US 12,503,438 B2Granted

Compounds for the treatment of kinase-dependent disorders

AssigneeExelixis, Inc.

InventorsLynne Canne Bannen, Minna Bui, Faming Jiang, Kin Tso, Yong Wang, Wei Xu

Life of this patent

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Abstract

Disclosed herein are compounds of Formula (I) which inhibit, regulate and/or modulate tyrosine kinase receptors, particularly Axl and Mer signal transduction pathways related to the changes in cellular activities, compositions containing the compounds, methods of using the compounds to treat kinase-dependent diseases and conditions, and methods for making the compounds.

Claims10

Dependent claims

A compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thiazolyl, tetrahydrofuranyl, pyrrolidinyl, dihydrofuranyl, pyrrolopyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl, or pyrazolopyridinyl;
R1 is —H, C1-6 alkyl, C1-6 alkoxy, halo, or C1-6 alkyl-NHC(O)—;
each R3 is independently selected from the group consisting of —H, halo, —OH, —CN, optionally substituted (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, —NH2, —NH (C1-C6) alkyl, —N(C1-C6 alkyl)2, and (C3-C6) cycloalkyl, wherein the (C1-C6) alkoxy, —NH (C1-C6) alkyl, —N(C1-C6 alkyl)2, and (C3-C6) cycloalkyl of R3 are each optionally substituted with 1, 2, or 3 independently selected Rg substituents;
R4 is C1-6 alkyl or halo;
R8 is —H or C1-6 alkyl;
R9 is —H;
or R8 and R9 together with the atoms to which they are attached form fused 5-10 membered heteroaryl or fused 5-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 independently selected Rg substituents and wherein the 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl has 0-2 additional heteroatoms as ring members selected from N and S;
each Rb is independently C1-6 alkyl, C1-6 alkoxy, CN, halo, OH, oxo, NH2, HO—C1-6 alkyl-, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4alkyl-, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl-C1-4 alkyl-, C1-6 alkyl-SO2—, C1-6 alkyl-C(O)—, —NH—(C1-C6) alkyl, —N ((C1-C6) alkyl)2, phenyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C1-4 alkyl-, wherein the C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4alkyl-, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl-C1-4alkyl-, phenyl, 5-6 membered heteroaryl, and 5-6 membered heteroaryl-C1-4 alkyl- are each optionally substituted with 1 or 2 independently selected Rg substituents;
each R8 is independently selected from the group consisting of halo, —OH, —CN, —COOH, —COO—(C1-C4) alkyl, C1-6 alkyl-C(O)—, —NH2, —NH—(C1-C6) alkyl, —N ((C1-C6) alkyl)2, —(C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and (C3-C6) cycloalkyl;
the ring nitrogen atom on the quinoline in Formula (Ia) is optionally oxidized;
the subscript n is an integer of 1, 2, 3, or 4;
the subscript m is an integer of 1, 2, or 3;
and
the subscript q is an integer of 0, 1, 2, or 3.

12 more elements

A compound selected from:

1-N′-(4-fluorophenyl)-1-N-[4-[7-[1-(2-methoxyethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[1-(trifluoromethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-[1-(difluoromethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-[1-(2-fluoroethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-[1-(2,2-difluoroethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-methylpyrazol-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[1-(2-hydroxyethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1, 1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(1-ethylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-propan-2-ylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(1-cyclopropylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(1-tert-butylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[1-(oxetan-3-yl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-pyridin-3-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-pyridin-4-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-pyrimidin-5-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-pyridazin-4-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide
1-N-[4-[7-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(2-methylpyridin-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(2-methoxypyridin-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1, 1-dicarboxamide;
1-N-[4-[7-(2,6-dimethylpyridin-4-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(2-fluoropyridin-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(2-cyanopyridin-4-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[6-(trifluoromethyl) pyridin-3-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[2-(trifluoromethyl) pyridin-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(6-methylpyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(6-aminopyridin-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1H-pyrazolo [3,4-b]pyridin-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(5-cyanopyridin-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(6-fluoropyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(6-cyanopyridin-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(6-cyclopropylpyridin-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(5-fluoropyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(5-methylpyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(5-methoxypyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[5-(trifluoromethyl) pyridin-3-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(6-pyrrolidin-1-ylpyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(6-propan-2-yloxypyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1, 1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(6-hydroxypyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(2-hydroxypyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(3,5-dimethyl-1,2-oxazol-4-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(2-methylpyrazol-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-phenylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1,2-oxazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-piperidin-4-ylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-[1-(1-acetylpiperidin-4-yl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(2-trimethylsilylethynyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-(7-ethynylquinolin-4-yl)oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1H-triazol-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1,3-oxazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1H-pyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1H-pyrazol-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-methylimidazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1, 1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1H-imidazol-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1,3,4-oxadiazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1H-imidazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-methylimidazol-2-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[6-methoxy-7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[6-(methylcarbamoyl)-7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-methylsulfonylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-(5-fluoro-2-methyl-2,3-dihydroindole-1-carbonyl)-N-[4-[7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1-carboxamide;
1-(5-fluoro-2,3-dihydroindole-1-carbonyl)-N-[4-[7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1-carboxamide;
1-N′-(4-fluoro-2,6-dimethylphenyl)-1-N-[4-[7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N′-methyl-1-N-[4-[7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-pyrrolidin-3-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-[1-(difluoromethyl)pyrazol-3-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-pyridin-2-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(2-methyltriazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(4-methylimidazol-1-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[rac-(3R)-oxolan-3-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[(3R)-oxolan-3-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(3-amino-1H-pyrazol-4-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(3-methylpyrazol-1-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(1-acetylpyrrolidin-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-methylsulfonylpyrrolidin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-[1-(fluoromethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(2,5-dihydrofuran-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(4-methylpyrazol-1-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(2-aminopyridin-4-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(1-cyclopropylpyrazol-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(5-methyl-1H-pyrazol-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[5-(trifluoromethyl)-1H-pyrazol-3-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(1,5-dimethylpyrazol-3-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-[1-(fluoromethyl)pyrazol-3-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-[2-(fluoromethyl)pyrazol-3-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-pyrazolo [1,5-a]pyridin-2-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-[2,5-difluoro-4-[6-methyl-7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(1H-pyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(1H-pyrazol-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[6-methyl-7-(1-methylpyrazol-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-oxidopyridin-1-ium-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N-(4-fluorophenyl)-1-N′-[2,3,5-trifluoro-4-[6-methyl-7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-di carboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-[2-(4-methylpiperazin-1-yl) pyridin-4-yl]quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-[2-chloro-5-fluoro-4-[6-methyl-7-(1-methylpyrazol-4-yl)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-(4-fluorophenyl)-1-N′-[3-fluoro-4-(7-pyridin-3-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-(7-pyrimidin-4-ylquinolin-4-yl)oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-[2,5-difluoro-4-(7-pyridin-3-ylquinolin-4-yl)oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1,3-thiazol-5-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-methyl-2-oxopyridin-4-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-[4-[7-[1-(difluoromethyl)pyrazol-4-yl]quinolin-4-yl]oxy-2,5-difluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1-methyl-6-oxopyridin-3-yl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-(4-fluorophenyl)-1-N-[4-[7-(1H-imidazol-2-yl)-6-methylquinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide;
1-N′-[2,5-difluoro-4-[7-(1H-imidazol-2-yl)-6-methylquinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-[3-fluoro-4-[7-(1H-imidazol-2-yl)-6-methylquinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N′-[4-[7-[1-(difluoromethyl)pyrazol-4-yl]quinolin-4-yl]oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
1-N-[4-[7-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
and
1-N-[4-[7-[1-(difluoromethyl)pyrazol-4-yl]quinolin-4-yl]oxyphenyl]-1-N′-(4-fluorophenyl)-1-N′-methylcyclopropane-1,1-dicarboxamide,
or a pharmaceutically acceptable salt thereof.

111 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/616,120Filed 3 Jun 2020 · us provisional application
Priority: 4 Jun 2019
Published: US 2023/0043835 A19 Feb 2023
Granted: 23 Dec 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 215/233
Attached in position 2 or 4: only one oxygen atom which is attached in position 4
A61P 35/00
Antineoplastic agents
A61P 37/00
Drugs for immunological or allergic disorders
C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond

Family

Application62/856,920Us provisional application · filed 4 Jun 2019
US 2023/0043835 A1Pre-grant publication · published 9 Feb 2023
US 12,503,438 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thiazolyl, tetrahydrofuranyl, pyrrolidinyl, dihydrofuranyl, pyrrolopyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-yl, or pyrazolopyridinyl;
R1 is —H, C1-6 alkyl, C1-6 alkoxy, halo, or C1-6 alkyl-NHC(O)—;
each R3 is independently selected from the group consisting of —H, halo, —OH, —CN, optionally substituted (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, —NH2, —NH (C1-C6) alkyl, —N(C1-C6 alkyl)2, and (C3-C6) cycloalkyl, wherein the (C1-C6) alkoxy, —NH (C1-C6) alkyl, —N(C1-C6 alkyl)2, and (C3-C6) cycloalkyl of R3 are each optionally substituted with 1, 2, or 3 independently selected Rg substituents;
R4 is C1-6 alkyl or halo;
R8 is —H or C1-6 alkyl;
R9 is —H;
or R8 and R9 together with the atoms to which they are attached form fused 5-10 membered heteroaryl or fused 5-10 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 independently selected Rg substituents and wherein the 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl has 0-2 additional heteroatoms as ring members selected from N and S;
each Rb is independently C1-6 alkyl, C1-6 alkoxy, CN, halo, OH, oxo, NH2, HO—C1-6 alkyl-, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4alkyl-, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl-C1-4 alkyl-, C1-6 alkyl-SO2—, C1-6 alkyl-C(O)—, —NH—(C1-C6) alkyl, —N ((C1-C6) alkyl)2, phenyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C1-4 alkyl-, wherein the C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-4alkyl-, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkyl-C1-4alkyl-, phenyl, 5-6 membered heteroaryl, and 5-6 membered heteroaryl-C1-4 alkyl- are each optionally substituted with 1 or 2 independently selected Rg substituents;
each R8 is independently selected from the group consisting of halo, —OH, —CN, —COOH, —COO—(C1-C4) alkyl, C1-6 alkyl-C(O)—, —NH2, —NH—(C1-C6) alkyl, —N ((C1-C6) alkyl)2, —(C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylthio, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, and (C3-C6) cycloalkyl;
the ring nitrogen atom on the quinoline in Formula (Ia) is optionally oxidized;
the subscript n is an integer of 1, 2, 3, or 4;
the subscript m is an integer of 1, 2, or 3;
and
the subscript q is an integer of 0, 1, 2, or 3.

12 more elements

Facts

Application

17/616,120Filed 3 Jun 2020 · us provisional application

Priority

4 Jun 2019

Published

US 2023/0043835 A19 Feb 2023

Granted

23 Dec 2025

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 215/233
Attached in position 2 or 4: only one oxygen atom which is attached in position 4
A61P 35/00
Antineoplastic agents
A61P 37/00
Drugs for immunological or allergic disorders
C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond