IP Library › Granted Patent US 12,264,139

Granted Patent B2

US 12,264,139 · App. 17/343,994 · Granted Apr 1, 2025

Aryl sulfonamides as BLT1 antagonists

Inventors: Yongxin Han (Needham, MA); Jongwon Lim (Lexington, MA); Satyanarayana Tummanapalli (Hyderabad, IN); Phieng Siliphaivanh (Newton, MA); Kerrie Spencer (Woonsocket, RI)

Assignee: Merck Sharp & Dohme LLC

C07D311/22 C07D405/06 C07D405/14 C07D409/06 C07D413/06 C07D417/06

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Quick Facts

Patent No.: US 12,264,139
App. No.: 17/343,994
Granted: Apr 1, 2025
Kind: B2

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Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are antagonists of leukotriene B 4 receptor 1 (BLT1) and may be useful in the treatment, prevention and suppression of diseases mediated by the leukotriene B 4 receptor 1 (BLT1). The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, insulin resistance, hyperglycemia, dyslipidemia, lipid disorders, obesity, hypertension, Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, metabolic syndrome, atherosclerosis, and cancer.

Claims (169)

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is selected from:

(1) pyridine,

(2) thiophene, and

(3) pyrazine,

wherein pyridine, thiophene, and pyrazine, are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, and halogen;

B is selected from:

(1) phenyl,

(2) pyrazine,

(3) pyridine, and

(4) pyridazine,

wherein phenyl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl, halogen and CF 3 , and wherein pyrazine, pyridine and pyridazine are unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl, halogen, and CF 3 ;

X is selected from:

(1) —NHSO 2 CF 3 ,

(2) —NHSO 2 CH 2 CF 3 ,

(3) —NHSO 2 CHF 2 ,

(4) —NHSO 2 C 1-6 alkyl,

(5) —NHSO 2 CH 2 C 3-6 cycloalkyl, and

(6) —NHSO 2 C 3-6 cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl;

Z is selected from:

(1) hydrogen, and

(2) C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl;

R a is selected from:

(1) hydrogen,

(2) halogen, and

(3) C 1-6 alkyl; and

R b is selected from:

(1) hydrogen,

(2) halogen, and

(3) C 1-6 alkyl.

2. The compound according to claim 1 wherein Z is -hydrogen or C 1-6 alkyl, wherein alkyl is unsubstituted; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein X is selected from:

(1) —NHSO 2 CF 3 ,

(2) —NHSO 2 CH 2 CF 3 ,

(3) —NHSO 2 CHF 2 ,

(4) —NHSO 2 C 1-6 alkyl, and

(5) —NHSO 2 C 3-6 cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein X is —NHSO 2 CF 3 ; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein A is pyridine; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein B is phenyl; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein B is pyridine, wherein pyridine is unsubstituted or substituted with 1-3 substituents independently selected from halogen; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R a and R b are independently selected from: hydrogen, and C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R a and R b are hydrogen; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein

A is selected from:

(1) pyridine,

(2) thiophene, and

(3) pyrazine,

wherein pyridine, thiophene, and pyrazine; are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, and halogen;

B is selected from:

(1) phenyl,

(2) pyrazine,

(3) pyridine, and

(4) pyridazine,

wherein pyrazine, pyridine and pyridazine are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl, halogen, and CF 3 ;

X is selected from:

(1) —NHSO 2 CF 3 ,

(2) —NHSO 2 CH 2 CF 3 ,

(3) —NHSO 2 CHF 2 ,

(4) —NHSO 2 C 1-6 alkyl, and

(5) —NHSO 2 C 3-6 cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl;

and

R a and R b are independently selected from: hydrogen, and C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 wherein

A is selected from:

(1) pyridine,

(2) thiophene, and

(3) pyrazine,

wherein pyridine, thiophene, and pyrazine, are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, and halogen;

B is phenyl;

X is —NHSO 2 CF 3 ; and

R a and R b are hydrogen;

or a pharmaceutically acceptable salt thereof.

12. A compound selected from:

(1) N-(2-((3,4-Rac-cis)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;

(2) N-(2-((3,4-Rac-trans)-3-benzyl-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;

(3) 1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((5-phenylthiophen-2-yl)methyl) chroman-7-yl)phenyl) methanesulfonamide;

(4) 1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(pyridin-3-ylmethyl) chroman-7-yl)phenyl) methanesulfonamide;

(5) 1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiophen-3-ylmethyl) chroman-7-yl)phenyl) methanesulfonamide;

(6) 1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-((5-methylpyridin-2-yl)methyl) chroman-7-yl)phenyl) methanesulfonamide;

(7) 1,1,1-Trifluoro-N-(2-{(rac-trans)-3-[(3-fluoropyridin-2-yl)methyl]-4-hydroxy-3,4-dihydro-2H-chromen-7-yl}phenyl) methanesulfonamide;

(8) 1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(6-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl) methanesulfonamide;

(9) 1,1,1-Trifluoro-N-(2-{(rac-trans)-4-hydroxy-3-[(3-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl) methanesulfonamide;

(10) 1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;

(11) 1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(pyridin-4-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;

(12) 1,1,1-Trifluoro-N-{2-[(rac-trans)-4-hydroxy-3-(pyrazin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;

(13) 1,1,1-Trifluoro-N-(2-((rac-trans)-3-((5-fluoropyridin-2-yl)methyl)-4-hydroxychroman-7-yl)phenyl) methanesulfonamide;

(14) N-(2-((3,4-Rac-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)phenyl) methanesulfonamide;

(15) 1,1,1-Trifluoro-N-(2-((3,4-rac-trans)-4-hydroxy-3-(thiophen-2-ylmethyl) chroman-7-yl)phenyl) methanesulfonamide;

(16)-1,1,1-Trifluoro-N-(2-((rac-trans)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl) chroman-7-yl)phenyl) methanesulfonamide;

(17) (2-((3S,4R)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl) chroman-7-yl)phenyl)((trifluoromethyl) sulfonyl)amide;

(18) (2-((3R,4S)-4-hydroxy-3-((5-phenylpyridin-2-yl)methyl) chroman-7-yl)phenyl)((trifluoromethyl) sulfonyl)amide;

(19) 1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;

(20) 1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}-methanesulfonamide;

(21) N-{2-[(3R,4S)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;

(22) N-{2-[(3S,4R)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;

(23) 1, 1,1-Trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(3-methylpyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}phenyl) methanesulfonamide;

(24) 1,1,1-trifluoro-N-{2-[(3R,4S)-4-hydroxy-3-(thiophen-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;

(25) 1,1,1-trifluoro-N-{2-[(3S,4R)-4-hydroxy-3-(thiophen-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;

(26) 1,1,1-Trifluoro-N-(2-{(3,4-trans)-4-hydroxy-3-[(6-methyl-pyridin-2-yl)methyl]-3,4-dihydro-2H-chromen-7-yl}-phenyl) methanesulfonamide;

(27) 1,1,1-Trifluoro-N-(2-{(3,4-trans)-3-[(3-fluoropyridin-2-yl)methyl]-4-hydroxy-3,4-dihydro-2H-chromen-7-yl}phenyl) methanesulfonamide;

(28) N-{2-[(3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;

(29) N-{2-[(3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl)-3,4-dihydro-2H-chromen-7-yl]phenyl}methanesulfonamide;

(30) 1,1,1-Trifluoro-N-(3-((3,4-rac-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl) pyrazin-2-yl) methanesulfonamide;

(31) 2,2,2-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl) pyrazin-2-yl) ethanesulfonamide;

(32) 2,2,2-Trifluoro-N-(3-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl) pyridin-2-yl) ethanesulfonamide;

(33) 2,2,2-Trifluoro-N-(3-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl) pyridin-2-yl) ethanesulfonamide;

(34) 2,2,2-Trifluoro-N-(2-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)phenyl) ethanesulfonamide;

(35) 2,2,2-Trifluoro-N-(2-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)phenyl) ethanesulfonamide;

(36) 1,1-Difluoro-N-(2-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)phenyl) methanesulfonamide;

(37) 1,1-Difluoro-N-(2-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)phenyl) methanesulfonamide;

(38) 1,1,1-Trifluoro-N-(4-fluoro-2-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)phenyl) methanesulfonamide;

(39) 1,1,1-Trifluoro-N-(5-fluoro-3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl) pyridin-2-yl) methanesulfonamide;

(40) 1,1,1-Trifluoro-N-(5-fluoro-3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl) pyridin-2-yl) methanesulfonamide;

(41) 1,1-Difluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl) pyridin-2-yl) methanesulfonamide;

(42) 1,1,1-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl) pyridin-2-yl) methanesulfonamide;

(43) 2,2,2-Trifluoro-N-(3-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)-5-(trifluoromethyl) pyrazin-2-yl) ethanesulfonamide;

(44) N-(6-chloro-4-((3R,4S)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide;

(45) N-(4-((3,4-trans)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoro-methanesulfonamide;

(46) N-(6-chloro-4-((3S,4R)-4-hydroxy-3-(pyridin-2-ylmethyl) chroman-7-yl)pyridazin-3-yl)-1,1,1-trifluoromethanesulfonamide; and

(47) 1,1,1-trifluoro-N-(4-fluoro-2-(4-hydroxy-3-(1-(pyridin-2-yl)ethyl) chroman-7-yl)phenyl) methanesulfonamide;

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method of treating a disorder, condition or disease that is mediated by antagonism of the BLT1 receptor in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 .

15. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

16. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is selected from:

(1) pyridine,

(2) thiophene, and

(3) pyrazine,

wherein pyridine, thiophene, and pyrazine are unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, and halogen;

B is selected from:

(1) phenyl,

(2) pyrazine,

(3) pyridine, and

(4) pyridazine,

X is selected from:

(1) —NHSO 2 CF 3 ,

(2) —NHSO 2 CH 2 CF 3 ,

(3) —NHSO 2 CHF 2 ,

(4) —NHSO 2 C 1-6 alkyl,

(5) —NHSO 2 CH 2 C 3-6 cycloalkyl, and

(6) —NHSO 2 C 3-6 cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from C 1-6 alkyl;

Z is phenyl,

wherein phenyl is unsubstituted or substituted with 1-4 substituents independently selected from C 1-6 alkyl;

R a is selected from:

(1) hydrogen,

(2) halogen, and

(3) C 1-6 alkyl; and

R b is selected from:

(1) hydrogen,

(2) halogen, and

(3) C 1-6 alkyl.

17. The compound according to claim 16 wherein R a and R b are independently selected from: hydrogen, and C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

18. The compound of claim 16 selected from:

(1) N-(2-((3,4-Rac-cis)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;

(2) N-(2-((3,4-Rac-trans)-3-([1,1′-biphenyl]-4-ylmethyl)-4-hydroxychroman-7-yl)phenyl)-1,1,1-trifluoromethanesulfonamide;

(3) N-{2-[(3S,4R)-3-(biphenyl-4-ylmethyl)-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide; and

(4) N-{2-[(3R,4S)-3-(biphenyl-4-ylmethyl)-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]phenyl}-1,1,1-trifluoromethanesulfonamide;

or a pharmaceutically acceptable salt thereof.

Assignments (4)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 10, 2021

From: HAN, YONGXIN; LIM, JONGWON; SILIPHAIVANH, PHIENG; SPENCER, KERRIE

To: MERCK SHARP & DOHME CORP.

Reel/Frame 056498/0036 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 10, 2021

From: TUMMANAPALLI, SATYANARAYANA

To: ALBANY MOLECULAR RESEARCH INC.

Reel/Frame 056498/0117 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 10, 2021

From: ALBANY MOLECULAR RESEARCH INC.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 056498/0206 →

Continuity (3)

Continuation 15768880

Provisional Application 62260926 · Nov 30, 2015

Related Publication 20220363656A1 · Nov 17, 2022

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