Nicotinamide phosphoribosyltransferase inhibitors and methods for use of the same
AssigneeThe Trustees of Indiana University
InventorsTom G. DRIVER, Roberto F. MACHADO, Najing SU, Xinyu GUAN, Wrickban MAZUMDAR, Kira RATIA, Jason Ralph HICKOK, Angelia Denise LOCKETT
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Abstract
Disclosed herein are compounds that can act as inhibitors of nicotinamide phosphoribosyltransferase (“NAMPT”), and methods for their use in treating or preventing diseases, such as pulmonary arterial hypertension (“PAH”). The compounds described herein can include compounds of Formula (II) and pharmaceutically acceptable salts thereof: wherein the substituents are as described.
Claims21
A compound of Formula (II), or a pharmaceutically acceptable salt thereof:
- wherein
- is a single bond or a double bond;
- each of x and y independently is 0, 1, or 2;
- A is
- T is CRaRb or SiR1R2, provided that when T is SiR1R2, then is a single bond;
- each of G, U, V, and W independently is CR4 or N, provided that at least three of G, U, V, and W are CR4;
- Z is CH2 or C═O;
- Ra is H, C1-4alkyl, or CH2CO2R5;
- Rb, when present, is H or C1-4alkyl;
- each of R1 and R2 independently is C1-4alkyl or phenyl;
- R3 is H, C1-4alkyl, or aryl;
- each R4 independently is H, halo, C1-4alkyl, OH, OC1-4alkyl, OBn, O(C═O)(CH2)n(C═O)(CH2CH2O)mC1-4alkyl, or O(C═O)(CH2)n(C═O)(CH2CH2O)mH, or two adjacent R4 groups are each OC1-4alkyl, and together with the carbon atoms to which they are attached, form a five- or six-membered ring;
- R5 is H, C1-4alkyl, (CH2CH2O)mC1-4alkyl, or (CH2CH2O)mH;
- n is 1-4;
- and
- m is 1-10;
- with the proviso that when y is 2, then the two carbon atoms adjacent to N can optionally be fused to a phenyl group, the compound or salt thereof is not
- and with the proviso that when is a single bond, A is
- Z is CH2, each of G, V, U, and W is CH, T is CH2, y is 2, the two carbon atoms adjacent to N are fused to a phenyl group, and R3 is H, x is 2.
-30. (canceled)
A compound having the structure
- or a pharmaceutically acceptable salt thereof.
A method of treating a subject having a disease or disorder wherein inhibition of nicotinamide phosphoribosyltransferase would provide a benefit, the method comprising:
- administering to the subject a therapeutically effective amount of a compound or salt of Formula (II):
- wherein:
- is a single bond or a double bond;
- each of x and y independently is 0, 1, or 2;
- A is
- T is CRaRb or SiR1R2, provided that when T is SiR1R2, then is a single bond;
- each of G, U, V, and W independently is CR4 or N, provided that at least three of G, U, V, and W are CR4;
- Z is CH2 or C═O;
- Ra is H, C1-4alkyl, or CH2CO2R5;
- Rb, when present, is H or C1-4alkyl;
- each of R1 and R2 independently is C1-4alkyl or phenyl;
- R3 is H, C1-4alkyl, or aryl;
- each R4 independently is H, halo, C1-4alkyl, OH, OC1-4alkyl, OBn, O(C═O)(CH2)n(C═O)(CH2CH2O)mC1-4alkyl, or
- O(C═O)(CH2)n(C═O)(CH2CH2O)mH, or two adjacent R4 groups are each OC1-4alkyl, and together with the carbon atoms to which they are attached, form a five- or six-membered ring;
- R5 is H, C1-4alkyl, (CH2CH2O)mC1-4alkyl, or (CH2CH2O)mH;
- n is 1-4;
- and
- m is 1-10.
Dependencies are inferred from the claim text.