Sulfonamide derivatives and methods of use thereof for improving the pharmacokinetics of a drug

Patent metadata

Field	Value
Publication number	US-9556202-B2
Application number	US-201314410846-A
Country	US
Kind code	B2
Filing date	Jun 25, 2013
Priority date	Jun 27, 2012
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The present invention relates to Sulfonamide Derivatives of Formula (I):

and pharmaceutically acceptable salts thereof, wherein A, W, X, R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein. The present invention also relates to compositions comprising at least one Sulfonamide Derivative, and methods of using the Sulfonamide Derivatives for improving the pharmacokinetics of a drug.

First claim

What is claimed is:

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
A is a 5 or 6-membered heteroarylene group;
W is N or —CH—;
X is N or —C(R 3 )—;
R 1 is selected from —(C 1 -C 6 alkylene)-aryl, —(C 1 -C 6 alkylene)-(5 or 6-membered heteroaryl), —(C 1 -C 6 alkylene)-O-aryl, —(C 1 -C 6 alkylene)-O-(5 or 6-membered heteroaryl) and C 3 -C 6 cycloalkyl, wherein any aryl, heteroaryl or C 3 -C 6 cycloalkyl group can be optionally substituted with up to four R 7 groups, which can be the same or different, and wherein said C 3 -C 6 cycloalkyl group can be fused to a benzene ring and said fused benzene ring can be optionally substituted with up to four R 7 groups, which can be the same or different;
each occurrence of R 2 is independently selected from H, C 1 -C 6 alkyl, —OH, —O—(C 1 -C 6 alkyl) and —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl);
R 3 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl and —CN, or R 3 and an R 2 group, together with the carbon atoms to which they are attached, can combine to form a cyclopropyl ring;
R 4 is H, or R 4 and an R 2 group, can join to form a group selected from —CH 2 —CH 2 —CH 2 —, —C(O)—O—CH 2 —, —CH 2 —O—CH 2 — and —CH 2 —N(R 8 )—CH 2 —;
R 5 is —NH(R 6 ), 5 or 6-membered monocyclic heterocycloalkyl or 9 or 10-membered bicyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can optionally form a spirocycle with a C 3 -C 6 cycloalkyl group or another 5 or 6-membered monocyclic heterocycloalkyl group, and wherein said 5 or 6-membered monocyclic heterocycloalkyl group and said 9 or 10-membered bicyclic heterocycloalkyl group can be optionally substituted on one or more ring carbon atoms with up to four R 7 groups, which can be the same or different, and wherein a ring carbon atom of a 5 or 6-membered monocyclic heterocycloalkyl group may be functionalized as a carbonyl group
R 6 is C 1 -C 6 alkyl or 5 or 6-membered heteroaryl, wherein said C 1 -C 6 alkyl group is optionally substituted with 1 or 2 groups, each independently being NH 2 or halo, and wherein said 5 or 6-membered heteroaryl group can be optionally substituted with up to four R 7 groups;
each occurrence of R 7 is independently selected from C 1 -C 6 alkyl, 5 or 6-membered heterocycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, halo, —CN, —N(R 8 ) 2 , —CH 2 N(R 8 ) 2 , —OR 8 , —C(O)OR 8 , —SR 8 , —S(O) 2 R 8 and —C(O)N(R 8 ) 2 , wherein said 5 or 6-membered heterocycloalkyl group can be optionally substituted with a group selected from C 1 -C 6 alkyl, halo, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, halo, —CN, —N(R 8 ) 2 and —OR 8 ; and
each occurrence of R 8 is independently H or C 1 -C 6 alkyl.

2. The compound of claim 1 , wherein A is thiazolyl, pyridyl or pyrazinyl.

3. The compound of claim 1 , having the formula (Ia):

or a pharmaceutically acceptable salt thereof,
wherein:
R 5 is 5 or 6-membered monocyclic heterocycloalkyl, 9 or 10-membered bicyclic heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl group can optionally form a spirocycle with a C 3 -C 6 cycloalkyl group or another 5 or 6-membered monocyclic heterocycloalkyl group, and wherein said 5 or 6-membered monocyclic heterocycloalkyl group, said 9 or 10-membered bicyclic heterocycloalkyl and said spirocycle can be optionally substituted on one ring carbon atom with C 1 -C 6 alkyl or halo; and
each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl or halo.

4. The compound of claim 1 , wherein R 5 is 5 or 6-membered monocyclic heterocycloalkyl, which can optionally form a spirocycle and/or be optionally substituted as described in claim 1 .

5. The compound of claim 1 , wherein R 5 is 9 or 10-membered bicyclic heterocycloalkyl, which can be optionally substituted as described in claim 1 .

6. The compound of claim 1 , wherein R 5 is selected from:

7. The compound of claim 3 , wherein R 7 is halo.

8. The compound of claim 7 , wherein R 7 is F.

9. The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 , further comprising an anti-HIV drug.

12. The pharmaceutical composition of claim 11 , wherein said anti-HIV drug is selected from an HIV protease inhibitor, an HIV integrase inhibitor, a nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse-transcriptase inhibitor.

13. The pharmaceutical composition of claim 12 , wherein said anti-HIV drug is selected from raltegravir, lamivudine, abacavir, darunavir, ritonavir, dolutegravir, atazanavir, elvitegravir and lopinavir.

14. The pharmaceutical composition of claim 13 , further comprising a second anti-HIV drug, which is selected from an HIV protease inhibitor, an HIV integrase inhibitor, a nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse-transcriptase inhibitor.

15. A method for improving the pharmacokinetics of a therapeutic compound that is metabolized by a CYP3A enzyme in subject, said method comprising administering to said subject in need of such treatment a combination of: (a) said therapeutic compound that is metabolized by a CYP3A enzyme and (b) a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein said therapeutic compound is an anti-HIV drug.

17. The method of claim 16 , wherein said anti-HIV drug is selected from an HIV protease inhibitor, an HIV integrase inhibitor, a nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse-transcriptase inhibitor.

18. The method of claim 17 , wherein said anti-HIV drug is selected from raltegravir, lamivudine, abacavir, ritonavir, dolutegravir, atazanavir, darunavir, elvitegravir and lopinavir.

19. The method of claim 18 , wherein said anti-HIV drug is raltegravir.

20. The method of claim 15 , wherein the therapeutic compound of (a) is metabolized by CYP3A4.

Assignees

• Merck Sharp & Dohme

Inventors

• Coburn Craig A
• Maletic Milana
• Soll Richard
• Li Chunsing
• Luo Yunfu
• Qi Zhiqi

Classifications

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title