Granted Patent B2

US 9,994,518 · App. 15/318,207 · Granted Jun 12, 2018

Abstract

Claims (87)

1. A compound of Formula IVA:

or a salt thereof,

wherein:

R Ia is a moiety of the formula: (a) NH 2 —SO 2 —; (b) NR′ 2 —SO 2 NR″—, wherein R′ is independently for each occurrence: (i) —H; (ii) linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms; or (iii) one of R′ is —H and the other is t-BOC; and R″ is: (a) —H; or (b) linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms; or (iv) one of R′ is —H and the other R′ together with R″ and the —N—SO 2 —N— moiety to which they are attached form a heterocycle of up to 6 ring atoms;

R Ib has the formula: —CH 2 —X—, wherein X is —O—, —S—, CH 2 —;

R Id and R Ie are independently for each occurrence —H or linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms; or

R Id and R Ie together with the cyclopropyl moiety to which they are attached from a spirocycle of up to 8 carbon atoms;

R Ic is:

(a) a heteroaryl of the formula:

wherein:

n=0, 1, or 2;

one of R IIa or R IIb is a bond to the cyclopropyl core of Formula IVA and the other is —H or —R IIc , wherein,

R IIc is: (i) linear-, branched-, or cyclic-alkoxy of up to 6 carbon, which may optionally be substituted with one or more halogen; (ii) linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms, which may optionally be substituted with halogen or linear-, branched-, or cyclic-alkoxy of up to 6 carbon atoms;

(b) heteroaryl of the formula

wherein:

R IId is —H or linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms; or

(c) aryl of the formula

wherein:

n=1 or 2;

R IIIa is: (i) halogen; (ii) —CN; (iii) linear-, branched-, or cyclic-alkoxy of up to 6 carbon atoms which may optionally be substituted with one or more (1) halogen; or (2) linear-, branched-, or cyclic alkoxy of up to 6 carbon atoms; (iv) linear-, branched-, or cyclic-alkyl of up to 6 carbon atoms which may optionally be substituted with one or more: (1) halogen; or (2) linear-, branched-, or cyclic alkoxy of up to 6 carbon atoms.

2. A compound of claim 1 , or a salt thereof, wherein, R Id and R Ie are independently for each occurrence: (a) —H, or (b) methyl.

3. A compound of claim 2 , or a salt thereof, wherein R Id and R Ie are joined together to form, together with the cyclopropyl moiety to which they are attached, a spirocyclo moiety of 7 carbon atoms.

4. A compound, or a salt thereof, of claim 1 wherein, —R Ib -R Ic is —CH 2 —X—R AH , wherein:

X is —CH 2 —, —S—, or —O—; and

R AH is:

5. A compound which is:

±trans 4-{3-[(5-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

±trans 4-{2-[(5-chloro-2-methoxyphenoxy)methyl]spiro[2.4]hept-1-yl}benzenesulfonamide;

±trans 4-[(1R,3R)-3-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-2,2-dimethylcyclopropyl]-benzene sulfonamide;

±trans 4-{(1R,2R)-2-[2-(5-chloro-2-methoxyphenyl)ethyl]spiro[2.4]hept-1-yl}benzene-sulfonamide;

N-(4-{(1S,3S)-3-[(5-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl)-methanesulfonamide;

N-{4-[(1S,3S)-3-{[(6-methoxypyridin-3-yl)oxy]methyl}-2,2-dimethylcyclopropyl]phenyl}-methanesulfonamide;

N-(4-{(1S,3S)-3-[(4-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl)-methanesulfonamide;

N-(4-{(1S,3S)-3-[(4-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl) sulfuric diamide;

N-(4-{(1S,3S)-3-[(5-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl) sulfuric diamide;

4-[(1S,3S)-3-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;

4-{(1S,3S)-3-[(5-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-{(1R,3R)-3-[(5-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-[(1S,3S)-2,2-dimethyl-3-{[(4-methylphenyl)sulfanyl]methyl}cyclopropyl]benzene-sulfonamide;

4-[(1R,3R)-3-{[(5-chloro-2-methoxyphenyl)sulfanyl]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;

4-[(1R,3R)-2,2-dimethyl-3-{[(4-methylphenyl)sulfanyl]methyl}cyclopropyl]benzene-sulfonamide;

4-[(1S,3S)-3-{[(5-chloro-2-methoxyphenyl)sulfanyl]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;

N-{4-[(1S,3S)-3-{[(6-methoxypyridin-3-yl)oxy]methyl}-2,2-dimethylcyclopropyl]phenyl}-sulfuric diamide;

N-{4-[(1S,3S)-2,2-dimethyl-3-{[(6-methylpyridin-3-yl)oxy]methyl}cyclopropyl]phenyl}sulfuric diamide;

N-{4-[(1S,3S)-2,2-dimethyl-3-{[(2-methylpyridin-3-yl)oxy]methyl}cyclopropyl]phenyl}-methanesulfonamide;

N-{4-[(1S,3S)-2,2-dimethyl-3-{[(2-methylpyridin-3-yl)oxy]methyl}cyclopropyl]phenyl}sulfuric diamide;

4-[(1R,3R)-3-{[(2,6-dimethoxypyridin-3-yl)oxy]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;

4-[(1R,3R)-3-{[2-(difluoromethoxy)-5-fluorophenoxy]methyl}-2,2-dimethylcyclopropyl]-benzenesulfonamide;

N-(4-{(1S,3S)-3-[(4-chloro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl)-sulfuric diamide;

N-(4-{(1S,3S)-3-[(4-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}phenyl)-sulfuric diamide;

4-{(1S,3S)-2,2-dimethyl-3-[(pyridin-3-yloxy)methyl]cyclopropyl}benzenesulfonamide;

4-[(1S,3S)-3-{[(2,6-dimethoxypyridin-3-yl)oxy]methyl}-2,2-dimethylcyclopropyl]-benzenesulfonamide;

4-[(1R,3R)-2,2-dimethyl-3-{[(6-methylpyridin-3-yl)oxy]methyl}cyclopropyl]benzene-sulfonamide;

4-{(1R,3R)-3-[(2-cyano-4-fluorophenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-{(1R,3R)-3-[(4-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-{(1S,3S)-3-[(4-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-{(1S,3S)-3-[(4-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-{(1S,3S)-3-[(2-cyano-4-fluorophenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-[(1S,3S)-2,2-dimethyl-3-{[(6-methylpyridin-3-yl)oxy]methyl}cyclopropyl]benzene-sulfonamide;

4-[(1S,3S)-2,2-dimethyl-3-{[(2-methylpyridin-3-yl)oxy]methyl}cyclopropyl]benzene-sulfonamide;

4-{(1R,3R)-3-[(4-fluoro-2-methylphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-{(1S,3S)-3-[(5-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-{(1R,2R)-2-[(2-cyano-4-fluorophenoxy)methyl]cyclopropyl}benzenesulfonamide;

4-[(1R,2R)-2-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}cyclopropyl]benzenesulfonamide;

4-[(1R,2R)-2-{[(2,6-dimethoxypyridin-3-yl)oxy]methyl}cyclopropyl]benzenesulfonamide;

4-{(1R,2R)-2-[(5-chloro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;

4-{(1R,2R)-2-[(4-fluoro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;

4-[(1R,3R)-3-{[2-(difluoromethoxy)phenoxy]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;

4-{(1R,3R)-3-[(5-fluoro-2-methoxyphenoxy)methyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide;

4-{(1S,2S)-2-[(4-fluoro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;

4-{(1S,2S)-2-[(2-cyano-4-fluorophenoxy)methyl]cyclopropyl}benzenesulfonamide;

4-[(1S,2S)-2-{[4-fluoro-2-(trifluoromethyl)phenoxy]methyl}cyclopropyl]benzene sulfonamide;

4-{(1S,2S)-2-[(5-chloro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;

4-{(1R,3R)-3-[2-(2-methoxyphenyl)ethyl]-2,2-dimethylcyclopropyl}benzenesulfonamide;

4-{(1R,2R)-2-[2-(5-chloro-2-methoxyphenyl)ethyl]spiro[2.4]hept-1-yl}benzenesulfonamide;

4-{(1S,2S)-2-[2-(5-chloro-2-methoxyphenyl)ethyl]spiro[2.4]hept-1-yl}benzenesulfonamide;

4-{(1S,2S)-2-[2-(5-chloro-2-methoxyphenyl)ethyl]cyclopropyl}benzenesulfonamide;

4-{(1S,3S)-3-[2-(5-chloro-2-methoxyphenyl)ethyl]-2,2 dimethylcyclopropyl}benzene-sulfonamide;

4-{(1S,2R)-2-[(5-chloro-2-methoxyphenoxy)methyl]cyclopropyl}benzenesulfonamide;

4-{(1R,3R)-3-[2-(5-chloro-2-methoxyphenyl)ethyl]-2,2-dimethylcyclopropyl}benzene-sulfonamide; or

4-[(1R,3R)-3-{[(5-chloropyridin-2-yl)oxy]methyl}-2,2-dimethylcyclopropyl]benzene-sulfonamide;

4-[(1S,3S)-2,2-dimethyl-3-{[(2-methylpyrimidin-5-yl)oxy]methyl}cyclopropyl]benzene-sulfonamide;

4-{(1S,3S)-2,2-dimethyl-3-[(pyrimidin-5-yloxy)methyl]cyclopropyl}benzenesulfonamide; or

4-{(1S,2R)-2-[(2-cyano-4-fluorophenoxy)methyl]cyclopropyl}benzenesulfonamide;

or a pharmaceutically acceptable salt of any of the foregoing.

6. A pharmaceutical formulation comprising at least one compound of claim 1 and at least one excipient.

7. A method of treating Alzheimer's disease (AD), schizophrenia, or Parkinson's disease (PD) comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical formulation of claim 6 .

Assignments (6)