US 2026/0048047 A1 · SMALL-MOLECULE ACTIVATORS OF MYCOBACTERIUM TUBERCULOSIS ADENYLYL CYCLASE

Abstract

The present application discloses novel compounds, and compositions comprising said compounds, that are effective small-molecule agonists that stimulate overproduction of cytosolic cyclic AMP (cAMP) in Mycobacterium tuberculosis (Mtb) which inhibits cholesterol metabolism. These small-molecule agonists demonstrate potentiation of current tuberculosis (TB) therapeutics, exhibiting potential as a promising new class of agents for the treatment of TB. The application further discloses methods of treatment of TB using compositions comprising the disclosed novel compounds in combination therapy with current TB therapeutics.

A compound of Formula I or Formula II,

wherein:
A is selected from the group consisting of:
each R1 is independently H or (C1-C6)alkyl;
Z1 is CH or N;
u is 0 to 2;
v is 0 to 2;
both R2 are absent or both R2 together form a (C1-C2)alkylenyl bridge between two ring carbon atoms, provided that u and v are not both 0;
Z2 is CH, CR3, or N;
R3 is OH, CF3, or (C1-C6)alkyl;
t is 0 or 1;
B is selected from the group consisting of:
L is a bond;
or if A is A3 and B is B1, B2, or B6, L may be —C(═O)—, —C(═O)N(R9)—, —CH2—, or —O—:
R9 is H, (C1-C6)alkyl, or (C1-C6)heteroalkyl;
Q is 3- to 8-membered monocyclic, 6- to 16-membered bicyclic, 4- to 14-membered fused bicyclic, or 5- to 11-membered spirocyclic cycloalkyl or heterocycloalkyl, Ph, or 5- to 8-membered heteroaryl, each optionally substituted with (Q′)r;
or if A is A3 and B is Bi, B2, or B6, Q may be (C1-C6)alkyl or (C1-C6)heteroalkyl;
each Q′ is independently halo, halo (C1-C6) alkyl, haloalkoxy, —CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)heteroalkyl, OH, oxo, amino, amido, imino, (C1-C6)alkyl ester, carboxyl, —SF5, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, 3- to 7-membered spirocyclic cycloalkyl or heterocycloalkyl, aryl, or 5- to 6-membered heteroaryl;
and
r is 0-5;
with the proviso that the compound of Formula I is not V-9, 2-(4-methyl-1,2,5-oxadiazol-3-yl)-1-(4-(5-(p-tolyl)-2H-tetrazol-2-yl)piperidin-1-yl)ethan-1-one;
2-(4-methyl-1,2,5-oxadiazol-3-yl)-1-(4-(5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)ethan-1-one;
2-(4-methyl-1,2,5-oxadiazol-3-yl)-1-(4-(5-(6-methylpyridin-3-yl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)ethan-1-one;
2-(4-methyl-1,2,5-oxadiazol-3-yl)-1-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethan-1-one;
1-(3-(5-cyclopropylpyrimidin-2-yl)azetidin-1-yl)-2-(4-methyl-1,2,5-oxadiazol-3-yl)ethan-1-one;
8) 1-(4-(5-(furan-3-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)-2-(2H-tetrazol-2-yl)ethan-1-one;
2-(2H-tetrazol-2-yl)-1-(3-(5-(thiophen-3-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-yl)ethan-1-one;
2-(1H-tetrazol-5-yl)-1-(4-(3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethan-1-one;
2-(5-isopropyl-1H-tetrazol-1-yl)-1-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)ethan-1-one;
1-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one;
1-(3-(5-(1-(cyclopropylmethyl)pyrrolidin-2-yl)-1,2,4-oxadiazol-3-yl)azetidin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one;
1-(3-(4-phenyl-1H-1,2,3-triazol-1-yl)azetidin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one;
1-(3-(4-phenyl-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one;
1-(3-(5-cyclopropylpyrimidin-2-yl)azetidin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one;
1-(4-(6-cyclopropylpyridazin-3-yl)piperazin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one;
1-(4-(6-(1H-1,2,4-triazol-1-yl)pyridazin-3-yl)piperazin-1-yl)-2-(1H-tetrazol-1-yl)ethan-1-one;
1-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)-2-(isoxazol-3-yl)ethan-1-one;
2-(isoxazol-3-yl)-1-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)azetidin-1-yl)ethan-1-one;
or 1-(3-(3-isobutyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2-(4-methyl-1,2,5-oxadiazol-3-yl)ethan-1-one;
or any pharmaceutically acceptable salts or any stereochemically isomeric forms thereof.

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Small-molecule activators of mycobacterium tuberculosis adenylyl cyclase

Life of this patent

Small-molecule activators of mycobacterium tuberculosis adenylyl cyclase

Life of this patent

Abstract

Claims21