Substituted pyrrolo[2,3-d]pyrimidines as antimicrobials
The present disclosure relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, reducing the risk of, and delaying the onset of microbial infections in humans and animals. In some embodiments, the present disclosure provides a compound of Formula (A): or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
1. A compound of Formula (A):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
J is:
wherein:
R 1 is H or C 1-3 alkyl;
R 2 is H or C 1-3 alkyl; and
R 3 is H or C 1-3 alkyl; or
wherein:
(a) R 1 is C 1-3 alkyl;
R 2 is H or C1-3 alkyl; and
R 3 is H or C1-3 alkyl; or
(b) R 1 is H or C1-3 alkyl;
R 2 is C 1-3 alkyl; and
R 3 is H or C1-3 alkyl; or
(c) R 1 is H or C1-3 alkyl;
R 2 is H or C1-3 alkyl; and
R 3 is C 1-3 alkyl;
R 4 is H or C1-3 alkyl;
(A) R 5 is H or C 1-6 alkyl; and
R 6 and R 7 , together with the carbon and nitrogen atoms to which they are attached, form a heterocyclyl having any of the following formulas:
wherein the heterocyclyl is optionally substituted on a ring carbon atom with a C 1-6 alkyl substituent; and
wherein the C 1-6 alkyl substituent is optionally substituted with one or more OH substituents; or
(B) R 5 and R 7 , together with the carbon and nitrogen atoms to which they are attached, form a heterocyclyl having any of the following formulas:
R 6 is H, C 1-6 alkyl, C 2-6 alkenyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C(O)OR a , OR a , SR a , SC(NH)NH 2 , C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl; and
each R a is independently H or C 1-6 alkyl;
R 8 is H or halogen;
X is a 5- or 6-membered heterocyclyl or phenyl, wherein the 5- or 6-membered heterocyclyl or phenyl is optionally substituted with one or more independently selected R x substituents;
each R x is independently halogen, C 1-6 alkyl, C 1-4 haloalkyl, C(O)R c , C(O)OR c , NR c R c , OR c , C 3-6 cycloalkyl, or aryl, wherein each C 1-6 alkyl is optionally and independently substituted with one or more independently selected R b substituents; or
two adjacent R x , together with the atoms to which they are attached, form a 5- or 6-membered ring;
each R b is independently C 2-6 alkenyl, C(O)OR c , NR c R c , OR c , OC(NH)NH 2 , C 3-6 cycloalkyl, or aryl;
each R c is independently H, C 1-6 alkyl, CH 2 -aryl, C(O)aryl, or aryl, wherein each C 1-6 alkyl and each aryl is optionally and independently substituted with one or more independently selected R d substituents; and
each R d is independently C 1-3 alkyl, NH 2 , NHC 1-3 alkyl, N(C 1-3 alkyl) 2 , NO 2 , OH, or OC 1-3 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
(a) R 1 is C 1-3 alkyl;
R 2 is H; and
R 3 is H; or
(b) R 1 is H;
R 2 is C 1-3 alkyl; and
R 3 is H; or
(c) R 1 is H;
R 2 is H; and
R 3 is C 1-3 alkyl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
(a) R 1 is CH 3 ;
R 2 is H; and
R 3 is H; or
(b) R 1 is H;
R 2 is CH 3 ; and
R 3 is H; or
(c) R 1 is H;
R 2 is H; and
R 3 is CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
(a) R 1 is C 1-3 alkyl;
R 2 is H; and
R 3 is C 1-3 alkyl; or
(b) R 1 is C 1-3 alkyl;
R 2 is C 1-3 alkyl; and
R 3 is H; or
(c) R 1 is H;
R 2 is C 1-3 alkyl; and
R 3 is C 1-3 alkyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
(a) R 1 is CH 3 ;
R 2 is H; and
R 3 is CH 3 ; or
(b) R 1 is CH 3 ;
R 2 is CH 3 ; and
R 3 is H; or
(c) R 1 is H;
R 2 is CH 3 ; and
R 3 is CH 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 5 and R 7 , together with the carbon and nitrogen atoms to which they are attached, form:
7. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 5 and R 7 , together with the carbon and nitrogen atoms to which they are attached, form:
8. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 5 and R 7 , together with the carbon and nitrogen atoms to which they are attached, form:
9. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with one or more independently selected halogen substituents.
10. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with one or more independently selected OR a substituents.
11. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6 is C 1-6 alkyl, wherein the C 1-6 alkyl is substituted with one or more SC(NH)NH 2 substituents.
12. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6 and R 7 , together with the carbon and nitrogen atoms to which they are attached, form:
13. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R 6 and R 7 , together with the carbon and nitrogen atoms to which they are attached, form:
14. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X is pyrrolidinyl, wherein the pyrrolidinyl is optionally substituted with one or more independently selected R x substituents.
15. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X is phenyl, wherein the phenyl is optionally substituted with one or more independently selected R x substituents.
16. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R x is independently halogen or C 1-6 alkyl, wherein each C 1-6 alkyl is optionally and independently substituted with one or more independently selected R b substituents.
17. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein two adjacent R x , together with the atoms to which they are attached, form a 5- or 6-membered ring.
18. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein each R b is independently CH═CH 2 , NH 2 , or OH.