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Claims for Patent: 8,178,563

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Claims for Patent: 8,178,563

Title:Compounds and compositions as hedgehog pathway modulators
Abstract: The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula I.
Inventor(s): Gao; Wenqi (San Diego, CA), Jiang; Jiqing (San Diego, CA), Wan; Yongqin (Irvine, CA), Cheng; Dai (San Diego, CA), Han; Dong (San Diego, CA), Wu; Xu (San Diego, CA), Pan; Shifeng (San Diego, CA)
Assignee: IRM LLC (Hamilton, BM)
Application Number:12/299,290
Patent Claims: 1. A compound of Formula I: ##STR00156## or a pharmaceutically acceptable salt or stereoisomer thereof, in which: R.sub.1 is selected from cyano, C.sub.1-6alkyl, halosubstituted-C.sub.1-6alkyl, C.sub.1-6alkoxy, halosubstituted-C.sub.1-6alkoxy, dimethyl-amino, C.sub.1-6alkyl-sulfanyl and C.sub.3-8heterocycloalkyl optionally substituted with up to two C.sub.1-6alkyl radicals; R.sub.2 and R.sub.5 are independently selected from hydrogen, cyano, halo, C.sub.1-6alkyl, halosubstituted-C.sub.1-6alkyl, C.sub.1-6alkoxy, halosubstituted-C.sub.1-6alkoxy and dimethylamino; R.sub.3 and R.sub.4 are independently selected from hydrogen, halo, cyano, C.sub.1-6alkyl, halosubstituted-C.sub.1-6alkyl, C.sub.1-6alkoxy and halosubstituted-C.sub.1-6alkoxy; R.sub.6 and R.sub.7 are independently selected from hydrogen, fluoro, chloro, bromo, C.sub.1-6alkyl, halosubstituted-C.sub.1-6alkyl, C.sub.1-6alkoxy and halosubstituted-C.sub.1-6alkoxy; with the proviso that R.sub.6 and R.sub.7 are not both hydrogen; R.sub.8 is selected from hydrogen, halo, C.sub.1-6alkyl, halosubstituted-C.sub.1-6alkyl, C.sub.1-6alkoxy and halosubstituted-C.sub.1-6alkoxy; R.sub.9 is selected from --S(O).sub.2R.sub.11, --OR.sub.11, --C(O)R.sub.11, --NR.sub.12aR.sub.12b and --R.sub.11; wherein R.sub.11 is selected from thiomorpholino, sulfonomorpholino, morpholino, cyclohexyl, phenyl, azepan-1-yl, 2-oxopiperazin-1-yl, 1,4-oxazepan-4-yl, piperidin-1-yl, tetrahydro-2H-pyran-4-yl, piperidin-3-yl, piperazinyl, pyrrolidinyl and 1,4-diazepan-1-yl; R.sub.12a and R.sub.12b are independently selected from isobutyl, hydroxy-ethyl, wherein said thiomorpholino, sulfonomorpholino, morpholino, cyclohexyl, phenyl, azepan-1-yl, 2-oxopiperazin-1-yl, 1,4-oxazepan-4-yl, piperidin-1-yl, tetrahydro-2H-pyran-4-yl, piperidin-3-yl, piperazinyl, pyrrolidinyl or 1,4-diazepan-1-yl of R.sub.9 can be optionally substituted with 1 to 3 radicals independently selected from methyl, ethyl, methoxy, benzyl, thienyl-methyl, pyridinyl-methyl, benzo[d][1,3]dioxo1-6-yl and 2,3-dihydrobenzo[b][1,4]dioxin-7-yl; wherein said benzyl substituent of R.sub.9 is optionally substituted with 1 to 3 radicals independently selected from methoxy, ethoxy, methyl-piperazinyl, methyl, trifluoromethoxy, chloro, fluoro and trifluoromethyl.

2. The compound of claim 1 in which: R.sub.6 and R.sub.7 are independently selected from hydrogen methyl, chloro, fluoro, bromo, trifluoromethyl and methoxy; with the proviso that R.sub.6 and R.sub.7 are not both hydrogen; and R.sub.8 is selected from hydrogen, fluoro, chloro, methyl and trifluoromethyl.

3. The compound of claim 2 in which: R.sub.1 is selected from cyano, methyl, ethyl, t-butyl, propyl, isobutyl, isopropyl, isopropyloxy, butoxy, methoxy, dimethyl-amino, ethoxy, methyl-sulfanyl, trifluoromethyl, trifluoromethoxy and piperazinyl optionally substituted with up to 2 methyl radicals; R.sub.2 and R.sub.5 are independently selected from hydrogen, chloro, fluoro, cyano, methyl, trifluoromethyl, isopropyloxy, methoxy, ethoxy, trifluoromethoxy and dimethylamino; and R.sub.3 and R.sub.4 are independently selected from hydrogen, chloro, methyl, methoxy and cyano.

4. The compound of claim 3 in which R.sub.8 is hydrogen.

5. A compound of claim 1 selected from the group consisting of: N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoro- methoxy)-[1,1'-biphenyl]-3-carboxamide, 4'-cyano-6-methyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Cyano-2-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Methoxy-2-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Methoxy-2-methyl-biphenyl-3-carboxylic acid [6-(2-methyl-morpholin-4-yl)-pyridin-3-yl]-amide, 6-Chloro-4'-dimethylamino-biphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide, 6-Chloro-4'-dimethylamino-biphenyl-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide, 6-Chloro-4'-dimethylamino-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 6-Chloro-4'-methoxy-biphenyl-3-carboxylic acid [6-(2-methyl-morpholin-4-yl)-pyridin-3-yl]-amide, 6-Chloro-4'-methoxy-biphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide, 6-Chloro-4'-methoxy-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 6-Chloro-4'-methoxy-biphenyl-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide, 4'-Methoxy-6-methyl-biphenyl-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide, 4'-Methoxy-6-methyl-biphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide, 4'-Methoxy-6-methyl-biphenyl-3-carboxylic acid [6-(2-methyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Dimethylamino-6-methyl-biphenyl-3-carboxylic acid [6-(2-methyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Dimethylamino-6-methyl-biphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide, 4'-Dimethylamino-6-methyl-biphenyl-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide, 4'-Methoxy-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Ethoxy-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 6-Methyl-4'-methylsulfanyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Dimethylamino-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 3'-Chloro-6-methyl-4'-trifluoromethyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 6,4'-Dimethyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Ethyl-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-tert-Butyl-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 6-Methyl-4'-propyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Isobutyl-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Isopropyl-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 6-Methyl-4'-trifluoromethyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 6-Methyl-4'-trifluoromethoxy-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid (6-[1,4]oxazepan-4-yl-pyridin-3-yl)-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(2-methyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl)-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methoxy-biphenyl-3-carboxylic acid (6-azepan- 1-yl-pyridin-3-yl)-amide, 4'-Cyano-2-methoxy-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Cyano-2-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 3'-Fluoro-4'-methoxy-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Isopropoxy-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Butoxy-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 3'-Chloro-4'-methoxy-6-methyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Methoxy-6,3'-dimethyl-biphenyl-3-carboxylic acid (6-azepan-1-yl-pyridin-3-yl)-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-benzyl-[1,4]diazepan-1-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-thiophen-3-ylmethyl-[1,4]diazepan-1-yl)-pyridin-3-yl]-amide, 4'-Cyano-2-methyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Methoxy-2-methyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, 2-Methyl-4'-trifluoromethyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, 2-Methyl-4'-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Cyano-2-methyl-biphenyl-3-carboxylic acid [6-(2-methyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-pyridin-4-ylmethyl-[1,4]diazepan-1-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-pyridin-3-ylmethyl-[1,4]diazepan-1-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(2,6-dimethoxy-benzyl)-[1,4]diazepan-1-yl]-pyridin-3yl}-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(2-ethoxy-benzyl)-[1,4]diazepan- 1-yl]-pyridin-3}-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid (6-{4-[2-(4-methyl-piperazin-1-yl)-benzyl]-[1,4]diazepan-1-yl}-pyridin-3-- yl)-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(4-methoxy-2,3-dimethyl-benzyl)-[1,4]diazepan-1-yl]-pyridin-3-yl}-a- mide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-pyridin-2-ylmethyl-[1,4]diazepan-1- yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(2-trifluoromethoxy-benzyl)-[1,4]diazepan-1-yl]-pyridin-3-yl}-amide- , 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(2-chloro-5-trifluoromethyl-benzyl)-[1,4]diazepan-1-yl]-pyridin-3-y- l}-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(2,3-difluoro-benzyl)-[1,4]diazepan-1-yl]-pyridin-3-yl}-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(2-chloro-4-fluoro-benzyl)-[1,4]diazepan-1-yl]-pyridin-3-yl}-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(2,6-difluoro-benzyl)-[1,4]diazepan-1-yl]-pyridin-3-yl}-amide, 4'-Cyano-6-trifluoromethyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, 2-Chloro-4'-cyano-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-ethyl-biphenyl-3-carboxylic acid [6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(3-fluoro-benzyl)-piperazin-1-yl]-pyridin-3-yl}-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(2-trifluoromethoxy-benzyl)-piperazin-1-yl]-pyridin-3-yl}-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid {6-[4-(3-chloro-benzyl)-piperazin-1-yl]-pyridin-3-yl}-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-benzyl-piperazin-1-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-3-yl]-amide, 4'-Cyano-6-methyl-biphenyl-3-carboxylic acid [6-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyridin-3-yl]-amide, (R)-2-methyl-N-(6-(2-methylmorpholino)pyridin-3-yl)-4'-(trifluoromethoxy)- biphenyl-3-carboxamide, 4'-cyano-2-methyl-N-(6-sulfonylmorpholinopyridin-3-yl)biphenyl-3-carboxam- ide, (S)-4'-cyano-2-methyl-N-(6-(2-methylmorpholino)pyridin-3-yl)biphenyl-- 3-carboxamide, (R)-6-chloro-N-(6-(2-methylmorpholino)pyridin-3-yl)-4'-(trifluoromethoxy)- biphenyl-3-carboxamide, 2-methyl-N-(6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)-4'-(trifluoromet- hoxy)biphenyl-3-carboxamide, N-(6-(4-ethylpiperazine-1-carbonyl)pyridin-3-yl)-2-methyl-4'-(trifluorome- thoxy)biphenyl-3-carboxamide, 2-methyl-N-(6-(2-oxopiperazin-1-yl)pyridin-3-yl)-4'-(trifluoromethoxy)bip- henyl-3-carboxamide, 2-methyl-N-(6-(2-oxo-4-(pyridin-4-ylmethyl)piperazin-1-yl)pyridin-3-yl)-4- '-(trifluoromethoxy)biphenyl-3-carboxamide; 2-methyl-N-(6-(1-(pyridin-4-ylmethyl)piperidin-3-yl)pyridin-3-yl)-4'-(tri- fluoromethoxy)biphenyl-3-carboxamide, and N-(6-(1-ethylpiperidin-3-yl)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)b- iphenyl-3-carboxamide, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. A method of inhibiting the hedgehog pathway in a cell, comprising contacting the cell with a compound of claim 1.

7. The method of claim 6 wherein the cell has a phenotype of Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function.

8. The method of claim 6, wherein the compound is administered to an animal as part of a therapeutic application, wherein the therapeutic application is selected from pancreatic cancer, prostate cancer, medulloblastoma, basal cell carcinoma, and small-cell lung cancer.

9. A method for inhibiting unwanted proliferation of a cell, comprising contacting the cell with a compound of claim 1, wherein the cell is selected from pancreatic cancer, prostrate cancer, medulloblastoma, basal cell carcinoma and small-cell lung cancer.

10. A compound, N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoro- methoxy)[1,1'-biphenyl]-3-carboxamide, of the formula: ##STR00157## or a pharmaceutically acceptable salt thereof.

11. A compound, N-(6((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluorom- ethoxy)-[1,1'-biphenyl]-3-carboxamide, of the formula: ##STR00158## or a pharmaceutically acceptable salt or stereoisomer thereof.

12. A compound, N-(6((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluorom- ethoxy)-[1,1'-biphenyl]-3-carboxamide, of the formula: ##STR00159##
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