Antimicrobials and methods of making and using same
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 (I) or tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
1. A compound of Formula (I):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
R 1 is selected from the group consisting of H, halo, and C 1-4 alkoxy;
R 2 is selected from the group consisting of H, halo, C 1-6 alkyl, C 1-4 haloalkyl, and OR a1 ;
R 3 is selected from the group consisting of H, C 1-6 alkyl, C 1-4 haloalkyl, and C(O)OR a1 ;
W is selected from the group consisting of N and CR 4 ;
R 4 is selected from the group consisting of H, halo, OR a2 , SR a2 , 5-6 membered heterocycloalkyl, S(O) 2 R b2 , C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with a substituent selected from the group consisting of ORa 2 ;
R 5 is selected from the group consisting of H, halo, C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with a substituent selected from the group consisting of ORa a2 ;
R 7B is H;
R 6 and R 7A together with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms form a 5- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N, O and S;
X is selected from the group consisting of O and NR 8 ;
R 8 is selected from the group consisting of H, C 1-6 alkyl, and C 1-4 haloalkyl, wherein the C 1-6 alkyl is optionally substituted with R 8A ;
R 8A is selected from the group consisting of OR a3 and 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with one or two C 1-6 alkyl;
R 9 is selected from the group consisting of H, C 2-4 alkenyl, C 1-4 haloalkyl and C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of amino, C 1-4 alkoxy, C 3-5 cycloalkyl, and 3- to 6-membered heterocycloalkyl;
R 10 is selected from the group consisting of H and C 2-6 alkenyl;
R A is selected from the group consisting of H and C 1-6 alkyl;
L is selected from the group consisting of C 1-6 alkyl and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OR a4 , and SR a4 ;
R 11 is selected from the group consisting of H, C 1-6 alkyl, C 3-5 cycloalkyl, C 1-4 haloalkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of CN, OR a5 , SR a5 , C(O)NR c5 R d5 , NR c5 R d5 , and S(O) 2 R b5 ;
R 12 is selected from the group consisting of H and C 1-6 alkyl; or
R 11 and R 12 together with the carbon atom to which they are attached form a C 3-5 cycloalkyl;
R 13 is selected from the group consisting of H, halo, and C 1-6 alkyl;
R 14 is selected from the group consisting of H, halo, and C 1-6 alkyl; and
R B is selected from the group consisting of H and C(═NR e5 )R b5 ; or
R 11 and R B together with the carbon atom to which R 11 is attached and the nitrogen atom to which R B is attached form a 5- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 6-membered heterocycloalkyl is optionally substituted with oxo;
each R a1 , R a2 , R a3 , R a4 , R a5 , R b2 , R b5 , R c5 , and R d5 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-4 haloalkyl, and 5-membered heteroaryl; and
R e5 is selected from the group consisting of H and C 1-4 alkyl;
provided that the compound is not one of the following compounds:
2. The compound of claim 1 , wherein
R 1 is selected from the group consisting of H and halo;
L is selected from the group consisting of C 1-6 alkyl and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OR a4 , and SR a4 ; and
R e5 is selected from the group consisting of H and C 1-4 alkyl.
3. The compound of claim 1 , wherein
R 1 is halo; or
R 1 is selected from the group consisting of H and fluoro; or
R 1 is fluoro; or
R 1 is C 1-4 alkoxy; or
R 1 is methoxy.
4. The compound of claim 1 , wherein
R 2 is selected from the group consisting of H, halo, C 1-4 haloalkyl, and C 1-4 haloalkoxy; or
R 2 is selected from the group consisting of halo, C 1-4 haloalkyl, and C 1-4 haloalkoxy; or
R 2 is selected from the group consisting of H, trifluoromethoxy, trifluoromethyl and chloro; or
R 2 is selected from the group consisting of trifluoromethoxy, trifluoromethyl and chloro.
5. The compound of claim 1 , wherein
R 1 is halo and R 2 is halo; or
R 1 is fluoro and R 2 is chloro.
6. The compound of claim 1 , wherein
R 3 is selected from the group consisting of H, C 1-4 haloalkyl, and C(O)OR a1 ; or
R 3 is selected from the group consisting of H, C 1-4 haloalkyl, and C(O)C 1-4 alkoxy; or
R 3 is selected from the group consisting of H, trifluoromethyl, and C(═O)(methoxy); or
R 3 is H.
7. The compound of claim 1 , wherein
W is CR 4 .
8. The compound of claim 1 , wherein
R 4 is selected from the group consisting of H, halo, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, S(C 1-4 alkyl), 6-membered heterocycloalkyl, and S(O) 2 C 1-4 alkyl; or
R 4 is selected from the group consisting of halo, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, S(C 1-4 alkyl), 6-membered heterocycloalkyl, and S(O) 2 C 1-4 alkyl; or
R 4 is selected from the group consisting of H, fluoro, chloro, methylthio, methoxy, methyl, S(═O) 2 (methyl), trifluoromethoxy, and N-morpholino; or
R 4 is selected from the group consisting of fluoro, chloro, methylthio, methoxy, methyl, S(═O) 2 (methyl), trifluoromethoxy, and N-morpholino; or
R 4 is H.
9. The compound of claim 1 , wherein
R 5 is halo; or
R 5 is selected from the group consisting of H and F; or
R 5 is F; or
R 5 is H.
10. The compound of claim 1 , wherein
R 5 is halo and R 4 is selected from the group consisting of halo, S(C 1-4 alkyl), and 6-membered heterocycloalkyl; or
R 5 is halo, and R 4 is S(C 1-4 alkyl); or
R 5 is fluoro and R 4 is selected from the group consisting of fluoro, methylthio, and N-morpholino; or
R 5 is fluoro and R 4 is methylthio.
11. The compound of claim 1 , wherein
R 6 and R 7A together with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms form a 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N, O and S; or
R 6 and R 7A together with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms form a ring of any one of the following formulae:
or
R 6 and R 7A together with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms form a ring of the following formulae:
wherein x indicates a point of attachment to the ring containing the W atom and substituted with R 5 ; or
R 6 and R 7A together with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms form a ring of any one of the following formulae:
or
R 6 and R 7A together with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms form a ring of formula:
wherein x indicates a point of attachment to the ring containing the W atom and substituted with R 5 ; or
R 6 and R 7A together with the carbon atoms to which they are attached and the X atom connecting the two carbon atoms form a ring of any one of the following formulae:
wherein x indicates a point of attachment to the ring containing the W atom and substituted with R 5 .
12. The compound of claim 1 , wherein
X is NR 8 .
13. The compound of claim 1 , wherein
R 8 is selected from the group consisting of H, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-6 alkyl substituted with C 1-6 alkoxy, and C 1-6 alkyl substituted with 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted with 1, or 2 C 1-6 alkyl; or
R 8 is selected from the group consisting of H, methyl, 3-fluoropropyl, 2-methoxyethyl, 3-hydroxypropyl, 2-(pyridinyl)ethyl, 2-(imidazolyl)ethyl, (imidazolyl)methyl, and (oxazolyl)methyl, wherein each pyridinyl, imidazolyl, and oxazolyl is optionally substituted with 1 or 2 methyl; or
R 8 is selected from the group consisting of the following formulae:
or
R 8 is selected from the group consisting of methyl, 3-fluoropropyl, 2-methoxyethyl, and 3-hydroxypropyl; or
R 8 is H.
14. The compound of claim 1 , wherein
R 9 is H; or
R 9 is C 1-6 alkyl; or
R 9 is methyl.