Granted Patent B2

US 12,390,440 · App. 17/801,328 · Granted Aug 19, 2025

Inventors: Todd M. Maddux (Kalamazoo, MI); Tomasz Respondek (Kalamazoo, MI)

Assignee: Zoetis Services LLC

A61K31/351A61K31/7048A61K31/7052A61P11/00A61P29/00A61P31/04A61P37/02C07D498/04C07D519/00C07H17/08

Abstract

Claims (67)

1. A Formula (1) compound

wherein W is H or a Formula (A) compound

wherein X is —R a , —R c NR 5 R 6 , —R c OR 7 , —R c SR 7 , —R c N 3 , —R c CN or —R c X′;

X′ is F, CI, I or Br;

R a , R b , R 1 and R 2 are each independently H or C 1 -C 6 alkyl;

or R 1 is benzyl optionally substituted with at least one R 9 substituent;

or R 1 is a —CH 2 Het wherein Het is a 5-6 membered heteroaryl ring containing at least one heteroatom selected from N, O and S; and wherein the heteroaryl ring is optionally substituted with at least one R 9 substituent;

R c is C 1 -C 4 alkyl;

R 5 and R 6 are each independently selected from H; C 1 -C 6 alkyl or C 1 -C 6 alkoxy each optionally substituted with at least one hydroxy; cyano, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —C(O)R 8 , —C(O)NR a R 8 , —C(O)R c NR a R b , —C(O)OR c R 8 , —C(O)ONR a R b , —R c NR a C(O)R 8 , —R c C(O)OH, —R c C(O)NR a R b , —R c NR a C(O)H, —S(O) p R 8 , —R c S(O) p R 8 , —R c NR a R b , —R c OR a , —S(O) p R 8 NR a R b , —R c S(O) p NR a R b or —R c NR a S(O) p R 8 ; or C 0 -C 4 alkylaryl, C 0 -C 4 alkylC 3 -C 6 cycloalkyl, C 0 -C 4 alkylheterocycle and C 0 -C 4 alkylheteroaryl; wherein the heterocycle and heteroaryl rings are a 5-6 membered monocyclic ring or a 9-10 membered fused ring, each containing at least one heteroatom selected from the group consisting of N, O and S; and wherein the aryl, cycloalkyl, heterocycle and heteroaryl rings are each optionally substituted with at least one R 10 substituent;

or R 5 and R 6 taken together with the nitrogen atom to which they are attached form Ring B, a 4-8 membered heterocyclic ring or a 5 membered heteroaryl ring, each optionally containing at least one additional heteroatom selected from N, O and S; each ring is optionally substituted with at least one R 9 substituent; and wherein each ring is optionally fused with Y;

R 7 is H, C 1 -C 6 alkyl, —R c NR a R b , —R c OR a , —R c S(O) p R a , —R c NR a C(O)R b , —R c C(O)NR a R b , —R c NR a C(O)NR a R b or —R c NR a C(O)OR b ;

R 8 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 0 -C 4 alkylC 3 -C 6 cycloalkyl, —NR a R b , phenyl, a 5-6 membered heterocyclic ring or heteroaryl ring each containing at least one heteroatom selected from N, O and S; and wherein the cycloalkyl, phenyl, heterocycle and heteroaryl moieties are each optionally substituted with at least one substituent selected from C 1 -C 4 alkyl, halogen, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy;

R 9 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 0 -C 4 alkyIC 3 -C 6 cycloalkyl, halogen, oxo, hydroxy, cyano, —NR a R b , C 1 -C 6 haloalkyl, C 1 -C 6 aloalkoxy, —S(O) p R 8 , phenyl, and a 5-6 membered heterocyclic or heteroaryl ring each containing at least one heteroatom selected from the group consisting of N, O and S;

R 10 is independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 0 -C 4 alkylC 3 -C 6 cycloalkyl, halogen, —NR a R b , —S(O) p R 8 , nitro, oxo, cyano, —C(O)H, —C(O)R 8 , —C(O)OR a , —OC(O)OR a , —NHR c C(O)R a , —C(O)NR a R b , hydroxy, a 5-6 membered heterocyclic ring, a 5-6 membered heteroaryl ring, a 9-10 membered fused heteroaryl ring and wherein each heterocyclic and heteroaryl ring contain at least one heteroatom selected from the group consisting of N, O and S; and phenyl; and wherein the phenyl, heterocyclic and heteroaryl rings are each optionally substituted with at least one R 9 substituent;

Y is phenyl, pyridinyl, pyrimidyl, pyrazolyl, thienyl, thiazolyl, triazolyl, isothiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, furanyl, indolyl, benzothienyl or naphthyl; and

p is the integer 0, 1 or 2; stereoisomers thereof, and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 , wherein Formula (A) is selected from the group consisting of Formula (A0), Formula (A1), Formula (A2), Formula (A3), Formula (A4), Formula (A5), or Formula (A6)

stereoisomers thereof, and pharmaceutically acceptable salts thereof.

3. A Formula (1) compound of claim 1 that is

stereoisomers thereof, and pharmaceutically acceptable salts thereof.

4. A compound of claim 3 , wherein R 2 is H, methyl, ethyl or propyl, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

5. A compound of claim 4 , wherein

R 2 is H or methyl;

R 5 is H or C 1 -C 6 alkyl;

R 6 is H; C 1 -C 6 alkyl or C 1 -C 6 alkoxy each optionally substituted with at least one hydroxy;

C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —C(O)R 8 , —C(O)NR a R 8 , —C(O)R c NR a R b , —R c S(O) p R 8 , —R c NR a R b , —R c OR a or —S(O) p R 8 ; or phenyl, C 1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1 -C 2 alkylcyclopropyl, C 1 -C 2 alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C 1 -C 2 alkyloxazolidinyl, C 1 -C 2 alkylpyrrolidinyl, C 1 -C 2 alkylpiperidinyl, C 1 -C 2 alkylpiperazinyl, C 1 -C 2 morpholinyl, C 1 -C 2 morpholinyl, C 1 -C 2 piperadinyl, C 1 -C 2 tetrahydropyranyl, C 1 -C 2 tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C 1 -C 2 alkylpyrazolyl, C 1 -C 2 alkylimidazolyl, C 1 -C 2 alkylpyridinyl, C 1 -C 2 alkylpyrimidinyl or C 1 -C 2 alkylpyrazinyl; and wherein the phenyl, cycloalkyl, heterocycle and heteroaryl rings are each optionally substituted with at least one R 10 substituent independently selected from methyl, ethyl, methoxy, ethoxy, —CHF 2 , —CF 3 , —OCF 3 , F, Cl, —NHCH 3 , —N(CH 3 ) 2 , —S(O) 2 CH 3 , cyano and hydroxy; stereoisomers thereof, and pharmaceutically acceptable salts thereof.

6. A compound of claim 5 , wherein

R 6 is H; C 1 -C 6 alkyl or C 1 -C 6 alkoxy each optionally substituted with at least one hydroxy;

C 1 -C 6 haloalkyl, —OCF 3 , —C(O)NR a R 8 , —R c S(O) p R 8 , —R c NR a R b , —R c OR a or —S(O) p R 8 ; or phenyl, Cialkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1 -C 2 alkylcyclopropyl, and C 1 -C 2 alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C 1 -C 2 alkyloxazolidinyl, C 1 -C 2 alkylpyrrolidinyl, C 1 -C 2 alkylpiperidinyl, C 1 -C 2 alkylpiperazinyl, C 1 -C 2 morpholinyl, C 1 -C 2 tetrahydropyranyl, C 1 -C 2 tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C 1 -C 2 alkylpyrazolyl, C 1 -C 2 alkylimidazolyl, C 1 -C 2 alkylpyridinyl, C 1 -C 2 alkylpyrimidinyl or C 1 -C 2 alkylpyrazinyl; and wherein the phenyl, cycloalkyl, heterocycle and heteroaryl rings are each optionally substituted with at least one R 10 substituent independently selected from methyl, ethyl, methoxy, ethoxy, —CHF 2 , —CF 3 , —OCF 3 , F, CI, —NHCH 3 , —N(CH 3 ) 2 , —S(O) 2 CH 3 , cyano and hydroxy; stereoisomers thereof, and pharmaceutically acceptable salts thereof.

7. A compound of claim 6 that is a compound selected from the group consisting of

(2R,3S,4R,5R,8R,10R,11R,12S, 13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-(((2-hydroxyethyl)amino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8, 10, 12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S, 14R)-13-(((2R,4R,5S,6S)-5-(((1,3-dihydroxypropan-2-yl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-3,5,8, 10, 12, 14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S, 14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-13-(((2R,4R,5S,6S)-5-((ethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4, 10-trihydroxy-3,5,8, 10, 12, 14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((methylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10, 12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclobutylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-3,5,8, 10, 12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((cyclopropylmethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-3,5,8, 10, 12, 14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(methylsulfonyl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S, 14R)-13-(((2R,4R,5S,6S)-5-((((1H-1,2,4-triazol-5-yl)methyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-3,5,8, 10, 12, 14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(2-oxopyrrolidin-1-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8, 10, 12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

2-((((2S,3S,4R,6R)-6-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8, 10, 12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-13-yl)oxy)-3-hydroxy-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl)methyl)amino)-N,N-dimethylethane-1-sulfonamide;

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8, 10,12, 14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

2-((((2S,3S,4R,6R)-6-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-3,5,8, 10, 12, 14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-13-yl)oxy)-3-hydroxy-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl)methyl)amino)ethane-1-sulfonamide;

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8, 10, 12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

(2R,3S,4R,5R,8R,10R,11R,12S,13S, 14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(2-oxooxazolidin-3-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8, 10, 12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; and

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-(((2-hydroxypropyl)amino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8, 10, 12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; stereoisomers thereof, and pharmaceutically acceptable salts thereof.

8. A compound of claim 1 that is

wherein R 1 is H or C 1 -C 6 alkyl;

R 2 is H or methyl;

Ring B is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each optionally substituted with at least one R 9 substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, —N(CH 3 ) 2 , hydroxy, —CHF 2 , —CF 3 , —OCHF 2 , —OCF 3 and oxo; and

n is the integer 0, 1, 2 or 3; stereoisomers thereof, and pharmaceutically acceptable salts thereof.

9. A compound of claim 8 selected from (2R,3S,4R,5R,8R, 10R, 11R, 12S, 13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(morpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8, 10, 12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one or

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((3aR,4S,6R,7aS)-1,6-dimethyl-2-(trifluoromethyl)hexahydro-2H-pyrano[4,3-d]oxazol-4-yl)oxy)-2-ethyl-3,4, 10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8, 10, 12, 14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

10. A compound of claim 1 that

wherein R a and R 2 are each independently H or methyl;

R 1 is H, methyl or ethyl; or R 1 is benzyl, —CH 2 pyridine, —CH 2 pyrimidine, —CH 2 pyrazole or —CH 2 imidazole; each optionally substituted with at least one R 9 substituent selected from methyl, ethyl, methoxy, ethoxy, F, CI, hydroxy, —CF 3 and —OCF 3 ;

R 7 is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH 2 NH 2 , —CH 2 NHCH 3 or —CH 2 N(CH 3 ) 2 ;

X′ is F or CI; stereoisomers thereof, and pharmaceutically acceptable salts thereof.

11. A composition comprising a compound of claim 1 , stereoisomer thereof, and pharmaceutically acceptable salt thereof; and wherein the composition further comprises a pharmaceutically acceptable carrier.

12. A composition comprising a compound of claim 7 , stereoisomer thereof, and pharmaceutically acceptable salt thereof; and wherein the composition further comprises a pharmaceutically acceptable carrier.

13. A method of treating an inflammatory response due to a bacterial, viral or fungal infection or stress in an animal by administering to said animal in need thereof, a therapeutically effective amount of a compound of claim 1 , stereoisomer thereof, and pharmaceutically acceptable salt thereof; and wherein said treating the inflammatory response in an animal prevents or mitigates the progression of bovine respiratory disease or swine respiratory disease.

14. The method of claim 13 , wherein treating the inflammatory response in an animal prevents or mitigates the progression of bovine respiratory disease.

15. A method of treating an inflammatory response due to a bacterial, viral or fungal infection or stress in an animal by administering to said animal in need thereof; a therapeutically effective amount of a compound of claim 7 , stereoisomer thereof, and pharmaceutically acceptable salt thereof; and wherein said treating the inflammatory response in an animal prevents or mitigates the progression of bovine respiratory disease or swine respiratory disease.

16. A compound of claim 10 that is a Formula (1.1) compound, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

17. A composition comprising a compound of claim 8 , stereoisomer thereof, and pharmaceutically acceptable salt thereof, and wherein the composition further comprises a pharmaceutically acceptable carrier.

18. A method of treating an inflammatory response due to a bacterial, viral or fungal infection or stress in an animal by administering to said animal in need thereof; a therapeutically effective amount of a compound of claim 8 , stereoisomer thereof, and pharmaceutically acceptable salt thereof; and wherein said treating the inflammatory response in an animal prevents or mitigates the progression of bovine respiratory disease or swine respiratory disease.

19. A composition comprising a compound of claim 10 , stereoisomer thereof, and pharmaceutically acceptable salt thereof, and wherein the composition further comprises a pharmaceutically acceptable carrier.

20. A composition comprising a compound of claim 16 , stereoisomer thereof, and pharmaceutically acceptable salt thereof, and wherein the composition further comprises a pharmaceutically acceptable carrier.

Assignments (1)

Continuity (2)

References Cited (31)