US 11,957,671 B2
Benzodioxane modulators of leukotriene A4 hydrolase (LTA4H) for prevention and treatment of aging-associated diseases
Meghan Kerrisk Campbell, San Francisco, CA (US); Eva Czirr, Foster City, CA (US); and Reema Harish, Redwood City, CA (US)
Assigned to Alkahest, Inc., San Carlos, CA (US)
Filed by Alkahest, Inc., San Carlos, CA (US)
Filed on Oct. 31, 2022, as Appl. No. 17/977,687.
Claims priority of provisional application 63/342,572, filed on May 16, 2022.
Claims priority of provisional application 63/327,496, filed on Apr. 5, 2022.
Claims priority of provisional application 63/293,560, filed on Dec. 23, 2021.
Claims priority of provisional application 63/274,222, filed on Nov. 1, 2021.
Prior Publication US 2023/0146135 A1, May 11, 2023
Int. Cl. A61K 31/453 (2006.01); A61P 25/28 (2006.01)
CPC A61K 31/453 (2013.01) [A61P 25/28 (2018.01)] 13 Claims
 
1. 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):

OG Complex Work Unit Chemistry
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 having from 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 (4- to 14-membered)N-heterocyclic ring of the following formula:

OG Complex Work Unit Chemistry
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 at least a nonaromatic N-heterocyclic ring of each of said bridged bicyclic radical, spirocyclic radical, or 6 to 11-membered fused bicyclic radical 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 have an aromatic ring,
wherein said ring B may additionally have from one to three additional ring heteroatoms independently selected from N, O and S; and
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;
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.