[go: up one dir, main page]

WO2013009830A1 - Méthodes de traitement - Google Patents

Méthodes de traitement Download PDF

Info

Publication number
WO2013009830A1
WO2013009830A1 PCT/US2012/046201 US2012046201W WO2013009830A1 WO 2013009830 A1 WO2013009830 A1 WO 2013009830A1 US 2012046201 W US2012046201 W US 2012046201W WO 2013009830 A1 WO2013009830 A1 WO 2013009830A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
trifluoromethyl
oxadiazol
methyl
benzamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2012/046201
Other languages
English (en)
Inventor
Shomir Ghosh
Mercedes Lobera
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tempero Pharmaceuticals Inc
Original Assignee
Tempero Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tempero Pharmaceuticals Inc filed Critical Tempero Pharmaceuticals Inc
Publication of WO2013009830A1 publication Critical patent/WO2013009830A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a method of treating a B-cell lymphoma, particularly B-cell lymphomas associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma), by administering to a patient in need thereof a compound that inhibits HDAC activity.
  • B-cell lymphoma particularly B-cell lymphomas associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma
  • Chromatin organization involves DNA wound around histone octamers that form nucleosomes.
  • Core histones with N-terminal tails extending from compact nucleosomal core particles can be acetylated or deacetylated at epsilon lysine residues affecting histone-DNA and histone-non-histone protein interactions.
  • Histone deacetylases Histone deacetylases
  • HDACs catalyze the deacetylation of histone and non-histone proteins and play an important role in epigenetic regulation.
  • HDACs There are currently 18 known HDACs that are organized into three classes: class I HDACs (HDAC1 , HDAC2, HDAC3, HDAC8 and
  • HDAC1 1 are mainly localized to the nucleus; class II HDACs (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10), which shuttle between the nucleus and the cytoplasm; and class III HDACs (SIRT1-7), whose cellular localization includes various organelles.
  • HDAC9 is a class lla histone deacetylase highly expressed in human B cells. Relative to normal B cells, expression of HDAC9 is deregulated in cell lines derived from B cell tumours and HDAC9 is highly overexpressed in cells derived from patients with non- Hodgkin's lymphoma
  • HDAC4 and HDAC9 have booth been reported to be overexpressed in CD19+ cells from patients with Waldenstrom Macroglobulinemia (Sun et al., Clinical Lymphoma, Myeloma &
  • Class lla HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) have been reported to associate with Bcl-6, a transcription factor implicated in the pathogenesis of B-cell malignancies (Lemercier et al, Journal of Biological Chemistry, 2002, p. 22045, and Petrie et al, Journal of Biological Chemistry, 2003, p. 16059). Due to these interactions class lla HDACs have been suggested to modulate the transcriptional repression of BCL6 and participate in its role in B-cell activation and differentiation, inflammation, and cell-cycle regulation (Verdin et al. TRENDS in Genetics, 2003, p. 286) .
  • HDAC6 a class lib HDAC, has been reported to play an important role in aggresomal protein degradation, making it a target for the treatment of B cell malignancies (Simms-Waldrip et al., Molecular Genetics and Metabolism, 2008, p. 283)
  • a small molecule selective inhibitor of HDAC activity (more specifically, an inhibitor of HDAC4 and/or HDAC5 and/or HDAC6 and/or HDAC7 and/or HDAC8 and/or HDAC9 activity) is expected to be beneficial in the treatment of B-cell malignancies by targeting one or several of the above enzymes.
  • the invention is directed to a method of treatment of a B-cell lymphoma comprising administering, to a patient in need thereof, a compound of 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 (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
  • any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (CrC 4 )alkoxy, halo(CrC 4 )alkoxy, -NR A R A and
  • n is 0-4; when n is 0, R 2 and R 3 are independently selected from H and optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(C 1 -C 4 )alkyl-,
  • R 2 is selected from -NR A R B , -(C C 4 )alkyl-NR A R B , -CONR A R B , -(Ci-C 4 )alkyl-CONR A R B , -C0 2 H, -(Ci-C 4 )alkyl-C0 2 H, hydroxyl, hydroxy(C C 4 )alkyl-, (Ci-C 3 )alkoxy, and (Ci-C 3 )alkoxy(Ci-C 4 )alkyl-, and R 3 is selected from H and optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl
  • aryl, cycloalkyi and each of the (CrC 4 )alkyl moieties of said optionally substituted (Ci-C 4 )alkyl, aryl(Ci-C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(Ci-C 4 )alkyl- of any R 2 and R 3 are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C 4 )alkyl, halo(Ci-C 4 )alkyl, (C C 4 )alkoxy, halo(Ci-C 4 )alkoxy, -NR A R A ,
  • L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted,
  • L when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (CrC 4 )alkyl;
  • R 4 is H, (Ci-C 4 )alkyl, halo, halo(Ci-C 4 )alkyl, (C C 4 )alkoxy,
  • optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(CrC 4 )alkyl, (CrC 4 )alkoxy, (C 1 -C 4 )alkylthio-, halo(C C 4 )alkoxy, hydroxyl, -NR A R C and -((d-C 4 )alkyl)NR A R c ; or L-R 4 , taken together, form a 1 ,3-benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group wherein said benzofuranyl, tetrahydroisoquinolyl or isoindolinyl group where
  • each R A is independently selected from H and (CrC 4 )alkyl
  • R B is H, (Ci-C 4 )alkyl, halo(Ci-C 4 )alkyl,
  • R c is H, (Ci-C 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 (Ci-C 4 )alkyl;
  • each R x is independently selected from H, (CrC 6 )alkyl, and optionally substituted (C 2 -C 6 )alkyl, where said optionally substituted (C 2 -C 6 )alkyl is optionally substituted by hydroxyl, cyano, amino, (C C 4 )alkoxy, (C 1 -C 4 )alkyl)NH-, or ((C 1 -C 4 )alkyl)((C 1 -C 4 )alkyl)N-; and
  • each R Y is independently selected from H, (C 1 -C 4 )alkyl, phenyl, and
  • the invention is further directed to the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt, thereof in therapy, particularly the use of a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to treat a B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
  • a B-cell lymphoma particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocy
  • the invention is still further directed to the manufacture of a medicament containing a compound of Formula I, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy, particularly for use to treat a B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
  • a B-cell lymphoma particularly a B-cell lymphoma associated with deacetylases, particularly Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B
  • R 1 is a 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, Xi is CH and X 2 is N or X 3 is S, Xi is N and X 2 is CH), oxazolyl (X 3 is O, Xi is CH and X 2 is N or X 3 is O, Xi is N and X 2 is CH), thienyl (X ⁇ and X 2 are CH, X 3 is S) or furanyl (Xi and X 2 are CH, X 3 is O) ring moiety.
  • Y is -C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached form a thienyl, thiazolyl or oxazolyl ring moiety, more specifically a thienyl moiety.
  • Y is -C(O)-, X-i, X 2 , and X 3 , taken together with the atoms to which they are attached, form a furanyl or furyl (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.
  • R 1 , R 2 , R 3 ,R 4 , A, Z, n and L are as defined herein.
  • R 1 , R 2 , R 3 ,R 4 , A, Z, n and L are as defined herein.
  • the invention is further directed to methods of treatment and uses of a compound of Formula (l-c), (l-d) -e):
  • R 1 , R 2 , R 3 ,R 4 , A, Z, n and L are as defined herein.
  • the invention is still further directed to methods of treatment and uses of a compound of Formula (l-f), (l-g), (l-h), (l-i) or (l-j):
  • the invention is still further directed to methods of treatment and uses of a compound of Formula (l-k), (l-l), (l-m), or (l-n):
  • A is a phenyl group optionally substituted by 1-2 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C C 4 )alkyl, (d-C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and
  • 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 -((C C 4 )alkyl)NR A R A , where each R A is
  • A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group.
  • A is a
  • cyclopropyl, cyclopentyl or cyclohexyl group optionally substituted by 1-2 groups independently selected from (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, -NR A R A and
  • A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1-2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NR A R A and -((C C 4 )alkyl)NR A R A , where each R A is independently H or methyl.
  • A is a cyclopropyl, cyclopentyl or cyclohexyl group.
  • A is naphthyl, optionally substituted by 1-2 groups independently selected from (CrC 4 )alkyl, halogen, cyano, halo(C C 4 )alkyl, (d-C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and
  • A is a 4-7 membered heterocycloalkyi group optionally substituted by 1-3 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, oxo, -NR A R A and -((Ci-C 4 )alkyl)NR A R A .
  • A is a 9-10 membered heteroaryl optionally substituted by 1 -2 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C 4 )alkoxy, oxo, -NR A R A and -((Ci-C 4 )alkyl)NR A R A .
  • A is isoquinolyl, indazolyl, tetrahydroisoquinolinonyl, isoindolinonyl, and indolinyl.
  • A is a 5-6 membered heteroaryl optionally substituted by 1 -2 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(C C 4 )alkyl, (C C 4 )alkoxy, halo(C C 4 )alkoxy, -NR A R A and -((CrC 4 )alkyl)NR A R A .
  • A is a 5-6 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl,
  • A is oxazolyl, pyrazolyl, or thienyl optionally substituted by a methyl group.
  • A is pyrazolyl or thienyl, optionally substituted by a methyl group.
  • A is thienyl.
  • A is oxazolyl.
  • A is a pyridyl or pyridyl-N-oxide group optionally substituted by 1 -2 groups independently selected from (d-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (C C 4 )alkoxy, halo(C 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 x - or -NR x S0 2 -.
  • Z is -NHCH(CF 3 )- or -CH(CF 3 )NH-.
  • Z is -CH(CF 3 )- or -(C 1 -C 4 )alkyl-.
  • Z is -NR X - or -(C C 3 )alkyl-NR x -.
  • each R x may be independently selected from H, (C 1 -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
  • each R x is independently H, methyl or cyanoethyl, more specifically, R x is H or methyl.
  • n is 0-4; particularly
  • n is 1 or n is 0.
  • one of R 2 and R 3 is other than hydrogen.
  • both R 2 and R 3 are C 1-4 alkyl (e.g., methyl).
  • one of R 2 and R 3 is H and the other of R 2 and R 3 is C 1-4 alkyl (e.g., 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, 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, (C C 4 )alkyl, phenyl(C C 2 )alkyl- and (C 3 -C 6 )cycloalkyl(CrC 2 )alkyl-, and each R Yb is independently selected from H and (Ci-C 4 )alkyl, specifically H and methyl.
  • R 2 and R 3 are independently selected from H and optionally substituted (Ci-C 4 )alkyl
  • R 2 and R 3 are independently selected from H and optionally substituted (C 1 -C 4 )alkyl, phenyl(d-C 2 )alkyl-, and
  • R 2 and R 3 are independently selected from H, fluoro, and optionally substituted (Ci-C 4 )alkyl, phenyl(Ci-C 4 )alkyl-, and
  • R 2 is selected from amino, (Ci-C 4 )alkylamino, ((Ci-C 3 )alkyl)((Ci-C 3 )alkyl)amino,
  • R 3 is selected from H and optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl-, and (C 3 -C7)cycloalkyl(C C 4 )alkyl-.
  • n when n is 1-4, R 2 is selected from amino, hydroxyl, and (C 1 -C 4 )alkoxy, and R 3 is selected from H and optionally substituted (Ci-C 4 )alkyl, phenyl(C 1 -C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C 1 -C 2 )alkyl-.
  • n is 1-3
  • R 2 is hydroxyl and R 3 is H or methyl; more specifically, n is 1 , R 2 is hydroxyl and R 3 is H or methyl.
  • R 2 and R 3 are independently selected from H and optionally substituted (CrC 4 )alkyl, phenyl(Ci-C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl-.
  • R 2 is selected from H and optionally substituted (Ci-C 4 )alkyl, phenyl(Ci-C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl- and R 3 is selected from H and methyl.
  • R 2 and R 3 are independently selected from H and methyl. In more specific embodiments, both R 2 and R 3 are H or both R 2 and R 3 are methyl.
  • the aryl, phenyl, cycloalkyi and each of the (CrC 4 )alkyl or (Ci-C 2 )alkyl moieties of said optionally substituted (Ci-C 4 )alkyl, aryl(Ci-C 4 )alkyl-, phenyl (Ci-C 4 )alkyl- (C 3 -C 7 )cycloalkyl(Ci-C 4 )alkyl- and (C 3 -C 6 )cycloalkyl(C C 2 )alkyl- of any R 2 and R 3 are optionally substituted by 1 , 2 or 3 halogen (specifically fluorine) groups and/or 1 or 2 groups independently selected from cyano, (Ci-C 4 )alkyl, halo(C 1 -C 4 )alkyl,
  • 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 heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N, O and S and said optionally substituted cycloalkyi or heterocycloalkyl group is optionally substituted by a substituent selected from
  • each R Yb is independently selected from H and (Ci-C 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 heterocycloalkyl group, wherein said heterocycloalkyl group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyi or heterocycloalkyl group is optionally substituted by a substituent selected from (Ci-C 4 )alkyl, aryl(Ci-C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C C 2 )alkyl-.
  • 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, tetrahydrofuranyl, piperidinyl, 1-methyl-pyrrolidinyl, 1-benzyl-pyrrolidinyl, 1-cyclopropylmethyl-pyrrolidinyl, oxetanyl, azetidinyl, 1-methyl-azetidinyl, 1-benzyl- azetidinyl, or 1-cyclopropylmethyl-azetidinyl group.
  • 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.
  • L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and methyl.
  • L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano and methyl.
  • L is pyrazolyl, oxadiazolyl, 1 -methyl-imidazolyl, thiazolyl, thienyl, triazolyl, pyridyl, phenyl, oxazolyl or isoxazolyl, any of which is substituted by a methyl group.
  • L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is substituted by a methyl group.
  • R 4 is H, halogen, (Ci-C 4 )alkyl, halo(C C 2 )alkyl, (C C 2 )alkoxy, ((Ci-C 2 )alkyl)((Ci-C 2 )alkyl)N(Ci-C 3 )alkoxy-, ((Ci-C 2 )alkyl)((CrC 2 )alkyl)N(Ci-C 3 )alkyl-, (Ci-C 2 )haloalkyl, (C C 3 )alkylamino, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl, where said optionally substituted cycloalkyl, phenyl, heterocycloalkyl or heteroaryl is optionally substituted by 1 or
  • R 4 is H, methyl, bromo, trifluoromethyl
  • pyridyl dimethylaminoethoxy-, dimethylaminopropyl-, and optionally substituted pyridyl, cyclohexyl, piperidinyl, piperazinyl, imidazolyl, thienyl, or phenyl, where the pyridyl, cyclohexyl, piperidinyl, piperizinyl, imidazolyl, thienyl, or phenyl are optionally substituted by 1 -2 substituents independently selected from methyl, chloro, bromo, fluoro, trifluoromethyl, methoxy, and cyano.
  • R 4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, phenyl, 4-chlorophenyl, 2-bromophenyl-,4- fluorophenyl, 4-cyanophenyl, 3-trifluoromethylphenyl, 4-methoxyphenyl, cyclohexyl, imidazolyl, thienyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl.
  • L-R 4 taken together, form a 1 ,3-benzodioxolyl, thienopyrimidinyl , benzo-isothiazolyl,
  • 2,3-dihydro-1 ,4-benzodioxinyl benzofuranyl, benzimidazolyl, benzimidazolonyl, tetrahydroisoquinolyl, indolinyl or isoindolinyl group, optionally substituted with 1 or 2 groups independently selected from methyl, trifluoromethyl, chloro, fluoro, cyano, methoxy, phenyl, and morpholinylpropyl-.
  • L-R 4 taken together, form a 1 ,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group.
  • each R A and R c is independently selected from H and (Ci-C 4 )alkyl; specifically each R A and R c is
  • each R Y is independently selected from H, (C 1 -C 4 )alkyl, phenyl, and -(C 1 -C 4 )alkylphenyl; specifically each R Y is independently selected from H, methyl, ethyl, phenyl, benzyl and -ethylphenyl.
  • 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.
  • Ci-C 4 refers to an alkyl containing from 1 to 4 carbon atoms.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as “haloalkyl” or “cycloalkyl-alkyl” or “arylalkyl”, the term “alkyl” is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • arylalkyl is intended to mean the radical -alkylaryl, wherein the alkyl moiety thereof is a divalent straight or branched-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by the bonding arrangement present in a benzyl group (-CH 2 -phenyl).
  • alkyl may be used to define a divalent substituent, such as a group bonded to two other groups.
  • alkyl is intended to encompass a divalent straight or branched-chain hydrocarbon radical.
  • pentyl is intended to represent a pentylene diradical -wherein the pentyl moiety is any one of a divalent straight (-CH 2 CH 2 CH 2 CH 2 -) or branched (-CH 2 CH(CH 3 )CH 2 CH 2 - -CH 2 CH 2 CH(CH 2 CH 3 )-, -CH 2 CH 2 C(CH 3 ) 2 -) chain 5-carbon radical.
  • cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring.
  • (C 3 -C 8 )cycloalkyl refers to a non-aromatic cyclic
  • hydrocarbon ring having from three to eight ring carbon atoms.
  • (C 3 -C 8 )cycloalkyl groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkoxy refers to a group containing an alkyl radical attached through an oxygen linking atom.
  • (Ci-C 4 )alkoxy refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom.
  • Exemplary "(d-C 4 )alkoxy” groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and f-butoxy.
  • Aryl represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents defined herein, and to which may be fused one or more cycloalkyl rings, which may be
  • aryl is phenyl
  • Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.
  • Heterocycloalkyl represents a group or moiety comprising a stable, non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • the heterocycloalkyl may be attached by any atom of the monocyclic or bicyclic radical which results in the creation of a stable structure.
  • This term encompasses bicyclic heterocycloalkyl moieties where the rings are joined at two atoms per ring, as exemplified by the bonding arrangement in 2,5-diazabicyclo[2.2.1 ]heptyl, 2- azabicyclo[2.2.1 ]heptyl, 2-oxa-5-azabicyclo[2.2.1 ]heptyl, 7-oxa-2-azabicyclo[2.2.1 ]heptyl, 2-thia-5-azabicyclo[2.2.1 ]heptyl,7-azabicyclo[2.2.1 ]heptyl, 2,6- diazatricyclo[3.3.1 .13,7]decyl, 2-azatricyclo[3.3.1 .13,7]decyl, 2,4,9- triazatricyclo[3.3.1 .13,7]decyl, 8-azabicyclo[3.2.1 ]octyl, 2,5-diazabicyclo[2.2.2]octyl,
  • This term specifically excludes bicyclic heterocycloalkyl moieties where the rings are joined at a single atom per ring (spiro), as exemplified by the bonding arrangement in a 1 -oxa-2-azaspiro[4.5]dec-2-en-3-yl group.
  • heterocycloalkyls include, but are not limited to, azetidinyl, pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl), dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]non
  • heterocycloalkyi groups are
  • 5-membered and/or 6-membered heterocycloalkyi groups such as pyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or tetrahydrofuranyl), tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl or pyrazolinyl, piperidyl (or piperidinyl), piperazinyl, morpholinyl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxanyl, tetrahydro-2H-1 ,4-thiazinyl, 1 ,4-dioxanyl, 1 ,3-oxathianyl, and 1 ,3-dithianyl.
  • pyrrolidyl or pyrrolidinyl
  • tetrahydrofuryl or tetrahydrofuranyl
  • Heteroaryl represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyi ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents defined herein.
  • heteroaryls include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl (or furanyl), isothiazolyl, furazanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridyl (or pyridinyl), pyridyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, benzo[b]thienyl, isobenzofuryl, 2,3- dihydrobenzofuryl, chromenyl, chromanyl, indolizinyl, isoindolyl,
  • benzimidazolyl tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolinyl, indolinyl, cinnolinyl, pteridinyl, isothiazolyl.
  • heteroaryl groups present in the compounds of Formula I 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 Formula I 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.
  • R 1 is -CF 3 ;
  • A is optionally substituted (C 3 -C 6 )cycloalkyl, phenyl, naphthyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, or 9-10 membered heteroaryl,
  • any optionally substituted cycloalkyl, phenyl, naphthyl, heterocycloalkyl, or heteroaryl is optionally substituted by 1-3 groups independently selected from (C 1 -C 4 )alkyl, halogen, cyano, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, -NR A R A and
  • R 2 and R 3 are independently selected from H and optionally substituted (C C 4 )alkyl, aryl(C C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(CrC 4 )alkyl-,
  • aryl, cycloalkyi and each of the (CrC 4 )alkyl moieties of said optionally substituted (CrC 4 )alkyl, aryl(d-C 4 )alkyl-, and (C 3 -C 7 )cycloalkyl(CrC 4 )alkyl- of any R 2 and R 3 are optionally substituted by 1 , 2 or 3 groups independently selected from halogen, cyano, (C C 4 )alkyl, halo(CrC 4 )alkyl, (C C 4 )alkoxy, halo(Ci-C 4 )alkoxy, halogen, -NR A R A , -((C C 4 )alkyl)NR A R A , (C C 4 )alkoxy, hydroxyl, cyano, halo(Ci-C 4 )alkyl, and
  • 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 (CrC 4 )alkyl,
  • L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted,
  • L when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and (C 1 -C 4 )alkyl;
  • R 4 is H, (CrC 4 )alkyl, halo, halo(Ci-C 4 )alkyl, (C C 4 )alkoxy,
  • optionally substituted cycloalkyi, phenyl, heterocycloalkyi or heteroaryl is optionally substituted by 1 , 2 or 3 groups independently selected from (Ci-C 4 )alkyl, halogen, cyano, halo(Ci-C 4 )alkyl, (CrC 4 )alkoxy, (Ci-C 4 )alkylthio-, halo(Ci-C 4 )alkoxy, hydroxyl, -NR A R C and -((Ci-C 4 )alkyl)NR A R c ;
  • each R A is independently selected from H and (C 1 -C 4 )alkyl;
  • R c is H, (C 1 -C 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 an optionally substituted 4-8 membered heterocyclic ring, optionally containing one additional heteroatom selected from N, O and S;
  • each R x is independently selected from H, (CrC 6 )alkyl, and optionally substituted
  • (C 2 -C 6 )alkyl where said optionally substituted (C 2 -C 6 )alkyl is optionally substituted by hydroxyl, cyano, amino, (C C 4 )alkoxy, (Ci-C 4 )alkyl)NH-, or ((Ci-C 4 )alkyl)((C C 4 )alkyl)N-; and
  • each R Y is independently selected from H, (Ci-C 4 )alkyl, phenyl, and
  • the method excludes treatment with the following compounds:
  • the invention is further directed to a method of treatment or use of a compound according to Formula I, wherein:
  • R 1 is CHF 2 or 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 a phenyl group optionally substituted by 1 group selected from methyl, ethyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, -NR A R A and -((Ci-C 4 )alkyl)NR A R A , or
  • A is a cyclopropyl, cyclopentyl or cyclohexyl group, optionally substituted by 1 -2 groups independently selected from methyl, ethyl, tert-butyl, methoxy, ethoxy, -NR A R A and -((Ci-C 4 )alkyl)NR A R A , or
  • A is a 5-6 membered heteroaryl or a 9-10 membered heteroaryl optionally substituted by 1 group selected from methyl, ethyl, fluoro, trifluoromethyl, -NR A R A and -((CrC 4 )alkyl)NR A R A , where the 5-6 membered heteroaryl or 9-10 membered heteroaryl contains 1 ring heteroatom selected form N, O and S and optionally contains 1 additional ring nitrogen atom,
  • each R A is independently H or methyl;
  • n 0-3 and R 2 and R 3 are independently selected from H and optionally substituted (Ci-C 4 )alkyl, phenyl(C C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(Ci-C 2 )alkyl-, or
  • n 1 -3 and R 2 is hydroxyl and R 3 is H or methyl, or
  • n is 0-3 and 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, halo(Ci-C 4 )alkyl, halogen, cyano,
  • R Ya is selected from H, (Ci-C 4 )alkyl phenyl(Ci-C 2 )alkyl- and (C 3 -C 6 )cycloalkyl(d-C 2 )alkyl-, and each R Yb is independently selected from H and (CrC 4 )alkyl;
  • L is 5-6 membered heteroaryl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 or 2 substituents independently selected from halogen, cyano and methyl;
  • R 4 is H, halogen, (d-C 4 )alkyl, halo(C C 2 )alkyl, (C C 2 )alkoxy,
  • the invention is further directed to a method of treatment or use of a compound according to Formula I, as defined herein wherein:
  • n 0-3 and R 2 and R 3 are independently selected from H and optionally substituted (Ci-C 4 )alkyl, phenyl(C C 2 )alkyl-, and (C 3 -C 6 )cycloalkyl(C C 2 )alkyl-, or
  • n 1 -3 and R2 is hydroxyl and R 3 is H or methyl, or
  • n is 0-3 and 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 heterocycloalkyl group contains 1 heteroatom selected from N and O and said optionally substituted cycloalkyl or heterocycloalkyl group is optionally substituted by a substituent selected from (C 1 -C 4 )alkyl, aryl(C 1 -C 2 )alkyl-, and
  • R x is H, methyl or cyanoethyl
  • L is a 5-membered heteroaryl, pyridyl or phenyl which is substituted by R 4 and is optionally further substituted, wherein when L is further substituted, L is substituted by 1 substituent selected from chloro, fluoro, cyano and methyl; and
  • R 4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-,
  • the invention is further directed to a method of treatment or use of a compound according to Formula I, wherein:
  • R 1 is CHF 2 or CF 3 ;
  • Y is a bond
  • X- ⁇ is O
  • X 2 and X 3 are N
  • Y is -C(O)-, Xi and X 2 are CH, and X 3 is S, or
  • Y is -C(O)-, X ⁇ is O, and X 2 and X 3 are CH;
  • A is an unsubstituted phenyl group or a phenyl group substituted by an ethyl, fluoro, cyano or methoxy group, or a thienyl, pyridyl, cydopropyl, cyclopentyl or cyclohexyl group;
  • n 0 or 1 and both R 2 and R 3 are H or both R 2 and R 3 are methyl, or
  • n 1 and R 2 is hydroxyl and R 3 is H or methyl, or
  • n 0 or 1 and 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;
  • L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is optionally substituted by a methyl group;
  • R 4 is H, methyl, bromo, trifluoromethyl, dimethylaminoethoxy-, phenyl, 4-chlorophenyl,
  • L-R 4 taken together, form a 1 ,3-benzodioxolyl, tetrahydroisoquinolyl or isoindolinyl group; or a salt, particularly a pharmaceutically acceptable salt, thereof.
  • the invention is more specifically directed to a method of treatment or use of a compound according to Formula I, wherein:
  • R 1 is CHF 2 or CF 3 ;
  • Y is a bond, Xi is O, and X 2 and X 3 are N;
  • A is an unsubstituted phenyl or pyridyl group
  • n 1 ;
  • R 2 and R 3 are both methyl, or
  • R 2 is hydroxyl and R 3 is methyl, or
  • R 2 and R 3 are both hydrogen, or
  • R 2 is methyl and R 3 is hydrogen, or
  • R 2 is hydroxyl and R 3 is hydrogen, or
  • R 2 is dimethylamino and R 3 is H, or
  • R 2 is ⁇ , ⁇ -dimethylaminoethyl and R 3 is H, or
  • R 2 and R 3 taken together with the atom to which they are connected form a tetrahydropyranyl, 2,2-dimethyl-tetrahydropyranyl, or a 1-methyl-piperidinyl group;
  • L is thiazolyl, thienyl, triazolyl, pyridyl, phenyl, or oxazolyl, any of which is optionally substituted by a methyl group;
  • R 4 is phenyl, optionally substituted by halo (chloro or fluoro), cyano,
  • optionally substituted means unsubstituted groups or rings (e.g., cycloalkyi, heterocycle, and heteroaryl rings) and groups or rings substituted with one or more specified substituents.
  • Representative compounds of Formula I include:
  • Particular compounds of Formula I include:
  • the term "compound(s) of Formula I" means a compound of Formula I, including any stereoisomer thereof (e.g., including any enantiomer or diastereomer of a compound recited above), in any form, for example, any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof), any solvate form (particularly a hydrate thereof (including mono-, di- and hemi- hydrates and including any hydrate of a salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms of any of the above)), and mixtures of various forms.
  • Compound names were generated using the software naming program ChemDraw 1 1.0 available from CambridgeSoft Corporation., 100 CambridgePark Drive, Cambridge, MA 02140, USA (http://www.cambridgesoft.com).
  • the invention also includes the use of various deuterated forms of the compounds of Formula I. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula I.
  • the invention further includes the use of various radio-labelled or other isotopically enriched forms of the compounds of Formula I, such as compounds that contain a 2 H, 3 H, 14 C, 11 C, or 18 F atom. Similarly, a person of ordinary skill in the art will know how to synthesize such radio- labelled or isotopically enriched forms of the compounds of Formula I.
  • the present invention is directed to a method of treating a B-cell lymphoma, particularly a B-cell lymphoma associated with deacetylases, which comprises
  • this invention is directed to a method of treatment of Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma), comprising administering a therapeutically effective amount of the compound of Formula I or a salt thereof, particularly a pharmaceutically acceptable salt thereof, to a patient, specifically a human, in need thereof.
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • follicular lymphoma immunoblastic large cell lymphoma
  • precursor B-lymphoblastic lymphoma precursor B-lymphoblastic lymphoma
  • mantle cell lymphoma mantle cell lymphoma
  • 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.
  • 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 e.g., the identity of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmaceutical characteristics), disease or condition and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a patient, where the disease condition is caused or mediated by HDAC.
  • the methods of treatment for mitigation of a disease condition include the use of the compounds in Formula I in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease.
  • B-cell lymphomas associated with deacetylases examples include Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, and Waldenstrom Macroglobulinemia (lymphoplasmacytic lymphoma).
  • this invention is directed to inhibitors of HDAC and their use to stop or reduce the growth of neoplastic cells, e.g., cancer cells and tumor cells.
  • the compounds of Formula I may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • the compounds of Formula I may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of Formula I depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of Formula I depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Treatment of a B-cell lymphoma may be achieved using the compounds of Formula I as a monotherapy, or in dual or multiple combination therapy, such as in combination with other agents, for example, in combination with one or more of the following agents: antibodies (such as rituxumab, alone or in combination with
  • cyclophosphamide chemotherapeutic regimens
  • proteasome inhibitors such as bortezomib
  • HDAC inhibitors such as vorinostat, romidepsin, valproic acid, panobinostat, mocetinostat, givinostat, belinostat and entinostat
  • mTOR inhibitors such as
  • the invention is directed to the administration of a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically-acceptable excipient to treat B cell lymphomas.
  • compositions useful in 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 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 Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof.
  • the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of Formula I.
  • the pharmaceutical compositions typically contain one compound of Formula I. However, in certain embodiments, the pharmaceutical compositions may contain more than one compound of Formula I. In addition, the pharmaceutical compositions may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a material, composition or vehicle involved in giving form or consistency to the composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of Formula I when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically-acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • the compounds of Formula I and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of Formula I once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants,
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions useful in the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to the use of a solid oral dosage form , such as a tablet or capsule, comprising an effective amount of a compound of Formula I and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • Tablets are prepared using conventional methods and are formulated as follows:
  • Capsules are prepared using conventional methods and are formulated as follows
  • WO201 1/088181 "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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne une méthode de traitement du lymphome à cellules B consistant à administrer un composé présentant la formule dans laquelle X1, X2, X3, R1, R2, R3, R4, Y, A, Z, L et n sont tels que définis dans les présentes.
PCT/US2012/046201 2011-07-13 2012-07-11 Méthodes de traitement Ceased WO2013009830A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161507335P 2011-07-13 2011-07-13
US61/507,335 2011-07-13

Publications (1)

Publication Number Publication Date
WO2013009830A1 true WO2013009830A1 (fr) 2013-01-17

Family

ID=47506482

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/046201 Ceased WO2013009830A1 (fr) 2011-07-13 2012-07-11 Méthodes de traitement

Country Status (1)

Country Link
WO (1) WO2013009830A1 (fr)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2513403A (en) * 2013-04-26 2014-10-29 Agency Science Tech & Res WNT pathway modulators
WO2015172196A1 (fr) * 2014-05-13 2015-11-19 Monash University Composés hétérocycliques et leur utilisation
WO2016179554A1 (fr) * 2015-05-07 2016-11-10 Chdi Foundation, Inc. Inhibiteurs d'histone désacétylase, compositions et méthodes d'utilisation correspondantes
WO2016179550A1 (fr) * 2015-05-07 2016-11-10 Chdi Foundation, Inc. Inhibiteurs d'histone désacétylase, compositions et méthodes d'utilisation de ceux-ci
WO2017085100A1 (fr) * 2015-11-19 2017-05-26 Basf Se Oxadiazoles substitués pour lutter contre des champignons phytopathogènes
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
CN108137517A (zh) * 2015-10-02 2018-06-08 先正达参股股份有限公司 杀微生物的噁二唑衍生物
CN108347937A (zh) * 2015-11-19 2018-07-31 巴斯夫欧洲公司 用于防除植物病原性真菌的取代噁二唑
US10081624B2 (en) 2014-08-26 2018-09-25 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10208032B2 (en) 2013-12-24 2019-02-19 Oncotartis Inc. Benzamide and nicotinamide compounds and methods of using same
US10308643B2 (en) 2015-07-17 2019-06-04 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10357484B2 (en) 2015-07-17 2019-07-23 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10406146B2 (en) 2015-08-25 2019-09-10 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10435399B2 (en) 2017-07-31 2019-10-08 Takeda Pharmaceutical Company Limited HDAC6 inhibitory heterocyclic compound
US10492494B2 (en) 2015-11-13 2019-12-03 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
WO2020032071A1 (fr) * 2018-08-08 2020-02-13 日本農薬株式会社 Composé oxadiazoline ou sels de celui-ci, bactéricide agricole ou horticole contenant ledit composé, et procédé d'utilisation associé
US10640497B2 (en) 2015-12-02 2020-05-05 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10687532B2 (en) 2015-11-13 2020-06-23 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
CN111646986A (zh) * 2017-09-13 2020-09-11 厦门稀土材料研究所 烟酸衍生物及其制备方法与用途
US10798941B2 (en) 2016-01-08 2020-10-13 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10899724B2 (en) 2015-10-02 2021-01-26 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10986839B2 (en) 2016-04-11 2021-04-27 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US11083196B2 (en) 2016-03-24 2021-08-10 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11453661B2 (en) 2019-09-27 2022-09-27 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11897871B1 (en) 2021-06-14 2024-02-13 Scorpion Therapeutics, Inc. Methods for treating cancer
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US11974572B2 (en) 2017-03-31 2024-05-07 Sygenta Participations Ag Fungicidal compositions
US12528767B2 (en) 2019-07-30 2026-01-20 Eikonizo Therapeutics, Inc. HDAC6 inhibitors and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018045A1 (fr) * 1999-09-08 2001-03-15 Sloan-Kettering Institute For Cancer Research Structure cristalline d'une deacetylase et ses inhibiteurs
US20050256153A1 (en) * 2004-05-17 2005-11-17 Dhanoa Dale S Thienopyridinone compounds and methods of treatment
US20090048228A1 (en) * 2004-12-10 2009-02-19 Barbara Attenni Heterocycle Derivatives As Histone Deacetylase (Hdac) Inhibitors
US20100197723A1 (en) * 2008-12-03 2010-08-05 Shomir Ghosh Bicyclic compounds and methods of making and using same
US20110117073A1 (en) * 2009-09-16 2011-05-19 Avila Therapeutics, Inc. Protein Kinase Conjugates and Inhibitors
WO2011088187A1 (fr) * 2010-01-13 2011-07-21 Tempero Pharmaceuticals, Inc. Composés et procédés

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018045A1 (fr) * 1999-09-08 2001-03-15 Sloan-Kettering Institute For Cancer Research Structure cristalline d'une deacetylase et ses inhibiteurs
US20050256153A1 (en) * 2004-05-17 2005-11-17 Dhanoa Dale S Thienopyridinone compounds and methods of treatment
US20090048228A1 (en) * 2004-12-10 2009-02-19 Barbara Attenni Heterocycle Derivatives As Histone Deacetylase (Hdac) Inhibitors
US20100197723A1 (en) * 2008-12-03 2010-08-05 Shomir Ghosh Bicyclic compounds and methods of making and using same
US20110117073A1 (en) * 2009-09-16 2011-05-19 Avila Therapeutics, Inc. Protein Kinase Conjugates and Inhibitors
WO2011088187A1 (fr) * 2010-01-13 2011-07-21 Tempero Pharmaceuticals, Inc. Composés et procédés

Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2513403A (en) * 2013-04-26 2014-10-29 Agency Science Tech & Res WNT pathway modulators
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
USRE47193E1 (en) 2013-10-14 2019-01-08 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
AU2014369926B2 (en) * 2013-12-24 2019-07-18 Oncotartis, Inc. Benzamide and nicotinamide compounds and methods of using same
US10208032B2 (en) 2013-12-24 2019-02-19 Oncotartis Inc. Benzamide and nicotinamide compounds and methods of using same
US10538520B2 (en) 2013-12-24 2020-01-21 Oncotartis Inc. Benzamide and nicotinamide compounds and methods of using same
WO2015172196A1 (fr) * 2014-05-13 2015-11-19 Monash University Composés hétérocycliques et leur utilisation
US10081624B2 (en) 2014-08-26 2018-09-25 Takeda Pharmaceutical Company Limited Heterocyclic compound
EA036965B1 (ru) * 2015-05-07 2021-01-20 Сиэйчдиай Фаундэйшн, Инк. Ингибиторы деацетилаз гистонов и композиции и способы их применения
CN107735088B (zh) * 2015-05-07 2021-11-02 Chdi基金会股份有限公司 组蛋白脱乙酰酶抑制剂及其组合物和使用方法
WO2016179554A1 (fr) * 2015-05-07 2016-11-10 Chdi Foundation, Inc. Inhibiteurs d'histone désacétylase, compositions et méthodes d'utilisation correspondantes
US10047073B2 (en) 2015-05-07 2018-08-14 Chdi Foundation, Inc Histone deacetylase inhibitors and compositions and methods of use thereof
AU2016256917B2 (en) * 2015-05-07 2021-08-26 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
JP2018515492A (ja) * 2015-05-07 2018-06-14 シーエイチディーアイ ファウンデーション，インコーポレーテッド ヒストンデアセチラーゼ阻害薬及び組成物並びにそれらの使用の方法
JP2018515489A (ja) * 2015-05-07 2018-06-14 シーエイチディーアイ ファウンデーション，インコーポレーテッド ヒストンデアセチラーゼ阻害薬及び組成物並びにそれらの使用の方法
US10053434B2 (en) 2015-05-07 2018-08-21 Chdi Foundation, Inc. Histone deacetylase inhibitors and compositions and methods of use thereof
CN107735088A (zh) * 2015-05-07 2018-02-23 Chdi基金会股份有限公司 组蛋白脱乙酰酶抑制剂及其组合物和使用方法
WO2016179550A1 (fr) * 2015-05-07 2016-11-10 Chdi Foundation, Inc. Inhibiteurs d'histone désacétylase, compositions et méthodes d'utilisation de ceux-ci
EA035592B1 (ru) * 2015-05-07 2020-07-13 Сиэйчдиай Фаундэйшн, Инк. Ингибиторы деацетилаз гистонов и композиции и способы их применения
US10308643B2 (en) 2015-07-17 2019-06-04 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10357484B2 (en) 2015-07-17 2019-07-23 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10406146B2 (en) 2015-08-25 2019-09-10 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10501425B2 (en) 2015-10-02 2019-12-10 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11066375B2 (en) 2015-10-02 2021-07-20 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10899724B2 (en) 2015-10-02 2021-01-26 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
CN108137517A (zh) * 2015-10-02 2018-06-08 先正达参股股份有限公司 杀微生物的噁二唑衍生物
US11180462B2 (en) 2015-10-02 2021-11-23 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10492494B2 (en) 2015-11-13 2019-12-03 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10687532B2 (en) 2015-11-13 2020-06-23 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US10674727B2 (en) 2015-11-19 2020-06-09 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
WO2017085100A1 (fr) * 2015-11-19 2017-05-26 Basf Se Oxadiazoles substitués pour lutter contre des champignons phytopathogènes
CN108347937A (zh) * 2015-11-19 2018-07-31 巴斯夫欧洲公司 用于防除植物病原性真菌的取代噁二唑
CN108289449A (zh) * 2015-11-19 2018-07-17 巴斯夫欧洲公司 用于防除植物病原性真菌的取代噁二唑
US10640497B2 (en) 2015-12-02 2020-05-05 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10798941B2 (en) 2016-01-08 2020-10-13 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11259524B2 (en) 2016-01-08 2022-03-01 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US11083196B2 (en) 2016-03-24 2021-08-10 Syngenta Participations Ag Microbiocidal oxadiazole derivatives
US10986839B2 (en) 2016-04-11 2021-04-27 Basf Se Substituted oxadiazoles for combating phytopathogenic fungi
US12370194B2 (en) 2017-03-10 2025-07-29 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US11974572B2 (en) 2017-03-31 2024-05-07 Sygenta Participations Ag Fungicidal compositions
US10435399B2 (en) 2017-07-31 2019-10-08 Takeda Pharmaceutical Company Limited HDAC6 inhibitory heterocyclic compound
CN111646986B (zh) * 2017-09-13 2022-03-25 厦门稀土材料研究所 烟酸衍生物及其制备方法与用途
CN111646986A (zh) * 2017-09-13 2020-09-11 厦门稀土材料研究所 烟酸衍生物及其制备方法与用途
US12010995B2 (en) 2018-08-08 2024-06-18 Nihon Nohyaku Co., Ltd. Oxadiazoline compounds or salts thereof, agrohorticultural fungicides containing the compounds, and methods of using the same
JP7407114B2 (ja) 2018-08-08 2023-12-28 日本農薬株式会社 オキサジアゾリン化合物又はその塩類及び該化合物を含有する農園芸用殺菌剤並びにその使用方法
WO2020032071A1 (fr) * 2018-08-08 2020-02-13 日本農薬株式会社 Composé oxadiazoline ou sels de celui-ci, bactéricide agricole ou horticole contenant ledit composé, et procédé d'utilisation associé
JPWO2020032071A1 (ja) * 2018-08-08 2021-08-26 日本農薬株式会社 オキサジアゾリン化合物又はその塩類及び該化合物を含有する農園芸用殺菌剤並びにその使用方法
US12528767B2 (en) 2019-07-30 2026-01-20 Eikonizo Therapeutics, Inc. HDAC6 inhibitors and uses thereof
US11958845B2 (en) 2019-09-27 2024-04-16 Takeda Pharmaceutical Company Limited Heterocyclic compound
US12384770B2 (en) 2019-09-27 2025-08-12 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11453661B2 (en) 2019-09-27 2022-09-27 Takeda Pharmaceutical Company Limited Heterocyclic compound
US12084434B2 (en) 2021-06-14 2024-09-10 Scorpion Therapeutics, Inc. Methods for treating cancer
US12312341B2 (en) 2021-06-14 2025-05-27 Scorpion Therapeutics, Inc. Methods for treating cancer
US11897871B1 (en) 2021-06-14 2024-02-13 Scorpion Therapeutics, Inc. Methods for treating cancer

Similar Documents

Publication Publication Date Title
WO2013009830A1 (fr) Méthodes de traitement
WO2013009810A1 (fr) Méthodes de traitement
WO2013009827A1 (fr) Méthodes de traitement
US11339130B1 (en) Calpain modulators and therapeutic uses thereof
AU2011205283B2 (en) Compounds and methods
WO2013006408A1 (fr) Composés et procédés
US20090325956A1 (en) Aromatic amine derivative and use thereof
RU2770824C2 (ru) Противоопухолевый агент
US20220184075A1 (en) Pharmaceutical composition containing hdac6 inhibitor as active ingredient for prevention or treatment of itching
MX2013005124A (es) Estimuladores de la gcs.
AU2012345557A1 (en) Novel trifluoromethyl-oxadiazole derivatives and their use in the treatment of disease
AU2010308306A1 (en) Combination cancer therapy with HSP90 inhibitory compounds
EP3291815A1 (fr) Méthodes de traitement d'une maladie neurodégénérative
PT1700856E (pt) Derivado de tiazole
CN105085428B (zh) 芳杂环类衍生物及其在药物上的应用
RU2006136881A (ru) Фармацевтическая композиция, содержащая производное бензодиазепина и ингибитор белка слияния rsv
ES2643340T3 (es) Agentes para tratar y/o prevenir trastornos del sueño
BRPI0614929A2 (pt) uso de derivados de azabicicloexano
JP2017119702A (ja) ギラン・バレー症候群に伴う神経因性疼痛の予防又は治療剤
KR20100029097A (ko) 안트라닐아미드 피리딘우레아와 벤즈아미드 유도체의 상승작용적 조합물
WO2013009812A1 (fr) Méthodes de traitement
CN102188705A (zh) 包含双环辛烷类衍生物的药物组合物
EA019194B1 (ru) Применение 4-циклопропилметокси-n-(3,5-дихлор-1-оксидопиридин-4-ил)-5-(метокси)пиридин-2-карбоксамида для лечения моторных нарушений, связанных с болезнью паркинсона
CA3174216A1 (fr) Medicament pour prevenir ou traiter le syndrome du colon irritable ou lamaladie inflammatoire de l'intestin
JPWO2018186366A1 (ja) 新規サイクリン依存性キナーゼ８及び／又は１９阻害剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12811930

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12811930

Country of ref document: EP

Kind code of ref document: A1