Compounds and formulations for treating ophthalmic diseases

1 . A compound represented by the structure of Formula (IVa):

or a pharmaceutically acceptable salt thereof, wherein:

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are independently selected from CR 15 and N, wherein 0, 1, 2,

or 3 of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are N; and wherein one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is the attachment point to the rest of the molecule;

R 14 is selected from:

hydrogen;

C 1 -C 6 alkyl which is optionally substituted with one or more substituents independently selected from R 9 ; and

C 3 -C 6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from R 9 ;

each R 15 is independently selected from:

hydrogen, halogen, —CN, —OH, —OR 13 , —N(R 12 ) 2 , —C(═O)R 12 , —C(═O)OR 12 , —C(═O)N(R 12 ) 2 , —NR 12 C(═O)R 12 , —NR 12 C(═O)N(R 12 ) 2 , —SR 12 , —S(═O)R 13 , —SO 2 R 13 , —SO 2 N(R 12 ) 2 , and —NO 2 ;

C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from R 9 ; and

C 3 -C 6 cycloalkyl and 4-6-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from R 9 ;

R 1 is selected from hydrogen; and C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from R 9 ;

R 2 and R 3 are independently selected from hydrogen; and C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from R 9 ;

or R 1 and R 2 are taken together with the intervening atoms to which they are attached to form a 5- to 8-membered heterocycle, which is optionally substituted with one or more substituents independently selected from R 9 ;

or R 2 and R 3 are taken together with the intervening atoms to which they are attached to form a 4- to 10-membered heterocycle, which is optionally substituted with one or more substituents independently selected from R 9 ;

R 7 is selected from:

hydrogen;

C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from R 9 ; and

C 3 -C 6 cycloalkyl and 4-6-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from R 9 ; and

each R 8 is independently selected from:

hydrogen, halogen, —CN, —OH, —OR 13 , —N(R 12 ) 2 , —C(═O)R 12 , —C(═O)OR 12 , —C(═O)N(R 12 ) 2 , —NR 12 C(═O)R 12 , —NR 12 C(═O)N(R 12 ) 2 , —SR 12 , —S(═O)R 13 , —SO 2 R 13 , —SO 2 N(R 12 ) 2 , and —NO 2 ;

C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from R 9 ;

C 3 -C 6 cycloalkyl and 4-6-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from R 9 ;

each R 9 is independently selected from halogen, ═O, ═S, —CN, —OH, —OR 13 , —N(R 12 ) 2 , —C(═O)R 12 , —C(═O)OR 12 , —OC(═O)R 12 , —C(═O)N(R 12 ) 2 , —NR 12 C(═O)R 12 , —NR 12 C(═O)N(R 12 ) 2 , —OC(═O)N(R 12 ) 2 , —NR 12 C(═O)OR 12 , —OC(═O)OR 12 , —SR 12 , —S(═O)R 13 , —SO 2 R 13 , —SO 2 N(R 12 ) 2 , —NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 carbocycle, and 3- to 6-membered heterocycle;

each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 6 carbocycle, and 3- to 6-membered heterocycle; and

each R 13 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 6 carbocycle, and 3- to 6-membered heterocycle.

2 . The compound or salt of claim 1 , wherein the compound of Formula (IVa) is represented by Formula (IVb):

or a pharmaceutically acceptable salt thereof.

3 . The compound or salt of claim 1 , wherein R 7 is selected from:

hydrogen; and

C 1 -C 6 alkyl which is optionally substituted with one or more substituents independently selected from R 9 .

4 . The compound or salt of claim 3 , wherein R 7 is selected from hydrogen and methyl.

5 . The compound or salt of claim 1 , wherein each R 8 is independently selected from:

hydrogen, halogen, —CN, and —OR 13 ; and

C 1 -C 6 alkyl which is optionally substituted with one or more substituents independently selected from R 9 .

6 . The compound or salt of claim 1 , wherein each R 15 is independently selected from hydrogen, halogen, —CN, —OH, —OR 13 , —N(R 12 ) 2 , C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl.

7 . The compound or salt of claim 1 , wherein R 14 is selected from:

hydrogen; and

C 1 -C 3 alkyl which is optionally substituted with one or more substituents independently selected from R 9 .

8 . The compound or salt of claim 7 , wherein R 14 is selected from hydrogen and methyl.

9 . The compound or salt of claim 8 , wherein R 14 is hydrogen.

10 . A compound selected from:

or a pharmaceutically acceptable salt thereof.

11 . The compound or salt of claim 10 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

12 . The compound or salt of claim 10 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

13 . The compound or salt of claim 10 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

14 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15 . A method for treating or preventing an ophthalmic disease in a subject, the method comprising administering to the eye of a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

16 . The method of claim 15 , wherein the ophthalmic disease is a near vision disorder.

17 . The method of claim 16 , wherein the near vision disorder is cataract or presbyopia.

18 . A method of reducing aggregation of an α-crystallin protein by at least 5% in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19 . The method of claim 18 , wherein aggregation of an a-crystallin protein is reduced by at least 10%.

20 . The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.