Alkynyl phenyl derivative compounds for treating ophthalmic diseases and disorders

1. A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound having the structure of Formula (E):

or a pharmaceutically acceptable salt thereof, wherein:

m is 0, 1, 2, or 3;

R 21 and R 22 are each independently hydrogen, C 1 -C 5 alkyl or fluoroalkyl;

R 3 and R 4 are each hydrogen;

R 5 is aryl or carbocyclyl;

each R 6 is the same or different and independently hydrogen or C 1 -C 5 alkyl;

R 9 is alkyl;

R 12 and R 13 are the same or different and independently hydrogen, or —C(═O)R 9 ; and

each R 14 is the same or different and independently alkyl, halo, fluoroalkyl or —OR 6 .

2. The method of claim 1 , wherein R 5 is carbocyclyl.

3. The method of claim 2 wherein the compound of Formula (E) has the structure of Formula (G):

or a pharmaceutically acceptable salt thereof, wherein:

m is 0, 1, 2, or 3;

p is 1, 2, 3, 40 or 5;

q is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

R 21 and R 22 are each the same or different and independently hydrogen, C 1 -C 5 alkyl or fluoroalkyl;

R 3 and R 4 are each hydrogen;

each R 6 is the same or different and independently hydrogen or C 1 -C 5 alkyl;

R 9 is alkyl;

R 12 and R 13 are the same or different and independently hydrogen, or —C(═O)R 9 ;

each R 14 is the same or different and independently alkyl, halo, fluoroalkyl or —OR 6 ; and

each R 19 is the same or different and independently alkyl, —OR 6 , halo or fluoroalkyl.

4. The method of claim 3 , wherein each of R 12 and R 13 is hydrogen.

5. The method of claim 4 , wherein m is 0.

6. The method of claim 5 , wherein R 21 and R 22 are each independently hydrogen or C 1 -C 5 alkyl.

7. The method of claim 6 , wherein, q is 0 or 1, and each R 19 is independently alkyl or —OR 6 , wherein R 6 is hydrogen or C 1 -C 5 alkyl.

8. The method of claim 1 , wherein the compound is chosen from:

1-((3-(2-aminoethoxy)phenyl)ethynyl)cyclopentanol;

1-((3-(2-aminoethoxy)phenyl)ethynyl)cyclohexanol;

2-(3-(cyclohexylethynyl)phenoxy)ethanamine;

1-((3-(1-aminopropan-2-yloxy)phenyl)ethynyl)cyclopentanol;

1-((3-(1-aminopropan-2-yloxy)phenyl)ethynyl)cyclohexanol;

1-((3-(1-aminopropan-2-yloxy)phenyl)ethynyl)cycloheptanol;

2-(3-(cycloheptylethynyl)phenoxy)ethanamine;

2-(3-(cycloheptylethynyl)phenoxy)propan-1-amine;

2-(3-(cyclohexylethynyl)phenoxy)propan-1-amine;

2-(3-(cyclopentylethynyl)phenoxy)propan-1-amine;

2-(3-(cyclopentylethynyl)phenoxy)-ethanamine;

1-((3-(2-aminoethoxy)phenyl)ethynyl)-cycloheptanol; or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein R 5 is aryl.

10. The method of claim 1 , wherein the compound is 2-(3-(phenylethynyl)phenoxy)ethanamine, 3-((3-(2-aminoethoxy)phenyl)ethynyl)benzonitrile, 2-(3-((2-methoxyphenyl)ethynyl)phenoxy)ethanamine, or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is chosen from:

1-((3-(2-aminoethoxy)phenyl)ethynyl)-cyclopentanol;

1-((3-(2-aminoethoxy)phenyl)ethynyl)-cyclohexanol;

1-((3-(2-aminoethoxy)phenyl)ethynyl)-cycloheptanol;

2-(3-(cyclopentylethynyl)phenoxy)-ethanamine;

2-(3-(cyclohexylethynyl)phenoxy)ethanamine;

2-(3-(cycloheptylethynyl)phenoxy)ethanamine;

2-(3-(cyclopropylethynyl)-phenoxy)ethanamine;

(S)-1-((3-(1-aminopropan-2-yloxy)phenyl)ethynyl)cyclohexanol;

1-((3-(2-aminoethoxy)phenyl)ethynyl)cyclooctanol;

2-((3-(2-Aminoethoxy)-phenyl)ethynyl)cyclohexanol;

1-(2-(3-(2-Aminoethoxy)-phenyl)ethynyl)cyclobutanol;

2-(3-(cyclooctylethynyl)-phenoxy)ethanamine, or a pharmaceutically acceptable salt thereof.

12. A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound having the structure of Formula (F):

or a pharmaceutically acceptable salt thereof, wherein:

m is 0, 1, 2, or 3;

R 21 and R 22 are each independently hydrogen, C 1 -C 5 alkyl or fluoroalkyl;

R 3 and R 4 are each hydrogen;

each R 6 is the same or different and independently hydrogen or C 1 -C 5 alkyl;

R 9 is alkyl;

R 12 and R 13 are the same or different and independently hydrogen, alkyl or —C(═O)R 9 ;

each R 14 is the same or different and independently alkyl, halo, fluoroalkyl or —OR 6 ; and

R 16 , R 17 and R 18 are each the same or different and independently hydrogen, alkyl, —OR 6 , carbocyclyl or aryl.

13. The method of claim 12 , wherein each of R 12 and R 13 is hydrogen.

14. The method of claim 13 , wherein each of R 21 and R 22 is independently hydrogen or C 1 -C 5 alkyl.

15. The method of claim 14 , wherein m is 0.

16. The method of claim 15 , wherein each of R 16 , R 17 and R 18 is independently hydrogen, alkyl or —OR 6 , wherein each R 6 is independently hydrogen or C 1 -C 5 alkyl.

17. The method of claim 15 , wherein each of R 16 , R 17 and R 18 is independently hydrogen, alkyl or aryl.

18. The method of claim 12 , wherein the compound is chosen from:

4-((3-(2-aminoethoxy)phenyl)ethynyl)heptan-4-ol;

1-(3-(2-aminoethoxy)phenyl)-3-ethylpent-1-yn-3-ol;

1-(3-(2-aminoethoxy)phenyl)-3-isopropyl-4-methylpent-1-yn-3-ol;

5-((3-(2-aminoethoxy)phenyl)ethynyl)nonan-5-ol;

4-(3-(2-aminoethoxy)phenyl)-2-methylbut-3-yn-2-ol;

2-(3-(hept-1-ynyl)phenoxy)ethanamine;

4-(3-(2-aminoethoxy)phenyl)but-3-yn-1-ol;

2-(3-(3-phenylprop-1-ynyl)phenoxy)ethanamine;

2-(3-(4-methylpent-1-ynyl)phenoxy)ethanamine;

6-(3-(2-aminoethoxy)phenyl)hex-5-yn-1-ol;

2-(3-(3-ethylpent-1-ynyl)phenoxy)propan-1-amine;

2-(3-(3-propylhex-1-ynyl)phenoxy)propan-1-amine;

1-(3-(2-aminoethoxy)phenyl)-3-ethylpent-1-yn-3-ol;

4-((3-(1-aminopropan-2-yloxy)phenyl)ethynyl)heptan-4-ol;

2-(3-(3-ethylpent-1-ynyl)phenoxy)ethanamine;

2-(3-(3-propylhex-1-ynyl)phenoxy)ethanamine, or a pharmaceutically acceptable salt thereof.

19. A method for treating an ophthalmic disease or disorder resulting at least in part from lipofuscin pigment accumulation in an eye of a subject, comprising administering to the subject a pharmaceutical composition comprising a compound chosen from:

4-((3-(2-aminoethoxy)phenyl)ethynyl)-heptan-4-ol;

1-(3-(2-aminoethoxy)phenyl)-3-ethylpent-1-yn-3-ol;

1-(3-(2-aminoethoxy)phenyl)-3-isopropyl-4-methylpent-1-yn-3-ol;

5-((3-(2-aminoethoxy)phenyl)ethynyl)-nonan-5-ol;

4-(3-(2-aminoethoxy)phenyl)-2-methylbut-3-yn-2-ol;

2-(3-(4-methylpent-1-ynyl)phenoxy)ethanamine;

6-(3-(2-aminoethoxy)phenyl)hex-5-yn-1-ol;

2-(3-(3-phenylprop-1-ynyl)phenoxy)ethanamine;

4-(3-(2-aminoethoxy)phenyl)but-3-yn-1-ol;

2-(3-(hept-1-ynyl)phenoxy)ethanamine;

2-(3-(3-cyclopentylprop-1-ynyl)phenoxy)ethanamine;

2-(3-(4-phenylbut-1-ynyl)phenoxy)ethanamine;

5-(3-(2-aminoethoxy)phenyl)pent-4-yn-1-ol;

2-(3-(hex-1-ynyl)phenoxy)ethanamine;

2-(3-(3-methoxyprop-1-ynyl)phenoxy)ethanamine;

1-(3-(2-aminoethoxy)phenyl)hex-1-yn-3-ol;

1-(3-(2-aminoethoxy)phenyl)-3-methylhex-1-yn-3-ol;

1-(3-(2-aminoethoxy)phenyl)-4-methylpent-1-yn-3-ol;

2-(3-(4-methoxybut-1-ynyl)phenoxy)ethanamine;

5-(3-(2-aminoethoxy)-phenyl)-N-methylpent-4-ynamide;

5-(3-(2-aminoethoxy)phenyl)-N,N-dimethylpent-4-ynamide;

5-(3-(2-aminoethoxy)phenyl)pent-4-ynamide;

2-(3-(5-methoxypent-1-ynyl)phenoxy)ethanamine, or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 wherein the ophthalmic disease or disorder is dry age-related macular degeneration or Stargardt's macular dystrophy.

21. The method of claim 1 resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject, wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

22. The method of claim 12 wherein the ophthalmic disease or disorder is dry age-related macular degeneration or Stargardt's macular dystrophy.

23. The method of claim 12 resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject, wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).

24. The method of claim 19 wherein the ophthalmic disease or disorder is dry age-related macular degeneration or Stargardt's macular dystrophy.

25. The method of claim 19 resulting in a reduction of lipofuscin pigment accumulated in an eye of the subject, wherein the lipofuscin pigment is N-retinylidene-N-retinyl-ethanolamine (A2E).