IP Library › Granted Patent US 9,884,878
Granted Patent B2
US 9,884,878 · App. 14/728,128 · Granted Feb 6, 2018

FLAP modulators

Inventors: Genesis M. Bacani (San Diego, CA); Wendy Eccles (San Diego, CA); Anne E. Fitzgerald (San Diego, CA); Steven D. Goldberg (Encinitas, CA); Michael D. Hack (San Diego, CA); Natalie A. Hawryluk (San Diego, CA); William M. Jones (San Diego, CA); John M. Keith (San Diego, CA); Paul Krawczuk (San Diego, CA); Alec D. Lebsack (Ladera Ranch, CA); Alice Lee-Dutra (San Diego, CA); Jing Liu (San Diego, CA); Kelly J. McClure (Ramona, CA); Steven P. Meduna (San Diego, CA); Daniel J. Pippel (Del Mar, CA); Mark D. Rosen (San Diego, CA); Zachary S. Sales (Escondido, CA)
Assignee: JANSSEN PHARMACEUTICA NV
C07F7/0812C07D209/08C07D213/73C07D235/10C07D237/20C07D241/20C07D241/26C07D263/48C07D277/62C07D285/12C07D401/04C07D401/10C07D401/12C07D401/14C07D403/10C07D403/12C07D403/14C07D405/12C07D405/14C07D409/12C07D413/10C07D413/12C07D413/14C07D417/10C07D471/04C07D487/04C07D487/08C07D491/08C07D491/10C07D491/107C07D495/10C07D498/04C07F5/025C07F7/08
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Quick Facts
Patent No.
US 9,884,878
App. No.
14/728,128
Granted
Feb 6, 2018
Kind
B2
Abstract

The present invention relates to compounds of Formula (I), or a form thereof, wherein ring A, R 1 , R 2 , R 3 , R 3 ′, L, W, and V are as defined herein, useful as FLAP modulators. The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention.

Claims (130)

1. A compound of Formula (I)

wherein

L is a bond, —CH 2 —, —SO 2 —, —CH 2 —SO 2 —, —SO 2 —CH 2 —, —SO 2 —NR—, —SO 2 —NR—CH 2 —, —CH 2 —SO 2 —NR—, —NR—, —NR—SO 2 —, —S—, —S—CH 2 —, —CH 2 —S—, —C(═O)—, —O—, —O—CH 2 —, —NR—C(═O)—, or —C(═O)—NR—, wherein R is H, C 1-2 alkyl, C 1-2 alkyl-OH or cyclopropyl;

R 1 is H, halo, methyl, CF 3 , —O—CF 3 , or —O—CH 3 ;

R 2 is H, cyano, halo, 2-(trimethylsilyl)ethoxy, phenyl, C 1-6 alkyl, heteroaryl, heterocyclyl, C 3-9 cycloalkyl, provided R 2 is not H if L is a bond, and wherein said phenyl, C 1-6 alkyl, heteroaryl, heterocyclyl or C 3-9 cycloalkyl is optionally and independently substituted selected from the group consisting of:

methyl, ethyl, oxo, fluoro, hydroxyl, cyano, amino, methoxy, tert-butoxy, acetyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, azetidin-1-yl, azetidin-3-yl, pyrrolidin-1-yl, 2,4-dihydro-3H-1,2,4-triazol-3-one-4-yl, 1H-imidazol-4-yl, pyrazin-2-yl, pyrimidin-2-yl, 1,3-oxazolidin-2-one-5-yl, N-benzamide, 4-methylpiperazin-1-yl, morpholin-4-yl, CF 3 , —SO 2 —CH 3 , —C(═O)-cyclopropyl, —NHCH 3 , —N(CH 3 ) 2 , —NHAc, —NHCO 2 t-Bu, —CH 2 —NH 2 , —C(═O)—NH 2 , —C(═O)—N(ethyl) 2 , —NH—C(═O)—NH 2 , —NH—C(═O)—CH 3 , —C(═O)—(C 1 -C 4 alkyl), —C(═O)—OH, —C(═O)—NH(C 1 -C 4 alkyl)-(CH 2 ) n —OH, and —(CH 2 ) n —CN, wherein n is 1 or 2;

V is CH, CR′, or N, wherein R′ is methyl or F;

W is CR″ or N, wherein R″ is H, F, hydroxyl, amino, CH 3 or —O—CH 3 ;

ring A is selected from the group consisting of:

R 3 is H, F, methyl, or —O—CH 3 ;

R 3 ′ is H or F;

R 4 is H, methyl, cyano, amino, halo, —COOH, or —O—CH 3 ;

R 5 is H, methyl, cyano, or —CF 3 ;

R 6 is H, cyano, amino, halo, or —CF 3 ; and

R 7 is halo, amino, —CONH 2 , cyano, —O—CH 3 , —CF 3 , or —COO-ethyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein

L is a bond, —O—, —SO 2 —NH—, —NH—SO 2 —, —SO 2 —, —S—, —C(═O)—, fluoro or —C(═O)—NH—;

R 1 is H, bromo or CF 3 ;

R 2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, tetrahydro-2H-thiopyran-4-yl, morpholin-2-yl, morpholin-4-yl, thiomorpholin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl, provided R 2 is not H if L is a bond, and wherein R 2 is optionally substituted with hydroxyl, fluoro, amino, oxo, methyl, or —CH 2 —NH 2 ;

V is CH or N;

W is CR″ or N, wherein R″ is H or F;

ring A is

R 3 is H;

R 3 ′ is H;

R 4 is H or cyano; and

R 5 is H or cyano;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein

L is a bond, —O—, —SO 2 —NH—, —NH—SO 2 —, —SO 2 —, —S—, or —C(═O)—;

R 1 is H or CF 3 ;

R 2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, tetrahydro-2H-thiopyran-4-yl, morpholin-2-yl, morpholin-4-yl, thiomorpholin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, or pyrimidin-4-yl, provided R 2 is not H if L is a bond, and wherein R 2 is optionally substituted with hydroxyl, fluoro, amino, oxo, methyl, or —CH 2 —NH 2 ;

V is CH or N;

W is CR″ or N, wherein R″ is H or F;

R 3 is H, and

R 3 ′ is H;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is selected from the group consisting of:

3′-Fluoro-N-[(1S)-2-hydroxy-1-methylethyl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,

3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,

3′-Fluoro-N-[(3S)-2-oxopyrrolidin-3-yl]-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,

5-[2′-(Cyclopropylsulfonyl)-3-fluorobiphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine,

3′-Fluoro-N-(2-hydroxyethyl)-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,

3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]methanesulfonamide,

3′-Fluoro-N,N-dimethyl-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,

2-[3-Fluoro-2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,

N,N-Diethyl-3′-fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,

2-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,

2-[3-Fluoro-2′-(morpholin-4-ylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,

3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-N-(2,2,2-trifluoro-1-methylethyl)biphenyl-2-sulfonamide,

2-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,

3′-Fluoro-N-[(1R)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrol o[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,

3′-Fluoro-N-methyl-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,

3′-Fluoro-N-[(1S)-2-hydroxy-1-methylethyl]-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-sulfonamide,

1-{[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]sulfonyl}piperidin-4-amine,

2-{2′-[(1, 1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-5H-pyrrolo[2,3-b]pyrazine,

2-[3,5′-Difluoro-2′-(methylsulfanyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,

2-[2′-(Ethylsulfanyl)-3-fluorobiphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,

7-[3-Fluoro-2′-(methylsulfonyl)biphenyl-4-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,

7-[3-Fluoro-2′-(piperidin-1-ylsulfonyl)biphenyl-4-yl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,

4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-sulfonamide,

4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1S)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,

1-{[4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}piperidin-4-amine,

4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]biphenyl-2-sulfonamide,

4′-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide,

7-{2′-[(1, 1-Dioxidothiomorpholin-4-yl)sulfonyl]-3-fluorobiphenyl-4-yl}-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,

N-tert-Butyl-4′-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-3′-fluorobiphenyl-2-sulfonamide,

2-(2-Fluoro-4-{2-[(1-methylethyl)sulfanyl]-5-(trifluoromethyl)pyridin-3-yl}phenyl)-5H-pyrrolo[2,3-b]pyrazine,

2-{2-Fluoro-4-[2-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine,

2-{2-Fluoro-4-[2-(2-methylpropoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2, 3-b]pyrazine,

2-{2-Fluoro-4-[2-(1-methylethoxy)pyridin-3-yl]phenyl}-5H-pyrrolo[2,3-b]pyrazine,

2-{4-[2-(Cyclopropylmethoxy)pyridin-3-yl]-2-fluorophenyl}-5H-pyrrolo[2,3-b]pyrazine,

N-tert-Butyl-3′-fluoro-4′-(7H-pyrrolo[2, 3-d]pyrimidin-2-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-(1,8-naphthyridin-3-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-quinoxalin-6-ylbiphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-(1H-indol-5-yl)biphenyl-2-sulfonamide,

4′-(1H-Benzimidazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,

4′-(1H-Benzimidazol-5-yl)-3′-fluoro-N-methylbiphenyl-2-sulfonamide,

4′-(1,3-Benzothiazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-(1H-pyrrolo[3,2-b]pyridin-6-yl)biphenyl-2-sulfonamide,

3′-Fluoro-N-methyl-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-4′-(2, 3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-3′-fluorobiphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-(3H-imidazo[4, 5-b]pyridin-6-yl)biphenyl-2-sulfonamide,

4′-(5-amino-1,3,4-thiadiazol-2-yl)-N-(tert-butyl)-3′-fluoro-[1,1′-biphenyl]-2-sulfonamide,

(R)-4′-(5-amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-N-(1-hydroxypropan-2-yl)-[1,1′-biphenyl]-2-sulfonamide,

4-((4′-(5-amino-1,3,4-thiadiazol-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-yl)sulfonyl)thiomorpholine 1,1-dioxide,

N-tert-Butyl-3′-fluoro-4′-(1H-imidazo[4, 5-b]pyrazin-5-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]biphenyl-2-sulfonamide,

4′-(7-Amino-1H-indol-5-yl)-3′-fluoro-N-[1-(hydroxymethyl)cyclopentyl]biphenyl-2-sulfonamide,

3′-Fluoro-4′-[3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N-methylbiphenyl-2-sulfonamide,

4′-(7-Amino-1H-indol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,

2-[3,4′-Difluoro-2′-(methyl sulfonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,

N-[4′-(5-Aminopyrazin-2-yl)-3′-fluorobiphenyl-2-yl]-N-methylmethanesulfonmide,

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]ethanesulfonamide,

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-N-methylmethanesulfonamide,

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-N-methylethanesulfonamide,

N-[3′-Fluoro-4′-(5H-pyrrolo[2,3-b]pyrazin-2-yl)biphenyl-2-yl]-2-methylpropane-1-sulfonamide,

5-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine,

2-[3-Fluoro-2′-(morpholin-4-ylcarbonyl)biphenyl-4-yl]-5H-pyrrolo[2,3-b]pyrazine,

4-{[3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-yl]oxy}pyrimidin-2-amine,

2-{[3′-Fluoro-4′-(1H-pyrrolo[2,3-b]pyridin-5-yl)biphenyl-2-yl]oxy}pyrimidin-4-amine,

5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-1H-pyrrolo[2,3-b]pyridine,

5-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-1H-benzimidazole,

6-[3-Fluoro-2′-(pyrimidin-2-yloxy)biphenyl-4-yl]-3H-imidazo[4, 5-b]pyridine,

4′-(2-Amino-1,3-oxazol-4-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,

4′-(2-Amino-1,3-thiazol-4-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,

4′-(2-Amino-1,3-thiazol-4-yl)-N,N-diethyl-3′-fluorobiphenyl-2-sulfonamide,

4-[3-Fluoro-2′-(pyrrolidin-1-yl sulfonyl)biphenyl-4-yl]-1,3-thiazol-2-amine,

N-tert-Butyl-3′-fluoro-4′-(8-fluoroimidazo[1,2-a]pyridin-2-yl)biphenyl-2-sulfonamide,

4′-(5-Aminoimidazo[1,2-a]pyridin-2-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,

2-[2′-(tert-Butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-6-carboxamide,

2-[2′-(tert-Butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-6-carboxamide,

N-tert-Butyl-4′-(5-cyanoimidazo[1,2-a]pyridin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,

N-tert-Butyl-4′-(6-cyanoimidazo[1,2-a]pyridin-2-yl)-3′-fluorobiphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]biphenyl-2-sulfonamide,

Ethyl 2-[2′-(tert-butylsulfamoyl)-3-fluorobiphenyl-4-yl]imidazo[1,2-a]pyridine-5-carboxylate,

N-tert-Butyl-3′-fluoro-4′-(5-methoxyimidazo[1,2-a]pyridin-2-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-3′-fluoro-4′-(2-oxo-2,3-dihydro-1H-indol-5-yl)biphenyl-2-sulfonamide,

N-tert-Butyl-4′-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)-3′-fluorobiphenyl-2-sulfonamide,

4′-(3-Amino-1H-indazol-5-yl)-N-tert-butyl-3′-fluorobiphenyl-2-sulfonamide,

5-(4′-Bromo-2′,3-difluorobiphenyl-4-yl)-1H-pyrrolo[2,3-b]pyridine,

5-{2-Fluoro-4-[2-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}-1H-pyrrolo[2,3-b]pyridine,

N-{3-[3-Fluoro-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pyridin-2-yl}-2,2-dimethylpropanamide, and

5-(2-Fluoro-4-(2-(isopropylsulfonyl)pyridine-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine.

5. A pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 5 comprising at least one compound of claim 4 .

Continuity (4)
Continuation 14169770 · Jan 31, 2014
Provisional Application 61760627 · Feb 4, 2013
Provisional Application 61800353 · Mar 15, 2013
Related Publication 20150259357A1 · Sep 17, 2015