Piperidines as menin inhibitors
AssigneeThe Regents of the University of Michigan
InventorsShaomeng Wang, Angelo Aguilar, Ke Zheng, Shilin Xu, Tianfeng Xu, Denzil Bernard, Liyue Huang
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Abstract
The present disclosure provides compounds represented by Formula I: and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R2, R3a, R3b, A, G, X, and Y are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat a condition or disorder responsive to menin inhibition such as cancer.
Claims20
A method of treating a disease or condition that is cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection in a patient need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula VIi, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
- wherein:
- X-Y is:
- —N(R1a)—C(═O)—;
- —C(═O)—O—;
- —C(═O)—N(R1b)—;
- —CH2N(R1c)—CH2—;
- —C(═O)N(R1d)—CH2—;
- —CH2CH2—N(R1e)—;
- —CH2N(R1f)—C(═O)—;
- or
- —CH2O—CH2—;
- R1a is hydrogen or alkyl;
- R1b is hydrogen, alkyl, or aralkyl;
- R1c is hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aralkyl, (heteroaryl)alkyl, alkylcarbonyl, arylcarbonyl, or alkoxycarbonyl;
- R1d is hydrogen, alkyl, or aralkyl;
- R1e is hydrogen, alkyl, or (aryloxy)alkyl;
- R1f is hydrogen or alkyl;
- R2 is hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclo, optionally substituted heteroaryl, or aralkyl;
- R3a and R3b are, independently, hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, or haloalkoxy;
- R17a is hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, sulfonamido, optionally substituted heteroaryl, optionally substituted heterocyclo, carboxamido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, carboxy, or carboxyalkyl;
- and
- R17b and R17c are, independently, hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, or haloalkoxy.
A method of treating a disease or condition that is cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection in a patient need thereof, comprising administering to the patient a therapeutically effective amount of a compound selected from one or more of:
A method of treating a disease or condition that is cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection in a patient need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula X, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
- wherein:
- Y is cyano, hydroxy, or —CH2—R12;
- R3a and R3b are, independently, hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, or haloalkoxy;
- R12 is hydroxy, amino, optionally substituted heteroaryl, optionally substituted heterocyclo, or —NHC(═O)—R16;
- R16 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl;
- R17a is hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, haloalkoxy, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, (cycloalkyl)alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclosulfonyl, sulfonamido, optionally substituted heteroaryl, optionally substituted heterocyclo, carboxamido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, carboxy, carboxyalkyl;
- R18 is halo, nitro, cyano, hydroxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, —OC(═O)-amino, —N(R19a)C(═O)—R19b, or N(R20a)SO2—R20b;
- R19a is hydrogen or alkyl;
- R19b is amino, alkoxy, alkyl, or optionally substituted aryl;
- R20a is hydrogen or alkyl;
- and
- R20b is amino, alkyl, or optionally substituted aryl.
A method of treating a disease or condition that is cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection in a patient need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula Xi, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
- wherein:
- Y is cyano or —CH2—R12;
- R3a and R3b are, independently, hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, or haloalkoxy;
- R12 is amino or heteroaryl;
- R17a is chloro, cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl;
- R17b and R17c are, independently, hydrogen or halo;
- R18 is —OC(═O)-amino or —NHC(═O)—R19b;
- R19b is amino, alkoxy, alkyl, or optionally substituted aryl;
- and
- R24 is hydrogen or fluoro.
A method of treating a disease or condition that is cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection in a patient need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula Xi, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
- wherein:
- Y is cyano or —CH2—R12;
- R3a and R3b are, independently, hydrogen, alkyl, halo, hydroxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkoxy, or haloalkoxy;
- R12 is optionally substituted 5-membered heteroaryl;
- R17a is chloro, cyano, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl;
- R17b and R17c are, independently, hydrogen or halo;
- R18 is —OC(═O)-amino or —NHC(═O)—R19b;
- R19b is amino, alkoxy, alkyl, or optionally substituted aryl;
- and
- R24 is hydrogen or fluoro.
Dependencies are inferred from the claim text.