WO2013006408A1 - Compounds and methods - Google Patents

Compounds and methods 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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French (fr)
Inventor
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/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
    • C07D413/12—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.

Abstract

Disclosed are compounds having formula I, wherein X1, X2, X3, R1, R2, R3, R4, R5, Y, A, Z, L, m and n 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 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.
HDAC4, HDAC5 and HDAC9 are highly expressed in the brain. HDAC4 has been linked to a variety of neurodegenerative disorders: it is a downstream target of Parkin (associating it to Parkinson's disease), it's is a major component of intranuclear inclusions produced in NIIND. HDAC4 also contains a conserved glutamine rich domain, such domain has been observed to increase susceptibility to amyloid formation associated with Alzheimer's disease (Majdzadeh et al. Front. Biosci., 2009, p. 1072). Heterozygotes of HDAC4 knockouts crossed to R6/2 mice (Huntington's disease model) led to improved motor/behavior and reduced aggregation
(http://bmi.epfl.ch/files/content/sites/bmi/files/shared/Abstract Gillian Bates.pdf). HDAC4 and HDAC5 localization are regulated by neuronal activity, and HDAC5 nuclear import is increased in diseased neurons of Huntington's disease patients.
HDAC7, another class lla HDAC, has been implicated in regulating ataxin-7 turnover in a SCA-7 model (Mookerjee S et al., J Neurosci., 2009, p. 15134).
HDAC6, a class lib HDAC, is expressed in most neurons and most abundantly in cerebellar Purkinje cells, the degeneration of this type of neurons is observed in patients with spinocerebellar ataxia type 1 (SCA1 ) or SCA7. HDAC6 is involved in regulating microtubule dynamics and protein degradation and a defect in microtubule-based transport may contribute to the neuronal toxicity observed in Huntington's disease (Kazantsev et al. Nature Reviews Drug Discovery, 2008, p. 854). Additionally, HDAC6 activity has been shown to be required for autophagic degradation of aggregated huntingtin, suggesting a role in protecting cells from polyQ toxicity (Iwata, et al., J. Biol. Chem., 2005, p. 40282).
HDAC9 is a class lla histone deacetylase highly expressed in human B cells. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell 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 lla HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) have been reported to associate with Bcl-6, a transcription factor implicated in the pathogenesis of B-cell malignancies (Lemercier et al, Journal of Biological Chemistry, 2002, p. 22045, and Petrie et al, Journal of Biological Chemistry, 2003, p. 16059). Due to these interactions class I la
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) 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.
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.
Based on the above evidence, a small molecule selective inhibitor of HDAC activity (more specifically, an inhibitor of HDAC4 and/or HDAC5 and/or HDAC6 and/or HDAC7 and/or HDAC8 and/or HDAC9 activity) is expected to modulate autoimmune diseases and further is expected to be beneficial in the treatment of neurodegenerative diseases and in the treatment of cancers.
SUMMARY OF THE INVENTION
The invention is directed to a compound according to Formula I:
Figure imgf000004_0001
wherein:
R1 is halo(C1-C4)alkyl, wherein said halo(C1-C4)alkyl contains at least 2 halo groups;
Y is a bond and Xi is O, N or NH, X2 is N or CH and X3 is N or NH,
or Y is -C(O)- and Xi and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and Xi is O, X2 is CH or N, and X3 is CH or N;
A is optionally substituted phenyl or 5-6 membered heteroaryl, wherein said optionally substituted phenyl or heteroaryl is optionally substituted by 1 -3 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
Z is -C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -S02-, -S02NRx-, -NRxS02-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(C C4)alkyl-, -NRX-, or -(C C3)alkyl-NRx-; each Rx is independently selected from H, (Ci-C6)alkyl, and optionally substituted (C2-C6)alkyl, where said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (CrC4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-; and
n is 0, 1 or 2 and m is 0, 1 or 2; provided that 0< m+n <3;
R2 is H, fluoro, (Ci-C4)alkyl, -(C C4)alkyl-NRARB, -CONRARB, -C02H,
-(Ci-C4)alkyl-CONRARB, -(C C4)alkyl-C02H, hydroxy(Ci-C4)alkyl-, halo(C C4)alkyl-, cyano(C1-C4)alkyl-, or (C1-C3)alkoxy(C1-C4)alkyl-;
wherein RA and RB are each independently selected from H and
(C C4)alkyl;
R3 is H or (C C4)alkyl;
or R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 or 2 heteroatoms independently selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by 1 , 2 or 3 substituents independently selected from (Ci-C4)alkyl,
halo(CrC4)alkyl, halogen, cyano, aryl(Ci-C4)alkyl-, (C3-C7)cycloalkyl(Ci-C4)alkyl-, -ORY, -NRYRY, -C(=0)ORY, -C(=0)NRYRY, -NRYC(=0)RY, -S02NRYRY, -NRYS02RY, -OC(=0)NRYRY, -NRYC(=0)ORY, and -N RYC(=0)N RYRY;
each RY is independently selected from H, (Ci-C4)alkyl, phenyl, and
-(CrC4)alkylphenyl;
R4 is H or (Ci-C4)alkyl;
L is 5-6 membered heterocycloalkyi, 5-6 membered heteroaryl, phenyl,
-(CrC4)alkyl-5-6 membered heterocycloalkyi-, -(CrC4)alkyl-5-6 membered heteroaryl- or -(CrC4)alkyl-phenyl- wherein each of said 5-6 membered heterocycloalkyi, 5-6 membered heteroaryl, or phenyl is substituted by R5 and is optionally further substituted,
wherein when any of said 5-6 membered heterocycloalkyi, 5-6 membered heteroaryl, or phenyl is further substituted, said 5-6 membered heterocycloalkyi, 5-6 membered heteroaryl, or phenyl is substituted by 1 or 2 substituents independently selected from halogen, cyano (Ci-C4)alkoxy and (CrC4)alkyl; R5 is H, (Ci-C4)alkyl, halo, halo(C C4)alkyl, (Ci-C4)alkoxy, cyano, ((Ci-C4)alkyl)((Ci-C4)alkyl)N(CrC4)alkoxy, ((Ci-C4)alkyl)((Ci-C4)alkyl)N(C C4)alkyl-,
(CrC4)haloalkoxy-, (Ci-C4)alkylamino, optionally substituted (C3-Ci2)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl,
wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from
(CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (d-C4)alkoxy, (CrC4)alkylthio-, halo(Ci-C4)alkoxy, hydroxyl, -NRARC and -((C C4)alkyl)NRARc;
or L and R5, taken together, form a 9-10 membered bicyclic heterocyclic or carbocyclic group, wherein at least one ring of the bicyclic group is aromatic and said heterocyclic or carbocyclic group is optionally substituted by 1 , 2 or 3 groups each independently selected from (C1-C4)alkyl, halogen, cyano, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C C4)alkylthio-, halo(C C4)alkoxy, hydroxyl, -NRARC, -((C C4)alkyl)NRARc, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(C1-C4)alkyl-, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl;
or L and R4, taken together with the nitrogen atom to which they are attached, form a 9-10 membered bicyclic heterocyclic group (provided that the 9-10 membered bicyclic heterocyclic group is not tetrahydroisoquinolyl or isoindolinyl), wherein at least one ring of the bicyclic group is aromatic and said heterocyclic group is optionally substituted by 1 , 2 or 3 groups each independently selected from (Ci-C4)alkyl halogen, cyano,
halo(C C4)alkyl, (C C4)alkoxy, (C C4)alkylthio-, halo(Ci-C4)alkoxy, hydroxyl, -NRARC, -((Ci-C4)alkyl)NRARc, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(CrC4)alkyl-, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl;
wherein:
RA is independently selected from H and (CrC4)alkyl;
Rc is H, (CrC4)alkyl, phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, or RA and Rc taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C1-C4)alkyl and
said optionally substituted (C3-C6)cycloalkyl, phenyl, phenyl(C1-C4)alkyl-, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups each independently selected from (Ci-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkylthio-, halo(Ci-C4)alkoxy, hydroxyl, amino, (Ci-C4)alkyl-amino-, amino(Ci-C4)alkyl-, ((Ci-C4)alkyl)amino-(Ci-C4)alkyl-,
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, and ((Ci-C4)alkyl)((C C4)alkyl)amino-(Ci-C4)alkyl-; 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 thereof, a method of inhibiting HDAC by contacting a cell with the compound of Formula I or a salt thereof, and 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.
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.
In one embodiment of this invention, R1 is a fluoro- alkyl group containing at least 2 fluoro groups (atoms). In another embodiment, R1 is a (CrC2)alkyl group containing at least 2 fluoro groups. In a specific embodiment, R1 is CHF2 or CF3; more specifically, R1 is CF3
In selected embodiments, when Y is a bond, X-i, X2, and X3, taken together with the atoms to which they are attached, form an oxadiazolyl (Xi is O, X2 and X3 are N), oxazolyl (Xi is O, X2 is CH, X3 is N), imidazolyl (Xi is N or NH, X2 is CH, X3 is N or NH); or a triazolyl (Xi is N or NH, X2 is N, X3 is N or NH) ring moiety. In specific embodiments, when Y is a bond, X-i, X2, and X3, taken together with the atoms to which they are attached form an oxadiazolyl ring moiety.
In selected embodiments, when Y is -C(O)-, X-i, X2, and X3, taken together with the atoms to which they are attached, form an thiazolyl (X3 is S, X-i is CH and X2 is N or X3 is S, X is N and X2 is CH), oxazolyl (X3 is O, X^ is CH and X2 is N or X3 is O, X^ is N and X2 is CH), thienyl (Xi and X2 are CH, X3 is S) or furanyl (Xi and X2 are CH, X3 is O) ring moiety. In specific embodiments, when Y is -C(O)-, X-i, X2, and X3, taken together with the atoms to which they are attached form a thienyl, thiazolyl or oxazolyl ring moiety, more specifically a thienyl moiety.
In selected embodiments, when Y is -C(O)-, X-i, X2, and X3, taken together with the atoms to which they are attached, form a furanyl or furyl (Xi is O, X2 and X3 are CH), oxazolyl (Xi is O, X2 is CH, and X3 is N), isoxazolyl (Xi is O, X2 is N, and X3 is CH), or oxadiazolyl (Xi is O, X2 and X3 are N) ring moiety. In specific embodiments, when Y is - C(O)-, X-i, X2, and X3, taken together with the atoms to which they are attached form a furanyl (furyl) ring moiety.
The invention is further directed to a compound of Formula (l-a):
Figure imgf000008_0001
wherein R1, R2, R3, R4, R5, A, Z, n, m and L are as defined herein.
The invention is still further directed to a compound of Formula (l-b):
Figure imgf000008_0002
wherein R1, R2, R3, R4, R5, A, Z, n, m and L are as defined herein.
The inven (l-c), (l-d) or (l-e):
Figure imgf000008_0003
(l-c),
Figure imgf000008_0004
The invention is still further directed to a compound of Formula (l-f), (l-g), (l-h), (l-i) or (l-j):
Figure imgf000009_0001
wherein R1, R2, R3, R4, R5, 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
(l-n):
Figure imgf000009_0002
(l-k),
Figure imgf000009_0003
Figure imgf000010_0001
wherein R1, R2, R3, R4, R5, A, Z, n, m and L are as defined herein.
In another embodiment, A is a phenyl group optionally substituted by 1-2 groups independently selected from (d-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (CrC4)alkoxy, halo(C C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA. In further embodiments, A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and
-((Ci-C4)alkyl)NRARA, where each RA is independently H or methyl. In specific
embodiments, A is an unsubstituted phenyl group. In other embodiments, A is a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group.
In another embodiment, A is a 5-6 membered heteroaryl optionally substituted by 1-2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA, where each RA is independently H or methyl. In still further embodiments, A is a 5-6 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl, -NRARA and -((C C4)alkyl)NRARA, where each RA is independently H or methyl and the 5-6 membered heteroaryl contains 1 ring heteroatom selected form N, O and S and optionally contains 1 additional ring nitrogen atom. In selected embodiments, A is oxazolyl, pyrazolyl, or thienyl optionally substituted by a methyl group.
In yet other embodiments, A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1-2 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (C C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA. In further embodiments, A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and -((C C4)alkyl)NRARA, where each RA is
independently H or methyl. In selected embodiments, A is pyridyl or pyridyl-N-oxide. In specific embodiments, A is pyridyl.
In another embodiment of this invention, Z is -C(=0)NRx-, -NRxC(=0)NRx, or -NRxC(=0)-; particularly -C(=0)NRx- or -NRxC(=0)-. In another embodiment of this invention, Z is -S02NR - or -NR S02-. In another embodiment of this invention, Z is
-NHCH(CF3)- or -CH(CF3)NH-. In another embodiment of this invention, Z is -CH(CF3)- or -(Ci-C4)alkyl-. In another embodiment of this invention, Z is -NRX- or
-(CrC3)alkyl-NRx-.
For each of the above embodiments of Z, Rx, or for -NRxC(=0)NRx, each Rx, may be independently selected from H, (d-C4)alkyl, and optionally substituted (C2-C4)alkyl, where said optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (C C4)alkoxy, (CrC4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-. For each of the above embodiments of Z, Rx, or for -NRxC(=0)NRx, each Rx, may be independently selected from H, methyl, ethyl, tert-butyl, hydroxyethyl-, methoxymethyl-, cyanoethyl-, N- methylaminoethyl- and dimethylaminoethyk In selected embodiments, each Rx is
independently H, methyl or cyanoethyl, more specifically, Rx is H or methyl.
In particular embodiments, Z is -C(=0)NRx-, -S02-, -S02NRx-, -CH(CF3)NH-, methyl (methylenyl), ethyl (ethylenyl), -NRX-, or -(C C3)alkyl-NRx-, where each Rx is independently H, methyl or ethyl. In specific embodiments, each Rx is H. In selected embodiments, Z is -C(=0)NH-, -S02NH-, -CH(CF3)NH-, ethyl (ethylenyl), -CH2NH-, -CH2N(CH2CH3)-, -CH(CH3)N(CH2CH3)-, or -CH(CH3)NH-. In other embodiments, Z is -C(=0)NH- or -CH2NH-; specifically, Z is -C(=0)NH-.
In another embodiment of this invention, n + m = 1 or 2, wherein n is 0 and m is 1 or 2; or n is 1 or 2 and m is 0. In specific embodiments, n + m = 1 , wherein n is 1 and m is 0.
In one embodiment, both R2 and R3 are hydrogen. In another embodiment, both R2 and R3 are Ci-4 alkyl (e.g., methyl).
In another embodiment of this invention, R2 is selected from amino(Ci-C4)alkyl-, (Ci-C3)alkylamino(Ci-C4)alkyl-, ((Ci-C3)alkyl)((Ci-C3)alkyl)amino(Ci-C4)alkyl-, -CONH2, -CONH(Ci-C3)alkyl, -CON((Ci-C3)alkyl)((C C3)alkyl), -(C C4)alkyl-CONH2,
-(Ci-C4)alkyl-CONH(CrC3)alkyl, -(Ci-C4)alkyl-CON((C C3)alkyl)((Ci-C3)alkyl), -C02H, -C02(Ci-C3)alkyl, -(CrC4)alkyl-C02H, -(C C4)alkyl-C02(Ci-C3)alkyl, hydroxy(C C4)alkyl-, and (Ci-C4)alkoxy(Ci-C4)alkyl- and R3 is H or (C C4)alkyl.
In another embodiment of this invention, R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom
selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (C1-C4)alkyl,
halo(C1-C4)alkyl, halogen, cyano, aryl(C1-C4)alkyl-, (C3-C7)cycloalkyl(C1-C4)alkyl-, -ORY, -NRYRY, -C(=0)ORY, -C(=0)NRYRY, -NRYC(=0)RY, -S02NRYRY, -NRYS02RY, -OC(=0)NRYRY, -NRYC(=0)ORY, and -N RYC(=0)N RYRY, wherein each RY is
independently selected from H, (CrC4)alkyl and phenyl.
In another embodiment of this invention, R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5, or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (Ci-C4)alkyl,
halo(Ci-C4)alkyl, halogen, cyano, aryl(C C2)alkyl-, (C3-C6)cycloalkyl(Ci-C2)alkyl-, -ORYa, -NRYaRYb, -C(=0)ORYa, -C(=0)NRYaRYb, -NRYbC(=0)RYa, -S02NRYaRYb, and
-NRYbS02RYa, where RYa is selected from H, (CrC4)alkyl, phenyl(C C2)alkyl- and (C3-C6)cycloalkyl(Ci-C2)alkyl-, and each RYb is independently selected from H and (CrC4)alkyl, specifically H and methyl.
In specific embodiments of this invention, R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (Ci-C4)alkyl, aryl(Ci-C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyk
In selected embodiments of this invention, R2 and R3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl, cyclopropyl, cyclohexyl, 1 -ethyl-piperidinyyl,
tetrahydrofuranyl, piperidinyl, 1 -methyl-pyrrolidinyl, 1-benzyl-pyrrolidinyl, 1- cyclopropylmethyl-pyrrolidinyl, oxetanyl, azetidinyl, 1 -methyl-azetidinyl, 1-benzyl- azetidinyl, or 1 -cyclopropylmethyl-azetidinyl group. In specific embodiments of this invention, R2 and R3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, cyclopentyl, 1-methyl-piperidinyl group.
In another embodiment of this invention, R4 is H or (Ci-C2)alkyl; more specifically, R4 (CrC2)alkyl. In specific embodiments, R4 is methyl or ethyl.
In another embodiment of this invention, L is an optionally substituted 5-6 membered heterocycloalkyi, 5-6 membered heteroaryl or phenyl group, which is substituted by R5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano, (CrC4)alkyl and (CrC4)alkoxy.
In another embodiment of this invention, 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 R5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from halogen, cyano, (CrC4)alkyl and (CrC4)alkoxy specifically halogen, cyano, methoxy and methyl.
In one other embodiment, 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,
wherein when 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. In selected embodiments, 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.
In specific embodiments, L is a thiazolyl, thienyl, pyrazolyl, pyrrolidinyl, triazolyl, phenyl, pyridyl, piperidinyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, or oxazolyl group.
In another embodiment of this invention, R5 is H, halogen, (Ci-C4)alkyl, cyano, halo(CrC2)alkyl, (C C2)alkoxy, ((Ci-C2)alkyl)((Ci-C2)alkyl)N(Ci-C3)alkoxy-,
((Ci-C2)alkyl)((CrC2)alkyl)N(Ci-C3)alkyl-, (C C3)alkylamino, optionally substituted
(C3-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-C4)alkyl, halogen, cyano, halo(Ci-C2)alkyl, (C C2)alkoxy, halo(Ci-C2)alkoxy, hydroxyl, -NRARC and
-((Ci-C4)alkyl)NRARc.
In a selected embodiments, R5 is H, (Ci-C2)alkoxy, (Ci-C4)alkyl, fluoro(Ci-C2)alkyl, cyano, or an optionally substituted phenyl, cyclohexyl, tricyclo[3.3.1 .13,7]decyl,
morpholinyl, thienyl, furanyl, pyrimidinyl, piperidinyl, pyridyl, or indolyl group, where the phenyl, cyclohexyl, tricyclo[3.3.1.13,7]decyl, morpholinyl, thienyl, furanyl, pyrimidinyl, piperidinyl, pyridyl, or indolyl groups is optionally substituted by 1-2 substituents each independently selected from (Ci-C4)alkyl, (Ci-C3)alkoxy, halogen, fluoro(Ci-C2)alkyl and cyano. In a selected embodiments, R5 is H, (d-C2)alkoxy, (CrC4)alkyl, fluoro(CrC2)alkyl, cyano, cyclohexyl, tricyclo[3.3.1.13,7]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.
In a selected embodiments, R5 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 .13,7]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.
In other embodiments of this invention, L and R5, 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-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (d-C^alkoxy, halo(CrC4)alkoxy, hydroxyl, -NRARC, -((Ci-C4)alkyl)NRARc, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(Ci-C4)alkyl-, optionally substituted 5-6 membered
heterocycloalkyi and optionally substituted 5-6 membered heteroaryl;
wherein:
RA is independently selected from H, methyl and ethyl;
Rc is H, methyl, ethyl, phenyl, 5-6 membered heterocycloalkyi, or 5-6 membered heteroaryl, or RA and Rc 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 (CrC4)alkyl and
said optionally substituted (C3-C6)cycloalkyl, phenyl, phenyl(Ci-C4)alkyl-, 5-6 membered heterocycloalkyi or 5-6 membered heteroaryl is optionally substituted by 1 or 2 groups each independently selected from (Ci-C4)alkyl, halogen, cyano, (CrC3)alkoxy, (Ci-C3)alkyl-amino-, ((Ci-C3)alkyl)amino-(C C3)alkyl-, ((Ci-C3)alkyl)((C C3)alkyl)amino-, and ((Ci-C3)alkyl)((C C3)alkyl)amino-(Ci-C3)alkyl-.
In another embodiment of this invention, each RA and Rc is independently selected from H and (C1-C4)alkyl; specifically each RA and Rc is independently selected from H, methyl and ethyl.
In other embodiments of this invention, L and R5, 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-C4)alkyl, (C3-C6)cycloalkyl, halogen, (CrC3)alkoxy, optionally substituted phenyl or phenyl(Ci-C4)alkyl-, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl.
In selected embodiments of this invention, L and R5, 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, benzyl, 2-fluorophenyl, 4-fluorophenyl, cyclohexyl, pyrrolidinyl, furanyl, pyrid-2- yl,or pyrid-3-yl.
In other embodiments of this invention, L and R4, 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 R5 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. In the embodiments of this invention, when L and R4 are taken together with the nitrogen atom to which they are attached to form a 9-10 membered bicyclic heterocyclic group, that 9-10 membered bicyclic heterocyclic group is not a tetrahydroisoquinolyl or isoindolinyl group.
In other embodiments of this invention, when L and R4, taken together with the nitrogen atom to which they are attached, form a 9-10 membered bicyclic heterocyclic group, R5 is selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARC, -((Ci-C4)alkyl)NRARc, optionally substituted
(C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(Ci-C4)alkyl-, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl, wherein RA, Rc and said optionally substituted (C3-C6)cycloalkyl, phenyl, phenyl(Ci-C4)alkyl-, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are as defined above.
In selected embodiments of this invention, L and R4, 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: R1 is -CF3;
Y is a bond and Xi is O, N or NH, X2 is N or CH and X3 is N or NH,
or Y is -C(O)- and Xi and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and Xi is O, X2 is CH or N, and X3 is CH or N;
A is optionally substituted phenyl or pyridyl,
wherein said optionally substituted phenyl or pyridyl is optionally substituted by 1 to 2 groups each independently selected from (d-C4)alkyl, halogen, cyano,
halo(Ci-C4)alkyl, (C C4)alkoxy, halo(Ci-C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
Z is -C(=0)NH-;
n is 1 and m is 0, or n is 0 and m is 1 ;
R2 is H, fluoro, -(C C4)alkyl-NRARB, -(C C4)alkyl-CONRARB, -(C C4)alkyl-C02H, hydroxy(C C4)alkyl-, halo(C C4)alkyl-, or (C C3)alkoxy(Ci-C4)alkyl-;
wherein RA and RB are each independently selected from H and
(C C4)alkyl;
R3 is H or methyl;
R4 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 R5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from halogen, cyano, (Ci-C4)alkyl and (Ci-C4)alkoxy R5 is H, (CrC4)alkyl, halo, halo(CrC4)alkyl, (CrC4)alkoxy, cyano,
((Ci-C4)alkyl)((Ci-C4)alkyl)N(CrC4)alkoxy, ((Ci-C4)alkyl)((Ci-C4)alkyl)N(C C4)alkyl-,
(CrC4)haloalkoxy-, (Ci-C4)alkylamino, optionally substituted (C3-Ci0)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,
wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (C1-C4)alkyl, halogen, cyano, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio-, halo(C C4)alkoxy, hydroxyl, -NRARC and -((C C4)alkyl)NRARc;
or L and R5, 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
(CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, halo(CrC4)alkoxy, hydroxyl, -NRARC, -((Ci-C4)alkyl)NRARc, optionally substituted (C3-C6)cycloalkyl, optionally
substituted phenyl or phenyl(Ci-C4)alkyl-, optionally substituted 5-6 membered
heterocycloalkyi and optionally substituted 5-6 membered heteroaryl;
or L and R4, 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-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARC, -((Ci-C4)alkyl)NRARc, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(Ci-C4)alkyl-,
optionally substituted 5-6 membered heterocycloalkyi and optionally substituted 5-6 membered heteroaryl;
wherein:
RA is H or (d-C4)alkyl; Rc is H, (C C4)alkyl, phenyl, 5-6 membered
heterocycloalkyi, or 5-6 membered heteroaryl, or RA and Rc taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by
(Ci-C4)alkyl;
said optionally substituted (C3-C6)cycloalkyl, phenyl, phenyl(Ci-C4)alkyl-, 5-6 membered heterocycloalkyi or 5-6 membered heteroaryl is optionally substituted by 1 or 2 groups each independently selected from (Ci-C4)alkyl, halogen, halo(Ci-C4)alkyl,
(Ci-C4)alkoxy, hydroxyl, amino, (Ci-C4)alkyl-amino-, amino(Ci-C4)alkyl-,
((Ci-C4)alkyl)amino-(Ci-C4)alkyl- ((Ci-C4)alkyl)((C C4)alkyl)amino-, and
((Ci-C4)alkyl)((Ci-C4)alkyl)amino-(Ci-C4)alkyl-;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
The invention is specifically directed to a compound according to Formula I, wherein:
R1 is CHF2 or CF3; specifically, CF3;
Y is a bond, Xi is O, and X2 and X3 are N, or
Y is -C(O)-, Xi and X2 are CH, and X3 is S, or
Y is -C(O)-, Xi is O, and X2 and X3 are CH;
A is an unsubstituted phenyl or pyridyl group;
Z is -C(=0)NH-;
n + m = 1 , and both R2 and R3 are H;
or n is 0 and m is 1 or 2; or n is 1 or 2 and m is 0, specifically n is 1 and m is 0, and R2 is H, methyl, ethyl, hydroxymethyl-, aminomethyl-, methoxymethyl-, carboxy (H02C-), amido (H2NC(0)-), and R3 is H or methyl; or n + m = 1 , and both R2 and R3 are methyl;
L is thiazolyl, thienyl, pyrazolyl, pyrrolidinyl, triazolyl, phenyl, pyridyl, piperidinyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, isoxazolyl or oxazolyl;
R5 is H, methyl, ethyl, cyano, fluoro, methoxy, trifluoromethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, cyclohexyl, tricyclo[3.3.1.13,7]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 R5, 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,
[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, benzyl, 2-fluorophenyl, 4-fluorophenyl, cyclohexyl, pyrrolidinyl, furanyl, pyrid-2-yl,or pyrid-3-yl; or
L and R4, taken together with the nitrogen atom to which they are attached, form an indolyl group, optionally substituted by methoxy;
or a salt, particularly a pharmaceutically acceptable salt, thereof.
As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety, which may be unsubstituted or substituted by one, or more of the substituents defined herein. Exemplary alkyls include, but are not limited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, f-butyl, n-pentyl, iso-pentyl (3- methyl-butyl), neo-pentyl (2,2-dimethylpropyl), etc. The term "C1-C4" refers to an alkyl containing from 1 to 4 carbon atoms.
When the term "alkyl" is used in combination with other substituent groups, such as "haloalkyl" or "cycloalkyl-alkyl" or "arylalkyl", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical. For example, "arylalkyl" is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by the bonding arrangement present in a benzyl group (-CH2-phenyl).
In addition, the term "alkyl" may be used to define a divalent substituent, such as a group bonded to two other groups. In this instance, the term "alkyl" is intended to
encompass a divalent straight or branched-chain hydrocarbon radical. For example, "pentyl" is intended to represent a pentylene diradical -wherein the pentyl moiety is any one of a divalent straight (-CH2CH2CH2CH2CH2-) or branched (-CH2CH(CH3)CH2CH2- -CH2CH2CH(CH2CH3)-, -CH2CH2C(CH3)2-) chain 5-carbon radical. As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "(C3-C8)cycloalkyl" refers to a non-aromatic cyclic
hydrocarbon ring having from three to eight ring carbon atoms. Exemplary
"(C3-C8)cycloalkyl" groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
"Alkoxy" refers to a group containing an alkyl radical attached through an oxygen linking atom. The term "(CrC4)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-C4)alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy.
"Aryl" represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be unsubstituted or substituted by one or more substituents defined herein.
Generally, in the compounds of this invention, aryl is phenyl.
Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
"Heterocycloalkyl" represents a group or moiety comprising a stable, non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein. The heterocycloalkyl may be attached by any atom of the monocyclic or bicyclic radical which results in the creation of a stable structure. This term encompasses bicyclic heterocycloalkyl moieties where the rings are joined at two atoms per ring, as exemplified by the bonding arrangement in 2,5-diazabicyclo[2.2.1 ]heptyl, 2- azabicyclo[2.2.1 ]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 7-oxa-2-azabicyclo[2.2.1 ]heptyl, 2-thia-5-azabicyclo[2.2.1 ]heptyl,7-azabicyclo[2.2.1 ]heptyl, 2,6- diazatricyclo[3.3.1.13,7]decyl, 2-azatricyclo[3.3.1 .13,7]decyl, 2,4,9- triazatricyclo[3.3.1 .13,7]decyl, 8-azabicyclo[3.2.1 ]octyl, 2,5-diazabicyclo[2.2.2]octyl, 2- azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, octahydro-1 H- pyrrolo[3,2-6]pyridyl group. This term specifically excludes bicyclic heterocycloalkyl moieties where the rings are joined at a single atom per ring (spiro), as exemplified by the bonding arrangement in a 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl group. Illustrative examples of heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azabicylo[3.2.1 ]octyl, azabicylo[3.3.1 ]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl and 1 ,5,9-triazacyclododecyl.
Generally, in the compounds of this invention, 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.
"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. 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 (tetrahydroisoquinolyl or tetrahydroisoquinyl) , 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.
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.
As used herein, 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.
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 sodium 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.
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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 3H, 11C, 14C, 18F, 123l or 125l.
Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H or 14C have been incorporated, are useful in drug and/or substrate tissue distribution assays.
Tritiated, ie. 3H, and carbon-14, ie. 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (positron emission tomography).
Since 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 R1 and R2 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 include the compounds of Examples 1 -24
Representative compounds of this invention include:
A/-(2-((5-cyanopyridin-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-((5-cyanopyridin-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-(methyl(5-methylpyridin-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(3-((5-cyanopyridin-2-yl)(methyl)amino)propyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-((5-cyanopyridin-2-yl)(ethyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-((5-fluoropyridin-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide, /V-(2-((5-methoxypyridin-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
/V-(2-(((5-cyanopyridin-2-yl)methyl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
/V-(2-(methyl(5-(trifluoromethyl)pyridin-2-yl)am
1 ,2,4-oxadiazol-3-yl)benzamide,
and a salt, particularly a pharmaceutically acceptable salt, thereof.
Representative compounds of this invention also include:
A/-(2-(((2-(4-fluorophenyl)oxazol-4-yl)methyl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(benzo[c ]oxazol-2-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(benzo[c ]thiazol-2-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(methyl(2-methylbenzo[d]thiazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(benzofuran-5-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
A/-(2-((1 -(2,4-difluorophenyl)piperidin-4-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-(benzo[d][1 ,3]dioxol-5-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-(methyl(1 -phenylpiperidin-4-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
A/-(2-((1 -(4-fluorophenyl)piperidin-4-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-((2,3-Dihydrobenzo[b][1 ,4]dioxin-6-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-((1 -(4-chlorophenyl)piperidin-4-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-((5-methoxy-1 ,2,3,4-tetrahydronaphthalen-2-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
A/-(2-((6-methoxybenzo[d]thiazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide, /V-f2-((6-methoxy-1 ,2,3,4-tetrahydronaphthalen-2-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
W-(2-(5-methoxy-1 H-indol-1 -yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
and a salt, particularly a pharmaceutically acceptable salt, thereof.
Other compounds of this invention include:
N-(2-((5-methoxypyridin-2-yl)(methyl)amino)ethyl)-5-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)nicotinamide,
N-(2-((5-methoxypyridin-2-yl)(methyl)amino)ethyl)-3-(5-(2,2,2- trifluoroacetyl)thiophen-2-yl)benzamide,
N-(2-((5-methoxypyridin-2-yl)(methyl)amino)ethyl)-3-(5-(2,2,2- trifluoroacetyl)oxazol-2-yl)benzamide,
N-(2-((2-(4-fluorophenyl)oxazol-4-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((2-(4-fluorophenyl)thiazol-4-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((5-(4-fluorophenyl)-1 H-1 ,2,4-triazol-3-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(4-phenylpyrimidin-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-(pyridin-2-yl)oxazol-4-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-((5-methoxypyridin-2-yl)(methyl)amino)ethyl)-4-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-((4-cyclohexylthiazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(5-(5-methylpyridin-2-yl)thiophen-2-yl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((4-(4-fluorophenyl)oxazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((4-(4-methoxyphenyl)oxazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((5-(4-fluorophenyl)oxazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide, N-(2-(methyl(2-morpholinothiazol-4-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-(pyridin-2-yl)thiazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-phenyloxazol-4-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(5-(p-tolyl)-1 ,2,4-oxadiazol-3-yl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(1 -methyl-3-(p-tolyl)-1 H-pyrazol-5-yl)amino)ethyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((3-(4-fluorophenyl)-1 ,2,4-oxadiazol-5-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(5-(thiazol-2-yl)thiophen-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-(pyrimidin-5-yl)thiazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-(piperidin-1-yl)thiazol-4-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-((4-(4-cyanophenyl)thiazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(4-(p-tolyl)thiazol-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-((4-(adamantan-1-yl)thiazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((5-(furan-2-yl)-1 ,3,4-thiadiazol-2-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((4-(1 H-indol-3-yl)thiazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(5-phenylbenzo[d]oxazol-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(4-(thiophen-2-yl)thiazol-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(3-phenyl-1 H-1 ,2,4-triazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)-
1 ,2,4-oxadiazol-3-yl)benzamide, N-(2-((1 -cyclohexylpyrrolidin-3-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ^ oxadiazol-3-yl)benzamide,
N-(2-(methyl(1 -phenylpyrrolidin-3-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(3-phenyl-1 ,2,4-oxadiazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(quinolin-7-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide,
N-(2-(methyl(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)amino)ethyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-methylbenzo[d]thiazol-6-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(thiazolo[4,5-c]pyridin-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(5-methylbenzo[d]oxazol-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-(methyl(thiazolo[5,4-b]pyridin-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide,
N-(2-((1 -benzyl-1 H-benzo[d]imidazol-2-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((5-(tert-butyl)benzo[d]thiazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((2-cyclopropylbenzo[d]oxazol-5-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(3-phenylbenzo[b]thiophen-6-yl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-(pyridin-2-yl)benzo[d]oxazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-(pyridin-3-yl)benzo[d]thiazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(4-(pyrrolidin-1-yl)quinazolin-7-yl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((1 -(4-fluorophenyl)-1 H-indol-5-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((2-(2-fluorophenyl)benzo[d]oxazol-5-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide, N-(2-((2-(furan-2-yl)benzo[d]thiazol-5-yl)(methyl)amino)ethyl)-3-(5-(trifluorom 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-(methyl(2-phenylimidazo[1 ,2-a]pyridin-6-yl)amino)ethyl)-3-(5-(trifluorom 1 ,2,4-oxadiazol-3-yl)benzamide,
N-(2-((2-cyclohexylbenzo[d]oxazol-5-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-
1 ,2,4-oxadiazol-3-yl)benzamide,
or a salt, particularly a pharmaceutically acceptable salt, thereof.
Compound names were generated using the software naming program
ChemDraw 1 1 .0 available from CambridgeSoft Corporation., 100 CambridgePark Drive, Cambridge, MA 02140, USA (http://www.cambridgesoft.com).
The compounds of Formula I can be prepared according to the methods outlined below. Scheme 1
Figure imgf000030_0001
(CF3CO)20
ridine
Figure imgf000030_0002
Scheme 2
Figure imgf000031_0001
DMF, 150 °C
Figure imgf000031_0002
Scheme 3
Figure imgf000031_0003
Scheme 4
Figure imgf000031_0004
Figure imgf000031_0005
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 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
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. Specifically, 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. As used herein, "patient" refers to a mammal, specifically, a human. A therapeutically "effective amount" is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, e.g., a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to inhibit the activity of HDAC such that a disease condition which is mediated by that activity is reduced, alleviated or prevented. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pXC5o), efficacy (EC5o), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
"Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is 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.
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, 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. 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.
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, 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. 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.
In one embodiment, 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.
In another embodiment, 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.
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.
Other cancers that may be treated using the compounds of this invention include 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
Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
The 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. 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.
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.
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.
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.
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:
Figure imgf000039_0001
Na2S04 sodium sulfate
NH4CI ammonium chloride
NiCI2-6H20 nickel (II) chloride hexahydrate
NMP W-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
EXAMPLE 1
3- W-H drox carbamimido l benzoic acid
Figure imgf000040_0001
8-Hydroxyquinoline (5 mg, 0.03 mmol) was added to a solution of 3-cyanobenzoic acid (1 g, 6.8 mmol) in 50 mL ethanol. To this reaction mixture were added first hydroxylamine hydrochloric acid (950 mg, 13.6 mmol) in water (8 mL) followed by sodium carbonate (1.2 g, 10.9 mmol) in water (12 mL). The mixture was heated to reflux for 4 h. After removal of ethanol under reduced pressure, the residue was diluted with water, and the aqueous solution was acidified with 10% HCI to pH ~3. The white precipitate was filtrated, washed with water and acetone and then dried under reduced pressure to afford compound S- W-hydroxycarbamimidoy benzoic acid (1 g, yield 82%): 1H NMR (400 MHz, CDCI3) δ 13.03 (br s, 1 H), 9.76 (s, 1 H), 8.27-8.26 (m, 1 H), 7.95-7.89 (m, 2H), 7.53 (t, J = 7.8 Hz, 1 H), 5.94 (br s, 2H). MS (ESI) m/z: Calculated for C8H8N203: 180.05; found: 180.9 (M+H)+. -(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoic acid
Figure imgf000040_0002
A solution of compound S-iW-hydroxycarbamimidoy benzoic acid (1 g, 5.6 mmol in anhydrous pyridine (15 mL) was cooled to 0 °C and trifluoroacetic anhydride (2.3 mL, 16.7 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and further heated to 50 °C for 3 h. The reaction mixture was poured into ice- water and adjusted to pH ~4 by addition of 1 .5N HCI. The product was extracted with EtOAc and the solvent removed under reduced pressure. The crude product was purified by column chromatography [silica gel 60-120 mesh, eluent: 10% EtOAc in petroleum ether] to afford 3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoic acid (400mg, yield 28%): 1H NMR (400 MHz, CDCI3) δ 13.44 (br s, 1 H), 8.56 (s, 1 H), 8.30 (d, J = 7.9 Hz, 1 H), 8.21 (d, J = 7.9 Hz, 1 H), 7.78 (t, J = 7.8 Hz, 1 H). MS (ESI) m/z: Calculated for
CioH5F3N203: 258.03; found: 257 (M-H)\
ferf-Butyl (3-(methylamino)propyl)carbamate
Figure imgf000041_0001
A solution of /V-methyl-1 ,3-propanediamine (6 g, 67.9 mmol) in THF (50 ml.) was cooled to 0 °C, and a solution of di-ferf-butyl dicarbonate (4.6 ml_, 20.3 mmol) in THF (50 ml.) was added dropwise. The reaction mixture was allowed to come to room
temperature, further stirred for 18 h, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel 230-400 mesh, eluent 10% MeOH in CHCI3 to get the undesired regioisomer ferf-butyl (3- aminopropyl)(methyl)carbamate, followed by 15% MeOH in CHCI3 to get the desired product) to afford ferf-butyl (3-(methylamino)propyl)carbamate (1 g, yield 8%) as a viscous light-yellow liquid. 1 H NMR (400MHz, CDCI3) δ 5.06 (br s, 1 H), 3.22 - 3.20 (m, 2H), 2.68 - 2.65 (t, J = 6.7 Hz, 2H), 2.44 (s, 3H), 2.23 (br s, 1 H), 1.72 - 1.66 (m, 2H), 1 .45 (s, 9H). MS (ESI) m/z: Calculated for C9H20N2O2: 188.15; found: 189.2 (M+H)+. ferf-Butyl (3-((5-cyanopyridin-2-yl)(methyl)amino)propyl)carbamate
Figure imgf000041_0002
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 H20 and brine, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15-20% EtOAc in petroleum ether) to afford ferf-butyl (3-((5-cyanopyridin-2-yl)(methyl)amino)propyl)carbamate (450 mg, yield 86%). 1H NMR (400MHz, CDCI3) δ 8.40 (d, J = 2.2 Hz, 1 H), 7.62 - 7.59 (dd, J = 9.1 Hz, J = 2.4 Hz, 1 H), 6.48 (d, J = 9.0 Hz, 1 H), 5.16 (br s, 1 H), 3.73 - 3.69 (t, J = 6.7 Hz, 2H), 3.14 - 3.10 (m, 2H), 3.06 (s, 3H), 1.83 - 1.76 (m, 2H), 1.46 (s, 9H). MS (ESI) m/z:
Calculated for C15H22N4O2: 290.17; found: 291 .2 (M+H)+.
6-((3-Aminopropyl)(methyl)amino)nicotinonitrile TFA salt
Figure imgf000043_0001
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 CH2CI2 (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. MS (ESI) m/z: Calculated for Ci0H14N4: 190.12; found: 191 .2 (M+H)+.
A -(3-((5-Cyanopyridin-2-yl)(methyl)amino)propyl)-3-(5-(trifluoromethyl)-1 ,2,4- -3-yl)benzamide
Figure imgf000043_0002
3-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoic acid (75 mg, 0.29 mmol) was dissolved in dry DMF (5 mL), and HATU (130 mg, 0.34 mmol) followed by 6-((3- aminopropyl)(methyl)amino)nicotinonitrile TFA salt (176 mg, 0.58 mmol), and NMM (0.15 mL, 1.45 mmol) were added at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 4 h. The reaction mixture was then diluted with EtOAc, and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 40% EtOAc in petroleum ether) to get Λ/-(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. 1 H NMR (400 MHz, CDCI3) δ 8.58 - 8.55(m, 2H), 8.31 (d, J = 7.6 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H), 7.86 (br s, 1 H), 7.71 - 7.66 (m, 2H), 6.59 (d, J = 9.2 Hz, 1 H), 3.91 - 3.88 (t, J = 6.0 Hz, 2H), 3.50 - 3.46 (q, J = 6.0 Hz, 2H), 3.10 (s, 3H), 1.99 - 1.93 (m, 2H). MS (ESI) m/z: Calculated for
C2oHi7F3N602: 430.14; found: 431.2 (M+H)+. EXAMPLE 2
6-Formylnicotinonitrile
Figure imgf000044_0001
A mixture of 5-cyano-2-methylpyridine (750 mg, 6.3 mmol) and iodine (1.5 g, 5.7 mmol) in DMSO (10 mL) was heated to 150 °C under nitrogen for 20 min. The reaction mixture was cooled to room temperature and quenched with 10% aqueous NaHC03 solution. The organic product was extracted with EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude 6-formylnicotinonitrile (400 mg), which was carried through without further purification. ferf-Butyl (2-(methylamino)ethyl)carbamate
Figure imgf000044_0002
This compound was synthesized from /V-methylethylenediamine as described in example 1 step 3 (300 mg, yield 6%) as a viscous liquid. 1H NMR (400MHz, DMSO-d6) δ 6.70 (m, 1 H), 3.00 - 2.95 (q, J = 6.3 Hz, 2H), 2.50 - 2.48 (m, 2H), 2.25 (s, 3H), 1.36 (s, 9H). MS (ESI) m/z: Calculated for C8H18N202: 274.14; found: 175.2 (M+H)+. ferf-Butyl (2-(((5-cyanopyridin-2-yl)methyl)(methyl)amino)ethyl)carbamate
Figure imgf000044_0003
A solution of ferf-butyl (2-(methylamino)ethyl)carbamate (150 mg, 0.86 mmol) in 1 ,2-dichloroethane (5 mL) was added to a solution of 6-formylnicotinonitrile (120 mg, 0.86 mmol) in 1 ,2-dichloroethane (5 mL), followed by sodium triacetoxyborohydride (0.36 mL, 2.58 mmol) at 0 °C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. The reaction mixture was then quenched with 10% aqueous NaHC03 solution and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (neutral alumina, eluent 5% MeOH in CH2CI2) to afford ferf-butyl (2-(((5-cyanopyridin-2- yl)methyl)(methyl)amino)ethyl)carbamate (200 mg, yield 23%) as a brown liquid. MS (ESI) m/z: Calculated for Ci5H22N402: 290.17; found: 291.2 (M+H)+.
6-(((2-Aminoethyl)(methyl)amino)methyl)nicotinonitrile TFA salt
Figure imgf000045_0001
This compound was synthesized from ferf-butyl (2-(((5-cyanopyridin-2- yl)methyl)(methyl)amino)ethyl)carbamate as described in example 1 step 5 (100 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for CioH14N4: 190.12; found: 191.2 (M+H)+.
W-(2-(((5-Cyanopyridin-2-yl)methyl)(methyl)a^
Figure imgf000045_0002
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. 1H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.90 (m, 1 H), 8.76 - 8.73 (t, J = 5.6 Hz, 1 H), 8.49 (m, 1 H), 8.23 - 8.20 (dd, J = 7.8 Hz, 1 .5 Hz, 1 H), 8.17 - 8.15 (m, 1 H), 8.1 1 - 8.09 (m, 1 H), 7.75 - 7.71 (t, J = 7.8 Hz, 1 H), 7.66 - 7.64 (m, 1 H), 3.75 (s, 2H), 3.46 - 3.42 (q, J = 6.0 Hz, 2H), 2.62 - 2.58 (t, J = 6.4 Hz, 2H), 2.27 (s, 3H). MS (ESI) m/z: Calculated for C2oH17F3N602: 430.14; found: 431.2 (M+H)+.
EXAMPLE 3
- 2-Aminoeth l amino nicotinonitrile
Figure imgf000045_0003
A mixture of ethylenediamine (14.5 ml_, 216 mmol) and 6-chloronicotinonitrile (1 g, 7.2 mmol) was stirred at room temperature for 2 h. Potassium carbonate (4 g, 28.8 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was then filtered and the residue was washed with DMF. The combined filtrates were concentrated under reduced pressure and the residual ethylenediamine was removed by co- evaporation with DMF. EtOAc was added to the concentrated reaction mixture and solvent was evaporated again to obtain solid product which was washed with diethyl ether to afford 6-((2-aminoethyl)amino)nicotinonitrile (1 g, yield 85%). 1H NMR (400MHz, MeOD) δ 8.36 (d, J = 1.8 Hz, 1 H), 7.65 - 7.63 (dd, J = 8.8 Hz, J = 2.3 Hz, 1 H), 6.65 (d, J = 8.8 Hz, 1 H), 3.66 - 3.63 (t, J = 6.0 Hz, 2H), 3.10 - 3.07 (t, J = 6.0 Hz, 2H). MS (ESI) m/z: Calculated for C8H10N4: 162.09; found: 163.2 (M+H)+.
A -(2-((5-Cyanopyridin-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide
Figure imgf000046_0001
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. 1 H NMR (400 MHz, DMSO-d6) δ 8.92 - 8.90 (t, J = 5.0 Hz, 1 H), 8.52 (m, 1 H), 8.41 - 8.40 (d, J = 2.1 Hz, 1 H), 8.23 - 8.21 (m, 1 H), 8.14 - 8.12 (m, 1 H), 7.77 - 7.72 (m, 2H), 7.69 - 7.67 (m, 1 H), 6.57 (d, J = 9.2 Hz, 1 H), 3.58 - 3.52 (m, 2H), 3.49 - 3.47 (m, 2H). MS (ESI) m/z: Calculated for Ci8H13F3N602: 402.1 1 ; found: 403.2 (M+H)+.
EXAMPLE 4
Figure imgf000046_0002
This compound was synthesized from ethylethylenediamine as described in example 1 step 3 (1.17 g, yield 1 1 %) as a viscous liquid. 1 H NMR (400MHz, CDCI3) δ 4.99 (br s, 1 H), 3.24 - 3.22 (m, 2H), 2.75 - 2.72 (m, 2H), 2.69 - 2.63 (q, J = 7.1 Hz, 2H), 1 .44 (s, 9H), 1 .13 - 1.09 (t, J = 7.1 Hz, 3H). MS (ESI) m/z: Calculated for C9H20N2O2: 188.15; found: 189.2 (M+H)+. -Butyl (2-((5-cyanopyridin-2-yl)(ethyl)amino)ethyl)carbamate
Figure imgf000047_0001
This compound was synthesized from 6-chloronicotinonitrile and ferf-butyl (2- (ethylamino)ethyl)carbamate as described in example 1 step 4 (300 mg, yield 57%). 1H NMR (300MHz, CDCI3) δ 8.38 (d, J = 2.0 Hz, 1 H), 7.61 - 7.57 (dd, J = 9.1 Hz, J = 2.3 Hz, 1 H), 6.56 (d, J = 9.0 Hz, 1 H), 4.94 (br s, 1 H), 3.71 - 3.67 (t, J = 6.4 Hz, 2H), 3.57 - 3.50 (q, J = 7.2 Hz, 2H), 3.37 - 3.32 (q, J = 5.8 Hz, 2H), 1.42 (s, 9H), 1.23 - 1 .18 (t, J = 7.0 Hz, 3H). MS (ESI) m/z: Calculated for Ci5H22N402: 290.17; found: 291.2 (M+H)+.
6-((2-Aminoethyl)(ethyl)amino)nicotinonitrile TFA salt
Figure imgf000047_0002
This compound was synthesized from ferf-butyl (2-((5-cyanopyridin-2- yl)(ethyl)amino)ethyl)carbamate as described in example 1 step 5 (300 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for Ci0H14N4: 190.12; found: 191.2 (M+H)+.
A -(2-((5-Cyanopyridin-2-yl)(ethyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-
3-yl)benzamide
Figure imgf000047_0003
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. 1H NMR (400 MHz, CDCI3) δ 8.57 (d, J = 2.0 Hz, 1 H), 8.37 - 8.36 (t, J = 1.4 Hz, 1 H), 8.27 - 8.24 (dt, J = 7.7 Hz, 1 .3 Hz, 1 H), 8.05 - 8.03 (dt, J = 7.9 Hz, J = 1.3 Hz, 1 H), 7.91 (br s ,1 H), 7.64 - 7.60 (m, 2H), 6.61 (d, J = 9.0 Hz, 1 H), 3.96 - 3.94 (t, J = 5.6 Hz, 2H), 3.77 - 3.73 (m, 2H), 3.57 - 3.51 (q, J = 7.3 Hz, 2H), 1.29 - 1.25 (t, J = 7.2 Hz, 3H). MS (ESI) m/z: Calculated for C20H17I
430.14; found: 431.2 (M+H)+.
EXAMPLE 5
-Butyl (2-(methyl(5-methylpyridin-2-yl)amino)ethyl)carbamate
Figure imgf000048_0001
This compound was synthesized from 2-bromo-5-methylpyridine and ferf-butyl (2- (methylamino)ethyl)carbamate as described in example 1 step 4 (85 mg, yield 22%). 1H N MR (300MHz, CDCI3) δ 7.96 - 7.95 (m, 1 H), 7.31 - 7.30 (m, 1 H), 6.46 (d, J = 8.6 Hz, 1 H), 5.23 (br s, 1 H), 3.69 - 3.65 (t, J = 6.2 Hz, 2H), 3.37 - 3.31 (q, J = 5.6 Hz, 2H), 3.02 (s, 3H), 2.19 (s, 3H), 1 .42 (s, 9H). MS (ESI) m/z: Calculated for Ci4H23N302: 265.18; found: 266.2 (M+H)+.
A i-Methyl-A i-iS-methylpyridin^-ylJethane-l ^-diamine
Figure imgf000048_0002
This compound was synthesized from ferf-butyl (2-(methyl(5-methylpyridin-2- yl)amino)ethyl)carbamate as described in example 1 step 5 (100 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for C9H15N3: 165.13; found: 166.2 (M+H)+.
A -(2-(Methyl(5-methylpyridin-2-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- -yl)benzamide
Figure imgf000048_0003
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. 1H NMR (400 MHz, CDCI3) 5 9.04 (br s, 1 H), 8.49 (m, 1 H), 8.23 - 8.21 (m, 1 H), 8.17 - 8.16 (m, 1 H), 8.1 1 - 8.09 (m, 1 H), 7.61 - 7.57 (t, J = 7.8 Hz, 1 H), 7.34 - 7.32 (dd, J = 8.7 Hz, 2.1 Hz, 1 H), 6.50 (d, J = 8.8 Hz, 1 H), 3.88 - 3.86 (m, 2H), 3.71 - 3.69 (m, 2H), 3.05 (s, 3H), 2.17 (s, 3H). MS (ESI) m/z: Calculated for Ci9H18F3N502: 405.14; found: 406.2 (M+H)+.
EXAMPLE 6
-Butyl (2-((5-fluoropyridin-2-yl)(methyl)amino)ethyl)carbamate
Figure imgf000049_0001
This compound was synthesized from ferf-butyl (2-(methylamino)ethyl)carbamate and 2-bromo-5-fluoropyridine as described in example 1 step 4 (90 mg, yield 1 1 %). 1H NMR (300MHz, CDCI3) δ 8.00 (d, J = 2.9 Hz, 1 H), 7.30 (m, 1 H), 6.51 - 6.49 (m, 1 H), 5.08 (br s, 1 H), 3.70 (m, 2H), 3.36 - 3.34 (m, 2H), 3.05 (s, 3H), 1 .40 (s, 9H). MS (ESI) m/z: Calculated for Ci3H2oFN302: 269.15; found: 270.2 (M+H)+. -iS-Fluoropyridin^-ylJ-A i-methylethane-l ^-diamine
Figure imgf000049_0002
This compound was synthesized from ferf-butyl (2-((5-fluoropyridin-2- yl)(methyl)amino)ethyl)carbamate as described in example 1 step 5 (70 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for C8H12FN3: 169.10; found: 170.2 (M+H)+. A -(2-((5-Fluoropyridin-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,^
-3-yl)benzamide
Figure imgf000050_0001
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%). 1H NMR (400 MHz, DMSO-d6) δ 8.92 - 8.89 (t, J = 5.6 Hz, 1 H), 8.43 (m, 1 H), 8.21 - 8.19 (m, 1 H), 8.07 - 8.05 (m, 2H), 7.73 - 7.69 (t, J = 7.9 Hz, 1 H), 7.59 - 7.54 (m, 1 H), 6.84 - 6.82 (m, 1 H), 3.74 - 3.70 (t, J = 6.3 Hz, 2H), 3.52 - 3.48 (q, J = 6.0 Hz, 2H), 3.05 (s, 3H). MS (ESI) m/z: Calculated for Ci8H15F4N502: 409.12; found: 410.2 (M+H)+.
EXAMPLE 7
ferf-Butyl (2-((5-methoxypyridin-2-yl)(methyl)amino)ethyl)carbamate
Figure imgf000050_0002
This compound was synthesized from 2-bromo-5-methoxypyridine and ferf-butyl (2-(methylamino)ethyl)carbamate as described in example 1 step 4 (120 mg, yield 16%). 1H NMR (400MHz, CDCI3) δ 7.88 (d, J = 2.7 Hz, 1 H), 7.16 - 7.13 (dd, J = 9.1 Hz, J = 3.2 Hz, 1 H), 6.50 (d, J = 9.1 Hz, 1 H), 5.16 (br s, 1 H), 3.79 (s, 3H), 3.66 - 3.63 (t, J = 6.0 Hz, 2H), 3.36 - 3.32 (m, 2H), 3.02 (s, 3H), 1 .43 (s, 9H). MS (ESI) m/z: Calculated for C14H23N303: 281 .17; found: 282.2 (M+H)+.
A i-iS-Methoxypyridin^-ylJ-A i-methylethane-l ^-diamine TFA salt
Figure imgf000050_0003
This compound was synthesized from ferf-butyl (2-((5-methoxypyridin-2- yl)(methyl)amino)ethyl)carbamate as described in example 1 step 5 (200 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for C9H15N30: 181 .12; found: 182.2 (M+H)+.
A -(2-((5-Methoxypyridin-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- -3-yl)benzamide
Figure imgf000051_0001
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. 1H NMR (400 MHz, MeOD) δ 8.43 (t, J = 1 .5 Hz, 1 H), 8.28 - 8.25 (dt, J = 7.8 Hz, 1.4 Hz, 1 H), 7.98 - 7.96 (dt, J = 7.8 Hz, 1 .4 Hz, 1 H), 7.79 (d, J = 3.0 Hz, 1 H), 7.68 - 7.64 (t, J = 7.8 Hz, 1 H), 7.22 - 7.19 (dd, J = 9.2 Hz, 3.1 Hz, 1 H), 6.71 - 6.69 (d, J = 9.3 Hz, 1 H), 3.81 - 3.78 (m, 2H), 3.70 (s, 3H), 3.64 - 3.61 (t, J = 6.0 Hz, 2H), 3.07 (s, 3H). MS (ESI) m/z: Calculated for Ci9H18F3N503: 421 .14; found: 422.2 (M+H)+.
EXAMPLE 8
ferf-Butyl (2-(methyl(5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)carbamate
Figure imgf000051_0002
This compound was synthesized from 2-bromo-5-trifluoromethylpyridine and ferf- butyl (2-(methylamino)ethyl)carbamate as described in example 1 step 4 (500 mg, yield 72%). 1H NMR (300MHz, CDCI3) δ 8.36 (m, 1 H), 7.63 - 7.60 (dd, J = 9.0 Hz, J = 2.2 Hz, 1 H), 6.55 (d, J = 9.0 Hz, 1 H), 4.95 (br s, 1 H), 3.79 - 3.75 (m, 2H), 3.39 - 3.33 (q, J = 6.1 Hz, 2H), 3.10 (s, 3H), 1 .39 (s, 9H). MS (ESI) m/z: Calculated for
Figure imgf000051_0003
319.15; found: 320.2 (M+H)+. -methyl-A i-(5-(trifluoromethyl)pyridin-2-yl)ethane-1 ,2-diamine TFA salt
Figure imgf000052_0001
This compound was synthesized from ferf-butyl (2-(methyl(5- (trifluoromethyl)pyridin-2-yl)amino)ethyl)carbamate as described in example 1 step mg, crude) and it was carried through without further purification. MS (ESI) m/z:
Calculated for C9H12F3N3: 219.10; found: 220.2 (M+H)+.
A -(2-(Methyl(5-(trifluoromethyl)pyridin-2-yl)amino)ethyl)-3-(5-(trifluoromethy
oxadiazol-3-yl)benzamide
Figure imgf000052_0002
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. 1H NMR (400 MHz, MeOD) δ 8.37 - 8.36 (m, 1 H), 8.29 - 8.28 (m, 1 H), 8.26 - 8.23 (m, 1 H), 7.94 - 7.91 (m, 1 H), 7.66 - 7.60 (m, 2H), 6.77 - 6.74 (d, J = 9.0 Hz, 1 H), 3.97 - 3.94 (t, J = 5.9 Hz, 2H), 3.70 - 3.67 (m, 2H), 3.16 (s, 3H). MS (ESI) m/z: Calculated for Ci9H15F6N502: 459.1 1 ; found: 460.2 (M+H)+.
EXAMPLE 9
ferf-Butyl (2-((5-cyanopyridin-2-yl)(methyl)amino)ethyl)carbamate
Figure imgf000052_0003
This compound was synthesized from 6-chloronicotinonitrile and ferf-butyl (2- (methylamino)ethyl)carbamate as described in example 1 step 4 (150 mg, yield 63%). 1H NMR (300MHz, CDCI3) δ 8.39 (d, J = 2.2 Hz, 1 H), 7.62 - 7.58 (dd, J = 9.0 Hz, J = 2.2 Hz, 1 H), 6.53 (d, J = 9.2 Hz, 1 H), 4.84 (br s, 1 H), 3.79 - 3.74 (q, J = 6.1 Hz, 2H), 3.38 - 3.32 (q, J = 6.1 Hz, 2H), 3.12 (s, 3H), 1 .40 (s, 9H). MS (ESI) m/z: Calculated for Ci4H2oN402: 276.16; found: 277.2 (M+H)+. -Methyl-A i-iS-itrifluoromethylJpyridin^-ylJethane-l -diamine TFA salt
Figure imgf000053_0001
0°C-rt, 2
This compound was synthesized from ferf-butyl (2-((5-cyanopyridin-2- yl)(methyl)amino)ethyl)carbamate as described in example 1 step 5 (200 mg, crude) and it was carried through without further purification. MS (ESI) m/z: Calculated for C9H12N4: 176.1 1 ; found: 177.2 (M+H)+.
A -(2-((5-Cyanopyridin-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- -3-yl)benzamide
Figure imgf000053_0002
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. 1H NMR (400 MHz, CDCI3) δ 8.55 (d, J = 1.8 Hz, 1 H), 8.32 (m, 1 H), 8.27 - 8.24 (dt, J = 7.8 Hz, 1 .3 Hz, 1 H), 8.02 - 7.99 (m, 1 H), 7.64 - 7.59 (m, 3H), 6.58 - 6.56 (d, J = 9.0 Hz, 1 H), 4.02 - 3.99 (m, 2H), 3.78 - 3.74 (m, 2H), 3.16 (s, 3H). MS (ESI) m/z: Calculated for
Ci9H15F3N602: 416.12; found: 417.2 (M+H)+.
EXAMPLE 10
2-(2-(Methylamino)ethyl)isoindoline-1 ,3-dione
Figure imgf000053_0003
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. MS (ESI) m/z: Calculated for Cn H12N202: 204.09; found: 205 (M+H)+. ferf-Butyl (2-(1 ,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate
Figure imgf000054_0001
(Boc)20 (4.36 g, 20 mmol) was added dropwise to a solution of 2-(2- (methylamino)ethyl)isoindoline-1 ,3-dione (2.04 g, crude) in MeOH (50 mL). The mixture was stirred at 50 °C for 36 h, then concentrated to dryness. The crude product was dissolved in 100 mL of ethyl acetate. The mixture was washed with brine (30 mL), dried over Na2S04. After removal of solvent, the crude product was purified by flash
chromatography (PE/EtOAc = 10/1 ) to give ferf-butyl (2-(1 ,3-dioxoisoindolin-2- yl)ethyl)(methyl)carbamate as a white solid (1 .28 g, yield 40%). 1 H NMR (CDCI3,
400MHz): δ 7.87-7.82 (s, 2H), 7.74-7.66 (m, 2H), 3.85-3.83 (m, 2H), 3.55-3.51 (m, 2H), 2.91 (s, 3H). MS (ESI) m/z: Calculated for Ci6H20N2O4: 304.14; found: 327 (M+Na)+. ferf-Butyl (2-aminoethyl)(methyl)carbamate
Figure imgf000054_0002
Hydrazine hydrate (400, 8 mmol) was added dropwise to a solution of ferf-butyl (2- (1 ,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (1 .2 g, 4 mmol) in MeOH (40 mL). Then the mixture was stirred at reflux for 5 h. After cooling to RT, the solution was filtered to remove insoluble materials and the filtrate was concentrated to dryness under reduced pressure to give an oily residue, to which was added CH2CI2 (100 mL), and then washed with brine (15 ml). The organic solvent was dried (Na2S04) and concentrated to dryness to give ferf-butyl (2-aminoethyl)(methyl)carbamate (700 mg) as a colorless oil, which was carried through without further purification. ferf-Butyl methyl(2-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamido)ethyl)carbamate
Figure imgf000055_0001
3-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoic acid (1 .24 g, 4.8 mmol), EDCI (922 mg, 4.8 mmol), HOBt (648 mg, 4.8 mmol), and DIPEA (774 mg, 6mmol) were added to a solution of crude ferf-butyl (2-aminoethyl)(methyl)carbamate in DCM (50ml_). The reaction mixture was stirred at room temperature overnight. Water (20 ml.) was added to the mixture and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (40 ml. x 3). The combined organic solvents was washed with brine (30 ml_), dried over Na2S04. After removal of solvents, the crude compound was purified by flash column (EtOAc: PE = 2:1 ) to provide ferf-butyl methyl(2-(3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamido)ethyl)carbamate as a white solid (1.1 g, yield 66%). MS (ESI) m/z: Calculated for Ci8H2i F3N404: 414.15; found: 437 (M+Na)+. A -( -(Methylamino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000055_0002
The mixture of ferf-butyl methyl(2-(3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamido)ethyl)carbamate (1.1 g, 2.65 mmol) and HCI in methanol (10ml_, 5N) was stirred at room temperature for 1 h. LC-MS checked that the reaction was complete. After removal of solvent, the desired A/-(2-(methylamino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide was obtained (0.94 g, yield 100%) as a white solid. MS (ESI) m/z: Calculated for Ο^Η^3Ν402: 314.10; found: 315 (M+H)+.
A -(2-(((2-(4-Fluorophenyl)oxazol-4-yl)methyl)(methyl)amino)ethyl)-3-(5- -l ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000055_0003
2-(4-Fluorophenyl)oxazole-4-carbaldehyde (27 mg, 0.14mmol) and AcOH (1 ml.) were added to a stirred solution of A/-(2-(methylamino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide (50 mg, 0.14 mmol) in 5 ml. of methanol under N2. The resulting mixture was stirred at room temperature for 1 h, and NaBCNH3 (1 1 mg,
0.14mmol) was added to this mixture. The mixture was stirred for additional 2 h at room temperature and LC-MS checked that the reaction was complete. 10 ml. of water was added to this mixture and the mixture was extracted with ethyl acetate. The combined organic solvents were washed with water (15ml_), brine (15ml_) and dried over Na2S04. Removal of solvent gave a residue and the residue was purified by Pre-HPLC to give N- (2-(((2-(4-Fluorophenyl)oxazol-4-yl)methyl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-
1 ,2,4-oxadiazol-3-yl)benzamide as a yellowish solid (30 mg, yield 44%). 1H NMR (CDCI3, 500MHz): δ 8.66 (s, 1 H), 8.52 (s, 1 H), 8.16 (d, J = 8.0Hz, 1 H), 8.00 (d, J = 8.0Hz, 1 H), 7.91 -7.88 (m, 3H), 7.51 (t, J = 8.0Hz, 1 H), 7.08 (t, J = 8.5Hz, 2H), 4.30 (s, 2H), 4.01 -3.31 (m, 4H), 2.98 (s, 3H). MS (ESI) m/z: Calculated for C23H19F4N503: 489.14; found: 490 (M+H)+.
EXAMPLE 11
A -(2-(Benzo[<^oxazol-2-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-
3-yl)benzamide
Figure imgf000056_0001
2-Chlorobenzo[c/]oxazole (22 mg, 0.14mmol), K2C03 (39 mg, 0.28mmol), and Cul (6 mg, 0.03mmol) were added to a stirred solution of A/-(2-(methylamino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide (50 mg, 0.14 mmol) in 5 ml. of DMF under N2. The resulting mixture was stirred at 80 °C overnight. After cooling to room temperature, the mixture was extracted with ethyl acetate (25ml_ x 3). The combined organic solvents were washed with water (15ml_), brine (15ml_) and dried over Na2S04. Removal of solvent gave a residue that was purified by Pre-HPLC to give N-(2- (benzo[c ]oxazol-2-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide as a yellowish solid (17 mg, yield 28%). 1H NMR (DMSO-d6, 500MHz): δ 8.98 (s, 1 H), 8.42 (s, 1 H), 8.16 (d, J = 8.0Hz, 1 H), 8.04 (d, J = 8.0Hz, 1 H), 7.66 (t, J = 7.5Hz, 1 H), 7.29-6.90 (m, 4H), 3.74-3.61 (m, 4H), 3.19 (s, 3H). MS (ESI) m/z: Calculated for C2oH16F3N503: 431 .12; found: 432 (M+H)+. EXAMPLE 12
2-(2-(Benzo[d]thiazol-2-yl(methyl)amino)ethyl)isoindoline-1 ,3-dione
Figure imgf000057_0001
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%). 1H NMR (CDCI3, 400MHz): δ 7.67 (dd, J = 3.2Hz, 5.6 Hz, 2H), 7.52 (dd, J = 2.8 Hz, 5.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 7.05 (t, J = 7.6 Hz, 1 H), 6.87 (t, J = 7.6 Hz, 1 H), 3.95 (t, J = 5.6 Hz, 2H), 3.85 (J = 5.6 Hz, 2H), 3.14 (s, 3H). MS (ESI) m/z: Calculated for Ci8H15N302S: 337.09; found: 338 (M+H)+. -(BenzoIcflthiazol^-ylJ-A i-methylethane-l ^-diamine
Figure imgf000057_0002
This compound was synthesized from 2-(2-(benzo[d]thiazol-2- yl(methyl)amino)ethyl)isoindoline-1 ,3-dione as described in example 10 step 3 to give a 150 mg crude product which was carried through without further purification. MS (ESI) m/z: Calculated for Ci0H13N3S: 207.08; found: 208 (M+H)+. A -(2-(benzo[<^thiazol-2-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadi
-yl)benzamide
Figure imgf000057_0003
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%). 1H NMR (DMSO-d4, 400MHz): δ 8.92 (t, J = 5.6 Hz, 1 H), 8.45 (s, 1 H), 8.16 (d, J = 7.6 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.69-7.65 (m, 2H), 7.38 (d, J = 7.6 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 6.98 (t, J = 8.0 Hz, 1 H), 3.75 (t, J = 5.6 Hz, 2H), 3.63-3.59 (m, 2H), 3.17 (s, 3H). MS (ESI) m/z: Calculated for C2oH16F3N502S: 447.10; found: 448 (M+H)+.
EXAMPLE 13
Figure imgf000058_0001
Triethylamine (202mg, 2mmol) and Boc20 (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 Na2S04. Removal of solvents under reduce pressure gave a crude product. It was purified by flash column (PE: EtOAc = 3:1 ) to get tert-butyl (2-methylbenzo[d]thiazol-5-yl)carbamate (100mg, yield 38%). MS (ESI) m/z: Calculated for Ci3H16N202S: 264.09; found: 265.1 (M+H)+. ferf-Butyl methyl(2-methylbenzo[d]thiazol-5-yl)carbamate
Figure imgf000058_0002
NaH (60% in mineral oil, 17mg, 0.418mmol) was added to a solution of ferf-butyl (2-methylbenzo[d]thiazol-5-yl)carbamate (100mg, 0.38mmol) in DMF (20ml) under N2, then it was stirred at rt for 30min. CH3I (54mg, 0.38mmol) was added drop wise to the mixture, then it was stirred at rt for 3 hours. The reaction was complete monitored by LCMS. It was extracted with EA (15ml x 3). The combined organic solvent was washed with solution of LiCI and water, dried over Na2S04. Removed solvents under reduce pressure afforded a crude product. It was purified by flash column (PE: EA=3:1 ) to get ferf-butyl methyl(2-methylbenzo[d]thiazol-5-yl)carbamate (80mg, yield 76%). MS (ESI) m/z: Calculated for Ci4H18N202S: 278.1 1 ; found: 279.1 (M+H)+. lbenzo d]thiazol-5-amine
Figure imgf000058_0003
Saturated HCI in methanol (4ml) was added to a solution of ferf-butyl methyl(2- methylbenzo[d]thiazol-5-yl)carbamate (80mg, 0.29mmol) in MeOH (10ml), then it was stirred at rt overnight. The reaction was complete monitored by LCMS. MeOH was removed under reduced pressure to get a residue, it was poured into 10ml water and basified with 10%NaOH until pH=8. The mixture was extracted with EtOAc (10ml x 3), dried over Na2S04, and concentrated t under reduce pressure to get crude Λ/,2- dimethylbenzo[c/]thiazol-5-amine (45mg, yield 86%). which was carried through without further purification. MS (ESI) m/z: Calculated for C9H10N2S: 178.06; found: 179.1 (M+H)+.
A -(2,2-Dimethoxyethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000059_0001
3-(5-(Trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzoic acid (8.3 g, 32.2 mmol), EDCI
(1 1 g, 57.2 mmol), HOBt (7.8 g, 57.2 mmol), and DIPEA (14.7 g, 1 14.3mmol) were added to a solution of 2,2-dimethoxyethanamine (3g 28.6mmol) in DCM (80ml_). The reaction mixture was stirred at room temperature overnight. Water (80 ml.) was added to the mixture and the organic phase was separated. The aqueous phase was extracted with CH2CI2 (80 ml. x 3). The combined organic solvents were washed with brine (100 ml_), dried over Na2S04. After removal of solvents, the crude compound was purified by flash column (PE: EtOAc = 3:1 ) to provide A/-(2,2-dimethoxyethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide (6.2 g, yield 62%) as a yellow solid. -(2-Oxoethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000059_0002
A solution of A/-(2,2-dimethoxyethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide (3g, 8.69mmol) and TFA (3.8g, 33mmol) in water (21 ml) and DCM (30ml) was stirred at rt for 18 hours. The reaction was complete checked by LCMS, then the mixture was extracted with DCM (30ml x 3), dried over Na2S04. Removal of solvents under reduce pressure gave a crude A/-(2-oxoethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol- 3-yl)benzamide (1.5 g, yield 58%) as a yellow solid, which was carried through without further purification. MS (ESI) m/z: Calculated for C12H8F3N3O3: 299.05; found: 300.1 (M+H)+. A -(2-(Methyl(2-methylbenzo[d]thiazol-5-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-
Figure imgf000060_0001
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. NaHC03 (aq, 20 mL) was added to the mixture to quench the reaction, the organic phase was separated. The aqueous phase was extracted with CH2CI2 (10 mL x 3). The combined organic solvents were dried over Na2S04. 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 %). 1 H NMR (DMSO-d6, 400MHz): & 8.90 (s, 1 H), 8.46 (s, 1 H), 8.20 (d, J = 8.0Hz, 1 H), 8.07 (d, J = 7.6Hz, 1 H), 7.73-7.68 (m, 2H), 7.24 (d, J = 2.4Hz, 1 H), 6.97 (d, J=1 1 .2Hz, 1 H), 3.59 (br, 2H), 3.50 (br, 2H), 3.00 (s, 3H), 2.70 (s, 3H). MS (ESI) m/z: Calculated for C2i H18F3N502S: 461 .1 1 ; found: 462.1 (M+H)+.
EXAMPLE 14
ferf-Butyl benzofuran-5-ylcarbamate
Figure imgf000060_0002
This compound was synthesized from benzofuran-5-amine as described in example 13 step 1 (150mg, yield 64%). ferf-Butyl benzofuran-5-yl(methyl)carbamate
Figure imgf000060_0003
This compound was synthesized from ferf-butyl benzofuran-5-ylcarbamate as described in example 13 step 2 (120mg, yield 80%).
W-Methylbenzofuran-5-amine
Figure imgf000061_0001
This compound was synthesized from ferf-butyl benzofuran-5-yl(methyl)carbamate as described in example 13 step 3 (60mg, yield 85%). MS (ESI) m/z: Calculated for C9H9NO: 147.07; found: 148.1 (M+H)+. A -(2-(Benzofuran-5-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide
Figure imgf000061_0002
This compound was synthesized from A/-Methylbenzofuran-5-amine and N-(2- oxoethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide as described in example 13 step 4 (45 mg, yield 30%). 1H NMR (DMSO-d6, 400MHz): & 8.89 (s, 1 H), 8.48 (s, 1 H), 8.20 (d, J = 8.0Hz, 1 H), 8.08 (d, J = 8.4Hz, 1 H), 7.80 (s, 1 H), 7.71 (t, J = 8.0Hz, 1 H), 7.38 (d, J = 9.2Hz, 1 H), 6.93 (s, 1 H), 6.87 (d, J = 8.8Hz, 1 H), 6.77 (s, 1 H), 3.54-3.48 (m, 4H), 2.95 (s,3H). MS (ESI) m/z: Calculated for Czi H^FslSUOs: 430.13; found: 431 .1 (M+H)+.
EXAMPLE 15
8- 2 4-Difluorophen l -1 ,4-dioxa-8-azaspiro[4.5]decane
Figure imgf000061_0003
1-Bromo-2,4-difluorobenzene (1000 mg, 5.2 mmol), Pd2(dba)3 (970 mg, 1 mmol), x-Phos (720 mg, 1 .5 mmol), and t-BuONa (1 .5g, 15.6 mmol) were added to a solution of 1 ,4-dioxa-8-azaspiro[4.5]decane (900 mg, 6.2 mmol) in 5 ml. of xylene under N2. The resulting mixture was sealed and heated under MW at 120 °C for 60 min. After cooling to room temperature, water (50 ml.) was added and ethyl acetate (50 ml. x 3) was used to extract organic compounds. The mixture was washed with brine (50 ml. x 3), dried over Na2S04. After removal of solvent, the residue was purified by silica gel column with EtOAc/ PE: 1/10 to obtain 8-(2,4-difluorophenyl)-1 ,4-dioxa-8-azaspiro[4.5]decane (610 mg, yield 46%) as a yellow oil. MS (ESI) m/z: Calculated for Ci3H15F2N02: 255.1 1 ; found: 256.0 (M+H)+. -(2,4-Difluorophenyl)piperidin-4-one
Figure imgf000062_0001
A solution of 8-(2,4-difluorophenyl)-1 ,4-dioxa-8-azaspiro[4.5]decane (225mg, 0.88 mmol) in TFA/H20 (10/5mL) was stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in water (10ml_), and extracted with ethyl acetate (10 mL x 3). The organic phases were dried over Na2S04. After filtration, the filtrate was concentrated to dryness to yield 1 -(2,4-difluorophenyl)piperidin-4-one as a yellow oil (160mg, yield 86%), which was carried through without further purification. MS (ESI) m/z: Calculated for CiiHnF2NO: 21 1 .08; found: 212.1 (M+H)+.
A -(2-((1 -(2,4-Difluorophenyl)piperidin-4-yl)(methyl)amino)ethyl)-3-(5- -1 ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000062_0002
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. 1 H NMR (DMSO- d6, 400MHz): δ 8.73 (t, J = 5.6 Hz, 1 H), 8.53 (s, 1 H), 8.21 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.73 (t, J = 7.6 Hz, 1 H), 7.19-7.13 (m, 1 H), 7.01-7.08 (m, 1 H), 6.93-6.98 (m, 1 H), 3.40-3.27 (m, 5H), 2.66-2.59 (m, 4H), 2.30 (s, 3H), 1 .76 (d, 2H), 1.63-1 .53 (m, 2H). MS (ESI) m/z: Calculated for C24H24F5N502: 509.19; found: 510.0 (M+H)+. EXAMPLE 16
ferf-Butyl benzo[d][1 ,3]dioxol-5-ylcarbamate
Figure imgf000063_0001
This compound was synthesized from benzo[d][1 ,3]dioxol-5-amine as described in example 13 step 1 (200mg, yield: 100%). ferf-Butyl benzo[d][1 ,3]dioxol-5-yl(methyl)carbamate
Figure imgf000063_0002
This compound was synthesized from tert-butyl benzo[d][1 ,3]dioxol-5-ylcarbamate as described in example 13 step 2 (200mg, yield: 100%).
A -Methylbenzo[d][1 ,3]dioxol-5-amine
Figure imgf000063_0003
This compound was synthesized from tert-butyl benzo[d][1 ,3]dioxol-5- yl(methyl)carbamate as described in example 13 step 3 (90mg, yield 100%).
W-(2-(benzo[d][1 ,3]dioxol-5-yl(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- -3-yl)benzamide
Figure imgf000063_0004
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%). 1 H NMR (DMSO-d6, 400MHz): & 8.86 (s, 1 H), 8.49 (s, 1 H), 8.21 (d, J = 7.6Hz, 1 H), 8.09 (d, J = 8.0Hz, 1 H), 7.73 (t, J = 8.0Hz, 1 H), 6.73 (d, J = 8.4Hz, 1 H), 6.53 (d, J = 2.8Hz, 1 H), 6.17 (d, J=8.4, 1 H), 5.84 (s, 2H), 3.43-3.40 (m, 4H), 2.87 (s, 3H). MS (ESI) m/z: Calculated for C20H17F3N4O4: 434.12; found: 435.1 (M+H)+. EXAMPLE 17
8-Phenyl-1 ,4-dioxa-8-azaspiro[4.5]decane
Figure imgf000064_0001
This compound was synthesized from 1 ,4-dioxa-8-azaspiro[4.5]decane and iodobenzene as described in example 15 step 1 (1 .03 g, yield: 81 %) as a yellow oil. MS (ESI) m/z: Calculated for Ci3H17N02: 219.13; found: 220.0 (M+H)+.
1 -Phenylpiperidin
Figure imgf000064_0002
O N— '
The solution of 8-phenyl-1 ,4-dioxa-8-azaspiro[4.5]decane (930 mg, 4.25 mmol) in THF (20 mL) and 3M HCI solution (30 mL) was stirred at room temperature overnight. Then 10 mL of water was added to the mixture, NaOH was used to neutralize the aqueous phase to pH=7~8. The mixture was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (15 mLx3), dried over Na2S04. After removal of solvent, the residue was purified by silica gel column (EtOAc/ PE: 1/7) to obtain 1 -phenylpiperidin-4-one (500 mg, yield 67%) as a yellow oil. MS (ESI) m/z:
Calculated for Cn H13NO: 175.10; found: 176.0 (M+H)+.
A -(2-(Methyl(1 ^henylpiperidin-4-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide
Figure imgf000064_0003
1 -Phenylpiperidin-4-one (42 mg, 0.24 mmol) and NaBH3CN (30mg, 0.48 mmol) were added to a solution of A/-(2-(methylamino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4- oxadiazol-3-yl)benzamide (70 mg, 0.2 mmol) in 1 ,2-dichloroethane (8 mL) was added at 0°C under N2. The mixture was stirred at R.T overnight. Then 10 mL of water was added to the mixture. The mixture was then extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with brine (15 mLx3), dried over Na2S04. After removal of solvent, the residue was purified by Pre-HPLC to obtain A/-(2-(methyl(1- phenylpiperidin-4-yl)amino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazo
(25 mg, yield: 26%) as a colorless oil. 1 H NMR (DMSO-d6, 400MHz): δ 8.71 (t, J = 5.6 Hz, 1 H), 8.51 (t, J = 1.6 Hz, 1 H), 8.21-8.19 (m, 1 H), 8.12-8.10 (m, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.18-7.14 (m, 1 H), 6.90 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1 H), 3.71 (d, J = 12.4 Hz, 2H), 3.37-3.32 (m, 3H), 2.66-2.59 (m, 4H), 2.27 (s, 3H), 1.77 (d, J = 1 1 .6 Hz, 2H), 1 .51 -1.47 (m, 2H). MS (ESI) m/z: Calculated for C24H26F3N502: 473.20; found: 474.2 (M+H)+.
EXAMPLE 18
-(4-Fluorophenyl)-1 ,4-dioxa-8-azaspiro[4.5]decane
Figure imgf000065_0001
This compound was synthesized from 1 ,4-dioxa-8-azaspiro[4.5]decane and 1 - fluoro-4-iodobenzene as described in example 15 step 1 (624 mg, yield: 90%) as a yellow oil.. MS (ESI) m/z: Calculated for Ci3H16FN02: 237.12; found: 238.1 (M+H)+.
1 -(4-Fluorophenyl)piperidin-4-one
Figure imgf000065_0002
This compound was synthesized from 8-(4-fluorophenyl)-1 ,4-dioxa-8- azaspiro[4.5]decane as described in example 17 step 2 (406 mg, yield: 79%) as a yellow oil. MS (ESI) m/z: Calculated for Cn H12FNO: 193.09; found: 194.1 (M+H)+.
A -(2-((1 -(4-Fluorophenyl)piperidin-4-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-
1 ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000065_0003
This compound was synthesized from 1-(4-fluorophenyl)piperidin-4-one and Λ/-(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. 1 H NMR (DMSO-d6, 400MHz): 5 8.73-8.72 (m, 1 H), 8.51 (s, 1 H), 8.21 (d, J = 7.6 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.22 (t, J = 8.0 Hz, 1 H), 7.02-6.89 (m, 4H), 3.60 (d, J = 12.4 Hz, 1 H), 3.37-3.35 (m, 3H), 2.66- 2.56 (m, 4H), 2.27 (s, 3H), 1.77 (d, J = 1 1 .6 Hz, 2H), 1.51 -1 .46 (m, 2H). MS (ESI) m/z:
Calculated for C24H25F4N502: 491.19; found: 492.2 (M+H)+.
EXAMPLE 19
W-(2-((2,3-Dihydrobenzo[b][1 ,4]dioxin-6-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000066_0001
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
described in example 13 step 4 (25 mg, yield 30%). 1H NMR (DMSO-d6, 400MHz): &
8.85 (s, 1 H), 8.48 (s, 1 H), 8.21 (d, J = 8.0Hz, 1 H), 8.08 (d, J = 7.6Hz, 1 H), 7.72 (t, J =
8.0Hz, 1 H), 6.66 (d, J = 8.4Hz, 1 H), 6.29 (d, J=8.4, 2H), 4.15 (br, 2H), 4.10 (br, 2H), 3.41 (s, 4H), 2.84 (s, 3H). MS (ESI) m/z: Calculated for C2^9F3H404: 448.14; found: 449.1 (M+H)+.
EXAMPLE 20
ferf-Butyl (1 -(4-chlorophenyl)piperidin-4-yl)carbamate
Pd2(dba)3 ,X-p os, .— . .— .
BOCHN- ΛΗ + t-BuONa, ^ BocH ^ / N→f_VCI
^— f \=/ Xylene, MW=120°C
This compound was synthesized from tert-butyl piperidin-4-ylcarbamate and 1- chloro-4-iodobenzene as described in example 15 step 1 (840 mg, yield 65%) as a pink solid. MS (ESI) m/z: Calculated for C16H23CIN2O2: 310.14; found: 31 1 .0 (M+H)+. ferf-Butyl (1 -(4-chlorophenyl)piperidin-4-yl)(methyl)carbamate / . . . -CI
\ / \— /
Figure imgf000066_0002
NaH (968 mg, 24 mmol) was added to a stirred solution of ferf-butyl (1-(4- chlorophenyl)piperidin-4-yl)carbamate (750 mg, 2.4 mmol) in 200 mL of THF under N2.
The resulting mixture was stirred at room temperature for 30 min. Then CH3I (686 mg, 4.8 mmol) was added and the mixture was stirred at room temperature overnight. 10 ml_ water was added to the mixture and the mixture was extracted with EtOAc (15ml_ x 3), and dried over Na2S04. After removal of solvent, ferf-butyl (1 -(4-chlorophenyl)piperidin-4- yl)(methyl)carbamate was obtained (800 mg, yield 90%) as a yellow oil, which was carried through without further purification. MS (ESI) m/z: Calculated for C17H25CIN2O2: 324.16; found: 325.1 (M+H)+. -(4-Chlorophenyl)-A -methylpiperidin-4-amine
Figure imgf000067_0001
The solution of tert-butyl (1-(4-chlorophenyl)piperidin-4-yl)(methyl)carbamate (400 mg, 1.23 mmol) in 20 ml. of saturated HCI in MeOH was stirred at room temperature for 2h. After removal of solvent, 1-(4-chlorophenyl)-/V-methylpiperidin-4-amine was obtained (254 mg, yield 92%) as a yellow solid, which was carried through without further purification. MS (ESI) m/z: Calculated for C12H17CIN2: 224.1 1 ; found: 225.2 (M+H)+.
A -(2-((1 -(4-chlorophenyl)piperidin-4-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)-
1 ,2,4-oxadiazol-3-yl)benzamid
Figure imgf000067_0002
overnight This compound was synthesized from 1-(4-chlorophenyl)-/V-methylpiperidin-4- amine and A/-(2-(methylamino)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)benzamide as described in example 17 step 3 (12 mg, yield: 7%) as a yellow solid. 1 H NMR (DMSO- d6, 400MHz): δ 8.71 (t, J = 5.6 Hz, 1 H), 8.51 (s, 1 H), 8.21 (d, J = 8.0 Hz, 1 H), 8.1 1 (d, J = 8.0 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.18-7.16 (m, 2H), 6.92 (d, J = 9.2 Hz, 2H), 3.70 (d, J = 12.0 Hz, 2H), 3.36-3.33 (m, 3H), 2.65-2.58 (m, 4H), 2.26 (s, 3H), 1.77-1 .46 (m, 4H). MS (ESI) m/z: Calculated for C24H25CIF3N502: 507.16; found: 508.2 (M+H)+. EXAMPLE 21
W-(2-((5-methoxy-1 ,2,3,4-tetrahydronaphthalen-2-yl)(methyl)amino)ethyl)-3-(5- -1 ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000068_0001
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%). 1H NMR (DMSO-d6, 400MHz): δ 8.72 (s, 1 H), 8.52 (s, 1 H), 8.21 (d, J = 7.6Hz, 1 H), 8.1 1 (d, J = 6.4Hz, 1 H), 7.72 (t, J = 7.6Hz, 1 H), 7.03 (t, J = 8Hz, 1 H), 6.70 (d, J = 8.8Hz, 1 H), 6.65 (d, J = 7.6Hz, 1 H), 3.72 (s, 3H), 3.39 (d, J = 6Hz, 2H), 2.84-2.62 (m,6H), 2.32 (s, 3H), 1.96 (s, 1 H), 1 .50 (s, 1 H). MS (ESI) m/z: Calculated for C24H25F3N4O3: 474.19; found: 475.0 (M+H)+.
EXAMPLE 22
2-(2-((6-Methoxybenzo[d]thiazol-2-yl)(methyl)amino)ethyl)isoindoline-1 ,3-dione
Figure imgf000068_0002
This compound was synthesized from 2-bromo-6-methoxybenzo[d]thiazole and 2- (2-(methylamino)ethyl)isoindoline-1 ,3-dione as described in example 1 1 step 1 (80 mg, yield 43%). MS (ESI) m/z: Calculated for Ci9H17N303S: 367.10; found: 368.0 (M+H)+. -(6-Methoxybenzo[d]thiazol-2-yl)-N1 -methylethane-1 ,2-diamine
Figure imgf000068_0003
This compound was synthesized from 2-(2-((6-methoxybenzo[d]thiazol-2- yl)(methyl)amino)ethyl)isoindoline-1 ,3-dione as described in example 10 step 3 to give a 90 mg crude product which was carried through without further purification. MS (ESI) m/z: Calculated for Cn H15N3OS: 237.09; found: 238 (M+H)+.
A -(2-((6-Methoxybenzo[d]thiazol-2-yl)(methyl)amino)ethyl)-3-(5-(trifluoromethyl)- -oxadiazol-3-yl)benzamide
Figure imgf000069_0001
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%). 1H NMR (DMSO-d4, 400MHz): δ 8.99 (J = 5.2 Hz, 1 H), 8.45 (s, 1 H), 8.17 (d, J = 7.6 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.32 (d, J = 2.89 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 6.81 (dd, J = 2.8 Hz, 8.8 Hz, 1 H), 3.73 -3.70 (m, 5H), 3.6 (q, J = 5.6 Hz, 1 H), 3.25 (s, 3H). MS (ESI) m/z:
Calculated for C2i H18F3N503S: 477.1 1 ; found: 477.9 (M+H)+.
EXAMPLE 23
A -^2-((6-Methoxy-1 ,2,3,4-tetrahydronaphthalen-2-yl)(methyl)amino)ethyl)-3-(5- (trifluoromethyl)-l ,2,4-oxadiazol-3-yl)benzamide
Figure imgf000069_0002
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%). 1HNMR (DMSO-d6, 400MHz): δ 8.75 (s, 1 H), 8.52 (s, 1 H), 8.22 (d, J = 7.6Hz, 1 H), 8.12 (d, J = 8Hz, 1 H), 7.73 (t, J = 8Hz, 1 H), 6.96 (d, J = 8.4Hz, 1 H), 6.63 (t, J = 8Hz, 2H), 3.68 (s, 3H), 3.41 (s, 2H), 2.83-2.62 (m, 8H), 2.33 (s, 3H), 1 .93 (s, 1 H), 1 .54 (s, 1 H). MS (ESI) m/z: Calculated for C^HzsFalSUOa:
474.19; found: 475.0 (M+H)+. EXAMPLE 24
-(5-Methoxy-1 H-indol-1 -yl)ethanamine
Figure imgf000070_0001
A solution of 5-methoxy-1 H-indole (147mg, 1 mol) in THF (4ml_) was added slowly to a suspension of NaH (120mg, 3mmol) in THF (5mL) at cooled 0 °C. After the addition, the reaction mixture was stirred at room temperature for 30min. Then 2-bromoethanamine hydrobromide (204.9mg, 1 mmol) was added. The reaction mixture was stirred at 70 °C overnight, and quenched with water (5.7ml_). It was extracted with ethyl acetate (30ml_ x 3), the organic phase was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated to dryness and purified by column chromatography on silica gel
(DCM/MeOH=10/1 ) to obtain 2-(5-methoxy-1 H-indol-1 -yl)ethanamine (70mg, yield 36.8%). MS (ESI) m/z: Calculated for CnH14N20: 190.1 1 ; found: 191.1 (M+H)+.
W-(2-(5-Methoxy-1 H-indol-1 -yl)ethyl)-3-(5-(trifluoromethyl)-1 ,2,4-oxadiazol-3- yl)benzamide
Figure imgf000070_0002
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 %). 1H NMR (CDCI3, 400MHz): δ 8.24 (s, 1 H), 8.17 (d, J = 7.6Hz, 1 H), 7.79 (d, J = 8Hz, 1 H), 7.51 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 8.8 Hz, 1 H), 7.02 (dd, J = 2.4z, J = 12Hz,1 H), 6.79 (dd, J = 8.8Hz, J = 2.4Hz, 1 H), 6.39 (d, J = 2.8 Hz, 1 H), 6.05 (s, 1 H), 4.34 (t, J = 5.6 Hz , 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.77 (s, 3H). MS (ESI) m/z: Calculated for C2i H17F3N403: 430.13; found: 431.0 (M+H)+. Pharmaceutical Compositions
Example A
Tablets are prepared using conventional methods and are formulated as follows:
Inqredient Amount per tablet
Compound of Example 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 of Example 3 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 I la 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 (I DBS), from 1 1 point 3x dilution series starting from 100uM 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 -8 exhibited a plC50 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 plC50 between approximately 6.0 and 9,.0.
References:
US 20060269559, US Patent No. 7,521 ,044, WO2007084775, WO201 1/088181 , WO201 1/088187, WO201 1/088192
"Deacetylase inhibition promotes the generation and function of regulatory T cells," R.Tao, E. F. de Zoeten, E. O" zkaynak, C. Chen, L. Wang, P. M. Porrett, B. Li, L. A.
Turka, E. N. Olson, M. I. Greene, A. D. Wells, W. W. Hancock, Nature Medicine, 13 (1 1 ), 2007.
"Expression of HDAC9 by T Regulatory Cells Prevents Colitis in Mice," E. F. de
Zoeten, L. Wang, H. Sai, W. H. Dillmann, W. W. Hancock, Gastroenterology. 2009 Oct 28.
"Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells," L. Wang, E. F. de Zoeten, M. I. Greene and W. W. Hancock, Nature Review Drug Discovery. 8(12):969-81 , 2009 and references therein.
"HDAC7 targeting enhances FOXP3+ Treg function and induces long-term allograft survival," L. Wang, et al., Am. J. Transplant 9, S621 (2009).
"Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes," A. Nebbioso, F. Manzo, M. Miceli, M. Conte, L. Manente, A. Baldi, A. De Luca, D. Rotili, S. Valente, A. Mai, A. Usiello, H. Gronemeyer, L. Altucci, EMBO reports 10 (7) , 776-782, 2009. and references therein.
"Myocyte Enhancer Factor 2 and Class II Histone Deacetylases Control a Gender- Specific Pathway of Cardioprotection Mediated by the Estrogen Receptor," E. van Rooij, J. Fielitz, L. B. Sutherland, V. L. Thijssen, H. J. Crijns, M. J. Dimaio, J. Shelton, L. J. De Windt, J. A. Hill, E.N. Olson, Circulation Research, Jan 2010.

Claims

What is claimed is:
1. A compound according to Formula I:
Figure imgf000073_0001
wherein:
R1 is halo(CrC4)alkyl, wherein said halo(CrC4)alkyl contains at least 2 halo groups;
Y is a bond and X-\ is O, N or NH, X2 is N or CH and X3 is N or NH,
or Y is -C(O)- and Xi and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and X-, is O, X2 is CH or N, and X3 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 (CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl,
(C C4)alkoxy, halo(C C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
Z is -C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -S02-, -S02NRx-, -NRxS02-, -NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(C C4)alkyl-, -NRX-, or -(C C3)alkyl-NRx-; each Rx is independently selected from H, (Ci-C6)alkyl, and optionally substituted (C2-C6)alkyl, where said optionally substituted (C2-C6)alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC4)alkoxy, (CrC4)alkyl)NH-, or ((Ci-C4)alkyl)((Ci-C4)alkyl)N-; and n is 0, 1 or 2 and m is 0, 1 or 2; provided that 0< m+n <3;
R2 is H, fluoro, (C C4)alkyl, -(C C4)alkyl-NRARB, -CONRARB, -C02H,
-(CrC4)alkyl-CONRARB, -(C C4)alkyl-C02H, hydroxy(C C4)alkyl-, halo(C C4)alkyl-, cyano(C C4)alkyl- or (CrC3)alkoxy(CrC4)alkyl-;
wherein RA and RB are each independently selected from H and (CrC4)alkyl;
R3 is H or (C C4)alkyl;
or R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5, 6, or 7 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 or 2 heteroatoms independently selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by 1 , 2 or 3 substituents independently selected from (Ci-C4)alkyl,
halo(C C4)alkyl, halogen, cyano, aryl(C C4)alkyl-, (C3-C7)cycloalkyl(Ci-C4)alkyl-, -ORY, -NRYRY, -C(=0)ORY, -C(=0)NRYRY, -NRYC(=0)RY, -S02NRYRY, -NRYS02RY,
-OC(=0)NRYRY, -NRYC(=0)ORY, and -N RYC(=0)N RYRY; each RY is independently selected from H, (Ci-C4)alkyl, phenyl, and -(C-|-C4)alkylphenyl;
R4 is H or (Ci-C4)alkyl;
L is 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, -(Ci-C4)alkyl- 5-6 membered heterocycloalkyl-, -(Ci-C4)alkyl-5-6 membered heteroaryl- or -(Ci-C4)alkyl- phenyl- wherein each of said 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl is substituted by R5 and is optionally further substituted,
wherein when any of said 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl is further substituted, said 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, or phenyl is substituted by 1 or 2 substituents independently selected from halogen, cyano (C C4)alkoxy and (C C4)alkyl;
R5 is H, (C C4)alkyl, halo, halo(C C4)alkyl, (C C4)alkoxy, cyano,
((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkoxy, ((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkyl-, (CrC4)haloalkoxy-, (Ci-C4)alkylamino, optionally substituted (C3-Ci2)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered bicyclic heteroaryl,
wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, (C C4)alkylthio-, halo(C C4)alkoxy, hydroxyl, -NRARC and -((Ci-C4)alkyl)NRARc;
or L and R5, taken together, form a 9-10 membered bicyclic heterocyclic or carbocyclic group, wherein at least one ring of the bicyclic group is aromatic and said heterocyclic or carbocyclic group is optionally substituted by 1 , 2 or 3 groups each independently selected from (Ci-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (Ci-C4)alkoxy, (CrC4)alkylthio-, halo(C C4)alkoxy, hydroxyl, -NRARC, -((C C4)alkyl)NRARc, optionally substituted
(C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(C1-C4)alkyl-, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl;
or L and R4, 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, provided that the bicyclic heterocyclic group is not tetrahydroisoquinolyl or isoindolinyl, and said heterocyclic group is optionally substituted by 1 , 2 or 3 groups each independently selected from (CrC4)alkyl halogen, cyano, halo(CrC4)alkyl, (CrC4)alkoxy, (C C4)alkylthio-, halo(C C4)alkoxy, hydroxyl, -NRARC, -((C C4)alkyl)NRARc, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(Ci-C4)alkyl-, optionally substituted 5-6 membered heterocycloalkyi and optionally substituted 5-6 membered heteroaryl;
wherein:
RA is independently selected from H and (CrC4)alkyl;
Rc is H, (Ci-C4)alkyl, phenyl, 5-6 membered heterocycloalkyi, or 5-6 membered heteroaryl, or RA and Rc taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S and optionally substituted by (C C4)alkyl and
said optionally substituted (C3-C6)cycloalkyl, phenyl, phenyl(Ci-C4)alkyl-, 5-6 membered heterocycloalkyi or 5-6 membered heteroaryl is optionally substituted by 1 , 2 or 3 groups each independently selected from (Ci-C4)alkyl, halogen, cyano, halo(CrC4)alkyl, (C-|-C4)alkoxy, (C-|-C4)alkylthio-, halo(C-|-C4)alkoxy, hydroxyl, amino, (CrC4)alkyl-amino-, amino(Ci-C4)alkyl-, ((Ci-C4)alkyl)amino-(Ci-C4)alkyl-, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino-, and ((Ci-C4)alkyl)((Ci-C4)alkyl)amino-(Ci-C4)alkyl-;
or a salt thereof.
2. The compound or salt according to claim 1 , wherein R1 is a fluoro-alkyl group containing at least 2 fluoro atoms.
3. The compound or salt according to claim 1 , wherein R1 is a (CrC2)alkyl group containing at least 2 fluoro atoms.
4. The compound or salt according to claim 1 , wherein R1 is CHF2 or CF3.
5. The compound or salt according to claim 1 , wherein R1 is CF3.
6. The compound or salt according to any one of claims 1-5, wherein when Y is a bond, X^ is O, X2 and X3 are N, or X is O, X2 is CH, X3 is N, or X is N or NH, X2 is CH, X3 is N or NH; or X, is N or NH, X2 is N, X3 is N or NH.
7. The compound or salt according to any one of claims 1-5, wherein when Y is a bond, Xi is O, X2 and X3 are N.
8. The compound or salt according to any one of claims 1 -5, wherein when Y is -C(O)-, X3 is S, Xi is CH and X2 is N, or X3 is S, Xi is N and X2 is CH, or X3 is O, Xi is CH and X2 is N, or X3 is O, Xi is N and X2 is CH, or Xi and X2 are CH, X3 is S or Xi and X2 are CH, X3 is O.
9. The compound or salt according to any one of claims 1 -5, wherein when Y is -C(O)-, X3 is S, Xi is CH and X2 is N, or X3 is S, Xi is N and X2 is CH, or X3 is O, Xi is CH and X2 is N, or X3 is O, Xi is N and X2 is CH, or Xi and X2 are CH, X3 is S. 10. The compound or salt according to any one of claims 1 -5, wherein when Y is
-C(O)-, Xi and X2 are CH, X3 is S.
1 1 . The compound or salt according to any one of claims 1 -5, wherein when Y is -C(O)-, Xi is O, X2 and X3 are CH, or Xi is O, X2 is CH, and X3 is N, or Xi is O, X2 is N, and X3 is CH, or Xi is O, X2 and X3 are N.
12. The compound or salt according to any one of claims 1 -5, wherein when Y is -C(O)-, Xi is O, X2 and X3 are CH. 13. The compound or salt according to any one of claims 1 -12, wherein A is a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and
-((Ci-C4)alkyl)NRARA, where each RA is independently H or methyl. 14. The compound or salt according to any one of claims 1 -12, wherein A is an unsubstituted phenyl group.
15. The compound or salt according to any one of claims 1 -12, wherein A is a 5-6 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl, -NRARA and -((C C4)alkyl)NRARA, where each RA is independently H or methyl and the 5-6 membered heteroaryl contains 1 ring heteroatom selected form N, O and S and optionally contains 1 additional ring nitrogen atom.
16. The compound or salt according to any one of claims 1-12, wherein A is oxazolyl, pyrazolyl, or thienyl, optionally substituted by a methyl group.
17. The compound or salt according to any one of claims 1 -12, wherein A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NRARA and -((Ci-C4)alkyl)NRARA, where each RA is independently H or methyl.
18. The compound or salt according to any one of claims 1 -12, wherein A is pyridyl.
19. The compound or salt according to any one of claims 1 -18, wherein Z is
-C(=0)NRx-, -NRxC(=0)NRx, -NRxC(=0)-, -NRxS02-, -S02NRx-, -NHCH(CF3)-,
-CH(CF3)NH-, -CH(CF3)-, -(C C4)alkyl-, or -(C C3)alkylNRx-.
20. The compound or salt according to claim 19, wherein Rx, or for
-NRxC(=0)NRx, each Rx, may be independently selected from H, (d-C4)alkyl, and optionally substituted (C2-C4)alkyl, where said optionally substituted (C2-C4)alkyl is optionally substituted by hydroxyl, cyano, amino, (CrC4)alkoxy, (CrC4)alkyl)NH-, or
((Ci-C4)alkyl)((CrC4)alkyl)N-.
21. The compound or salt according to claim 19, wherein R is H, methyl or cyanoethyl.
22. The compound or salt according to claim 19, wherein R is H.
23. The compound or salt according to any one of claims 1 -18, wherein Z is
-NHCH(CF3)-, -CH(CF3)NH-, -CH(CF3)-, -(C1-C4)alkyl- or -CH2NH-.
The compound or salt according to any one of claims 1 -18, wherein Z is
-C(=0)NH-.
25. The compound or salt according to any one of claims 1-24, wherein n + m = 1 or 2.
26. The compound or salt according to any one of claims 1 -25, wherein n is 0 and m is 1 or 2; or n is 1 or 2 and m is 0. 27. The compound or salt according to any one of claims 1-24, wherein n + m = 1 .
28. The compound or salt according to any one of claims 1-27, wherein n is 1 and m is 0. 29. The compound or salt according to any one of claims 1 -28, wherein both R2 and
R3 are hydrogen.
30. The compound or salt according to any one of claims 1 -28, wherein both R2 and R3 are (C C4)alkyl.
31. The compound or salt according to any one of claims 1 -28, wherein R2 is selected from amino(Ci-C4)alkyl-, (Ci-C3)alkylamino(Ci-C4)alkyl-,
((Ci-C3)alkyl)((Ci-C3)alkyl)amino(Ci-C4)alkyl-, -CONH2, -CONH(d-C3)alkyl,
-CON((Ci-C3)alkyl)((CrC3)alkyl), -(C C4)alkyl-CONH2, -(Ci-C4)alkyl-CONH(C C3)alkyl, -(Ci-C4)alkyl-CON((Ci-C3)alkyl)((CrC3)alkyl), -C02H, -C02(C C3)alkyl,
-(C C4)alkyl-C02H, -(C C4)alkyl-C02(Ci-C3)alkyl, hydroxy(Ci-C4)alkyl-, and
(Ci-C4)alkoxy(C C4)alkyl- and R3 is H or (C C4)alkyl.
32. The compound or salt according to any one of claims 1 -28, wherein R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4,
5, or 6 membered cycloalkyi or heterocycloalkyi group, wherein said heterocycloalkyi group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyi group is optionally substituted by a substituent selected from (CrC4)alkyl, halo(CrC4)alkyl, halogen, cyano, aryl(C1-C2)alkyl-,
(C3-C6)cycloalkyl(C1-C2)alkyl-, — ORYa, -NRYaRYb, -C(=0)ORYa, -C(=0)NRYaRYb,
-NRYbC(=0)RYa, -S02NRYaRYb, and -NRYbS02RYa, where RYa is selected from H,
(Ci-C4)alkyl, phenyl(Ci-C2)alkyl- and (C3-C6)cycloalkyl(C C2)alkyl-, and each RYb is independently selected from H and (CrC4)alkyl, specifically H and methyl.
33. The compound or salt according to any one of claims 1 -28, wherein R2 and R3 taken together with the atom to which they are connected form an optionally substituted 4, 5 or 6 membered cycloalkyi or 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 (C C4)alkyl, aryl(C C2)alkyl-, and (C3-C6)cycloalkyl(Ci-C2)alkyl-.
34. The compound or salt according to any one of claims 1 -33, wherein
L is an optionally substituted 5-6 membered heterocycloalkyi, 5-6 membered heteroaryl or phenyl group, which group is substituted by R5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano, (C C4)alkyl and (C C4)alkoxy.
35. The compound or salt according to any one of claims 1 -33, 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 heterocycloalkyi, 5- membered heteroaryl, 6-membered heteroaryl or phenyl is substituted by R5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from halogen, cyano, methoxy and methyl.
36. The compound or salt according to any one of claims 1 -33, wherein 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.
37. The compound or salt according to any one of claims 1 -33, wherein L is a thiazolyl, thienyl, phenyl, pyrazolyl, pyrrolidinyl, triazolyl, pyridyl, piperidinyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, isoxazolyl or oxazolyl group.
38. The compound or salt according to any one of claims 1 -37, wherein R4 is H or (CrC2)alkyl.
39. The compound or salt according to any one of claims 1 -37, wherein R4 (Ci-C2)alkyl.
40. The compound or salt according to any one of claims 1 -37, wherein R4 is methyl or ethyl.
41. The compound or salt according to any one of claims 1 -40, wherein R5 is H, halogen, (C1-C4)alkyl, halo(C1-C2)alkyl, (C1-C2)alkoxy, cyano,
((C1-C2)alkyl)((C1-C2)alkyl)N(C1-C3)alkoxy-, ((C1-C2)alkyl)((C1-C2)alkyl)N(C1-C3)alkyl-, (Ci-C3)alkylamino, optionally substituted (C3-Ci0)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyi, or optionally substituted 5-6 or 9-10 membered heteroaryl, where said optionally substituted cycloalkyl, phenyl,
heterocycloalkyi or heteroaryl is optionally substituted by 1 or 2 groups independently selected from (Ci-C4)alkyl, halogen, cyano, halo(Ci-C2)alkyl, (Ci-C2)alkoxy,
halo(Ci-C2)alkoxy, hydroxyl, -NRARC and -((C C4)alkyl)NRARc.
42. The compound or salt according to any one of claims 1 -40, wherein R5 is H, (Ci-C2)alkoxy, (C C4)alkyl, fluoro(C C2)alkyl, cyano, cyclohexyl, tricyclo[3.3.1 .13'7]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.
43. The compound or salt according to any one of claims 1 -40, wherein R5 is H, methyl, ethyl, cyano, fluoro, methoxy, trifluoromethyl, phenyl, 4-chlorophenyl, 4- fluorophenyl, 2,4-difluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, cyclohexyl, tricyclo[3.3.1.13,7]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. 44. The compound or salt according to claim 40, wherein L and R5, 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-C4)alkyl, halogen, cyano, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(C C4)alkoxy, hydroxyl, -NRARC, -((d-C4)alkyl)NRARc, optionally substituted
(C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(CrC4)alkyl-, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl;
45. The compound or salt according to claim 40, wherein L and R5, 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 (C1-C4)alkyl, (C3-C6)cycloalkyl, halogen, (C1-C3)alkoxy, optionally substituted phenyl or phenyl(C1-C4)alkyl-, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl. 46. The compound or salt according to any one of claims 1 -40, wherein L and R5, 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, benzyl, 2-fluorophenyl, 4-fluorophenyl, cyclohexyl, pyrrolidinyl, furanyl, pyrid-2-yl,or pyrid-3-yl.
47. The compound or salt according to any one of claims 1 -33, wherein L and R4, 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 (C1-C4)alkyl, halogen, cyano, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C C4)alkoxy, hydroxyl, -NRARC, -((C1-C4)alkyl)NRARc, optionally substituted
(C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(C1-C4)alkyl-, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl.
48. The compound or salt according to any one of claims 1 -33, wherein L and R4, taken together with the nitrogen atom connecting them, form an indolyl group, optionally substituted by methoxy. 49. The compound or salt according to any one of claims 1 -41 or 44, wherein RA is independently selected from H, methyl and ethyl.
50. The compound or salt according to any one of claims 1 -41 or 44, wherein Rc is H, methyl, ethyl, phenyl, 5-6 membered heterocycloalkyi, or 5-6 membered heteroaryl.
51. The compound or salt according to any one of claims 1 -41 or 44, wherein RA and Rc 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 (Ci-C4)alkyl.
52. The compound or salt according to any one of claims 1 -41 or 44, wherein said optionally substituted (C3-C6)cycloalkyl, phenyl, phenyl(Ci-C4)alkyl-, 5-6 membered heterocycloalkyi or 5-6 membered heteroaryl is optionally substituted by 1 or 2 groups each independently selected from (Ci-C4)alkyl, halogen, cyano, (CrC3)alkoxy,
(Ci-C3)alkyl-amino-, ((Ci-C3)alkyl)amino-(C C3)alkyl-, ((Ci-C3)alkyl)((C C3)alkyl)amino-, and ((Ci-C3)alkyl)((Ci-C3)alkyl)amino-(Ci-C3)alkyl-.
53. The compound or salt according to any one of claims 1 -41 or 44, wherein each RA and Rc is independently selected from H and (CrC4)alkyl.
54. The compound or salt according to any one of claims 1 -41 or 44, wherein each RA and Rc is independently selected from H, methyl and ethyl.
55. The compound or salt according to claim 1 , wherein:
R1 is -CF3;
Y is a bond and Xi is O, N or NH, X2 is N or CH and X3 is N or NH,
or Y is -C(O)- and X-, and X2 are CH or N, X3 is O or S,
or Y is -C(O)- and Xi is O, X2 is CH or N, and X3 is CH or N;
A is optionally substituted phenyl or pyridyl, wherein said optionally substituted phenyl or pyridyl is optionally substituted by 1 to 2 groups each independently selected from (Ci-C4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, halo(C C4)alkoxy, -NRARA and -((C C4)alkyl)NRARA;
Z is -C(=0)NH-;
n is 1 and m is 0, or n is 0 and m is 1 ;
R2 is H, fluoro, -(C C4)alkyl-NRARB, -(C C4)alkyl-CONRARB, -(Ci-C4)alkyl-C02H, hydroxy(C C4)alkyl-, halo(C C4)alkyl-, or (Ci-C3)alkoxy(Ci-C4)alkyl-;
wherein RA and RB are each independently selected from H and (CrC4)alkyl;
R3 is H or methyl;
R4 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 R5 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from halogen, cyano, (CrC4)alkyl and (CrC4)alkoxy R5 is H,
(CrC4)alkyl, halo, halo(CrC4)alkyl, (CrC4)alkoxy, cyano,
((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkoxy, ((C1-C4)alkyl)((C1-C4)alkyl)N(C1-C4)alkyl-,
(CrC4)haloalkoxy-, (Ci-C4)alkylamino, optionally substituted (C3-Ci0)cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl,
wherein said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (CrC4)alkyl, halogen, cyano, halo(C C4)alkyl, (C C4)alkoxy, (C C4)alkylthio-, halo(C C4)alkoxy, hydroxyl, -NRARC and -((Ci-C4)alkyl)NRARc;
or L and R5, 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
(CrC4)alkyl, halogen, cyano, halo(CrC4)alkyl, (d-C4)alkoxy, halo(CrC4)alkoxy, hydroxyl,
-NRARC, -((Ci-C4)alkyl)NRARc, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(C1-C4)alkyl-, optionally substituted 5-6 membered
heterocycloalkyl and optionally substituted 5-6 membered heteroaryl;
or L and R4, 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 (CrC4)alkyl, halogen, cyano, halo(Ci-C4)alkyl,
(Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxyl, -NRARC, -((Ci-C4)alkyl)NRARc, optionally substituted (C3-C6)cycloalkyl, optionally substituted phenyl or phenyl(Ci-C4)alkyl-,
optionally substituted 5-6 membered heterocycloalkyi and optionally substituted 5-6 membered heteroaryl;
wherein:
RA is H or (Ci-C4)alkyl; Rc is H, (C C4)alkyl, phenyl, 5-6 membered heterocycloalkyi, or 5-6 membered heteroaryl, or RA and Rc taken together with the atom to which they are attached form a 4-8 membered heterocyclic ring, optionally containing one additional
heteroatom selected from N, O and S and optionally substituted by (CrC4)alkyl;
said optionally substituted (C3-C6)cycloalkyl, phenyl, phenyl(C1-C4)alkyl-, 5-6 membered heterocycloalkyi or 5-6 membered heteroaryl is optionally substituted by 1 or 2 groups each independently selected from (Ci-C4)alkyl, halogen, halo(CrC4)alkyl,
(Ci-C4)alkoxy, hydroxyl, amino, (Ci-C4)alkyl-amino-, amino(Ci-C4)alkyl-, ((Ci-C4)alkyl)amino- (C C4)alkyl-, ((C C4)alkyl)((Ci-C4)alkyl)amino-, and ((C C4)alkyl)((C C4)alkyl)amino- (Ci-C4)alkyl-;
56. The compound or salt according to claim 65, wherein:
R1 is CHF2 or CF3; specifically, CF3;
Y is a bond, Xi is O, and X2 and X3 are N, or
Y is -C(O)-, Xi and X2 are CH, and X3 is S, or
Y is -C(O)-, Xi is O, and X2 and X3 are CH;
A is an unsubstituted phenyl or pyridyl group;
Z is -C(=0)NH-;
n + m = 1 , and both R2 and R3 are H;
or n is 0 and m is 1 or 2; or n is 1 or 2 and m is 0, specifically n is 1 and m is 0, and R2 is H, methyl, ethyl, hydroxymethyl-, aminomethyl-, methoxymethyl-, carboxy (H02C-), amido, and R3 is H or methyl;
or n + m = 1 and both R2 and R3 are methyl;
L is thiazolyl, thienyl, pyrazolyl, pyrrolidinyl, triazolyl, phenyl, pyridyl, piperidinyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, isoxazolyl or oxazolyl;
R5 is H, methyl, ethyl, cyano, fluoro, methoxy, trifluoromethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, cyclohexyl, tricyclo[3.3.1.13,7]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 R5, 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,
[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, benzyl, 2-fluorophenyl, 4-fluorophenyl, cyclohexyl, pyrrolidinyl, furanyl, pyrid-2-yl,or pyrid-3-yl; or
L and R4, taken together with the nitrogen atom to which they are attached, form an indolyl group, optionally substituted by methoxy.
57. A pharmaceutical composition comprising the compound or salt according to any one of claims 1-56 and one or more pharmaceutically-acceptable excipients.
58. A method of inhibiting a HDAC enzyme comprising contacting a cell with the compound or salt according to any one of claims 1 -56.
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