IP Library › Granted Patent US 8,377,928

Granted Patent B2

US 8,377,928 · App. 12/743,023 · Granted Feb 19, 2013

3-aminosulfonyl substituted indole derivatives and methods of use thereof

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Quick Facts

Patent No.: US 8,377,928
App. No.: 12/743,023
Granted: Feb 19, 2013
Kind: B2

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Abstract

The present invention relates to 3-Aminosulfonyl Substituted Indole Derivatives of Formula (I): The invention also relates to compositions comprising at least one 3-Aminosulfonyl Substituted Indole Derivative, and methods of using the 3-Aminosulfonyl Substituted Indole Derivatives for treating or preventing a viral infection or a virus-related disorder in a patient.

Claims (91)

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is a bond, —[C(R 12 ) 2 ] r —, —[C(R 12 ) 2 ] r —O—[C(R 12 ) 2 ] q —, —[C(R 12 ) 2 ] r —N(R 9 )—[C(R 12 ) 2 ] q , —, —[C(R 12 ) 2 ] q —CH═CH—[C(R 12 ) 2 ] q —, —[C(R 12 ) 2 ] q —C≡C—[C(R 12 ) 2 ] q —, or —[C(R 12 ) 2 ] q —SO 2 —[C(R 12 ) 2 ] q —;

R 2 is —[C(R 12 ) 2 ] q —C(O)N(R 9 )SOR 11 , —[C(R 12 ) 2 ] q —C(O)N(R 9 )SO 2 R 11 , —[C(R 12 ) 2 ] q —C(O)N(R 9 )SO 2 N(R 9 ) 2 ,

R 4 , R 5 , R 6 and R 7 are each, independently, H, alkyl, alkenyl, alkynyl, aryl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkenyl, —[C(R 12 ) 2 ] q -heteroaryl, —[C(R 12 ) 2 ] q -haloalkyl, —[C(R 12 ) 2 ] q -hydroxyalkyl, halo, hydroxy, —OR 9 , —CN, —[C(R 12 ) 2 ] q —C(O)R 8 , —[C(R 12 ) 2 ] q —C(O)OR 9 , —[C(R 12 ) 2 ] q —C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —OR 9 , —[C(R 12 ) 2 ] q —N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHC(O)R 8 , —[C(R 12 ) 2 ] q —NR 8 C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHSO 2 R 11 , —[C(R 12 ) 2 ] q —S(O) p R 11 , —[C(R 12 ) 2 ] q —SO 2 N(R 9 ) 2 or —SO 2 N(R 9 )C(O)N(R 9 ) 2 ;

each occurrence of R 8 is independently H, alkyl, alkenyl, alkynyl, —[C(R 12 ) 2 ] q -aryl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkenyl, —[C(R 12 ) 2 ] q -heteroaryl, haloalkyl or hydroxyalkyl;

each occurrence of R 9 is independently H, alkyl, alkenyl, alkynyl, —[C(R 12 ) 2 ] q -aryl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkenyl, —[C(R 12 ) 2 ] q -heteroaryl, haloalkyl or hydroxyalkyl;

R 10 is H, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, wherein a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl group can be optionally and independently substituted with up to 4 substituents, which are each independently selected from H, alkyl, alkenyl, alkynyl, aryl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkenyl, —[C(R 12 ) 2 ] q -heteroaryl, —[C(R 12 ) 2 ] q -haloalkyl, —[C(R 12 ) 2 ] q -hydroxyalkyl, halo, hydroxy, —OR 9 , —CN, —[C(R 12 ) 2 ] q —C(O)R 8 , —[C(R 12 ) 2 ] q —C(O)OR 9 , —[C(R 12 ) 2 ] q —C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —OR 9 , —[C(R 12 ) 2 ] q —N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHC(O)R 8 , —[C(R 12 ) 2 ] q —NR 8 C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHSO 2 R 11 , —[C(R 12 ) 2 ] q —S(O) p R 11 , —[C(R 12 ) 2 ] q —SO 2 N(R 9 ) 2 and —SO 2 N(R 9 )C(O)N(R 9 ) 2 , such that when R 1 is a bond, R 10 is not H;

each occurrence of R 11 is independently alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, haloalkyl, hydroxy or hydroxyalkyl, wherein a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl group can be optionally and independently substituted with up to 4 substituents, which are each independently selected from —H, alkyl, alkenyl, alkynyl, aryl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkenyl, —[C(R 12 ) 2 ] q -heteroaryl, —[C(R 12 ) 2 ] q -haloalkyl, —[C(R 12 ) 2 ] q -hydroxyalkyl, halo, hydroxy, —OR 9 , —CN, —[C(R 12 ) 2 ] q —C(O)R 8 , —[C(R 12 ) 2 ] q —C(O)OR 9 , —[C(R 12 ) 2 ] q —C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —OR 9 , —[C(R 12 ) 2 ] q —N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHC(O)R 8 , —[C(R 12 ) 2 ] q —NR 8 C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHSO 2 alkyl, —[C(R 12 ) 2 ] q —NHSO 2 cycloalkyl, —[C(R 12 ) 2 ] q —NHSO 2 aryl, —[C(R 12 ) 2 ] q —SO 2 N(R 9 ) 2 and —SO 2 N(R 9 )C(O)N(R 9 ) 2 ;

each occurrence of R 12 is independently H, halo, —N(R 9 ) 2 , —OR 9 , alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, wherein a cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group can be optionally and independently substituted with up to 4 substituents, which are each independently selected from alkyl, halo, haloalkyl, hydroxyalkyl, hydroxy, —CN, —C(O)alkyl, —C(O)Oalkyl, —C(O)NHalkyl, —C(O)N(alkyl) 2 , —O-alkyl, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —NHC(O)alkyl, —NHSO 2 alkyl, —SO 2 alkyl or —SO 2 NH-alkyl, or two R 12 groups, together with the carbon atoms to which they are attached, join to form a cycloalkyl, heterocycloalkyl or C═O group;

each occurrence of R 20 is independently alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, or both R 20 groups and the carbon atoms to which they are attached, join to form a cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group wherein a cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group can be substituted with up to 4 groups, which are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxy, —OR 9 , —CN, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkenyl, —[C(R 12 ) 2 ] q -haloalkyl, —[C(R 12 ) 2 ] q -hydroxyalkyl, —[C(R 12 ) 2 ] q —C(O)R 8 , —[C(R 12 ) 2 ] q —C(O)OR 9 , —[C(R 12 ) 2 ] q —C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —OR 9 , —[C(R 12 ) 2 ] q —N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHC(O)R 8 , —[C(R 12 ) 2 ] q —NR 8 C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHSO 2 R 11 , —[C(R 12 ) 2 ] q —S(O) p R 11 , —[C(R 12 ) 2 ] q —SO 2 N(R 9 ) 2 and —SO 2 N(R 9 )C(O)N(R 9 ) 2 ;

R 21 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl or haloalkyl, or R 21 and R 22 and the nitrogen atoms to which they are attached, join to form a group having the formula:

R 22 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl or haloalkyl;

R 23 is an optional substituent selected from alkyl, aryl, —CN, —OH, —O-alkyl, cycloalkyl, halo, heterocycloalkyl, and heteroaryl;

n is an integer ranging from 1 to 3;

each occurrence of p is independently 0, 1 or 2;

each occurrence of q is independently an integer ranging from 0 to 4; and

each occurrence of r is independently an integer ranging from 1 to 4.

2. The compound of claim 1 , wherein R 2 is —C(O)NHSO 2 R 11 or —C(O)NHSO 2 N(R 9 ) 2 wherein R 9 is H, alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, and R 11 is alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycloalkyl or hydroxyalkyl.

3. The compound of claim 2 , wherein R 21 and R 22 and the nitrogen atoms to which they are attached, join to from a group having the formula:

R 21 is H, alkyl, haloalkyl, and heterocycloalkyl; and

R 23 represents up to 4 optional and additional substituents each independently selected from H, alkyl, halo, haloalkyl, hydroxyl, and heterocycloalkyl.

4. The compound of claim 2 , wherein R 1 is —CH 2 —.

5. The compound of claim 2 , wherein R 4 and R 7 are each independently H, alkyl, halo or hydroxy;

R 5 is H, alkyl, —O-alkyl, —O-haloalkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NH 2 or —CN; and

R 6 is H, alkyl, —O-alkyl, —O-haloalkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NH 2 or —CN.

6. The compound of claim 2 , wherein R 10 is aryl or heteroaryl.

7. The compound of claim 1 having the formula:

or a pharmaceutically acceptable salt, thereof,

wherein:

R 1 is —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, or

R 2 is —C(O)NHSO 2 R 11 , —C(O)NHSO 2 N(R 9 ) 2 , —C(O)N(alkyl)SO 2 R 11 or —C(O)N(alkyl)SO 2 N(R 9 ) 2 ;

R 4 , R 5 , R 6 and R 7 are each, independently, H, alkyl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, haloalkyl, halo, hydroxy, —OR 9 or —N(R 9 ) 2 ;

each occurrence of R 9 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl or hydroxyalkyl;

R 10 is:

each occurrence of R 11 is independently alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycloalkyl or hydroxyalkyl;

each occurrence of R 12 is independently H, halo, —N(alkyl) 2 , —OH, —O-alkyl, alkyl, cycloalkyl or heterocycloalkyl, or two R 12 groups, together with the carbon atoms to which they are attached, join to form a cycloalkyl, heterocycloalkyl or C═O group;

R 13 is H, F, Br or Cl;

R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , —CN, halo, —O-alkyl, —O-haloalkyl, —NHSO 2 -alkyl, —NO 2 , —C(O)NH 2 , —C(O)NH-alkyl, —C(O)OH, hydroxy, —NH 2 , —SO 2 alkyl, —SO 2 NHalkyl, —S-alkyl, —CH 2 NH 2 , —CH 2 OH, —SO 2 NH 2 , —NHC(O)-alkyl, —C(O)O-alkyl, —C(O) heterocycloalkyl and heteroaryl;

R 21 is H, alkyl, haloalkyl, and heterocycloalkyl or R 21 R 22 and the nitrogen atoms to which they are attached, join to from a group having the formula:

R 23 represents up to 4 optional and additional substituents each independently selected from H, alkyl, halo, hydroxyl, and heterocycloalkyl;

each occurrence of q is independently an integer ranging from 0 to 4; and

represents a pyridyl group, wherein the ring nitrogen atom can be at any of the five unsubstituted ring atom positions.

8. A compound having the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is a bond, —[C(R 12 ) 2 ] r —, —[C(R 12 ) 2 ] r —O—[C(R 12 ) 2 ] q —, —[C(R 12 ) 2 ] r —N(R 9 )—[C(R 12 ) 2 ] q —, —[C(R 12 ) 2 ] q —CH═CH—[C(R 12 ) 2 ] q —, —[C(R 12 ) 2 ] q —C≡C—[C(R 12 ) 2 ] q —, or —[C(R 12 ) 2 ] q —SO 2 —[C(R 12 ) 2 ] q —;

R 2 is —C(O)R 9 , —C(O)OR 9 , —C(O)OCH 2 OR 9 , —C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —C(O)OR 9 , —[C(R 12 ) 2 ] q —C(O)N(R 9 ) 2 , -alkyl, —[C(R 12 ) 2 ] q -aryl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, —[C(R 12 ) 2 ] q -heteroaryl or —[C(R 12 ) 2 ] q -heterocycloalkenyl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 4 substituents, which are the same or different, and are selected from alkyl, alkenyl, alkynyl, aryl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q —heterocycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkenyl, —[C(R 12 ) 2 ] q -heteroaryl, —[C(R 12 ) 2 ] q -haloalkyl, —[C(R 12 ) 2 ] q -hydroxyalkyl, halo, hydroxy, —OR 9 , —CN, —[C(R 12 ) 2 ] q —C(O)R 8 , —[C(R 12 ) 2 ] q —C(O)OR 9 , —[C(R 12 ) 2 ] q —C(O)N(R 9 ) 2 , —[C (R 12 ) 2 ] q —OR 9 , —[C(R 12 ) 2 ] q —N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHC(O)R 8 , —[C(R 12 ) 2 ] q —NR 8 C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHSO 2 R 11 , —[C(R 12 ) 2 ] q —S(O) p R 11 , —[C(R 12 ) 2 ] q —SO 2 N(R 9 ) 2 and —SO 2 N(R 9 )C(O)N(R 9 ) 2 ;

R 4 is H, alkyl, halo or hydroxy;

R 5 is H, alkyl, —O-alkly, —O-haloalkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NH 2 or —CN;

R 6 is H, alkyl, —O-alkyl, —O-haloalkyl, cycloalkyl, halo, haloalky, hydroxy, hydroxyalkyl, —NH 2 or —CN;

R 7 is H, alkyl, halo or hydroxy;

R 10 is H, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, wherein a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl group can be optionally and independently substituted with up to 4 substituents, which are each independently selected from —H, alkyl, alkenyl, alkynyl, aryl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -cycloalkenyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkenyl, —[C(R 12 ) 2 ] q -heteroaryl, —[C(R 12 ) 2 ] q -haloalkyl, —[C(R 12 ) 2 ] q -hydroxyalkyl, halo, hydroxy, —OR 9 , —CN, —[C(R 12 ) 2 ] q —C(O)R 8 , —[C(R 12 ) 2 ] q —C(O)OR 9 , —[C(R 12 ) 2 ] q —C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —OR 9 , —[C(R 12 ) 2 ] q —N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHC(O)R 8 , —[C(R 12 ) 2 ] q —NR 8 C(O)N(R 9 ) 2 , —[C(R 12 ) 2 ] q —NHSO 2 R 11 , —[C(R 12 ) 2 ] q —S(O) p R 11 , —[C(R 12 ) 2 ] q —SO 2 N(R 9 ) 2 and —SO 2 N(R 9 )C(O)N(R 9 ) 2 , such that when R 1 is a bond, R 10 is not H;

R 21 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl or haloalkyl, or R 21 and R 22 and the nitrogen atoms to which they are attached, join to form a group having the formula:

R 22 is H, alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl or haloalkyl;

R 23 is an optional substituent selected from alkyl, aryl, —CN, —OH, —O-alkyl, cycloalkyl, halo, heterocycloalkyl, and heteroaryl;

n is an integer ranging from 1 to 3;

each occurrence of p is independently 0, 1 or 2;

each occurrence of q is independently an integer ranging from 0 to 4; and

each occurrence of r is independently an integer ranging from 1 to 4.

9. The compound of claim 8 , wherein R 2 is —C(O)OR 9 or —C(O)N(R 9 ) 2 , wherein R 9 is H, alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl.

10. The compound of claim 9 , wherein R 21 and R 22 and the nitrogen atoms to which they are attached, join to form a group having the formula:

wherein R 21 is H, alkyl, haloalkyl, and heterocycloalkyl; and

R 23 represents up to 4 optional and additional substituents each independently selected from H, alkyl, halo, hydroxyl, and heterocycloalkyl.

11. The compound of claim 9 , wherein R 1 is —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, or

12. The compound of claim 9 , wherein R 10 is aryl or heteroaryl.

13. The compound of claim 8 having the formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, or

R 2 is —C(O)OR 9 or —C(O)N(R 9 ) 2 , wherein R 9 is H, alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;

R 4 , R 5 , R 6 and R 7 are each, independently, H, alkyl, —[C(R 12 ) 2 ] q -cycloalkyl, —[C(R 12 ) 2 ] q -heterocycloalkyl, haloalkyl, halo, hydroxy, —OR 9 or —N(R 9 ) 2 ;

each occurrence of R 9 is independently H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl or hydroxyalkyl;

R 10 is:

such that when R 1 is a bond, R 10 is not H;

each occurrence of R 11 is independently alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycloalkyl or hydroxyalkyl;

R 13 is H, F, Br or Cl;

R 14 represents up to 4 optional and additional substituents, each independently selected from alkyl, cycloalkyl, CF 3 , —CN, halo, —O-alkyl, —O-haloalkyl, —NHSO 2 -alkyl, —C(O)NH 2 , —C(O)NH-alkyl, —C(O)OH, hydroxy, —NH 2 , —SO 2 alkyl, —SO 2 NHalkyl, —S-alkyl, —CH 2 NH 2 , —CH 2 OH, —SO 2 NH 2 , —NHC(O)-alkyl, —C(O)O-alkyl, —C(O)-heterocycloalkyl and heteroaryl;

R 21 is H, alkyl, haloalkyl, and heterocycloalkyl or R 21 and R 22 and the nitrogen atoms to which they are attached, join to from a group having the formula:

R 23 represents up to 4 optional and additional substituents each independently selected from H, alkyl, halo, —OH and heterocycloalkyl;

each occurrence of q is independently an integer ranging from 0 to 4; and

represents a pyridyl group, wherein the ring nitrogen atom can be at any of the five unsubstituted ring atom positions.

14. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

15. A composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier.

Assignments (2)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →

CHANGE OF NAME Recorded Aug 30, 2012

From: SCHERING CORPORATION

To: MERCK SHARP & DOHME CORP.

Reel/Frame 028884/0151 →