Benzodioxane Modulators of Leukotriene A4 Hydrolase (LTA4H) for Prevention and Treatment of Aging-Associated Diseases

A method of improving cognitive function in a subject diagnosed with an age-related cognitive disease, the method comprising administering a therapeutically effective amount of a compound of formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• X is N or CH;
• n is an integer from 0 to 3;
• R1 is selected from halo, —OH, —CN, —(C1-C6)alkyl, —O(C1-C6)alkyl, and —(C3-C6)cycloalkyl;
• R2 and R3 are each independently selected from —H and —(C1-C6)alkyl;
• wherein R2 and R3 may join to form a 3- to 6-membered ring optionally comprising one to three heteroatoms, and further optionally substituted with one to three groups selected from halo, —OH, (═O), —(C1-C6)alkyl, —O(C1-C6)alkyl, —C(O)O—H, —C(O)(C1-C6)alkyl, and —C(O)NH2;
• A is a group of formula —NR4R5, wherein R4 and R5 are each independently selected from —H, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, -(4- to 14-membered)heterocycloalkyl, —(C6-C10)aryl and -(5-11-membered)heteroaryl;
• wherein each of the foregoing —(C1-C6)alkyl, —(C3-C6)cycloalkyl, -(4- to 14-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl of said R4 and R5 groups is optionally independently substituted by one to three R6 groups;
• wherein two R6 groups when attached to the same carbon atom of said —(C1-C6)alkyl may join to form a 3- to 6-membered ring optionally comprising one to three heteroatoms, and further optionally substituted with one to three groups selected from halo, —OH, (═O), —(C1-C6)alkyl, —O(C1-C6)alkyl, —C(O)O—H, —C(O)(C1-C6)alkyl, and —C(O)NH2;
• or A is a (4- to 14-membered)N-heterocyclic ring of formula B:
• wherein said ring B is:
• (a) a non-aromatic 4-8 membered monocyclic radical;
• or (b) a bridged bicyclic radical, a spirocyclic radical, or a 6 to 11-membered fused bicyclic radical, wherein each of said bridged bicyclic radical, spirocyclic radical, and 6 to 11-membered fused bicyclic radical comprises at least a nonaromatic N-heterocyclic ring which is attached to the carbon atom 1 of the compound of formula (I);
• wherein each of said bridged bicyclic radical, spirocyclic radical, and 6 to 11-membered fused bicyclic radical may optionally comprise an aromatic ring;
• wherein said ring B may additionally comprise one to three additional ring heteroatoms independently selected from N, O and S;
• wherein said ring B may be further optionally substituted by one to three groups selected from halo, —OH, (═O), —C(O)O—H, —C(O)O—(C1-C6)alkyl, and —(C1-C6)alkyl;
• and wherein L is absent or a linker selected from —(C1-C6)alkylene-;
• each R6 is independently selected from halo, —OR7, —CF3, —CN, —(C1-C6)alkyl, —O(C1-C6)alkyl, —C(O)R7, —C(O) 2R7, —C(O)N(R7)2, —N(R7)2, —NHC(O)R7, —NHC(O)N(R7)2, —S(O)2R7, —NH—S(O)2-R7, —(C3-C6)cycloalkyl, -(4- to 14-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl;
• wherein each of said, —(C1-C6)alkyl, —O(C1-C6)alkyl, —(C3-C6)cycloalkyl, -(4- to 14-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl of said R6 group is optionally substituted where possible with one to three groups selected from halo, —OH, —CF3, —CN, (═O), —(C1-C6)alkyl, —C(O)O—H, —C(O)O—(C1-C6)alkyl, —NH2, —NH(C1-C6)alkyl, —N((C1-C6)alkyl)2, —S(O)2(C1-C6)alkyl, —(C3-C6)cycloalkyl, -(4- to 14-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl;
• and each R7 is independently selected from —H, —(C1-C6)alkyl, —(C1-C6)alkyl-OH, —(C1-C6)alkyl-O—(C1-C6)alkyl, —O(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C3-C6)cycloalkyl-OH, -(4- to 14-membered)heterocycloalkyl, —(C6-C10)aryl, and -(5- to 11-membered)heteroaryl;
• wherein each of said R7 groups is optionally substituted where possible with a group selected from —OH, —NH(C1-C6)alkyl, —NHC(O)(C1-C6)alkyl, —C(O)NH2, —S(O)2(C1-C6)alkyl, and -(4- to 14-membered)heterocycloalkyl;
• wherein said -(4- to 14-membered)heterocycloalkyl group is optionally substituted where possible with a (═O) group;
• and one or more additional active agents.