US 9,850,203 B2Granted

Autotaxin inhibitor compounds

AssigneePharmakea, Inc.

InventorsJohn Howard Hutchinson, David Lonergan, Fei Huang, Martin Rowbottom, Imelda Calderon

Life of this patent

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Abstract

Described herein are compounds that are autotaxin inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with autotaxin activity.

Claims20

Dependent claims

A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,
R1 is H, D, halogen, —CN, —C(═O)H, —NH2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, —O C1-C4alkyl or C1-C4deuteroalkyl;
X is —O—, —S—, —S(═O)—, or —S(═O)2—;
Ring A is a monocyclic aryl, bicyclic aryl, monocyclic heterocycloalkyl, monocyclic heteroaryl or bicyclic heteroaryl;
each R2 is independently selected from H, halogen, —CN, —NO2, —OH, —OR9, —SR9, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —C(═O)R9, —OC(═O)R9, —CO2R10, —OCO2R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O)R9, —NHC(═O)OR9, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;
m is 0, 1, or 2;
L1 is absent, C1-C6alkylene, C1-C6fluoroalkylene, or C3-C6cycloalkylene;
R3 is —CO2H, —CO2(C1-C6alkyl), —OH, —B(OH)2, —C(═O)NHSO2R9, —C(═O)N(R10)2, —C(═O)NH—OH, —C(═O)NH—CN, —SO2NHC(═O)R9, —OP(═O)(OH)2, —P(═O)(OH)2, tetrazolyl, or carboxylic acid bioisostere;
R4 is H, halogen, —CN, —NO2, —OH, —OR9, —SR9, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —C(═O)R9, —OC(═O)R9, —CO2R10, —OCO2R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O)R9, —NHC(═O)OR9, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, C3-C6cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl;
R5 is H, halogen, —CN, —OH, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4alkoxy, or C1-C4fluoroalkoxy;
L2 is absent or C1-C6 alkylene;
R6 is H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, or C3-C8cycloalkyl;
R7 is C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R9, or —S(═O)2R9, wherein if R7 is substituted, then R7 is substituted with 1 to 4 R8 groups;
or R6 and R7 are taken together with the nitrogen atom to which they are attached to form an unsubstituted N-containing heterocycle or a substituted N-containing heterocycle that is substituted with 1-4 R8 and 0 or 1 R12 groups;
each R8 and R12 substituent is independently selected from the group consisting of H, halogen, OH, —CN, —NO2, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C1-C6alkoxy, C2-C10heterocycloalkyl, —C(═O)R9, —S(═O)2R9, S(═O)R9, SR9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —OC(═O)R9, —CO2R10, —OCO2R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O)R9, —NHC(═O)OR9, substituted or unsubstituted aryl, C1-C6alkylene-substituted or unsubstituted aryl, —Y—C1-C6alkylene-substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C6alkylene-substituted or unsubstituted heteroaryl, and —Y—C1-C6alkylene-substituted or unsubstituted heteroaryl;
Y is O or S;
or two R8 substituents on the same carbon atom are taken together to form ═O, or two R8 substituents on the same or different carbon atoms are taken together to form to form a substituted or unsubstituted ring containing 0, 1, 2, or 3 heteroatoms in the ring selected from —NR11—, —S(═O)n—, and —O—;
n is 0, 1, or 2;
R9 is C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C3-C6cycloalkyl, a substituted or unsubstituted phenyl, C1-C4alkylene-substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic heteroaryl, C1-C4alkylene-substituted or unsubstituted monocyclic heteroaryl, a substituted or unsubstituted bicyclic heteroaryl, or a C1-C4alkylene-substituted or unsubstituted bicyclic heteroaryl;
each R10 is independently selected from H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C3-C6cycloalkyl, a substituted or unsubstituted phenyl, C1-C4alkylene-substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic heteroaryl, C1-C4alkylene-substituted or unsubstituted monocyclic heteroaryl, a substituted or unsubstituted bicyclic heteroaryl, or a C1-C4alkylene-substituted or unsubstituted bicyclic heteroaryl;
or
two R10 groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle;
and
R11 is H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C3-C8cycloalkyl, —C(═O)R9, —S(═O)2R9, —CO2R9, —C(═O)N(R10)2, substituted or unsubstituted aryl, C1-C4alkylene-substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C1-C4alkylene-substituted or unsubstituted heteroaryl.

21 more elements

A compound that is:

3-((6-Chloro-1-(2-((3,5-dichlorophenyl)amino)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(phenylamino)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(isoxazol-4-ylamino)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(methyl(phenyl)amino)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(cyclohexylamino)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(isopropylamino)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(dimethylamino)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((1-(Benzylcarbamoyl)-6-chloro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(piperidin-l-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(4-((3,4-difluorobenzyl)oxy)piperidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorobenzyl)piperidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)acetyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(3-oxo-3-(phenylamino)propyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(indolin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-(6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxo-7-azaspiro[3.5]nonan-7-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(2-cyano-7-azaspiro[3.5]nonan-7-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorophenyl)pyrrolidin-l-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorobenzyl)pyrrolidin-l-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-((4-fluorobenzyl)oxy)pyrrolidin-l-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-(4-trifluoromethylbenzyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indo1-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-cyanopyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(3-oxo-3-(pyrrolidin-1-yl)propyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(3-(indolin-1-yl)-3-oxopropyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(3-oxo-3-(spiro[cyclopropane-1,3′-indolin]-1′-yl)propyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopropane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(5′-fluorospiro[cyclopropane-1,3′-indolin]-1′-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(4′-fluorospiro[cyclobutane-1,3′-indolin]-1′-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(6-fluoro-3,3-dimethylindolin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-oxo-2,7-diazaspiro[4.5]decan-7-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(3,4-dihydroquinolin-1(2H)-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(1′-methylspiro[indoline-3,4′-piperidin]-1′-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopentane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(1-(pyrrolidine-1-carbonyl)-6-azaspiro[2.5]octan-6-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxo-1,7-diazaspiro[3.5]nonan-7-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(3-(3,3-difluoropyrrolidin-1-yl)azetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(4,4-dimethylpiperidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(3-(1,1-dioxidothiomorpholino)azetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(7-oxo-2,6-diazaspiro[3.4]octan-2-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((1-(2-((1R,5S,6R)-6-Carbamoyl-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-methylazetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(10-oxo-3,9-diazaspiro[5.6]dodecan-3-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxopyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(4-(4-fluorobenzyl)piperidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((1-(2-(4-(2-(1H-Pyrazol-1-yl)ethyl)piperidin-1-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(4-phenethylpiperidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(4-(pyridin-4-ylmethyl)piperidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorobenzyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid Enantiomer A;
3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorobenzyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid Enantiomer B;
3-((1-(2-(8-Benzyl-2,8-diazaspiro[4.5]decan-2-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-7-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(4,6-difluoroindolin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(5-chloroindolin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(6-chloroindolin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid Enantiomer A;
3-((6-Chloro-7-fluoro-1-(2-(3-(4-fluorophenyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid Enantiomer B;
6-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)ethyl)-1H-indol-3-yl)thio)picolinic acid;
Methyl 6-((6-chloro-7-fluoro-1-(2-(indolin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)picolinate;
6-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopropane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)picolinic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopropane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-1-(2-(5-methoxyindolin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-[6-Chloro-7-fluoro-1-[2-(5′-fluorospiro[cyclopropane-1,3′-indoline]-1′-yl)-2-oxo-ethyl]-2-methyl-indol-3-yl]sulfanyl-2-fluoro-benzoic acid;
6-((6-Chloro-7-fluoro-1-(2-(4′-fluorospiro[cyclobutane-1,3′-indolin]-1′-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)picolinic acid;
3-((6-Chloro-7-fluoro-1-(2-(4′-fluorospiro[cyclobutane-1,3′-indolin]-1′-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopentane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-phenethylpyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-propylpyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(6-(trifluoromethyl)indolin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(4-fluoroindolin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)piperidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(2-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((1-(2-(3-(1H-Pyrazol-1-yl)azetidin-1-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
6-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)picolinic acid;
3-((6-chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(7-methyl-1,7-diazaspiro[3.5]nonan-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-(pyridin-4-ylmethyl)pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(3-(pyridin-4-yl)pyrrolidin-1-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(isoindolin-2-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(5-methylindolin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(3-((1-methyl-1H-pyrazol-4-yl)methyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((1-(2-(2-(2-(1H-Pyrazol-1-yl)ethyl)piperidin-1-yl)-2-oxoethyl)-6-chloro-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(5-azaspiro[2.4]heptan-5-yl)ethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(3-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-1-(2-(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(hexahydro-1H-isoindol-2(3H)-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)benzoic acid;
3-((6-chloro-7-fluoro-1-(2-(indolin-1-yl)ethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-1-(2-(2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclobutane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-chloro-7-fluoro-2-methyl-1-(2-(spiro[cyclopropane-1,3′-indolin]-1-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-(spiro[cyclobutane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(spiro[cyclopentane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluoro-N-(phenylsulfonyl)benzamide;
3-((6-Chloro-7-fluoro-1-(2-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-1-(2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
(R)-3-((6-Chloro-7-fluoro-1-(2-(3-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-1-(2-((3S,4S)-3-hydroxy-4-morpholinopyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-1-(2-((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
(S)-3-((6-chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid Enantiomer A;
(R)-3-((6-chloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid Enantiomer B;
3-((6-Chloro-1-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-1-(2-(3-hydroxy-3-phenylpyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-1-(2-((3S,4S)-3-(dimethylamino)-4-hydroxypyrrolidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-1-(2-((3S,4S)-3-hydroxy-4-(4-methylpiperazin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-1-(2-(3-((dimethylamino)methyl)azetidin-1-yl)-2-oxoethyl)-7-fluoro-2-methyl-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-Chloro-7-fluoro-2-methyl-1-(2-oxo-2-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((2,6-dichloro-7-fluoro-1-(2-oxo-2-(spiro[cyclobutane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((2,6-dichloro-7-fluoro-1-(2-oxo-2-(spiro[cyclopropane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-(indolin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-oxo-2-(spiro[cyclobutane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-oxo-2-(spiro[cyclopropane-1,3′-indolin]-1′-yl)ethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((2,6-dichloro-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-(3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
3-((6-chloro-2-cyclopropyl-7-fluoro-1-(2-(methoxy(methyl)amino)-2-oxoethyl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid;
or a pharmaceutically acceptable salt, or solvate thereof.

126 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/023,465Filed 25 Sep 2014 · us provisional application
Priority: 26 Sep 2013
Published: US 2016/0214935 A128 Jul 2016
Granted: 26 Dec 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification56 codes

C07D 209/30
Indoles; Hydrogenated indoles: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen,…
A61K 9/0014
Galenical forms characterised by the site of application: skin, i.e. galenical aspects of topical compositions
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/06
Medicinal preparations characterised by special physical form: ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Family

Application61/883,026Us provisional application · filed 26 Sep 2013
Application62/038,052Us provisional application · filed 15 Aug 2014
US 2016/0214935 A1Pre-grant publication · published 28 Jul 2016
US 9,850,203 B2This patent

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

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Abstract

A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

wherein,
R1 is H, D, halogen, —CN, —C(═O)H, —NH2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, —O C1-C4alkyl or C1-C4deuteroalkyl;
X is —O—, —S—, —S(═O)—, or —S(═O)2—;
Ring A is a monocyclic aryl, bicyclic aryl, monocyclic heterocycloalkyl, monocyclic heteroaryl or bicyclic heteroaryl;
each R2 is independently selected from H, halogen, —CN, —NO2, —OH, —OR9, —SR9, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —C(═O)R9, —OC(═O)R9, —CO2R10, —OCO2R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O)R9, —NHC(═O)OR9, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;
m is 0, 1, or 2;
L1 is absent, C1-C6alkylene, C1-C6fluoroalkylene, or C3-C6cycloalkylene;
R3 is —CO2H, —CO2(C1-C6alkyl), —OH, —B(OH)2, —C(═O)NHSO2R9, —C(═O)N(R10)2, —C(═O)NH—OH, —C(═O)NH—CN, —SO2NHC(═O)R9, —OP(═O)(OH)2, —P(═O)(OH)2, tetrazolyl, or carboxylic acid bioisostere;
R4 is H, halogen, —CN, —NO2, —OH, —OR9, —SR9, —S(═O)R9, —S(═O)2R9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —C(═O)R9, —OC(═O)R9, —CO2R10, —OCO2R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O)R9, —NHC(═O)OR9, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4hydroxyalkyl, C1-C4heteroalkyl, C3-C6cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl;
R5 is H, halogen, —CN, —OH, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C1-C4alkoxy, or C1-C4fluoroalkoxy;
L2 is absent or C1-C6 alkylene;
R6 is H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, or C3-C8cycloalkyl;
R7 is C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —C(═O)R9, or —S(═O)2R9, wherein if R7 is substituted, then R7 is substituted with 1 to 4 R8 groups;
or R6 and R7 are taken together with the nitrogen atom to which they are attached to form an unsubstituted N-containing heterocycle or a substituted N-containing heterocycle that is substituted with 1-4 R8 and 0 or 1 R12 groups;
each R8 and R12 substituent is independently selected from the group consisting of H, halogen, OH, —CN, —NO2, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C1-C6alkoxy, C2-C10heterocycloalkyl, —C(═O)R9, —S(═O)2R9, S(═O)R9, SR9, —S(═O)2N(R10)2, —NR10S(═O)2R9, —OC(═O)R9, —CO2R10, —OCO2R9, —N(R10)2, —C(═O)N(R10)2, —OC(═O)N(R10)2, —NHC(═O)R9, —NHC(═O)OR9, substituted or unsubstituted aryl, C1-C6alkylene-substituted or unsubstituted aryl, —Y—C1-C6alkylene-substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C6alkylene-substituted or unsubstituted heteroaryl, and —Y—C1-C6alkylene-substituted or unsubstituted heteroaryl;
Y is O or S;
or two R8 substituents on the same carbon atom are taken together to form ═O, or two R8 substituents on the same or different carbon atoms are taken together to form to form a substituted or unsubstituted ring containing 0, 1, 2, or 3 heteroatoms in the ring selected from —NR11—, —S(═O)n—, and —O—;
n is 0, 1, or 2;
R9 is C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C3-C6cycloalkyl, a substituted or unsubstituted phenyl, C1-C4alkylene-substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic heteroaryl, C1-C4alkylene-substituted or unsubstituted monocyclic heteroaryl, a substituted or unsubstituted bicyclic heteroaryl, or a C1-C4alkylene-substituted or unsubstituted bicyclic heteroaryl;
each R10 is independently selected from H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C3-C6cycloalkyl, a substituted or unsubstituted phenyl, C1-C4alkylene-substituted or unsubstituted phenyl, a substituted or unsubstituted monocyclic heteroaryl, C1-C4alkylene-substituted or unsubstituted monocyclic heteroaryl, a substituted or unsubstituted bicyclic heteroaryl, or a C1-C4alkylene-substituted or unsubstituted bicyclic heteroaryl;
or
two R10 groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted heterocycle;
and
R11 is H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6deuteroalkyl, C3-C8cycloalkyl, —C(═O)R9, —S(═O)2R9, —CO2R9, —C(═O)N(R10)2, substituted or unsubstituted aryl, C1-C4alkylene-substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C1-C4alkylene-substituted or unsubstituted heteroaryl.

21 more elements

Facts

Application

15/023,465Filed 25 Sep 2014 · us provisional application

Priority

26 Sep 2013

Published

US 2016/0214935 A128 Jul 2016

Granted

26 Dec 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification56 codes

C07D 209/30
Indoles; Hydrogenated indoles: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen,…
A61K 9/0014
Galenical forms characterised by the site of application: skin, i.e. galenical aspects of topical compositions
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/06
Medicinal preparations characterised by special physical form: ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels