Back to results
US 2020/0345693 A1Published application
Thioindirubins
AssigneesCity of Hope, National and Kapodistrian University of Athens
InventorsSangkil Nam, David Horne, Ravi Salgia, Alexios Leandros Skaltsounis, Nicolas Gaboriaud-Kolar, Panagiotis Gerolymatos, Nikolaos Lougiakis
Life of this patent
Estimating the term…
Abstract
Disclosed herein inter alia are compositions and methods for treating cancer using thioindirubin derivatives.
Claims49
A compound, or pharmaceutically acceptable salt thereof, having structural Formula (I):
- wherein:
- n1, n2, n3, n4 and n6 are independently an integer from 0 to 4;
- m2, m3, v1, v2, v3, v4 and v6 are independently 1 or 2;
- z1 and z2 are independently an integer from 1 to 4;
- X is ═O, ═S or ═NR1;
- Y is ═O, ═S or ═NR6;
- R1 is hydrogen, halogen, oxo, —CX13, —CHX12, —CH2X1, —N3, —CN, —SOn1R1A, —SOv1NR1BR1C, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —OCX13, —OCHX12, —OCH2X1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R2 is independently hydrogen, halogen, —CX23, —CHX22, —CH2X2, —N3, —CN, —SOn2R2A, —SOv2NR2BR2C, —NHNR2BR2C, —ONR2BR2C, —NHC(O)NHNR2BR2C, —NHC(O)NR2BR2C, —N(O)m2, —N2BR2C, —C(O)R2D, —C(O)OR2D, —C(O)NR2BR2C, —OR2A, —NR2BSO2R2A, —NR2BC(O)R2D, —NR2BC(O)OR2D, —NR2BOR2D, —OCX23, —OCHX22, —OCH2X2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R3 is independently hydrogen, halogen, —CX33, —CHX32, —CH2X3, —N3, —CN, —SOn3R3A, —SOv3NR3BR3C, —NHNR3BR3C, ONR3BR3C, —NHC(O)NHNR3BR3C, —NHC(O)NR3BR3C, —N(O)m3, —NR3BR3C, —C(O)R3D, —C(O)OR3D, —C(O)NR3BR3C, —OR3A, —NR3BSO2R3A, —NR3BC(O)R3D, —NR3BC(O)OR3D, —NR3BOR3D, —OCX33, —OCHX32, —OCH2X3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R4 is hydrogen, halogen, oxo, —CX43, —CHX42, —CH2X4, —CN, —SOn4R4A, —SOv4NR4BR4C, —NR4BR4C, —C(O)R4D, —C(O)OR4D, —C(O)NR4BR4C, —OR4A, —OCX43, —OCHX42, —OCH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R6 is hydrogen, halogen, oxo, —CX63, —CHX62, —CH2X6, —N3, —CN, —SOn6R6A, —SOv6NR6BR6C, —NR6BR6C, —C(O)R6D, —C(O)OR6D, —C(O)NR6BR6C, —OR6A, —OCX63, —OCHX62, —OCH2X6, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R6A, R6B, R6C and R6D are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —COOH, —CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R1B and R1C, R2B and R2C, R3B and R3C, R4B and R4C and R6B and R6C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- and
- X1, X2, X3, X4 and X6 are independently —Cl, —Br, —I or —F,
- provided that when X is ═O and Y is ═O, then at least one of R2, R3 and R4 is not hydrogen.
13 more elements
3-4. (canceled)
(canceled)
11-15. (canceled)
17-28. (canceled)
30-31. (canceled)
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or pharmaceutically acceptable salt thereof, having structural Formula (I):
- wherein:
- n1, n2, n3 and n4 are independently an integer from 0 to 4;
- m2, m3, v1, v2, v3 and v4 are independently 1 or 2;
- z1 and z2 are independently an integer from 1 to 4;
- X is ═O, ═S or ═NR′;
- R1 is hydrogen, halogen, —CX13, —CHX12, —CH2X1, —N3, —CN, —SOn1R1A, —SOv1NR1BR1C, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —OCX3, —OCHX12, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R2 is independently hydrogen, halogen, —CX23, —CHX22, —CH2X2, —N3, —CN, —SOn2R2A, —SOv2NR2BR2C, —NHNR2BR2C, —ONR2BR2C, —NHC(O)NHNR2BR2C, —NHC(O)NR2BR2C, —N(O)m2, —N2BR2C, —C(O)R2D, —C(O)OR2D, —C(O)NR2BR2C, —OR2A, —NR2BSO2R2A, —NR2BC(O)R2D, —NR2BC(O)OR2D, —NR2BOR2D, —OCX23, —OCHX22, —OCH2X2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R3 is independently hydrogen, halogen, —CX33, —CHX32, —CH2X3, —N3, —CN, —SOn3R3A, —SOv3NR3BR3C, —NHNR3BR3C, ONR3BR3C, —NHC(O)NHNR3BR3C, —NHC(O)NR3BR3C,—N(O)m3, —NR3BR3C, —C(O)R3D, —C(O)OR3D, —C(O)NR3BR3C, —OR3A, —NR3BSO2R3A, —NR3BC(O)R3D, —NR3BC(O)OR3D, —NR3BOR3D, —OCX33, —OCHX32, —OCH2X3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R4 is hydrogen, halogen, —CX43, —CHX42, —CH2X4, —CN, —SOn4R4A, —SOv4NR4BR4C, —NR4BR4C, —C(O)R4D, —C(O)OR4D, —C(O)NR4BR4C, —OR4A, —OCX43, —OCHX42, —OCH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C and R4D, are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —C3, —COOH, —CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R1B and R1C, R2B and R2C, R3B and R3C and R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- and
- X1, X2, X3 and X4 are independently —Cl, —Br, —I or —F.
10 more elements
37-38. (canceled)
(canceled)
44-48. (canceled)
50-61. (canceled)
63-64. (canceled)
(canceled)
A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, having structural Formula (I):
- wherein:
- n1, n2, n3 and n4 are independently an integer from 0 to 4;
- m2, m3, m5, v1, v2, v3 and v4 are independently 1 or 2;
- z1 and z2 are independently an integer from 1 to 4;
- X is ═O, ═S or ═NR′;
- R1 is hydrogen, halogen, —CX13, —CHX12, —CH2X1, —N3, —CN, —SOn1R1A, —SOv1NR1BR1C, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —OCX3, —OCHX12, —OCH2X1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R2 is independently hydrogen, halogen, —CX23, —CHX22, —CH2X2, —N3, —CN, —SOn2R2A, —SOv2NR2BR2C, —NHNR2BR2C, —ONR2BR2C, —NHC(O)NHNR2BR2C, —NHC(O)NR2BR2C, —N(O)m2, —N2BR2C, —C(O)R2D, —C(O)OR2D, —C(O)NR2BR2C, —OR2A, —NR2BSO2R2A, —NR2BC(O)R2D, —NR2BC(O)OR2D, —NR2BOR2D, —OCX23, —OCHX22, —OCH2X2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R3 is independently hydrogen, halogen, —CX33, —CHX32, —CH2X3, —N3, —CN, —SOn3R3A, —SOv3NR3BR3C, —NHNR3BR3C, ONR3BR3C, —NHC(O)NHNR3BR3C, —NHC(O)NR3BR3C, —N(O)m3, —NR3BR3C, —C(O)R3D, —C(O)OR3D, —C(O)NR3BR3C, —OR3A, —NR3BSO2R3A, —NR3BC(O)R3D, —NR3BC(O)OR3D, —NR3BOR3D, —OCX33, —OCHX32, —OCH2X3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R4 is hydrogen, halogen, —CX43, —CHX42, —CH2X4, —CN, —SOn4R4A, —SOv4NR4BR4C, —NR4BR4C, —C(O)R4D, —C(O)OR4D, —C(O)NR4BR4C, —OR4A, —OCX43, —OCHX42, —OCH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C and R4D, are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —C3, —COOH, —CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R1B and R1C, R2B and R2C, R3B and R3C and R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- and
- X1, X2, X3 and X4 are independently —Cl, —Br, —I or —F.
10 more elements
(canceled)
(canceled)
75-76. (canceled)
A method of modulating a kinase, comprising contacting the kinase with a compound, or pharmaceutically acceptable salt thereof, having structural Formula (I):
- wherein:
- n1, n2, n3 and n4 are independently an integer from 0 to 4;
- m2, m3, v1, v2, v3 and v4 are independently 1 or 2;
- z1 and z2 are independently an integer from 1 to 4;
- X is ═O, ═S or ═NR1;
- R1 is hydrogen, halogen, —CX13, —CHX12, —CH2X1, —N3, —CN, —SOn1R1A, —SOv1NR1BR1C, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —OCX3, —OCHX12, —OCH2X1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R2 is independently hydrogen, halogen, —CX23, —CHX22, —CH2X2, —N3, —CN, —SOn2R2A, —SOv2NR2BR2C, —NHNR2BR2C, —ONR2BR2C, —NHC(O)NHNR2BR2C, —NHC(O)NR2BR2C, —N(O)m2, —N2BR2C, —C(O)R2D, —C(O)OR2D, —C(O)NR2BR2C, —OR2A, —NR2BSO2R2A, —NR2BC(O)R2D, —NR2BC(O)OR2D, —NR2BOR2D, —OCX23, —OCHX22, —OCH2X2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R3 is independently hydrogen, halogen, —CX33, —CHX32, —CH2X3, —N3, —CN, —SOn3R3A, —SOv3NR3BR3C, —NHNR3BR3C, ONR3BR3C, —NHC(O)NHNR3BR3C, —NHC(O)NR3BR3C, —N(O)m3, —NR3BR3C, —C(O)R3D, —C(O)OR3D, —C(O)NR3BR3C, —OR3A, —NR3BSO2R3A, —NR3BC(O)R3D, —NR3BC(O)OR3D, —NR3BOR3D, —OCX33, —OCHX32, —OCH2X3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R4 is hydrogen, halogen, —CX43, —CHX42, —CH2X4, —CN, —SOn4R4A, —SOv4NR4BR4C, —NR4BR4C, —C(O)R4D, —C(O)OR4D, —C(O)NR4BR4C, —OR4A, —OCX43, —OCHX42, —OCH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C and R4D, are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —C3, —COOH, —CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R1B and R1C, R2B and R2C, R3B and R3C and R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- and
- X1, X2, X3 and X4 are independently —Cl, —Br, —I or —F.
10 more elements
(canceled)
81-83. (canceled)
A method of modulating STAT or STAT3, comprising contacting STAT or STAT3 with a compound, or pharmaceutically acceptable salt thereof, having structural Formula (I):
- wherein:
- n1, n2, n3 and n4 are independently an integer from 0 to 4;
- m2, m3, v1, v2, v3 and v4 are independently 1 or 2;
- z1 and z2 are independently an integer from 1 to 4;
- X is ═O, ═S or ═NR1;
- R1 is hydrogen, halogen, —CX13, —CHX12, —CH2X1, —N3, —CN, —SOn1R1A, —SOv1NR1BR1C, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —OCX13, —OCHX12, —OCH2X1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R2 is independently hydrogen, halogen, —CX23, —CHX22, —CH2X2, —N3, —CN, —SOn2R2A, —SOv2NR2BR2C, —NHNR2BR2C, —ONR2BR2C, —NHC(O)NHNR2BR2C, —NHC(O)NR2BR2C, —N(O)m2, —N2BR2C, —C(O)R2D, —C(O)OR2D, —C(O)NR2BR2C, —OR2A, —NR2BSO2R2A, —NR2BC(O)R2D, —NR2BC(O)OR2D, —NR2BOR2D, —OCX23, —OCHX22, —OCH2X2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R3 is independently hydrogen, halogen, —CX33, —CHX32, —CH2X3, —N3, —CN, —SOn3R3A, —SOv3NR3BR3C, —NHNR3BR3C, —ONR3BR3C, —NHC(O)NHNR3BR3C, —NHC(O)NR3BR3C, —N(O)m3, —NR3BR3C, —C(O)R3D, —C(O)OR3D, —C(O)NR3BR3C, —OR3A, —NR3BSO2R3A, —NR3BC(O)R3D, —NR3BC(O)OR3D, —NR3BOR3D, —OCX33, —OCHX32, —OCH2X3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R4 is hydrogen, halogen, —CX43, —CHX42, —CH2X4, —CN, —SOn4R4A, —SOv4NR4BR4C, —NR4BR4C, —C(O)R4D, —C(O)OR4D, —C(O)NR4BR4C, —OR4A, —OCX43, —OCHX42, —OCH2X4, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C and R4D, are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —C3, —COOH, —CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R1B and R1C, R2B and R2C, R3B and R3C and R4B and R4C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- and
- X1, X2, X3 and X4 are independently —Cl, —Br, —I or —F.
10 more elements
86-88. (canceled)
Dependencies are inferred from the claim text.