Spiroindolinone derivatives

1. A compound of the formula

wherein

X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy and vinyl,

one of R 1 and R 2 is selected from the group consisting of lower alkyl substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,

one of R 3 and R 4 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl; and substituted cycloalkenyl and the other is hydrogen,

R is selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl

or a pharmaceutically acceptable salt thereof.

2. A compound of the formula

wherein

X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl methoxy and vinyl,

one of R 1 and R 2 is selected from the group consisting of lower alkyl substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,

one of R 3 and R 4 is selected from the group consisting of lower alkyl substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,

R is selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl,

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 wherein

X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy and vinyl,

R 1 is hydrogen,

R 3 is hydrogen,

R 2 /R 4 is independently selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl and

R is selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl.

4. The compound of claim 3 wherein

X is chlorine or bromine,

R 4 is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of

and

R 2 is independently selected from the group consisting of lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkenyl and substituted cycloalkenyl.

5. A compound of claim 1 selected from the group consisting of

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-6′-(5-fluoro-2-methylphenyl)-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione;

Chiral (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-6′-(5-fluoro-2-methylphenyl)-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-6′-(5-fluoro-2-methylphenyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

Chiral (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

Chiral (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-2′-(3-dimethylaminopropyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-(2-methoxyethyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione and

racemic (6′R, 3R, 8′S)-2′-(2-acetoxyethyl)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione.

6. A compound of claim 1 selected from the group consisting of

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-(2-hydroxyethyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

Chiral (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-(2-hydroxyethyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1, 2, 4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-2′-(2-acetylaminoethyl)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-(2-hydroxycarbonyl-methyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-2′-(2-fluorocarbonyl-methyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-2′-[(2-hydroxyethylamino)carbonyl-methyl]6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

Chiral (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-[(2-hydroxyethylamino)carbonyl-methyl]N′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-2′-[(2-cyclopropylamino)carbonyl-methyl]-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

Chiral (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-[(2-cyclopropylamino)carbonyl-methyl]6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione and

racemic (6′R, 3R, 8′S)-2′-(2-aminocarbonyl-methyl)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione.

7. A compound of claim 1 selected from the group consisting of

racemic (6′R, 3R, 8′S)-2′-(2-aminocarbonyl-methyl)-6-chloro-8′-(3-chlorophenyl)-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-[(1-methanesulfonyl-piperidin-4-yl)aminocarbonyl-methyl]-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-2′-[(1-methanesulfonyl-piperidin-4-yl)aminocarbonyl-methyl]-6′-(1-methylene-propyl)-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-6′-isopropenyl-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

Chiral (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-6′-isopropenyl-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-6′-isopropenyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′S, 3R, 8′R)-6-chloro-8′-(3-chlorophenyl)-6′-isopropenyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6′-(2-allyloxy-5-iodo-phenyl)-6-chloro-8′-(3-chlorophenyl)-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione,

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-6′-(5-ethynyl-2-hydroxy-phenyl)-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dion,

racemic (6′R, 3R, 8′S)-6-8′-(3-chlorophenyl)-6′-[2-(2,3-dihydroxy-propoxy)-5-iodo-phenyl)-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione and

racemic (6′R, 3R, 8′S)-6-chloro-8′-(3-chlorophenyl)-6′-[2-(2,3-dihydroxy-propoxy)-5-ethynyl-phenyl)-2′-methyl-6′,7′,8′,9′-tetrahydro spiro[3H-indole-3,7′-(2H-pyrido[2,1-c][1,2,4]triazine)]-2,3′(1H)-dione.

8. A pharmaceutical formulation comprising a compound of the formula

wherein

X is selected from the group consisting of hydrogen, halogen, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, methoxy and vinyl,

one of R 1 and R 2 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,

one of R 3 and R 4 is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl and the other is hydrogen,

R is selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl,

or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient.