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US 2022/0064174 A1Published application
Txnip-trx complex inhibitors and methods of using the same
AssigneeCity of Hope
InventorsRama Natarajan, Feng Miao, Nagarajan Vaidehi, Supriyo Bhattacharya
Life of this patent
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Abstract
Disclosed herein, inter alia, are compounds and methods for inhibiting the thioredoxin-thioredoxin-interacting-protein (TXNIP-TRX) complex.
Claims24
A compound, or a pharmaceutically acceptable salt thereof, having the formula:
- wherein
- L1 is a covalent linker;
- R1 is hydrogen, halogen, —CX13, —CHX12, —CH2X1, —OCX13, —OCHX12, —OCH2X1, —CN, —SOn1R1D, —SOv1NR1AR1B, —NR1CNR1AR1B, —ONR1AR1B, —NHC(O)NR1CNR1AR1B, —NHC(O)NR1AR1B, —N(O)m1, —NR1AR1B, —C(O)R1C, —C(O)OR1C, —C(O)NR1AR1B, —OR1D, —SR1D, —SeR1D, —NR1ASO2R1D, —NR1AC(O)R1C, —NR1AC(O)OR1C, —NR1AOR1C, —SF5, —N3, 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 hydrogen, halogen, —CX23, —CHX22, —CH2X2, —OCX23, —OCHX22, —OCH2X2, —CN, —SOn2R2D, —SOv2NR2AR2B, —NR2CNR2AR2B, —ONR2AR2B, —NHC(O)NR2CNR2AR2B, —NHC(O)NR2AR2B, —N(O)m2, —NR2AR2B, —C(O)R2C, —C(O)OR2C, —C(O)NR2AR2B, —OR2D, —SR2D, —SeR2D, —NR2ASO2R2D, —NR2AC(O)R2C, —NR2AC(O)OR2C, —NR2AOR2C, —SF5, —N3, 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, and R2D are independently hydrogen, oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SeH, —SO3H, —OSO3H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —N3, —SF5, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
- R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- X1 and X2 are independently —F, —Cl, —Br, or —I;
- n1 and n2 are independently an integer from 0 to 4;
- m1, m2, v1, and v2 are independently 1 or 2;
- R3 is independently halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SeH, —SO3H, —OSO3H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —N3, —SF5, 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;
- two adjacent R3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- and
- z3 is an integer from 0 to 4.
11 more elements
A compound, or a pharmaceutically acceptable salt thereof, having the formula:
- wherein
- Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
- W1 is N or C(R4);
- W2 is N or C(R5);
- R4 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SeH, —SO3H, —OSO3H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —N3, —SF5, 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;
- R5 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SeH, —SO3H, —OSO3H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —N3, —SF5, 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 independently halogen, —CX63, —CHX62, —CH2X6, —OCX63, —OCHX62, —OCH2X6, —CN, —SOn6R6D, —SOv6NR6AR6B, —NR6CNR6AR6B, —ONR6AR6B, —NHC(O)NR6CNR6AR6B, —NHC(O)NR6AR6B, —N(O)m6, —NR6AR6B, —C(O)R6C, —C(O)OR6C, —C(O)NR6AR6B, —OR6D, —SR6D, —SeR6D, —NR6ASO2R6D, —NR6AC(O)R6C, —NR6AC(O)OR6C, —NR6AOR6C, —SF5, —N3, 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;
- two adjacent R6 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R7 is independently halogen, oxo, —CX73, —CHX72, —CH2X7, —OCX73, —OCHX72, —OCH2X7, —CN, —SOn7R7D, —SOv7NR7AR7B, —NR7CN7AR7B, —ONR7AR7B, —NHC(O)NR7CNR7AR7B, —NHC(O)NR7AR7B, —N(O)m7, —NR7AR7B, —C(O)R7C, —C(O)OR7C, —C(O)NR7AR7B, —OR7D, —SR7D, —SeR7D, —NR7ASO2R7D, —NR7AC(O)R7C, —NR7AC(O)OR7C, —NR7AOR7C, —SF5, —N3, 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;
- two adjacent R7 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- two R7 substituents bonded to the same carbon atom may optionally be joined to form a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
- R8 is independently halogen, oxo, —CX83, —CHX82, —CH2X8, —OCX83, —OCHX82, —OCH2X8, —CN, —SOn8R8D, —SOv8NR8AR8B, —NR8CNR8AR8B, —ONR8AR8B, —NHC(O)NR8CNR8AR8B, —NHC(O)NR8AR8B, —N(O)m8, —NR8AR8B, —C(O)R8C, —C(O)OR8C, —C(O)NR8AR8B, —OR8D, —SR8D, —SeR8D, —NR8ASO2R8D, —NR8AC(O)R8C, —NR8AC(O)OR8C, —NR8AOR8C, —SF5, —N3, 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;
- two adjacent R8 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
- R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R8A, R8B, R8C, and R8D are independently hydrogen, oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SeH, —SO3H, —OSO3H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —N3, —SF5, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
- R6A and R6B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- R7A and R7B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- R8A and R8B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
- X6, X7, and X8 are independently —F, —Cl, —Br, or —I;
- n6, n7, and n8 are independently an integer from 0 to 4;
- m6, m7, m8, v6, v7, and v8 are independently 1 or 2;
- z6 is an integer from 0 to 3;
- z7 is an integer from 0 to 9;
- and
- z8 is an integer from 0 to 7.
21 more elements
Dependencies are inferred from the claim text.