Compounds and compositions as hedgehog pathway inhibitors
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Abstract
The invention provides a method, compounds and compositions 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 GIi gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula (I).
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Citations
18 Claims
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1. A compound having the structure of Formula I:
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18)
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2. The compound of claim 1, wherein R1 is H.
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3. The compound of claim 2, wherein
Q1 is selected from phenyl, pyrazolyl, pyrrolyl, imidazolyl, benzimidazolyl, benzoxazolyl, purinyl, thiazolyl, oxazolyl, pyridinyl, indolyl, thiazolo[5,4-d]pyrimidinyl, 1H-imidazo[4,5-c]pyridinyl, pyrimidinyl pyridazinyl, pyrazinyl, quinolinyl and isoquinolinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from R9 and R13. -
4. The compound of claim 3, wherein
L1 is a bond, and Q1 is selected from phenyl, imidazolyl, benzimidazolyl, benzoxazolyl, purinyl, thiazolo[5,4-d]pyrimidinyl, oxazolyl, pyrazolyl, pyridinyl, 1H-imidazo[4,5-c]pyridinyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl and isoquinolinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from R9 and R13; -
or L1 is —
O—
, —
O(CR14R14)m—
, —
(CR14R14)mO—
or —
C(O)NR16—
, and Q1 is selected from phenyl and pyridinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from R9 and R13.
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5. The compound of claim 4, wherein
L2 is a bond, and each R6 is independently selected from H, S(O)R13, SO2R13, SO2NR16R17, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, heteroaryl, heterocycloalkyl, -
6. The compound of claim 5, wherein
L2 is a bond, and each R6 is independently selected from H, S(O)R13, SO2R13, SO2NR16R17, C1-C6alkyl, C1-C6haloalkyl, cyclopropyl, cyclohexyl, cycloheptyl, -
7. The compound of claim 6, wherein each R9 is independently selected from H, CN, F, Cl, methyl, ethyl, isopropyl, tert-butyl, —
- CF3, —
OCH3, —
OCH2CH3, —
OCF3, L3OR13, L3NR16R17, L3R13, L3R14, pyridinyl, pyrimidinyl, thiazolyl, furanyl, tetrazolyl and phenyl optionally substituted with 1 to 2 substituents selected from CN, L3NR16R17 and OR13,wherein the pyridinyl, pyrimidinyl, thiazolyl, furanyl and tetrazolyl are optionally substituted with 1 to 2 substituents selected from C1-C6alkyl, L3NR16R17 and L3OR13.
- CF3, —
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8. The compound of claim 7, wherein each R13 is independently selected from H, C1-C6alkyl and heteroaryl,
where the heteroaryl of R13 are optionally substituted with 1 to 3 substituents selected from C1-C6alkyl and C1-C6alkyl substituted with 1-4 — - OH groups.
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9. The compound of claim 8, wherein each R13 is independently selected from H, methyl, ethyl, isopropyl, tert-butyl and pyrazolyl.
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10. The compound of claim 9, wherein each R14 and R15 are independently selected from H, F methyl ethyl, OH and CN.
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11. The compound of claim 10, wherein each R16 and R17 are independently selected from H, methyl, ethyl and C1-C6alkyl substituted with 1-4 —
- OH groups.
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12. The compound of claim 11, wherein R2 and R3 are each H, and R4 is H or —
- C(O)N(CH3)2.
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13. The compound of claim 12, wherein each R5 is independently selected from H, Cl, F, CN, methyl, methoxy, —
- OCF3, —
CH2OH, —
C(O)OH, —
CH2N(CH3)2 and —
C(O)NHCH3.
- OCF3, —
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14. The compound of claim 13, wherein each R is —
- Cl or methyl.
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15. The compound of claim 14, wherein Y1 is CH;
- Y2 is CH;
Y3 is CH;
Y4 is CH;
Y5 is CH;
Y6 is CH and Y7 is N.
- Y2 is CH;
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16. The compound of claim 1, selected from
4-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-1-1{4}-thian-1-one; -
1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one; 4-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiane-1,1-dione; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(1H-1,3-benzodiazol-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(1-ethylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-methanesulfonylethan-1-one; (2R)-1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-hydroxypropan-1-one; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dihydroxypropan-1-one; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-hydroxypropan-1-one; 1-[4-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)piperidin-1-yl]ethan-1-one; 4-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thian-1-one; 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinoline-2-sulfonamide; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-3-hydroxy-2,2-dimethylpropan-1-one; 2-methanesulfonyl-N-[3-(5-methoxy-1H-1,3-benzodiazol-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-{4-chloro-3-[6-(dimethylamino)-1H-1,3-benzodiazol-2-yl]phenyl}-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-[(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinoline-2-sulfonyl)amino]ethan-1-ol; (2R)-3-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propane-1,2-diol; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-methanesulfinylethan-1-one; (2S)-1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-hydroxypropan-1-one; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-cyclohexyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-hydroxyethan-1-one; 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-N-methyl-1,2,3,4-tetrahydroisoquinoline-2-sulfonamide; 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-2-oxido-2-(1-oxo-thian-4-yl)-1,2,3,4-tetrahydroisoquinolin-2-ium; (2S)-1-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dihydroxypropan-1-one; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(oxan-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-cycloheptyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(pentan-3-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-2-(1-ethylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-one; 2-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propane-1,3-diol; 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-2-[(2S)-2,3-dihydroxypropyl]-1,2,3,4-tetrahydroisoquinolin-1-one; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-[1-(propan-2-yl)piperidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-5-amine; (2R)-1-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dihydroxypropan-1-one; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(oxan-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propane-1,2-diol; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-N-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxamide; 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinoline-2-carboxamide; 3-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-3-oxopropanoic acid; tert-butyl 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinoline-2-carboxylate; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(propan-2-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(3-methanesulfinylpropyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; (2S,3S)-4-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)butane-1,2,3-triol; 4-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-1-oxidopyridin-1-ium; 3-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)propanoic acid; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-[5-({4-methyl-3-[5-(pyridin-3-yl)-1H-imidazol-2-yl]phenyl}amino)-1,2,3,4-tetrahydroisoquinolin-2-yl]-thiane-1,1-dione; 2-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)acetic acid; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-{2-[(dimethylamino)methyl]-2-methylpropyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-methylpropan-1-one; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-one; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propanoic acid; 2-methanesulfonyl-N-[4-methyl-3-{5-(pyrimidin-5-yl)-1H-imidazol-2-yl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-{5-(pyridin-3-yl)-1H-imidazol-2-yl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(5-fluoro-1H-1,3-benzodiazol-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(7H-purin-8-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2-difluoropropanoic acid; 2-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-methylpropanoic acid; 2-[(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]-2-ethylbutanoic acid; 3-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2-dimethyl-3-oxopropanoic acid; 1-[(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]cyclopropane-1-carboxylic acid; 1-[(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]cyclobutane-1-carboxylic acid; 1-(5-{[3-(1H-1,3-benzodiazol-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one; 3-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2-difluoropropan-1-ol; 1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-hydroxyethan-1-one; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-[(1-methylcyclopropyl)carbonyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 1-[(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl]cyclopropan-1-ol; 4-[5-({4-methyl-3-[5-(pyridin-3-yl)-1H-imidazol-2-yl]phenyl}amino)-1,2,3,4-tetrahydroisoquinolin-2-yl]-thiane-1,1-dione; 3-hydroxy-2-(hydroxymethyl)-2-methyl-1-[5-({4-methyl-3-[5-(pyridin-3-yl)-1H-imidazol-2-yl]phenyl}amino)-1,2,3,4-tetrahydroisoquinolin-2-yl]propan-1-one; 2-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)propanoic acid; (2R)-2-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propanoic acid; (2S)-2-(5-{[4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propanoic acid; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(1-methylcyclopropyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-{[3-(1H-1,3-benzodiazol-2-yl)-4-methylphenyl]amino}-2-[(2S)-2,3-dihydroxypropyl]-1,2,3,4-tetrahydroisoquinolin-1-one; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoacetic acid; [1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclopropyl]methanol; 3-(5-{[3-(1H-1,3-benzodiazol-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2-difluoropropan-1-ol; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(2H-1,2,3,4-tetrazol-5-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-(2H-1,2,3,4-tetrazol-5-yl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-2-[1-(hydroxymethyl)cyclopropyl]-1,2,3,4-tetrahydroisoquinolin-1-one; [1-(5-{[3-(1H-1,3-benzodiazol-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclopropyl]methanol; 4-{3-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}benzonitrile; 2-methanesulfonyl-N-{4-methyl-3-[5-(6-methylpyridin-3-yl)-1H-imidazol-2-yl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; [1-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclopropyl]methanol; (2S)-3-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propane-1,2-diol; 2-methanesulfonyl-N-{4-methyl-3-[5-(methylamino)pyrimido[5,4-d][1,3]thiazol-2-yl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-[(1-methylcyclopropyl)methyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-chloro-3-(4-phenyl-1,3-oxazol-2-yl)phenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(1H-1,3-benzodiazol-2-yl)-4-methylphenyl]-2-[(1-methylcyclopropyl)methyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(6-methoxypyridin-3-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(4-methoxyphenyl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-{3-[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]-4-methylphenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-(2-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}-1H-imidazol-5-yl)benzonitrile; 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}benzonitrile; N-{3-[6-(dimethylamino)-1H-imidazo[4,5-c]pyridin-2-yl]-4-methylphenyl}-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-{3-[5-(6-methoxypyridin-2-yl)-1H-imidazol-2-yl]-4-methylphenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(1,3-benzoxazol-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(5-{4-[(dimethylamino)methyl]phenyl}-1H-imidazol-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-(3-{5-[2-(dimethylamino)pyrimidin-5-yl]-1H-imidazol-2-yl}-4-methylphenyl)-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-(3-{4-[(dimethylamino)methyl]phenyl}-4-methylphenyl)-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(4-phenylphenyl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-(3-{6-methoxy-1H-imidazo[4,5-c]pyridin-2-yl}-4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[5-(1H-1,3-benzodiazol-2-yl)-6-methylpyridin-3-yl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-(5-{[2-(2,2-difluoro-3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-2-methylphenyl)benzonitrile; N-[3(4-tert-butylphenyl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 1-(4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}phenyl)ethan-1-one; 2-methanesulfonyl-N-(4-methyl-3-phenylphenyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-{4-methyl-3-[4-(propan-2-yl)phenyl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-{4-methyl-3-[4(1H-pyrazol-1-ylmethyl)phenyl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}benzonitrile; 2-methanesulfonyl-N-{4-methyl-3-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; N-{3-[4-(furan-2-yl)phenyl]-4-methylphenyl}-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(4-fluorophenyl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-(4-methyl-3-phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-{3-[2-(dimethylamino)pyrimidin-5-yl]-4-methylphenyl}-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[4-(1H-1,3-benzodiazol-2-yl)-5-chloropyridin-2-yl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-{[3-(1H-1,3-benzodiazol-2-yl)-4-methylphenyl]amino}-2-[(1-methylcyclopropyl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one; 2-methanesulfonyl-N-[4-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}pyridine-2-carbonitrile; N-[3-(benzyloxy)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-{2-fluoro-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]phenyl}benzonitrile; 4-{3-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]phenyl}benzonitrile; 4-{2-chloro-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]phenyl}benzonitrile; 3-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}-N-methylbenzamide; 2-methanesulfonyl-N-{4-methyl-3-[4-(trifluoromethyl)phenyl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-{4-methyl-3-[4-(trifluoromethoxy)phenyl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}-N,N-dimethylbenzamide; 2-(4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}phenyl)acetonitrile; 2-methanesulfonyl-N-{4-methyl-3-[3-(pyrrolidin-1-ylcarbonyl)phenyl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; methyl 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}benzoate 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}benzamide; 2-methanesulfonyl-N-{4-methyl-3-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}benzoic acid; N-(2-hydroxyethyl)-4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}benzamide; N-(2,3-dihydroxypropyl)-4-[5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl]benzamide; N,N-bis(2-hydroxyethyl)-4-[5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl]benzamide; N-(2-hydroxypropyl)-4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}benzamide; 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methoxyphenyl}benzonitrile; 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-(trifluoromethoxy)phenyl}benzonitrile; N-[3-(1H-indol-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(1-methyl-1H-indol-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-{4-methyl-3-[5-(trifluoromethyl)pyridin-2-yl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 6-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}pyridine-3-carbonitrile; 2-(4-cyanophenyl)-4-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]benzonitrile; (4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}phenyl)methanol; 3-{[(4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}-phenyl)methyl]amino}propane-1,2-diol; 2-{[(4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}-phenyl)methyl]amino}ethan-1-ol; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-phenylbenzamide; N-(4-cyanophenyl)-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylbenzamide; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-N-(4-methoxyphenyl)-2-methylbenzamide; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-(pyridin-2-yl)benzamide; 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}-3-methylbenzonitrile; N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(6-methoxypyridin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenoxymethyl}benzonitrile; 2-methanesulfonyl-N-{4-methyl-3-[5-(trifluoromethyl)pyridin-2-yl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-{3-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]phenyl}-3-methylbenzonitrile; 2-methanesulfonyl-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(6-methylpyridazin-3-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-{5-chloro-2-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pyridin-4-yl}benzonitrile; 2-(4-cyanophenyl)-4-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]benzoic acid; N-[3-(5-chloropyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(5-methoxypyridin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-{2-chloro-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pyridin-3-yl}benzonitrile; 2-methanesulfonyl-N-[3-(5-methoxypyrimidin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 6-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}pyridine-3-carbonitrile; 4-[2-(hydroxymethyl)-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]phenyl]benzonitrile; 4-{2-[(dimethylamino)methyl]-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]phenyl}benzonitrile; 2-(4-cyanophenyl)-4-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-N-methylbenzamide; 1-(5-{[3-(5-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-methylpropan-2-ol; 2-(2-fluoro-2-methylpropyl)-N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-[4-(trifluoromethyl)phenyl]benzamide; N-(4-fluorophenyl)-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylbenzamide; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-(4-methylphenyl)benzamide; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-[4-(trifluoromethoxy)phenyl]benzamide; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-phenylbenzamide; 2-methanesulfonyl-N-[4-methyl-3-(pyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(5-methoxypyrazin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(6-methylpyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(4-methylpyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-N,2-dimethyl-N-phenylbenzamide; N-(2-hydroxyethyl)-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-phenylbenzamide; (2S)-3-(5-{[3-(5-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propane-1,2-diol; 6-(2-methyl-5-{[2-(3,3,3-trifluoropropyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-phenyl)pyridine-3-carbonitrile; N-{3-[(dimethylamino)methyl]-5-(5-fluoropyridin-2-yl)-4-methylphenyl}-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 6-(5-{[2-(2-fluoro-2-methylpropyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-2-methylphenyl)pyridine-3-carbonitrile; 6-(5-{[2-(2-hydroxy-2-methylpropyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-2-methylphenyl)pyridine-3-carbonitrile; 2-(2-fluoro-2-methylpropyl)-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methyl-1-(5-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propan-2-ol; N-[5-(5-fluoropyridin-2-yl)-6-methylpyridin-3-yl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-chloro-2-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-N-phenylpyridine-4-carboxamide; 2-methanesulfonyl-N-[3-(5-methoxypyridin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-{2-chloro-5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]pyridin-3-yl}benzonitrile; N-[3-(5-chloropyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 6-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}pyridazine-3-carbonitrile; 5-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}pyrazine-2-carbonitrile; (2S)-3-(5-{[4-methyl-3-(6-methylpyridazin-3-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propane-1,2-diol; (2S)-3-(5-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propane-1,2-diol; 6-(5-{[2-(2,2-difluoro-3-hydroxypropyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-2-methylphenyl)pyridine-3-carbonitrile; 2,2-difluoro-3-(5-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)propan-1-ol; 2-(2,2-dimethylpropyl)-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(pyridin-2-yloxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(pyridin-2-ylmethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(5-methylpyrimidin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(4-fluoropyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(6-fluoropyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(4-methylpyrimidin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(5-fluoropyrimidin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-{[2-(2-fluoro-2-methylpropyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-2-methyl-N-phenylbenzamide; 5-{[2-(2-hydroxy-2-methylpropyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-2-methyl-N-phenylbenzamide; 2-(2-methanesulfonylethyl)-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(2,2-difluoropropyl)-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-phenylpyridine-3-carboxamide; 3-chloro-6-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-N-phenylpyridine-2-carboxamide; N-[3-(3-fluoropyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(3-fluoro-5-methylpyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(isoquinolin-3-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(4-methoxypyridin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[4-methyl-3-(quinolin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N,N-dimethyl-2-(5-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)acetamide; 4-(5-{[3-(5-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiane-1,1-dione; 4-(5-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiane-1,1-dione; 2-methanesulfonyl-N-{4-methyl-3-[(pyridin-2-yloxy)methyl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methyl-N-[4-(trifluoromethyl)phenyl]benzamide; 2-methanesulfonyl-N-[3-(4-methoxypyrimidin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(5-methoxypyrazin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(4,5-dimethylpyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-chloro-6-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-N-phenylpyridine-2-carboxamide; 6-(5-{[2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-2-methylphenyl)pyridine-3-carbonitrile; 5-{[2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]amino}-2-methyl-N-phenylbenzamide; 3-(5-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 3-(5-{[3-(5-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-2-(3,3,3-trifluoropropyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-2-(3,3,3-trifluoropropyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-{3-[5-(dimethylamino)pyrazin-2-yl]-4-methylphenyl}-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(5-fluoropyrimidin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-{3-[6-(dimethylamino)pyridazin-3-yl]-4-methylphenyl}-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[3-(6-methoxypyrazin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; N-[3-(5-chloropyridin-2-yl)-4-methylphenyl]-2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(2-methanesulfonylethyl)-N-[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(2-methanesulfonylethyl)-N-{4-methyl-3-[5-(trifluoromethyl)pyridin-2-yl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(3-fluoropyridin-2-yl)-4-methylphenyl]-2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-[2-(ethanesulfonyl)ethyl]-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(2-methanesulfonylethyl)-N-[4-methyl-3-(pyridin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(2-methanesulfonylethyl)-N-[4-methyl-3-(5-methylpyrimidin-2-yl)phenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(2-methanesulfonylethyl)-N-[3-(5-methoxypyrazin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[4-methyl-3-(pyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 3-(5-{[3-(5-methoxypyrazin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 3-(5-{[4-methyl-3-(5-methylpyrimidin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 3-(5-{[3-(3-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 4-(5-{[3-(3-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiane-1,1-dione; 2-methanesulfonyl-N-[3-(5-methoxypyridazin-3-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(3,5-difluoropyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[5-chloro-6-(5-methylpyridin-2-yl)pyridin-2-yl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[5-methyl-6-(5-methylpyridin-2-yl)pyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[3-(3-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; 3-(5-{[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; N-[5-chloro-6-(5-methylpyridin-2-yl)pyridin-2-yl]-2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; (3R)-3-(5-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; (3S)-3-(5-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 2-[2-(ethanesulfonyl)ethyl]-N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-[2-(ethanesulfonyl)ethyl]-N-[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-[2-(ethanesulfonyl)ethyl]-N-[3-(3-fluoropyridin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(2-methanesulfonylethyl)-N-{4-methyl-3-[5-(trifluoromethyl)pyridin-2-yl]phenyl}-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[5-methyl-6-(5-methylpyridin-2-yl)pyridin-2-yl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; (3S)-3-(5-{[3-(3-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; (3R)-3-(5-{[3-(3-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; N-[3-(5-chloro-3-fluoropyridin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-{3-[5-(dimethylamino)pyridin-2-yl]-4-methylphenyl}-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]-2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; 3-(5-{[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 2-[2-(ethanesulfonyl)ethyl]-N-[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[5-chloro-6-(5-fluoropyridin-2-yl)pyridin-2-yl]-2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[5-chloro-6-(5-fluoropyridin-2-yl)pyridin-2-yl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(isoquinolin-3-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 4-(5-{[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiane-1,1-dione; 3-(5-{[3-(5-ethoxypyrazin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 2-(2-methanesulfonylethyl)-N-[5-methyl-6-(5-methylpyridin-2-yl)pyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(5-ethoxypyrazin-2-yl)-4-methylphenyl]-2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-(2-methanesulfonylethyl)-N-[5-methyl-6-(pyridin-2-yl)pyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 2-methanesulfonyl-N-[5-methyl-6-(pyridin-2-yl)pyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[3-(5-ethoxypyrazin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; N-[3-(5-ethoxypyrazin-2-yl)-4-methylphenyl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[3-(isoquinolin-3-yl)-4-methylphenyl]-2-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[3-(isoquinolin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; 3-(5-{[5-chloro-6-(5-methylpyridin-2-yl)pyridin-2-yl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; 2-(ethanesulfonyl)-N-[6-(6-methoxypyridazin-3-yl)-5-methylpyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[6-(6-methoxypyridazin-3-yl)-5-methylpyridin-2-yl]-2-(propane-2-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; (3R)-3-(5-{[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; (3S)-3-(5-{[3-(6-methoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 3-(5-{[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 3-(5-{[3-(isoquinolin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 3-(5-{[3-(3,5-difluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; 3-(5-{[3-(3,5-difluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 4-(5-{[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiane-1,1-dione; N-[6-(6-ethoxypyridazin-3-yl)-5-methylpyridin-2-yl]-2-(propane-2-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[6-(6-ethoxypyridazin-3-yl)-5-methylpyridin-2-yl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thietane-1,1-dione; 2-(ethanesulfonyl)-N-[6-(5-ethoxypyrazin-2-yl)-5-methylpyridin-2-yl]-1,2,3,4-tetrahydroisoquinolin-5-amine; N-[6-(5-ethoxypyrazin-2-yl)-5-methylpyridin-2-yl]-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[6-(6-ethoxypyridazin-3-yl)-5-methylpyridin-2-yl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; 4-(5-{[3-(5-ethoxypyrazin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiane-1,1-dione; N-[6-(5-ethoxypyrazin-2-yl)-5-methylpyridin-2-yl]-2-(propane-2-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; 3-(5-{[3-(3,5-difluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; (3R)-3-(5-{[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; (3S)-3-(5-{[3-(6-ethoxypyridazin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; (3R)-3-(5-{[3-(3-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; (3S)-3-(5-{[3-(3-fluoropyridin-2-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)-thiolane-1,1-dione; N-(4-chloro-3-(4-phenyl-1H-imidazol-2-yl)phenyl)-2-(1-ethylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine; and N-(3-(isoquinolin-3-yl)-4-methylphenyl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-amine.
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18. A pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) of claim 1 and one or more pharmaceutically acceptable excipients.
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2. The compound of claim 1, wherein R1 is H.
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17. A compound selected from
N-(3-(isoquinolin-3-yl)-4-methylphenyl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-amine; -
4-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclohexan-1-one; 4-(5-{[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclohexan-1-ol; 3-{5-[(2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]-2-methylphenyl}-1,7-dimethyl-1,2-dihydro-1,6-naphthyridin-2-one, N-(3-(5-fluoropyrimidin-2-yl)-4-methylphenyl)-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-amine, and 2-{[2-(dimethylamino)ethane]sulfonyl}-N-[3-(3-fluoropyridin-2-yl)-4-methylphenyl]-1,2,3,4-tetrahydroisoquinolin-5-amine.
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Specification
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Current AssigneeNovartis Ag
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Original AssigneeIRM LLC
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InventorsCheng, Dai, Han, Dong, Zhang, Guobao, Wan, Yongqin, Xie, Yun Feng, Jiang, Jiqing, Gao, Wenqi, Pan, Shifeng
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Primary Examiner(s)Moore, Susanna
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Assistant Examiner(s)Jaisle, Cecilia M
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Application NumberUS13/060,426Publication NumberTime in Patent Office1,450 DaysField of Search546/140, 546/141, 546/143, 546/118, 514/426, 514/309, 514/308, 514/310, 514/264.11, 514/263.22, 514/260.1, 514/269, 514/255.05, 514/252.04, 514/303, 544/279, 544/238, 544/264, 544/255, 544/298, 544/405, 544/331, 544/58.2, 544/408US Class Current514/252.04CPC Class CodesA61K 31/47 Quinolines; IsoquinolinesA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 35/00 Antineoplastic agentsA61P 37/02 ImmunomodulatorsA61P 43/00 Drugs for specific purposes...C07D 217/04 with hydrocarbon or substit...C07D 217/08 with a hetero atom directly...C07D 401/12 linked by a chain containin...C07D 401/14 containing three or more he...C07D 403/12 linked by a chain containin...C07D 403/14 containing three or more he...C07D 405/12 linked by a chain containin...C07D 405/14 containing three or more he...C07D 409/14 containing three or more he...C07D 417/12 linked by a chain containin...C07D 471/04 Ortho-condensed systemsC07D 473/00 Heterocyclic compounds cont...C07D 487/04 Ortho-condensed systemsC07D 513/04 Ortho-condensed systems