HIV inhibiting 1,2,4-triazin-6-one derivatives

• US 7,923,554 B2
• Filed: 08/10/2005
• Issued: 04/12/2011
• Est. Priority Date: 08/10/2004
• Status: Expired due to Fees

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Janssen, Paul Adriaan Jan, Koymans, Lucien Maria Henricus, Hoornaert, Georges Joseph Cornelius, Vinkers, Hendrik Maarten, Daeyaert, Frederik Frans Desiré, de Jonge, Marc René, Kilonda, Amuri, Lewi, Paulus Joannes, Heeres, Jan
• Primary Examiner(s): Balasubramanian; Venkataraman
• Application Number:
  US11/573,224
• Publication Number:
  US 20090012092A1
• Time in Patent Office: 2,071 Days
• Field of Search: 544/182, 514/242, 514/182
• US Class Current: 544/182
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07D 253/075 Two hetero atoms, in positions 3 and 5

Abstract

The present invention relates to HIV replication inhibitors of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein ring A and ring B represent phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; n and m are 1 to 4; R¹ represents hydrogen; aryl; formyl; C_1-6alkylcarbonyl; C_1-6alkyloxycarbonyl; optionally substituted C_1-6alkyl; C_1-6alkyloxyC_1-6alkylcarbonyl substituted with C_1-6alkyloxycarbonyl; R² or R⁴ represents hydrogen; hydroxy; halo; optionally substituted C_1-6alkyl; optionally substituted C_2-6alkenyl; optionally substituted C_2-6alkynyl; C_3-7cycloalkyl; C_1-6alkyloxy; C_1-6alkyloxycarbonyl; C_1-6alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(C_1-6alkyl)amino; polyhaloC_1-4alkyl; polyhaloC_1-4alkyloxy; polyhaloC_1-4alkylthio; —S(═O)_pR⁶; —NH—S(═O)_pR⁶; —C(═O)R⁶; —NHC(═O)H; —C(═O)NHNH₂; NHC(═O)R⁶; C(═NH)R⁶; or R⁷; R^2a or R³ represents cyano; aminocarbonyl; amino; halo; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹⁶; optionally substituted C_1-6alkyl; optionally substituted C_1-6alkyloxy; optionally substituted C_1-6alkyloxyC_1-6alkyl; optionally substituted C_2-6alkenyl; optionally substituted C_2-6alkynyl; —C(═N—O—R⁸)—C_1-4alkyl; R⁷ or —X₃—R⁷; X₁ or X₂ represents —NR¹—; —NH—NH—; —N═N—; —O—; —C(═O)—; —C_1-4alkanediyl-; —CHOH—; —S—; —S(═O)_p—; —X₄—C_1-4alkanediyl-; —C_1-4alkanediyl-X₄—; or —C_1-4alkanediyl-X₄—C_1-4alkanediyl-; their use as a medicine, their use for the manufacture of a medicament for the treatment or the prevention of HIV infection; their processes for preparation and pharmaceutical compositions comprising them.

Claims

1. A compound of formula

2. A compound according to claim 1 wherein

R¹³ and R¹⁴ each independently represent C_1-6alkyl optionally substituted with cyano or aminocarbonyl, C_2-6alkenyl optionally substituted with cyano or aminocarbonyl, C_2-6alkynyl optionally substituted with cyano or aminocarbonyl;

R¹⁵ represents C_1-6alkyl optionally substituted with cyano or aminocarbonyl;

R¹⁶ represents C_1-6alkyl optionally substituted with cyano or aminocarbonyl, or R⁷.

3. A compound according to claim 1 wherein the compound has the formula

4. A compound according to claim 3 wherein the compound has the formula

5. A compound according to claim 4 wherein the compound has the formula

6. A compound according to claim 5 wherein the compound has the formula

7. A compound according to claim 1 wherein the compound has the formula

8. A compound according to claim 7 wherein the compound has the formula

9. A compound according to claim 8 wherein the compound has the formula

10. A compound according to claim 9 wherein the compound has the formula

11. A compound according to claim 1 wherein

m is 1 or 2;

R⁴ represents halo;

C_1-6alkyl;

C_1-6alkyloxy; and

R³ represents cyano;

aminocarbonyl;

amino;

halo;

NHR¹³;

NR¹³R¹⁴;

—

C(═

O)—

NHR¹³;

—

C(═

O)—

NR¹³R¹⁴;

—

C(═

O)—

R¹⁵;

—

CH═

N—

NH—

C(═

O)—

R¹⁶;

C_1-6alkyl optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl, —

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl, —

C(═

O)—

O-polyhaloC_1-6alkyl or R⁷;

C_1-6alkyloxy optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl,

—

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl, —

C(═

O)—

O-polyhaloC_1-6alkyl or R⁷;

C_1-6alkyloxyC_1-6alkyl optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰,

—

C(═

O)—

C_1-6alkyl, —

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl,

—

C(═

O)—

O-polyhaloC_1-6alkyl or R⁷;

C_2-6alkenyl optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl, —

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl, —

C(═

O)-β

-polyhaloC_1-6alkyl or R⁷;

C_2-6alkynyl optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl, —

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl, —

C(═

O)—

O-polyhaloC_1-6alkyl or R⁷.

12. A compound according to claim 11 wherein R³ represents cyano;

aminocarbonyl;

C_1-6alkyl substituted with cyano or aminocarbonyl;

C_2-6alkenyl substituted with cyano or aminocarbonyl;

or C_2-6alkynyl substituted with cyano or aminocarbonyl.

13. A compound according to claim 1 wherein

n is 1 or 2;

R² represents halo;

C_1-6alkyl;

C_1-6alkyloxy; and

R^2a represents cyano;

aminocarbonyl;

amino;

halo;

NHR¹³;

NR¹³R¹⁴;

—

C(═

O)—

NHR¹³;

—

C(═

O)—

NR¹³R¹⁴;

—

C(═

O)—

R¹⁵;

—

CH═

N—

NH—

C(═

O)—

R¹⁶;

C_1-6alkyl optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl, —

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl, —

C(═

O)—

O-polyhaloC_1-6alkyl or R⁷;

C_1-6alkyloxy optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl,

—

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl, —

C(═

O)—

O-polyhaloC_1-6alkyl or R⁷;

C_1-6alkyloxyC_1-6alkyl optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰,

—

C(═

O)—

C_1-6alkyl, —

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl,

—

C(═

O)—

O-polyhaloC_1-6alkyl or R⁷;

C_2-6alkenyl optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl, —

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl, —

C(═

O)-β

-polyhaloC_1-6alkyl or R⁷;

C_2-6alkynyl optionally substituted with one or more substituents each independently selected from halo, cyano, hydroxy, NR⁹R¹⁰, —

C(═

O)—

NR⁹R¹⁰, —

C(═

O)—

C_1-6alkyl, —

C(═

O)—

O—

C_1-6alkyl, —

C(═

O)-polyhaloC_1-6alkyl, —

C(═

O)—

O-polyhaloC_1-6alkyl or R⁷.

14. A compound according to claim 13 wherein R^2a represents cyano;

aminocarbonyl;

C_1-6alkyl substituted with cyano or aminocarbonyl;

C_2-6alkenyl substituted with cyano or aminocarbonyl;

or C_2-6alkynyl substituted with cyano or aminocarbonyl.

15. A compound according to claim 1 wherein R^2a is cyano, aminocarbonyl, C_1-6alkyl substituted with cyano or aminocarbonyl, or C_2-6alkenyl substituted with cyano or aminocarbonyl.

16. A compound according to claim 1 wherein R³ is cyano, aminocarbonyl, C_1-6alkyl substituted with cyano or aminocarbonyl, or C_2-6alkenyl substituted with cyano or aminocarbonyl.

17. A compound as claimed in claim 1 wherein

n is 1, 2 or 3;

m is 1, 2 or 3;

R¹ represents hydrogen;

C_1-6alkyl optionally substituted with cyano, aminocarbonyl or hydroxy;

each R² independently represents hydrogen;

halo;

C_1-6alkyl;

or C_1-6alkyloxy;

R^2a represents cyano;

aminocarbonyl;

halo;

C_1-6alkyl optionally substituted with cyano or aminocarbonyl;

C_1-6alkyloxy optionally substituted with cyano or aminocarbonyl;

or C_2-6alkenyl optionally substituted with cyano or aminocarbonyl;

X₁ represents —

NR¹—

;

—

O—

;

—

S—

;

or —

S(═

O)_p—

;

X₂ represents —

NR¹—

;

—

O—

;

—

S—

;

or —

S(═

O)_p—

;

R³ represents cyano;

aminocarbonyl;

halo;

C_1-6alkyl optionally substituted with cyano or aminocarbonyl;

C_1-6alkyloxy optionally substituted with cyano or aminocarbonyl;

or C_2-6alkenyl optionally substituted with cyano or aminocarbonyl;

each R⁴ independently represents hydrogen;

halo;

C_1-6alkyl;

or C_1-6alkyloxy;

p is 2.

18. A compound according to claim 1 wherein R¹ represents hydrogen or C_1-6alkyl optionally substituted with R⁵.

19. A compound according to claim 1 wherein X₁ represents —

NR¹—

;

—

O—

;

—

S—

;

or —

S(═

O)_p—

.

20. A compound according to claim 1 wherein X₂ represents —

NR¹—

;

—

O—

;

—

S—

;

or —

S(═

O)_p—

.

21. A compound according to claim 1 wherein R⁵ represents cyano, aminocarbonyl or hydroxy.

22. The method of treating HIV infection comprising administering a therapeutically effective amount of a compound as claimed in claim 1 to a human in need of such treatment.

23. The method of treating drug or multidrug resistant HIV infection comprising administering a therapeutically effective amount of a compound as claimed in claim 1 to a human in need of such treatment.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound as claimed in claim 1.

25. A process for preparing a pharmaceutical composition according to claim 24 characterized in that a therapeutically effective amount of a compound as claimed therein is intimately mixed with a pharmaceutically acceptable carrier.