WO2013006408A1 - Composés et procédés - Google Patents

Composés et procédés Download PDF

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Publication number
WO2013006408A1
WO2013006408A1 PCT/US2012/044840 US2012044840W WO2013006408A1 WO 2013006408 A1 WO2013006408 A1 WO 2013006408A1 US 2012044840 W US2012044840 W US 2012044840W WO 2013006408 A1 WO2013006408 A1 WO 2013006408A1
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alkyl
optionally substituted
compound
phenyl
crc
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PCT/US2012/044840
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English (en)
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Shomir Ghosh
Mercedes Lobera
Darby R. Schmidt
Erkan Baloglu
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Tempero Pharmaceuticals, Inc.
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Publication of WO2013006408A1 publication Critical patent/WO2013006408A1/fr

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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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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 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.
  • HDAC4 has been linked to a variety of neurodegenerative disorders: it is a downstream target of Parkin (associating it to Parkinson's disease), it's is a major component of intranuclear inclusions produced in NIIND. HDAC4 also contains a conserved glutamine rich domain, such domain has been observed to increase susceptibility to amyloid formation associated with Alzheimer's disease (Majdzadeh et al. Front. Biosci., 2009, p. 1072). Heterozygotes of HDAC4 knockouts crossed to R6/2 mice (Huntington's disease model) led to improved motor/behavior and reduced aggregation
  • HDAC4 and HDAC5 localization are regulated by neuronal activity, and HDAC5 nuclear import is increased in diseased neurons of Huntington's disease patients.
  • HDAC7 another class lla HDAC, has been implicated in regulating ataxin-7 turnover in a SCA-7 model (Mookerjee S et al., J Neurosci., 2009, p. 15134).
  • HDAC6 a class lib HDAC, is expressed in most neurons and most abundantly in cerebellar Purkinje cells, the degeneration of this type of neurons is observed in patients with spinocerebellar ataxia type 1 (SCA1 ) or SCA7.
  • SCA1 spinocerebellar ataxia type 1
  • HDAC6 is involved in regulating microtubule dynamics and protein degradation and a defect in microtubule-based transport may contribute to the neuronal toxicity observed in Huntington's disease (Kazantsev et al. Nature Reviews Drug Discovery, 2008, p. 854). Additionally, HDAC6 activity has been shown to be required for autophagic degradation of aggregated huntingtin, suggesting a role in protecting cells from polyQ toxicity (Iwata, et al., J. Biol. Chem., 2005, p. 40282).
  • HDAC9 is a class lla histone deacetylase highly expressed in human B cells. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell tumors and HDAC9 is highly overexpressed in cells derived from patients with non- Hodgkin's lymphoma
  • HDAC4 and HDAC9 have both been reported to be overexpressed in CD19+ cells from patients with Waldenstrom Macroglobulinemia (Sun et al., Clinical Lymphoma, Myeloma &
  • HDAC4 HDAC5, HDAC7 and HDAC9
  • Bcl-6 a transcription factor implicated in the pathogenesis of B-cell malignancies
  • 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 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.
  • inhibition of Class II HDAC activity represents a novel approach for disrupting or intervening in cell cycle regulation.
  • Class II HDAC inhibitors have therapeutic potential in the study and/or treatment of diseases or conditions ameliorated by modulating HDAC activity (in particular, cell proliferative diseases (such as cancer), diabetes (type I and/or type II diabetes), inflammation, cardiac disease, obesity, stroke, epilepsy, depression, immunological disease or viral or fungal infection.
  • cell proliferative diseases such as cancer
  • diabetes type I and/or type II diabetes
  • inflammation inflammation
  • cardiac disease obesity, stroke, epilepsy, depression, immunological disease or viral or fungal infection.
  • a small molecule selective inhibitor of HDAC activity (more specifically, an inhibitor of HDAC4 and/or HDAC5 and/or HDAC6 and/or HDAC7 and/or HDAC8 and/or HDAC9 activity) is expected to modulate autoimmune diseases and further is expected to be beneficial in the treatment of neurodegenerative diseases and in the treatment of cancers.
  • the invention is directed to a compound according to Formula I:
  • R 1 is halo(C 1 -C 4 )alkyl, wherein said halo(C 1 -C 4 )alkyl contains at least 2 halo groups;
  • Y is a bond and Xi is O, N or NH, X 2 is N or CH and X 3 is N or NH,
  • Y is -C(O)- and Xi and X 2 are CH or N, X 3 is O or S,
  • Y is -C(O)- and Xi is O, X 2 is CH or N, and X 3 is CH or N;
  • A is optionally substituted phenyl or 5-6 membered heteroaryl, wherein said optionally substituted phenyl or heteroaryl is optionally substituted by 1 -3 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, -NR A R A and -((C C 4 )alkyl)NR A R A ;
  • n 0, 1 or 2 and m is 0, 1 or 2; provided that 0 ⁇ m+n ⁇ 3;
  • R 2 is H, fluoro, (Ci-C 4 )alkyl, -(C C 4 )alkyl-NR A R B , -CONR A R B , -C0 2 H,
  • R A and R B are each independently selected from H and
  • R 3 is H or (C C 4 )alkyl
  • R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 or 2 heteroatoms independently selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by 1 , 2 or 3 substituents independently selected from (Ci-C 4 )alkyl,
  • each R Y is independently selected from H, (Ci-C 4 )alkyl, phenyl, and
  • R 4 is H or (Ci-C 4 )alkyl
  • L is 5-6 membered heterocycloalkyi, 5-6 membered heteroaryl, phenyl,
  • R A is independently selected from H and (CrC 4 )alkyl
  • R c is H, (CrC 4 )alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or R A and R c taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C 1 -C 4 )alkyl and
  • said optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, phenyl(C 1 -C 4 )alkyl-, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups each independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (Ci-C 4 )alkoxy, (Ci-C 4 )alkylthio-, halo(Ci-C 4 )alkoxy, hydroxyl, amino, (Ci-C 4 )alkyl-amino-, amino(Ci-C 4 )alkyl-, ((Ci-C 4 )alkyl)amino-(Ci-C 4 )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.
  • R 1 is a fluoro- alkyl group containing at least 2 fluoro groups (atoms). In another embodiment, R 1 is a (CrC 2 )alkyl group containing at least 2 fluoro groups. In a specific embodiment, R 1 is CHF 2 or CF 3 ; more specifically, R 1 is CF 3
  • X-i, X 2 , and X 3 taken together with the atoms to which they are attached, form an oxadiazolyl (Xi is O, X 2 and X 3 are N), oxazolyl (Xi is O, X 2 is CH, X 3 is N), imidazolyl (Xi is N or NH, X 2 is CH, X 3 is N or NH); or a triazolyl (Xi is N or NH, X 2 is N, X 3 is N or NH) ring moiety.
  • Y is a bond
  • X-i, X 2 , and X 3 taken together with the atoms to which they are attached form an oxadiazolyl ring moiety.
  • Y is -C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached, form an thiazolyl (X 3 is S, X-i is CH and X 2 is N or X 3 is S, X is N and X 2 is CH), oxazolyl (X 3 is O, X ⁇ is CH and X 2 is N or X 3 is O, X ⁇ is N and X 2 is CH), thienyl (Xi and X 2 are CH, X 3 is S) or furanyl (Xi and X 2 are CH, X 3 is O) ring moiety.
  • Y is -C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached form a thienyl, thiazolyl or oxazolyl ring moiety, more specifically a thienyl moiety.
  • Y when Y is -C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached, form a furanyl or furyl (Xi is O, X 2 and X 3 are CH), oxazolyl (Xi is O, X 2 is CH, and X 3 is N), isoxazolyl (Xi is O, X 2 is N, and X 3 is CH), or oxadiazolyl (Xi is O, X 2 and X 3 are N) ring moiety.
  • Y when Y is - C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached form a furanyl (furyl) ring moiety.
  • the invention is further directed to a compound of Formula (l-a):
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, Z, n, m and L are as defined herein.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, Z, n, m and L are as defined herein.
  • the invention is still further directed to a compound of Formula (l-f), (l-g), (l-h), (l-i) or (l-j):
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, Z, n, m and L are as defined herein.
  • the invention is still further directed to a compound of Formula (l-k), (l-l), (l-m), or
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, Z, n, m and L are as defined herein.
  • A is a phenyl group optionally substituted by 1-2 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (CrC 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and -((C C 4 )alkyl)NR A R A .
  • A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A R A and
  • A is an unsubstituted phenyl group. In other embodiments, A is a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group.
  • A is a 5-6 membered heteroaryl optionally substituted by 1-2 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, -NR A R A and -((C C 4 )alkyl)NR A R A , where each R A is independently H or methyl.
  • A is a 5-6 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl, -NR A R A and -((C C 4 )alkyl)NR A R A , where each R A is independently H or methyl and the 5-6 membered heteroaryl contains 1 ring heteroatom selected form N, O and S and optionally contains 1 additional ring nitrogen atom.
  • A is oxazolyl, pyrazolyl, or thienyl optionally substituted by a methyl group.
  • A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1-2 groups independently selected from (CrC 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (C C 4 )alkoxy, halo(Ci-C 4 )alkoxy, -NR A R A and -((C C 4 )alkyl)NR A R A .
  • A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A R A and -((C C 4 )alkyl)NR A R A , where each R A is
  • A is pyridyl or pyridyl-N-oxide. In specific embodiments, A is pyridyl.
  • Z is -S0 2 NR - or -NR S0 2 -.
  • Z is
  • Z is -NHCH(CF 3 )- or -CH(CF 3 )NH-.
  • Z is -CH(CF 3 )- or -(Ci-C 4 )alkyl-.
  • Z is -NR X - or
  • each R x may be independently selected from H, (d-C 4 )alkyl, and optionally substituted (C 2 -C 4 )alkyl, where said optionally substituted (C 2 -C 4 )alkyl is optionally substituted by hydroxyl, cyano, amino, (C C 4 )alkoxy, (CrC 4 )alkyl)NH-, or ((Ci-C 4 )alkyl)((Ci-C 4 )alkyl)N-.
  • each R x may be independently selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N- methylaminoethyl- and dimethylaminoethyk In selected embodiments, each R x is
  • R x is H or methyl.
  • both R 2 and R 3 are hydrogen. In another embodiment, both R 2 and R 3 are Ci -4 alkyl (e.g., methyl).
  • R 2 is selected from amino(Ci-C 4 )alkyl-, (Ci-C 3 )alkylamino(Ci-C 4 )alkyl-, ((Ci-C 3 )alkyl)((Ci-C 3 )alkyl)amino(Ci-C 4 )alkyl-, -CONH 2 , -CONH(Ci-C 3 )alkyl, -CON((Ci-C 3 )alkyl)((C C 3 )alkyl), -(C C 4 )alkyl-CONH 2 ,
  • R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom
  • R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (Ci-C 4 )alkyl,
  • R Ya is selected from H, (CrC 4 )alkyl, phenyl(C C 2 )alkyl- and (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl-, and each R Yb is independently selected from H and (CrC 4 )alkyl, specifically H and methyl.
  • R 2 and R 3 taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (Ci-C 4 )alkyl, aryl(Ci-C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyk
  • R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl, cyclopropyl, cyclohexyl, 1 -ethyl-piperidinyyl,
  • R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl group.
  • R 4 is H or (Ci-C 2 )alkyl; more specifically, R 4 (CrC 2 )alkyl. In specific embodiments, R 4 is methyl or ethyl.
  • L is an optionally substituted 5-6 membered heterocycloalkyi, 5-6 membered heteroaryl or phenyl group, which is substituted by R 5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano, (CrC 4 )alkyl and (CrC 4 )alkoxy.
  • L is a 5-6 membered heterocycloalkyi group containing 1 -2 nitrogen atoms or a 5-membered heteroaryl group containing one nitrogen, oxygen or sulfur atom and optionally containing 1 or 2 additional nitrogen atoms or a 6-membered heteroaryl group containing 1-2 nitrogen atoms or a phenyl group, wherein the 5-6 membered heterocycloalkyl, 5-membered heteroaryl, 6-membered heteroaryl or phenyl is substituted by R 5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from halogen, cyano, (CrC 4 )alkyl and (CrC 4 )alkoxy specifically halogen, cyano, methoxy and methyl.
  • L is an optionally substituted 5-6 membered
  • heterocycloalkyl containing 1 nitrogen atom and optionally containing one additional heteroatom selected from nitrogen, oxygen and sulfur, an optionally substituted 5- membered heteroaryl group containing one nitrogen, oxygen or sulfur atom and optionally containing 1 or 2 additional nitrogen atoms or a 6-membered heteroaryl group containing 1-2 nitrogen atoms, or an optionally substituted phenyl,
  • said 5-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl or phenyl is optionally substituted, said 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl is substituted by a chloro, fluoro, cyano, methoxy, or methyl substituent.
  • L is thiazolyl, thienyl, pyrazolyl, pyrrolidinyl, triazolyl, 1 -methyl-imidazolyl, phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, pyrimidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, or oxazolyl, any of which is substituted by a methyl group.
  • L is a thiazolyl, thienyl, pyrazolyl, pyrrolidinyl, triazolyl, phenyl, pyridyl, piperidinyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, or oxazolyl group.
  • R 5 is H, halogen, (Ci-C 4 )alkyl, cyano, halo(CrC 2 )alkyl, (C C 2 )alkoxy, ((Ci-C 2 )alkyl)((Ci-C 2 )alkyl)N(Ci-C 3 )alkoxy-,
  • (C 3 -Cio)cycloalkyl optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 or 9-10 membered heteroaryl, where said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 or 2 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 2 )alkyl, (C C 2 )alkoxy, halo(Ci-C 2 )alkoxy, hydroxyl, -NR A R C and
  • R 5 is H, (Ci-C 2 )alkoxy, (Ci-C 4 )alkyl, fluoro(Ci-C 2 )alkyl, cyano, or an optionally substituted phenyl, cyclohexyl, tricyclo[3.3.1 .1 3,7 ]decyl,
  • morpholinyl, thienyl, furanyl, pyrimidinyl, piperidinyl, pyridyl, or indolyl group where the phenyl, cyclohexyl, tricyclo[3.3.1.1 3,7 ]decyl, morpholinyl, thienyl, furanyl, pyrimidinyl, piperidinyl, pyridyl, or indolyl groups is optionally substituted by 1-2 substituents each independently selected from (Ci-C 4 )alkyl, (Ci-C 3 )alkoxy, halogen, fluoro(Ci-C 2 )alkyl and cyano.
  • R 5 is H, (d-C 2 )alkoxy, (CrC 4 )alkyl, fluoro(CrC 2 )alkyl, cyano, cyclohexyl, tricyclo[3.3.1.1 3,7 ]decyl, morpholinyl, thienyl, furanyl, pyrimidinyl, piperidinyl, or an optionally substituted phenyl, pyridyl, or indolyl group, where the phenyl, pyridyl, or indolyl group is optionally substituted by 1 -2 substituents each independently selected from methyl, chloro, bromo, fluoro, trifluoromethyl, methoxy, and cyano.
  • R 5 is H, methyl, ethyl, cyano, fluoro, methoxy, trifluoromethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, cyclohexyl, tricyclo[3.3.1 .1 3,7 ]decyl, morpholin-4-yl, thienyl, furanyl, pyrimidin-5-yl, piperidin-1-yl, pyrid-2-yl, 5-methyl-pyrid-2-yl, pyrid-3-yl, or indolyl.
  • L and R 5 taken together with the nitrogen atom to which they are attached, form a 9-10 membered bicyclic heterocyclic group, wherein at least one ring of the bicyclic group is aromatic and the bicyclic heterocyclic group is optionally substituted by 1 or 2 groups each independently selected from
  • (Ci-C 4 )alkyl halogen, cyano, halo(Ci-C 4 )alkyl, (d-C ⁇ alkoxy, halo(CrC 4 )alkoxy, hydroxyl, -NR A R C , -((Ci-C 4 )alkyl)NR A R c , optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted phenyl or phenyl(Ci-C 4 )alkyl-, optionally substituted 5-6 membered
  • heterocycloalkyi and optionally substituted 5-6 membered heteroaryl;
  • R A is independently selected from H, methyl and ethyl
  • R c is H, methyl, ethyl, phenyl, 5-6 membered heterocycloalkyi, or 5-6 membered heteroaryl, or R A and R c taken together with the atom to which they are attached form a 5- 6 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (CrC 4 )alkyl and
  • said optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, phenyl(Ci-C 4 )alkyl-, 5-6 membered heterocycloalkyi or 5-6 membered heteroaryl is optionally substituted by 1 or 2 groups each independently selected from (Ci-C 4 )alkyl, halogen, cyano, (CrC 3 )alkoxy, (Ci-C 3 )alkyl-amino-, ((Ci-C 3 )alkyl)amino-(C C 3 )alkyl-, ((Ci-C 3 )alkyl)((C C 3 )alkyl)amino-, and ((Ci-C 3 )alkyl)((C C 3 )alkyl)amino-(Ci-C 3 )alkyl-.
  • each R A and R c is independently selected from H and (C 1 -C 4 )alkyl; specifically each R A and R c is independently selected from H, methyl and ethyl.
  • L and R 5 taken together, form a optionally substituted benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, 3a,4,5,6,7,7a-hexahydro-1 ,3-benzothiazolyl, quinolyl, 1 ,2,3,4-tetrahydronaphthyl, 2,3- dihydro-1 ,4-benzodioxolyl, 1 ,3-benzodioxolyl, [1 ,3]thiazolo[4,5-c]pyridinyl,
  • [1 ,3]thiazolo[5,4-6]pyridinyl, imidazo[1 ,2-a]pyridinyl, or quinazolinyl group optionally substituted by (Ci-C 4 )alkyl, (C 3 -C 6 )cycloalkyl, halogen, (CrC 3 )alkoxy, optionally substituted phenyl or phenyl(Ci-C 4 )alkyl-, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl.
  • L and R 5 taken together, form optionally substituted benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, 3a,4,5,6,7,7a-hexahydro-1 ,3-benzothiazolyl, quinolyl, 1 ,2,3,4- tetrahydronaphthyl, 2,3-dihydro-1 ,4-benzodioxolyl, 1 ,3-benzodioxolyl, [1 ,3]thiazolo[4,5- c]pyridinyl, [1 ,3]thiazolo[5,4-6]pyridinyl, imidazo[1 ,2-a]pyridinyl, or quinazolinyl group, wherein said group is optionally substituted by methyl, tert-butyl, cyclopropyl, methoxy, phenyl, benzy
  • L and R 4 taken together with the nitrogen atom to which they are attached, form a 9-10 membered bicyclic heterocyclic group, wherein at least one ring of the bicyclic group is aromatic and the bicyclic heterocyclic group is substituted by R 5 and is optionally further substituted, wherein when the bicyclic heterocyclic group is further substituted, it is substituted by a substituent selected from chloro, fluoro, cyano and methyl.
  • R 5 is selected from (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, hydroxyl, -NR A R C , -((Ci-C 4 )alkyl)NR A R c , optionally substituted
  • (C 3 -C 6 )cycloalkyl optionally substituted phenyl or phenyl(Ci-C 4 )alkyl-, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl
  • R A , R c and said optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, phenyl(Ci-C 4 )alkyl-, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are as defined above.
  • L and R 4 taken together with the nitrogen atom connecting them, form an indolyl group, optionally substituted by methoxy.
  • Another embodiment of this invention is directed to a compound of Formula I wherein: R 1 is -CF 3 ;
  • Y is a bond and Xi is O, N or NH, X 2 is N or CH and X 3 is N or NH,
  • Y is -C(O)- and Xi and X 2 are CH or N, X 3 is O or S,
  • Y is -C(O)- and Xi is O, X 2 is CH or N, and X 3 is CH or N;
  • A is optionally substituted phenyl or pyridyl
  • optionally substituted phenyl or pyridyl is optionally substituted by 1 to 2 groups each independently selected from (d-C 4 )alkyl, halogen, cyano,
  • n 1 and m is 0, or n is 0 and m is 1 ;
  • R 2 is H, fluoro, -(C C 4 )alkyl-NR A R B , -(C C 4 )alkyl-CONR A R B , -(C C 4 )alkyl-C0 2 H, hydroxy(C C 4 )alkyl-, halo(C C 4 )alkyl-, or (C C 3 )alkoxy(Ci-C 4 )alkyl-;
  • R A and R B are each independently selected from H and
  • R 3 is H or methyl
  • R 4 is methyl or ethyl
  • L is a 5-6 membered heterocycloalkyl group containing 1-2 nitrogen atoms or a 5- membered heteroaryl group containing one nitrogen, oxygen or sulfur atom and optionally containing 1 or 2 additional nitrogen atoms or a 6-membered heteroaryl group containing 1-2 nitrogen atoms or a phenyl group, wherein the 5-6 membered heterocycloalkyl, 5- membered heteroaryl, 6-membered heteroaryl or phenyl is substituted by R 5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from halogen, cyano, (Ci-C 4 )alkyl and (Ci-C 4 )alkoxy R 5 is H, (CrC 4 )alkyl, halo, halo(CrC 4 )alkyl, (CrC 4 )alkoxy, cyano,
  • optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio-, halo(C C 4 )alkoxy, hydroxyl, -NR A R C and -((C C 4 )alkyl)NR A R c ;
  • bicyclic heterocyclic group or L and R 5 , taken together, form a 9-10 membered bicyclic heterocyclic group, wherein at least one ring of the bicyclic group is aromatic and the bicyclic heterocyclic group is optionally substituted by 1 or 2 groups each independently selected from
  • (CrC 4 )alkyl halogen, cyano, halo(CrC 4 )alkyl, (CrC 4 )alkoxy, halo(CrC 4 )alkoxy, hydroxyl, -NR A R C , -((Ci-C 4 )alkyl)NR A R c , optionally substituted (C 3 -C 6 )cycloalkyl, optionally
  • heterocycloalkyi and optionally substituted 5-6 membered heteroaryl;
  • bicyclic heterocyclic group wherein at least one ring of the bicyclic group is aromatic and the bicyclic heterocyclic group is optionally substituted by 1 or 2 groups each independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, hydroxyl, -NR A R C , -((Ci-C 4 )alkyl)NR A R c , optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted phenyl or phenyl(Ci-C 4 )alkyl-,
  • R A is H or (d-C 4 )alkyl
  • R c is H, (C C 4 )alkyl, phenyl, 5-6 membered
  • heterocycloalkyi or 5-6 membered heteroaryl, or R A and R c taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by
  • said optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, phenyl(Ci-C 4 )alkyl-, 5-6 membered heterocycloalkyi or 5-6 membered heteroaryl is optionally substituted by 1 or 2 groups each independently selected from (Ci-C 4 )alkyl, halogen, halo(Ci-C 4 )alkyl,
  • the invention is specifically directed to a compound according to Formula I, wherein:
  • R 1 is CHF 2 or CF 3 ; specifically, CF 3 ;
  • Y is a bond, Xi is O, and X 2 and X 3 are N, or
  • Y is -C(O)-, Xi and X 2 are CH, and X 3 is S, or
  • Y is -C(O)-, Xi is O, and X 2 and X 3 are CH;
  • A is an unsubstituted phenyl or pyridyl group
  • n + m 1 , and both R 2 and R 3 are H;
  • L is thiazolyl, thienyl, pyrazolyl, pyrrolidinyl, triazolyl, phenyl, pyridyl, piperidinyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, isoxazolyl or oxazolyl;
  • R 5 is H, methyl, ethyl, cyano, fluoro, methoxy, trifluoromethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, cyclohexyl, tricyclo[3.3.1.1 3,7 ]decyl, morpholin-4-yl, thienyl, furanyl, pyrimidin-5-yl, piperidin-1- yl, pyrid-2-yl, 5-methyl-pyrid-2-yl, pyrid-3-yl, or indolyl; or
  • L and R 5 taken together, form an optionally substituted benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, 3a,4,5,6,7,7a-hexahydro-1 ,3-benzothiazolyl, quinolyl, 1 ,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1 ,4-benzodioxolyl, 1 ,3-benzodioxolyl,
  • alkyl represents a saturated, straight or branched hydrocarbon moiety, which may be unsubstituted or substituted by one, or more of the substituents defined herein.
  • exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, f-butyl, n-pentyl, iso-pentyl (3- methyl-butyl), neo-pentyl (2,2-dimethylpropyl), etc.
  • C1-C4" refers to an alkyl containing from 1 to 4 carbon atoms.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as “haloalkyl” or “cycloalkyl-alkyl” or “arylalkyl”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • arylalkyl is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by the bonding arrangement present in a benzyl group (-CH 2 -phenyl).
  • alkyl may be used to define a divalent substituent, such as a group bonded to two other groups. In this instance, the term “alkyl” is intended to
  • 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.
  • (CrC 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 "(Ci-C 4 )alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy.
  • Aryl represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be unsubstituted or substituted by one or more substituents defined herein.
  • aryl is phenyl
  • Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
  • Heterocycloalkyl represents a group or moiety comprising a stable, non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • the heterocycloalkyl may be attached by any atom of the monocyclic or bicyclic radical which results in the creation of a stable structure.
  • This term encompasses bicyclic heterocycloalkyl moieties where the rings are joined at two atoms per ring, as exemplified by the bonding arrangement in 2,5-diazabicyclo[2.2.1 ]heptyl, 2- azabicyclo[2.2.1 ]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 7-oxa-2-azabicyclo[2.2.1 ]heptyl, 2-thia-5-azabicyclo[2.2.1 ]heptyl,7-azabicyclo[2.2.1 ]heptyl, 2,6- diazatricyclo[3.3.1.13,7]decyl, 2-azatricyclo[3.3.1 .13,7]decyl, 2,4,9- triazatricyclo[3.3.1 .13,7]decyl, 8-azabicyclo[3.2.1 ]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2- aza
  • This term specifically excludes bicyclic heterocycloalkyl moieties where the rings are joined at a single atom per ring (spiro), as exemplified by the bonding arrangement in a 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl group.
  • heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azabicylo[3.2.1 ]octyl, azabicylo[3.3.1 ]octyl
  • heterocycloalkyl groups are
  • 5-membered and/or 6-membered heterocycloalkyl groups such as pyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl or pyrazolinyl, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, tetrahydro-2H-1 ,4-thiazinyl, 1 ,4-dioxanyl, 1 ,3-oxathianyl, and 1 ,3-dithianyl.
  • pyrrolidyl or pyrrolidinyl
  • tetrahydrofuryl or tetrahydrofuranyl
  • Heteroaryl represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, isobenzofuryl, 2,3- dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl,
  • 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,
  • Haldroxy or “hydroxyl” is intended to mean the radical -OH.
  • the term "compound(s) of the invention” means a compound of formula (I) (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.
  • any salt or non-salt form e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof
  • any physical form thereof e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrate
  • optionally substituted means unsubstituted groups or rings (e.g., 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.
  • 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.
  • 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.
  • 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 piperaz
  • 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 sodium 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 subject invention also includes isotopically-labeled compounds which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 3 H, 11 C, 14 C, 18 F, 123 l or 125 l.
  • Isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 14 C have been incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, ie. 3 H, and carbon-14, ie. 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).
  • 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 Formula I 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 R 1 and R 2 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.
  • Representative compounds of this invention include:
  • Representative compounds of this invention also include:
  • ChemDraw 1 1 .0 available from CambridgeSoft Corporation., 100 CambridgePark Drive, Cambridge, MA 02140, USA (http://www.cambridgesoft.com).
  • the invention also includes various deuterated forms of the compounds of
  • Each available hydrogen atom attached to a carbon atom may be any available hydrogen atom attached to a carbon atom.
  • 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
  • the present invention is directed to a method of inhibiting a HDAC which comprises contacting the acetylase with a compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, specifically, contacting a cell with the compound of Formula I or a salt thereof.
  • This invention is also directed to a method of treatment of a HDAC-mediated disease or disorder comprising administering a
  • this invention is directed to a method of treatment of a disease or condition ameliorated by inhibition of HDAC activity in a patient, specifically in a human, comprising administering to the patient a therapeutically effective amount of a compound of this invention.
  • patient refers to a mammal, specifically, a human.
  • a therapeutically "effective amount” is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to inhibit the activity of HDAC such that a disease condition which is mediated by that activity is reduced, alleviated or prevented.
  • the amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC 5 o), efficacy (EC 5 o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by a 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, 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, spondylarthritis, Sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, eczema, gastritis, or thyroiditis.
  • the inflammatory disorder include, but are not limited
  • 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
  • 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, artherosclerosis 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, artherosclerosis
  • 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.
  • this invention is further directed to the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt, thereof in therapy, particularly the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to treat a disease or condition ameliorated by inhibition of HDAC activity.
  • this invention is directed to the manufacture of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt, thereof for use in therapy, particularly for use in the treatment of a disease or condition ameliorated by inhibition of HDAC activity.
  • 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.
  • B-cell lymphomas particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and
  • inhibitors of the invention may be employed alone or in combination with standard anti-cancer regimens for neoplastic cell, e.g., tumor and cancer, treatments.
  • 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.
  • Treatment of a neurodegenerative disease or disorder may be achieved using the compounds of Formula I as a monotherapy, or in dual or multiple combination therapy, for example, in combination with one or more of the following agents: DNA methyltransferase inhibitors, acetyl transferase enhancers, proteasome or HSP90 inhibitors, , and drugs that are currently used for the treatment of Alzheimer's disease (such as a cholinesterase inhibitor (galantamine, rivastigmine, donepezil, or tacrine, or memantine), Parkinson's disease (such as levodopa, alone or combined with carbidopa or combined with benserazide, a dopamine agonist, such as pramipexole, ropinirole, or apomorphine , a MAO B inhibitor, such as selegiline or rasagiline, or a Catechol O-methyltransferase (COMT) inhibitor, such as tolcapone.
  • entacapone alone or combined with carbidopa and levodopa or an anticholinergic, such as benztropine or trihexyphenidy, or a glutamate (NMDA) blocking drug, such as amantadine), neuronal intranuclear inclusion disease, Huntington's disease (such as tetrabenazine, haloperidol and clozapine, antiseizure drugs such as clonazepam and antianxiety drugs such as diazepam), and spinocerebellar ataxia, which are administered in effective amounts as is known in the art.
  • NMDA glutamate
  • Treatment of a B-cell lymphoma may be achieved using the compounds of Formula I as a monotherapy, or in dual or multiple combination therapy, for example, in combination with one or more of the following agents: antibodies (such as rituxumab, alone or in combination with cyclophosphamide), chemotherapeutic regimens, proteasome inhibitors (such as bortezomib), HDAC inhibitors (such as vorinostat, romidepsin, valproic acid, panobinostat, mocetinostat, givinostat, belinostat and entinostat), mTOR inhibitors (such as temsirolimus, deforolimus, everolimus,and rapamycin), DNA methyltransferase inhibitors, acetyl transferase enhancers, proteasome or HSP90 inhibitors, which are administered in effective amounts as is known in the art.
  • antibodies such as rituxumab, alone or in combination with cyclopho
  • the compounds of the invention will be normally, but not necessarily, 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 (3-(methylamino)propyl)carbamate 500 mg, 2.7 mmol was dissolved in dry DMF (0.5 ml_). 6-Chloronicotinonitrile (250 mg, 1 .80 mmol), followed by 2,2,6,6- tetramethylpiperidine (760 mg, 5.4 mmol) were added, and the mixture was heated in a sealed tube to 150 °C for 8 h. The reaction mixture was cooled to room temperature, and extracted with EtOAc. The combined extracts were washed with H 2 0 and brine, and concentrated under reduced pressure.
  • Trifluoroacetic acid (0.6 mL) was added dropwise to the cold solution ferf-butyl (3- ((5-cyanopyridin-2-yl)(methyl)amino)propyl)carbamate (150 mg, 0.51 mmol) in CH 2 CI 2 (5 mL) at 0 °C and the reaction mixture was further stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to afford 6-((3- aminopropyl)(methyl)amino)nicotinonitrile TFA salt (200 mg, crude), which was carried through without further purification.
  • the crude product was purified by column chromatography (silica 60-120 mesh, eluant 40% EtOAc in petroleum ether) to get ⁇ /-(3- ((5-cyanopyridin-2-yl)(methyl)amino)propyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide (50 mg, yield 41 %) as an off-white solid.
  • This compound was synthesized from 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoic acid and 6-(((2-aminoethyl)(methyl)amino)methyl)nicotinonitrile TFA salt as described in example 1 step 6 (41 mg, yield 24%) as a yellow viscous liquid.
  • This compound was synthesized from 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoic acid and 6-((2-aminoethyl)amino)nicotinonitrile as described in example 1 step 6 (30 mg, yield 24%) as a white solid.
  • This compound was synthesized from 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoic acid and 6-((2-aminoethyl)(ethyl)amino)nicotinonitrile TFA salt as described in example 1 step 6 (60 mg, yield 48%) as an off-white solid.
  • This compound was synthesized from 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoic acid and A/i-methyl-/ ⁇ /i-(5-methylpyridin-2-yl)ethane-1 ,2-diamine TFA salt as described in example 1 step 6 (50 mg, yield 64%) as a white solid.
  • This compound was synthesized from 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoic acid and A/i-(5-fluoropyridin-2-yl)-/ ⁇ /i-methylethane-1 ,2-diamine TFA salt as described in example 1 step 6 (50 mg, yield 45%).
  • This compound was synthesized from 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoic acid and A/i-(5-methoxypyridin-2-yl)-/ ⁇ /i-methylethane-1 ,2-diamine TFA salt as described in example 1 step 6 (15 mg, yield 12%) as a pale yellow liquid.
  • This compound was synthesized from 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoic acid and A/i-methyl-/ ⁇ /i-(5-(trifluoromethyl)pyridin-2-yl)ethane-1 ,2-diamine TFA salt as described in example 1 step 6 (70 mg, yield 33%) as an off-white solid.
  • This compound was synthesized from 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzoic acid and /Vi-Methyl-/Vi-(5-(trifluoromethyl)pyridin-2-yl)ethane-1 ,2-diamine TFA salt as described in example 1 step 6 (70 mg, yield 36%) as an off-white solid.
  • Phthalic anhydride (6.0 g, 40 mmol) was added to a solution of /V-methyl-1 ,2- ethanediamine (2.9 g, 38 mmol) in water (40 mL). The mixture was stirred at 100 °C for 3 h. The solvent was distilled off under reduced pressure and acetone (40 mL) was added to the resulting residue. The insoluble solid was removed by filtration and the filtrate was concentrated to dryness to give crude 2-(2-(methylamino)ethyl)isoindoline-1 ,3-dione (6.1 g) as a white solid, which was used to next step without further purification.
  • This compound was synthesized from 2-bromobenzo[c//thiazole and 2-(2- (methylamino)ethyl)isoindoline-1 ,3-dione as described in example 1 1 step 1 (250 mg, yield 74%).
  • This compound was synthesized from /V7-(benzo[tf]thiazol-2-yl)-/V7-methylethane- 1 ,2-diamine and 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoic acid as described in example 10 step 4 (25mg, Yield 30%).
  • Triethylamine (202mg, 2mmol) and Boc 2 0 (218mg, 1 mmol) were added to a solution of 2-methylbenzo[d]thiazol-5-amine (164mg, 1 mmol) in THF (20ml). Then the mixture was stirred at rt overnight. The reaction was complete checked by LC-MS. The reaction mixture was concentrated to remove the THF and poured into water (10ml), it was extracted with EtOAc (30ml x 3), dried over Na 2 S0 4 . Removal of solvents under reduce pressure gave a crude product.
  • A/,2-Dimethylbenzo[c/]thiazol-5-amine (45mg, 0.253mmol) was added to a solution of A/-(2-oxoethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide (76mg 0.253mmol) in 1 ,2-dichloroethane (10ml). Then the mixture was cooled to 0 °C, and NaBH(OAc) 3 (81 mg, 0.38mmol) was added. The mixture was allowed to warm up to room temperature slowly and stirred at room temperature overnight. NaHC0 3 (aq, 20 mL) was added to the mixture to quench the reaction, the organic phase was separated.
  • the aqueous phase was extracted with CH 2 CI 2 (10 mL x 3 ). The combined organic solvents were dried over Na 2 S0 4 . After removal of solvents, the crude compound was purified by Pre-HPLC to yield A/-(2-(methyl(2-methylbenzo[d]thiazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide as a yellow solid (20 mg, yield 17 %).
  • This compound was synthesized from A/-(2-(methylamino)ethyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide and 1 -(2,4-difluorophenyl)piperidin-4-one as described in example 13 step 4 (34 mg, yield 20%) as a yellow oil.
  • This compound was synthesized from A/-methylbenzo[d][1 ,3]dioxol-5-amine and N-(2-oxoethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide as described in example 13 step 4 (20 mg, 12%).
  • This compound was synthesized from 1-(4-fluorophenyl)piperidin-4-one and ⁇ /-(2- (methylamino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide as described in example 17 step 3 (14 mg, yield: 18%) as a colorless oil.
  • This compound was synthesized from A/-methyl-2,3-dihydrobenzo[b][1 ,4]dioxin-6- amine and A/-(2-oxoethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide as
  • This compound was synthesized from 5-methoxy-3,4-dihydronaphthalen-2(1 H)- one and A/-(2-(methylamino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide as described in example 17 step 3 (30 mg, 40%).
  • This compound was synthesized from A/i-(6-methoxybenzo[d]thiazol-2-yl)-N1 - methylethane-1 ,2-diamine and 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoic acid as described in example 10 step 4 (25mg, Yield: 26%).
  • This compound was synthesized from 6-methoxy-3,4-dihydronaphthalen-2(1 H)- one and A/-(2-(methylamino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide as described in example 17 step 3 (20 mg, 27%).
  • This compound was synthesized from 2-(5-methoxy-1 H-indol-1 -yl)ethanamine and 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoic acid as described in example 10 step 4 (45mg, yield 45 %).
  • 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 I la 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).
  • plC 50 s For concentration/dose response experiments, normalized data were fit and plC 50 s determined using conventional techniques. The plC 50 s are averaged to determine a mean value, for a minimum of 2 experiments. As determined using the above method, the compounds of Examples 1 -8 exhibited a plC 50 between approximately 4.8 and 9.0. For instance, the compounds of Examples 3 and 5 inhibited HDAC9 in the above method with a mean plC 50 between approximately 6.0 and 9,.0.
  • 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.
  • 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.

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Abstract

La présente invention concerne des composés ayant la formule I, dans laquelle X1, X2, X3, R1, R2, R3, R4, R5, Y, A, Z, L, m et n sont tels que définis présentement, et des procédés de fabrication et d'utilisation de ceux-ci.
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