Compounds and formulations for treating ocular diseases

Abstract

The present disclosure is directed to compounds, compositions, formulations, and methods of their use in the treatment and prevention of ocular conditions, including cataracts and presbyopia.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 072,724, filed August 31, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Background of the Invention Cataracts affect over 24 million Americans age 40 or older, and by age 75, half of all Americans have a cataract. A cataract is a clouding of the eye's lens that affects vision. The traditional treatment for cataracts is surgical replacement with an artificial intraocular lens. However, surgical cataract treatment is expensive, and the artificial lens does not have the same overall optical quality as a normal lens.

[0003] It is estimated that approximately 112 million Americans currently suffer from presbyopia. Presbyopia is age-related farsightedness that typically begins between the ages of 40 and 50 and initially causes blurred vision, difficulty seeing in dim light, and eye strain. In healthy eyes, the lens can focus light from objects at various distances through a process called accommodation, in which the surrounding muscles slightly change the shape of the lens, altering how light passes through the lens and reaches the retina, where an image is formed. During accommodation, the muscles around the lens contract, changing the shape of the lens and enhancing the eye's ability to focus. This allows for focus adjustment and clear vision at both near and far distances. With age, the lens stiffens due to misfolding of its structural crystalline proteins. This increased lens stiffness limits the eye's ability to adjust focus for reading or other tasks requiring clear vision at close range. While surgery is an option, reading glasses, or eyeglasses with bifocal lenses, are the most common method of correcting presbyopia.

[0004] Because cataracts and presbyopia affect billions of people worldwide, there is a great need for new methods to treat and prevent these diseases. Summary of the Invention

[0005] Provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for treating ocular diseases such as cataracts and presbyopia.

[0006] Provided herein are compounds represented by formula (I) or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising said compounds: TIFF0007801312000001.tif35128In formula, R A is an optionally substituted bicyclic heteroaryl, where R A The above substituents are independently R a More selected; Each R a is independent, 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 , -NR 12 SO2R 12 , -SR 12 , -S(=O)R 13 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C to C, each of which may be substituted with one or more independently selected substituents from 10 Carbocyclic and 3- to 10-membered heterocyclic rings More selected; R B is an optionally substituted bicyclic heteroaryl, where R B The above substituents are independently R b More selected; Each R b is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, -NR 12 SO2R 13 , -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C to C, each of which may be substituted with one or more independently selected substituents from 10 Carbocyclic and 3- to 10-membered heterocyclic rings More selected; R 1 is hydrogen; and, R 9 selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; R 2 and R 3 are independently hydrogen; and R 9 selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 carbocycle, and 3-6 membered heterocycle, each optionally substituted with one or more independently selected substituents; Or, R 1 and R 2 together with the intervening atoms to which they are attached, R 9 or form a 5- to 8-membered heterocycle optionally substituted with one or more independently selected substituents; Or, R 2 and R 3 together with the intervening atoms to which they are attached, R 9 form a 4- to 10-membered heterocycle optionally substituted with one or more independently selected substituents; R 4 , R 5 , and R 6 is independent, Hydrogen, halogen, -CN, -OH, -OR 11 , -C(=O)N(R 10 )2, and -N(R 10 )2; and R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents from More selected; Each R 9 are independently 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 , -SO2R 13 , -SO2N(R 12 )2, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 carbocycle, and 3-6 membered heterocycle; Each R 10 are independently hydrogen; and R 9 selected from C1-C6 alkyl, C3-C6 carbocycle, and 3-6 membered heterocycle, each optionally substituted with one or more independently selected substituents; Each R 11 are independent, R 9 selected from C1-C6 alkyl, C3-C6 carbocycle, and 3-6 membered heterocycle, each optionally substituted with one or more independently selected substituents; Each R 12 is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 carbocycle, and 3-6 membered heterocycle; and Each R 13 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 carbocycle, and 3-6 membered heterocycle.

[0007] In some embodiments, R A is an optionally substituted 9- or 10-membered bicyclic heteroaryl, where R A The above substituents are independently R aIn some embodiments, R A is optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted azaindolyl, optionally substituted pyrrolopyridinyl, optionally substituted pyrazolopyrimidinyl, optionally substituted imidazolopyrimidinyl, optionally substituted benzisoxazolyl, optionally substituted benzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzothiadiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, or optionally substituted quinazolinyl, wherein R A The above substituents are independently R a In some embodiments, R A is optionally substituted indolyl, optionally substituted indazolyl, optionally substituted azaindolyl, optionally substituted pyrrolopyridinyl, optionally substituted pyrazolopyrimidinyl, optionally substituted quinolinyl, or optionally substituted imidazolopyrimidinyl, wherein R A The above substituents are independently R a In some embodiments, R A teeth, TIFF0007801312000002.tif22128;X 1 , X 2 , X 3 , X 4 , and X 5 is an independent CR 8 and N, where X 1 , X 2 , X 3 , X 4 , and X 5 0, 1, or 2 of are N; R 7 is hydrogen; R 9C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 and each R is selected from C-C cycloalkyl and 4- to 6-membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents; 8 are independently 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2;R 9 C-C alkyl, C-C alkenyl, and C-C alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 is selected from C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more more independently selected substituents.

[0008] In some embodiments, the compound of formula (I) is represented by formula (II): TIFF0007801312000003.tif52128In formula, X 1 , X 2 , X 3 , X 4 , and X 5 is an independent CR 8 and N, where X 1 , X 2 , X 3 , X 4 , and X 50 or 1 of is N; R 7 is hydrogen; and R 9 selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; Each R 8 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -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 , -SO2R 13 , and -SO2N(R 12 )2; and R 9 and C1-C6 alkyl optionally substituted with one or more independently selected substituents.

[0009] In some embodiments, R B is an optionally substituted 9- or 10-membered bicyclic heteroaryl, where R B The above substituents are independently R b In some embodiments, R B is optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted azaindolyl, optionally substituted pyrazolopyrimidinyl, optionally substituted imidazolopyrimidinyl, optionally substituted benzisoxazolyl, optionally substituted benzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzothiadiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, or optionally substituted quinazolinyl, wherein RB The above substituents are independently R b In some embodiments, R B is optionally substituted indolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, or optionally substituted indazolyl, where R B The above substituents are independently R b In some embodiments, R B teeth, TIFF0007801312000004.tif21128;Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0, 1, 2, or 3 of Y are N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is the point of attachment to the remainder of the molecule; R 14 is hydrogen; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 and each R is selected from C-C cycloalkyl and 4- to 6-membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents; 15 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -C(=O)R 12 , -C(=O)OR 12 , -C(=O)N(R12 )2, -NR 12 C(=O)R 12 , -NR 12 C(=O)N(R 12 )2, -SR 12 , -S(=O)R 13 , -SO2R 13 , -SO2N(R 12 )2, and -NO2;R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 is selected from C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more more independently selected substituents.

[0010] In some embodiments, the compound of Formula (I) or Formula (II) is represented by Formula (III) or a pharmaceutically acceptable salt thereof: TIFF0007801312000005.tif60128In formula, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0 or 1 of Y is N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 one of which is the point of attachment to the remainder of the molecule; R 14 teeth, hydrogen; R 9C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents from selected from; and Each R 15 is independent, Hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -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 , -SO2R 13 , and -SO2N(R 12 )2; and R 9 C1-C6 alkyl optionally substituted with one or more independently selected substituents is selected from.

[0011] In some embodiments, the compound of Formula (III) is represented by Formula (IIIa-3) or a pharmaceutically acceptable salt thereof: TIFF0007801312000006.tif49128.

[0012] In some embodiments, the compound of formula (III) is represented by formula (IIIb-3) or a pharmaceutically acceptable salt thereof: TIFF0007801312000007.tif55128In formula, Y 1 and Y 2 0 or 1 of is N.

[0013] In some embodiments, the compound of formula (III) is represented by formula (IIIc-3) or a pharmaceutically acceptable salt thereof: TIFF0007801312000008.tif55128.

[0014] In some embodiments, R2 and R 3 are independently hydrogen; and R 9 In some embodiments, R is selected from C1-C6 alkyl, each of which may be substituted with one or more independently selected substituents. 2 and R 3 is independently selected from hydrogen; and C1-C6 alkyl. In some embodiments, R 2 and R 3 are independently selected from C1 to C6 alkyl.

[0015] In some embodiments, R 2 and R 3 together with the intervening atoms to which they are attached, R 9 In some embodiments, R forms a 4- to 8-membered heterocycle, which may be substituted with one or more independently selected substituents. 2 and R 3 together with the intervening atoms to which they are attached, R 9 In some embodiments, R forms a 4-8 membered heterocycloalkyl, optionally substituted with one or more independently selected substituents. 2 and R 3 together with the intervening atoms to which they are attached, R 9 and optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted tetrahydrofuropyrrolyl, each of which may be substituted with one or more independently selected substituents.

[0016] In some embodiments, R 1 is hydrogen; and, R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 1 is selected from hydrogen; and C1-C6 alkyl. In some embodiments, R 1 is hydrogen.

[0017] In some embodiments, R 1 and R 2 together with the intervening atoms to which they are attached, R 9 Forms a 5- to 8-membered heterocycloalkyl optionally substituted with one or more independently selected substituents.

[0018] In some embodiments, the compound of formula (III) is represented by formula (IIId-3) or a pharmaceutically acceptable salt thereof: TIFF0007801312000009.tif55128In formula, Y 1 and Y 2 0 or 1 of is N; and k is 1, 2, 3, or 4.

[0019] In some embodiments, k is 1 or 2.

[0020] In some embodiments, R 4 , R 5 , and R 6 are independently hydrogen, -OR 11 , and -N(R 10 )2; and R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 4 , R 5 , and R 6 are hydrogen atoms.

[0021] In some embodiments, the compound of Formula (I) or Formula (II) is represented by Formula (IV) or a pharmaceutically acceptable salt thereof: TIFF0007801312000010.tif48128.

[0022] In some embodiments, the compound of formula (IV) is represented by formula (IVa) or a pharmaceutically acceptable salt thereof: TIFF0007801312000011.tif62128In formula, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 is an independent CR 15 and N, where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0, 1, 2, or 3 of Y are N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 one of which is the point of attachment to the remainder of the molecule; R 14 teeth, hydrogen; R 9 C1-C6 alkyl optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents selected from; and Each R 15 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0023] In some embodiments, the compound of formula (IVa) is represented by formula (IVb): TIFF0007801312000012.tif57128.

[0024] In some embodiments, R 7 is hydrogen; and, R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 7 is selected from hydrogen and C1-C6 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. 7 is selected from hydrogen and methyl.

[0025] In some embodiments, each R 8 are independently hydrogen, halogen, -CN, and -OR 13 ; and R 9 In some embodiments, each R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 8 are independently hydrogen, halogen, -CN, -OR 13 , C1-C6 alkyl, C1-C6 fluoroalkyl, and C1-C6 hydroxyalkyl. In some embodiments, each R 8 are independently hydrogen, halogen, -CN, -OR 13and C1-C6 alkyl.

[0026] In some embodiments, each R 15 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -C(=O)OR 12 , and -NR 12 SO2R 13 ; and R 9 In some embodiments, each R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 15 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, C1-C6 alkyl, and C1-C6 fluoroalkyl.

[0027] In some embodiments, R 14 is hydrogen; and, R 9 In some embodiments, R is selected from C1-C3 alkyl, optionally substituted with one or more independently selected substituents. 14 is selected from hydrogen and C1-C3 alkyl. In some embodiments, R 14 is selected from hydrogen and methyl. In some embodiments, R 14 is hydrogen.

[0028] Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and their substituents will be chosen by one skilled in the art to provide stable moieties and compounds.

[0029] Also disclosed herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0030] Also disclosed herein is a method for treating eye disease, comprising administering the compound or composition disclosed herein to the eye of a subject in need thereof.In some embodiments, the compound or composition is administered locally by intravitreal injection or intracameral injection.In some embodiments, the eye disease is cataract.In some embodiments, the eye disease is presbyopia.

[0031] Also disclosed herein are methods for reducing α-crystallin protein aggregation by at least 5% in a subject in need thereof, comprising administering a compound or composition disclosed herein to the eye of the subject in need thereof. In some embodiments, α-crystallin protein aggregation is reduced by at least 10%. In some embodiments, α-crystallin protein aggregation is reduced by at least 20%.

[0032] [The present invention 1001] A compound represented by the structure of formula (I) or a pharmaceutically acceptable salt thereof: TIFF0007801312000013.tif35128 During the ceremony, R A is an optionally substituted bicyclic heteroaryl, where R A The above substituents are independently R a More selected; Each R a is independent, 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(R12 ) 2 , -NR 12 C(=O)OR 12 , -OC(=O)OR 12 , -NR 12 SO 2 R 12 , -SR 12 , -S(=O)R 13 , -SO 2 R 13 , -SO 2 N(R 12 ) 2 , and -NO 2 ; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 10 Carbocyclic and 3- to 10-membered heterocyclic rings More selected; R B is an optionally substituted bicyclic heteroaryl, where R B The above substituents are independently R b More selected; Each R b is independent, 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 , -NR 12 SO 2 R 13 , -NO 2 ; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 10 Carbocyclic and 3- to 10-membered heterocyclic rings More selected; R 1 is hydrogen; and, R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl; R 2 and R 3 are independently hydrogen; and R 9 C, each of which may be substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2~C 6 Alkynyl, C 3 ~C 6 selected from carbocycles and 3- to 6-membered heterocycles; Or, R 1 and R 2 together with the intervening atoms to which they are attached, R 9 or form a 5- to 8-membered heterocycle optionally substituted by one or more independently selected substituents; Or, R 2 and R 3 together with the intervening atoms to which they are attached, R 9 form a 4- to 10-membered heterocycle optionally substituted by one or more independently selected substituents; R 4 、R 5 , and R 6 is independent, Hydrogen, halogen, -CN, -OH, -OR 11 , -C(=O)N(R 10 ) 2 , and -N(R 10 ) 2 ; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl More selected; Each R 9 are independently 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 selected from carbocycles and 3- to 6-membered heterocycles; Each R 10 are independently hydrogen; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 3 ~C 6 selected from carbocycles and 3- to 6-membered heterocycles; Each R 11 are independent, R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 3 ~C 6 selected from carbocycles and 3- to 6-membered heterocycles; Each R 12 are independently 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 selected from carbocycles, and 3- to 6-membered heterocycles; and Each R 13 is independently C 1~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, C 3 ~C 6 It is selected from a carbocycle and a 3- to 6-membered heterocycle. [The present invention 1002] R A is an optionally substituted 9- or 10-membered bicyclic heteroaryl, where R A The above substituents are independently R a 1001. A compound or salt of the present invention selected from: [The present invention 1003] R A is optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted azaindolyl, optionally substituted pyrrolopyridinyl, optionally substituted pyrazolopyrimidinyl, optionally substituted imidazolopyrimidinyl, optionally substituted benzisoxazolyl, optionally substituted benzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzothiadiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, or optionally substituted quinazolinyl, wherein R A The above substituents are independently R a The compound or salt of the present invention 1001 or 1002 selected from: [The present invention 1004] R A is optionally substituted indolyl, optionally substituted indazolyl, optionally substituted azaindolyl, optionally substituted pyrrolopyridinyl, optionally substituted pyrazolopyrimidinyl, optionally substituted quinolinyl, or optionally substituted imidazolopyrimidinyl, wherein R A The above substituents are independently R a The compound or salt of the present invention 1003 selected from: [The present invention 1005] R A but, TIFF0007801312000014.tif22128 and; X 1 、X 2 、X 3 、X 4 , and X 5 became independent and became a CR 8 and N, where X 1 、X 2 、X 3 、X 4 , and X 5 0, 1, or 2 of are N; R7 but, hydrogen; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 6 Cycloalkyl and 4-6 membered heterocycloalkyl selected from; and Each R 8 became independent, 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 ; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3~C 6 Cycloalkyl and 4-6 membered heterocycloalkyl Selected from: The compound or salt of any one of 1001 to 1004 of the present invention. [The present invention 1006] The compound or salt of the present invention, wherein the compound of formula (I) is represented by formula (II) or a pharmaceutically acceptable salt thereof: TIFF0007801312000015.tif52128 During the ceremony, X 1 、X 2 、X 3 、X 4 , and X 5 is an independent CR 8 and N, where X 1 、X 2 、X 3 、X 4 , and X 5 0 or 1 of is N; R 7 teeth, hydrogen; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl selected from; and Each R 8 is independent, Hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 ) 2 , -C(=O)OR 12 , -C(=O)N(R 12 ) 2 , -NR 12 C(=O)R 12 , -NR12 C(=O)N(R 12 ) 2 , -SR 12 , -SO 2 R 13 , and -SO 2 N(R 12 ) 2 ; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl is selected from. [The present invention 1007] R B is an optionally substituted 9- or 10-membered bicyclic heteroaryl, where R B The above substituents are independently R b The compound or salt of any one of 1001 to 1006 of the present invention selected from the group consisting of: [The present invention 1008] R B is optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted azaindolyl, optionally substituted pyrazolopyrimidinyl, optionally substituted imidazolopyrimidinyl, optionally substituted benzisoxazolyl, optionally substituted benzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzothiadiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, or optionally substituted quinazolinyl, wherein R B The above substituents are independently R b The compound or salt of any one of 1001 to 1007 of the present invention selected from the group consisting of: [The present invention 1009] R B is optionally substituted indolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, or optionally substituted indazolyl, wherein R B The above substituents are independently R b The compound or salt of the present invention 1008 selected from: [The present invention 1010] R B but, TIFF0007801312000016.tif21128 and; Y 1 、Y 2 、Y 3 、Y 4 、Y 5 , and Y 6 became independent and became a CR15 and N, where Y 1 、Y 2 、Y 3 、Y 4 、Y 5 , and Y 6 0, 1, 2, or 3 of Y are N; and 1 、Y 2 、Y 3 、Y 4 、Y 5 , and Y 6 is the point of attachment to the remainder of the molecule; R 14 but, hydrogen; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 6 Cycloalkyl and 4-6 membered heterocycloalkyl selected from; and Each R 15 became independent, 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 ; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 6 Cycloalkyl and 4-6 membered heterocycloalkyl Selected from: A compound or salt of any one of 1001 to 1009 of the present invention. [The present invention 1011] The compound or salt of the present invention, wherein the compound of formula (I) or formula (II) is represented by formula (III) or a pharmaceutically acceptable salt thereof: TIFF0007801312000017.tif60128 During the ceremony, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 , and Y 6 is an independent CR 15 and N, where Y 1 、Y 2 、Y 3 、Y 4 、Y 5 , and Y 6 0 or 1 of Y is N; and 1 、Y 2 、Y 3 、Y 4、Y 5 , and Y 6 one of which is the point of attachment to the remainder of the molecule; R 14 teeth, hydrogen; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl selected from; and Each R 15 is independent, Hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 ) 2 , -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 , -SO 2 R 13 , and -SO 2 N(R 12 ) 2 ; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl is selected from. [The present invention 1012] The compound or salt of the present invention, wherein the compound of formula (III) is represented by formula (IIIa-3) or a pharmaceutically acceptable salt thereof: TIFF0007801312000018.tif50128 。 [The present invention 1013] The compound or salt of the present invention, wherein the compound of formula (III) is represented by formula (IIIb-3) or a pharmaceutically acceptable salt thereof: TIFF0007801312000019.tif55128 In the formula, Y 1 and Y 2 0 or 1 of is N. [The present invention 1014] The compound or salt of the present invention, wherein the compound of formula (III) is represented by formula (IIIc-3) or a pharmaceutically acceptable salt thereof: TIFF0007801312000020.tif55128 。 [The present invention 1015] R 2 and R 3 are independently hydrogen; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 3 ~C 6 The compound or salt of any one of 1001 to 1014 of the present invention, which is selected from a carbocycle and a 3- to 6-membered heterocycle. [The present invention 1016] R 2 and R 3 are independently hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 6 The compound or salt of the present invention 1015, which is selected from a carbocycle and a 3- to 6-membered heterocycle. [The present invention 1017] R 2 and R 3 independently C 1 ~C 6 The compound or salt of the present invention 1016, wherein the compound or salt is selected from alkyl. [The present invention 1018] R 2 and R 3 together with the intervening atoms to which they are bonded, R 9 The compound or salt of any one of 1001 to 1014 of the present invention, which forms a 4- to 8-membered heterocycle optionally substituted with one or more substituents independently selected from: [The present invention 1019] R 2 and R 3 together with the intervening atoms to which they are bonded, R 9 The compound or salt of 1018 of the present invention, which forms a 4- to 8-membered heterocycloalkyl optionally substituted with one or more independently selected substituents. [The present invention 1020] R 2 and R 3 together with the intervening atoms to which they are bonded, R 9 optionally substituted azetidinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, or optionally substituted tetrahydrofuropyrrolyl, each of which is optionally substituted by one or more independently selected substituents from The compound or salt of the present invention 1019, which forms: [The present invention 1021] R 1 is hydrogen; and, R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 The compound or salt of any one of 1001 to 1020 of the present invention, wherein the compound or salt is selected from alkyl. [The present invention 1022] R 1 is hydrogen; and C 1 ~C 6 The compound or salt of the present invention 1021, selected from alkyl. [The present invention 1023] R 1 The compound or salt of the present invention 1022, wherein is hydrogen. [The present invention 1024] R 1 and R 2 together with the intervening atoms to which they are bonded, R 9 The compound or salt of any one of 1001 to 1014 of the present invention, which forms a 5- to 8-membered heterocycloalkyl optionally substituted with one or more independently selected substituents from the group consisting of: [The present invention 1025] The compound or salt of the present invention 1024, wherein the compound of formula (III) is represented by formula (IIId-3) or a pharmaceutically acceptable salt thereof: TIFF0007801312000021.tif55128 During the ceremony, Y 1 and Y 2 0 or 1 of is N; and k is 1, 2, 3, or 4. [The present invention 1026] 1025. The compound or salt of claim 10, wherein k is 1 or 2. [The present invention 1027] R 4 、R 5 , and R 6 became independent, Hydrogen, -OR 11 , and -N(R 10 ) 2 ; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl The compound or salt of any one of 1001 to 1026 of the present invention selected from the group consisting of: [The present invention 1028] R 4 、R 5 , and R 6 The compound or salt of any one of 1001 to 1027 according to the present invention, wherein each of [The present invention 1029] The compound or salt of any one of claims 1001 to 1006, wherein the compound of formula (I) or formula (II) is represented by formula (IV) or a pharmaceutically acceptable salt thereof: TIFF0007801312000022.tif48128 。 [The present invention 1030] The compound or salt of the present invention, wherein the compound of formula (IV) is represented by formula (IVa) or a pharmaceutically acceptable salt thereof: TIFF0007801312000023.tif62128 During the ceremony, Y 1 、Y 2 、Y 3 、Y 4 , and Y 5 is an independent CR 15 and N, where Y 1 、Y 2 、Y 3 、Y 4 、Y 5 , and Y 6 0, 1, 2, or 3 of Y are N; and 1 、Y 2 、Y 3 、Y 4 、Y 5 , and Y 6 one of which is the point of attachment to the remainder of the molecule; R 14 teeth, hydrogen; R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 alkyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 6 Cycloalkyl and 3-6 membered heterocycloalkyl selected from; and Each R 15 is independent, 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 ; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 Alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from3 ~C 6 Cycloalkyl and 4-6 membered heterocycloalkyl is selected from. [The present invention 1031] The compound or salt of the present invention 1030, wherein the compound of formula (IVa) is represented by formula (IVb) or a pharmaceutically acceptable salt thereof: TIFF0007801312000024.tif57128 。 [The present invention 1032] R 7 but, hydrogen; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl The compound or salt of any one of 1005 to 1031 of the present invention selected from the group consisting of: [The present invention 1033] R 7 is hydrogen and C 1 ~C 6 The compound or salt of the present invention 1032, selected from alkyl. [The present invention 1034] R 7 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. [This invention 1035] R 7 The compound or salt of the present invention 1034, wherein is selected from hydrogen and methyl. [The present invention 1036] Each R 8 became independent, Hydrogen, halogens, -CN, and -OR 13 ; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl The compound or salt of any one of 1005 to 1035 of the present invention selected from the group consisting of: [This invention 1037] Each R 8 are independently hydrogen, halogen, -CN, -OR 13 、C 1 ~C 6 Alkyl, C1 ~C 6 Fluoroalkyl, and C 1 ~C 6 The compound or salt of the present invention 1036, selected from hydroxyalkyl. [The present invention 1038] Each R 8 are independently hydrogen, halogen, -CN, -OR 13 , and C 1 ~C 6 The compound or salt of the present invention 1037, wherein the compound or salt is selected from alkyl. [This invention 1039] Each R 15 became independent, Hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 ) 2 , -C(=O)OR 12 , and -NR 12 SO 2 R 13 ; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl The compound or salt of any one of 1010 to 1038 of the present invention selected from the group consisting of: [The present invention 1040] Each R 15 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 ) 2 、C 1 ~C 6 Alkyl, and C 1 ~C 6 1039. A compound or salt of the present invention selected from fluoroalkyl. [This invention 1041] R 14 but, hydrogen; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 3 Alkyl The compound or salt of any one of 1010 to 1040 of the present invention selected from the group consisting of: [The present invention 1042] R 14 is hydrogen and C 1 ~C 3 The compound or salt of the present invention 1041, wherein the compound or salt is selected from alkyl. [This invention 1043] R 14 1042. A compound or salt of the present invention, wherein is selected from hydrogen and methyl. [This invention 1044] R 14 The compound or salt of the present invention 1043, wherein is hydrogen. [This invention 1045] The compound is TIFF0007801312000025.tif218135TIFF0007801312000026.tif241134TIFF0007801312000027.tif243142TIFF0007801312000028.tif243142TIFF0007801312000029.tif88128 1001. A compound or salt of the present invention selected from the group consisting of: [The present invention 1046] The compound is TIFF0007801312000030.tif126133TIFF0007801312000031.tif215134TIFF0007801312000032.tif213138 1001. A compound or salt of the present invention selected from the group consisting of: [This invention 1047] The compound is TIFF0007801312000033.tif153136 1001. A compound or salt of the present invention selected from the group consisting of: [This invention 1048] The compound is TIFF0007801312000034.tif159138 1001. A compound or salt of the present invention selected from the group consisting of: [This invention 1049] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1048 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. [The present invention 1050] 1. A method for treating or preventing an eye disease in a subject, comprising: The method comprises the step of administering to the eye of a subject in need thereof any of the compounds of present inventions 1001 to 1048, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of present invention 1049. [This invention 1051] 1050. The method of claim 1050, wherein the eye disease is near vision impairment. [This invention 1052] 1051. The method of claim 1051, wherein said near vision impairment is cataract or presbyopia. [This invention 1053] 1. A method for reducing alpha-crystallin protein aggregation by at least 5% in a subject in need thereof, comprising: The method comprises the step of administering to a subject in need thereof an effective amount of any of the compounds of the present invention 1001 to 1048, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention 1049. [This invention 1054] The method of claim 1053, wherein α-crystallin protein aggregation is reduced by at least 10%. [This invention 1055] The method of claim 1054, wherein alpha-crystallin protein aggregation is reduced by at least 20%. Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0033] Detailed Description of the Invention definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are incorporated by reference.

[0034] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0035] "Alkyl" refers to a straight or branched hydrocarbon chain radical (i.e., C1-C6) consisting solely of carbon and hydrogen atoms, containing no unsaturated bonds, and preferably having from 1 to 15 carbon atoms. 15 In certain embodiments, alkyl contains 1 to 13 carbon atoms (i.e., C1-C 13In certain embodiments, an alkyl contains 1 to 8 carbon atoms (i.e., a C1-C8 alkyl). In other embodiments, an alkyl contains 1 to 5 carbon atoms (i.e., a C1-C5 alkyl). In other embodiments, an alkyl contains 1 to 4 carbon atoms (i.e., a C1-C4 alkyl). In other embodiments, an alkyl contains 1 to 3 carbon atoms (i.e., a C1-C3 alkyl). In other embodiments, an alkyl contains 1 to 2 carbon atoms (i.e., a C1-C2 alkyl). In other embodiments, an alkyl contains 1 carbon atom (i.e., a C1 alkyl). In other embodiments, an alkyl contains 5 to 15 carbon atoms (i.e., a C5-C 15 In another embodiment, an alkyl contains 5 to 8 carbon atoms (i.e., a C5-C8 alkyl). In another embodiment, an alkyl contains 2 to 5 carbon atoms (i.e., a C2-C5 alkyl). In another embodiment, an alkyl contains 3 to 5 carbon atoms (i.e., a C3-C5 alkyl). In certain embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless stated otherwise in the specification, an alkyl group may be substituted with one or more substituents, such as those described herein.

[0036] "Alkenyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms (i.e., C2 to C6 12 alkenyl) refers to a straight or branched hydrocarbon chain radical group. In certain embodiments, alkenyl contains 2 to 10 carbon atoms (i.e., C2-C 10alkenyl). In certain embodiments, an alkenyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkenyl). In other embodiments, an alkenyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). An alkenyl can be attached to the remainder of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless stated otherwise in the specification, an alkenyl group can be optionally substituted with one or more substituents, such as those described herein.

[0037] "Alkynyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having 2 to 12 carbon atoms (i.e., C2 to C6 12 Alkynyl refers to a straight or branched hydrocarbon chain radical group. In certain embodiments, an alkynyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, an alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). An alkynyl can be attached to the remainder of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless stated otherwise in the specification, an alkynyl group can be optionally substituted with one or more substituents, such as those described herein.

[0038] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen atoms, containing no unsaturated bonds, and preferably having 1 to 12 carbon atoms, that connects the remainder of the molecule to a radical group, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, an alkylene contains 1 to 10 carbon atoms (i.e., a C1-C8 alkylene). In certain embodiments, an alkylene contains 1 to 8 carbon atoms (i.e., a C1-C8 alkylene). In other embodiments, an alkylene contains 1 to 5 carbon atoms (i.e., a C1-C5 alkylene). In other embodiments, an alkylene contains 1 to 4 carbon atoms (i.e., a C1-C4 alkylene). In another embodiment, the alkylene contains 1 to 3 carbon atoms (i.e., a C1-C3 alkylene). In another embodiment, the alkylene contains 1 to 2 carbon atoms (i.e., a C1-C2 alkylene). In another embodiment, the alkylene contains 1 carbon atom (i.e., a C1 alkylene). In another embodiment, the alkylene contains 5 to 8 carbon atoms (i.e., a C5-C8 alkylene). In another embodiment, the alkylene contains 2 to 5 carbon atoms (i.e., a C2-C5 alkylene). In another embodiment, the alkylene contains 3 to 5 carbon atoms (i.e., a C3-C5 alkylene). Unless stated otherwise in the specification, an alkylene chain may be substituted with one or more substituents, such as those described herein.

[0039] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, preferably having 2 to 12 carbon atoms, that attaches the rest of the molecule to a radical group. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, the alkenylene contains 2 to 10 carbon atoms (i.e., C2 to C6). 10 alkenylene). In certain embodiments, an alkenylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, an alkenylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene contains 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, an alkenylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkenylene). Unless stated otherwise in the specification, an alkenylene chain may be substituted with one or more substituents, such as those described herein.

[0040] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, preferably having 2 to 12 carbon atoms, that attaches the rest of the molecule to a radical group. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, the alkynylene contains 2 to 10 carbon atoms (i.e., C2 to C6). 10alkynylene). In certain embodiments, the alkynylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, the alkynylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, the alkynylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, the alkynylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, the alkynylene contains 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, the alkynylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, the alkynylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkynylene). Unless stated otherwise in the specification, the alkynylene chain may be substituted with one or more substituents, such as those described herein.

[0041] "Aryl" refers to an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon from 5 to 18 carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise in the specification, the term "aryl" or the prefix "ar-" (e.g., in "aralkyl") is meant to include aryl radicals that may be substituted with one or more substituents, such as those described herein.

[0042] "Aralkyl" is a group of the formula -R c -aryl radical, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical may be optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical may be optionally substituted as described above for an aryl group.

[0043] "Aralkenyl" is a group of the formula -R d -aryl radical, where R d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical may be optionally substituted as described above for an alkenylene group.

[0044] "Aralkynyl" is a group of the formula -R e -aryl radical, where R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical may be optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical may be optionally substituted as described above for an alkynylene chain.

[0045] "C x~y " or "C x ~C y The term "alkyl," when used with a chemical moiety such as alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, "C x~y The term "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups, containing x to y carbon atoms in the chain. x~y alkenyl" and "C x~y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0046] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles can be monocyclic or polycyclic and can include 3- to 10-membered monocycles, 6- to 12-membered bicycles, and 6- to 12-membered bridged rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, a carbocycle is aryl. In some embodiments, a carbocycle is cycloalkyl. In some embodiments, a carbocycle is cycloalkenyl. In exemplary embodiments, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, as long as valences permit. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, carbocycles may be optionally substituted with one or more substituents such as those described herein.

[0047] "Cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. In certain embodiments, cycloalkyls contain 3-10 carbon atoms. In other embodiments, cycloalkyls contain 5-7 carbon atoms. A cycloalkyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals that are optionally substituted with one or more substituents, such as those described herein.

[0048] "Cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. In another embodiment, a cycloalkenyl contains 5 to 7 carbon atoms. A cycloalkenyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise in the specification, the term "cycloalkenyl" is meant to include cycloalkenyl radicals that are optionally substituted with one or more substituents, such as those described herein.

[0049] "Halo" or alternatively "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0050] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl radical may be substituted as described herein.

[0051] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxy radicals, e.g., hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, etc. In some embodiments, the alkyl portion of the hydroxyalkyl radical may be substituted as described herein.

[0052] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing carbon atoms and one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles can be monocyclic or polycyclic and can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring in a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle is heteroaryl. In some embodiments, the heterocycle is heterocycloalkyl. In exemplary embodiments, a heterocycle, e.g., pyridyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.

[0053] "Heterocycloalkyl" refers to a saturated ring containing carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyls can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. The heteroatoms in a heterocycloalkyl radical can be oxidized. One or more nitrogen atoms, if present, can be quaternized. A heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl, e.g., any carbon or nitrogen atom of the heterocycloalkyl, valence permitting. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above, which may be substituted with one or more substituents, such as those described herein.

[0054] "Heterocycloalkenyl" refers to an unsaturated ring containing carbon atoms and at least one heteroatom, and at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. In another embodiment, heterocycloalkenyl contains 5-7 ring atoms. Heterocycloalkenyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazolinone (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine. Unless stated otherwise specifically in the specification, the term "heterocycloalkenyl" is meant to include heterocycloalkenyl radicals that are optionally substituted with one or more substituents, such as those described herein.

[0055] "Heteroaryl" refers to an aromatic ring containing carbon atoms and one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. As used herein, a heteroaryl ring can be selected from monocyclic or bicyclic fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroatoms in a heteroaryl radical can be oxidized. One or more nitrogen atoms, if present, can be quaternized. A heteroaryl can be attached to the remainder of the molecule through any atom of the heteroaryl, e.g., a carbon or nitrogen atom of the heteroaryl, if valence permits. Examples of heteroaryl are azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1, 2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2- Oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclo[4,5]thieno[2,3-d]pyrimidinyl, 5, ... Hepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless otherwise indicated in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above, which may be optionally substituted with one or more substituents, such as those described herein.

[0056] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, including their racemic and optically pure forms, and all tautomeric forms, are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomer (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, e.g., ortho, meta, and para isomers around a phenyl ring.

[0057] "Tautomer" refers to a molecule in which a proton shift from one atom of the molecule to another atom of the same molecule is possible. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerism is possible, it is believed that a chemical equilibrium of tautomers exists. Unless otherwise stated, chemical structures depicted herein are intended to include structures that are different tautomers of the depicted structure. For example, a chemical structure depicted with an enol moiety also includes the keto tautomeric form of the enol moiety. The exact ratio of tautomers will vary depending on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium are: Includes TIFF0007801312000035.tif83128.

[0058] The compounds disclosed herein may, in some embodiments, be present in different isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C and / or 14The compound is used in a form with an increased C content. In one specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can increase the duration of action of a drug by improving metabolic stability and / or efficacy.

[0059] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium. 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0060] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 It can be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125All isotopic substitutions with I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0061] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 It is substituted with an H atom. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0062] Deuterium-substituted compounds can be synthesized using a variety of methods, such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0063] Deuterated starting materials are readily available and can be subjected to the synthetic methods described herein to result in the synthesis of deuterated compounds. Many deuterated reagents and components are commercially available from chemical distributors such as Aldrich Chemical Co.

[0064] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be utilized to transfer deuterated carbon atoms to reaction substrates under nucleophilic substitution reaction conditions. The use of CD3I is illustrated, by way of example only, in the following reaction scheme: TIFF0007801312000036.tif40128

[0065] A deuterium transfer reagent such as lithium aluminum deuteride (LiAlD4) is utilized to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated by way of example only in the following reaction scheme: TIFF0007801312000037.tif11156

[0066] By way of example only, deuterium gas and a palladium catalyst are utilized to reduce unsaturated carbon-carbon bonds and effect reductive displacement of aryl carbon-halogen bonds, as shown in the reaction scheme below. TIFF0007801312000038.tif33137

[0067] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, etc. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0068] The expression "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0069] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances utilized in pharmaceutical formulations.

[0070] In certain embodiments, the term "prevent" or "preventing" in relation to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0071] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbon or heteroatoms of the structure. It is understood that "substituted" or "substituted with" implicitly includes the proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom.

[0072] Substituents can include any of the substituents described herein, e.g., halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, carbocycle, heterocycle, cycloalkyl, heterocycloalkyl, aromatic, and heteroaromatic moieties. In some embodiments, substituents can include any of the substituents described herein, e.g., halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-ORa , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may include alkyl, alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -Rb -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a is, as far as valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -Rb -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); where each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain; and each R c is a straight or branched alkylene, alkenylene, or alkynylene chain.

[0073] As used herein, the terms "treat," "treating," or "treatment" can include alleviating, ameliorating, or reducing the symptoms of a disease or condition, preventing further symptoms, alleviating or preventing the underlying cause of the symptoms, inhibiting the disease or condition, e.g., halting the onset of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving the symptoms caused by the disease or condition, or arresting the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0074] The compounds of the present invention also include crystalline and amorphous forms of the compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0075] Introduction Alpha-crystallin is a major structural protein found in the eye and may maintain the refractive index and transparency of the lens. Alpha-crystallin is composed of two homologous subunits, alpha-A-crystallin (cryAA) and alpha-B-crystallin (cryAB), which belong to a family of small heat shock proteins (sHSPs) containing a conserved crystallin domain. alpha-A is 173 amino acids long, and alpha-B is 175 amino acids long. The two alpha-crystallin genes, alpha-A and alpha-B, encode proteins that share 57% sequence identity. The ratio of alpha-A to alpha-B in most vertebrate lenses can be 3:1, but this ratio can vary depending on species and age. While alpha-A-crystallin protein is found primarily in the lens and rarely in other tissues, alpha-B-crystallin protein is ubiquitously expressed and can be found in other tissues such as the brain, heart, and muscle.

[0076] These α-crystallin subunits act as molecular chaperones to prevent cellular aggregation and inactivation of client proteins under various stress conditions. However, the chaperone activity of these α-crystallin subunits can be lost or reduced by aging or certain genetic or environmental factors, which can cause α-crystallin aggregation and precipitation and lead to cataracts.

[0077] In certain aspects, the present disclosure provides compounds, formulations, and methods for treating visual disorders associated with aggregation of α-crystallin proteins in the lens. In particular, the present disclosure provides compounds, formulations, and methods for treating cataracts and presbyopia.

[0078] Compounds of the Disclosure The present disclosure provides compounds and salts for use in the treatment of eye diseases, and their formulations.The compounds and salts of the present disclosure can be used for the treatment or prevention of visual impairment, such as near vision impairment.In certain embodiments, the compounds of the present disclosure reduce the aggregation of α-crystallin protein in the lens of the eye.The compounds and salts of the present disclosure can be used in the formulations, methods and combined therapies described herein.In certain embodiments, the compounds and salts of the present disclosure are used for the treatment or prevention of cataract or presbyopia.

[0079] In one aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof: TIFF0007801312000039.tif35128In formula, R A is an optionally substituted bicyclic heteroaryl, where R A The above substituents are independently R a More selected; Each R a is independent, Halogen, =O, =S, -CN, -OH, -OR 13 , -N(R 12 )2, -C(=O)R 12 , -C(=O)OR 12 , -OC(=O)R12 , -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 , -NR 12 SO2R 12 , -SR 12 , -S(=O)R 13 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C to C, each of which may be substituted with one or more independently selected substituents from 10 Carbocyclic and 3- to 10-membered heterocyclic rings More selected; R B is an optionally substituted bicyclic heteroaryl, where R B The above substituents are independently R b More selected; Each R b is independent, 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 , -SR12 , -S(=O)R 13 , -SO2R 13 , -SO2N(R 12 )2, -NR 12 SO2R 13 , -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C to C, each of which may be substituted with one or more independently selected substituents from 10 Carbocyclic and 3- to 10-membered heterocyclic rings More selected; R 1 is hydrogen; and, R 9 selected from C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; R 2 and R 3 are independently hydrogen; and R 9 selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 carbocycle, and 3-6 membered heterocycle, each optionally substituted with one or more independently selected substituents; Or, R 1 and R 2 together with the intervening atoms to which they are attached, R 9 or form a 5- to 8-membered heterocycle optionally substituted with one or more independently selected substituents; Or, R 2 and R 3 together with the intervening atoms to which they are attached, R 9 form a 4- to 10-membered heterocycle optionally substituted with one or more independently selected substituents; R 4 , R 5 , and R 6 is independent, Hydrogen, halogen, -CN, -OH, -OR11 , -C(=O)N(R 10 )2, and -N(R 10 )2; and R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents from More selected; Each R 9 are independently 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 , -SO2R 13 , -SO2N(R 12 )2, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 carbocycle, and 3-6 membered heterocycle; Each R 10 are independently hydrogen; and R 9 selected from C1-C6 alkyl, C3-C6 carbocycle, and 3-6 membered heterocycle, each optionally substituted with one or more independently selected substituents; Each R 11 are independent, R 9 selected from C1-C6 alkyl, C3-C6 carbocycle, and 3-6 membered heterocycle, each optionally substituted with one or more independently selected substituents; Each R 12are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 carbocycle, and 3-6 membered heterocycle; and Each R 13 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 carbocycle, and 3-6 membered heterocycle.

[0080] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and their substituents will be chosen by one of skill in the art to provide stable moieties and compounds. For example, in some embodiments, R A is an optionally substituted 9- or 10-membered bicyclic heteroaryl, where R A The above substituents are independently R a is selected from.

[0081] In some embodiments, R A is optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted azaindolyl, optionally substituted pyrrolopyridinyl, optionally substituted pyrazolopyrimidinyl, optionally substituted imidazolopyrimidinyl, optionally substituted benzisoxazolyl, optionally substituted benzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzothiadiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, or optionally substituted quinazolinyl, wherein R A The above substituents are independently R a In some embodiments, R Ais optionally substituted indolyl, optionally substituted indazolyl, optionally substituted azaindolyl, optionally substituted pyrrolopyridinyl, optionally substituted pyrazolopyrimidinyl, optionally substituted quinolinyl, or optionally substituted imidazolopyrimidinyl, wherein R A The above substituents are independently R a In some embodiments, R A is optionally substituted indolyl, optionally substituted benzimidazolyl, or optionally substituted indazolyl, where R A The above substituents are independently R a In some embodiments, R A is an optionally substituted indolyl, where R A The above substituents are independently R a In some embodiments, R A is an optionally substituted N-substituted indole, where R A The above substituents are independently R a In some embodiments, R A is an optionally substituted N-alkyl indole, where R A The above substituents are independently R a In some embodiments, R A is an optionally substituted N-methylindole, where R A The above substituents are independently R a is selected from.

[0082] In some embodiments, R A teeth, TIFF0007801312000040.tif22128, where: X 1 , X 2 , X 3 , X 4 , and X 5 is an independent CR 8 and N, where X 1 , X 2 , X 3, X 4 , and X 5 0, 1, or 2 of are N; R 7 teeth, hydrogen; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents selected from; and Each R 8 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0083] In some embodiments, the compound of formula (I) is represented by formula (II): TIFF0007801312000041.tif52128In formula, X 1 , X 2 , X 3 , X 4 , and X 5 is an independent CR 8 and N, where X 1 , X 2 , X 3 , X 4 , and X 5 0, 1, or 2 of are N; R 7 teeth, hydrogen; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents selected from; and Each R 8 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0084] In some embodiments, R 7 teeth, hydrogen; and R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents from selected from; and Each R 8 is independent, Hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -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 , -SO2R 13 , and -SO2N(R 12 )2; and R 9 C1-C6 alkyl optionally substituted with one or more independently selected substituents is selected from.

[0085] In some embodiments, X 1 , X 2 , X 3 , X 4 , and X 5 0 or 1 of is N.

[0086] In some embodiments, X 1 is CR 8 and X 2 , X 3 , X 4 , and X 5 is an independent CR 8and N, where X 2 , X 3 , X 4 , and X 5 In some embodiments, 0, 1, or 2 of X are N. 1 is CR 8 and X 2 , X 3 , X 4 , and X 5 is an independent CR 8 and N, where X 2 , X 3 , X 4 , and X 5 0 or 1 of is N.

[0087] In some embodiments, X 1 is CR 8 and X 2 is CR 8 and X 3 is CR 8 and X 4 is CR 8 and X 5 is CR 8 is.

[0088] In some embodiments, X 1 is N;X 2 is CR 8 and X 3 is CR 8 and X 4 is CR 8 and X 5 is CR 8 is.

[0089] In some embodiments, X 1 is CR 8 and X 2 is N;X 3 is CR 8 and X 4 is CR 8 and X 5 is CR 8 is.

[0090] In some embodiments, X1 is CR 8 and X 2 is CR 8 and X 3 is N;X 4 is CR 8 and X 5 is CR 8 is.

[0091] In some embodiments, X 1 is CR 8 and X 2 is CR 8 and X 3 is CR 8 and X 4 is N; and X 5 is CR 8 is.

[0092] In some embodiments, X 1 is CR 8 and X 2 is CR 8 and X 3 is CR 8 and X 4 is CR 8 and X 5 is N.

[0093] In some embodiments, R B is an optionally substituted 9- or 10-membered bicyclic heteroaryl, where R B The above substituents are independently R b is selected from.

[0094] In some embodiments, R Bis optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted azaindolyl, optionally substituted pyrrolopyridinyl, optionally substituted pyrazolopyrimidinyl, optionally substituted imidazolopyrimidinyl, optionally substituted benzisoxazolyl, optionally substituted benzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzothiadiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, or optionally substituted quinazolinyl, wherein R B The above substituents are independently R b In some embodiments, R B is optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted benzimidazolyl, optionally substituted azaindolyl, optionally substituted pyrazolopyrimidinyl, optionally substituted imidazolopyrimidinyl, optionally substituted benzisoxazolyl, optionally substituted benzoxazolyl, optionally substituted benzisoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzoxadiazolyl, optionally substituted benzothiadiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted quinoxalinyl, or optionally substituted quinazolinyl, wherein R B The above substituents are independently R b In some embodiments, R B is optionally substituted indolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, or optionally substituted indazolyl, wherein R B The above substituents are independently R bIn some embodiments, R B is optionally substituted indolyl, optionally substituted benzimidazolyl, or optionally substituted indazolyl, where R B The above substituents are independently R b In some embodiments, R B is an optionally substituted indolyl, where R B The above substituent is R b More independently selected.

[0095] In some embodiments, R B teeth, TIFF0007801312000042.tif21128, where: Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 became independent and became a CR 15 and N, where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0, 1, 2, or 3 of Y are N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 one of which is the point of attachment to the remainder of the molecule; R 14 teeth, hydrogen; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents selected from; and Each R 8 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0096] In some embodiments, the compound of Formula (I) or Formula (II) is represented by Formula (III) or a pharmaceutically acceptable salt thereof: TIFF0007801312000043.tif60128In formula, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0, 1, 2, or 3 of Y are N; and 1 , Y 2 , Y3 , Y 4 , Y 5 , and Y 6 one of which is the point of attachment to the remainder of the molecule; R 14 teeth, hydrogen; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents selected from; and Each R 8 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0097] In some embodiments, R 14 teeth, hydrogen; and R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents from selected from; and Each R 15 is independent, Hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -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 , -SO2R 13 , and -SO2N(R 12 )2; and R 9 C1-C6 alkyl optionally substituted with one or more independently selected substituents is selected from.

[0098] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0 or 1 of Y is N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0099] In some embodiments, Y 1 is CR 15 and Y2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0, 1, or 2 of Y are N; and 2 , Y 3 , Y 4 , Y 5 , and Y 6 In some embodiments, one of Y is the point of attachment to the remainder of the molecule. 1 is CR 15 and Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0 or 1 of Y is N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 In some embodiments, one of Y is the point of attachment to the remainder of the molecule. 1 is CR 15 and Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0 or 1 of Y is N; and 3 , Y 4 , Y 5 , and Y6 One of the is the point of attachment to the rest of the molecule.

[0100] In some embodiments, Y 1 is CR 15 and;Y 2 is CR 15 and;Y 3 is CR 15 and;Y 4 is CR 15 and;Y 5 is CR 15 and Y 6 is CR 15 where Y 3 , Y 4 , Y 5 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0101] In some embodiments, Y 1 is N;Y 2 is CR 15 and;Y 3 is CR 15 and;Y 4 is CR 15 and;Y 5 is CR 15 and Y 6 is CR 15 where Y 3 , Y 4 , Y 5 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0102] In some embodiments, Y 1 is CR 15 and;Y 2 is N;Y 3 is CR 15 and;Y 4 is CR 15 and;Y 5 is CR 15 and Y 6 is CR 15 where Y 3 , Y 4 , Y 5, and Y 6 One of the is the point of attachment to the rest of the molecule.

[0103] In some embodiments, Y 1 is CR 15 and;Y 2 is CR 15 and;Y 3 is N;Y 4 is CR 15 and;Y 5 is CR 15 and Y 6 is CR 15 where Y 4 , Y 5 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0104] In some embodiments, Y 1 is CR 15 and;Y 2 is CR 15 and;Y 3 is CR 15 and;Y 4 is N;Y 5 is CR 15 and Y 6 is CR 15 where Y 3 , Y 5 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0105] In some embodiments, Y 1 is CR 15 and;Y 2 is CR 15 and;Y 3 is CR 15 and;Y 4 is CR 15 and;Y 5 is N; and Y 6 is CR 15 where Y 3 , Y 4 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0106] In some embodiments, Y 1 is CR 15 and;Y 2 is CR 15 and;Y 3 is CR 15 and;Y 4 is CR 15 and;Y 5 is CR 15 and Y 6 is N; where Y 3 , Y 4 , and Y 5 One of the is the point of attachment to the rest of the molecule.

[0107] In some embodiments, the compound of Formula (III) is represented by Formula (IIIa-1), (IIIa-2), (IIIa-3), or (IIIa-4), or a pharmaceutically acceptable salt thereof: TIFF0007801312000044.tif111128.

[0108] In some embodiments, the compound of formula (III) is represented by formula (IIIa-1). In some embodiments, the compound of formula (III) is represented by formula (IIIa-2). In some embodiments, the compound of formula (III) is represented by formula (IIIa-3). In some embodiments, the compound of formula (III) is represented by formula (IIIa-4).

[0109] In some embodiments, the compound of Formula (III) is represented by Formula (IIIb-1), (IIIb-2), (IIIb-3), or (IIIb-4), or a pharmaceutically acceptable salt thereof: TIFF0007801312000045.tif116128In formula, Y 1 and Y 2 0 or 1 of is N.

[0110] In some embodiments, the compound of formula (III) is represented by formula (IIIb-1). In some embodiments, the compound of formula (III) is represented by formula (IIIb-2). In some embodiments, the compound of formula (III) is represented by formula (IIIb-3). In some embodiments, the compound of formula (III) is represented by formula (IIIb-4).

[0111] In some embodiments, Y 1 is CR 15 and Y 2 is CR 15 In some embodiments, Y 1 is N; and Y 2 is CR 15 In some embodiments, Y 1 is CR 15 and Y 2 is N.

[0112] In some embodiments, the compound of formula (III) is represented by formula (IIIc-1), (IIIc-2), (IIIc-3), or (IIIc-4), or a pharmaceutically acceptable salt thereof: TIFF0007801312000046.tif119128.

[0113] In some embodiments, the compound of formula (III) is represented by formula (IIIc-1). In some embodiments, the compound of formula (III) is represented by formula (IIIc-2). In some embodiments, the compound of formula (III) is represented by formula (IIIc-3). In some embodiments, the compound of formula (III) is represented by formula (IIIc-4).

[0114] In some embodiments, X 1 , X 2 , X 3 , X 4 , and X 5 0 or 1 of is N.

[0115] In some embodiments, X 1 is CR 8and X 2 , X 3 , X 4 , and X 5 is an independent CR 8 and N, where X 2 , X 3 , X 4 , and X 5 In some embodiments, 0, 1, or 2 of X are N. 1 is CR 8 and X 2 , X 3 , X 4 , and X 5 is an independent CR 8 and N, where X 2 , X 3 , X 4 , and X 5 0 or 1 of is N.

[0116] In some embodiments, X 1 is CR 8 and X 2 is CR 8 and X 3 is CR 8 and X 4 is CR 8 and X 5 is CR 8 is.

[0117] In some embodiments, X 1 is N;X 2 is CR 8 and X 3 is CR 8 and X 4 is CR 8 and X 5 is CR 8 is.

[0118] In some embodiments, X 1 is CR 8 and X 2 is N;X 3 is CR 8 and X 4 is CR 8and X 5 is CR 8 is.

[0119] In some embodiments, X 1 is CR 8 and X 2 is CR 8 and X 3 is N;X 4 is CR 8 and X 5 is CR 8 is.

[0120] In some embodiments, X 1 is CR 8 and X 2 is CR 8 and X 3 is CR 8 and X 4 is N; and X 5 is CR 8 is.

[0121] In some embodiments, X 1 is CR 8 and X 2 is CR 8 and X 3 is CR 8 and X 4 is CR 8 and X 5 is N.

[0122] In some embodiments, R 2 and R 3 are independently hydrogen; and R 9 In some embodiments, R is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 carbocycle, and 3-6 membered heterocycle, each of which is optionally substituted with one or more independently selected substituents. 2 and R 3 are independently hydrogen; optionally substituted C1-C6 alkyl; and R 9In some embodiments, R is selected from optionally substituted C3-C6 cycloalkyl and optionally substituted 3-6 membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, cyclopropyl ... 2 and R 3 are independently hydrogen; optionally substituted C1-C6 alkyl; and R 9 In some embodiments, R is selected from optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more independently selected substituents. 2 and R 3 are independently hydrogen; optionally substituted C1-C6 alkyl; and R 9 In some embodiments, R is selected from optionally substituted phenyl and optionally substituted pyridinyl, each of which is optionally substituted with one or more independently selected substituents. 2 and R 3 are independently hydrogen; and R 9 In some embodiments, R is selected from optionally substituted C1-C6 alkyl, each of which is optionally substituted with one or more independently selected substituents. 2 and R 3 are independent, R 9 In some embodiments, R is selected from optionally substituted C1-C6 alkyl, each of which is optionally substituted with one or more independently selected substituents. 2 and R 3 is independently selected from hydrogen; and C1-C6 alkyl. In some embodiments, R 2 and R 3 is independently selected from C1-C6 alkyl. In some embodiments, R 2 and R 3 is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. 2 and R 3is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. 2 and R 3 are each methyl.

[0123] In some embodiments, R 2 is hydrogen; and R 3 is R 9 and optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3-6 membered heterocycloalkyl, each of which may be substituted with one or more independently selected substituents.

[0124] In some embodiments, R 2 and R 3 are hydrogen atoms.

[0125] In some embodiments, R 2 and R 3 together with the intervening atoms to which they are attached, R 9 In some embodiments, R forms a 4-8 membered heterocycloalkyl, optionally substituted with one or more independently selected substituents. 2 and R 3 together with the intervening atoms to which they are attached, R 9 In some embodiments, R is an optionally substituted azetidinyl, an optionally substituted pyrrolidinyl, an optionally substituted piperidinyl, an optionally substituted morpholinyl, or an optionally substituted tetrahydrofuropyrrolyl, each of which is optionally substituted with one or more independently selected substituents. 2 and R 3 together with the intervening atoms to which they are attached, R 9 In some embodiments, R forms an azetidinyl, which may be substituted with one or more independently selected substituents. 2 and R 3together with the intervening atoms to which they are attached, R 9 In some embodiments, R forms a pyrrolidinyl, which may be substituted with one or more independently selected substituents. 2 and R 3 together with the intervening atoms to which they are bonded, are halogens, -CN, -OH, -OR 13 , -N(R 12 )2, C1-C6 alkyl, and C1-C6 haloalkyl to form an optionally substituted azetidinyl or an optionally substituted pyrrolidinyl. In some embodiments, R 2 and R 3 are taken together with the intervening atoms to which they are attached to form an optionally substituted azetidinyl or an optionally substituted pyrrolidinyl, optionally substituted with one or more substituents independently selected from -F, -Cl, -Br, -CN, -OH, -OCH, -OCHCH, -OCH(CH), -OCF, -NH, -NHCH, -N(CH), -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CHCH(CH), -CH(CH)CHCH, -C(CH), -CHF, -CHF, and -CF. 2 and R 3 together with the intervening atoms to which they are attached form an optionally substituted azetidinyl or an optionally substituted pyrrolidinyl, optionally substituted with one or more substituents independently selected from -F, -OH, -OCH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, and -CF3.

[0126] In some embodiments, R 1 is hydrogen; and, R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 1is selected from hydrogen; and C1-C6 alkyl. In some embodiments, R 1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. 1 is hydrogen or methyl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is methyl.

[0127] In some embodiments, R 1 is R 9 In some embodiments, R is a C1-C6 alkyl optionally substituted with one or more independently selected substituents. 1 is C1-C6 alkyl. In some embodiments, R 1 is R 9 In some embodiments, R is a C1-C6 alkyl substituted with 1, 2, or 3 independently selected substituents. 1 is R 9 In some embodiments, R is a C1-C6 alkyl substituted with 1, 2, or 3 independently selected substituents. 1 is halogen, -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 , -SO2R 13 , -SO2N(R 12)2, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 carbocycle, and 3-6 membered heterocycle. In some embodiments, R 1 is halogen, -CN, -OH, -OR 13 , -N(R 12 )2, C1-C6 alkyl substituted with 1, 2, or 3 substituents independently selected from C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, R 1 is halogen, -CN, -OH, -OR 13 , -N(R 12 )2, C2-C4 alkynyl, and C1-C4 haloalkyl. In some embodiments, R 1 is a C1-C6 alkyl substituted with 1 or 2 substituents independently selected from -F, -Cl, -Br, -CN, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -NH2, -NHCH3, -N(CH3)2, -C≡CH, -C≡CCH3, -C≡CCH2CH3, -C≡CCH(CH3)2, -CH2F, -CHF2, and -CF3. 1 is a C1-C6 alkyl substituted with one or two substituents independently selected from -F, -CN, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -NH2, -NHCH3, -N(CH3)2, -C≡CH, and -CF3. In some embodiments, R 1 is a C1-C6 alkyl substituted with one substituent selected from -F, -CN, -OCH3, -OCH2CH3, -C≡CH, and -CF3.

[0128] In some embodiments, R 1 and R 2together with the intervening atoms to which they are attached, R 9 In some embodiments, R forms a 5-8 membered heterocycloalkyl, optionally substituted with one or more independently selected substituents. 1 and R 2 together with the intervening atoms to which they are attached, R 9 and forming an optionally substituted 5- to 6-membered heterocycloalkyl, which may be substituted with one or more further independently selected substituents.

[0129] In some embodiments, the compound of formula (III) is represented by formula (IIId-1), (IIId-2), (IIId-3), or (IIId-4), or a pharmaceutically acceptable salt thereof: TIFF0007801312000047.tif116128In formula, Y 1 and Y 2 0 or 1 of is N; and k is 1, 2, 3, or 4.

[0130] In some embodiments, the compound of formula (III) is represented by formula (IIId-1). In some embodiments, the compound of formula (III) is represented by formula (IIId-2). In some embodiments, the compound of formula (III) is represented by formula (IIId-3). In some embodiments, the compound of formula (III) is represented by formula (IIId-4).

[0131] In some embodiments, Y 1 is CR 15 and Y 2 is CR 15 In some embodiments, Y 1 is N; and Y 2 is CR 15 In some embodiments, Y 1 is CR 15 and Y 2 is N.

[0132] In some embodiments, k is 1, 2, or 3. In some embodiments, k is 1 or 2. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4.

[0133] In some embodiments, R 4 , R 5 , and R 6 are each independently hydrogen, halogen, -CN, -OH, or -OR 11 , and -N(R 10 )2; and R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 4 , R 5 , and R 6 are independently hydrogen, halogen, -OR 11 , and -N(R 10 )2; and R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 4 , R 5 , and R 6 are independently hydrogen, -OR 11 , and -N(R 10 )2; and R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 4 , R 5 , and R 6 are independently hydrogen, -OR 11 , and -N(R 10 )2; and C1-C6 alkyl. In some embodiments, R 4 , R 5 , and R 6 are hydrogen atoms.

[0134] In some embodiments, the compound of Formula (I) or Formula (II) is represented by Formula (IV) or a pharmaceutically acceptable salt thereof: TIFF0007801312000048.tif48128In formula, R 7 teeth, hydrogen; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents selected from; and Each R 8 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0135] In some embodiments, the compound of formula (IV) is represented by formula (IVa) or a pharmaceutically acceptable salt thereof: TIFF0007801312000049.tif62128In formula, R 7 teeth, hydrogen; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents More selected; Each R 8 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents More selected; Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 is an independent CR 15 and N, where Y 1 , Y 2 , Y 3 , Y 4 , Y5 , and Y 6 0, 1, 2, or 3 of Y are N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 one of which is the point of attachment to the remainder of the molecule; R 14 teeth, hydrogen; R 9 C1-C6 alkyl optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents selected from; and Each R 15 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0136] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0 or 1 of Y is N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0137] In some embodiments, Y 1 is CR 15 and Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0, 1, or 2 of Y are N; and 2 , Y 3 , Y 4 , Y 5 , and Y 6 In some embodiments, one of Y is the point of attachment to the remainder of the molecule. 1 is CR 15 and Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 2 , Y 3 , Y 4 , Y 5 , and Y 60 or 1 of Y is N; and 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 In some embodiments, one of Y is the point of attachment to the remainder of the molecule. 1 is CR 15 and Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 is an independent CR 15 and N, where Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 0 or 1 of Y is N; and 3 , Y 4 , Y 5 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0138] In some embodiments, Y 1 is CR 15 and;Y 2 is CR 15 and;Y 3 is CR 15 and;Y 4 is CR 15 and;Y 5 is CR 15 and Y 6 is CR 15 where Y 3 , Y 4 , Y 5 , and Y 6 One of the is the point of attachment to the rest of the molecule.

[0139] In some embodiments, the compound of formula (IV) is represented by formula (IVb): TIFF0007801312000050.tif57128In formula, R 7 teeth, hydrogen; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents More selected; Each R 8 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents More selected; R 14 teeth, hydrogen; R 9 C1-C6 alkyl optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 3-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents selected from; and Each R 15 is independent, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0140] In some embodiments, R 7 teeth, hydrogen; and R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents from selected from; and Each R 8 is independent, Hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -C(=O)OR 12 , -C(=O)N(R 12 )2, -NR 12 C(=O)R 12 , -NR 12 C(=O)N(R12 )2, -SR 12 , -SO2R 13 , and -SO2N(R 12 )2; and R 9 C1-C6 alkyl optionally substituted with one or more independently selected substituents is selected from.

[0141] In some embodiments, R 14 teeth, hydrogen; and R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents from selected from; and Each R 15 is independent, Hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -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 , -SO2R 13 , and -SO2N(R 12 )2; and R 9 C1-C6 alkyl optionally substituted with one or more independently selected substituents is selected from.

[0142] In some embodiments, R 7 is hydrogen; and, R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 7 is selected from hydrogen and C1-C6 alkyl. In some embodiments, R 7is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. 7 is selected from hydrogen and methyl. In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is methyl.

[0143] In some embodiments, at least one R 8 teeth, 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 , -SO2R 13 , -SO2N(R 12 )2, and -NO2; R 9 C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each optionally substituted with one or more independently selected substituents; and R 9 C3-C6 cycloalkyl and 4-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents is selected from.

[0144] In some embodiments, each R 8 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, and -C(=O)OR 12 ;R 9 C1-C6 alkyl optionally substituted by one or more independently selected substituents; and R 9In some embodiments, each R is selected from the group consisting of 3- to 10-membered heterocycles, optionally substituted with one or more independently selected substituents. 8 are independently hydrogen, halogen, -CN, and -OR 13 ; and R 9 In some embodiments, each R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 8 are independently hydrogen, halogen, -CN, -OR 13 , C1-C6 alkyl, C1-C6 fluoroalkyl, and C1-C6 hydroxyalkyl. In some embodiments, each R 8 are independently hydrogen, halogen, -CN, -OR 13 and C1-C6 alkyl. In some embodiments, each R 8 is independently selected from hydrogen, F, Cl, Br, —CN, —OMe, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl, —CF, —CHF, and —CHF. In some embodiments, each R 8 are independently selected from hydrogen, F, Cl, Br, —CN, —OMe, methyl, ethyl, isopropyl, and —CF 3 .

[0145] In some embodiments, each R 15 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -C(=O)OR 12 , and -NR 18 SO2R 17 ;R 9 C1-C6 alkyl optionally substituted by one or more independently selected substituents; and R 9 In some embodiments, each R is selected from the group consisting of 3- to 10-membered heterocycles, optionally substituted with one or more independently selected substituents. 15 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -C(=O)OR12 , and -NR 18 SO2R 17 ; and R 9 In some embodiments, each R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 15 are independently hydrogen, halogen, -CN, -OH, -OR 13 , -N(R 12 )2, C1-C6 alkyl, and C1-C6 fluoroalkyl. In some embodiments, each R 15 is independently selected from hydrogen, F, Cl, Br, —CN, —OH, —OMe, —NH, —NHMe, —NMe, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl, —CF, —CHF, and —CHF. In some embodiments, each R 15 are independently selected from hydrogen, F, Cl, Br, —CN, —OMe, methyl, ethyl, isopropyl, and —CF 3 .

[0146] In some embodiments, R 14 is hydrogen; and, R 9 In some embodiments, R is selected from C1-C6 alkyl, optionally substituted with one or more independently selected substituents. 14 is selected from hydrogen and C1-C6 alkyl. In some embodiments, R 14 is hydrogen; and, R 9 In some embodiments, R is selected from C1-C3 alkyl, optionally substituted with one or more independently selected substituents. 14 is selected from hydrogen and C1-C3 alkyl. In some embodiments, R 14 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. 14 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. 14is selected from hydrogen and methyl. In some embodiments, R 14 is hydrogen. In some embodiments, R 14 is methyl.

[0147] In some embodiments, each R 9 are independently halogen, -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 , -SO2R 13 , -SO2N(R 12 )2, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 carbocycle, and 3-6 membered heterocycle. In some embodiments, each R 9 are independently halogen, -CN, -OH, -OR 13 , -N(R 12 )2, -C(=O)OR 12 , -OC(=O)R 12 , -C(=O)N(R 12 )2, -NR 12 C(=O)R 12 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, each R 9 are independently halogen, -CN, -OH, -OR 13 , -N(R 12)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, each R 9 are independently halogen, -CN, -OH, -OR 13 , -N(R 12 )2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each R 9 are independently selected from -F, -Cl, -Br, -CN, -OH, -OCH, -OCHCH, -OCH(CH), -OCF, -NH, -NHCH, -N(CH), -CH, -CHCH, -CHCHCH, -CH(CH), -CHCHCHCH, -CH(CH), -CH(CH)CHCH, -C(CH), -CHF, -CHF, and -CF.

[0148] In some embodiments, each R 10 are independently hydrogen; and R 9 In some embodiments, each R is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and monocyclic heteroaryl, each optionally substituted with one or more independently selected substituents. 10 are independently hydrogen; and R 9 In some embodiments, each R is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents. 10 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and monocyclic heteroaryl. In some embodiments, each R 10 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, each R 10is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each R 10 are independently selected from hydrogen, —F, —Cl, —Br, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH2CH3, —C(CH3)3, —CH2F, —CHF2, and —CF3.

[0149] In some embodiments, each R 11 are independent, R 9 In some embodiments, each R is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and monocyclic heteroaryl, each optionally substituted with one or more independently selected substituents. 11 are independent, R 9 In some embodiments, each R is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl, each optionally substituted with one or more independently selected substituents. 11 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and monocyclic heteroaryl. In some embodiments, each R 11 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, each R 11 is independently selected from C1-C6 alkyl and C1-C6 haloalkyl. In some embodiments, each R 11 are independently selected from -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, and -CF3.

[0150] In some embodiments, each R 12is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and monocyclic heteroaryl. In some embodiments, each R 12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, each R 12 is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, each R 12 are independently selected from hydrogen, —F, —Cl, —Br, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3)CH2CH3, —C(CH3)3, —CH2F, —CHF2, and —CF3.

[0151] In some embodiments, each R 13 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, and monocyclic heteroaryl. In some embodiments, each R 13 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3-6 membered heterocycloalkyl. In some embodiments, each R 13 is independently selected from C1-C6 alkyl and C1-C6 haloalkyl. In some embodiments, each R 13 are independently selected from -F, -Cl, -Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2F, -CHF2, and -CF3.

[0152] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and their substituents will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0153] In some embodiments, the compounds or salts described herein are compounds described in Table 1 or pharmaceutically acceptable salts thereof.

[0154] [Table 1] TIFF0007801312000052.tif248168TIFF0007801312000053.tif227168TIFF0007801312000054.tif234168 TIFF0007801312000055.tif233168TIFF0007801312000056.tif242168TIFF0007801312000057.tif249168 TIFF0007801312000058.tif246168TIFF0007801312000059.tif251168TIFF0007801312000060.tif245168 TIFF0007801312000061.tif242168TIFF0007801312000062.tif228168TIFF0007801312000063.tif221168

[0155] Further forms of the compound The present invention provides any one salt of the compounds described herein.Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts.The acid that is added to a compound to form an acid addition salt can be an organic acid or an inorganic acid.The base that is added to a compound to form a base addition salt can be an organic base or an inorganic base.In some embodiments, the pharmaceutically acceptable salt is a metal salt.

[0156] Metal salts can be formed by the addition of an inorganic base to the compounds of the present invention. Inorganic bases consist of a metal cation paired with a basic counterion, such as hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0157] In some embodiments, the metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0158] Ammonium salts can result from the addition of ammonia or an organic amine to a compound of the invention. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, piperazole, imidazole, pyrazine, or piperazine.

[0159] In some embodiments, the ammonium salt is a triethylamine salt, a diisopropylamine salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, an imidazole salt, or a pyrazine salt.

[0160] Acid addition salts can be formed by adding an acid to a compound of the present invention. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucaronic acid, saccharinic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0161] In some embodiments, the salt is hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisinate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, methanesulfonate (mesylate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

[0162] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomers. The compounds and salts presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers may be carried out by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, incorporated herein by reference for this disclosure.) Stereoisomers may also be obtained by stereoselective synthesis.

[0163] The methods, compositions, and formulations described herein include the use of amorphous and crystalline forms (also known as polymorphs).Active metabolites of the compounds or salts described herein that have the same type of activity are included in the scope of this disclosure.In addition, the compounds described herein can exist in unsolvated form and in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc.Solvated forms of the compounds and salts presented herein are also considered to be disclosed herein.

[0164] According to another aspect, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are easily synthesized from readily available starting materials. Synthetic chemical transformations and methodologies useful in synthesizing the compounds described herein are known in the art, and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0165] In some embodiments, the compounds described herein modulate the conformation of αB-crystallin (cryAB). In certain embodiments, compounds or salts described herein that modulate the conformation of cryAB can be identified using the assay methods described in Examples A-1 and A-2. In some embodiments, the melting temperature (T m ) difference (ΔT mA compound is considered active if the change in melting temperature (ΔT) is greater than two or three times the standard deviation of the negative control (protein containing only DMSO vehicle without compound). m ) does not exceed two times the standard deviation of the negative control, a compound is considered to be inactive.

[0166] Pharmaceutical preparations In certain embodiments, provided herein are compositions comprising a therapeutically effective amount of any compound or salt described herein (also referred to herein as a "medicament"). In certain embodiments, the composition comprises a therapeutically effective amount of any compound or salt described herein and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical formulation can be used in any of the methods described herein.

[0167] In certain embodiments, the compounds described herein are used to treat ocular disorders such as cataracts or presbyopia. Ocular formulations can be administered by injection, for example, intravitreal or intracameral injection. Ocular formulations can be administered topically, for example, in the form of an ointment, cream, or eye drops.

[0168] Methods of the present disclosure The present disclosure provides compounds and formulations for use in reducing or preventing the aggregation of α-crystallin proteins. The aggregation of α-crystallin has been implicated in a variety of diseases that can be treated or prevented using the compounds and formulations described herein. Such diseases include, for example, cataracts, nuclear sclerosis, presbyopia, neurological disorders, Alexander disease, Creutzfeldt-Jakob disease, Alzheimer's disease, and Parkinson's disease.

[0169] In certain embodiments, the methods provided herein may be used to treat diseases or conditions in which it would be beneficial to reduce or reverse the likelihood of α-crystallin aggregation. The compounds or salts disclosed herein may be used as pharmacological chaperones for α-crystallin.

[0170] The methods provided herein may be used to treat visual disorders such as, for example, cataracts, age-related cataracts, diabetic cataracts, surgical cataracts, radiation-induced cataracts, genetic disease-induced cataracts, infection-induced cataracts, medication-induced cataracts, or early-onset genetic forms of cataracts.

[0171] As discussed herein, visual impairment refers to the pathological vision that can be related to the abnormal aggregation of crystallin protein in the lens of eye.The abnormal aggregation of crystallin protein can be the main factor that causes visual impairment, or can be one of the mechanisms that cause visual impairment.The visual impairment of the present disclosure includes but is not limited to cataracts such as nuclear cataract, cortical cataract, posterior capsular cataract, congenital cataract, early-onset hereditary cataract, metabolic (diabetic) cataract, posterior cataract, blunt trauma cataract, penetrating trauma cataract, post-vitrectomy cataract, radiation-induced cataract; presbyopia such as early presbyopia, functional presbyopia, absolute presbyopia, early presbyopia or nighttime presbyopia.

[0172] The method of the present invention can also be used to treat diseases caused by αA or αB-crystallin mutations.Mutations in αA or αB-crystallin can cause hereditary cataracts.Examples of αA-crystallin mutations include, but are not limited to, W9X, R12C, R21L, R21W, R49C, R54C, F71L, G98R, D105H, R116C, and R116H.Examples of αB-crystallin mutations include, but are not limited to, 150delA (αB184), R11H, P20S, R56W, R69C, D109H, R120G, D140N, and A171T.In some cases, the αB-crystallin mutation is D109H or R120G.

[0173] In certain embodiments, compounds and preparations disclosed herein can be used to treat the visual impairment of subjects, such as cataract or presbyopia.In certain embodiments, compounds and preparations disclosed herein can be used to treat the cataract of subjects, such as nuclear cataract, cortical cataract, posterior capsular cataract, congenital cataract, secondary cataract, traumatic cataract, radiation cataract.In certain embodiments, subjects have one or more symptoms of cataract, such as cloudy vision, blurred vision, unclear vision, difficulty seeing at night, sensitivity to light and glare, needing brighter light for reading and other activities, seeing "halos" around lights, frequently changing the power of glasses or contact lenses, color fading and yellowing, and double vision in one eye.

[0174] In certain embodiments, compounds and preparations disclosed herein can be used to treat presbyopia of target, such as early presbyopia, functional presbyopia, absolute presbyopia, early presbyopia or nighttime presbyopia.In certain embodiments, target has one or more symptoms of presbyopia, such as: reduced ability to focus on near objects, eye strain, difficulty reading small letters, fatigue when reading or looking at bright screens, difficulty seeing close objects clearly, reduced contrast when reading printed text, needing brighter and more direct light to read, needing to hold reading material further away to see reading material clearly, or headache, especially headache when using near vision.In some embodiments, target does not have cataract in the eye that suffers from presbyopia.

[0175] In certain embodiments, the subject is visually impaired in one eye, hi certain embodiments, the subject is visually impaired in both eyes.

[0176] The subject of the present disclosure can be any vertebrate. In some preferred embodiments, the subject is a human. The subject can be of any age. In some embodiments, the subject can be 25 to 100 years old, or 40 to 100 years old, or 50 to 100 years old. The subject can be over 1 year old, over 2 years old, over 5 years old, over 10 years old, over 18 years old, over 20 years old, over 25 years old, over 30 years old, over 35 years old, over 40 years old, over 45 years old, over 50 years old, over 60 years old, over 70 years old, over 80 years old, or over 90 years old. The subject can be 25 years old or older.

[0177] The methods provided herein can be used to treat diseases or conditions believed to benefit from reducing or reversing the likelihood of α-crystallin aggregation by administering an effective amount of at least one of the compounds or formulations described herein. An effective amount can be an amount that reduces or inhibits α-crystallin aggregation. In certain embodiments, the compounds and formulations of the present disclosure reduce α-crystallin aggregation in the eye by about 1% to about 100%, about 1% to about 90%, about 1% to about 80%, about 1% to about 70%, about 10% to about 50%, about 20% to about 40%, about 50% to about 90%, or 60% to about 95% relative to pre-treatment levels of α-crystallin aggregation.

[0178] In certain embodiments, the compounds or salts of the present disclosure are pharmacological chaperones that bind to α-crystallin, e.g., the pharmacological chaperones can bind to a concave pocket near the antiparallel β-strand dimer interface of α-crystallin. The concave pocket of α-crystallin can include serine 66, leucine 79, aspartic acid 80, valine 81, lysine 82, histidine 83, phenylalanine 84, valine 97, isoleucine 114, serine 115, arginine 116, aspartic acid 117, phenylalanine 118, histidine 119, arginine 120, lysine 121, and tyrosine 122 of αB-crystallin or αA-crystallin. In certain embodiments, the pharmacological chaperone can be, for example, a small molecule or a sterol or sterol mimetic.

[0179] The compounds and formulations disclosed herein may be used to inhibit α-crystallin aggregation by at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% when compared to pre-treatment levels or levels observed in a biologically relevant control subject or specimen to which the compound has not been administered. The compounds and formulations disclosed herein may inhibit α-crystallin aggregation by 1% to 100%, 5% to 90%, 10% to 80%, 20% to 50%, 50% to 95%, 60% to 99%, or 40% to 70% when compared to pre-treatment levels or levels observed in biologically relevant control subjects or specimens to which the compounds are not administered.

[0180] In certain embodiments, the amyloidogenic protein may be selected from the group consisting of Hsp27, αA-crystallin, αB-crystallin, βB2-crystallin βB1-crystallin, γD-crystallin, Hsp22, Hsp20, HSPB2, HSPB3, HSPB7, HSPB9, HSPB10, tau, α-synuclein, IAPP, β-amyloid, PrP, Huntington's disease, calcitonin, atrial natriuretic factor, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, β2-microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, myocilin, and SIBM.

[0181] Alpha-crystallin aggregation in the lens can be measured, for example, by in vivo dynamic light scattering, light scattering assay, electron microscopy, centrifugation protein solubility assay, filter trap protein solubility assay, thioflavin T fluorescence assay, high performance liquid chromatography, gel permeation chromatography, size exclusion chromatography, anti-amyloid antibody assay. In certain embodiments, exemplary methods of the present disclosure for measuring alpha-crystallin aggregation in the lens are described in K. Dierks et al., SPIE Vol. 2330 Lasers in Ophthalmology 11, 112-121 (1994); R. Ansari, Journal of Biomedical Optics Jan / Feb, Vol.9, No.1, 22-37 (2004); and X. Pei et al., Br J Ophthalmol 92, 1471-1475 (2008), the contents of each of which are incorporated herein by reference.

[0182] The compounds disclosed herein may inhibit cataract formation by at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% when compared to levels observed in a biologically relevant control subject or specimen that is not administered the compound.

[0183] In certain embodiments, prior to treatment, the subject has experienced near vision loss. The subject may have experienced near vision loss that first occurred when the subject was 25 years of age or older. The subject may have been about 25-50 years of age, e.g., about 25-40 years of age, e.g., about 25-35 years of age, when the subject experienced near vision loss. The subject may have been diagnosed, e.g., diagnosed by a medical professional, as suffering from near vision loss, or may self-identify as suffering from near vision loss.

[0184] In certain embodiments, the subject has not yet experienced a decline in near vision. The subject may have one or more risk factors for the development of presbyopia. Risk factors include, but are not limited to, age over 40 years old, hyperopia, occupations requiring near vision, sex, eye disease or trauma, systemic disease, drug exposure (prescription and non-prescription), iatrogenic factors, proximity to the equator, exposure to high levels of ultraviolet light, malnutrition, decompression sickness, and exposure to high ambient temperatures.

[0185] The subject may exhibit one or more symptoms of hyperopia. Some symptoms of hyperopia include blurred vision, difficulty seeing objects up close, and crossing of the eyes in children (esotropia). The subject may experience loss of near vision. The loss of near vision may or may not be hyperopic. In some embodiments, the loss of near vision is unrelated to the focusing of light rays behind the retina. In some embodiments, the subject may not exhibit one or more symptoms of hyperopia.

[0186] Loss of near vision can be identified by eye examination methods, such as eye examinations commonly used in the field.Loss of near vision can be determined by evaluating one or more of the following: near vision, habitual distance vision, corrected near vision, refractive error, refractive power, Jaeger score, LogMAR score, ETDRS scale, reading speed, lens accommodation amplitude, or any other method known in the field.Subject can show age-related near vision loss, as determined by one or more of the following methods:

[0187] Vision acuity, or visual acuity, is typically measured by having a subject distinguish between different sizes of optotypes on a chart viewed at a predetermined distance. Optotypes can be stylized letters or symbols. Viewing distance typically refers to the accommodation of the eye's lens for either near or distance vision. To measure near vision, the chart would be viewed at a predetermined reading distance, typically designated as 1. Numerous charts are known in the art, and commonly used charts include the Snellen, LogMar, and ETDRS charts. Some examples of eye charts that can be used with illiterate subjects include, but are not limited to, the Tumbling E, Landolt C, and LEA tests. Acuity scores are assigned using reference values ​​based on the size of the optotypes that are considered to be distinguishable by individuals with "normal" vision. For example, in distance vision tests, each line of the optotype indicates the distance at which a subject with "normal" vision can read. The subject then looks at the chart from 20 feet (or 6 meters) and reads from the largest optotype to the smallest optotype, stopping at the smallest line they can read without making any mistakes, or with no more than one mistake, or with no more than two mistakes. If the smallest optotype the subject can read is marked 40 feet, then the subject's visual acuity is 20 / 40, meaning that they can read at 20 feet what a subject with "normal" vision can read at 40 feet. An efficient way to describe visual acuity is by converting fractions to decimals, so a subject with 20 / 40 visual acuity would be thought of as having a distance visual acuity of 0.5 in decimal.

[0188] Near visual acuity may be measured in the same manner, but at a shorter viewing distance. In an exemplary near visual acuity test, the subject is instructed to cover one eye and use the other eye to view an eye chart from a distance of 16 inches. The examiner determines the size of the smallest letters the subject can read with no more than one letter error and correlates that letter size with the distance at which a subject with "normal" vision can read. Fractions may be converted to decimals to produce decimal visual acuity values.

[0189] The subject of the disclosed method may have a visual impairment determined by near visual acuity of 0.9 or less. The subject of the disclosed method may have a visual impairment determined by near visual acuity of 0.8 or less. The subject of the disclosed method may have a visual impairment determined by near visual acuity of 0.6 or less. The subject of the disclosed method may have a visual impairment determined by near visual acuity of 0.4 or less.

[0190] Spectacle distance vision is the subject's vision with correction. In some cases, there is no correction, and in other cases, this can be glasses or contact lenses. When spectacle distance vision includes glasses or contact lenses, the correction may not be optimal for the subject's current needs.

[0191] In certain embodiments, the subject may experience difficulty reading. The subject may have trouble reading small print or print that they were previously able to read without difficulty. The subject may have a reduced reading speed. The subject may complain of eye strain after reading for long periods of time.

[0192] In certain embodiments, the subject has a near vision defect that can be corrected with eyeglasses or contact lenses having a power of about +.5D or more, about +1D or more, or about +2D or more. In some embodiments, the subject of the present disclosure can be identified as someone who occasionally or habitually uses eyeglasses or contact lenses to correct a near vision defect. The subject of the present disclosure can be someone who occasionally or habitually uses reading glasses.

[0193] Near vision loss can be determined by measuring the optical power of the eye's lens. Refractive power (also called dioptric power, refractive power, focal power, or converging power) is the degree to which the lens focuses light. Refractive power is equal to the reciprocal of the focal length in meters and is expressed in diopters. For example, a lens that can focus parallel rays of light at a focal point one-third of a meter has a power of 3 diopters. The ability to focus on near objects declines throughout life, plateauing at 0.5 to 1 diopter at age 60.

[0194] An eye with too much or too little refractive power to focus light onto the retina may have refractive error, which may be assessed using one or more of the following: a retinoscope, an autorefractor, a Shack-Hartmann wavefront sensor, or a pinhole obscuration disc.

[0195] The subject's lens may have a refractive power of less than 15 diopters before treatment with the compounds described herein. The subject's lens may have a refractive power of less than 20 diopters before treatment with the compounds described herein.

[0196] Near vision impairment can be determined by the Jaeger test scale. The Jaeger chart is a type of eye chart used to test near vision. It is a card with enlarged paragraphs of text printed on it. Several variations of the Jaeger chart exist. The card is held at a certain distance from the subject's eyes by the subject. The smallest letter the subject can read determines the visual acuity and Jaeger score (J1 to J11 or higher). For example, a subject who can read the fourth and more than four lines of the Jaeger chart has a visual acuity of J4.

[0197] Near vision impairment may be determined by a score of J2 or higher on the Jaeger scale of the Jaeger test. Near vision impairment may be determined by a score of J3 or higher on the Jaeger scale of the Jaeger test. Near vision impairment may be determined by a score of J4 or higher on the Jaeger scale of the Jaeger test. Near vision impairment may be determined by a score of J5 or higher on the Jaeger scale of the Jaeger test. Near vision impairment may be determined by a score of J6 or higher on the Jaeger scale of the Jaeger test. Near vision impairment may be determined by a score of J8 or higher on the Jaeger scale of the Jaeger test.

[0198] Near vision impairment can be determined by a LogMAR chart. When using a LogMAR chart, visual acuity is scored by reference to the logarithm of the minimum separation threshold angle. A subject who can distinguish details within only 1 minute of visual angle will have a LogMAR score of 0 (the logarithm of 1 to the base 10 is 0); a subject who can distinguish details within only 2 minutes of visual angle (i.e., reduced visual acuity) will have a LogMAR score of 0 (the logarithm of 2 to the base 10 is 0.3); etc. The LogMAR score is calculated based on the number of letters the subject correctly identifies (each line corresponds to 0.1 LogMAR units).

[0199] Near vision impairment may be determined by a LogMAR score of 0.3 or greater. Near vision impairment may be determined by a LogMAR score of 0.4 or greater. Near vision impairment may be determined by a LogMAR score of 0.5 or greater. Near vision impairment may be determined by a LogMAR score of 0.6 or greater.

[0200] Use of the disclosed methods may treat or prevent presbyopia. Use of the disclosed methods by subjects who have not yet experienced symptoms of presbyopia may prevent or delay the onset of presbyopia.

[0201] Use of the disclosed methods by a subject with presbyopia can prevent or slow the progression of presbyopia. In some embodiments, the subject does not experience a decrease in near vision over the period during which the compounds described herein are administered.

[0202] Use of the disclosed method by a subject with presbyopia can treat presbyopia and result in improvement of near vision. The improvement in the subject's near vision can include improvement in one or more of visual acuity, refractive power, lens accommodation amplitude, Jaeger scale score, LogMAR scale score, ETDRS scale, reading speed, or refractive error.

[0203] In certain embodiments, the improvement of the subject's near vision may include an improvement in near vision compared to the near vision value before treatment.In certain embodiments, the method of the present disclosure improves near vision impairment to a degree approximately equivalent to eyeglasses or contact lenses with a diopter of about +.5D or more, about +1D or more, or about +2D or more.In certain embodiments, the method of the present disclosure may replace treatment with eyeglasses or contact lenses or surgical procedures.

[0204] In certain embodiments, the disclosed methods result in an improvement in a subject's near vision. The disclosed methods may increase the refractive power of a subject's lens. In certain embodiments, the refractive power of the lens may improve by at least 0.1 diopters compared to the lens's pre-treatment refractive power. In certain embodiments, the refractive power of the lens may improve by at least 1 diopter compared to the lens's pre-treatment refractive power. In certain embodiments, the refractive power of the lens may improve by at least 5 diopters compared to the lens's pre-treatment refractive power. In certain embodiments, the refractive power of the lens may improve by 0.1 to 20 diopters compared to the lens's pre-treatment refractive power. In certain embodiments, the refractive power of the lens may improve by 0.1 to 10 diopters compared to the lens's pre-treatment refractive power. In certain embodiments, the refractive power of the lens may improve by 1 to 10 diopters compared to the lens's pre-treatment refractive power. In certain embodiments, the refractive power of the lens may improve by 1 to 5 diopters compared to the pre-treatment refractive power of the lens.

[0205] In certain embodiments, the treatment improves the subject's near vision by, for example, 1, 2, 3, 4, or 5 Jäger lines, as measured, for example, by the Jäger test scale, compared to pre-treatment measurements. The treatment may improve the subject's near vision by 1 to 7 Jäger lines, or 1 to 5 Jäger lines, or 1 to 3 Jäger lines, compared to pre-treatment measurements. In certain embodiments, the treatment corrects the subject's near vision by, for example, more than 0.02, 0.04, 0.06, 0.1, 0.2, 0.3, 0.4, 0.5, or 0.5 LogMAR units. The treatment may correct the subject's near vision by 0.02 to 0.9 LogMAR units, or 0.1 to 0.8 LogMAR units, or 0.2 to 0.5 LogMAR units.

[0206] The McDonald-Shadduck scoring system may be used to determine the severity of various ocular symptoms in rabbits upon administration of the compounds of the present invention. The scoring system may use a scale ranging from 0 to 6, with higher numbers indicating greater severity of the ocular condition. For example, the McDonald-Shadduck scoring system may be used to assess corneal opacity, corneal neovascularization, chemosis and swelling, conjunctival discharge, and corneal staining.

[0207] The McDonald-Shadduck scoring system may be used to grade conjunctival discharge. Conjunctival discharge may be used to describe discharge that is a whitish or gray precipitate. Clear, thick, clotted, or mucoid discharge seen in the medial canthus of the rabbit's eye is not scored as part of the conjunctival discharge scale.

[0208] Aqueous humor flare can be measured by the presence of the Tyndall phenomenon in the anterior chamber of the eye. The Tyndall phenomenon can be used to describe light scattering by particles in colloids or fine suspensions. The intensity of the Tyndall phenomenon can be scored by comparing the passage of a slit lamp beam through the anterior chamber with the normal Tyndall effect observed when the beam passes through the lens. The presence of aqueous humor flare can indicate a breakdown of the blood-aqueous barrier.

[0209] Iris infiltration can be measured using the McDonald-Shadduck scoring system. Primary, secondary, and tertiary vessels of the iris can be used to aid in determining a subjective ocular score for iris infiltration. The intensity of iris infiltration can be increased when the vessels are more engorged, with greater involvement of secondary and tertiary vessels. [Example]

[0210] I: Chemical synthesis The following examples illustrate various methods for preparing the compounds described herein.It is understood that those skilled in the art may be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art.It is also understood that those skilled in the art can prepare these compounds in a similar manner as described below by using appropriate starting materials and modifying synthetic routes as necessary.In general, starting materials and reagents can be obtained from commercial suppliers, or can be synthesized according to sources known to those skilled in the art, or can be prepared as described herein.

[0211] Unless otherwise noted, reagents and solvents were used as received from suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yield optimization was not performed. Reaction times are approximate and were not optimized. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (δ) and coupling constants (J) are reported in Hertz. The solvent peak was used as the reference peak for proton spectra.

[0212] Example 1: Preparation of N-(2-(1-methyl-1H-indol-3-yl)-2-(pyrrolidin-1-yl)ethyl)-1H-indole-6-sulfonamide (Compound 5) TIFF0007801312000064.tif63152

[0213] Step 1 (Intermediate 1-2): To a solution of 1-1 (20.0 g, 137.8 mmol, 1.0 equiv) in DMF (150 mL) was added NaH (6.1 g, 60% in mineral oil, 151.6 mmol, 1.1 equiv) portionwise at 0 °C. The mixture was stirred at 0 °C for 30 min, followed by the addition of iodomethane (10.3 mL, 165.4 mmol, 1.2 equiv) at 0 °C. The mixture was warmed to 25 °C and stirred for 1 h before being quenched with water (750 mL). The precipitate was filtered, washed with water (100 mL), and dried under vacuum to give compound 1-2 (20.1 g, 91% yield) as a brown solid. TIFF0007801312000065.tif20159

[0214] Step 2 (Intermediate 1-3): To a solution of 1-2 (3.0 g, 18.8 mmol, 1.0 equiv) in HO (30 mL) and dioxane (30 mL) was added NaHSO (2.93 g, 28.2 mmol, 1.5 equiv) at 25 °C. The mixture was stirred at 25 °C for 15 min. Subsequently, pyrrolidine (2.4 mL, 28.2 mmol, 1.5 equiv) was added to the mixture, which was stirred for an additional 35 min. NaCN was added and stirred at 25 °C for 3 h. The solid was filtered, rinsed with water (50 mL), and dried under vacuum. Compounds 1-3 (3.5 g, 78% yield) were obtained as white solids. TIFF0007801312000066.tif34164

[0215] Step 3 (Intermediate 1-4): Compound 1-3 (3.5 g, 14.6 mmol, 1.0 equiv.) was dissolved in EtOAc (75 mL) and MeOH (150 mL). Pd / C (2.4 g, 10% Pd on carbon, 2.3 mmol, 0.15 equiv.) and HCl (2.6 mL, 12 mol / L in water, 31.2 mmol, 2.1 equiv.) were then added at 25 °C. A balloon of H was attached to the flask. The mixture was stirred at 25 °C for 72 h and then filtered through Celite. The filtrate was concentrated to give a brown residue, which was purified by preparative HPLC (MeCN / HO=10:90, 0.1% HCl as additive) to give 1-4 (0.53 g, 11% yield) as a white solid. TIFF0007801312000067.tif27163

[0216] Step 4 (Intermediate 1-5): To a solution of 6-bromo-1H-indole (2.4 g, 12.2 mmol, 1.0 equiv) in THF (30 mL) was added NaH (0.49 g, 60% in mineral oil, 12.2 mmol, 1.0 equiv) at 0 °C. After stirring for 15 min, the mixture was cooled to -78 °C, and tBuLi (23.5 mL, 1.3 mol / L in hexane, 30.5 mmol, 2.5 equiv) was added dropwise. The mixture was stirred at -78 °C for 45 min. Then, SO (10.5 mL, 2.9 mol / L in THF, 30.5 mmol, 2.5 equiv) was added at -78 °C. The mixture was warmed to 25 °C and stirred for 16 h. Petroleum ether (30 mL) and AcOH (0.77 mL, 13.4 mmol, 1.1 equiv) were added. The mixture was stirred for 15 minutes and filtered. The filter cake was rinsed with petroleum ether (10 mL). The solid was suspended in DCM (35 mL), and then NCS (1.63 g, 12.2 mmol, 1.0 equiv.) was added. The mixture was stirred at 25 °C for 30 minutes and filtered. The filtrate was taken and dried to give a brown solid, which was purified on a silica gel column (petroleum ether / EtOAc = 20:1, then 5:1) to give compound 1-5 (1.1 g, 42% yield) as a yellow solid. TIFF0007801312000068.tif12144

[0217] Step 5 (Compound 5): To a solution of compound 1-4 (0.300 g, 0.79 mmol, 1.0 equiv.) and NEt (0.47 mL, 2.77 mmol, 3.5 equiv.) in DCM (5 mL) was added compound 1-5 (0.226 g, 0.87 mmol, 1.1 equiv.) at 25 °C. The mixture was stirred at 25 °C for 1 h, then diluted with DCM (30 mL), washed with water (2 * 10 mL), dried over Na SO , and concentrated. The crude product was purified by silica gel column (DCM / MeOH = 20:1) or preparative HPLC (MeCN / HO = 30:70, 0.1% HCl as additive) to give compound 5 (0.18 g, 53% yield) as a white solid. TIFF0007801312000069.tif42164

[0218] Example 2 Preparation of (S)—N-(2-(1-methyl-1H-indol-3-yl)-2-(pyrrolidin-1-yl)ethyl)-1H-indole-6-sulfonamide (Compound 24) and (R)—N-(2-(1-methyl-1H-indol-3-yl)-2-(pyrrolidin-1-yl)ethyl)-1H-indole-6-sulfonamide (Compound 25) TIFF0007801312000070.tif27163

[0219] Compounds 24 and 25 were prepared by chiral resolution of compound 5 (180 mg) using the following chiral preparative SFC method. TIFF0007801312000071.tif97131

[0220] Compound 24: 85 mg (47% yield, >99.9% ee) TIFF0007801312000072.tif35165

[0221] Compound 25: 78 mg (yield 43%, 96% ee) TIFF0007801312000073.tif34164

[0222] The following compounds were synthesized using the same procedures as in Examples 1-2 using the appropriate starting materials and reagents. TIFF0007801312000074.tif180137TIFF0007801312000075.tif188137 a [M-(CH3)2N] + ; b [M+e - ] -1

[0223] II: Bioassay Example A-1: ​​Kinetic turbidity agglutination assay of recombinant cryAB(R120) Recombinant cryAB(R120G) protein was diluted to 100 μM in assay buffer (50 mM Tris, 100 mM NaCl, 5 mM DTT, 0.01% Triton X-100, 0.05% PEG-8000). Compounds were dissolved in DMSO at 10 mM and then typically diluted to 2.5 mM in DMSO, with serial 2-fold dilutions as needed. Addition of 81 μL of assay buffer, followed by 15 μL of protein solution and 4 μL of compound to a 384-well black microplate was performed in quadruplicate to yield a final concentration of 15 μM cryAB(R120G) protein in 4% DMSO. The assay plate was incubated at 42°C in a plate reader, and absorbance at 550 nm was read every 3.5 minutes for 4 hours with orbital shaking between readings. The percent inhibition of protein aggregation at various compound concentrations was measured. ND indicates not assayed.

[0224] The results for selected compounds at various concentrations are shown in the table below. TIFF0007801312000076.tif180128TIFF0007801312000077.tif240112TIFF0007801312000078.tif240112TIFF0007801312000079.tif128128

[0225] IC of selected compounds 50 The values ​​are shown in the table below. TIFF0007801312000080.tif68161 a A ≦ 10.0 μM < B ≦ 50.0 μM < C ≦ 100 μM

[0226] Example A-2: CryAB binding assay Affinity was determined by microscale thermophoresis using a direct binding assay. Briefly, the α-crystallin domain of αB-crystallin containing the E117C mutation was alkylated with Cy5 dye, and binding was monitored at 100 nM protein in a Tris buffer solution at pH 8 containing 0.1% PEG-8000, 0.05% Tween-20, and 5% DMSO. Binding assays were performed by titrating the ligand against a mixture of dye-labeled proteins and monitoring the change in fluorescence indicative of binding. KD was calculated using the law of mass action equation based on the observed fluorescence measurements for each titration of each compound.

[0227] The results for selected compounds are shown in the table below. TIFF0007801312000081.tif46128 a A ≦ 10.0 μM < B ≦ 50.0 μM < C ≦ 100 μM

[0228] Example A-3: Treatment of Presbyopia Five presbyopic patients are identified based on the near vision impairment in LogMAR test.Patients are treated weekly with the compound composition described herein.Every month, the near vision of each patient is measured by LogMAR test.The near vision of each patient after treatment is compared with the vision before treatment.

[0229] Example A-4: Treatment of Near Vision Loss Five patients over 40 years old and without clinical signs of presbyopia are identified based on the results of LogMAR test.Patients are treated daily with eye drops containing the composition of compounds described herein.Every 6 months, the near vision of each patient is measured by LogMAR test.The near vision of each patient is compared with the vision before treatment.

Claims

1. A compound represented by the structure of formula (IVa) or a pharmaceutically acceptable salt thereof: During the ceremony, Y 1 and Y 2 is CH or N; Y 3 , Y 4 , Y 5 , and Y 6 is CH; and where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 one of which is the point of attachment to the remainder of the molecule; R 14 teeth, hydrogen; R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 alkyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 6 Cycloalkyl and 3- to 6-membered heterocycloalkyl Selected from: R 1 is hydrogen; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl; R 2 and R 3 are independently hydrogen; and R 9 C, each of which may be substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 selected from carbocycles, and 3- to 6-membered heterocycles; Or, R 1 and R 2 together with the intervening atoms to which they are attached, R 9 or form a 5- to 8-membered heterocycle optionally substituted with one or more independently selected substituents; Or, R 2 and R 3 together with the intervening atoms to which they are attached, R 9 form a 4- to 10-membered heterocycle optionally substituted with one or more independently selected substituents; R 7 but, hydrogen; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 6 Cycloalkyl and 4- to 6-membered heterocycloalkyl selected from; and Each R 8 became independent, 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 ; R 9 C, each of which is optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 2 ~C 6 alkynyl; and R 9 C, each of which is optionally substituted with one or more independently selected substituents from 3 ~C 6 Cycloalkyl and 4- to 6-membered heterocycloalkyl Selected from: Each R 9 are independently 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 selected from carbocycles, and 3- to 6-membered heterocycles; Each R 12 are independently 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 selected from carbocycle, and 3- to 6-membered heterocycle; and Each R 13 is independently C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Haloalkyl, C 3 ~C 6 It is selected from carbocycles and 3- to 6-membered heterocycles.

2. The compound or salt of claim 1, wherein the compound of formula (IVa) is a compound represented by formula (IVb) or a pharmaceutically acceptable salt thereof: wherein R 1 , R 2 , R 3 , R 7 , R 8 , and R 14 are as defined in claim 1, and each R 15 is H.

3. R 7 but, hydrogen; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl 2. The compound or salt of claim 1, selected from:

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

5. Each R 8 became independent, Hydrogen, halogens, -CN, and -OR 13 and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 6 Alkyl 2. The compound or salt of claim 1, selected from:

6. R 14 but, hydrogen; and R 9 C optionally substituted with one or more independently selected substituents from 1 ~C 3 Alkyl 2. The compound or salt of claim 1, selected from:

7. R 14 7. The compound or salt of claim 6, wherein is selected from hydrogen and methyl.

8. R 14 8. The compound or salt of claim 7, wherein is hydrogen.

9. the below described: A compound selected from the following, or a pharmaceutically acceptable salt thereof:

10. The compound is a compound of the formula:

10. The compound or salt of claim 9, which is selected from: or a pharmaceutically acceptable salt thereof.

11. The compound is a compound of the formula:

10. The compound or salt of claim 9, which is selected from: or a pharmaceutically acceptable salt thereof.

12. The compound is a compound of the formula:

10. The compound or salt of claim 9, which is selected from: or a pharmaceutically acceptable salt thereof.

13. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition for treating or preventing an eye disease in a subject, comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, The pharmaceutical composition is administered to the eye of a subject in need thereof.

15. 15. The pharmaceutical composition of claim 14, wherein the eye disease is near vision impairment.

16. 16. The pharmaceutical composition of claim 15, wherein the near vision impairment is cataract or presbyopia.

17. A pharmaceutical composition for reducing alpha-crystallin protein aggregation by at least 5% in a subject in need thereof, comprising an effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

18. 18. The pharmaceutical composition of claim 17, wherein alpha-crystallin protein aggregation is reduced by at least 10%.

19. The compound is a compound of the formula:

2. The compound or salt of claim 1, which is selected from: or a pharmaceutically acceptable salt thereof.

Images