkyl(Ci-C6)alkyl-) is substituted by Q2 and by 1 , 2 or 3 Q1 substituents,
wherein the (CrC8)alkyl group or the (CrC6)alkyl or (C2-C6)alkenyl moiety of the aryl(CrC6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(Ci-C6)alkyl- or
heterocycloalkyl(Ci-C6)alkyl- group is optionally substituted by cyano, halo(Ci-C2)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
((Ci-C4)alkyl)( (Ci-C4)alkyl)aminocarbonyl, hydroxy, (Ci-C4)alkylcarbonyl,
hydroxy(C2-C4)alkylamino-, amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-, or
((C1-C4)alkyl)amino(C2-C4)alkyl)((C1-C4)alkyl)amino-, any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(C1-C4)alkyl- group) is a 5-6 membered or 9-10 membered heteroaryl, wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom,
and any of said heterocycloalkyl (that is the heterocycloalkyl group or the heterocycloalkyl moiety of the heterocycloalkyl(Ci-C4alkyl- group) is a 5-6 membered heterocycloalkyl and contains a nitrogen, oxygen or sulfur ring atom,
wherein when any of said heteroaryl or heterocycloalkyl contains a substitutable nitrogen atom, said nitrogen atom is substituted by RY, wherein
RY is hydrogen, (C C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl,
(C3-C6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCHRYARYB, where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-,
or RY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O and S or an oxide thereof (e.g., S(=0) or S(=0)2);
wherein each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (C1-C6)alkyl, halo(C1-C6)alkyl, cyano(C1-C6)alkyl,
(d-C6)alkoxy, halo(C C6)alkoxy, (C1-C6)alkoxy(C2-C6)alkyl-, (C1-C6)alkoxy(C2-C6)alkoxy, hydroxy(C1-C6)alkyl-, hydroxy(C2-C6)alkoxy, amino, (C1-C6)alkylamino-,
((C1-C6)alkyl)((C1-C6)alkyl)amino-, amino(C2-C6)alkoxy, ((C1-C6)alkyl)amino(C2-C6)alkoxy, ((CrC6)alkyl) ((Ci-C6)alkyl)amino(C2-C6)alkoxy, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino-,(5-6 membered heterocycloalkyl)((Ci-C6)alkyl)amino-, hydroxy(C2-C6)alkylamino, (hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl,
hydroxy(C2-C6)alkylamino(Ci-C6)alkyl, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (hydroxy(C2-C6)alkyl) ((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-,
(hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(Ci-C6)alkyl, phenylamino-, (phenyl)((Ci-C6)alkyl)amino-, aminocarbonyl, (Ci-C6)alkylaminocarbonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminocarbonyl, amino(Ci-C6)alkyl-,
(Ci-C6)alkylamino(Ci-C6)alkyl-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl-, (5-6 membered heteroaryl)amino(Ci-C6)alkyl-, (5-6 membered
heteroaryl)((C1-C6)alkyl)amino(C1-C6)alkyl, (5-6 membered heterocycloalkyl)amino(C1-C6)alkyl-, (5-6 membered
heterocycloalkyl)((C1-C6)alkyl)amino(C1-C6)alkyl-, ((C1-C6)alkyl)amino(C2-C6)alkoxy, ((C1-C6)alkyl)((C1-C6)alkyl)amino(C2-C6)alkoxy, (C1-C6)alkylcarbonyl,
(Ci-C6)alkoxycarbonyl, (CrC6)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
heterocycloalkylsulfonyl, arylsulfonyl, arylsulfonylamino, aryloxy, aryl(Ci-C6)alkyl, aryloxy(Ci-C6)alkyl, aryl(C2-C6)alkenyl, amino(C2-C6)alkylamino-,
(Ci-C6)alkoxy(C2-C6)alkylamino-, ((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heteroaryl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)amino(C2-C6)alkylamino-, (5-6 membered
heterocycloalkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heterocycloalkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heteroaryl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(C1-C6)alkyl, (5-6 membered heterocycloalkyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered heterocycloalkyl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(C1-C6)alkyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C4)alkyl)amino(Ci-C6)alkyl,
((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-,
aminosulfonylamino((C2-C6)alkyl)amino,
aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl, and an optionally substituted aryl, aryloxy, aryl-(Ci-C6)alkyl-, aryl-(Ci-C6)alkoxy, heteroaryl, heteroaryloxy, heteroaryl-(Ci-C6)alkyl-, heteroaryl-(Ci-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl-(Ci-C6)alkyl-, (C3-C6)cycloalkyl-(Ci-C6)alkoxy heterocycloalkyl, heterocycloalkyl-(CrC6)alkyl-, or heterocycloalkyl-(CrC6)alkoxy group, wherein any of said aryl is phenyl or naphthyl, any of said heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl and any of said
heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl, and wherein any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (C1-C6)alkyl, aryl, halo(C1-C6)alkyl, (Ci-C6)alkoxy, aryloxy, halo(CrC6)alkoxy, hydroxy(Ci-C)alkyl-, hydroxy(C2-C4)alkoxy, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkoxy, amino, (Ci-C)alkylamino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino-, aminocarbonyl, (CrC)alkylaminocarbonyl, ((Ci-C)alkyl)( (Ci-C)alkyl)aminocarbonyl, amino(Ci-C)alkyl-, (Ci-C)alkylamino(Ci-C)alkyl-, ((Ci-C)alkyl)((Ci-C)alkyl)amino(Ci-C)alkyl- (C C6)alkylcarbonyl, (d-C6)alkoxycarbonyl, amino(C2-C)alkylamino-, ((Ci-C)alkyl)amino(C2-C)alkylamino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino(C2-C)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino((C2-C4)alkyl)amino(Ci-C4)alkyl,
((Ci-C)alkyl)amino(C2-C)alkyl((Ci-C)alkyl)amino- , ((Ci-C)alkyl)((Ci-C)alkyl)amino(C2-C)alkyl((Ci-C6)alkyl)amino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino(Ci-C4)alkyl, (Ci-C4)alkylsulfonyl, naphthylsulfonyl, aminosulfonyl, ((Ci-C6)alkyl)aminosulfonyl, ((C1-C6)alkyl)((C1-C6)alkyl)aminosulfonyl, aminosulfonylamino((C2-C4)alkyl)amino, aminosulfonylamino((C2-C4)alkyl)amino(C1-C4)alkyl,
((C1-C4)alkyl)((C1-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino,
((C1-C4)alkyl)((C1-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino(C1-C6)alkyl, piperidinyl(CrC4)alkoxy, pyrrolidinyl(Ci-C4)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(Ci-C4)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylpiperazinyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylpiperazinyl(Ci-C4)alkyl, (Ci-C4)alkylpiperazinyl, (Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, hydroxy(CrC4)alkylpiperazinyl,
hydroxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, (CrC4)alkoxypiperidinyl,
(Ci-C4)alkoxypiperidinyl(Ci-C4)alkyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl,
hydroxy(C2-C6)alkoxy(CrC6)alkyl, hydroxy(C2-C4)alkylamino,
hydroxy(C2-C4)alkylamino(Ci-C4)alkyl, (hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl,
(hydroxy(C2-C4)alkyl)(hydroxy(C2-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)(hydroxy(C2-C4)alkyl)amino(Ci-C4)alkyl, furanyl, benzofuranyl, pyrrolidinyl(Ci-C4)alkyl, pyrrolidinyl(Ci-C4)alkoxy, morpholinyl, morpholinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkyl, morpholinyl(Ci-C4)alkylamino,
morpholinyl(C1-C4)alkylamino(C1-C4)alkyl, piperazinyl,(C1-C4)alkylpiperazinyl(C1-C4)alkylamino,
(C1-C4)alkylpiperazinyl(C1-C4)alkylamino(C1-C6)alkyl, tetrahydropyrimidinyl, phenyl, naphthyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinyl(C1-C4)alkyl, piperidinylamino(C2-C )alkylamino, piperidinylamino(C2-C )alkylamino(Ci-C )alkyl,
((Ci-C )alkylpiperidinyl)(hydroxy(C2-C )alkyl)amino(C2-C )alkylamino,
((Ci-C )alkylpiperidinyl)(hydroxy(C2-C )alkyl)amino(C2-C )alkylamino(Ci-C )alkyl, aminosulfonylpiperazinyl(Ci-C )alkoxy, and thienyl(Ci-C )alkylamino,
or Q1 is a divalent (C3-C6)alkyl or -0(C2-C4)alkoxy (that is -0(C2-C4)alkyl-0-) moiety;
Q2 is hydrogen, halogen, cyano, (CrC6)alkyl, halo(CrC6)alkyl, (CrC6)alkoxy, halo(CrC6)alkoxy, amino, (Ci-C6)alkylamino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, phenylamino-, (phenyl)((Ci-C6)alkyl)amino-, aminocarbonyl, (d-C6)alkylaminocarbonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminocarbonyl, aminosulfonyl, (Ci-C6)alkylaminosulfonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonyl, amino(Ci-C6)alkyl-,
(Ci-C6)alkylamino(Ci-C6)alkyl-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl-,
hydroxy(CrC6)alkyl-, (CrC6)alkylcarbonyl, (Ci-C6)alkylsulfonyl, amino(C2-C6)alkylamino-, ((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((C1-C6)alkyl)((C1-C6)alkyl)amino(C2-C6)alkylamino-,
((C1-C6)alkyl)amino(C2-C6)alkyl)((C1-C6)alkyl)amino-, or
((C ^alkyl id-^alky aminoiCz-^alky aminoid-^alkyl,
where Q2 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C 6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCHRYARYB, or where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-;
or a salt thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to a method of treating a subject having a disease or disorder mediated by inhibition of a HDAC comprising administering the compound of Formula I, or a salt thereof, or a pharmaceutical composition comprising the compound of Formula I, or a salt thereof, to the subject.
This invention is also directed to a compound of Formula (I) wherein:
Ar is an optionally substituted aryl (arylene) or 5-6 membered, monocyclic or 9-10 membered, bicyclic heteroaryl (heteroarylene), wherein said optionally substituted aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of (Ci-C )alkyl, halogen, cyano, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA; wherein each RA is independently selected from the group consisting of H and (d-C4)alkyl;
each n is independently 0, 1 or 2;
k is 0, 1 or 2;
each Rx is independently selected from the group consisting of (CrC4)alkyl, halo(CrC4)alkyl, oxo, -NRARA, -((Ci-C4)alkyl)ORA, and -((C C4)alkyl)NRARA, or two Rx taken together with the atoms through which they are attached form a 3-7 membered saturated ring, optionally containing 1 or 2 heteroatoms each independently selected from N and O;
m is 0, 1 or 2 and X is N or CH, wherein
when m is 0, 1 or 2 and X is CH, then Z is NRZaS02, NRZaCO, NRZb, O, or NRZaC02,
when m is 0 and X is N, then Z is S02 or a direct bond, or
when m is 1 or 2 and X is N, then Z is S02, CO, C02, CONRZa, or a direct bond; wherein RZa is H or (C C6)alkyl, and RZb is H, (C C6)alkyl, or
-CO(CrC4)alkyl; and
R is H or a (CrC8)alkyl, halo(CrC4)alkyl, aryl, heteroaryl, heterocycloalkyl, aryl(C1-C6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(C1-C6)alkyl- or
heterocycloalkyl(C1-C6)alkyl- group,
wherein any of said aryl, heteroaryl, or heterocycloalkyl, (that is the aryl, heteroaryl or heterocycloalkyl group or the aryl, heteroaryl or heterocycloalkyl moiety of the aryl(CrC6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(Ci-C6)alkyl- or
heterocycloalkyl(Ci-C6)alkyl-) is substituted by Q2 and by 1 , 2 or 3 Q1 substituents,
wherein the (CrC8)alkyl group or the (CrC6)alkyl or (C2-C6)alkenyl moiety of the aryl(CrC6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(Ci-C6)alkyl- or
heterocycloalkyl(Ci-C6)alkyl- group is optionally substituted by cyano, halo(Ci-C2)alkyl, (Ci-C4)alkoxy, halo(CrC4)alkoxy, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
((CrC4)alkyl)( (Ci-C4)alkyl)aminocarbonyl, hydroxy, (CrC4)alkylcarbonyl,
hydroxy(C2-C4)alkylamino-, amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-, or
((Ci-C4)alkyl)amino(C2-C4)alkyl)((Ci-C4)alkyl)amino-,
any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(Ci-C4)alkyl- group) is a 5-6 membered or 9-10 membered heteroaryl, wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom,
and any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(CrC4alkyl- group) is a 5-6 membered heterocycloalkyi and contains a nitrogen, oxygen or sulfur ring atom,
wherein when any of said heteroaryl or heterocycloalkyi contains a substitutable nitrogen atom, said nitrogen atom is substituted by RY, wherein
RY is hydrogen, (C C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCHRYARYB, where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-,
or RY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O and S or an oxide thereof (e.g., SO or S02);
wherein each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (CrC6)alkyl, halo(CrC6)alkyl, cyano(CrC6)alkyl, (Ci-C6)alkoxy, halo(C C6)alkoxy, (Ci-C6)alkoxy(C2-C6)alkyl-, (Ci-C6)alkoxy(C2-C6)alkoxy, hydroxy(C1-C6)alkyl-, hydroxy(C2-C6)alkoxy, amino, (C1-C6)alkylamino-,
((C1-C6)alkyl)((C1-C6)alkyl)amino-, amino(C2-C6)alkoxy, ((C1-C6)alkyl)amino(C2-C6)alkoxy, ((C C6)alkyl) ((C1-C6)alkyl)amino(C2-C6)alkoxy, (5-6 membered
heteroaryl)((C1-C6)alkyl)amino-,(5-6 membered heterocycloalkyl)((C1-C6)alkyl)amino-, hydroxy(C2-C6)alkylamino, (hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl,
hydroxy(C2-C6)alkylamino(Ci-C6)alkyl, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (hydroxy(C2-C6)alkyl)
((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-,
(hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(Ci-C6)alkyl, phenylamino-, (phenyl)((Ci-C6)alkyl)amino-, aminocarbonyl, (d-C6)alkylaminocarbonyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminocarbonyl, amino(Ci-C6)alkyl-,
(Ci-C6)alkylamino(Ci-C6)alkyl-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl-,(5-6 membered heteroaryl)amino(Ci-C6)alkyl-, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)amino(Ci-C6)alkyl-, (5-6 membered
heterocycloalkyl)((C1-C6)alkyl)amino(C1-C6)alkyl-, ((C1-C6)alkyl)amino(C2-C6)alkoxy, ((C1-C6)alkyl)((C1-C6)alkyl)amino(C2-C6)alkoxy, (C C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
heterocycloalkylsulfonyl, arylsulfonyl, arylsulfonylamino, aryloxy, aryl(C1-C6)alkyl, aryloxy(Ci-C6)alkyl, aryl(C2-C6)alkenyl, amino(C2-C6)alkylamino-,
(Ci-C6)alkoxy(C2-C6)alkylamino-, ((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heteroaryl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)amino(C2-C6)alkylamino-, (5-6 membered
heterocycloalkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heterocycloalkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heteroaryl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heterocycloalkyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered heterocycloalkyl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(C1-C6)alkyl,
((C1-C6)alkyl)((C1-C6)alkyl)amino(C2-C6)alkyl((C1-C4)alkyl)amino(C1-C6)alkyl,
((C1-C6)alkyl)amino(C2-C6)alkyl)((C1-C6)alkyl)amino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-,
aminosulfonylamino((C2-C6)alkyl)amino,
aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl, and an optionally substituted aryl, aryloxy, aryl-(Ci-C6)alkyl-, aryl-(Ci-C6)alkoxy, heteroaryl, heteroaryloxy, heteroaryl-(Ci-C6)alkyl-, heteroaryl-(Ci-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl-(Ci-C6)alkyl-, (C3-C6)cycloalkyl-(Ci-C6)alkoxy heterocycloalkyl, heterocycloalkyl-(CrC6)alkyl-, or heterocycloalkyl-(CrC6)alkoxy group, wherein any of said aryl is phenyl or naphthyl, any of said heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl and any of said
heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl,
and wherein any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (C1-C6)alkyl, aryl, halo(C1-C6)alkyl, (C1-C6)alkoxy, aryloxy, halo(C1-C6)alkoxy, hydroxy(C1-C)alkyl-, hydroxy(C2-C4)alkoxy, (C1-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy,
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C4)alkoxy, amino, (C1-C)alkylamino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino-, aminocarbonyl, (CrC)alkylaminocarbonyl, ((Ci-C)alkyl)( (Ci-C)alkyl)aminocarbonyl, amino(Ci-C)alkyl-, (Ci-C)alkylamino(Ci-C)alkyl-,
((Ci-C)alkyl)((Ci-C)alkyl)amino(Ci-C)alkyl- (C C6)alkylcarbonyl, (Ci-C6)alkoxycarbonyl, amino(C2-C)alkylamino-, ((Ci-C)alkyl)amino(C2-C)alkylamino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino(C2-C)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino((C2-C4)alkyl)amino(Ci-C4)alkyl,
((Ci-C)alkyl)amino(C2-C)alkyl((Ci-C)alkyl)amino- ,((Ci-C)alkyl)((Ci-C)alkyl)amino(C2-C)alkyl((Ci-C6)alkyl)amino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino(Ci-C4)alkyl,
(Ci-C4)alkylsulfonyl, naphthylsulfonyl, aminosulfonyl, ((Ci-C6)alkyl)aminosulfonyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonyl, aminosulfonylamino((C2-C4)alkyl)amino, aminosulfonylamino((C2-C4)alkyl)amino(Ci-C4)alkyl,
((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino,
((C1-C4)alkyl)((C1-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino(C1-C6)alkyl, piperidinyl(C1-C4)alkoxy, pyrrolidinyl(C1-C4)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(C1-C4)alkyl, ((C1-C4)alkyl)((C1-C4)alkyl)aminosulfonylpiperazinyl, ((C1-C4)alkyl)((C1-C4)alkyl)aminosulfonylpiperazinyl(C1-C4)alkyl, (C1-C4)alkylpiperazinyl, (Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, hydroxy(CrC4)alkylpiperazinyl,
hydroxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, (CrC4)alkoxypiperidinyl,
(Ci-C4)alkoxypiperidinyl(Ci-C4)alkyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl,
hydroxy(C2-C6)alkoxy(Ci-C6)alkyl, hydroxy(C2-C4)alkylamino,
hydroxy(C2-C4)alkylamino(Ci-C4)alkyl, (hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl,
(hydroxy(C2-C4)alkyl)(hydroxy(C2-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)(hydroxy(C2-C4)alkyl)amino(Ci-C4)alkyl, furanyl, benzofuranyl, pyrrolidinyl(Ci-C4)alkyl, pyrrolidinyl(Ci-C4)alkoxy, morpholinyl, morpholinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkyl, morpholinyl(Ci-C4)alkylamino,
morpholinyl(Ci-C4)alkylamino(Ci-C4)alkyl,
piperazinyl,(Ci-C4)alkylpiperazinyl(Ci-C4)alkylamino,
(Ci-C4)alkylpiperazinyl(Ci-C4)alkylamino(Ci-C6)alkyl, tetrahydropyrimidinyl, phenyl, naphthyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinyl(C1-C4)alkyl, piperidinylamino(C2-C4)alkylamino, piperidinylamino(C2-C4)alkylamino(C1-C4)alkyl, ((C1-C4)alkylpiperidinyl)(hydroxy(C2-C4)alkyl)amino(C2-C4)alkylamino,
((C1-C4)alkylpiperidinyl)(hydroxy(C2-C4)alkyl)amino(C2-C4)alkylamino(C1-C4)alkyl, aminosulfonylpiperazinyl(CrC4)alkoxy, and thienyl(Ci-C4)alkylamino,
or Q1 is a divalent (C3-C6)alkyl or -0(C2-C4)alkoxy (that is -0(C2-C4)alkyl-0-) moiety;
Q2 is hydrogen, halogen, cyano, (CrC6)alkyl, halo(CrC6)alkyl, (d-C6)alkoxy, halo(CrC6)alkoxy, amino, (Ci-C6)alkylamino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, phenylamino-, (phenyl)((Ci-C6)alkyl)amino-, aminocarbonyl, (Ci-C6)alkylaminocarbonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminocarbonyl, aminosulfonyl, (Ci-C6)alkylaminosulfonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonyl, amino(Ci-C6)alkyl-,
(Ci-C6)alkylamino(Ci-C6)alkyl-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl-,
hydroxy(CrC6)alkyl-, (CrC6)alkylcarbonyl, (Ci-C6)alkylsulfonyl, amino(C2-C6)alkylamino-, ((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-, or
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl)amino(Ci-C6)alkyl,
where Q2 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C 6)cycloalkyl-(C1-C6)alkyl-, aryl(C C6)alkyl-, -S02N(C1-C6)alkyl(C1-C6)alkyl or -COCHRYARYB, or where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (C1-C6)alkyl, and amino(C1-C6)alkyl-;
or a salt thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof, and is further directed to a pharmaceutical composition comprising the compound of Formula I, or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is further directed to a pharmaceutical composition comprising a compound of the invention. The invention is still further directed to methods of inhibiting HDAC enzymes and treatment of conditions associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention. DETAILED DESCRIPTION OF THE INVENTION
The alternative definitions for the various groups and substituent groups of Formula I provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions. As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety. Exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, f-butyl, n-pentyl, iso-pentyl (3-methyl- butyl), neo-pentyl (2,2-dimethylpropyl), etc. The term "(Ci-C4)alkyl" refers to an alkyl containing from 1 to 4 carbon atoms.
As used herein, the term "alkenyl" represents an unsaturated, straight or branched hydrocarbon moiety. Exemplary alkenyls include, but are not limited to ethylene, n- propylene, isopropylene, n-butylene, n-butyldiene, etc. The term "C2-C4" alkenyl refers to an alkyl containing from 2 to 4 carbon atoms and one or two double bonds.
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 "(C1-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, monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms and to which may be fused one or more cycloalkyl rings.
Generally, in the compounds of this invention, aryl is phenyl.
Heterocyclic groups may be heteroaryl or heterocycloalkyi groups.
"Heterocycloalkyi" represents a group or moiety comprising a stable, non-aromatic, 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. The heterocycloalkyi 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 heterocycloalkyi 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 /-/-pyrrolo[3,2-6]pyridyl group. This term specifically excludes bicyclic heterocycloalkyi 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 monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. 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. This term is also intended to encompass heterocyclic groups containing nitrogen and/or sulfur where the nitrogen or sulfur heteroatoms are optionally oxidized. Illustrative examples of heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, isobenzofuryl, 2,3- dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthridinyl, quinzolinyl, benzothiazolyl,
benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, indolinyl, cinnolinyl, pteridinyl, isothiazolyl.
Some of the heteroaryl groups present in the compounds of 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, thiazolyl, triazolyl, and tetrazolyl or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and thiadiazolyl.
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.
When any of the terms defined herein, for, example "alkyl," is used in combination with other substituent groups, such as "haloalkyl" or "cycloalkyl-alkyl" or "arylalkyl", the term is intended to encompass a divalent 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 (an alkylene or alkylenyl moiety )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 terms alkyl, aryl, cycloalkyl, heteroaryl, etc. may be used to define a divalent substituent, such as a group bonded to two other groups. In this instance, such terms are intended to encompass divalent moieties. For example, "pentyl" may be used to represent a pentylenyl diradical -wherein the pentyl moiety is any one of a divalent straight (e.g. -CH2CH2CH2CH2CH2-) or branched (e.g. -CH2CH(CH3)CH2CH2-, -CH2CH2CH(CH2CH3)-, -CH2CH2C(CH3)2-) chain 5-carbon radical.
The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo
substituents. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH. The term "oxo" is intended to mean a keto diradical (=0), such as present on a pyrrolidin-2-one ring.
The compounds of the invention are only those which are contemplated to be "chemically stable" as will be appreciated by those skilled in the art.
In one embodiment, Ar is on optionally substituted phenyl (phenylene) or
6-membered heteroaryl (heteroarylene) group, wherein said 6-membered heteroaryl contains 1 , 2 or 3 nitrogen atoms, and said optionally substituted phenyl or heteroaryl is optionally substituted by a group selected from the group consisting of (Ci-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and
-((CrC4)alkyl)NRARA, wherein each RA is independently selected from the group consisting of H and (C1-C4)alkyl. In selected embodiments, Ar is optionally substituted phenyl, pyridyl or pyrimidinyl. In specific embodiments, Ar is unsubstituted phenyl or pyridyl.
In specific embodiments of the compounds of Formula (I), each n is 1 . In selected embodiments, one n is 0 and the other n is 1 or is 2. In other embodiments, each n is 0. In other embodiments one n is 1 and the other n is 2. Generally, in the embodiments of this invention, the total number of ring atoms in this heterocycloalkyl ring (the ring modified by X and 2 n variables) is 4-7, more specifically 5-6. In specific embodiments, the total number of ring atoms in this heterocycloalkyl ring is 6, such that each n is 1 or one n is 0 and the other n is 2.
In specific embodiments of the compounds of Formula (I), k is 0. In another embodiment, k is 1 and Rx is (C C2)alkyl, halo(C C2)alkyl, -NRARA, -((C C2)alkyl)ORA, or -((CrC2)alkyl)NRARA, wherein each RA is independently selected from the group consisting of H and (CrC2)alkyl, specifically H or methyl. In a selected embodiment, k is 2 and two Rx taken together with the atoms through which they are attached form a 3-6 membered ring, that is, two Rx taken together are a bond or a -CH2-, -CH2CH2-,
-CH2CH2CH2-, -CH2CH2CH2CH2-, -NH-, -NHCH2-, -OCH2-, -CH2NHCH2-, -NHCH2CH2-, or -NHCH2CH2CH2- moiety.
More specifically, two Rx taken together with the atoms through which they are attached form a 3-5 membered ring, thereby forming a bicydic ring moiety between the Ar and the (CH2)m moieties in Formula (I). For example, a 3-azabicyclo[3.1.0]hexanyl or 2,5- diazabicyclo[2.2.1]heptanyl ring moiety is formed when k is 2 and two Rx taken together with the atoms through which they are attached form a 3-5 membered ring (that is, the two Rx taken together are a bond or -CH2-).
In one embodiment, X is CH, m is 0, 1 or 2, and Z is NRZaS02, NRZaCO, NRZb, O, or NRZaC02. In selected embodiments, X is CH, m is 0 or 1 , and Z is NRZaS02, NRZaCO, NRZb, O, or NRZaC02. In specific embodiments, X is CH, m is 0 or 1 , and Z is NRZaCO, NRZb or NRZaC02. In another embodiment, RZa is H or (C C3)alkyl. In a selected embodiment, RZa is H or methyl. In specific embodiments, RZa is H. In specific embodiments, RZb is H. In other embodiments, RZa and RZb are each H. In selected embodiments, RZb is (CrC3)alkyl ( specifically, methyl, ethyl, n-propyl or isopropyl) or -CO(Ci-C2)alkyl (specifically, -CO(CH3)).
In selected embodiments of the compounds of this invention, X is N, m is 0, and Z is S02 or a direct bond. In other selected embodiments of the compounds of this invention, X is N, m is 1 or 2 and Z is S02, CO, C02, or a direct bond.
In selected embodiments of the method of this invention, X is N, m is 0 or 1 and Z is S02, CO, C02, CONH, or a direct bond. In one embodiment, R is H or a (C1-C4)alkyl, halo(C1-C4)alkyl, aryl, heteroaryl, heterocycloalkyi, aryl(C1-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(C1-C4)alkyl- or heterocycloalkyl(C1-C4)alkyl- group, wherein:
the alkyl group or the alkyl or alkenyl moiety of the aryl(Ci-C4)alkyl-,
aryl(C2-C6)alkenyl-, heteroaryl(Ci-C4)alkyl- or heterocycloalkyl(d-C4)alkyl- group is optionally substituted by (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, hydroxy, hydroxy(C2-C4)alkylamino-,
amino(C2-C4)alkylamino-, ((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-, or
((Ci-C4)alkyl)amino(C2-C4)alkyl)((Ci-C4)alkyl)amino-;
any of said aryl (that is, the aryl group or the aryl moiety of the aryl(Ci-C4)alkyl- or aryl(C2-C4)alkenyl- group) is a phenyl or naphthyl group substituted by 1-3 Q1 groups and Q2,
any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(Ci-C4)alkyl- group) is a 5-6 membered heteroaryl or 9-10 membered heteroaryl group substituted by 1 -2 Q1 and Q2 , wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom, and any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(C1-C4alkyl- group) is a 5-6 membered heterocycloalkyi substituted by Q2 and by 1 or 2 Q1 substituents and contains a nitrogen, oxygen or sulfur ring atom;
wherein when any of said heteroaryl or heterocycloalkyi contains a substitutable nitrogen atom, said nitrogen atom is substituted by RY, wherein
RY is hydrogen, (C C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCH RYARYB, where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-,
or RY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, SO and S02.
In one embodiment, R is H or a (Ci-C4)alkyl, halo(CrC4)alkyl, aryl, heteroaryl, heterocycloalkyi, aryl(Ci-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(Ci-C4)alkyl- or heterocycloalkyl(Ci-C4)alkyl- group, wherein:
the alkyl group or the alkyl or alkyenyl moiety of the aryl(Ci-C4)alkyl-,
aryl(C2-C6)alkenyl-, heteroaryl(Ci-C4)alkyl- or heterocycloalkyl(CrC4)alkyl- group is optionally substituted by (C1-C4)alkoxy, amino, (C1-C4)alkylamino-, ((C1-C4)alkyl)((C1-C4)alkyl)amino-, hydroxy, hydroxy(C2-C4)alkylamino-, amino(C2-C4)alkylamino-, ((C1-C4)alkyl)amino(C2-C4)alkylamino-,
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C4)alkylamino-, or
((Ci-C4)alkyl)amino(C2-C4)alkyl)((Ci-C4)alkyl)amino-;
any of said aryl (that is, the aryl group or the aryl moiety of the aryl(Ci-C )alkyl- or aryl(C2-C )alkenyl- group) is phenyl substituted by 1-3 Q1 groups (Q2 is H) or naphthyl substituted by 1 -2 Q1 groups and Q2,
any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(Ci-C )alkyl- group) is a 5-6 membered heteroaryl substituted by 1-2 Q1 groups (Q2 is H) or a 9-10 membered heteroaryl substituted by 1 -2 Q1 and Q2, wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom,
and any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(Ci-C alkyl- group) is a 5-6 membered heterocycloalkyi substituted by 1-2 Q1 groups (Q2 is H) and contains a nitrogen, oxygen or sulfur ring atom,
wherein when any of said heteroaryl or heterocycloalkyi contains a substitutable nitrogen atom, said nitrogen atom is substituted by RY, wherein
RY is hydrogen, (C C4)alkyl, (C C4)alkoxy(C2-C4)alkyl-, (C3-C 6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C4)alkyl-, aryl(C C4)alkyl-, -S02N(C1-C4)alkyl(C1-C4)alkyl or
-COCHRYARYB, where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC )alkyl, and amino(C-i-C )alkyl-,
or RY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, SO and S02.
In one embodiment, R is (CrC )alkyl, halo(CrC )alkyl, aryl, heteroaryl, heterocycloalkyi, aryl(Ci-C )alkyl-, heteroaryl(Ci-C )alkyl- or heterocycloalkyl(Ci-C )alkyl- group, wherein:
any of said aryl (that is, the aryl group or the aryl moiety of the aryl(Ci-C )alkyl- group) is phenyl, substituted by 1-2 Q1 (Q2 is H), or naphthyl, substituted by Q1 and Q2, any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(Ci-C )alkyl- group) is a 5-6 membered heteroaryl substituted by Q1 or a 9-10 membered heteroaryl substituted by Q1 and Q2 , wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom, and any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(C1-C4)alkyl- group) is a 5-6 membered heterocycloalkyi substituted by Q1 and contains a nitrogen, oxygen or sulfur ring atom, wherein when any of said heteroaryl or heterocycloalkyi contains a substitutable nitrogen atom, said nitrogen atom is substituted by RY, wherein
RY is hydrogen, (C C4)alkyl, (Ci-C4)alkoxy(C2-C4)alkyl-, (C3-C 6)cycloalkyl, (C3-C6)cycloalkyl-(Ci-C4)alkyl-, aryl(C C4)alkyl-, -S02N(Ci-C4)alkyl(Ci-C4)alkyl or
-COCHRYARYB, where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC4)alkyl, and amino(Ci-C4)alkyl-,
or RY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, SO and S02.
In another embodiment, R is (CrC4)alkyl, halo(CrC4)alkyl, aryl, heteroaryl, heterocyclkoalkyl, aryl(Ci-C4)alkyl-, heteroaryl(d-C4)alkyl- or heterocycloalkyl(CrC4)alkyl- group, wherein:
any of said aryl (that is, the aryl group or the aryl moiety of the aryl(Ci-C4)alkyl- group) is phenyl substituted by Q1 or naphthyl substituted by Q1 and Q2,
any of said heteroaryl (that is, the heteroaryl group or the heteroaryl moiety of the heteroaryl(C1-C4)alkyl- group) is a 5-membered heteroaryl selected furyl (furanyl), thienyl, and pyrrolyl substituted by RY, wherein any of said 5-membered heteroaryl is substituted by Q1,
or any of said heteroaryl is a 9-10 membered heteroaryl selected from the group consisting of quinolyl, indolyl substituted by RY, benzofuranyl, and benzothienyl, wherein said any of 9-10 memebered heteroaryl is substituted by Q1 and Q2,
and any of said heterocycloalkyi (that is the heterocycloalkyi group or the heterocycloalkyi moiety of the heterocycloalkyl(Ci-C4)alkyl- group) is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, and pyrrolidinyl substituted by RY, wherein any of said heterocycloalkyi is substituted by Q1.
In one embodiment, R is H. In another embodiment, R is (CrC4)alkyl,
halo(CrC4)alkyl, aryl, heteroaryl, heterocycloalkyi, aryl(Ci-C2)alkyl-,
heteroaryl(Ci-C2)alkyl- or heterocycloalkyl(CrC2)alkyl- group, wherein:
any of said aryl is phenyl substituted by 1-2 Q1 (Q2 is H) or naphthyl substituted by
Q2,
any of said heteroaryl is a 5-membered heteroaryl selected from the group consisting of furyl (furanyl), thienyl, and pyrrolyl substituted by RY, wherein any of said 5- membered heteroaryl is substituted by Q1, or any of said heteroaryl is a 9-10 membered heteroaryl selected from the group consisting of quinolyl, indolyl substituted by RY, benzofuranyl, and benzothienyl, and wherein any of said 9-10 membered heteroaryl is substituted by Q2,
and any of said heterocycloalkyl is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, and pyrrolidinyl substituted by RY, and wherein any of said heterocycloalkyl is substituted by Q1.
In another embodiment, R is aryl or aryl(Ci-C2)alkyl-, wherein any of said aryl is phenyl substituted by Q1 or naphthyl substituted by Q2.
In one embodiment, each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, trihalo(Ci-C6)alkyl, trihalo(CrC6)alkoxy, (Ci-C6)alkyl, (d-C6)alkyl substituted with aryl or (C3-Ci0)cycloalkyl, (CrC6)alkoxy, (Ci-C6)alkoxy(C2-C6)alkoxy, (CrC6)alkylcarbonyl, (CrC6)alkoxycarbonyl,
(Ci-C6)alkylsulfonyl, cyano(CrC6)alkyl, hydroxy(CrC6)alkyl, hydroxy(C2-C6)alkoxy, hydroxy(C2-C6)alkylamino, amino(C2-C6)alkoxy, aminocarbonyl,
(Ci-C6)alkylaminocarbonyl, di((Ci-C6)alkyl)aminocarbonyl, di(hydroxy(C2-C6)alkyl)amino, (aryl)((Ci-C6)alkyl)amino, di((Ci-C6)alkyl)amino(C2-C6)alkoxy,
di((Ci-C6)alkyl)amino(C2-C6)alkylamino,
di((C1-C6)alkyl)amino(C2-C6)alkylamino(C1-C6)alkyl, arylsulfonyl, arylsulfonylamino, aryloxy, aryloxy(C1-C6)alkyl, aryl(C2-C6)alkenyl, di((C1-C6)alkyl)amino,
di((Ci-C6)alkyl)amino(Ci-C6)alkyl, di((Ci-C6)alkyl)amino((C2-C6)alkyl)amino,
di((C1-C6)alkyl)amino((C2-C6)alkyl)amino(C1-C6)alkyl,
di((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C6)alkyl)amino,
di((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C6)alkyl)amino(Ci-C6)alkyl,
aminosulfonylamino((C2-C6)alkyl)amino,
aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl,
di((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino,
di((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl, cyano, thienyl, thienyl substituted with di((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C6)alkyl)amino(Ci-C6)alkyl, di((Ci-C6)alkyl)amino(Ci-C6)alkyl, (CrC6)alkylpiperazinyl(Ci-C6)alkyl,
hydroxy(Ci-C6)alkylpiperazinyl(Ci-C6)alkyl,
hydroxy(C2-C6)alkoxy(Ci-C6)alkylpiperazinyl(Ci-C6)alkyl,
di((Ci-C6)alkyl)aminosulfonylpiperazinyl(Ci-C6)alkyl, (CrC6)alkoxypiperidinyl, (Ci-C6)alkoxypiperidinyl(Ci-C6)alkyl, morpholinyl(Ci-C6)alkyl,
hydroxy(C2-C6)alkyl((Ci-C6)alkyl)amino(Ci-C6)alkyl, or
di(hydroxy(C2-C6)alkyl)amino(Ci-C6)alkyl, furanyl, furanyl substituted with
hydroxy(C1-C6)alkyl, benzofuranyl, imidazolyl, oxazolyl, oxazolyl substituted with aryl and (C1-C6)alkyl, (C1-C6)alkyltriazolyl, tetrazolyl, pyrrolidinyl, pyrrolyl, piperidinyl(C1-C6)alkoxy, morpholinyl, (C1-C6)alkylmorpholinyl, morpholinyl(C1-C6)alkoxy, morpholinyl(C1-C6)alkyl, morpholinyl(C1-C6)alkylamino, morpholinyl(C1-C6)alkylamino(C2-C6)alkyl, piperazinyl, (Ci-C6)alkylpiperazinyl, (Ci-C6)alkylpiperazinyl(Ci-C6)alkoxy, piperazinyl(CrC6)alkyl, naphthylsulfonylpiperazinyl, naphthylsulfonylpiperidinyl, naphthylsulfonyl:
(Ci-C6)alkylpiperazinyl(Ci-C6)alkyl, (Ci-C6)alkylpiperazinyl(Ci-C6)alkylamino,
(Ci-C6)alkylpiperazinyl(Ci-C6)alkylamino(Ci-C6)alkyl, (CrC6)alkylpiperazinylsulfonyl, aminosulfonylpiperazinyl(Ci-C6)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(Ci-C6)alkyl, di((Ci-C6)alkyl)aminosulfonylpiperazinyl, di((Ci-C6)alkyl)aminosulfonylpiperazinyl(Ci-C6)alkyl, hydroxy(CrC6)alkylpiperazinyl, hydroxy(Ci-C6)alkylpiperazinyl(Ci-C6)alkyl, (CrC6)alkoxypiperidinyl,
(Ci-C6)alkoxypiperidinyl(Ci-C6)alkyl, piperidinylamino(C2-C6)alkylamino,
piperidinylamino(C2-C6)alkylamino(Ci-C6)alkyl,
((Ci-C6)alkylpiperidinyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino,
((Ci-C6)alkylpiperidinyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, hydroxy(C2-C6)alkoxy(Ci-C6)alkylpiperazinyl,
hydroxy(C2-C6)alkoxy(Ci-C6)alkylpiperazinyl(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)((C1-C6)alkyl)amino,
(hydroxy(C2-C6)alkyl)((C1-C6)alkyl)amino(C1-C6)alkyl,
hydroxy(C2-C6)alkylamino(C1-C6)alkyl, di(hydroxy(C2-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkoxy, pyrazolyl, thiopyrazolyl, pyrazolyl substituted with two substituents selected from the group consisting of (CrC6)alkyl or trihalo(Ci-C6)alkyl, pyridinyl, pyridinyl substituted with (d-C6)alkoxy, aryloxy or aryl, pyrimidinyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinyl(Ci-C6)alkyl, 3,5,5-trimethyl-1 ,5,6,7-tetrahydro-4H-indazol-4-on-1 -yl, quinolinyl, indolyl, phenyl, and phenyl substituted with one, two or three (specifically 1 or 2) substituents independently selected from the group consisting of halogen, amino, nitro, (CrC6)alkyl, (CrC6)alkoxy, hydroxy(CrC4)alkyl, trifluoromethyl, trifluoromethyloxy, hydroxy(C2-C4)alkoxy,
(Ci-C4)alkylsulfonyl, (Ci-C4)alkoxy(C2-C4)alkoxy, (Ci-C4)alkoxycarbonyl,
amino(C2-C4)alkoxy, di((Ci-C4)alkyl)amino(C2-C4)alkoxy, di((Ci-C4)alkyl)amino, di((Ci-C4)alkyl)aminocarbonyl, di((Ci-C4)alkyl)amino(Ci-C4)alkyl,
di((Ci-C4)alkyl)amino(C2-C4)alkylamino(Ci-C4)alkyl,
di((Ci-C4)alkyl)amino((C2-C4)alkyl)amino,
di((Ci-C4)alkyl)amino((C2-C4)alkyl)amino(Ci-C4)alkyl,
di((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino,
di((C1-C4)alkyl)amino(C2-C4)alkyl((C1-C4)alkyl)amino(C1-C4)alkyl, aminosulfonylamino((C2-C4)alkyl)amino,
aminosulfonylamino((C2-C4)alkyl)amino(C1-C4)alkyl,
di((C1-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino,
di((Ci-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino(Ci-C6)alkyl, cyano,
piperidinyl(CrC4)alkoxy, pyrrolidinyl(Ci-C4)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(CrC4)alkyl, di((Ci-C4)alkyl)aminosulfonylpiperazinyl,
di((Ci-C4)alkyl)aminosulfonylpiperazinyl(Ci-C4)alkyl, hydroxy(CrC4)alkylpiperazinyl, hydroxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, (CrC4)alkoxypiperidinyl,
(Ci-C4)alkoxypiperidinyl(Ci-C4)alkyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl, di(hydroxy(C2-C4)alkyl)amino, di(hydroxy(C2-C4)alkyl)amino(Ci-C4)alkyl, furanyl, benzofuranyl, pyrrolidinyl(Ci-C4)alkyl, pyrrolidinyl(Ci-C4)alkoxy, morpholinyl, morpholinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkyl, morpholinyl(Ci-C4)alkylamino, morpholinyl(Ci-C4)alkylamino(Ci-C4)alkyl, piperazinyl, (Ci-C4)alkylpiperazinyl, (Ci-C4)alkylpiperazinyl(Ci-C4)alkoxy, piperazinyl(d-C4)alkyl, (Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, (Ci-C4)alkylpiperazinyl(Ci-C4)alkylamino,
(C1-C4)alkylpiperazinyl(C1-C4)alkylamino(C1-C6)alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinyl(C1-C4)alkyl, piperidinylamino(C2-C4)alkylamino, pipendinylamino(C2-C4)alkylamino(C1-C4)alkyl,
((C1-C4)alkylpiperidinyl)(hydroxy(C2-C4)alkyl)amino(C2-C4)alkylamino,
((Ci-C4)alkylpiperidinyl)(hydroxy(C2-C4)alkyl)amino(C2-C4)alkylamino(Ci-C4)alkyl, pyridinyl(Ci-C4)alkoxy, hydroxy(C2-C4)alkylamino, hydroxy(C2-C4)alkylamino(Ci-C4)alkyl, di((Ci-C4)alkyl)amino(C2-C4)alkylamino, aminothiadiazolyl,
aminosulfonylpiperazinyl(Ci-C4)alkoxy, and thienyl(Ci-C4)alkylamino.
In another embodiment, each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, trihalo(CrC6)alkyl,
trihalo(Ci-C6)alkoxy, (C C6)alkyl, (C C6)alkoxy, (Ci-C6)alkoxy(C2-C6)alkoxy,
(Ci-C6)alkylcarbonyl, (CrC6)alkylsulfonyl, cyano(CrC6)alkyl, hydroxy(C2-C6)alkyl, hydroxy(C2-C6)alkoxy, hydroxy(C2-C6)alkylamino, amino(C2-C6)alkoxy, aminocarbonyl, (Ci-C6)alkylaminocarbonyl, di((Ci-C6)alkyl)aminocarbonyl, di(hydroxy(C2-C6)alkyl)amino, di((Ci-C6)alkyl)amino(C2-C6)alkoxy, di((Ci-C6)alkyl)amino(C2-C6)alkylamino, arylsulfonyl, arylsulfonylamino, aryloxy, aryl(C2-C6)alkenyl, di((Ci-C6)alkyl)amino, cyano, thienyl, thienyl substituted with di((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C6)alkyl)amino(Ci-C6)alkyl, di((Ci-C6)alkyl)amino(Ci-C6)alkyl, (Ci-C6)alkylpiperazinyl(Ci-C6)alkyl or
di(hydroxy(C2-C6)alkyl)amino(C1-C6)alkyl, furanyl, imidazolyl, (C1-C6)alkyltriazolyl, tetrazolyl, piperidinyl(C1-C6)alkoxy, morpholinyl, (C1-C6)alkylmorpholinyl, morpholinyl(C1-C6)alkoxy, morpholinyl(C1-C6)alkyl, (C1-C6)alkylpiperazinyl(C1-C6)alkoxy, (C1-C6)alkylpiperazinyl(C1-C6)alkyl, (C1-C6)alkylpiperazinylsulfonyl,
aminosulfonylpiperazinyl(CrC6)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(CrC6)alkyl, di((Ci-C6)alkyl)aminosulfonylpiperazinyl, di((Ci-C6)alkyl)aminosulfonylpiperazinyl(Ci-C6)alkyl, hydroxy(CrC6)alkylpiperazinyl, hydroxyCi-alkylpiperazinyl(CrC6)alkyl, (CrC6)alkoxypiperidinyl,
(Ci-C6)alkoxypiperidinyl(Ci-C6)alkyl, hydroxy(C2-C6)alkoxy(Ci-C6)alkylpiperazinyl, hydroxy(C2-C6)alkoxy(Ci-C6)alkylpiperazinyl(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl, pyrrolidinyl(Ci-C6)alkoxy, pyrazolyl, pyrazolyl substituted with two substituents selected from the group consisting of
(Ci-C6)alkyl and trihalo(C C6)alkyl, 3,5,5-trimethyl-1 ,5,6,7-tetrahydro-4H-indazol-4-on-1- yl, pyridinyl, pyridinyl substituted with (d-C6)alkoxy or aryl, pyrimidinyl, quinolinyl, phenyl, phenyl substituted with one, two or three substituents independently selected from the group consisting of halogen, amino, (CrC6)alkyl, (Ci-C6)alkoxy, hydroxy(CrC4)alkyl, trifluoromethyl, trifluoromethyloxy, hydroxy(C2-C4)alkoxy, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, di((C1-C4)alkyl)amino(C2-C4)alkoxy, di((C1-C4)alkyl)amino, piperidinyl(C1-C4)alkoxy, pyrrolidinyl(C1-C4)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(C1-C4)alkyl, di((C1-C4)alkyl)aminosulfonylpiperazinyl, di((C1-C4)alkyl)aminosulfonylpiperazinyl(C1-C4)alkyl, hydroxy(C1-C4)alkylpiperazinyl, hydroxy(Ci-C4)alkylpiperazinyl(CrC4)alkyl, (CrC4)alkoxypiperidinyl,
(Ci-C4)alkoxypiperidinyl(CrC4)alkyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl, pyrrolidinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkyl, (Ci-C4)alkylpiperazinyl(CrC4)alkoxy, (Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, hydroxy(C2-C4)alkylamino,
di(hydroxy(C2-C4)alkyl)amino, di((Ci-C4)alkyl)amino(C2-C4)alkylamino, aminothiadiazolyl, aminosulfonylpiperazinyl(Ci-C4)alkoxy,and thienyl(Ci-C4)alkylamino.
In a further embodiment, each Q1 is independently hydrogen, halogen, hydroxy, amino, nitro, trihalo(Ci-C6)alkyl, trihalo(CrC6)alkoxy, (Ci-C6)alkyl, (CrC6)alkoxy,
(Ci-C6)alkylcarbonyl, (CrC6)alkoxycarbonyl, aminocarbonyl, (Ci-C6)alkylaminocarbonyl, di((Ci-C6)alkyl)aminocarbonyl, (CrC6)alkylsulfonyl, hydroxy(CrC6)alkyl, aryloxy, di((Ci-C6)alkyl)amino, cyano, thienyl, furanyl, furanyl substituted with hydroxy(CrC6)alkyl, benzofuranyl, imidazolyl, oxazolyl, oxazolyl substituted with aryl and (C1-C6)alkyl, (C1-C6)alkyltriazolyl, tetrazolyl, pyrrolidinyl, pyrrolyl, morpholinyl, (C1-C6)alkylmorpholinyl, piperazinyl, (C1-C6)alkylpiperazinyl, hydroxy(C1-C6)alkylpiperazinyl,
(C1-C6)alkoxypiperidinyl, pyrazolyl, pyrazolyl substituted with one or two substituents selected from the group consisting of (CrC6)alkyl or trihalo(Ci-C6)alkyl, 3,5,5-trimethyl- 1 ,5,6,7-tetrahydro-4/-/-indazol-4-on-1 -yl, pyridinyl, pyridinyl substituted with (Ci-C6)alkoxy, aryloxy or aryl, pyrimidinyl, quinolinyl, indole, phenyl, or phenyl substituted with one or two substituents independently selected from the group consisting of halogen, (d-C6)alkyl, (Ci-C6)alkoxy and trifluoromethyl.
In a still further embodiment, each Q1 is independently hydrogen, halogen, nitro, trihalo(Ci-C6)alkyl, trihalo(C C6)alkoxy, (Ci-C6)alkyl, (C C6)alkoxy, (C C6)alkylsulfonyl, (aryl)((Ci-C6)alkyl)amino, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
di((Ci-C4)alkyl)aminocarbonyl, arylsulfonyl, aryloxy, aryl(C2-C6)alkenyl,
di((Ci-C6)alky)amino, thienyl, thienyl substituted with
di((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C6)alkyl)amino(Ci-C6)alkyl,
di((Ci-C6)alkyl)amino(Ci-C6)alkyl, (Ci-C6)alkylpiperazinyl(Ci-C6)alkyl,
hydroxy(Ci-C6)alkylpiperazinyl(Ci-C6)alkyl, hydroxy(C2-C6)alkoxy(Ci-C6)alkylpiperazinyl- (Ci-C6)alkyl-, di((Ci-C6)alkyl)aminosulfonylpiperazinyl(Ci-C6)alkyl,
(C1-C6)alkoxypiperidinyl(C1-C6)alkyl, morpholinyl(C1-C6)alkyl,
hydroxy(C2-C6)alkyl((C1-C6)alkyl)amino(C1-C6)alkyl, or
di(hydroxy(C2-C6)alkyl)amino(C1-C6)alkyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, 3,5,5- trimethyl-1 ,5,6,7-tetrahydro-4H-indazol-4-on-1-yl, pyridinyl, pyridinyl substituted with
(Ci-C6)alkoxy, quinolinyl, indolyl, phenyl, or phenyl substituted with one, two or three substituents independently selected from the group consisting of halogen, amino,
(Ci-C6)alkyl, (CrC6)alkoxy, hydroxy(Ci-C4)alkyl, trifluoromethyl, trifluoromethyloxy, di((Ci-C4)alkyl)amino(C2-C4)alkoxy, di((Ci-C4)alkyl)amino,
di((Ci-C4)alkyl)amino(Ci-C4)alkyl, di((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino, di((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino(Ci-C4)alkyl,
hydroxy(Ci-C4)alkylpiperazinyl(CrC4)alkyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkyl piperazinyl (Ci-C4)alkyl, di(hydroxy(C2-C4)alkyl)amino(Ci-C4)alkyl, pyrrolidinyl(Ci-C4)alkyl, pyrrolidinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkyl, and
(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl.
In yet another embodiment, each Q1 is independently hydrogen, thienyl, thienyl substituted with di((Ci-C6)alkyl)amino(Ci-C6)alkyl, or (Ci-C6)alkylpiperazinyl(CrC6)alkyl, furanyl, phenyl, phenyl substituted with one substituent selected from the group consisting of di((Ci-C4)alkyl)amino(C2-C4)alkoxy, di((Ci-C4)alkyl)amino,
di((Ci-C4)alkyl)amino(Ci-C4)alkyl, di((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino(Ci-C4)alkyl, 3,5,5-trimethyl-1 , 5,6,7- tetrahydro-4H-indazol-4-on-1 -yl, pyrrolidinyl(C1-C4)alkyl, pyrrolidinyl(C1-C4)alkoxy or (C1-C4)alkylpiperazinyl(C1-C4)alkyl.
In a further embodiment, each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (CrC6)alkyl, halo(CrC6)alkyl,
(Ci-C6)alkoxy, halo(CrC6)alkoxy, (Ci-C6)alkoxy(C2-C6)alkyl-, hydroxy(CrC4)alkyl-, amino, (Ci-C4)alkylamino-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, phenylamino-,
(phenyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
((Ci-C4)alkyl)((Ci-C4)alkyl)aminocarbonyl, amino(Ci-C6)alkyl-,
(Ci-C4)alkylamino(Ci-C6)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl-,
(Ci-C6)alkylcarbonyl, (d-C6)alkoxycarbonyl, (Ci-C6)alkylsulfonyl, amino(C2-C6)alkylamino, (Ci-C6)alkoxy(C2-C6)alkylamino-, ((Ci-C4)alkyl)amino(C2-C6)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C6)alkylamino-,
((Ci-C4)alkyl)amino(Ci-C4)alkyl)((C2-C6)alkyl)amino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl)amino(Ci-C4)alkyl, and an optionally substituted aryl, aryloxy, aryl-(Ci-C6)alkyl-, aryl-(Ci-C6)alkoxy, heteroaryl, heteroaryloxy, heteroaryl-(Ci-C6)alkyl-, heteroaryl-(Ci-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl-(C1-C6)alkyl-, (C3-C6)cycloalkyl-(C1-C6)alkoxy heterocycloalkyl, heterocycloalkyl-(C1-C6)alkyl-, or heterocycloalkyl-(C1-C6)alkoxy group,
wherein any of said aryl is phenyl or naphthyl, any of said heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl and any of said
heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl,
and wherein any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (Ci-C6)alkyl, halo(CrC6)alkyl,
(Ci-C6)alkoxy, halo(CrC6)alkoxy, hydroxy(CrC4)alkyl-, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
((Ci-C4)alkyl)((Ci-C4)alkyl)aminocarbonyl, amino(Ci-C4)alkyl-,
(Ci-C4)alkylamino(Ci-C4)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl-,
(Ci-C6)alkylcarbonyl, (CrC6)alkoxycarbonyl, amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkyl)((Ci-C4)alkyl)amino-, and
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl) amino(Ci-C4)alkyl.
In one embodiment, each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, (C1-C4)alkyl, halo(Ci-C3)alkyl, (C1-C4)alkoxy, halo(C1-C2)alkoxy, (C1-C4)alkoxy(C2-C4)alkyl-, hydroxy(C1-C4)alkyl-, amino,
(C1-C4)alkylamino-, ((C1-C4)alkyl)((C1-C4)alkyl)amino-, phenylamino-,
(phenyl)((C1-C4)alkyl)amino-, aminocarbonyl, (C1-C4)alkylaminocarbonyl, ((d-C4)alkyl)( (Ci-C )alkyl)aminocarbonyl, amino(Ci-C )alkyl-, (Ci-C )alkylamino(Ci-C )alkyl-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl-, (C C4)alkylcarbonyl,
(Ci-C )alkoxycarbonyl, amino(C2-C )alkylamino-, (Ci-C )alkoxy(C2-C )alkylamino-, ((Ci-C )alkyl)amino(C2-C )alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C )alkyl)amino(Ci-C )alkyl)((C2-C )alkyl)amino-, and
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl)amino(Ci-C4)alkyl.
In one embodiment, Q1 is phenyl or a 5-6 membered monocyclic heteroaryl, wherein said phenyl or heteroaryl is optionally substituted by 1-2 substituents each independently selected from the group consisting of halogen, cyano, (Ci-C )alkyl, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C )alkoxy, 5-6 membered heterocycloalkyl- (Ci-C )alkyl-, 5-6 membered heterocycloalkyl-(Ci-C )alkoxy, amino, (Ci-C )alkylamino-, ((Ci-C )alkyl)((Ci-C )alkyl)amino-, aminocarbonyl, (Ci-C )alkylaminocarbonyl,
((Ci-C )alkyl)( (Ci-C )alkyl)aminocarbonyl, amino(Ci-C )alkyl-,
(C1-C4)alkylamino(C1-C4)alkyl-, ((C1-C4)alkyl)((C1-C4)alkyl)amino(C1-C4)alkyl-,
hydroxy(C1-C4)alkyl-, (C1-C4)alkylcarbonyl, amino(C2-C4)alkylamino-,
((C1-C4)alkyl)amino(C2-C4)alkylamino, ((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C4)alkylamino-, ((C1-C4)alkyl)amino(C2-C4)alkyl)((C1-C4)alkyl)amino-, and
((Ci-C )alkyl)((Ci-C )alkyl)amino(C2-C )alkyl)amino(Ci-C )alkyl, wherein any of said 5-6 membered heterocycloalkyl is optionally substituted by 1-2 (Ci-C )alkyl groups.
In one embodiment, Q1 is a 9-10 membered, bicyclic heteroaryl, optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, cyano, (Ci-C )alkyl, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C )alkoxy, oxo, amino, (Ci-C )alkylamino-, ((Ci-C )alkyl)((Ci-C )alkyl)amino-, aminocarbonyl,
(Ci-C )alkylaminocarbonyl, ((Ci-C )alkyl)( (Ci-C )alkyl)aminocarbonyl, amino(Ci-C )alkyl-, (Ci-C4)alkylamino(Ci-C4)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C C4)alkyl-,
hydroxy(Ci-C )alkyl-, (Ci-C )alkylcarbonyl, amino(C2-C )alkylamino-,
((Ci-C )alkyl)amino(C2-C )alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C )alkyl)amino(C2-C )alkyl)((Ci-C )alkyl)amino-, and
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl)amino(Ci-C4)alkyl.
In another embodiment Q1 is a divalent -CH2CH2CH2-, -CH2CH2CH2CH2-,
-OCH20- or -OCH2CH20- moiety. In another embodiment, when RY and Q1 taken together with the atoms thru which they are connected form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, S(=0), and S(=0)2, then RY and Q1 taken together are a divalent -CH2CH2-, -CH2CH2CH2-,
-CH2CH2CH2CH2-, -CH2CH2NH-, -CH2CH20-, -CH2CH2S(=0)2- or - S(=0)2CH2CH2- moiety.
In yet another embodiment, Q1 is selected from the group consisting of hydrogen, thienyl, thienyl substituted with ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl, or (Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, furanyl, phenyl, and phenyl substituted with one substituent selected from the group consisting of
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkoxy, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino(Ci-C4)alkyl, 3,5,5- trimethyl-1 ,5,6,7-tetrahydro-4H-indazol-4-on-1-yl, pyrrolidinyl(Ci-C4)alkyl,
pyrrolidinyl(Ci-C4)alkoxy and (Ci-C4)alkylpiperazinyl(Ci-C4)alkyl.
In a further embodiment, Q1 is hydrogen, halogen, hydroxy, amino, nitro, halo(CrC6)alkyl, halo(Ci-C6)alkoxy, (C C6)alkyl, (C C6)alkoxy, (Ci-C6)alkylcarbonyl, (Ci-C6)alkoxycarbonyl, hydroxy(CrC6)alkyl, aryloxy, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, cyano, thienyl, furanyl, furanyl substituted with hydroxy(C1-C6)alkyl-, benzofuranyl, imidazolyl, oxazolyl, oxazolyl substituted with aryl and/or (C1-C6)alkyl, (C1-C6)alkyltriazolyl, tetrazolyl, pyrrolidinyl, pyrrolyl, morpholinyl, (C1-C6)alkylmorpholinyl, piperazinyl,
(C1-C6)alkylpiperazinyl, hydroxy(C1-C6)alkylpiperazinyl, (C1-C6)alkoxypiperidinyl, pyrazolyl, pyrazolyl substituted with one or two substituents selected from the group consisting of (Ci-C6)alkyl and halo(C C6)alkyl, 3,5,5-trimethyl-1 ,5,6,7-tetrahydro-4H-indazol-4-on-1 -yl, pyridinyl, pyridinyl substituted with (d-C6)alkoxy, aryloxy or aryl, pyrimidinyl, quinolyl, indolyl, phenyl, or phenyl substituted with one or two substituents each independently selected from the group consisting of halogen, (CrC6)alkyl, (CrC6)alkoxy and
trifluoromethyl.
In one embodiment of this invention, each Q1 is H. In other specific embodiments of this invention, R is phenyl substituted by two Q1 groups, wherein one Q1 group is
Figure imgf000029_0001
and the other Q1 group is selected from the group consisting of
(Ci-C4)alkyl, aminocarbonyl, (Ci-C4)alkylaminocarbonyl, and ((C1-C4)alkyl)((C1-C4)alkyl)aminocarbonyl (specifically, the other Q1 group is
aminocarbonyl).
In one embodiment, Q2 is hydrogen, halogen, cyano, (Ci-C4)alkyl,
halo(Ci-C )alkyl, (Ci-C)alkoxy, halo(Ci-C )alkoxy, amino, (Ci-C )alkylamino-,
((Ci-C)alkyl)((Ci-C )alkyl)amino-, phenylamino-, (phenyl)((Ci-C )alkyl)amino-, aminocarbonyl, (Ci-C )alkylaminocarbonyl, ((Ci-C )alkyl)((Ci-C)alkyl)aminocarbonyl, aminosulfonyl, (Ci-C )alkylaminosulfonyl, ((Ci-C)alkyl)((Ci-C )alkyl)aminosulfonyl, amino(Ci-C )alkyl-, (Ci-C )alkylamino(Ci-C )alkyl-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl-, hydroxy(C C4)alkyl-, (C C4)alkylcarbonyl, (Ci-C)alkylsulfonyl, amino(C2-C )alkylamino-, ((Ci-C )alkyl)amino(C2-C )alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C)alkyl)amino(C2-C )alkyl)((Ci-C)alkyl)amino-, or
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl)amino(Ci-C4)alkyl.
In a further embodiment, Q2 is hydrogen, halogen, cyano, (CrC)alkyl, halo(Ci-C )alkyl, (Ci-C)alkoxy, halo(Ci-C )alkoxy, amino, (Ci-C )alkylamino-,
((Ci-C)alkyl)((Ci-C )alkyl)amino-, phenylamino-, (phenyl)((Ci-C )alkyl)amino-, aminocarbonyl, (Ci-C )alkylaminocarbonyl, ((Ci-C )alkyl)((Ci-C)alkyl)aminocarbonyl, amino(C1-C4)alkyl-, (C1-C4)alkylamino(C1-C4)alkyl-,
((C1-C4)alkyl)((C1-C4)alkyl)amino(C1-C4)alkyl-, hydroxy(C C4)alkyl-, (C C4)alkylcarbonyl, amino(C2-C4)alkylamino-, ((C1-C4)alkyl)amino(C2-C4)alkylamino-,
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C)alkyl)amino(C2-C )alkyl)((Ci-C)alkyl)amino-, or
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl)amino(Ci-C4)alkyl.
In one embodiment, Q2 is hydrogen, halogen, cyano, (Ci-C)alkyl,
halo(Ci-C )alkyl, (Ci-C)alkoxy, halo(Ci-C )alkoxy, (Ci-C)alkylcarbonyl, amino,
(Ci-C)alkylamino-, ((Ci-C)alkyl)((Ci-C )alkyl)amino-, amino(Ci-C )alkyl-,
(Ci-C4)alkylamino(Ci-C4)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C C4)alkyl-,
phenylamino-, (phenyl)((Ci-C )alkyl)amino-, aminocarbonyl (H2NC(=0)-),
(Ci-C)alkylaminocarbonyl, or ((Ci-C )alkyl)((Ci-C)alkyl)aminocarbonyl. In a further embodiment, Q2 is a divalent -OCH20- or -OCH2CH20- moiety. In a further embodiment, Q2 is hydrogen, halogen, (Ci-C2)alkyl, -CF3, (Ci-C2)alkoxy or
((Ci-C)alkyl)((Ci-C )alkyl)amino-, wherein any of said 5-6 membered heterocycloalkyi is optionally substituted by 1-2 (Ci-C)alkyl groups. In specific embodiments, Q2 is hydrogen or methyl.
In another embodiment, R is indolyl, optionally substituted by Q2. The invention is further directed to a compound according to Formula (l-a):
Figure imgf000031_0001
wherein:
A1 and A2 are each independently selected from the group consisting of CH and N; each n is independently 0, 1 or 2;
m is 0, 1 or 2 and X is N or CH, wherein
when m is 0, 1 or 2 and X is CH, then Z is NHS02, NHCO, NH, O, or NHC02,
when m is 0 and X is N, then Z is S02 or a direct bond, or
when m is 1 or 2 and X is N, then Z is S02, CO, C02, CONH, or a direct bond; and
R is (CrC4)alkyl, halo(Ci-C4)alkyl, or a group selected from the group consisting
Figure imgf000031_0002
wherein Q1 and Q2 are as defined herein and may be substituted on either ring of the illustrated bicyclic group;
Y is O, S or NRY,
where RY is hydrogen, (d-C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C 6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCHRYARYB, or where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-; or when Y is NRY (that is, R is indolyl) and Q2 is in the 7 position of the indolyl, then Q2 and RY taken together with the atoms through which they are attached to form a 5 or 6 membered ring.
In a further embodiment, RY is hydrogen, (d-C6)alkyl, (Ci-C6)alkoxyC2-6alkyl-, C3-6cycloalkyl, C3-6cycloalkyl-Ci-3alkyl-, phenyl-Ci-3alkyl-, or (Ci-C6)alkylcarbonyk In another embodiment, RY is hydrogen., (CrC5)alkyl, (Ci-C3)alkoxyC2-4alkyl-, C3-6cycloalkyl, C3-6cycloalkyl-Ci-2alkyl-, or benzyl. In specific embodiments, RY is H or methyl.
In selected embodiments of the compounds of Formula (l-a), R is selected from the group consisting of:
Figure imgf000032_0001
wherein Y is O, S or NRY, wherein RY Q1 and Q2 are as defined herein and Q2 may be substituted on either ring of the illustrated bicyclic group.
Specifically, the invention is directed to a compound according to Formula (l-b):
Figure imgf000032_0002
(l-b) wherein:
A1 is N and A2 is CH or N;
m is 0, 1 or 2 and X is CH or N, wherein:
when m is 0, 1 or 2, and X is CH, then Z is NHS02, NHCO, NH, O, or NHC02,
when m is 0 and X is N, then Z is S02 or a direct bond,
or when m is 1 or 2 and X is N, then Z is S02, CO, C02, CONH, or a direct bond;
p is 0 or 1 ; and R' is phenyl, naphthyl, furyl (furanyl), thienyl, quinolyl, indolyl substituted by RY, benzofuranyl, or benzothienyl, substituted by Q1 or Q2 as defined/illustrated herein.
In a further embodiment, the invention is directed to a compound according to Formula l-c) or (l-d):
Figure imgf000033_0001
wherein:
A1 is N and A2 is CH or N;
m is 0 or 1 ;
when m is 0 or 1 and X is CH, then Z is NH or O,
when m is 0 and X is N, then Z is S02 or a direct bond;
p is 0 or 1 ;
and RY and Q2 as defined herein.
In a further embodiment, the invention is directed to a compound according to any one of Formula (l-e):
Figure imgf000033_0002
wherein:
A1 is N and A2 is CH or N;
m is 0 or 1 ;
when m is 0, Z is S02 or a direct bond;
when m is 1 , Z is S02, CO, C02, CONH, or a direct bond;
p is 0 or 1 ;
and RQA is hydrogen, halogen, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(CrC4)alkoxy, 5-6 membered heterocycloalkyl-(Ci-C4)alkyl-, 5-6 membered heterocycloalkyl-(Ci-C4)alkoxy, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
((Ci-C4)alkyl)( (Ci-C4)alkyl)aminocarbonyl, amino(Ci-C4)alkyl-,
(Ci-C4)alkylamino(Ci-C4)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C C4)alkyl-,
hydroxy(Ci-C4)alkyl-, (Ci-C4)alkylcarbonyl, amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino((C2-C4)alkyl)((Ci-C4)alkyl)amino-, or
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino(Ci-C4)alkyl-;
and RQB is hydrogen, halogen, cyano, (C1-C4)alkyl, halo(CrC4)alkyl, (d-C4)alkoxy, or halo(C1-C4)alkoxy. In specific embodiments, RQB is hydrogen.
As used herein, the terms "compound(s) of the invention" or "compound(s) of this invention" mean 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 salt, particularly 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, solvate forms, including hydrate forms (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., cycloalkyl, heterocycle, and heteroaryl rings) and groups or rings substituted with one or more specified substituents.
The compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula I containing one or more chiral centers may be used as racemic mixtures, scalemic mixtures, or as diaseteromerically or enantiomerically pure materials.
Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer- specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
Because of their potential use in medicine, the salts of the compounds of
Formula I are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse,
J.Pharm.Sci (1977) 66, pp 1 -19. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Typically, a salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
When a compound of the invention is a base (contain a basic moiety), a desired salt form may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like, or with a pyranosidyl acid, such as glucuronic acid or galacturonic acid, or with an alpha-hydroxy acid, such as citric acid or tartaric acid, or with an amino acid, such as aspartic acid or glutamic acid, or with an aromatic acid, such as benzoic acid or cinnamic acid, or with a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like.
Suitable addition salts are formed from acids which form non-toxic salts and examples include acetate, p-aminobenzoate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, dihydrochloride, hydrofumarate, hydrogen phosphate, hydroiodide, hydromaleate, hydrosuccinate, hydroxynaphthoate, isethionate, itaconate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmate, palmitate, pantothenate, phosphate/diphosphate, pyruvate, polygalacturonate, propionate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate and valerate.
Other exemplary acid addition salts include pyrosulfate, sulfite, bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suberate, sebacate, butyne-1 ,4-dioate, hexyne-1 ,6-dioate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutrate, lactate, γ-hydroxybutyrate, mandelate, and sulfonates, such as xylenesulfonate, propanesulfonate, naphthalene-1 -sulfonate and naphthalene-2-sulfonate.
If an inventive basic compound is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound.
When a compound of the invention is an acid (contains an acidic moiety), a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like.
Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as N-methyl-D-glucamine, diethylamine, isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
Certain of the compounds of this invention may form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or a base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.
Compounds of the invention having both a basic and acidic moiety may be in the form of zwitterions, acid-addition salt of the basic moiety or base salts of the acidic moiety.
This invention also provides for the conversion of one pharmaceutically acceptable salt of a compound of this invention, e.g., a hydrochloride salt, into another
pharmaceutically acceptable salt of a compound of this invention, e.g., a sulfate salt.
For solvates of the compounds of Formula I, or salts thereof that are in crystalline form, the skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as
"hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
Because the compounds of Formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. The compounds of this invention may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist. The synthesis provided in these Schemes are applicable for producing compounds of the invention having a variety of different substituent groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of Formula I, they are illustrative of processes that may be used to make the compounds of the invention.
Intermediates (compounds used in the preparation of the compounds of the invention) may also be present as salts. Thus, in reference to intermediates, the phrase "compound(s) of formula (number)" means a compound having that structural formula or a pharmaceutically acceptable salt thereof.
Specific compounds of this invention are the compounds of Examples 1 -33, including salts, particularly pharmaceutically acceptable salts, thereof.
Other compounds that may be prepared using the methods described herein include:
1-(6-fluoro-1-methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1-methyl-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)ethanamine;
1-(1 ,6-dimethyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
3-(2-(4-((3'-((4-methylpiperazin-1-yl)methyl)-[1 , 1 '-biphenyl]-4-yl)sulfonyl)piperazin- 1-yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole;
1-(5-fluoro-1-propyl-1 H-indol-3-yl)-N-((3-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)-3-azabicyclo[3.1 .0]hexan-6-yl)methyl)methanamine;
1-(5-chloro-1 -propyl-1 H-indol-3-yl)-N-((3-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)-3-azabicyclo[3.1 .0]hexan-6-yl)methyl)methanamine;
1-methyl-3-((((3-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)-3- azabicyclo[3.1.0]hexan-6-yl)methyl)amino)methyl)-1 H-indole-5-carbonitrile;
1-(5-fluoro-1-methyl-1 H-indol-3-yl)-N-((3-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)-3-azabicyclo[3.1 .0]hexan-6-yl)methyl)methanamine;
1 -(5-chloro-1 -methyl-1 H-indol-3-yl)-N-((3-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)-3-azabicyclo[3.1 .0]hexan-6-yl)methyl)methanamine; 1-(1-methyl-1 H-indol-3-yl)-N-((3-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)-3-azabicyclo[3.1 .0]hexan-6-yl)methyl)methanamine;
1 -(1 -methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1 -methyl-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)ethanamine;
1-(6-fluoro-1 -methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 , 2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1 ,6-dimethyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3^ yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(5-iodo-1-methyl-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol^ yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1-methyl-6-(trifluoromethyl)-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)^ oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
N-((1 -methyl-1 H-indol-3-yl)methyl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)acetamide;
N-((1 -methyl-1 H-indol-3-yl)methyl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)ethanamine;
N-methyl-1 -(1 -methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1-propyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1 -(1 -ethyl-6-methoxy-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(5,6-dimethoxy-1 -methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(5-methyl-5H-[1 ,3]dioxolo[4,5-f]indol-7-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(4-chloro-1 -methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2, 4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1 -(6-chloro-1 -methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-methyl-3-((((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin- 4-yl)methyl)amino)methyl)-1 H-indole-5-carbonitrile;
1-(1-benzyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine; 1-(5-fluoro-1-isopropyl-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(5-fluoro-1-propyl-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(5-fluoro-1-methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1-(cyclopropylmethyl)-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1-(2-methoxyethyl)-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1-cyclopentyl-1 H-indol-3-yl)-N-((H^^
yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(5-fluoro-1-methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)-N- ((1 ,2,5-trimethyl-1 H-indol-3-yl)methyl)methanamine;
1-(5-chloro-1 ,2-dimethyl-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(4-fluoro-1-methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(7-fluoro-1-methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(5-fluoro-1-methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)-N- ((1 ,2,5-trimethyl-1 H-indol-3-yl)methyl)methanamine;
1-(5-chloro-1 ,2-dimethyl-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(4-fluoro-1-methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(7-fluoro-1-methyl-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine;
1-(5-methoxy-1-methyl-1 H-indol-3-yl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazo^ 3-yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine;
N-((1-methyl-1 H-indol-3-yl)methyl)-N-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazo^ yl)pyridin-2-yl)piperidin-4-yl)methyl)ethanamine; 1-(4-fluoro-1-(pentan-3-yl)-1 H-indol-3-yl)-N-((1 -(5-(5-(trifluoromethyl)-1 ,2,^ oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine;
(E)-4-(4-fluorophenyl)-2-(4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazin-1 -yl)but-3-en-1 -ol;
(E)-4-phenyl-2-(4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazin-1 -yl)but-3-en-1 -ol;
(E)-4-phenyl-2-(((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperidin-4-yl)methyl)amino)but-3-en-1 -ol;
(E)-4-phenyl-2-((1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperidin-4-yl)amino)but-3-en-1 -ol;
(E)-N-methyl-4-phenyl-2-(4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazin-1 -yl)but-3-enamide;
(E)-1 -morpholino-4-phenyl-2-(4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperazin-1 -yl)but-3-en-1 -one;
(E)-4-(4-phenyl-2-(4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazin-1 -yl)but-3-en-1 -yl)morpholine;
(E)-3-(2-(4-(1 -(4-methylpiperazin-1-yl)-4-phenylbut-3-en-2-yl)piperazin-1- yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole;
3-(2-(4-(naphthalen-2-ylsulfonyl)piperazin-1 -yl)pyrimidin-5-yl)-5-(trifluorometh 1 ,2,4-oxadiazole;
3-(2-(4-(naphthalen-2-ylmethyl)piperazin-1 -yl)pyrimidin-5-yl)-5-(trifluoromethyl)- 1 ,2,4-oxadiazole;
N-methyl-N-phenyl-6-((4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazin-1 -yl)sulfonyl)naphthalen-2-amine;
N,N-dimethyl-6-((4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazin-1 -yl)sulfonyl)naphthalen-2-amine;
N,N-dimethyl-1 -(1 -(naphthalen-2-ylsulfonyl)-4-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyrimidin-2-yl)piperazin-2-yl)methanamine;
(1 -(naphthalen-2-ylsulfonyl)-4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin- 2-yl)piperazin-2-yl)methanol;
3-(2-(4-(quinolin-7-ylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-5-(trifluoromethyl^^ oxadiazole;
3-(2-((1 S,4S)-5-(naphthalen-2-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole;
3-(4-ethoxy-2-(4-(naphthalen-2-ylsulfonyl)piperazin-1 -yl)pyrimidin-5-yl)-5- (trifluoromethyl)-1 ,2,4-oxadiazole; 3-(6-(4-([1 , 1 '-biphenyl]-4-ylsulfonyl)piperazin-1 -yl)pyridin-3-yl)-5-(trifluoromethyl)- 1 ,2,4-oxadiazole;
3-(6-(4-(naphthalen-2-ylsulfonyl)piperazin-1 -yl)pyridin-3-yl)-5-(trifluoromethyl)- 1 ,2,4-oxadiazole;
3-(6-(4-(naphthalen-2-ylmethyl)piperazin-1 -yl)pyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole;
N,N-dimethyl-1 -(1 -(naphthalen-2-ylsulfonyl)-4-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyridin-2-yl)piperazin-2-yl)methanamine;
3-(6-(4-(quinolin-7-ylsulfonyl)piperazin-1-yl)pyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole;
3-(6-(4-([1 , 1 '-biphenyl]-4-ylsulfonyl)piperazin-1 -yl)pyridin-3-yl)-5-(trifluoromethyl)- 1 ,2,4-oxadiazole;
(4'-((4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperazin-1- yl)sulfonyl)-[1 , 1 '-biphenyl]-4-yl)methanol;
3-(2-(4-((4-(thiophen-3-yl)phenyl)sulfonyl)piperazin-1 -yl)pyrimidin-5-yl)-5-
(trifluoromethyl)-1 ,2,4-oxadiazole;
3-(2-(4-((4-(1 H-pyrrol-2-yl)phenyl)sulfonyl)piperazin-1-yl)pyrimidin-5-yl)-5- (trifluoromethyl)-1 ,2,4-oxadiazole;
3-(2-(4-((4-(1 H-indol-5-yl)phenyl)sulfonyl)piperazin-1 -yl)pyrimidin-5-yl)-5- (trifluoromethyl)-l ,2,4-oxadiazole;
3-(2-(4-((3'-((4-methylpiperazin-1-yl)methyl)-[1 , 1 '-biphenyl]-4-yl)sulfonyl)piperazin-
1- yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole;
3-(2-(4-((3'-(pyrrolidin-1 -ylmethyl)-[1 ,1 '-biphenyl]-4-yl)sulfonyl)piperazin-1 - yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole;
N,N-dimethyl-1 -(3-(4-((4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazin-1 -yl)sulfonyl)phenyl)thiophen-2-yl)methanamine;
3-(2-(4-((2'-(2-(pyrrolidin-1-yl)ethoxy)-[1 , 1 '-biphenyl]-4-yl)sulfonyl)piperazin-1- yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole;
N,N-dimethyl-3-((4'-((4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazin-1 -yl)sulfonyl)-[1 ,1 '-biphenyl]-4-yl)oxy)propan-1 -amine;
N1 ,N1 ,N2-trimethyl-N2-(4'-((4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-
2- yl)piperazin-1 -yl)sulfonyl)-[1 , 1 '-biphenyl]-2-yl)ethane-1 ,2-diamine;
3-(2-(4-((4-(2-((4-methylpiperazin-1-yl)methyl)thiophen-3- yl)phenyl)sulfonyl)piperazin-1 -yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole;
N1 ,N1 ,N2-trimethyl-N2-(4'-((4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-
2-yl)piperazin-1 -yl)sulfonyl)-[1 , 1 '-biphenyl]-4-yl)ethane-1 ,2-diamine; 3-(2-(4-((3'-((4-methylpiperazin-1-yl)methyl)-[1 , 1 '-biphenyl]-4-yl)sulfonyl)piperazin- 1-yl)pynmidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole;
and salts, particularly pharmaceutically acceptable salts, thereof.
Compound names were generated using the software naming program
ChemDraw 1 1.0 available from CambridgeSoft Corporation., 100 Cambridge Park Drive, Cambridge, MA 02140, USA (http://www.cambridgesoft.com).
The compounds of Formula I can be prepared according to the methods outlined below.
Figure imgf000043_0001
Scheme 2
Figure imgf000043_0002
Figure imgf000044_0001
Scheme 4
Figure imgf000044_0002
The invention also includes 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. For example, deuterated alkyl groups (e.g., /V-(deutero-methyl) amines) may be prepared by conventional techniques (see for example: methyl-c/3-amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2). Employing such compounds will allow for the preparation of compounds of Formula I in which various hydrogen atoms of the N- methyl groups are replaced with a deuterium atom.
The present invention is directed to a method of inhibiting an HDAC which comprises contacting the acetylase with 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 inhibiting HDAC comprising contacting a cell with an effective amount of 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 an HDAC-mediated disease or disorder 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 (EC5o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
"Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by HDAC. The methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease. In one embodiment, this invention is directed to a method of treating, ameliorating, or preventing an autoimmune disorder, an immunological disease, an inflammatory disorder, transplant/graft rejection (e.g., allograft), lymphopenia, or graft-versus-host disease (GvHD) in a patient, specifically in a human, comprising administering to the patient a compound of this invention, in an amount sufficient to increase the level and/or activity of a Treg cell or a population of Treg cells in the patient, thereby treating, ameliorating, or preventing the autoimmune disorder, inflammatory disorder,
transplant/graft rejection, lymphopenia, or GvHD in the patient.
Additional examples of diseases and conditions that may be treated by the compounds of this invention include but not limited to type II diabetes mellitus, coronary artery disease, alopecia, allergies and allergic reactions, and sepsis/toxic shock.
Exemplary autoimmune disorders include, but are not limited to, multiple sclerosis, juvenile idiopathic arthritis, psoriatic arthritis, hepatitis C virus-associated mixed cryoglobulinemia, polymyositis, dermatomyositis, polyglandular syndrome type II, autoimmune liver disease, Kawasaki disease, myasthenia gravis, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX (syndrome)), type I diabetes, psoriasis, hypothyroidism, hemolytic anemia, autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED), thrombocytopenia, spondyloarthritis, Sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, eczema, gastritis, or thyroiditis. As part of a nonlimiting list, the inflammatory disorder can be contact hypersensitivity, atopic dermatitis or Still disease.
Additional examples of autoimmune diseases include but are not limited to autoimmune diseases include osteoarthritis, systemic sclerosis, sarcoidosis, insulin dependent diabetes mellitus (IDDM, type I diabetes), reactive arthritis, scleroderma, vasculitis, Wegener's granulomatosis, Hashimoto's disease, scleroderma, oophoritis, Lupus (SLE), Grave's disease, asthma, cryoglobulinemia, primary biliary sclerosis, pemphigus vulgaris, hemolytic anemia and pernicious anemia.
Examples of transplant/graft rejection (e.g., allograft), lymphopenia, or graft- versus-host disease (GvHD) are those arising from cell, tissue and organ transplantation procedures, such as therapeutic cell transplants such as stem cells, muscle cells such as cardiac cells, islet cells, liver cells, bone marrow transplants, skin grafts, bone grafts, lung transplants, kidney transplants, liver transplants, and heart transplants.
In another embodiment, this 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.
Other examples of diseases and conditions that may be treated by the compounds of this invention include but are not limited to cystic fibrosis, osteoporosis, obesity, epilepsy, depression, thalassemia, sickle cell anemia, amyotrophic lateral sclerosis (ALS) and hyperalgesia, cardiac disease (e.g., stroke, hypertension, atherothrombotic diseases, atherosclerosis or limitation of infarct size in acute coronary syndrome), diseases or disorders involving muscular atrophy, gentamicin-induced hearing loss, drug resistance (e.g., drug resistance in osteosarcoma and colon cancer cells), infectious diseases, and immune deficiency/immunocompromised patients. Examples of infectious diseases relate to various pathogen infections such as viral, fungal, bacterial, mycoplasm, and infections by unicellular and multicellular eukaryotic organisms. Common human pathogens include but are not limited to HIV, HSV, HPV, Hepatitis A, B and C viruses, influenza, denge, zostrella, rubella, RSV, rotavirus, gram positive, gram negative, streptococcus, tetanus, staphalococcus, tuberculosis, listeria, and malaria.
The compounds of the invention may be employed alone or in combination with standard anti-cancer regimens for neoplastic cell, e.g., tumor cell and cancer cell, treatments. Thus, 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 growth of cancer cells and/or tumor cells that are found in the following cancer types may be reduced by treatment with a compound of this invention: carcinoma (e.g., adenocarcinoma), heptaocellular carcinoma, sarcoma, myeloma (e.g., multiple myeloma), treating bone disease in multiple myeloma, leukemia, childhood acute lymphoblastic leukemia and lymphoma (e.g., cutaneous cell lymphoma), and mixed types of cancers, such as adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma, and teratocarcinoma. In one aspect of the invention, breast or prostate cancers or tumors are treated using the HDAC inhibitors of this invention. Other cancers that may be treated using the compounds of this invention include, but are not limited to, bladder cancer, breast cancer, prostate cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer, liver cancer, endometrial cancer, pancreatic cancer, cervical cancer, ovarian cancer; head and neck cancer, and melanoma.
The present invention is further 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. 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). 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.
The compounds of the invention 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 the invention 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 the invention 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 the invention 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 HDAC-mediated disease conditions may be achieved using the compounds of this invention 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 one or more immunosuppressants that do not activate the T suppressor cells including but are not limited to corticosteroids, rapamycin, Azathioprine, Mycophenolate, Cyclosporine, Mercaptopurine (6-MP), basiliximab, daclizumab, sirolimus, tacrolimus, Muromonab-CD3, cyclophosphamide, and
methotrexate, which are administered in effective amounts as is known in the art.
The compounds of the invention 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 pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection. Alternatively, the pharmaceutical compositions of the invention 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 this invention (i.e., 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 this invention.
The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention 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 the invention 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 the invention 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 the invention 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 of 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 a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention 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. EXAMPLES
The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
In the following experimental descriptions, the following abbreviations may be used: Abbreviation Meaning
AcOH acetic acid
aq aqueous
brine saturated aqueous NaCI
CH2CI2 methylene chloride
CH3CN or MeCN acetonitrile
CH3NH2 methylamine
d day
DMF Λ/,/ν-dimethylformamide
DMSO dimethylsulfoxide
equiv equivalents
Et ethyl
Et3N triethylamine
Et20 diethyl ether
EtOAc ethyl acetate
h, hr hour
HCI hydrochloric acid
/-Pr2NEt Λ/',Λ/'-diisopropylethylamine
KOf-Bu potassium ferf-butoxide
LCMS liquid chromatography-mass spectroscopy
Me methyl
MeOH or CH3OH methanol
MgS04 magnesium sulfate
min minute
MS mass spectrum
μνν microwave
NaBH4 sodium borohydride
Na2C03 sodium carbonate
NaHCOs sodium bicarbonate
NaOH sodium hydroxide
Na2S04 sodium sulfate
NH4CI ammonium chloride
NiCI2-6H20 nickel (II) chloride hexahydrate
NMP /v-methyl-2-pyrrolidone
Ph phenyl
rt room temperature
satd saturated
sex strong cation exchange
SPE solid phase extraction
TFA trifluoroacetic acid
THF tetrahydrofuran
fe retention time
Figure imgf000053_0001
ferf-Butyl ((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)carbamate: A mixture of ferf-butyl (piperidin-4-ylmethyl)carbamate (0.323 g, 1.505 mmol), 3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (0.1878 g, 0.752 mmol), and /'-Pr2NEt (0.329 ml_, 1.881 mmol) in DCM (10 ml.) was stirred at rt overnight. The DCM was removed under reduced pressure. 7 ml of anhydrous DMF was added. The mixture was heated at 70 °C for 4 h, cooled, and partitioned between 50% EtOAc in hexanes and water. The organic phase was separated, and the aqueous was further extracted with 50% EtOAc in hexanes twice. The combined organic phases were washed with water and brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% - 40% EtOAc in hexanes) to afford the title compound as a white solid (0.21 g, 63%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.88 (d, J = 1.96 Hz, 1 H), 8.04 - 8.12 (m, 1 H), 6.72 (d, J = 9.20 Hz, 1 H), 4.60 - 4.74 (br., 1 H), 4.51 (d, J = 13.31 Hz, 2H), 3.09 (t, J = 5.87 Hz, 2H), 2.96 (m, 2H), 1 .85 (d, J = 12.53 Hz, 3H), 1.48 (s, 9H), 1.29 (m, 2H). LCMS: fR = 1.03 min, 96%. MS (ESI): m/z 428 (M+H)+.
Figure imgf000053_0002
(1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)methanamine, trifluoroacetic acid salt: The solution of ferf-butyl ((1 -(5-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)carbamate (0.208 g, 0.487 mmol) and trifluoroacetic acid (3 ml, 38.9 mmol) in DCM (5 ml) was stirred at 20 °C for 2.5 h. The volatile solvents were removed under reduced pressure. The residue was triturated with diethyl ether, filtered, and washed with diethyl ether to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 1 H), 8.06 (dd, J = 2.25, 9.10 Hz, 1 H), 7.78 (br. s., 3H), 7.05 (d, J = 9.00 Hz, 1 H), 4.50 (d, J = 13.12 Hz, 2H), 2.96 (t, J = 1 1.84 Hz, 2H), 2.76 (br. s., 2H), 1.70 - 2.03 (m, 3H), 1.10 - 1.32 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -65.9, -73.9. LCMS: fR = 0.57 min, 100%. MS (ESI): m/z 328 (M+H)+.
EXAMPLE 3
Figure imgf000054_0001
1 -(1 -Methyl-1 H-indol-3-yl)-W-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2- yl)piperidin-4-yl)methyl)methanamine, hydrochloride salt: The mixture of (1 -(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methanamine,
trifluoroacetic acid salt (48.1 mg, 0.109 mmol) and /'-Pr2NEt (0.038 ml_, 0.218 mmol) in DCM (5 mL) was stirred for 5 min, and 1 -methyl-1 H-indole-3-carbaldehyde (18.22 mg, 0.1 14 mmol) and a few drops of glacial acetic acid were added. The resulting mixture was stirred at rt 30 min, and sodium triacetoxyborohydride (46.2 mg, 0.218 mmol) was added. The reaction was stirred at rt overnight and then purified by silica gel
chromatography (0% - 10% MeOH in DCM). The residue was dissolved in 1 ml of DCM and mixed with 1 M HCI/ether (1 ml). The white solid was collected by filtration, washed with hexanes, and dried in air flow to afford the title compound (36 mg, 61 .9%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 - 8.90 (m, 2H), 8.72 (d, J = 1 .96 Hz, 1 H), 8.00 - 8.1 1 (m, 1 H), 7.78 (d, J = 6.0 Hz, 1 H), 7.57 (s, 1 H), 7.48 (d, J = 6.0 Hz, 1 H), 7.23 (m, 1 H), 7.1 1 - 7.18 (m, 1 H), 7.01 - 7.07 (m, 1 H), 4.41 - 4.56 (m, 2H), 4.31 (br. s., 2H), 3.83 (s, 3H), 2.96 (br. s., 4H), 1 .97 - 2.14 (m, 1 H), 1 .77 - 1 .91 (m, 2H), 1.09 - 1.28 (m, 2H). LCMS: fR = 0.78 min, 100%. MS (ESI): m/z 471 (M+H)+.
Figure imgf000054_0002
A -((1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)benzenesulfonamide: Benzenesulfonyl chloride (0.013 mL, 0.100 mmol) was added to the solution of (1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2- yl)piperidin-4-yl)methanamine, trifluoroacetic acid salt (22 mg, 0.050 mmol) and /'-Pr2NEt (0.022 mL, 0.125 mmol) in DCM (5 mL). The resultant mixture was stirred at rt overnight and purified by silica gel chromatography directly (0% - 50% EtOAc/hexanes) to afford the title compound as a white solid (21 mg, 90%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.86 (d, J = 1 .96 Hz, 1 H), 8.07 (dd, J = 2.25, 9.10 Hz, 1 H), 7.90 (d, J = 7.24 Hz, 2H), 7.50 - 7.66 (m, 3H), 6.70 (d, J = 9.00 Hz, 1 H), 4.73 (t, J = 6.46 Hz, 1 H), 4.48 (d, J = 13.31 Hz, 2H), 2.81 - 3.01 (m, 4H), 1.72 - 1 .94 (m, 3H), 1.14 - 1.37 (m, 2H). LCMS: fR = 0.99 min, 100%. MS (ESI): m/z 468 (M+H)+.
Figure imgf000055_0001
A -((1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)naphthalene-2-sulfonamide: A procedure similar to the one used in the synthesis of Λ/-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)methyl)benzenesulfonamide (example 10) but using naphthalene-2-sulfonyl chloride was used to prepare the title compound as a white solid. 1H NMR (400 MHz,
CHLOROFORM-d) δ 8.85 (d, J = 1.96 Hz, 1 H), 8.46 (s, 1 H), 7.91 - 8.12 (m, 4H), 7.86 (dd, J = 1 .37, 8.61 Hz, 1 H), 7.60 - 7.74 (m, 2H), 6.68 (d, J = 9.00 Hz, 1 H), 4.74 (t, J = 6.46 Hz, 1 H), 4.46 (d, J = 13.31 Hz, 2H), 2.82 - 2.99 (m, 4H), 1.74 - 1.91 (m, 3H), 1 .14 - 1 .31 (m, 2H). LCMS: fR = 1.07 min, 100%. MS (ESI): m/z 518 (M+H)+.
Figure imgf000055_0002
2-Chloropyrimidine-5-carbonitrile: Prepared from 2-aminopyrimidine-5-carbonitrile according to the method reported in the patent WO2010009183 (Authored by D. A.
Wacker, et al).
Figure imgf000056_0001
ferf-Butyl ((1 -(5-cyanopyrimidin-2-yl)piperidin-4-yl)methyl)carbamate: The mixture of 2-chloropyrimidine-5-carbonitrile (0.90 g, 5.74 mmol), ferf-butyl (piperidin-4- ylmethyl)carbamate (1.818 g, 8.48 mmol), and /'-Pr2NEt (2.506 mL, 14.35 mmol) in anhydrous NMP (10 mL) was heated at 70 °C for 5 h, cooled to rt, and partitioned between 50% EtOAc/hexanes and water. The organic phase was separated, and the aqueous was further extracted with 50% EtOAc in hexanes twice. The combined organic phases were washed with water and brine, dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound as a brown solid (1.32 g, 71 %). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.49 (s, 2H), 4.88 (d, J = 13.31 Hz, 2H), 4.54 - 4.75 (m, 1 H), 3.02 - 3.16 (m, 2H), 2.96 (m, 2H), 1.84 (br., 3H), 1.47 (s, 9H), 1.23 (m, 2H).
LCMS: fR = 0.84 min, 98%. MS (ESI): m/z 318 (M+H)+.
Figure imgf000056_0002
ferf-Butyl ((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methyl)carbamate: 50% Hydroxylamine in water (1 .255 mL, 20.48 mmol) was added to a solution of ferf-butyl ((1-(5-cyanopyrimidin-2-yl)piperidin-4-yl)methyl)carbamate (1.3 g, 4.10 mmol) in THF. The resulting mixture was heated at 60 °C with stirring overnight. The solvent was removed under reduced pressure. The residue was washed with water, dried in air flow, and dissolved in dry THF (20ml). /'-Pr2NEt (2.146 mL, 12.29 mmol) and TFAA (1 .736 mL, 12.29 mmol) were added sequentially. The resulting mixture was heated at 50 °C for 3-4 h, cooled, concentrated under reduced pressure, dissolved in EtOAc (35ml), washed with NaHC03 solution and brine, dried overMgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% -80% EtOAc in hexanes) to afford the title compound as a white solid (0.335 g, 18%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (s, 2H), 4.95 (d, J = 13.51 Hz, 2H), 4.56 - 4.78 (m, 1 H), 3.09 (t, J = 5.87 Hz, 2H), 2.93 - 3.04 (m, 2H), 1.85 (br. s., 3H), 1 .48 (s, 9H), 1 .26 (br. s., 2H). 19F NMR (376 MHz, DMSO-d6) δ -65.7. LCMS: fR = 1.10 min, 97%. MS (ESI): m/z 429 (M+H)+.
Figure imgf000057_0001
(1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methanamine, trifluoroacetic acid salt: A procedure similar to the one used in the synthesis of (1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)methanamine, trifluoroacetic acid salt (example 8) but using ferf-butyl ((1-(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)carbamate was used to prepare the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 2H), 7.77 (br. s., 3H), 4.78 (d, J = 13.31 Hz, 2H), 3.05 (t, J = 1 1.75 Hz, 2H), 2.77 (br. S.. 2H), 1 .84 (d, J = 13.51 Hz, 3H), 1.19 (d, J = 8.81 Hz, 2H). LCMS: fR = 0.62 min, 98%. MS (ESI): m/z 329 (M+H)+.
Figure imgf000057_0002
1 -(1 -Methyl-1 H-indol-3-yl)-W-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin- 2-yl)piperidin-4-yl)methyl)methanamine, hydrochloride: A procedure similar to the one used in the synthesis of 1-(1 -methyl-1 /-/-indol-3-yl)-/V-((1-(5-(5-(trifluoromethyl)-1 , 2,4- oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine hydrochloride (example 9) but using (1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methanamine, trifluoroacetic acid salt was used to prepare the title compound as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 8.81 (br. s., 2H), 7.79 (d, J = 7.83 Hz, 1 H), 7.57 (s, 1 H), 7.49 (d, J = 8.22 Hz, 1 H), 7.24 (s, 1 H), 7.16 (d, J = 7.44 Hz, 1 H), 4.76 (d, J = 13.2 Hz, 2H), 4.32 (br. s., 2H), 3.83 (s, 3H), 3.03 (br. s., 2H), 2.90 (br. s., 2H), 2.00 - 2.17 (m, 1 H), 1.86 (d, J = 12 Hz, 2H), 1.20 (br. s., 2H). LCMS: fR = 0.80 min, 92%. MS (ESI): m/z 472 (M+H)+.
Figure imgf000058_0001
A -((1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methyl)acetamide: Acetyl chloride (4.24 μΙ_, 0.060 mmol) was added to a solution of (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine, trifluoroacetic acid salt (22 mg, 0.050 mmol) and /'-Pr2NEt (0.026 mL, 0.149 mmol) in DCM (3 mL) . The resultant mixture was stirred at rt overnight and purified directly by silica gel chromatography twice (0% - 80% EtOAc in hexanes) and (10% MeOH in DCM) respectively to yield the title compound as a white solid (16.7 mg, 86%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.95 (s, 2H), 5.68 (br. s., 1 H), 4.94 (d, J = 13.31 Hz, 2H), 3.20 (t, J = 6.07 Hz, 2H), 2.99 (t, J = 12.43 Hz, 2H), 2.02 (s, 3H), 1.86 (d, J = 1 1.94 Hz, 2H), 1.17 - 1.35 (m, 3H). LCMS: fR = 0.81 min, 100%. MS m/z = 371 (M+H)+.
Figure imgf000058_0002
A -((1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methyl)benzamide: A procedure similar to the one used in the synthesis of Λ/-((1-(5- (5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)acetamide (example 16) but using benzoyl chloride was used to prepare the title compound as a white solid. : 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.93 (s, 2H), 7.78 (d, J = 7.44 Hz, 2H), 7.38 - 7.60 (m, 3H), 6.31 (br. s., 1 H), 4.95 (d, J = 13.12 Hz, 2H), 3.41 (t, J = 6.26 Hz, 2H), 2.98 (t, J = 12.53 Hz, 2H), 2.02 (br. s., 1 H), 1 .91 (d, 2H), 1.13 - 1 .44 (m, 2H). LCMS: fR = 0.96 min, 100%. MS m/z = 433 (M+H)+.
EXAMPLE 11
Figure imgf000059_0001
1 -Methyl -Λ -((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methyl)-1H-indole-3-carboxamide: Oxalyl chloride (0.016 mL, 0.180 mmol) and a few drops of DMF were added to a cooled solution of 1-methyl-1 H-indole-3-carboxylic acid (0.01 1 mL, 0.072 mmol) in DCM (3 ml). The mixture was stirred at rt for 2 h, concentrated under reduced pressure to dryness, dissolved in 2 ml of DCM, and slowly added into a solution of (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperidin-4-yl)methanamine, trifluoroacetic acid salt (26.5 mg, 0.060 mmol) and /'- Pr2NEt (0.037 mL, 0.210 mmol) in DCM (3 mL). The resulting mixture was stirred at rt overnight and purified by silica gel chromatography directly (40% - 80% EtOAc in hexanes) to afford the product as a brown amorphous solid (28 mg, 91 %). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.96 (s, 2H), 7.95 (d, J = 7.44 Hz, 1 H), 7.73 (s, 1 H), 7.39 - 7.50 (m, 1 H), 7.26 - 7.39 (m, 2H), 6.15 (br. s., 1 H), 4.99 (d, J = 13.31 Hz, 2H), 3.87 (s, 3H), 3.49 (t, J = 6.46 Hz, 2H), 3.03 (t, J = 1 1.84 Hz, 2H), 2.03 - 2.18 (m, 1 H), 1 .99 (d, J = 12.72 Hz, 2H), 1 .27 - 1.48 (m, 2H). LCMS: fR = 0.98 min, 100%. MS m/z = 486 (M+H)+.
EXAMPLE 12
Figure imgf000059_0002
2,2,2-Trifluoro-A -((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperidin-4-yl)methyl)acetamide: Benzenesulfonyl chloride (0.026 mL, 0.199 mmol) was added to the solution of (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperidin-4-yl)methanamine, trifluoroacetic acid salt (44 mg, 0.099 mmol) and pyridine (0.024 mL, 0.298 mmol) in DCM (5 mL) . The resulting mixture was stirred at rt overnight and purified by silica gel chromatography directly (0% - 50% EtOAc in hexanes) to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (br. s., 1 H), 8.93 (s, 2H), 4.75 (br. s., 2H), 3.13 (t, J = 6.17 Hz, 2H), 3.02 (br. s., 2H), 1 .90 (br. s., 1 H), 1.74 (br. s., 2H), 1.15 (br. s., 2H). LCMS: fR = 0.99 min, 100%. MS m/z = 425 (M+H)+.
Figure imgf000060_0001
ferf-Butyl (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4- yl)carbamate: The mixture of ferf-butyl piperidin-4-ylcarbamate (0.332 g, 1 .659 mmol), 3- (6-chloropyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (0.207 g, 0.829 mmol), and /'- Pr2NEt (0.362 mL, 2.073 mmol) in NMP (5 mL) was heated at 70 °C for 4 h, cooled, and partitioned between EtOAc and water. The organic phase was separated, and the aqueous was further extracted with EtOAc twice. The combined organic phases were washed with water/brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% - 30% EtOAc in hexanes) to afford the title compound as a white solid (0.21 1 g, 57%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.87 (d, J = 2.15 Hz, 1 H), 8.08 (dd, J = 2.15, 9.00 Hz, 1 H), 6.72 (d, J = 9.00 Hz, 1 H), 4.44 - 4.56 (m, 1 H), 4.39 (d, J = 13.70 Hz, 2H), 3.76 (br. s., 1 H), 2.99 - 3.20 (m, 2H), 2.08 (d, J = 10.77 Hz, 2H), 1.31 - 1.53 (m, 1 1 H). LCMS: fR = 1.04 min, 92%. MS m/z = 414 (M+H)+.
Figure imgf000060_0002
1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-amine, trifluoroacetic acid salt: A procedure similar to the one used in the synthesis of (1 -(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methanamine,
trifluoroacetic acid salt (example 8) but using ferf-butyl (1-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)carbamate was used to prepare the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 2.15 Hz, 1 H), 8.13 (dd, J = 2.35, 9.00 Hz, 1 H), 7.92 (br. s., 3H), 7.10 (d, J = 9.20 Hz, 1 H), 4.53 (d, J = 13.31 Hz, 2H), 3.24 - 3.60 (m, 1 H), 3.07 (t, J = 12.04 Hz, 2H), 2.00 (d, J = 10.38 Hz, 2H), 1.37 - 1.61 (m, 2H). F NMR (376 MHz, DMSO-d6) δ -65.1 , -73.9. LCMS: fR = 0.59 min, 97%. MS m/z = 314 (M+H)+.
Figure imgf000061_0001
A -((1 -Methyl-1H-indol-3-yl)methyl)-1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyridin-2-yl)piperidin-4-amine, hydrochloride: A procedure similar to the one used in the synthesis of 1-(1-methyl-1 H-indol-3-yl)-/\/-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine hydrochloride (example 9) but using 1-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-amine trifluoroacetic acid salt was used to prepare the title compound as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (br. s., 2H), 8.78 (d, J = 2.15 Hz, 1 H), 8.14 (dd, J = 2.25, 9.10 Hz, 1 H), 7.81 (d, J = 7.83 Hz, 1 H), 7.62 (s, 1 H), 7.52 (d, J = 8.22 Hz, 1 H), 7.26 (t, J = 7.44 Hz, 1 H), 7.07 - 7.22 (m, 2H), 4.58 (br. s., 2H), 4.38 (br. s., 2H), 3.85 (s, 3H), 3.47 (br. s., 1 H), 2.89 - 3.16 (m, 2H), 2.28 (d, J = 10.57 Hz, 2H), 1.67 (br. s., 2H). LCMS: fR = 0.76 min, 91 %. MS m/z = 457 (M+H)+.
Figure imgf000061_0002
ferf-Butyl 4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperazine-1 - carboxylate: A procedure similar to the one used in the synthesis of ferf-butyl (1-(5-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)carbamate (example 20) but using ferf-butyl piperazine-1 -carboxylate was used to prepare the title compound as a white solid. : 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.89 (d, J = 1 .96 Hz, 1 H), 8.12 (dd, J = 2.35, 9.00 Hz, 1 H), 6.71 (d, J = 9.00 Hz, 1 H), 3.67 - 3.76 (m, 4H), 3.52 - 3.63 (m, 4H), 1.45 - 1.54 (m, 9H). LCMS: fR = 1 .13 min, 100%. MS m/z = 400 (M+H)+.
Figure imgf000062_0001
3-(6-(Piperazin-1 -yl)pyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole, trifluoroacetic acid salt: A procedure similar to the one used in the synthesis of (1-(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methanamine,
trifluoroacetic acid salt (example 8) but using ferf-butyl 4-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyridin-2-yl)piperazine-1-carboxylate was used to prepare the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.84 - 9.02 (br.s., 2H), 8.82 (d, J = 2.15 Hz, 1 H), 8.20 (dd, J = 2.35, 9.00 Hz, 1 H), 7.15 (d, J = 9.00 Hz, 1 H), 3.86 - 4.01 (m, 4H), 3.20-3.30 (m, 4H). LCMS: fR = 0.56 min, 100%. MS (ESI): m/z 300 (M+H)+.
Figure imgf000062_0002
3-(6-(4-((1 -Methyl-1 H-indol-3-yl)methyl)piperazin-1 -yl)pyridin-3-yl)-5-
(trifluoromethyl)-l ,2,4-oxadiazole, Hydrochloride: A procedure similar to the one used in the synthesis of 1 -(1 -methyl-1 /-/-indol-3-yl)-/V-((1-(5-(5-(trifluoromethyl)-1 , 2,4- oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine hydrochloride (example 9) but using 3-(6-(piperazin-1-yl)pyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole,
trifluoroacetic acid salt was used to prepare the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.31 - 10.82 (m, 1 H), 8.80 (d, J = 1 .96 Hz, 1 H), 8.19 (dd, J = 2.35, 9.00 Hz, 1 H), 7.87 (d, J = 7.83 Hz, 1 H), 7.65 (s, 1 H), 7.54 (d, J = 8.22 Hz, 1 H), 7.27 (t, J = 7.63 Hz, 1 H), 7.07 - 7.23 (m, 2H), 4.59 - 4.70 (m, 2H), 4.55 (d, J = 4.31 Hz, 2H), 3.87 (s, 3H), 3.46 - 3.66 (m, 2H), 3.28 - 3.47 (m, 2H), 3.16 (br. s., 2H). LCMS: fR = 0.77 min, 100%. MS m/z = 443 (M+H)+.
Figure imgf000063_0001
3-(6-(4-(Naphthalen-2-ylsulfonyl)piperazin-1 -yl)pyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole: A procedure similar to the one used in the synthesis of Λ/-((1-(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)naphthalene-2- sulfonamide (example 1 1 ) but using 3-(6-(piperazin-1-yl)pyridin-3-yl)-5-(trifluoromethyl)- 1 ,2,4-oxadiazole trifluoroacetic acid salt was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.80 (s, 1 H), 8.36 (s, 1 H), 7.85 - 8.14 (m, 4H), 7.52 - 7.85 (m, 3H), 6.63 (d, J = 9.00 Hz, 1 H), 3.73 - 3.91 (m, 4H), 3.10 - 3.32 (m, 4H). LCMS: fR = 1.12 min, 94%. MS m/z = 490 (M+H)+.
Figure imgf000063_0002
ferf-Butyl 4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperazine-1 - carboxylate: A mixture of ferf-butyl piperazine-1 -carboxylate (0.417 g, 2.239 mmol), 3- (2-chloropyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (0.2805 g, 1 .1 19 mmol), and /'- Pr2NEt (0.391 mL, 2.239 mmol) in NMP (6.5 mL) was heated at 70 °C for 4 h, cooled, and poured into water (15 ml). The off-white precipitate was isolated by filtration, washed with water, and dried in air flow to afford the title compound (0.40 g, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.96 (s, 2H), 3.82 - 4.09 (m, 4H), 3.36 - 3.71 (m, 4H), 1 .51 (s, 9H). LCMS: fR = 1.07 min, 100%. MS m/z = 401 (M+H)+.
Figure imgf000064_0001
3-(2-(Piperazin-1 -yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole,
trifluoroacetic acid salt: A procedure similar to the one used in the synthesis of 3-(6- (piperazin-1 -yl)pyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole, trifluoroacetic acid salt (example 24) but using ferf-butyl 4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperazine-1 -carboxylate was used to prepare the title compound as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 8.91 (br. s., 2H), 3.98 - 4.27 (m, 4H), 3.27 (br. s., 4H). LCMS: fR = 0.55 min, 100%. MS m/z = 301 (M+H)+.
Figure imgf000064_0002
3-(2-(4-((1 -Methyl-1 H-indol-3-yl)methyl)piperazin-1 -yl)pyrimidin-5-yl)-5- (trifluoromethyl)-1 ,2,4-oxadiazole, hydrochloride: A procedure similar to the one used in the synthesis of 3-(6-(4-((1 -methyl-1 H-indol-3-yl)methyl)piperazin-1 -yl)pyridin-3-yl)-5- (trifluoromethyl)-1 ,2,4-oxadiazole, hydrochloride (example 25) but using 3-(2-(piperazin- 1 -yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole, trifluoroacetic acid salt was used to prepare the title compound as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.51 - 10.68 (m, 1 H), 9.04 (s, 2H), 7.85 (d, J = 8.0 Hz, 1 H), 7.64 (s, 1 H), 7.54(d, J = 7.2 Hz, 1 H), 7.25 - 7.35 (m, 1 H), 7.16 - 7.23 (m, 1 H), 4.87 (br. s., 2H), 4.54 (d, J = 4.50 Hz, 2H), 3.87 (s, 3H), 3.52 - 3.62 (m, 2H), 3.39 - 3.52 (m, 2H), 3.18 (m, 2H). LCMS: fR = 0.75 min, 98%. MS (ESI): m/z AAA (M+H)+.
Figure imgf000065_0001
3-(2-(4-(Naphthalen-2-ylsulfonyl)piperazin-1 -yl)pyrimidin-5-yl)-5-(trifluoromethyl)- 1 ,2,4-oxadiazole: A procedure similar to the one used in the synthesis of 3-(6-(4-
(naphthalen-2-ylsulfonyl)piperazin-1-yl)pyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (example 26) but using 3-(2-(piperazin-1 -yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole, trifluoroacetic acid salt was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.87 (s, 2H), 8.36 (s, 1 H), 7.98 (d, J = 8.42 Hz, 2H), 7.91 (d, J = 7.63 Hz, 1 H), 7.76 (dd, J = 1.57, 8.61 Hz, 1 H), 7.59 - 7.70 (m, 2H), 3.96 - 4.19 (m, 4H), 3.18 (t, 4H). LCMS: fR = 1 .12 min, 100%. MS m/z = 491 (M+H)+.
Figure imgf000065_0002
3-(2-(4-(Phenylsulfonyl)piperazin-1 -yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole: A procedure similar to the one used in the synthesis of 3-(2-(4-(naphthalen- 2-ylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (example 30) but using benzenesulfonyl chloride was used to prepare the title compound as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.90 (s, 2H), 7.78 (d, J = 7.24 Hz, 2H), 7.58 - 7.67 (m, 1 H), 7.45 - 7.58 (m, 2H), 3.90 - 4.21 (m, 4H), 3.12 (t, 4H). LCMS: fR = 1.03 min, 100%. MS m/z = 441 (M+H)+.
Figure imgf000065_0003
Phenyl(4-(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperazin-1 - yl)methanone: A procedure similar to the one used in the synthesis of 3-(2-(4- (naphthalen-2-ylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole (example 30) but using benzoyl chloride was used to prepare the title compound as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.97 (s, 2H), 7.46 (s, 5H), 3.26 - 4.53 (m, 8H). LCMS: fR = 0.95 min, 98%. MS m/z = 405 (M+H)+. EXAMPLE 26
Figure imgf000066_0001
ferf-Butyl (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)carbamate: A procedure similar to the one used in the synthesis of ferf-butyl 4-(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperazine-1-carboxylate (example 27) but using ferf-butyl piperidin-4-ylcarbamate was used to prepare the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 2H), 6.88 (d, J = 8.0 Hz, 1 H), 4.51 - 4.69 (m, 2H), 3.52 - 3.69 (br. s., 1 H), 3.18 (m, 2H), 1 .76 - 1.91 (m, 2H), 1 .39 (s, 9H), 1 .21 - 1.47 (m, 2H). LCMS: fR = 1.05 min, 100%. MS (ESI): m/z 415 (M+H)+.
EXAMPLE 27
Figure imgf000066_0002
1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-amine, trifluoroacetic acid salt: A procedure similar to the one used in the synthesis of 3-(2- (piperazin-1 -yl)pyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4-oxadiazole trifluoroacetic acid salt (example 28) but using ferf-butyl (1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)piperidin-4-yl)carbamate was used to prepare the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 2H), 7.93 (br. s., 3H), 4.78 (d, J = 13.55 Hz, 2H), 3.39 (br. s., 1 H), 3.12 (t, J = 12.30 Hz, 2H), 2.01 (br. s., 2H), 1 .46 (dd, 2H). LCMS: fR = 0.52 min, 100%. MS (ESI): m/z 315 (M+H)+. EXAMPLE 28
Figure imgf000067_0001
W-((1 -Methyl-1H-indol-3-yl)methyl)-1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyrimidin-2-yl)piperidin-4-amine, hydrochloride: A procedure similar to the one used in the synthesis of 1-(1 -methyl-1 H-indol-3-yl)-/\/-((1-(5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine hydrochloride (example 9) but using 1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4-amine, trifluoroacetic acid salt was used to prepare the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.98 - 9.07 (m, 2H), 8.97 (s, 2H), 7.78 (d, J = 8.6 Hz, 1 H), 7.59 (s, 1 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.19 - 7.27 (m, 1 H), 7.10 - 7.18 (m, 1 H), 4.85 (d, J = 13.6 Hz, 2H), 4.36 (br. s., 2H), 3.82 (s, 3H), 3.40 - 3.56 (m, 1 H), 3.09 (m, 2H), 2.23 - 2.34 (m, 2H), 1 .52 - 1.73 (m, 2H). LCMS: fR = 0.70 min, 95%. MS (ESI): m/z 458 (M+H)+.
Figure imgf000067_0002
2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 -yl)benzonitrile:
3,6,6-Trimethyl-6,7-dihydro-1 H-indazol-4(5H)-one (0.535 g, 3 mmol) was dissolved in dry DMSO (15 mL). Sodium hydride (0.15 g, 3.75 mmol) was slowly added. After H2 evolution ceased, 2-bromo-4-fluorobenzonitrile (0.900 g, 4.50 mmol) was added. The resulting mixture was heated at 45 °C overnight, cooled, poured into satd. NH4CI solution (50 ml), and extracted with EtOAc three times. The combined organic phases were washed with water/brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% - 50% EtOAc in hexanes) to afford the title compound as a white solid (0.65 g, 60.5%). 1 H NMR (400 MHz,
CHLOROFORM-d) δ 8.01 (d, J = 2.15 Hz, 1 H), 7.82 (d, J = 8.61 Hz, 1 H), 7.63 (dd, J = 2.15, 8.42 Hz, 1 H), 2.90 (s, 2H), 2.59 (s, 3H), 2.47 (s, 2H), 1 .18 (s, 6H). LCMS: fR = 0.90 min, 100%. MS (ESI): m/z 358, 360 (M+H)+.
Figure imgf000068_0001
ferf-Butyl 4-(((2-cyano-5-(3,6,6-tri methyl -4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 - yl)phenyl)amino)methyl)piperidine-1 -carboxylate: A mixture of 2-bromo-4-(3,6,6- trimethyl-4-oxo-4,5,6,7-tetrahydro-1 /-/-indazol-1 -yl)benzonitrile (0.358 g, 1 mmol), ferf- butyl 4-(aminomethyl)piperidine-1-carboxylate (0.321 g, 1.500 mmol), and PdCI2(dppf)- CH2CI2 adduct (0.163 g, 0.200 mmol) in toluene (15 ml.) was degassed by vacuum- nitrogen back-filling cycles. Potassium ferf-butoxide (0.224 g, 2.000 mmol) was added. The resulting reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled, quenched with water, and extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% - 80% EtOAc in hexanes) to afford the title compound as a yellow solid (0.221 g, 44.1 %). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.47 (d, J = 8.22 Hz, 1 H), 6.86 (s, 1 H), 6.69 - 6.75 (m, 1 H), 4.84 - 5.00 (m, 1 H), 4.15 (br.s., 2H), 3.17 (m, 2H), 2.82 (s, 2H), 2.62 - 2.77 (m, 2H), 2.51 (s, 3H), 2.38 (s, 2H), 1 .73 - 1 .86 (m, 3H), 1 .44 (s, 9H), 1 .21 - 1 .27 (m, 2H), 1.10 (s, 6H). LCMS: fR = 1 .02min, 98%. MS (ESI): m/z 492 (M+H)+.
Figure imgf000068_0002
ferf-Butyl 4-(((2 -carbamoyl -5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazoM - yl)phenyl)amino)methyl)piperidine-1 -carboxylate: A mixture of ferf-butyl 4-(((2-cyano- 5-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 - yl)phenyl)amino)methyl)piperidine-1-carboxylate (0.22 g, 0.447 mmol), sodium hydroxide (aq. solution) (0.179 ml_, 0.895 mmol), and hydrogen peroxide (aq. solution) (0.2 ml_, 2.284 mmol) in ethanol (1.6 ml.) and DMSO (0.4 ml.) was heated at 50 °C for 3-4 h, cooled, diluted with water, and extracted with EtOAc twice. The combined organic phases were washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% - 80% EtOAc in hexanes) to afford the title compound as a yellow solid (0.223 g, 92%). LCMS: fR = 0.80
+H)+.
Figure imgf000069_0001
2-((Piperidin-4-ylmethyl)amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indazol-1 -yl)benzamide, trifluoroacetic acid salt: Trifluoroacetic acid (2.5 ml, 32.4 mmol) was added to a solution of ferf-butyl 4-(((2-carbamoyl-5-(3,6,6-trimethyl-4-oxo- 4,5,6,7-tetrahydro-1 H-indazol-1 -yl)phenyl)amino)methyl)piperidine-1 -carboxylate (0.243 g, 0.477 mmol) in DCM (10 ml.) . The mixture was stirred at 20 °C overnight, concentrated to dryness under reduced pressure, and triturated with diethyl ether. The yellow solid was collected by filtration and washed with diethyl ether to afford the title compound (0.223 g, 83%). 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (m, 1 H), 8.45 - 8.56 (m, 1 H), 8.12 - 8.32 (m, 1 H), 7.92 - 8.09 (br. s., 1 H), 7.79 (d, J = 8.42 Hz, 1 H), 7.24 - 7.40 (br. s., 1 H), 6.83 (d, J = 1.37 Hz, 1 H), 6.70 - 6.78 (dd, 1 H), 3.27 - 3.47 (m, 2H), 3.16 (m, 2H), 2.97 (s, 2H), 2.83 - 3.00 (m, 2H), 2.43 (s, 3H), 2.36 (s, 2H), 1 .83 - 2.00 (m, 3H), 1.30 - 1.49 (m, 2H), 1.05 (s,
= 0.51 min, 93%. MS m/z = 410 (M+H)+.
Figure imgf000069_0002
2-(((1 -(5-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-yl)piperidin-4- yl)methyl)amino)-4-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H-indazol-1 - yl)benzamide: A procedure similar to the one used in the synthesis of ferf-butyl 4-(5-(5- (trifluoromethyl)-l , 2, 4-oxadiazol-3-yl)pyrimidin-2-yl)piperazine-1 -carboxylate (example 27) but using 2-((piperidin-4-ylmethyl)amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1 H- indazol-1-yl)benzamide, trifluoroacetic acid salt was used to prepare the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 2H), 8.63 (m, 1 H), 7.98 (br. s., 1 H), 7.79 (d, J = 8.42 Hz, 1 H), 7.31 (br. s., 1 H), 6.83 (d, J = 1 .37 Hz, 1 H), 6.73 (dd, 1 H), 4.84 (br. s., 2H), 3.01 - 3.19 (m, 4H), 2.98 (s, 2H), 2.43 (s, 3H), 2.36 (s, 2H), 1 .85 - 2.09 (m, 3H), 1 .27 (m, 2H), 1 .05 (s, 6H). 19F NMR (376 MHz, DMSO-d6) δ -65.0. LCMS: fR = 1.05 min, 95%. MS m/z = 624 (M+H)+.
Figure imgf000070_0001
ferf-Butyl 4-((5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2- yl)amino)piperidine-1 -carboxylate: A mixture of ferf-butyl 4-aminopiperidine-1 - carboxylate (320 mg, 1.600 mmol), 3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole (200 mg, 0.8 mmol), and /'-Pr2NEt (0.349 mL, 2.000 mmol) in DMF (7 mL) was heated at 70 °C for 4 h, cooled, and partitioned between 50% EtOAc in hexanes and water. The organic phase was separated, and the aqueous was further extracted with 50% EtOAc in hexanes twice. The combined organic phases were washed with water/brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0% - 40% EtOAc/hexanes) to afford the title compound as a white solid (76 mg, 17.5%). LCMS: fR = 0.99 min, 76%. MS (ESI):
+H)+. It was used for the next step without further purification.
Figure imgf000070_0002
A -(Piperidin-4-yl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2 -amine, trifluoroacetic acid salt: A procedure similar to the one used in the synthesis of (1 -(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methanamine,
trifluoroacetic acid salt (example 8) was used to prepare the title compound as a white solid. LCMS: tR = 0.56 min, 85%. MS (ESI): m/z 314 (M+H)+. It was used for the next step without further purification.
Figure imgf000071_0001
Λ -(1 -((1 -Methyl-1 H-indol-3-yl)methyl)piperidin-4-yl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyridin-2-amine, hydrochloride: A procedure similar to the one used in the synthesis of 1-(1 -methyl-1 H-indol-3-yl)-/V-((1 -(5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine hydrochloride (example 9) but using N- (piperidin-4-yl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-amine trifluoroacetic acid salt was used to prepare the title compound as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.19 - 10.48 (br.s., 1 H), 8.62 (s, 1 H), 7.98 (d, J = 9.6 Hz, 1 H), 7.84 (d, J = 8 Hz, 1 H), 7.63 (s, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.25 (m, 1 H), 7.17 (m, 1 H), 6.71 (d, J = 9.2 Hz, 1 H), 4.44 (br. s., 2H), 4.05 (br.s., 1 H), 3.85 (s, 3H), 3.40 - 3.52 (m, 2H), 3.34 (br.s., 1 H), 3.00 - 3.17 (m, 2H), 2.07 - 2.17 (m, 2H), 1 .79 (m, 2H). LCMS: fR = 0.73 min, 98%. MS (ESI): m/z 457 (M+H)+.
Figure imgf000071_0002
ferf-Butyl 4-((5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2- yl)amino)piperidine-1 -carboxylate: A mixture of ferf-butyl 4-aminopiperidine-1 - carboxylate (0.401 g, 2.000 mmol), 3-(2-chloropyrimidin-5-yl)-5-(trifluoromethyl)-1 ,2,4- oxadiazole (0.251 g, 1 mmol), and /'-Pr2NEt (0.437 ml_, 2.500 mmol) in NMP (5 ml.) was heated at 75 °C overnight, cooled, and partitioned between EtOAc and water. The organic phase was separated, and the aqueous phase was further extracted with EtOAc twice. The combined organic phases were washed with water/brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% - 50% EtOAc in hexanes) to afford the title compound as an off- white solid (0.324 g, 75%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (s, 2H), 5.46 (d, J = 8.0Hz, 1 H), 4.10 (br. s., 3H), 2.83 - 3.15 (m, 2H), 2.06 (br. s., 2H), 1 .34 - 1 .60 (m, 1 1 H); LCMS: tR = 1.05 min, >95%; MS (ESI): m/z 415 (M+H)+. MPLE 32
Figure imgf000072_0001
A -(Piperidin-4-yl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-am
trifluoroacetic acid salt: A procedure similar to the one used in the synthesis of (1 -(5-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyridin-2-yl)piperidin-4-yl)methanamine,
trifluoroacetic acid salt (example 8) but using ferf-butyl 4-((5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyrimidin-2-yl)amino)piperidine-1 -carboxylate was used to prepare the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 8.47 - 8.69 (m, 1 H), 8.34 (d, J = 7.53 Hz, 2H), 4.02 - 4.25 (m, 1 H), 3.31 (br. s., 2H), 3.04 (d, J = 5.27 Hz, 2H), 2.03 (br. s., 2H), 1 .73 (br. s., 2H); LCMS: tR = 0.45 min, 100%; MS (ESI): m/z 315 (M+H)+.
Figure imgf000072_0002
Λ -(1 -((1 -Methyl-1 H-indol-3-yl)methyl)piperidin-4-yl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)pyrimidin-2-amine, hydrochloride: A procedure similar to the one used in the synthesis of 1-(1 -methyl-1 /-/-indol-3-yl)-/V-((1 -(5-(5-(trifluoromethyl)-1 , 2, 4-oxadiazol- 3-yl)pyridin-2-yl)piperidin-4-yl)methyl)methanamine hydrochloride (example 9) but using A/-(piperidin-4-yl)-5-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)pyrimidin-2-amine
trifluoroacetic acid salt was used to prepare the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.99 - 10.22 (m, 1 H), 8.87 (s, 2H), 8.35 (d, J = 7.03 Hz, 1 H), 7.81 (d, J = 7.78 Hz, 1 H), 7.60 (s, 1 H), 7.51 (d, J = 8.28 Hz, 1 H), 7.24 (m, 1 H), 7.16 (m, 1 H), 4.43 (br. s., 2H), 3.93 - 4.09 (m, 1 H), 3.84 (s, 3H), 3.46 (br. s., 2H), 3.00 - 3.18 (m,
2H), 2.07 (br. s., 2H), 1 .82 (m, 2H); LCMS: tR = 0.63 min, 97%; MS (ESI): m/z 458 (M+H)+. Pharmaceutical Compositions
Example A
Tablets are prepared using conventional methods and are formulated as follows:
Inqredient Amount per tablet
Compound 1 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
Histone Deacetylase 9 (HDAC9) Inhibition Assay:
Novel histone deacetylase 9 (HDAC9) inhibitors were characterized in an in vitro biochemical functional assay. The assay measures the increased fluorescent signal due to deacetylation, by HDAC9, of a fluorogenic substrate. The commercial available substrate is Class lla HDAC-specific and contains an acetylated lysine residue and would releases the fluorescent signal upon trypsin cleavage after deacetylation.
Specifically, test compounds diluted to various concentrations in 100% DMSO are first dispensed into 384-well assay plates. Recombinant HDAC9 isoform 4 (purchased from BPS Bioscience) in complete assay buffer (50 mM Tris-HCI, pH 8.0, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCI2, 0.05% BSA & 0.005% Tween 20) were then added to each well (5uL/well) using Multidrop Combi (Thermo Scientific), followed by 5 uL/well substrate (purchased from BPS Bioscience, 4.5 uM final). After 45 minutes incubation at room temperature, 10uL 2x developer solution (assay buffer with 40 uM Trypsin and 20 uM Trichostatin A) was added. The plates were then incubated 1 hour at room temperature before reading in fluorescent intensity mode at 450nm in an Envision (Perkin Elmer) plate reader. Percent Inhibition of HDAC9 activity by compounds in each test wells was calculated by normalizing to fluorescent signal in control wells containing DMSO only. The plC50s value of test compounds were calculated from non-linear curve fitting, using ActivityBase5 data analysis tool (IDBS), from 1 1 point 3x dilution series starting from 100 uM final compound concentration.
For concentration/dose response experiments, normalized data were fit and plC50s determined using conventional techniques. The plC50s are averaged to determine a mean value, for a minimum of 2 experiments. As determined using the above method, the compounds of Examples 1-33 exhibited a plC5o between 5.0 and 9.0 e.g., for example, the compound of Example 6 inhibited HDAC9 in the above method with a mean pICso of >6.
References:
US 20060269559, US Patent No. 7,521 ,044, WO2007084775
"Deacetylase inhibition promotes the generation and function of regulatory T cells,"
R.Tao, E. F. de Zoeten, E. O" zkaynak, C. Chen, L. Wang, P. M. Porrett, B. Li, L. A.
Turka, E. N. Olson, M. I. Greene, A. D. Wells, W. W. Hancock, Nature Medicine, 13 (1 1 ), 2007.
"Expression of HDAC9 by T Regulatory Cells Prevents Colitis in Mice," E. F. de Zoeten, L. Wang, H. Sai, W. H. Dillmann, W. W. Hancock, Gastroenterology. 2009 Oct 28.
"Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells," L. Wang, E. F. de Zoeten, M. I. Greene and W. W. Hancock, Nature Review Drug Discovery. 8(12):969-81 , 2009 and references therein.
"HDAC7 targeting enhances FOXP3+ Treg function and induces long-term allograft survival," L. Wang, et al., Am. J. Transplant 9, S621 (2009).
"Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes," A. Nebbioso, F. Manzo, M. Miceli, M. Conte, L. Manente, A. Baldi, A. De Luca, D. Rotili, S. Valente, A. Mai, A. Usiello, H. Gronemeyer, L. Altucci, EMBO reports 10 (7) , 776-782, 2009. and references therein.
"Myocyte Enhancer Factor 2 and Class II Histone Deacetylases Control a Gender-
Specific Pathway of Cardioprotection Mediated by the Estrogen Receptor," E. van Rooij, J. Fielitz, L. B. Sutherland, V. L. Thijssen, H. J. Crijns, M. J. Dimaio, J. Shelton, L. J. De Windt, J. A. Hill, E.N. Olson, Circulation Research, Jan 2010.

Claims

What is claimed is:
1. A method of inhibiting HDAC comprising contacting a cell with an effective amount of a compound according to Formula I:
Figure imgf000075_0001
(I)
wherein:
Ar is an optionally substituted aryl (arylene) or 5-6 membered, monocyclic or 9-10 membered, bicyclic heteroaryl (heteroarylene), wherein said optionally substituted aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of (CrC4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy,
halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
wherein each RA is independently selected from the group consisting of H and (Ci-C4)alkyl;
each n is independently 0, 1 or 2;
k is 0, 1 or 2;
each Rx is independently selected from the group consisting of (CrC4)alkyl, halo(C C4)alkyl, oxo, -NRARA, -((d-C4)alkyl)ORA, and -((C C4)alkyl)NRARA, or two Rx taken together with the atoms through which they are attached form a 3-7 membered saturated ring, optionally containing 1 or 2 heteroatoms each independently selected from N and O;
m is 0, 1 or 2;
X is N or CH, wherein when X is N, Z is S02, CO, C02, CONRZa, or a direct bond and when X is CH, Z is NRZaS02, NRZaCO, NRZb, O, or NRZaC02, wherein RZa is H or (Ci-C6)alkyl and RZb is H, (C C6)alkyl, or -CO(C C4)alkyl; and
R is H or a (CrC8)alkyl, halo(Ci-C4)alkyl, aryl, heteroaryl, heterocycloalkyl, aryl(CrC6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(Ci-C6)alkyl- or
heterocycloalkyl(Ci-C6)alkyl- group,
wherein any of said aryl, heteroaryl, or heterocycloalkyl is substituted by Q2 and by 1 , 2 or 3 Q1 substituents,
wherein the (CrC8)alkyl group or the (CrC6)alkyl or (C2-C6)alkenyl moiety of the aryl(CrC6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(Ci-C6)alkyl- or heterocycloalkyl(C1-C6)alkyl- group is optionally substituted by cyano, halo(C1-C2)alkyl, (C1-C4)alkoxy, halo(CrC4)alkoxy, amino, (C1-C4)alkylamino-,
((C1-C4)alkyl)((C1-C4)alkyl)amino-, aminocarbonyl, (C1-C4)alkylaminocarbonyl, ((Ci-C4)alkyl)( (Ci-C4)alkyl)aminocarbonyl, hydroxy, (Ci-C4)alkylcarbonyl,
hydroxy(C2-C4)alkylamino-, amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-, or
((Ci-C4)alkyl)amino(C2-C4)alkyl)((Ci-C4)alkyl)amino-,
any of said heteroaryl is a 5-6 membered or 9-10 membered heteroaryl, wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom,
and any of said heterocycloalkyl is a 5-6 membered heterocycloalkyl and contains a nitrogen, oxygen or sulfur ring atom,
wherein when any of said heteroaryl or heterocycloalkyl contains a substitutable nitrogen atom, said nitrogen atom is substituted by RY, wherein
RY is hydrogen, (C C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCHRYARYB, where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (C1-C6)alkyl, and amino(C1-C6)alkyl-,
or RY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O and S or an oxide thereof;
wherein each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (CrC6)alkyl, halo(CrC6)alkyl, cyano(CrC6)alkyl, (Ci-C6)alkoxy, halo(C C6)alkoxy, (Ci-C6)alkoxy(C2-C6)alkyl-, (Ci-C6)alkoxy(C2-C6)alkoxy, hydroxy(CrC6)alkyl-, hydroxy(C2-C6)alkoxy, amino, (Ci-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, amino(C2-C6)alkoxy, ((Ci-C6)alkyl)amino(C2-C6)alkoxy, ((CrC6)alkyl) ((Ci-C6)alkyl)amino(C2-C6)alkoxy, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino-,(5-6 membered heterocycloalkyl)((Ci-C6)alkyl)amino-, hydroxy(C2-C6)alkylamino, (hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl,
hydroxy(C2-C6)alkylamino(Ci-C6)alkyl, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (hydroxy(C2-C6)alkyl) ((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(C1-C6)alkyl, phenylamino-, (phenyl)((C1-C6)alkyl)amino-, aminocarbonyl, (C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)((C1-C6)alkyl)aminocarbonyl, amino(C1-C6)alkyl-,
(Ci-C6)alkylamino(Ci-C6)alkyl-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl-, (5-6 membered heteroaryl)amino(Ci-C6)alkyl-, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)amino(Ci-C6)alkyl-, (5-6 membered
heterocycloalkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl-, ((Ci-C6)alkyl)amino(C2-C6)alkoxy, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkoxy, (C C6)alkylcarbonyl,
(Ci-C6)alkoxycarbonyl, (CrC6)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
heterocycloalkylsulfonyl, arylsulfonyl, arylsulfonylamino, aryloxy, aryl(Ci-C6)alkyl, aryloxy(Ci-C6)alkyl, aryl(C2-C6)alkenyl, amino(C2-C6)alkylamino-,
(Ci-C6)alkoxy(C2-C6)alkylamino-, ((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heteroaryl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)amino(C2-C6)alkylamino-, (5-6 membered
heterocycloalkyl)amino(C2-C6)alkylamino(C1-C6)alkyl, (5-6 membered
heteroaryl)((C1-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)((C1-C6)alkyl)amino(C2-C6)alkylamino(C1-C6)alkyl, (5-6 membered heterocycloalkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heterocycloalkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heteroaryl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heterocycloalkyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered heterocycloalkyl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(Ci-C6)alkyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C4)alkyl)amino(Ci-C6)alkyl,
((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-,
aminosulfonylamino((C2-C6)alkyl)amino,
aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl, and an optionally substituted aryl, aryloxy, aryl-(Ci-C6)alkyl-, aryl-(Ci-C6)alkoxy, heteroaryl, heteroaryloxy, heteroaryl-(C1-C6)alkyl-, heteroaryl-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl-(C1-C6)alkyl-, (C3-C6)cycloalkyl-(C1-C6)alkoxy heterocycloalkyl, heterocycloalkyl-(C1-C6)alkyl-, or heterocycloalkyl-(C1-C6)alkoxy group, wherein any of said aryl is phenyl or naphthyl, any of said heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl and any of said
heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl,
and wherein any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (Ci-C6)alkyl, aryl, halo(CrC6)alkyl, (Ci-C6)alkoxy, aryloxy, halo(CrC6)alkoxy, hydroxy(Ci-C)alkyl-, hydroxy(C2-C4)alkoxy, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkoxy, amino, (Ci-C)alkylamino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino-, aminocarbonyl, (d-C)alkylaminocarbonyl, ((Ci-C)alkyl)( (Ci-C)alkyl)aminocarbonyl, amino(Ci-C)alkyl-, (Ci-C)alkylamino(Ci-C)alkyl-, ((Ci-C)alkyl)((Ci-C)alkyl)amino(Ci-C)alkyl- (C C6)alkylcarbonyl, (Ci-C6)alkoxycarbonyl, amino(C2-C)alkylamino-, ((Ci-C)alkyl)amino(C2-C)alkylamino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino(C2-C)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino,
((C1-C4)alkyl)((C1-C4)alkyl)amino((C2-C4)alkyl)amino(C1-C4)alkyl,
((C1-C)alkyl)amino(C2-C)alkyl((C1-C)alkyl)amino- ,((C1-C)alkyl)((C1-C)alkyl)amino(C2-C)alkyl((C1-C6)alkyl)amino,
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C4)alkyl((C1-C4)alkyl)amino(C1-C4)alkyl, (Ci-C4)alkylsulfonyl, naphthylsulfonyl, aminosulfonyl, ((Ci-C6)alkyl)aminosulfonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonyl, aminosulfonylamino((C2-C4)alkyl)amino, aminosulfonylamino((C2-C4)alkyl)amino(Ci-C4)alkyl,
((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino,
((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino(Ci-C6)alkyl, piperidinyl(CrC4)alkoxy, pyrrolidinyl(Ci-C4)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(Ci-C4)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylpiperazinyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylpiperazinyl(Ci-C4)alkyl, (Ci-C4)alkylpiperazinyl, (Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, hydroxy(CrC4)alkylpiperazinyl,
hydroxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, (CrC4)alkoxypiperidinyl,
(Ci-C4)alkoxypiperidinyl(Ci-C4)alkyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl,
hydroxy(C2-C6)alkoxy(CrC6)alkyl, hydroxy(C2-C4)alkylamino,
hydroxy(C2-C4)alkylamino(Ci-C4)alkyl, (hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)((C1-C4)alkyl)amino(C1-C4)alkyl, (hydroxy(C2-C4)alkyl)(hydroxy(C2-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)(hydroxy(C2-C4)alkyl)amino(C1-C4)alkyl, furanyl, benzofuranyl, pyrrolidinyl(C1-C4)alkyl, pyrrolidinyl(C1-C4)alkoxy, morpholinyl, morpholinyl(C1-C4)alkoxy, morpholinyl(Ci-C4)alkyl, morpholinyl(Ci-C4)alkylamino,
morpholinyl(Ci-C4)alkylamino(Ci-C4)alkyl,
piperazinyl,(Ci-C4)alkylpiperazinyl(Ci-C4)alkylamino,
(Ci-C4)alkylpiperazinyl(Ci-C4)alkylamino(Ci-C6)alkyl, tetrahydropyrimidinyl, phenyl, naphthyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinyl(Ci-C4)alkyl, piperidinylamino(C2-C4)alkylamino, piperidinylamino(C2-C4)alkylamino(Ci-C4)alkyl, ((Ci-C4)alkylpiperidinyl)(hydroxy(C2-C4)alkyl)amino(C2-C4)alkylamino,
((Ci-C4)alkylpiperidinyl)(hydroxy(C2-C4)alkyl)amino(C2-C4)alkylamino(Ci-C4)alkyl, aminosulfonylpiperazinyl(Ci-C4)alkoxy, and thienyl(Ci-C4)alkylamino,
or Q1 is a divalent (C3-C6)alkyl or -0(C2-C4)alkoxy moiety;
Q2 is hydrogen, halogen, cyano, (CrC6)alkyl, halo(CrC6)alkyl, (CrC6)alkoxy, halo(CrC6)alkoxy, amino, (Ci-C6)alkylamino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, phenylamino-, (phenyl)((Ci-C6)alkyl)amino-, aminocarbonyl, (d-C6)alkylaminocarbonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminocarbonyl, aminosulfonyl, (Ci-C6)alkylaminosulfonyl, ((C1-C6)alkyl)((C1-C6)alkyl)aminosulfonyl, amino(C1-C6)alkyl-,
(Ci-C6)alkylamino(Ci-C6)alkyl- ((C1-C6)alkyl)((C1-C6)alkyl)amino(C1-C6)alkyl-,
hydroxy(C1-C6)alkyl-, (C1-C6)alkylcarbonyl, (C1-C6)alkylsulfonyl, amino(C2-C6)alkylamino-, ((C1-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-, or
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl)amino(Ci-C6)alkyl,
where Q2 is hydrogen, (CrC6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C 6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCHRYARYB, or where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-;
or a salt thereof.
2. A compound of Formula (I)
Figure imgf000079_0001
(I) wherein:
Ar is an optionally substituted aryl (arylene) or 5-6 membered, monocyclic or 9-10 membered, bicyclic heteroaryl (heteroarylene), wherein said optionally substituted aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of (CrC4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
wherein each RA is independently selected from the group consisting of H and (Ci-C4)alkyl;
each n is independently 0, 1 or 2;
k is 0, 1 or 2;
each Rx is independently selected from the group consisting of (CrC4)alkyl, halo(Ci-C4)alkyl, oxo, -NRARA, -((Ci-C4)alkyl)ORA, and -((C C4)alkyl)NRARA, or two Rx taken together with the atoms through which they are attached form a 3-7 membered saturated ring, optionally containing 1 or 2 heteroatoms each independently selected from N and O;
m is 0, 1 or 2 and X is N or CH, wherein
when m is 0, 1 or 2 and X is CH, then Z is NRZaS02, NRZaCO, NRZb, O, or NRZaC02,
when m is 0 and X is N, then Z is S02 or a direct bond, or
when m is 1 or 2 and X is N, then Z is S02, CO, C02, CONRZa, or a direct bond; wherein RZa is H or (C C6)alkyl, and RZb is H, (C C6)alkyl, or -CO(Ci-C4)alkyl; and
R is H or a (CrC8)alkyl, halo(Ci-C4)alkyl, aryl, heteroaryl, heterocycloalkyl, aryl(CrC6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(Ci-C6)alkyl- or
heterocycloalkyl(Ci-C6)alkyl- group,
wherein any of said aryl, heteroaryl, or heterocycloalkyl is substituted by Q2 and by 1 , 2 or 3 Q1 substituents,
wherein the (CrC8)alkyl group or the (CrC6)alkyl or (C2-C6)alkenyl moiety of the aryl(CrC6)alkyl-, aryl(C2-C6)alkenyl-, heteroaryl(Ci-C6)alkyl- or
heterocycloalkyl(Ci-C6)alkyl- group is optionally substituted by cyano, halo(Ci-C2)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
((Ci-C4)alkyl)( (Ci-C4)alkyl)aminocarbonyl, hydroxy, (Ci-C4)alkylcarbonyl,
hydroxy(C2-C4)alkylamino-, amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkylamino-, ((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C4)alkylamino-, or
((C1-C4)alkyl)amino(C2-C4)alkyl)((C1-C4)alkyl)amino-,
any of said heteroaryl is a 5-6 membered or 9-10 membered heteroaryl, wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom,
and any of said heterocycloalkyl is a 5-6 membered heterocycloalkyl and contains a nitrogen, oxygen or sulfur ring atom,
wherein when any of said heteroaryl or heterocycloalkyl contains a substitutable nitrogen atom, said nitrogen atom is substituted by RY, wherein
RY is hydrogen, (C C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCHRYARYB, where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-,
or RY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O and S or an oxide thereof;
wherein each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (C1-C6)alkyl, halo(C1-C6)alkyl, cyano(C1-C6)alkyl,
(d-C6)alkoxy, halo(C C6)alkoxy, (C1-C6)alkoxy(C2-C6)alkyl-, (C1-C6)alkoxy(C2-C6)alkoxy, hydroxy(C1-C6)alkyl-, hydroxy(C2-C6)alkoxy, amino, (C1-C6)alkylamino-,
((C1-C6)alkyl)((C1-C6)alkyl)amino-, amino(C2-C6)alkoxy, ((C1-C6)alkyl)amino(C2-C6)alkoxy, ((CrC6)alkyl) ((Ci-C6)alkyl)amino(C2-C6)alkoxy, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino-,(5-6 membered heterocycloalkyl)((Ci-C6)alkyl)amino-, hydroxy(C2-C6)alkylamino, (hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl,
hydroxy(C2-C6)alkylamino(Ci-C6)alkyl, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino, (hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (hydroxy(C2-C6)alkyl) ((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-,
(hydroxy(C2-C6)alkyl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(Ci-C6)alkyl, phenylamino-, (phenyl)((Ci-C6)alkyl)amino-, aminocarbonyl, (Ci-C6)alkylaminocarbonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminocarbonyl, amino(Ci-C6)alkyl-,
(Ci-C6)alkylamino(Ci-C6)alkyl-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl-,(5-6 membered heteroaryl)amino(Ci-C6)alkyl-, (5-6 membered
heteroaryl)((C1-C6)alkyl)amino(C1-C6)alkyl, (5-6 membered heterocycloalkyl)amino(C1-C6)alkyl-, (5-6 membered
heterocycloalkyl)((C1-C6)alkyl)amino(C1-C6)alkyl-, ((C1-C6)alkyl)amino(C2-C6)alkoxy, ((C1-C6)alkyl)((C1-C6)alkyl)amino(C2-C6)alkoxy, (C1-C6)alkylcarbonyl,
(Ci-C6)alkoxycarbonyl, (CrC6)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
heterocycloalkylsulfonyl, arylsulfonyl, arylsulfonylamino, aryloxy, aryl(Ci-C6)alkyl, aryloxy(Ci-C6)alkyl, aryl(C2-C6)alkenyl, amino(C2-C6)alkylamino-,
(Ci-C6)alkoxy(C2-C6)alkylamino-, ((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heteroaryl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)amino(C2-C6)alkylamino-, (5-6 membered
heterocycloalkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered
heterocycloalkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heterocycloalkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino(Ci-C6)alkyl, (5-6 membered heteroaryl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered
heteroaryl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(C1-C6)alkyl, (5-6 membered heterocycloalkyl)(hydroxy(C2-C6)alkyl)amino(C2-C6)alkylamino-, (5-6 membered heterocycloalkyl)(hydroxy(C2-C6)alkyl))amino(C2-C6)alkylamino(C1-C6)alkyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C4)alkyl)amino(Ci-C6)alkyl,
((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl)((Ci-C6)alkyl)amino-,
aminosulfonylamino((C2-C6)alkyl)amino,
aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino,
((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonylamino((C2-C6)alkyl)amino(Ci-C6)alkyl, and an optionally substituted aryl, aryloxy, aryl-(Ci-C6)alkyl-, aryl-(Ci-C6)alkoxy, heteroaryl, heteroaryloxy, heteroaryl-(Ci-C6)alkyl-, heteroaryl-(Ci-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl-(Ci-C6)alkyl-, (C3-C6)cycloalkyl-(Ci-C6)alkoxy heterocycloalkyl, heterocycloalkyl-(CrC6)alkyl-, or heterocycloalkyl-(CrC6)alkoxy group, wherein any of said aryl is phenyl or naphthyl, any of said heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl and any of said
heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl, and wherein any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (C1-C6)alkyl, aryl, halo(C1-C6)alkyl, (Ci-C6)alkoxy, aryloxy, halo(CrC6)alkoxy, hydroxy(Ci-C)alkyl-, hydroxy(C2-C4)alkoxy, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkoxy, amino, (Ci-C)alkylamino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino-, aminocarbonyl, (CrC)alkylaminocarbonyl, ((Ci-C)alkyl)( (Ci-C)alkyl)aminocarbonyl, amino(Ci-C)alkyl-, (Ci-C)alkylamino(Ci-C)alkyl-,
((Ci-C)alkyl)((Ci-C)alkyl)amino(Ci-C)alkyl- (C C6)alkylcarbonyl, (Ci-C6)alkoxycarbonyl, amino(C2-C)alkylamino-, ((Ci-C)alkyl)amino(C2-C)alkylamino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino(C2-C)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino((C2-C4)alkyl)amino(Ci-C4)alkyl,
((Ci-C)alkyl)amino(C2-C)alkyl((Ci-C)alkyl)amino-,
((Ci-C)alkyl)((Ci-C)alkyl)amino(C2-C)alkyl((Ci-C6)alkyl)amino,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl((Ci-C4)alkyl)amino(Ci-C4)alkyl,
(Ci-C4)alkylsulfonyl, naphthylsulfonyl, aminosulfonyl, ((Ci-C6)alkyl)aminosulfonyl, ((C1-C6)alkyl)((C1-C6)alkyl)aminosulfonyl, aminosulfonylamino((C2-C4)alkyl)amino, aminosulfonylamino((C2-C4)alkyl)amino(C1-C4)alkyl,
((C1-C4)alkyl)((C1-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino,
((C1-C4)alkyl)((C1-C4)alkyl)aminosulfonylamino((C2-C4)alkyl)amino(C1-C6)alkyl, piperidinyl(CrC4)alkoxy, pyrrolidinyl(Ci-C4)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(Ci-C4)alkyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylpiperazinyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)aminosulfonylpiperazinyl(Ci-C4)alkyl, (Ci-C4)alkylpiperazinyl, (Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, hydroxy(CrC4)alkylpiperazinyl,
hydroxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, (CrC4)alkoxypiperidinyl,
(Ci-C4)alkoxypiperidinyl(Ci-C4)alkyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl,
hydroxy(C2-C6)alkoxy(CrC6)alkyl, hydroxy(C2-C4)alkylamino,
hydroxy(C2-C4)alkylamino(Ci-C4)alkyl, (hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl,
(hydroxy(C2-C4)alkyl)(hydroxy(C2-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)(hydroxy(C2-C4)alkyl)amino(Ci-C4)alkyl, furanyl, benzofuranyl, pyrrolidinyl(Ci-C4)alkyl, pyrrolidinyl(Ci-C4)alkoxy, morpholinyl, morpholinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkyl, morpholinyl(Ci-C4)alkylamino,
morpholinyl(C1-C4)alkylamino(C1-C4)alkyl, piperazinyl,(C1-C4)alkylpiperazinyl(C1-C4)alkylamino,
(C1-C4)alkylpiperazinyl(C1-C4)alkylamino(C1-C6)alkyl, tetrahydropyrimidinyl, phenyl, naphthyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinyl(C1-C4)alkyl, piperidinylamino(C2-C )alkylamino, piperidinylamino(C2-C )alkylamino(Ci-C )alkyl,
((Ci-C )alkylpiperidinyl)(hydroxy(C2-C )alkyl)amino(C2-C )alkylamino,
((Ci-C )alkylpiperidinyl)(hydroxy(C2-C )alkyl)amino(C2-C )alkylamino(Ci-C )alkyl, aminosulfonylpiperazinyl(Ci-C )alkoxy, and thienyl(Ci-C )alkylamino,
or Q1 is a divalent (C3-C6)alkyl or -0(C2-C )alkoxy moiety;
Q2 is hydrogen, halogen, cyano, (CrC6)alkyl, halo(CrC6)alkyl, (CrC6)alkoxy, halo(CrC6)alkoxy, amino, (Ci-C6)alkylamino-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino-, phenylamino-, (phenyl)((Ci-C6)alkyl)amino-, aminocarbonyl, (d-C6)alkylaminocarbonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminocarbonyl, aminosulfonyl, (Ci-C6)alkylaminosulfonyl, ((Ci-C6)alkyl)((Ci-C6)alkyl)aminosulfonyl, amino(Ci-C6)alkyl-,
(Ci-C6)alkylamino(Ci-C6)alkyl-, ((Ci-C6)alkyl)((Ci-C6)alkyl)amino(Ci-C6)alkyl-,
hydroxy(CrC6)alkyl-, (CrC6)alkylcarbonyl, (Ci-C6)alkylsulfonyl, amino(C2-C6)alkylamino-, ((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkylamino-,
((C1-C6)alkyl)amino(C2-C6)alkyl)((C1-C6)alkyl)amino-, or
((Ci-C6)alkyl)((Ci-C6)alkyl)amino(C2-C6)alkyl)amino(Ci-C6)alkyl,
where Q2 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C 6)cycloalkyl-(C1-C6)alkyl-, aryl(C C6)alkyl-, -S02N(C1-C6)alkyl(C1-C6)alkyl or -COCHRYARYB, or where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-;
or a salt thereof.
3. The method according to claim 1 or the compound or salt according to claim 2, wherein Ar is on optionally substituted phenyl or 6-membered heteroaryl group, wherein said 6-membered heteroaryl contains 1 , 2 or 3 nitrogen atoms, and said optionally substituted phenyl or heteroaryl is optionally substituted by a group selected from the group consisting of (Ci-C )alkyl, halogen, cyano, halo(Ci-C )alkyl, (Ci-C )alkoxy, halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA, wherein each RA is independently selected from the group consisting of H and (CrC )alkyl.
4. The method, compound or salt according to claim 3, wherein Ar is an optionally substituted phenyl, pyridyl or pyrimidinyl.
5. The method, compound or salt according to any one of claims 1 -4, wherein unsubstituted phenyl or pyridyl.
6. The method, compound or salt according to any one of claims 1 -5, wherein each n is 1 .
7. The method, compound or salt according to any one of claims 1 -5, wherein one n is 0 and the other n is 1.
8. The method, compound or salt according to any one of claims 1 -5, wherein one n is 0 and the other n is 2.
9. The method, compound or salt according to any one of claims 1 -8, wherein k is
0.
10. The method, compound or salt according to any one of claims 1 -8, wherein k is 1 and Rx is (C C2)alkyl, halo(C C2)alkyl, -NRARA, -((C C2)alkyl)ORA, or
-((C1-C2)alkyl)NRARA, wherein each RA is independently selected from the group consisting of H and (C1-C2)alkyl.
1 1 . The method, compound or salt according to any one of claims 1 -8, wherein k is 2 and two Rx taken together with the atoms through which they are attached form a 3-6 membered ring.
12. The method, compound or salt according to any one of claims 1-1 1 , wherein X is CH, m is 0, 1 or 2, and Z is NRZaS02, NRZaCO, NRZb, O, or NRZaC02.
13. The method, compound or salt according to any one of claims 1-1 1 , wherein X is CH, m is 0 or 1 , and Z is NRZaS02, NRZaCO, NRZb, O, or NRZaC02.
14. The method, compound or salt according to any one of claims 1-1 1 , wherein X is CH, m is 0 or 1 , and Z is NRZaCO, NRZb or NRZaC02.
15. The method, compound or salt according to any one of claims 1-14, wherein RZa is H or (Ci-C3)alkyl.
16. The method, compound or salt according to any one of claims 1-14, wherein RZa and RZb are each H.
17. The method, compound or salt according to any one of claims 1-11 , wherein X is N, m is 0, and Z is S02 or a direct bond.
18. The method, compound or salt according to any one of claims 1-11 , wherein X is N, m is 1 or 2 and Z is S02, CO, C02, or a direct bond.
19. The method, compound or salt according to any one of claims 1-18, R is H or R is a (Ci-C4)alkyl, halo(Ci-C4)alkyl, aryl, heteroaryl, heterocycloalkyi, aryl(Ci-C4)alkyl-, aryl(C2-C4)alkenyl-, heteroaryl(Ci-C4)alkyl- or heterocycloalkyl(d-C4)alkyl- group, wherein:
the alkyl group or the alkyl or alkenyl moiety of the aryl(Ci-C4)alkyl-,
aryl(C2-C6)alkenyl-, heteroaryl(Ci-C4)alkyl- or heterocycloalkyl(CrC4)alkyl- group is optionally substituted by (Ci-C4)alkoxy, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, hydroxy, hydroxy(C2-C4)alkylamino-,
amino(C2-C4)alkylamino-, ((C1-C4)alkyl)amino(C2-C4)alkylamino-,
((C1-C4)alkyl)((C1-C4)alkyl)amino(C2-C4)alkylamino-, or
((C1-C4)alkyl)amino(C2-C4)alkyl)((C1-C4)alkyl)amino-;
any of said aryl is a phenyl or naphthyl group substituted by 1-3 Q1 groups and Q2, any of said heteroaryl is a 5-6 membered heteroaryl or 9-10 membered heteroaryl group substituted by 1-2 Q1 and Q2 , wherein any of said heteroaryl contains a nitrogen, oxygen or sulfur ring atom and optionally contains one additional nitrogen ring atom, and any of said heterocycloalkyi is a 5-6 membered heterocycloalkyi substituted by Q2 and by 1 or 2 Q1 substituents and contains a nitrogen, oxygen or sulfur ring atom; wherein when any of said heteroaryl or heterocycloalkyi contains a substitutable nitrogen atom, said nitrogen atom is substituted by RY, wherein
RY is hydrogen, (C C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C6)cycloalkyl-(Ci-C6)alkyl-, aryl(C C6)alkyl-, -S02N(Ci-C6)alkyl(Ci-C6)alkyl or
-COCHRYARYB, where RYA and RYB are each independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-,
or RY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, SO and S02.
20. The method, compound or salt according to any one of claims 1-18, wherein R is (C1-C4)alkyl, halo(C1-C4)alkyl, aryl, heteroaryl, heterocyclkoalkyl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl- or heterocycloalkyl(C1-C4)alkyl- group, wherein:
any of said aryl is phenyl substituted by Q1 or naphthyl substituted by Q1 and Q2, any of said heteroaryl is a 5-membered heteroaryl selected furyl (furanyl), thienyl, and pyrrolyl substituted by RY, wherein any of said 5-membered heteroaryl is substituted by Q1,
or any of said heteroaryl is a 9-10 membered heteroaryl selected from the group consisting of quinolyl, indolyl substituted by RY, benzofuranyl, and benzothienyl, wherein said any of 9-10 memebered heteroaryl is substituted by Q1 and Q2,
and any of said heterocycloalkyl is selected from the group consisting of tetrahydrofuranyl, tetrahydrothienyl, and pyrrolidinyl substituted by RY, wherein any of said heterocycloalkyl is substituted by Q1.
21 . The method, compound or salt according to any one of claims 1-20, wherein each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, trihalo(CrC6)alkyl, trihalo(Ci-C6)alkoxy, (CrC6)alkyl, (CrC6)alkoxy, (C1-C6)alkoxy(C2-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkylsulfonyl, cyano(C1-C6)alkyl, hydroxy(C2-C6)alkyl, hydroxy(C2-C6)alkoxy, hydroxy(C2-C6)alkylamino,
amino(C2-C6)alkoxy, aminocarbonyl, (C1-C6)alkylaminocarbonyl,
di((C1-C6)alkyl)aminocarbonyl, di(hydroxy(C2-C6)alkyl)amino,
di((Ci-C6)alkyl)amino(C2-C6)alkoxy, di((Ci-C6)alkyl)amino(C2-C6)alkylamino, arylsulfonyl, arylsulfonylamino, aryloxy, aryl(C2-C6)alkenyl, di((Ci-C6)alkyl)amino, cyano, thienyl, thienyl substituted with di((Ci-C6)alkyl)amino(C2-C6)alkyl((Ci-C6)alkyl)amino(Ci-C6)alkyl, di((Ci-C6)alkyl)amino(Ci-C6)alkyl, (CrC6)alkylpiperazinyl(Ci-C6)alkyl or
di(hydroxy(C2-C6)alkyl)amino(Ci-C6)alkyl, furanyl, imidazolyl, (Ci-C6)alkyltriazolyl, tetrazolyl, piperidinyl(CrC6)alkoxy, morpholinyl, (CrC6)alkylmorpholinyl,
morpholinyl(Ci-C6)alkoxy, morpholinyl(Ci-C6)alkyl, (Ci-C6)alkylpiperazinyl(CrC6)alkoxy, (Ci-C6)alkylpiperazinyl(Ci-C6)alkyl, (CrC6)alkylpiperazinylsulfonyl,
aminosulfonylpiperazinyl(Ci-C6)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(Ci-C6)alkyl, di((Ci-C6)alkyl)aminosulfonylpiperazinyl,
di((Ci-C6)alkyl)aminosulfonylpiperazinyl(Ci-C6)alkyl, hydroxy(CrC6)alkylpiperazinyl, hydroxyCi-alkylpiperazinyl(CrC6)alkyl, (CrC6)alkoxypiperidinyl,
(Ci-C6)alkoxypiperidinyl(Ci-C6)alkyl, hydroxy(C2-C6)alkoxy(Ci-C6)alkylpiperazinyl, hydroxy(C2-C6)alkoxy(Ci-C6)alkylpiperazinyl(Ci-C6)alkyl,
(hydroxy(C2-C6)alkyl)((C1-C6)alkyl)amino, (hydroxy(C2-C6)alkyl)((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkoxy, pyrazolyl, pyrazolyl substituted with two substituents selected from the group consisting of
(Ci-C6)alkyl and trihalo(C C6)alkyl, 3,5,5-trimethyl-1 ,5,6,7-tetrahydro-4/-/-indazol-4-on-1- yl, pyridinyl, pyridinyl substituted with (CrC6)alkoxy or aryl, pyrimidinyl, quinolinyl, phenyl, phenyl substituted with one, two or three substituents independently selected from the group consisting of halogen, amino, (CrC6)alkyl, (d-C6)alkoxy, hydroxy(CrC4)alkyl, trifluoromethyl, trifluoromethyloxy, hydroxy(C2-C4)alkoxy, (Ci-C4)alkoxy(C2-C4)alkoxy, amino(C2-C4)alkoxy, di((Ci-C4)alkyl)amino(C2-C4)alkoxy, di((Ci-C4)alkyl)amino, piperidinyl(CrC4)alkoxy, pyrrolidinyl(Ci-C4)alkoxy, aminosulfonylpiperazinyl,
aminosulfonylpiperazinyl(Ci-C4)alkyl, di((Ci-C4)alkyl)aminosulfonylpiperazinyl, di((Ci-C4)alkyl)aminosulfonylpiperazinyl(Ci-C4)alkyl, hydroxy(CrC4)alkylpiperazinyl, hydroxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl, (CrC4)alkoxypiperidinyl,
(Ci-C4)alkoxypiperidinyl(Ci-C4)alkyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl, hydroxy(C2-C4)alkoxy(Ci-C4)alkylpiperazinyl(Ci-C4)alkyl,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino,
(hydroxy(C2-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C4)alkyl, pyrrolidinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkoxy, morpholinyl(Ci-C4)alkyl, (Ci-C4)alkylpiperazinyl(CrC4)alkoxy, (C1-C4)alkylpiperazinyl(C1-C4)alkyl, hydroxy(C2-C4)alkylamino,
di(hydroxy(C2-C4)alkyl)amino, di((C1-C4)alkyl)amino(C2-C4)alkylamino, aminothiadiazolyl, aminosulfonylpiperazinyl(C1-C4)alkoxy,and thienyl(C1-C4)alkylamino.
22. The method, compound or salt according to any one of claims 1-21 , wherein each Q1 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, (CrC6)alkyl, halo(CrC6)alkyl, (CrC6)alkoxy, halo(CrC6)alkoxy, (Ci-C6)alkoxy(C2-C6)alkyl-, hydroxy(CrC4)alkyl-, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, phenylamino-, (phenyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl, ((Ci-C4)alkyl)((Ci-C4)alkyl)aminocarbonyl, amino(Ci-C6)alkyl-, (Ci-C4)alkylamino(Ci-C6)alkyl-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(Ci-C6)alkyl-, (C C6)alkylcarbonyl,
(Ci-C6)alkoxycarbonyl, (CrC6)alkylsulfonyl, amino(C2-C6)alkylamino,
(Ci-C6)alkoxy(C2-C6)alkylamino-, ((Ci-C4)alkyl)amino(C2-C6)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C6)alkylamino-,
((Ci-C4)alkyl)amino(Ci-C4)alkyl)((C2-C6)alkyl)amino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl)amino(Ci-C4)alkyl, and an optionally substituted aryl, aryloxy, aryl-(Ci-C6)alkyl-, aryl-(Ci-C6)alkoxy, heteroaryl, heteroaryloxy, heteroaryl-(C1-C6)alkyl-, heteroaryl-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl-(C1-C6)alkyl-, (C3-C6)cycloalkyl-(C1-C6)alkoxy heterocycloalkyl, heterocycloalkyl-(C1-C6)alkyl-, or heterocycloalkyl-(C1-C6)alkoxy group,
wherein any of said aryl is phenyl or naphthyl, any of said heteroaryl is a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl and any of said
heterocycloalkyl is a 5-6 membered monocyclic heterocycloalkyl,
and wherein any of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1 -4 substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, oxo, (Ci-C6)alkyl, halo(CrC6)alkyl,
(Ci-C6)alkoxy, halo(CrC6)alkoxy, hydroxy(CrC4)alkyl-, amino, (Ci-C4)alkylamino-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
((Ci-C4)alkyl)((Ci-C4)alkyl)aminocarbonyl, amino(Ci-C4)alkyl-,
(Ci-C4)alkylamino(Ci-C4)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C C4)alkyl-,
(Ci-C6)alkylcarbonyl, (CrC6)alkoxycarbonyl, amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino(C2-C4)alkyl)((Ci-C4)alkyl)amino-, and
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl) amino(Ci-C4)alkyl.
23. The method, compound or salt according to any one of claims 1-21 , wherein , each Q1 is hydrogen, halogen, hydroxy, amino, nitro, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylcarbonyl, (C1-C6)alkoxycarbonyl,
hydroxy(CrC6)alkyl, aryloxy, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, cyano, thienyl, furanyl, furanyl substituted with hydroxy(Ci-C6)alkyl-, benzofuranyl, imidazolyl, oxazolyl, oxazolyl substituted with aryl and/or (Ci-C6)alkyl, (CrC6)alkyltriazolyl, tetrazolyl, pyrrolidinyl, pyrrolyl, morpholinyl, (Ci-C6)alkylmorpholinyl, piperazinyl, (CrC6)alkylpiperazinyl, hydroxy(CrC6)alkylpiperazinyl, (CrC6)alkoxypiperidinyl, pyrazolyl, pyrazolyl substituted with one or two substituents selected from the group consisting of (Ci-C6)alkyl and halo(CrC6)alkyl, 3,5,5-trimethyl-1 ,5,6,7-tetrahydro-4H-indazol-4-on-1-yl, pyridinyl, pyridinyl substituted with (CrC6)alkoxy, aryloxy or aryl, pyrimidinyl, quinolyl, indolyl, phenyl, or phenyl substituted with one or two substituents each independently selected from the group consisting of halogen, (CrC6)alkyl, (CrC6)alkoxy and trifluoromethyl.
24. The method, compound or salt according to any one of claims 1-21 , wherein Q1 is a 9-10 membered, bicyclic heteroaryl, optionally substituted by 1-4 substituents each independently selected from the group consisting of halogen, cyano, (Ci-C4)alkyl, halo(CrC4)alkyl, (CrC4)alkoxy, halo(CrC4)alkoxy, oxo, amino, (C1-C4)alkylamino-, ((C1-C4)alkyl)((C1-C4)alkyl)amino-, aminocarbonyl, (C1-C4)alkylaminocarbonyl,
((CrC4)alkyl)( (C1-C4)alkyl)aminocarbonyl, amino(C1-C4)alkyl-,
(C1-C4)alkylamino(C1-C4)alkyl-, ((C1-C4)alkyl)((C1-C4)alkyl)amino(C1-C4)alkyl-,
hydroxy(Ci-C )alkyl-, (Ci-C )alkylcarbonyl, amino(C2-C )alkylamino-,
((Ci-C )alkyl)amino(C2-C )alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C )alkyl)amino(C2-C )alkyl)((Ci-C )alkyl)amino-, and
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkyl)amino(Ci-C4)alkyl.
25. The method, compound or salt according to any one of claims 1-24, wherein each Q1 is H.
26. The method, compound or salt according to any one of claims 1-18, wherein
R is phenyl substituted by two Q1 groups, wherein one Q1 group is
Figure imgf000090_0001
and the other Q1 group is selected from the group consisting of (Ci-C )alkyl,
aminocarbonyl, (C-i-C )alkylaminocarbonyl, and ((Ci-C )alkyl)((Ci-C )alkyl)aminocarbonyl.
27. The method, compound or salt according to any one of claims 1-25, wherein Q2 is hydrogen, halogen, cyano, (Ci-C )alkyl, halo(Ci-C )alkyl, (Ci-C )alkoxy,
halo(Ci-C )alkoxy, (Ci-C )alkylcarbonyl, amino, (Ci-C )alkylamino-,
((Ci-C )alkyl)((Ci-C )alkyl)amino-, amino(Ci-C )alkyl-, (Ci-C )alkylamino(Ci-C )alkyl-, ((Ci-C )alkyl)((Ci-C )alkyl)amino(Ci-C )alkyl-, phenylamino-, (phenyl)((Ci-C )alkyl)amino-, aminocarbonyl, (Ci-C )alkylaminocarbonyl, or ((Ci-C )alkyl)( (Ci-C )alkyl)aminocarbonyl.
28. The method, compound or salt according to any one of claims 1-25, wherein Q2 is hydrogen, halogen, (CrC2)alkyl, -CF3, (d-C2)alkoxy or
((C1-C4)alkyl)((C1-C4)alkyl)amino-, wherein any of said 5-6 membered heterocydoalkyi is optionally substituted by 1-2 (d-C4)alkyl groups.
29. The method, compound or salt according to any one of claims 1-25, wherein Q2 is hydrogen or methyl.
30. The method, compound or salt according to any one of claims 1-25, wherein RY and Q1 taken together with the atoms thru which they are connected form a 5 or 6 membered saturated ring, optionally containing an additional heteroatom selected from N, O, S, SO, and S02.
31 . The method according to claim 1 or the compound or salt according to claim 2, or the method, compound or salt according to any one of claims 21 -30, wherein said compound has Formula (l-
Figure imgf000091_0001
wherein:
A1 and A2 are each independently selected from the group consisting of CH and N; each n is independently 0, 1 or 2;
m is 0, 1 or 2 and X is N or CH, wherein
when m is 0, 1 or 2 and X is CH, then Z is NHS02, NHCO, NH, O, or
NHC02,
when m is 0 and X is N, then Z is S02 or a direct bond, or
when m is 1 or 2 and X is N, then Z is S02, CO, C02, CONH, or a direct bond; and
R is (C1-C4)alkyl, halo(C1-C4)alkyl, or a group selected from the group consisting
Figure imgf000091_0002
wherein Q1 and Q2 may be substituted on either ring;
Y is O, S or NRY, where RY is hydrogen, (C C6)alkyl, (C1-C6)alkoxy(C2-C6)alkyl-, (C3-C 6)cycloalkyl, (C3-C 6)cycloalkyl-(C1-C6)alkyl-, aryl(C C6)alkyl-,
-S02N(Ci-C6)alkyl(Ci-C6)alkyl or -COCHRYARYB, or where RYA and RYB are each
independently selected from the group consisting of hydrogen, amino, (CrC6)alkyl, and amino(Ci-C6)alkyl-;
or when Y is NRY and Q1 is in the 7 position of the indolyl, then NRY and Q1 taken together with the atoms through which they are attached to form a 5 or 6 membered ring; or when R is indolyl and Y is NRY and Q2 is in the 7 position of the indolyl, then Q2 and RY taken together with the atoms through which they are attached to form a 5 or 6 membered ring.
32. The method, compound or salt according to claim 31 , wherein RY is hydrogen, (Ci-C6)alkyl, (Ci-C6)alkoxy(C2-C6)alkyl-, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(Ci-C3)alkyl-, phenyl-(Ci-C3)alkyl-, or (Ci-C6)alkylcarbonyk
33. The method, compound or salt according to claim 31 , wherein RY is hydrogen, (C1-C5)alkyl, (C1-C3)alkoxy(C2-C4)alkyl-, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C2)alkyl-, or benzyl.
34. The method, compound or salt according to claim 31 , wherein RY is H or methyl.
35. The method, compound or salt according to claim 31 , wherein R is selected from the group consisting of:
Figure imgf000092_0001
36. The method according to claim 1 or the compound or salt according to claim 2, or the method, compound or salt according to any one of claims 21 -30, wherein said compound has Formula (l-b):
Figure imgf000093_0001
wherein:
A1 is N and A2 is CH or N;
m is 0, 1 or 2 and X is CH or N, wherein:
when m is 0, 1 or 2, and X is CH, then Z is NHS02, NHCO, NH, O, or
NHC02,
when m is 0 and X is N, then Z is S02 or a direct bond,
or when m is 1 or 2 and X is N, then Z is S02, CO, C02, CONH, or a direct bond;
p is 0 or 1 ; and
R' is phenyl, naphthyl, furyl, thienyl, quinolyl, indolyl substituted by RY,
benzofuranyl, or benzothienyl.
37. The method according to claim 1 or the compound or salt according to claim 2, or the method, compound or salt according to any one of claims 21 -30, wherein said compound has Formula l-c) or (l-d):
Figure imgf000093_0002
Figure imgf000094_0001
wherein:
A1 is N and A2 is CH or N;
m is 0 or 1 ;
when m is 0 or 1 and X is CH, then Z is NH or O,
when m is 0 and X is N, then Z is S02 or a direct bond;
p is 0 or 1.
38. The method according to claim 1 or the compound or salt according to claim 2, wherein said compound has Formula (l-e):
Figure imgf000094_0002
wherein:
A1 is N and A2 is CH or N;
m is 0 or 1 ;
when m is 0, Z is S02 or a direct bond;
when m is 1 , Z is S02, CO, C02, CONH, or a direct bond;
p is 0 or 1 ;
and RQA is hydrogen, halogen, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, 5-6 membered heterocycloalkyl-(C1-C4)alkyl-, 5-6 membered heterocycloalkyl-(CrC4)alkoxy, amino, (Ci-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, aminocarbonyl, (Ci-C4)alkylaminocarbonyl,
((CrC4)alkyl)( (Ci-C4)alkyl)aminocarbonyl, amino(Ci-C4)alkyl-, (C1-C4)alkylamino(C1-C4)alkyl-, ((C1-C4)alkyl)((C1-C4)alkyl)amino(C1-C4)alkyl-,
hydroxy(C1-C4)alkyl-, (C1-C4)alkylcarbonyl, amino(C2-C4)alkylamino-,
((C1-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino-,
((Ci-C4)alkyl)amino((C2-C4)alkyl)((Ci-C4)alkyl)amino-, or
((Ci-C4)alkyl)((Ci-C4)alkyl)amino(C2-C4)alkylamino(Ci-C4)alkyl-;
and RQB is hydrogen, halogen, cyano, (Ci-C )alkyl, halo(Ci-C )alkyl, (Ci-C )alkoxy, or halo(Ci-C )alkoxy.
39. The method, compound or salt according to claim 38, wherein, RQB is hydrogen.
40. The compound or salt according to claim 1 , selected from the group consisting of any one of Examples 1-33.
41 . A pharmaceutical composition comprising the compound or salt according to any one of claims 1 -40 and one or more pharmaceutically-acceptable excipients.
42. A method of inhibiting HDAC comprising contacting a cell with an effective amount of the compound or salt according to any one of claims 1-40.
43. A method of treating an HDAC-mediated disease or condition in a patient comprising administering to said patient a therapeutically-effective amount of the compound or salt according to any one of claims 1-40.
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