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US 9,428,495 B2Granted
Selectively substituted quinoline compounds
AssigneeEisai R&D Management Co., Ltd.
InventorsEric Carlson, Hans Hansen, Lynn Hawkins, Sally Ishizaka, Matthew Mackey, Shawn Schiller, Chikako Ogawa, Heather Davis, Atsushi Endo
Life of this patent
Estimating the term…
Abstract
Embodiments of the disclosure relate to selectively substituted quinoline compounds that act as antagonists or inhibitors for Toll-like receptors 7 and/or 8, and their use in pharmaceutical compositions effective for treatment of systemic lupus erythematosus (SLE) and lupus nephritis.
Claims32
A compound of formula (I) or pharmaceutically acceptable salt thereof:
- wherein at least one of R1 and R2 is H, methyl, or ethyl, and the other is
- —H;
- or the other is
- C1-C6 alkyl that is optionally substituted with:
- —OH, methoxy, ethoxy, —OCH(CH3)2, —O(CH2)2CH3, phenyl, furanyl, —O(CH2)2OH, phenoxy, methylthio, —F, —N(CH3)2, cyano, pyridinyloxy, fluorophenoxy, isochromanyl, phenol, benzylamino, —NHCH3, oxo-, amino, carboxyl, 7-member spiroaminyl, a three to six member cycloalkyl, saturated or unsaturated and optionally including one or more heteroatoms selected from O and N, and optionally substituted at one or more C or N atoms by methyl, cyano, fluoro, methylamino, or trifluoromethyl;
- or the other is
- C3-C7 cycloalkane, saturated or unsaturated, optionally bridged, optionally including one or more heteroatoms selected from O, S, and N, and optionally substituted at one or more C or N atoms by methyl, ethyl, pyridinyl, azetidinyl, acetamidyl, carboxamidyl, cyano, fluoro, methylamino, or trifluoromethyl;
- or
- R1 and R2, together with the nitrogen atom to which they are attached, form an 8 to 11 member spirodiamine, an 8 member bicyclodiamine, a 7 member spiroxamine, a piperidinyl optionally substituted with ethyl, or a four to six member cycloalkyl, optionally substituted with at least one of carboxamidyl, aminomethyl, methyl, (ethylamino)methyl, (dimethylamino)methyl, dimethylamino, (methylamino)methyl, and amino;
- and wherein R3 is —H or methyl.
7 more elements
A compound of Formula (le) or pharmaceutically acceptable salt thereof, with relative stereochemistry indicated:
A compound of Formula (II) or pharmaceutically acceptable salt thereof:
- wherein
- R4 is methyl;
- R5 is C1-C5 alkyl that is saturated, partially saturated, or unsaturated, and that is optionally substituted with:
- —H, —cl, —F, —OH, —NH2, oxo- , —N(CH2CH3)2, phenyl, cyclohexyl, phenyltriazolyl, cyclohexyltriazolyl, pyridinyl, pyrrolidinyl,
- morpholinyl optionally substituted with methyl or hydroxymethyl, —O—, substituted with:
- C1-C6 alkyl, methylphenyl, methylcyclohexyl, pyridinyl, diazinyl, or phenyl optionally substituted with —F or methyl, —NH—, substituted with:
- C2-C7 alkyl that is linear, branched, or cyclic, saturated or unsaturated, and optionally substituted with oxo-, phenyl, methyl, or —OH,
- pyridinyl optionally substituted with methyl, methoxy, phenyl, or amino,
- diazinyl optionally substituted with ethyl,
- benzoimidazolyl, methylphenyl, phenylpyrazolyl, naphthyridyl,
- phenyl optionally substituted with —F, methyl, ethyl, or ethoxy,
- imidazolidinyl optionally substituted with methyl
- or R5 is
- wherein n is 1-3, and wherein the cyclic amine is optionally substituted with
- C1—C3 alkyl optionally substituted with
- —OH, —F, phenyl, -—NH2, cyclohexyl, —N(CH3)2, —c(O)NH2, methylsulfonamidyl, benzenesulfonamidyl, methylbenzenesulfonamidyl, or
- pyrrolidinyl optionally substituted with methyl or hydroxyl, or —NHC(O)R6, wherein R6 is
- C1-C5 alkyl, phenyl, pyridinyl, fluorophenyl, methylsulfonyl, fluorobenzenesulfonyl, dimethyl pyrazole sulfonyl, or
- pyrazolyl optionally substituted with methyl;
- piperidinyl optionally substituted with —C(O)CH3, —C(O)CH2CH3, methyl, oxo-,
- C(O)Ph, —NH2, —NH—C(O)CH3, or
- piperazinyl optionally substituted with —C(O)OC(CH3)3, methyl, —C(O)CH3, —C(O)Ph, C(O)CH(CH3)2, —C(O)CH3, or methylsulfonyl;
- or
- R5 is
- where n is 1 or 2, and wherein the cyclic diamine is optionally substituted on at least one carbon atom with
- methyl, oxo-, —N(CH3)2, amino, —CH2CH3, or
- piperidinyl optionally substituted with methyl, —C(O)CH3, —C(O)CH(CH3)2, —C(O)Ph, or —C(O)OC(CH3)3, and
- wherein R7 is —H, phenyl, —C(O)CH3, C1-C3 alkyl, —C(O)NH2, or —C(O)Ph;
- and
- R8 is methoxy or cyano.
27 more elements
A compound of Formula (III) or pharmaceutically acceptable salt thereof:
- wherein
- R11 is H or methyl;
- R10 is H or, when both R11 and R9 are H, is methyl-1,4′-bipiperidinyl;
- R9 is —H or is —CH2- substituted by 1,4′-bipiperidinyl, oxo-, hydroxyl, methylpyridinyl, or piperidinyl optionally substituted with hydroxyl, —N(CH3)2, or piperidinyl.
1 more element
Dependencies are inferred from the claim text.