1,3,5-triazine derivatives of spiro bicyclic oxalamide-compounds for treatment of hepatitis C

Patent metadata

Field	Value
Publication number	US-8987264-B2
Application number	US-201314073963-A
Country	US
Kind code	B2
Filing date	Nov 7, 2013
Priority date	Nov 9, 2012
Publication date	Mar 24, 2015
Grant date	Mar 24, 2015

Abstract

Compounds of Formula I, including pharmaceutically acceptable salts, as well as compositions containing these compounds, have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV:

First claim

We claim:

1. A compound of Formula I, and pharmaceutically acceptable salts thereof:

wherein
R 1 is selected from alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl, wherein the benzyl moiety is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
R 2 is selected from alkyl, (Ar 2 )alkyl, (Ar 2 )cycloalkyl, ((Ar 2 )cycloalkyl)alkyl, ((Ar 2 )alkyl)cycloalkyl, and (((Ar 2 )alkyl)cycloalkyl)alkyl;
R 3 is hydrogen or alkyl;
R 4 is hydrogen or alkyl;
R 5 is selected from

R 6 is selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
R 7 is selected from alkyl, cycloalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, and a bridged bicycloalkyl, and is substituted with 0-4 substituents selected from halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO 2 R 9 , N(R 10 )(R 11 ), tetrahydrofuranyl, tetrahydropyranyl, and Ar 4 ;
or R 7 is hydrogen, N-alkoxycarbonylpiperidinyl, piperidinonyl, or Ar 3 ;
R 8 is hydrogen or alkyl;
or R 7 and R 8 taken together with the nitrogen to which they are attached is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl;
R 9 is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, and ((alkoxy)alkoxy)alkoxy;
R 10 is selected from hydrogen, alkyl, cycloalkyl, alkylcarbonyl, and alkoxycarbonyl;
R 11 is hydrogen or alkyl;
or R 10 and R 11 taken together with the nitrogen to which they are attached is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl;
R 12 is hydrogen or alkyl;
R 13 is selected from hydrogen, alkyl, cycloalkyl, alkylcarbonyl, and alkoxycarbonyl;
R 14 is hydrogen or alkyl;
or R 13 and R 14 taken together with the nitrogen to which they are attached is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl;
Ar 1 is phenyl substituted with 1 CO(R 5 ) and with 0-3 substituents selected from R 6 ;
Ar 2 is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar 3 is selected from phenyl, indanyl, fluorenyl, biphenyl, terphenyl, pyridinyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, thiadiazolyl, triazolyl, benzoxazolyl, indolinyl, and dibenzofuranyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkenyl, haloalkyl, cycloalkyl, (CO 2 R 12 )alkyl, (CO 2 R 12 )alkenyl, (CON(R 13 )(R 14 ))alkyl, phenyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, CO 2 R 12 , CON(R 13 )(R 14 ), and PhCONHSO 2 ;
or Ar 3 is phenyl substituted with 1 substituent selected from benzyl, tetrazolyloxy, thiazolyl, phenylpyrazolyl, methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl, tetrazolyl, pyridinyl, and dimethoxypyrimidinyl;
Ar 4 is selected from phenyl, indanyl, tetrahydronaphthyl, isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, imidazolyl, and triazolyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy, N(R 13 )(R 14 ), and alkylCO; and
wherein a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, and p are each independently hydrogen, alkyl, or cycloalkyl.

2. The compound of claim 1 wherein R 1 is haloalkyl.

3. The compound of claim 2 wherein R 1 is trifluoroethyl.

4. The compound of claim 1 wherein R 1 is haloalkyl; R 2 is (Ar 2 )alkyl or (Ar 2 )cycloalkyl; R 3 is hydrogen; R 4 is hydrogen; R 7 is alkyl, cycloalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, or a bridged bicycloalkyl, and is substituted with 0-4 substituents selected from halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO 2 R 9 , N(R 10 )(R 11 ), tetrahydrofuranyl, tetrahydropyranyl, and Ar 4 ; or R 7 is Ar 3 ; and Ar 1 is phenyl para-substituted with 1 CO(R 5 ).

5. The compound of claim 1 wherein R 2 is (Ar 2 )alkyl or (Ar 2 )cycloalkyl.

6. The compound of claim 1 wherein R 3 is hydrogen and R 4 is hydrogen.

7. The compound of claim 1 wherein R 7 is Ar 3 .

8. The compound of claim 1 wherein Ar 1 is phenyl para-substituted with 1 CO(R 5 ).

9. The compound of claim 1 wherein R 7 is alkyl, cycloalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, or a bridged bicycloalkyl, and is substituted with 0-4 substituents selected from halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO 2 R 9 , N(R 10 )(R 11 ), tetrahydrofuranyl, tetrahydropyranyl, and Ar 4 .

10. The compound of claim 4 or 9 wherein R 5 is

11. A pharmaceutical composition comprising one or more compounds of claim 1 , and a pharmaceutically acceptable carrier.

12. A method of treating hepatitis C infection in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 .

13. The compound, and pharmaceutically acceptable salts thereof, which is selected from the group of

14. A pharmaceutical composition comprising one or more compounds of claim 13 , and a pharmaceutically acceptable carrier.

Assignees

• Bristol Myers Squibb Co

Inventors

• Wang Tao
• Yin Zhiwei
• Scola Paul Michael

Classifications

• C07D487/10 Primary

  Spiro-condensed systems · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title