Mixed lineage kinase inhibitors and method of treatments

1. A compound having the structure of Formula I

or a pharmaceutically acceptable isomer, isotope, enantiomer, or salt thereof, wherein

J has a structure of

 substituted with up to R 10 ,

or J has a structure of

 optionally substituted with up to four R 10 ,

each R 10 is independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, —OH, and —OCOR 6 ;

X is NR 12 or S;

one of X 1 , X 2 , X 3 , and X 4 is N and the other three of X 1 , X 2 , X 3 , and X 4 are CH;

Y is —W—(CH 2 ) n —R 1 ,

W is null, phenylene, or —NR 6 -phenylene, where the NR 6 is attached to the imidazopyridazine core structure of Formula I;

R 1 is —NR 2 R 3 , or piperazinyl, where the nitrogen atom of the piperazinyl is optionally substituted with alkyl or alkoxy;

R 2 is H or alkyl;

R 3 is selected from the group consisting of C 2 -C 10 alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, where any atom of R 3 is optionally substituted with one or more R 7 ; or R 2 and R 3 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclic ring optionally substituted with R 8 ;

R 4 is H or alkyl;

R 5 is H, alkyl, or NHR 9 ;

R 6 is H or alkyl;

each R 7 is independently alkyl, cycloalkyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR 11 , or —O—(CH 2 ) m —OH;

R 8 is alkoxy, hydroxyalkyl, or COOR 11 ;

R 9 is H, alkyl, or cycloalkyl;

R 11 is H, or alkyl;

R 12 is H, or alkyl;

n is 0 or 1;

m is 1, 2, or 3; and

p is 1, 2, or 3;

with the proviso that if J is an unsubstituted benzothiophene, then R 3 is either aryl or heteroaryl, where any atom of R 3 is optionally substituted with one or more R 7 .

2. The compound of claim 1 wherein J is selected from the group consisting of

3. The compound of claim 1 wherein J is

wherein each R 10 is independently selected from the group consisting of F, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH 3 ; and k is 0, 1, 2, or 3.

4. The compound of claim 1 wherein J is

wherein each R 10 is independently selected from the group consisting of F, Cl, —OH, methyl, methoxy, ethoxy, propoxy, isopropoxy, and —OCOCH 3 ; and k is 0, 1, 2, or 3.

5. The compound of claim 4 wherein X 1 is N, and each of X 2 , X 3 , and X 4 is CH.

6. The compound of claim 4 wherein X 2 is N, and each of X 1 , X 3 , and X 4 is CH.

7. The compound of claim 4 wherein X 3 is N, and each of X 1 , X 2 , and X 4 is CH.

8. The compound of claim 4 wherein X 4 is N, and each of X 1 , X 2 , and X 3 is CH.

9. The compound of claim 1 wherein Y is —W—(CH 2 ) n —R 1 .

10. The compound of claim 9 wherein R 1 is —NR 2 R 3 .

11. The compound of claim 10 wherein R 3 is selected from the group consisting of C 2 -C 10 alkyl, aryl, and cycloalkyl.

12. The compound of claim 11 wherein R 3 is phenyl optionally substituted with one or more R 7 , wherein each R 7 is independently selected from the group consisting of hydroxyl, methoxy, —COOH, —O—(CH 2 ) m —OH, cyclopropylmethoxy, cyclopentylmethoxy, and isopropyl.

13. The compound of claim 12 wherein each R 7 is independently selected from the group consisting of methoxy, —COOH, and —O—(CH 2 ) 3 —OH.

14. The compound of claim 10 wherein R 3 is C 2 -C 10 alkyl, aryl, and cycloalkyl, where any atom of R 3 is optionally substituted with one or more R 7 .

15. The compound of claim 1 wherein the compound is selected from any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer, or isotope thereof.

16. The compound of claim 15 wherein the compound is selected from any of:

or any pharmaceutically acceptable salt, tautomer, stereoisomer, or isotope thereof.

17. A pharmaceutical composition comprising a compound having the structure of Formula I

or a pharmaceutically acceptable isomer, isotope, enantiomer, or salt thereof, wherein

J has a structure of

 substituted with up to four R 10 ,

or J has a structure of

 optionally substituted with up to four R 10 ,

each R 10 is independently selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, —OH, and —OCOR 6 ;

X is NR 12 or S;

one of X 1 , X 2 , X 3 , and X 4 is N and the other three of X 1 , X 2 , X 3 , and X 4 are CH;

Y is —W—(CH 2 ) n —R 1 ,

W is null, phenylene, or —NR 6 -phenylene, where the NR 6 is attached to the imidazopyridazine core structure of Formula I;

R 1 is —NR 2 R 3 , or piperazinyl, where the nitrogen atom of the piperazinyl is optionally substituted with alkyl or alkoxy;

R 2 is H or alkyl; R 3 is selected from the group consisting of C 2 -C 10 alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, where any atom of R 3 is optionally substituted with one or more R 7 ; or R 2 and R 3 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclic ring optionally substituted with R 8 ;

R 4 is H or alkyl;

R 5 is H, alkyl, or NHR 9 ;

R 6 is H or alkyl;

each R 7 is independently alkyl, cycloalkyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, perhaloalkoxy, halo, oxo, —OH, hydroxyalkyl, —COOR 11 , or —O—(CH 2 ) m —OH;

R 8 is alkoxy, hydroxyalkyl, or COOR 11 ;

R 9 is H, alkyl, or cycloalkyl;

R 11 is H, or alkyl;

R 12 is H, or alkyl;

n is 0 or 1;

m is 1, 2, or 3;

p is 1, 2, or 3; and

together with at least one pharmaceutically acceptable carrier, diluent or excipient.

18. A pharmaceutical composition of claim 17 wherein the compound is selected from any of compounds shown below:

Compound #

Structure

3

4

5

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

83

85

86

87

92

93

118

166

167

168

169

170

171

172

173

174

175

176

177

178

179

181

182

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

218

219

220

221

.

19. A pharmaceutical composition comprising the compound in any one of claims 1 - 4 and 5 - 16 and a suitable excipient.