Compositions and methods for treating retinitis pigmentosa

Abstract

Described herein are certain methods of treating a subject with retinitis pigmentosa, the method comprising administering to the subject a therapeutically effective dose of a rhodopsin corrector molecule thereby treating the retinitis pigmentosa.

Description

WSGR Docket No.52652-721.601 COMPOSITIONS AND METHODS FOR TREATING RETINITIS PIGMENTOSA CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No.63 / 631,948 filed on April 9, 2024, U.S. Provisional Patent Application No.63 / 643,250 filed on May 6, 2024, and U.S. Provisional Patent Application No.63 / 775,873 filed on March 21, 2025, each of which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Autosomal dominant retinitis pigmentosa (adRP) is a progressive blindness disease with over 10,000 patients in the U.S. and Europe alone. Misfolding mutations of Rhodopsin constitute the most common cause of adRP. There is currently no approved pharmacologic treatment for rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP). Therefore, an approved RHO-adRP therapy would address an important unmet medical need. SUMMARY

[0003] Deep mutational scanning can be used to identify the effects of mutations on the function of a target protein, such as signaling, abundance, overexpression. Autosomal dominant retinitis pigmentosa (adRP) is a disease that leads to night blindness, peripheral vision loss, and complete blindness that can be caused by rod photoreceptor loss due to the mistrafficking of the Rhodopsin (RHO) protein. Mistrafficking can be caused by mutations in the Rhodopsin gene (Rho) resulting in misfolding of the protein, instability of the protein, retention of the protein in the ER, or disrupted vesicular traffic and endocytosis of the protein. Mutations in RHO with said mistrafficking can generally be classified as class 2 or class 3 mutants. Described herein are methods of identifying and treating mistrafficking mutants using a rhodopsin corrector molecule. Treatment with the rhodopsin corrector molecule broadly rescues mistrafficking mutants.

[0004] Described herein are certain methods of treating a subject with retinitis pigmentosa, the method comprising administering to the subject a therapeutically effective dose of a rhodopsin corrector molecule thereby treating the retinitis pigmentosa. In some embodiments, the retinitis pigmentosa comprises an autosomal dominant retinitis pigmentosa. In some embodiments, the method further comprises assaying a biological sample from the subject for a RHO gene mutation, wherein the subject is identified as having a RHO gene mutation if the assay determines the presence of a mutation compared to a wild-type RHO protein as shown in SEQ ID NO: 1 in the subject.WSGR Docket No.52652-721.601

[0005] In some embodiments, the subject is identified as having a RHO gene mutation that results in a mutation of a wild-type RHO protein. In some embodiments, the mutation of the wild-type RHO protein is a missense mutation. In some embodiments, a function of the mutation of the wild-type RHO protein is determined by a deep mutational scan of the wild-type RHO protein. In some embodiments, the subject is identified as having a RHO mutation that results in mistrafficking of RHO due to RHO misfolding, RHO instability, retention of RHO in the endoplasmic reticulum, disrupted vesicular traffic, and / or disrupted endocytosis. In some embodiments, the subject is identified as having a class 2 or class 3 RHO mutation. In some embodiments, the subject is identified as having a class 2 RHO mutation. In some embodiments, the subject is identified as having a class 3 RHO mutation. In some embodiments, the class 2 or class 3 mutation results in reduced RHO on the plasma membrane. In some embodiments, the class 2 or class 3 mutation results in RHO misfolding, RHO instability, retention of RHO in the endoplasmic reticulum, disrupted vesicular traffic, and / or disrupted endocytosis. In some embodiments, the class 2 or class 3 mutation comprises a missense mutation at any one or more of N15, T17, V20, P23, Q28, G51, P53, T58, V87, G89, G106, C110, E113, L125, W161, A164, C167, P171, Y178, E181, G182, C185, C187, G188, D190, H211, C222, P267, S270, K296, or R135. In some embodiments, the class 2 or class 3 mutation comprises N15S, T17M, V20G, P23A, P23H, P23L, Q28H, G51R, G51V, P53R, T58R, T58M, V87D, G89D, G106R G106W, C110F, C110R, C110S, C110Y, E113K, L125R, W161R, A164E, A164V, C167R, C167W, P171Q, P171L, P171S, Y178N, Y178D, Y178C, E181K, G182S, G182V, C185R, C187G, C187Y, G188R, G188E, D190N, D190G, D190Y, H211R, H211P, C222R, P267R, P267L, S270R, K296E, K296M, R135G, R135L, R135P, or R135W. In some embodiments, the class 2 or class 3 mutation comprises P23H. In some embodiments, the class 2 or class 3 mutation comprises a missense mutation at any one or more of M1, G3, T4, G6, N8, F9, Y10, V11, P12, F13, A16, G18, R21, S22, F24, E25, Y26, P27, Y30, L31, A32, F37, M39, L40, A41, Y43, M44, F45, L46, L47, I48, V49, L50, F52, I54, N55, F56, L57, L59, V61, I75, L76, N78, V81, L84, F85, V87, L88, G90, F91, T92, T94, L95, T97, S98, L99, H100, G101, Y102, F103, L112, G114, F115, F116, T118, L119, I123, W126, S127, L128, V129, V130, L131, A132, I133, E134, A153, V157, A158, F159, T160, V162, M163, L165, A166, A168, A169, P170, L172, A173, G174, W175, S176, R177, I179, P180, L183, Q184, S186, I189, Y191, Y192, T193, N200, F203, V204, Y206, M207, F208, V209, V210, F212, T213, I214, P215, M216, I217, I218, I219, F220, F221, M253, V254, M257, V258, A260, L262, I263, V266, Y268, V271, A272, F273, Y274, I275, F276, T277, H278, P285, M288, T289, I290, P291, F293, F294, S297, A299, I300, N302, P303, V304, I305, I307, M308, M309, N310, F313, R314, M317, T320, S334, A335, or E341. In some embodiments, the class 2 or class 3 mutation comprises any oneWSGR Docket No.52652-721.601 or more variants listed in Table 3. In some embodiments, the class 2 or class 3 mutation comprises any one or more of the variants listed in Table 4, 5, or 6. In some embodiments, the class 2 or class 3 mutation is determined by deep mutational scanning. In some embodiments, the rhodopsin corrector molecule is therapeutically effective at treating at least 80% of disease associated mutations. In some embodiments, the at least 80% of disease associated mutations are selected from the list consisting of F9L, N15S, T17K, T17M, V20L, R21P, P23H, P23L, F24C, Q28H, Q28K, Q28R, G51R, L59H, G89D, L95P, Y102N, G106R, L131R, R135G, R135L, R135P, R135W, P171S, A173P, I179N, P180A, P180L, P180S, E181K, G182D, G182E, G182S, Q184R, C185R, C185Y, S186P, G188E, D190E, D190G, D190N, D190Y, P267L, H278P, and T289P. In some embodiments, the rhodopsin corrector molecule is a gene therapy. In some embodiments, the gene therapy comprises overexpression of GRP78. In some embodiments, the rhodopsin corrector molecule comprises a small molecule. In some embodiments, the rhodopsin corrector molecule comprises 9-cis retinal, YC001, F5257-0462, or SRD005825. In some embodiments, the rhodopsin corrector molecule comprises 9-cis retinal. In some embodiments, the rhodopsin corrector molecule comprises YC001. In some embodiments, the rhodopsin corrector molecule comprises F5257-0462. In some embodiments, the rhodopsin corrector molecule comprises SRD005825.

[0006] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (I); wherein: Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y2and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, - C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-WSGR Docket No.52652-721.601 6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected fromWSGR Docket No.52652-721.601 halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0007] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (Ia).

[0008] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (II); wherein: X, Y, and Z are each independently C(R3) or N, wherein at least one of Y and Z is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups;WSGR Docket No.52652-721.601 each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;WSGR Docket No.52652-721.601 each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0009] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (IIa).

[0010] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (III); wherein: Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); J is O or S; R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-WSGR Docket No.52652-721.601 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; R3is selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-WSGR Docket No.52652-721.601 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0011] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (IIIa).

[0012] In some embodiments, each R3is independently selected from hydrogen, halogen, - CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments, each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments, each R3is hydrogen. In some embodiments, each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, and wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments, each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments, each R2is -CH3. In some embodiments, n is 1. In some embodiments, R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl, and wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments, R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments, R1is halogen. In some embodiments, Z1, Z2, and Z3are each independently C(R4). In some embodiments, Z1and Z2are each independently C(R4), and Z3is N. In some embodiments, each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups.

[0013] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (Ib);WSGR Docket No.52652-721.601 wherein: Z3is C(R4) or N; R1is selected from halogen, -CN, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl; and each R4is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl.

[0014] In some embodiments, R1is halogen or unsubstituted C1-6alkyl. In some embodiments, R1is halogen. In some embodiments, R1is unsubstituted C1-6alkyl. In some embodiments, Z3is C(R4). In some embodiments, Z3is N. In some embodiments, each R4is independently selected from hydrogen and halogen. In some embodiments, each R4is hydrogen.

[0015] In some embodiments, the rhodopsin corrector molecule is selected from:, or a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, the rhodopsin corrector molecule increases cell surface expression of rhodopsin compared to vehicle control. In some embodiments, the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 25% of that observed for wild-type rhodopsin. In some embodiments, the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 30% of that observed for wild-type rhodopsin. In some embodiments, the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 40% of that observed for wild-type rhodopsin. In some embodiments, the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 50% of that observed for wild-type rhodopsin. In some embodiments, the rhodopsin corrector molecule is administered to a human. In some embodiments, the rhodopsin corrector molecule is administered orally. In some embodiments, a therapeutically effective concentration of the rhodopsin corrector molecule is delivered to an ocular tissue. In some embodiments, a therapeutically effective concentration of the rhodopsin corrector molecule is delivered to the retina. In some embodiments, theWSGR Docket No.52652-721.601 therapeutically effective concentration of the rhodopsin corrector molecule increases cell surface expression of rhodopsin. In some embodiments, a therapeutically effective concentration of the rhodopsin corrector molecule drug is delivered to an ocular tissue. In some embodiments, the rhodopsin corrector molecule exhibits oral bioavailability of greater than about 50%. In some embodiments, the rhodopsin corrector molecule exhibits oral bioavailability of greater than about 70%. In some embodiments, the rhodopsin corrector molecule exhibits microsomal stability of greater than about 90 minutes. In some embodiments, the rhodopsin corrector molecule exhibits an EC50 for rescue of rhodopsin surface expression of 1 uM or less. In some embodiments, the rhodopsin corrector molecule exhibits an EC50 for rescue of rhodopsin surface expression of less than about 200 nM. In some embodiments, the rhodopsin corrector molecule exhibits an EC50 for rescue of rhodopsin surface expression of less than about 100 nM. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The novel features described herein are set forth with particularity in the appended claims. A better understanding of the features and advantages of the features described herein will be obtained by reference to the following detailed description that sets forth illustrative examples, in which the principles of the features described herein are utilized, and the accompanying drawings of which:

[0018] FIG.1 illustrates a schematic of healthy and disease states of autosomal dominant retinitis pigmentosa (adRP).

[0019] FIG.2 illustrates a schematic of the in vitro diagnostic assay for the quantification of RHO trafficking.

[0020] FIG.3 shows a heatmap of the amount of mutated RHO trafficked to the plasma membrane relative to wildtype RHO.

[0021] FIG.4 shows a heatmap of the amount of mutated RHO trafficked to the plasma membrane when rescued by a rhodopsin corrector molecule relative to wildtype RHO.

[0022] FIGs.5A-5B show a graph of the amount of select mutated RHO categorized by class trafficked to the plasma membrane relative to wildtype RHO.

[0023] FIGs.6A-6B show a graph of the amount of select mutated RHO categorized by class trafficked to the plasma membrane when rescued by a rhodopsin corrector molecule relative to wildtype RHO.

[0024] FIGs.7A-7AR show bar graphs of the relative amount of mutated RHO trafficked to the plasma membrane relative to wildtype RHO with and without treatment of a rhodopsin corrector molecule. Compounds were applied at 1 µM (FIGS.7 A, C, E, G, I, K, M, O, Q, S,WSGR Docket No.52652-721.601 U, W, Y, AA, AC, AE, AG, AI, AK, AM, AO, and AQ), or 10 µM (FIGS.7 B, D, F, H, J, L, N, P, R, T, V, X, Z, AB, AD, AF, AH, AJ, AL, AN, AP, and AR).

[0025] FIGs.8A-8B show retina from RhoWT, vehicle treated heterozygote RhoP23H / + (A, B, C and D) or Compound A treated heterozygote RhoP23H / + (C and D) mice counterstained by eosin and hematoxylin analyzed for OS thickness and ONL nuclei per column at 8 discrete locations (covering 1500 micrometer) in each direction from ONH. Contrast summary statistics revealed a significant increase in number of ONL nuclei per column (+0.44 nuclei count / column, p = 0.01) and OS thickness (+25%, p = 0.032) in drug treated versus vehicle treated animal retinas. Mut = mutation; ONH = optic nerve head; ONL = outer nuclear layer; OS = outer segment; Rho+ / + = RhoWT. Top panel, OS thickness; bottom panel, ONL nuclei number per column.

[0026] FIGs.9A-9C show retina from vehicle treated heterozygote RhoP23H / + or Compound treated heterozygote RhoP23H / + mice counterstained by eosin and hematoxylin analyzed for ONL thickness, ONL nuclei per column, and OS thickness 8 discrete locations (covering 1500 micrometer) in each direction from ONH. Contrast summary statistics revealed an increase in number of ONL nuclei per column (+0.29 nuclei count / column, p = 0.063) and significant increase of OS thickness (+27.6%, p = 0.0001) and ONL thickness (+6.25%, p = 0.033) in drug treated (100mg / kg BID) versus vehicle treated animal retinas. Mut = mutation; ONH = optic nerve head; ONL = outer nuclear layer; OS = outer segment; Rho+ / + = RhoWT. Top panel, OS thickness; bottom panel, ONL nuclei number per column.

[0027] FIG.10 shows retina from vehicle treated heterozygote RhoP23H / + or Compound A treated heterozygote RhoP23H / + mice counterstained by eosin and hematoxylin were analyzed for OS thickness and ONL nuclei per column at 8 discrete locations (covering 1500 micrometer) in each direction from ONH.

[0028] FIG.11 shows representative images from vehicle and Compound A treated animals. Contrast summary statistics revealed a significant increase in number of ONL nuclei per column (+1 nuclei count / column, p = 0.001) and OS thickness (+15%, p = 0.011) in drug treated versus vehicle treated animal retinas. Mut = mutation; ONH = optic nerve head; ONL = outer nuclear layer; OS = outer segment; Panel: OS thickness; Panel B: ONL nuclei number per column; Panel C: representative images of retina in vehicle and Compound A treated RhoP23H / + mice. DETAILED DESCRIPTION

[0029] Autosomal dominant retinitis pigmentosa (adRP) is a progressive blindness disease with no standard of care or approved therapies. Misfolding mutations of Rhodopsin (RHO) constitute the most common cause of adRP. Mutations have toxic gain-of-function effects andWSGR Docket No.52652-721.601 most frequently result in RHO misfolding and mistrafficking. Misfolded RHO accumulation causes cellular stress, which leads to death of photoreceptor cells (rods) and ultimately loss of central vision (cones). Properly folded RHO is trafficked to the rod outer segment preventing photoreceptor cell death and preserving vision.

[0030] Described herein is a method of treating a subject with retinitis pigmentosa, the method comprising administering to the subject a therapeutically effective dose of a rhodopsin corrector molecule, wherein the subject is identified as having a mistrafficking rhodopsin mutation and / or class 2 mutation or a class 3 mutation, thereby treating the retinitis pigmentosa.

[0031] Described herein is an in vitro assay for the determination of the class of adRP disease a given mutation causes and whether a rhodopsin corrector molecule will prevent or mitigate RHO misfolding, directly addressing the underlying mechanism of disease to restore Rhodopsin trafficking.

[0032] adRP has been classified into 7 distinct classes defined by key features, biochemical and cellular information as exemplified in Table 1 of Athanasiou, et al. (2018), Prog Retin Eye Res.62: 1-23, reproduced below in Table 1. Given that RHO mutations cause RP through multiple potential mechanisms, this classification is not mutually exclusive, with some mutants potentially leading to consequences that are applicable to more than one class. Table 1. Classification of adRP mutations

[0033] As shown in FIG.1, a schematic illustrates healthy and disease states of RP. In the healthy model, wildtype RHO is processed in the endoplasmic reticulum, trafficked to the plasma membrane, and functions to maintain vision. In the disease state, mutated RHO accumulates in the endoplasmic reticulum and is not trafficked to the plasma membrane, causing cellular stress, which leads to death of photoreceptor cells (rods) and ultimately loss of central vision (cones). Mutations that cause this cellular dysfunction wherein mutated RHO does not getWSGR Docket No.52652-721.601 trafficked to the plasma membrane, either by ER retention and instability or disrupted vesicular traffic and endocytosis, are categorized as class 2 and class 3 adRP mutations. In some embodiments, the class 2 or class 3 mutation results in reduced RHO on the plasma membrane. In some embodiments, the class 2 or class 3 mutation results in RHO misfolding, RHO instability, retention of RHO in the endoplasmic reticulum, disrupted vesicular traffic, and / or disrupted endocytosis.

[0034] A number of putative class 2 and class 3 mutations were identified by Athanasiou, et al. Some example of class 2 mutations are N15S, T17M, V20G, P23A, P23H, P23L, Q28H, G51V, G51R, P53R, T58R, T58M, V87D, G89D, G106R, G106W, C110F, C110R, C110S, C110Y, E113K, L125R, W161R, A164E, A164V, C167R, C167W, P171Q, P171L, P171S, Y178N, Y178D, Y178C, E181K, G182S, G182V, C185R, C187G, C187Y, G188R, G188E, D190N, D190G, D190Y, H211R, H211P, C222R, P267R, P267L, S270R, K296N, K296E, and K296M. Some examples of class 3 mutations are R135G, R135L, R135P, and R135W.

[0035] In order to identify adRP mutations as class 2 or class 3, an in vitro assay was developed to determine the mutation’s effects on RHO trafficking to the plasma membrane. As shown in FIG.2, a gene expressing a variant RHO with a single missense mutation is fused to gene expressing a transcription factor (TF) and integrated into a cell. Each cell has a single variant RHO gene and a unique barcode downstream of a response element (RE). A mutated RHO-transcription factor fusion that is properly folded and trafficked to the plasma membrane will encounter a plasma membrane specific protease. The protease will cleave the mutated RHO-transcription factor and the transcription factor will be released from the membrane. The transcription factor bind to the response element and will allow for transcription of the variant specific barcode, which can be read by next generation sequencing. By this method, a RHO mutation that prevents trafficking to the plasma membrane, i.e. a class 2 or class 3 RP disease, will have fewer barcode reads than wildtype or a mutation that does not prevent RHO trafficking as the mutated RHO-transcription factor fusion would not reach the plasma membrane to release the TF. The variant RHO barcode quantification is normalized against wildtype RHO as a trafficking score. The variant RHO that has less than about 50% of normalized trafficking score compared to wildtype is considered a class 2 or class 3 mutation. The in vitro assay can be performed in one dish with each cell containing a single RHO variant and barcode. Using the method described above, the in vitro assay can be used in a high-throughput manner to perform deep mutational screening of RHO mutations. The assay detected class 2 or class 3 RHO mutations, such as, M1, G3, T4, G6, N8, F9, Y10, V11, P12, F13, A16, G18, R21, S22, F24, E25, Y26, P27, Y30, L31, A32, F37, M39, L40, A41, Y43, M44, F45, L46, L47, I48, V49, L50, F52, I54, N55, F56, L57, L59, V61, I75, L76, N78, V81, L84, F85, V87, L88, G90, F91, T92,WSGR Docket No.52652-721.601 T94, L95, T97, S98, L99, H100, G101, Y102, F103, L112, G114, F115, F116, T118, L119, I123, W126, S127, L128, V129, V130, L131, A132, I133, E134, A153, V157, A158, F159, T160, V162, M163, L165, A166, A168, A169, P170, L172, A173, G174, W175, S176, R177, I179, P180, L183, Q184, S186, I189, Y191, Y192, T193, N200, F203, V204, Y206, M207, F208, V209, V210, F212, T213, I214, P215, M216, I217, I218, I219, F220, F221, M253, V254, M257, V258, A260, L262, I263, V266, Y268, V271, A272, F273, Y274, I275, F276, T277, H278, P285, M288, T289, I290, P291, F293, F294, S297, A299, I300, N302, P303, V304, I305, I307, M308, M309, N310, F313, R314, M317, T320, S334, A335, or E341. In some embodiments, the mutation is N15, T17, V20, P23, Q28, G51, P53, T58, V87, G89, G106, C110, E113, L125, W161, A164, C167, P171, Y178, E181, G182, C185, C187, G188, D190, H211, C222, P267, S270, K296, or R135. In some embodiments, the RHO mutation comprises M1A, M1C, M1D, M1E, M1F, M1G, M1H, M1I, M1K, M1L, M1N, M1P, M1Q, M1R, M1S, M1T, M1V, M1W, M1Y, G3E, T4D, T4P, T4R, G6C, G6D, G6E, G6F, G6H, G6I, G6K, G6L, G6M, G6N, G6P, G6Q, G6R, G6S, G6T, G6V, G6W, G6Y, N8P, F9A, F9C, F9D, F9E, F9G, F9H, F9I, F9K, F9L, F9M, F9N, F9P, F9Q, F9R, F9S, F9T, F9V, Y10A, Y10C, Y10D, Y10E, Y10G, Y10K, Y10P, Y10Q, Y10R, Y10S, Y10T, V11D, V11E, V11F, V11G, V11H, V11K, V11N, V11P, V11Q, V11R, V11S, V11W, V11Y, P12I, P12K, P12N, P12R, F13P, N15A, N15C, N15D, N15E, N15F, N15G, N15H, N15I, N15K, N15L, N15M, N15P, N15Q, N15R, N15S, N15T, N15V, N15W, N15Y, A16P, T17D, T17E, T17F, T17H, T17I, T17K, T17L, T17M, T17P, T17Q, T17R, T17W, T17Y, G18I, G18P, G18V, V20D, V20E, V20F, V20G, V20H, V20K, V20L, V20M, V20N, V20P, V20Q, V20R, V20W, V20Y, R21P, S22E, S22F, S22H, S22I, S22K, S22L, S22M, S22Q, S22R, S22V, S22W, S22Y, P23A, P23C, P23D, P23E, P23F, P23G, P23H, P23I, P23K, P23L, P23M, P23N, P23Q, P23R, P23S, P23T, P23V, P23W, P23Y, F24A, F24C, F24D, F24E, F24G, F24I, F24K, F24N, F24P, F24Q, F24R, F24S, F24T, F24V, E25P, Y26P, P27L, P27W, Q28D, Q28E, Q28F, Q28H, Q28I, Q28K, Q28N, Q28P, Q28R, Q28S, Q28T, Q28W, Q28Y, Y30G, Y30K, Y30P, Y30Q, Y30R, Y30W, L31D, L31E, L31G, L31H, L31K, L31N, L31P, L31Q, L31R, L31S, L31T, L31W, L31Y, A32D, A32H, A32N, A32P, A32Y, F37A, F37D, F37E, F37G, F37K, F37N, F37P, F37Q, F37S, M39D, M39P, L40D, L40K, L40P, L40R, A41D, Y43K, Y43P, Y43R, M44K, M44P, M44R, F45D, F45P, F45R, L46R, L47D, L47K, L47P, L47R, I48D, I48E, I48H, I48K, I48P, I48R, V49P, V49R, L50D, L50E, L50K, L50R, G51D, G51F, G51K, G51N, G51P, G51R, G51W, G51Y, F52D, F52E, F52K, F52N, F52P, F52Q, F52R, P53E, P53R, I54D, I54H, I54K, I54R, N55D, N55E, N55I, N55M, N55P, N55R, N55T, N55V, N55W, N55Y, F56D, F56E, F56K, F56P, F56R, L57D, L57K, L57P, L57R, T58D, L59D, L59E, L59H, L59K, L59N, L59R, V61D, V61P, V61R, I75D, I75R, L76D, N78A, N78F, N78I, N78K, N78L, N78P, N78R, N78V,WSGR Docket No.52652-721.601 N78W, N78Y, V81D, V81K, V81P, V81R, L84P, L84R, F85R, V87D, V87H, V87K, V87N, V87P, V87R, V87W, L88R, G89D, G89R, G90F, G90K, G90R, G90W, G90Y, F91R, T92D, T92E, T92K, T92R, T94K, T94R, T94Y, L95D, L95K, L95N, L95P, L95R, T97E, T97K, T97P, T97R, T97W, S98D, S98P, S98R, L99D, H100P, G101D, G101I, G101P, G101V, Y102D, Y102E, Y102I, Y102N, Y102P, Y102V, F103K, F103P, F103R, G106C, G106D, G106E, G106F, G106H, G106I, G106L, G106M, G106P, G106R, G106V, G106W, G106Y, C110A, C110D, C110E, C110F, C110G, C110H, C110I, C110K, C110L, C110M, C110N, C110P, C110Q, C110R, C110S, C110T, C110V, C110W, C110Y, L112D, L112P, E113G, E113K, E113P, E113R, E113W, G114C, G114D, G114E, G114F, G114H, G114I, G114K, G114L, G114M, G114N, G114P, G114Q, G114R, G114S, G114T, G114V, G114W, G114Y, F115D, F115E, F115H, F115K, F115N, F115P, F115Q, F115R, F116K, F116R, T118P, L119D, L119K, L119P, L119R, I123P, I123R, L125D, W126D, W126I, W126K, W126P, W126R, W126V, S127F, S127I, S127K, S127L, S127P, S127R, S127W, S127Y, L128P, V129H, V129K, V129R, V129Y, V130K, V130R, L131D, L131P, L131R, A132P, A132R, I133D, E134P, R135F, R135G, R135I, R135L, R135M, R135P, R135W, R135Y, A153V, V157H, V157K, V157R, A158D, F159D, F159E, F159K, F159P, F159R, T160D, T160F, T160H, T160K, T160R, T160W, T160Y, W161K, W161P, W161R, V162D, V162R, M163D, M163K, M163R, M163Y, A164D, A164E, A164F, A164H, A164I, A164K, A164L, A164N, A164P, A164Q, A164R, A164W, A164Y, L165D, L165E, L165K, L165P, L165R, A166K, A166P, A166R, C167P, C167W, A168D, A168E, A168F, A168H, A168I, A168K, A168L, A168M, A168N, A168P, A168Q, A168R, A168W, A168Y, A169D, A169K, A169P, A169R, P170D, P170E, P170H, P170I, P170K, P170N, P170R, P170T, P170V, P170Y, P171A, P171C, P171D, P171E, P171F, P171G, P171H, P171I, P171K, P171L, P171M, P171N, P171Q, P171R, P171S, P171T, P171V, P171W, P171Y, L172D, L172E, L172H, L172K, L172P, L172Q, L172R, A173P, G174C, G174P, W175C, W175D, W175E, W175G, W175K, W175N, W175P, W175Q, W175R, W175S, W175T, S176D, S176E, S176F, S176H, S176I, S176K, S176L, S176M, S176P, S176Q, S176R, S176T, S176V, S176W, S176Y, R177C, R177D, R177E, R177F, R177G, R177I, R177K, R177L, R177N, R177P, R177T, R177V, R177W, R177Y, Y178A, Y178C, Y178D, Y178E, Y178G, Y178H, Y178I, Y178K, Y178L, Y178M, Y178N, Y178P, Y178Q, Y178R, Y178S, Y178T, Y178V, Y178W, I179A, I179C, I179D, I179E, I179F, I179G, I179H, I179K, I179N, I179P, I179Q, I179R, I179S, I179W, I179Y, P180A, P180C, P180D, P180E, P180F, P180G, P180H, P180I, P180K, P180L, P180M, P180N, P180Q, P180R, P180S, P180T, P180V, P180W, P180Y, E181C, E181G, E181K, E181P, E181R, G182C, G182D, G182E, G182F, G182H, G182I, G182K, G182L, G182M, G182N, G182P, G182Q, G182R, G182S, G182T, G182V, G182W, G182Y, L183D, L183E, L183G, L183K, L183P, L183R, Q184A,WSGR Docket No.52652-721.601 Q184D, Q184E, Q184F, Q184H, Q184I, Q184K, Q184N, Q184P, Q184R, Q184S, Q184T, Q184V, Q184W, Q184Y, C185D, C185E, C185K, C185P, C185R, C185W, C185Y, S186K, S186P, S186R, C187A, C187D, C187E, C187F, C187G, C187H, C187I, C187K, C187L, C187M, C187N, C187P, C187Q, C187R, C187S, C187T, C187V, C187W, C187Y, G188C, G188E, G188H, G188I, G188K, G188L, G188M, G188P, G188Q, G188R, G188V, G188Y, I189C, I189D, I189E, I189G, I189K, I189N, I189Q, I189R, I189S, I189T, I189W, D190A, D190C, D190E, D190F, D190G, D190H, D190I, D190K, D190L, D190M, D190N, D190P, D190Q, D190R, D190S, D190T, D190V, D190W, D190Y, Y191D, Y191E, Y191G, Y191N, Y191P, Y191Q, Y191R, Y191S, Y192D, Y192G, Y192K, Y192P, T193E, T193P, T193W, N200E, N200F, N200L, N200W, F203C, F203D, F203E, F203G, F203H, F203I, F203K, F203L, F203M, F203N, F203P, F203Q, F203R, F203S, F203V, V204D, V204E, Y206D, Y206E, Y206G, Y206K, Y206L, Y206N, Y206P, Y206R, M207P, F208D, F208K, F208P, F208R, V209D, V209K, V209P, V210D, V210K, V210P, V210R, H211I, H211K, H211L, H211P, H211R, H211V, H211W, F212P, T213P, T213R, I214D, I214K, I214P, I214R, P215A, P215C, P215D, P215E, P215F, P215G, P215H, P215I, P215K, P215L, P215M, P215N, P215Q, P215R, P215S, P215T, P215V, P215W, P215Y, M216R, I217R, I218D, I218E, I218H, I218K, I218N, I218R, I218Y, I219D, I219E, I219P, F220R, F221D, C222D, C222R, M253K, V254K, M257D, M257G, M257P, V258R, A260R, L262R, I263R, V266D, V266H, V266K, V266R, P267C, P267D, P267E, P267F, P267H, P267I, P267K, P267L, P267M, P267N, P267R, P267V, Y268I, Y268P, S270P, V271P, A272F, F273D, F273P, Y274P, I275P, F276D, F276P, T277P, T277W, H278P, P285D, M288D, M288K, T289K, T289P, T289R, I290D, I290E, I290K, P291D, P291K, F293P, F293R, F294D, F294R, K296F, K296I, K296T, K296V, K296Y, S297D, S297R, A299D, I300D, I300E, I300H, I300K, I300P, I300Q, I300R, N302Q, P303E, P303F, P303L, P303W, P303Y, V304D, V304E, V304K, V304Q, V304R, I305D, I305E, I305H, I305K, I305Q, I305R, I305Y, I307D, I307E, I307K, I307R, M308D, M308P, M309P, N310P, F313A, F313D, F313K, F313P, F313S, R314D, R314P, M317D, M317P, M317R, T320C, S334E, A335M, or E341N. In some embodiments, the mutation is N15S, T17M, V20G, P23A, P23H, P23L, Q28H, G51R, G51V, P53R, T58R, T58M, V87D, G89D, G106R G106W, C110F, C110R, C110S, C110Y, E113K, L125R, W161R, A164E, A164V, C167R, C167W, P171Q, P171L, P171S, Y178N, Y178D, Y178C, E181K, G182S, G182V, C185R, C187G, C187Y, G188R, G188E, D190N, D190G, D190Y, H211R, H211P, C222R, P267R, P267L, S270R, K296E, K296M, R135G, R135L, R135P, or R135W.

[0036] In some embodiments, the rhodopsin correctors described herein are therapeutically effective at treating at least 50%, at least 60%, at least 70%, or at least 80% of disease associated mutations. In some embodiments, the disease associated mutations are P53R, L59R, C110R,WSGR Docket No.52652-721.601 G114V, S127F, A164E, P170R, P171L, P171Q, P171R, P171T, S176F, Y178C, Y178H, C187Y, G188R, H211R, P215L, F9L, N15S, T17K, T17M, V20L, R21P, P23H, P23L, F24C, Q28H, Q28K, Q28R, G51R, L59H, G89D, L95P, Y102N, G106R, L131R, R135G, R135L, R135P, R135W, P171S, A173P, I179N, P180A, P180L, P180S, E181K, G182D, G182E, G182S, Q184R, C185R, C185Y, S186P, G188E, D190E, D190G, D190N, D190Y, P267L, H278P, and T289P. In some embodiments, the at least 80% of disease associated mutations comprise F9L, N15S, T17K, T17M, V20L, R21P, P23H, P23L, F24C, Q28H, Q28K, Q28R, G51R, L59H, G89D, L95P, Y102N, G106R, L131R, R135G, R135L, R135P, R135W, P171S, A173P, I179N, P180A, P180L, P180S, E181K, G182D, G182E, G182S, Q184R, C185R, C185Y, S186P, G188E, D190E, D190G, D190N, D190Y, P267L, H278P, and T289P.Further described herein is an in vitro assay to determine whether a rhodopsin corrector molecule will prevent or mitigate RHO misfolding, directly addressing the underlying mechanism of disease to restore Rhodopsin trafficking.

[0037] The in vitro assay can be used as described above. Cells grown in a dish containing one RHO variant and barcode are additionally treated with a rhodopsin corrector molecule. The barcode reads are quantified and normalized against wildtype RHO as a trafficking score. The variant RHO barcode quantification is compared with and without treatment. A variant RHO that has less than about 50% of trafficking score compared to wildtype is considered a class 2 or class 3 mutation. A variant RHO treated with the corrector molecule that previously had less than about 50% of trafficking score compared to wildtype and after treatment has more than about 50% of trafficking score compared to wildtype is considered rescued. Using the above assay, class 2 or class 3 mutants were rescued by a corrector molecule, such as, M1A, M1F, M1I, M1K, M1T, G3E, T4D, T4P, T4R, G6C, G6D, G6E, G6F, G6H, G6I, G6K, G6L, G6M, G6N, G6P, G6Q, G6R, G6S, G6T, G6V, G6W, G6Y, N8P, F9A, F9C, F9D, F9E, F9G, F9H, F9I, F9K, F9L, F9M, F9N, F9P, F9Q, F9R, F9S, F9T, F9V, Y10A, Y10C, Y10D, Y10E, Y10G, Y10K, Y10P, Y10Q, Y10R, Y10S, Y10T, V11D, V11E, V11F, V11G, V11H, V11K, V11N, V11Q, V11R, V11S, V11Y, P12I, P12K, P12N, P12R, F13P, N15A, N15C, N15D, N15E, N15F, N15G, N15H, N15I, N15K, N15L, N15M, N15P, N15Q, N15R, N15S, N15T, N15V, N15W, N15Y, A16P, T17D, T17E, T17F, T17H, T17I, T17K, T17L, T17M, T17P, T17Q, T17R, T17W, T17Y, G18I, G18P, G18V, V20D, V20E, V20F, V20G, V20H, V20K, V20L, V20M, V20N, V20P, V20Q, V20R, V20W, V20Y, R21P, S22E, S22F, S22H, S22I, S22K, S22L, S22M, S22Q, S22R, S22V, S22W, S22Y, P23A, P23C, P23D, P23E, P23F, P23G, P23H, P23I, P23K, P23L, P23M, P23N, P23Q, P23R, P23S, P23T, P23V, P23W, P23Y, F24A, F24C, F24D, F24E, F24G, F24I, F24K, F24N, F24P, F24Q, F24R, F24S, F24T, F24V, E25P, Y26P, P27L, P27W, Q28D, Q28E, Q28F, Q28H, Q28I, Q28K, Q28N, Q28P, Q28R, Q28S, Q28T,WSGR Docket No.52652-721.601 Q28W, Q28Y, Y30G, Y30K, Y30P, Y30Q, Y30R, Y30W, L31D, L31E, L31G, L31K, L31N, L31P, L31Q, L31R, L31S, L31T, L31W, L31Y, A32D, A32H, A32N, A32P, A32Y, F37A, F37D, F37E, F37G, F37K, F37N, F37P, F37Q, F37S, M39D, M39P, L40D, L40K, L40P, L40R, A41D, Y43K, Y43P, Y43R, M44K, M44P, M44R, F45D, F45P, F45R, L46R, L47D, L47K, L47P, L47R, I48D, I48E, I48H, I48K, I48P, V49P, L50D, L50E, L50K, G51D, G51F, G51K, G51N, G51P, G51R, G51W, G51Y, F52E, F52K, F52N, F52P, F52Q, P53E, I54D, I54H, I54K, N55D, N55E, N55I, N55M, N55P, N55R, N55T, N55V, N55W, N55Y, F56E, F56K, L57D, L57K, L57P, L57R, T58D, L59D, L59E, L59H, L59N, V61D, V61P, V61R, I75D, I75R, L76D, N78A, N78I, N78K, N78L, N78P, N78V, N78Y, V81D, V81K, V81R, L84P, L84R, F85R, V87D, V87H, V87N, V87P, V87W, L88R, G89D, G89R, G90F, G90K, G90R, G90W, G90Y, F91R, T92D, T92E, T92K, T92R, T94K, T94R, T94Y, L95D, L95K, L95N, L95P, L95R, T97E, T97P, T97R, T97W, S98D, S98P, S98R, L99D, H100P, G101D, G101I, G101P, G101V, Y102D, Y102E, Y102I, Y102N, Y102P, Y102V, F103K, F103P, F103R, G106C, G106D, G106E, G106F, G106H, G106I, G106L, G106M, G106P, G106R, G106V, G106W, G106Y, C110D, C110E, C110F, C110K, C110L, C110M, C110S, C110W, L112D, L112P, E113G, E113K, E113R, E113W, G114C, G114E, G114I, G114K, G114P, G114R, G114S, G114T, F115H, F115N, F115P, F116K, F116R, T118P, L119K, L119R, L125D, W126D, W126I, W126P, W126V, S127F, S127I, S127L, V129H, V129K, V129Y, V130K, V130R, L131D, L131R, A132P, A132R, I133D, E134P, R135F, R135G, R135I, R135L, R135M, R135P, R135W, R135Y, A153V, V157H, V157K, V157R, A158D, F159D, F159E, F159K, F159P, T160F, T160H, T160W, T160Y, W161K, W161R, V162D, V162R, M163D, M163K, M163Y, A164D, A164F, A164P, A164W, L165D, L165E, L165K, L165P, L165R, A166K, A166P, C167W, A168E, A168I, A168K, A168N, A168P, A168Q, A168R, A168W, A169D, A169K, A169P, P170D, P170E, P170I, P170K, P170N, P170T, P170V, P170Y, P171A, P171G, P171I, P171L, P171N, P171Q, P171R, P171S, P171T, P171V, P171W, P171Y, L172D, L172E, L172H, L172K, L172P, L172Q, L172R, A173P, G174C, G174P, W175C, W175E, W175G, W175K, W175N, W175Q, W175S, W175T, S176D, S176E, S176F, S176H, S176I, S176P, S176T, R177C, R177D, R177E, R177F, R177G, R177I, R177K, R177L, R177N, R177T, R177W, R177Y, Y178C, Y178G, Y178H, Y178I, Y178L, Y178M, Y178N, Y178W, I179A, I179C, I179D, I179E, I179F, I179G, I179H, I179K, I179N, I179P, I179Q, I179R, I179S, I179W, I179Y, P180A, P180C, P180D, P180E, P180F, P180G, P180H, P180I, P180K, P180L, P180M, P180N, P180Q, P180R, P180S, P180T, P180V, P180W, P180Y, E181C, E181G, E181K, E181P, E181R, G182C, G182D, G182E, G182F, G182H, G182I, G182K, G182L, G182M, G182N, G182P, G182Q, G182R, G182S, G182T, G182V, G182W, G182Y, L183D, L183E, L183G, L183K, L183P, L183R, Q184A, Q184D, Q184E, Q184F, Q184H, Q184I,WSGR Docket No.52652-721.601 Q184K, Q184N, Q184P, Q184R, Q184S, Q184T, Q184V, Q184W, Q184Y, C185D, C185E, C185K, C185P, C185R, C185W, C185Y, S186K, S186P, S186R, C187A, C187E, C187I, C187K, C187L, C187M, C187N, C187Q, C187S, C187T, C187V, C187Y, G188C, G188E, G188H, G188I, G188K, G188M, G188Q, G188R, G188V, I189C, I189G, I189N, I189Q, I189R, I189S, I189T, D190A, D190C, D190E, D190F, D190G, D190H, D190I, D190K, D190M, D190N, D190P, D190Q, D190R, D190S, D190T, D190V, D190W, D190Y, Y191D, Y191E, Y191G, Y191N, Y191P, Y191Q, Y191R, Y191S, Y192D, Y192G, Y192K, Y192P, T193E, T193P, T193W, N200E, N200F, N200L, N200W, F203C, F203E, F203G, F203H, F203L, F203M, F203P, F203S, F203V, V204D, V204E, Y206E, Y206G, Y206L, Y206N, Y206P, F208D, F208K, F208R, V209D, V209K, V210D, V210P, H211L, H211R, H211V, H211W, I214D, I214K, I214P, P215A, P215K, P215L, I218E, I218H, I218N, I218Y, I219D, I219E, I219P, F221D, C222D, C222R, M253K, V254K, M257D, M257G, M257P, A260R, V266D, V266H, V266K, V266R, P267C, P267D, P267F, P267H, P267I, P267L, P267M, P267N, P267V, Y268I, Y268P, S270P, V271P, A272F, F273D, F273P, F276D, T277P, H278P, P285D, M288D, M288K, T289K, T289P, T289R, I290D, I290E, I290K, P291D, P291K, F293P, F293R, F294D, F294R, K296T, K296V, S297D, S297R, A299D, I300D, I300E, I300H, I300Q, N302Q, P303E, P303F, P303W, P303Y, V304D, V304E, V304K, V304Q, V304R, I305E, I305H, I305K, I305Q, I305Y, I307D, I307E, I307K, I307R, M308D, M308P, M309P, N310P, F313A, F313D, F313K, F313P, F313S, R314D, R314P, M317D, M317P, M317R, S334E, A335M, or E341N. In some embodiments, the mutations are determined by deep mutational scanning.

[0038] According to the disclosure, the assay allows for the determination of whether a patient expressing a mutant RHO will be a candidate for corrector molecule therapy. Patient specific mutations may be used in this assay to determine if they are candidates for corrector molecule therapy. Specific candidate corrector molecules can be assayed to determine if the candidate corrector molecules is capable of rescuing the RHO mutation in the host cell. Thus, this assay can be used to broadly identify RHO mutations and rhodopsin corrector molecule therapies without needing patient specific samples used in the assay.

[0039] The disclosure also provides for a method of determining whether a patient expressing a mutant RHO protein will be a candidate for rhodopsin corrector molecule therapy, wherein a person, for example, a patient's physician or doctor, can look up the patient specific mutation in RHO protein in a treatment reference table to determine if the patient's mutation will respond to the therapy. The reference table is generated from the results of the in vitro assay analysis of RHO mutants.

[0040] A patient may be selected by detecting the genetic presence or expression of a mutant Rho gene. The patient may be assayed for the sequence and / or level of expression of Rho genesWSGR Docket No.52652-721.601 which can be performed by detecting gene expression, e.g., mRNA expression, or the presence of a p articular mutant in the genome. Techniques selected from the group consisting of DNA or RNA sequencing, Northern blot analysis, polymerase chain reaction (PCR), reverse transcription-polymerase chain reaction (RT-PCR), or TaqMan-based assays can be used. The assay can be performed on a biological sample obtained from the individual. DNA or RNA seq1uenceing may be performed, for example, by Sanger sequencing, or a next generation sequencing technique. In certain embodiments, the biological sample comprises blood, serum, plasma, saliva, buccal swab, or a combination thereof.

[0041] Sequencing can be performed by various systems currently available, such as, without limitation, a sequencing system by Illumina, Pacific Biosciences, Oxford Nanopore, Element Biosciences (AVITI systems), or Life Technologies (Ion Torrent). Such devices may provide a plurality of raw genetic data corresponding to the genetic information of a subject (e.g., human), as generated by the device from a sample provided by the subject. Alternatively, or in addition, sequencing may be performed using nucleic acid amplification, polymerase chain reaction (PCR) (e.g., digital PCR, quantitative PCR, or real time PCR), or isothermal amplification. Such systems may provide a plurality of raw genetic data corresponding to the genetic information of a subject (e.g., human), as generated by the systems from a sample provided by the subject. In some examples, such systems provide sequencing reads (also “reads” herein). A read may include a string of nucleic acid bases corresponding to a sequence of a nucleic acid molecule that has been sequenced. In some situations, systems and methods provided herein may be used with proteomic information.

[0042] Next generation sequencing includes many technologies capable of generating large amounts of sequence information (e.g., high-throughput sequencing) and excluding Sanger sequencing or Maxam-Gilbert sequencing. Generally, next generation sequencing encompasses single molecule real-time sequencing, sequencing-by-synthesis, ion semiconductor sequencing and the like. Exemplary next-generation sequencing machines may comprise the MiniSeq, the iSeq100, the NextSeq 1000, the NextSeq 2000, the NovaSeq 6000, the NextSeq 550 series and the like from Illumina, Inc; Ion Torrent machines from Thermo Fisher Scientific; the AVITI systems from Element Biosciences, or the Sequel systems from Pacific Biosciences.

[0043] Furthermore, the disclosure also provides a “Treatment Reference Table” that provides information describing if a particular rhodopsin corrector molecule will be a successful therapy for enhancing the activity of a specific RHO mutation. According to the assay, the treatment reference table provides information indicating if a candidate corrector molecule can increase the presence of RHO on the plasma membrane, thereby rescuing RHO activity. Based on theWSGR Docket No.52652-721.601 response of different mutations to different corrector molecule therapies, the disclosure can provide corrector molecule therapies tailored to the patient's specific mutation. Methods of treatment

[0044] Autosomal dominant retinitis pigmentosa (adRP) is a progressive blindness disease with no standard of care or approved therapies. Described herein is a method of identifying mistrafficking and / or class 2 or class 3 adRP mutations. Further described herein is a method of treating a subject with retinitis pigmentosa, the method comprising administering to the subject a therapeutically effective dose of a rhodopsin corrector molecule, thereby treating the retinitis pigmentosa. In some embodiments, the retinitis pigmentosa comprises an autosomal dominant retinitis pigmentosa. In some embodiments, the subject is identified as having a mistrafficking and / or class 2 or class 3 rhodopsin mutation. In some embodiments, the subject is identified as having a class 2 or class 3 rhodopsin mutation. In some embodiments, the mutation is a mutation disclosed herein.

[0045] Described herein are methods of treating class 2 or class 3 adRP mutations using gene therapies. The gene therapies of this description can be delivered by a nucleic acids encoding a corrector molecule. Corrector molecules may act to increase in the folding, stability, or trafficking of mutant RHO to the plasma membrane. The increase in mutant RHO on the plasma membrane effectively treats the disease.

[0046] The nucleic acids of the disclosure are compatible with many vectors common in the art. Non-limiting examples of vectors include genomic integrated vectors, episomal vectors, plasmids, viral vectors, cosmids, bacterial artificial chromosomes, and yeast artificial chromosomes. Non-limiting examples of viral vectors compatible with the nucleic acids of the disclosure include vectors derived from lentiviruses, retroviruses, adenoviruses, and adeno- associated viruses. In certain embodiments, the nucleic acids of the disclosure are present on vectors comprising sequences that direct site specific integration into a defined location or a restricted set of sites in the genome (e.g. AttP-AttB recombination).

[0047] In certain embodiments, one of the plurality of nucleic acids as described herein is incorporated into a single vector. In certain embodiments, said single vector is transfected into a cell transiently. In certain embodiments, said single vector is transfected into a cell stably.

[0048] Vectors comprising the plurality of nucleic acids described herein or portions thereof may be constructed using many well-known molecular biology techniques. Detailed protocols for numerous such procedures, including amplification, cloning, mutagenesis, transformation, and the like, are described in, e.g., in Ausubel et al. Current Protocols in Molecular Biology (supplemented through 2012) John Wiley & Sons, New York 10 (“Ausubel”); Sambrook et al.WSGR Docket No.52652-721.601 Molecular Cloning – A Laboratory Manual (4th Ed.), Vol.1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 2012 (“Sambrook”); and Abelson et al. Guide to Molecular Cloning Techniques (Methods in Enzymology) volume 152 Academic Press, Inc., San Diego, CA (“Abelson”).

[0049] In some embodiments, the corrector molecule is a gene therapy. In some embodiments, the gene therapy comprises overexpression of GRP78. In certain embodiments, the gene therapy is a component of a vector that can be used to transfer the polypeptide encoding polynucleotide into a cell. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a genomic integrated vector, or “integrated vector,” which can become integrated into the chromosomal DNA of the host cell. Another type of vector is an “episomal” vector, e g., a nucleic acid capable of extra- chromosomal replication. Vectors capable of directing the expression of genes to which they are operatively linked are referred to herein as “expression vectors.” Suitable vectors comprise plasmids, bacterial artificial chromosomes, yeast artificial chromosomes, viral vectors and the like. In the expression vectors regulatory elements such as promoters, enhancers, polyadenylation signals for use in controlling transcription can be derived from mammalian, microbial, viral or insect genes. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants may additionally be incorporated. Vectors derived from viruses, such as lentiviruses, retroviruses, adenoviruses, adeno-associated viruses, and the like, may be employed. Plasmid vectors can be linearized for integration into a genomic region. In certain embodiments, the expression vector is a plasmid. In certain embodiments, the expression vector is a lentivirus, adenovirus, or adeno-associated virus. In certain embodiments, the expression vector is an adenovirus. In certain embodiments, the expression vector is an adeno-associated virus. In certain embodiments, the expression vector is a lentivirus.

[0050] In some embodiments, the gene therapy may be administered to the individual through any appropriate route, including but not limited to intravitreal injections, subconjuctival injection, and subretinal injection.

[0051] Described herein are methods of treating class 2 or class 3 adRP mutations using small molecules. Small molecules may act as a corrector molecule to increase the folding, stability, or trafficking of mutant RHO to the plasma membrane. The increase in mutant RHO on the plasma membrane effectively treats the disease. In some embodiments, the corrector molecule is a small molecule. In some embodiments, the corrector molecule is 9-cis retinal, YC001, F5257-0462, SRD005825, or a compound of Formula (I). In some embodiments, the corrector molecule is 9- cis retinal as disclosed in Mattle, et al. (2018), Proc Natl Acad Sci USA, 115(14):3640-3645. InWSGR Docket No.52652-721.601 some embodiments, the corrector molecule is YC001 as disclosed in Chen, et al. (2018), Nat Commun., 9(1):1976. In some embodiments, the corrector molecule is F5257-0462 as disclosed in Vats, et al. (2022), JCI Insight, 7(10):e153717. In some embodiments, the corrector molecule is SRD005825 Ahmed, et al. (2019), Transl Vis Sci Technol., 8(6):30. In some embodiments, the corrector molecule is a compound of Formula (I).

[0052] In some embodiments, the rhodopsin corrector molecule increases cell surface expression of RHO variants compared to vehicle control. In some embodiments, the rhodopsin corrector increases cell surface expression of rhodopsin compared to vehicle control by at least 2-fold, 3-fold, 5-fold or 10-fold. In some embodiments, the rhodopsin corrector molecule increases the cell surface expression of a rhodopsin mutant to at least about 10% of that observed for wild-type rhodopsin. In some embodiments, the rhodopsin corrector molecule increases the cell surface expression of a rhodopsin mutant to at least about 25% of that observed for wild-type rhodopsin. In some embodiments, the rhodopsin corrector molecule increases the cell surface expression of a rhodopsin mutant to at least about 30% of that observed for wild-type rhodopsin. In some embodiments, the rhodopsin corrector molecule increases the cell surface expression of a rhodopsin mutant to at least about 40% of that observed for wild-type rhodopsin. In some embodiments, the rhodopsin corrector molecule increases the cell surface expression of a rhodopsin mutant to at least about 50% of that observed for wild-type rhodopsin. In certain embodiments, the rhodopsin mutant is a mis trafficking mutant. In certain embodiments, the mistrafficking mutant is P23H.

[0053] The rhodopsin corrector molecules described herein comprise certain characteristics relating to potency, oral bioavailability and microsomal stability that are useful for the rhodopsin corrector molecules to be deployed in methods or for uses of treating patients with retinitis pigmentosa. In certain embodiments the rhodopsin correctors comprise a potency (e.g., EC50 for rescue of surface expression) of less than about 1 uM, 500 nM, 250 nM, 100 nM, 50 nM, or 25 nM. In certain embodiments the compounds comprise a potency (e.g., EC50for rescue of surface expression) of greater than about 500 nM, 250 nM, 100 nM, 50 nM, 25 nM, or 10 nM. In certain embodiments, the rhodopsin correctors described herein exhibit an oral bioavailability of greater than about 40%, 50%, 60%, 70%, 80% or more. In certain embodiments, the rhodopsin correctors described herein exhibit an oral bioavailability of less than about 50%, 60%, 70%, 80% or 90%. In certain embodiments, the rhodopsin correctors described herein exhibit a microsomal stability of greater than about 60 minutes, 70 minutes, 80 minutes, 90 minutes, or 100 minutes. In certain embodiments, the rhodopsin correctors described herein exhibit a microsomal stability of less than about 70 minutes, 80 minutes, 90 minutes, 100 minutes, or 120 minutes.WSGR Docket No.52652-721.601

[0054] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein: Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y2and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, - C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups;WSGR Docket No.52652-721.601 each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0055] In some embodiments of the methods described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1, Y2, and Y3are each C(R3). In some embodiments of the methods described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y1and Y3are C(R3) and Y2is N. In some embodiments of the methods described herein is a compound of Formula (I), or a some embodiments of the methods described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y2and Y3are C(R3) and Y1is N.WSGR Docket No.52652-721.601

[0056] In some embodiments of the methods described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):Formula (Ia).

[0057] In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0058] In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2isWSGR Docket No.52652-721.601 independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2OH. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0059] In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0060] In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1- 6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, - OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments of theWSGR Docket No.52652-721.601 methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen or C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is - OCH3. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0061] In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0062] In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independentlyWSGR Docket No.52652-721.601 selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments of the methods described herein is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0063] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:Formula (Ib); wherein: Z3is C(R4) or N; R1is selected from halogen, -CN, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl; and each R4is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl.

[0064] In some embodiments of the methods described herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen or unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments of the methods described herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments of the methods described herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is C(R4). In some embodiments of the methods described herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein Z3is N. In some embodiments of the methods described herein is a compoundWSGR Docket No.52652-721.601 of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments of the methods described herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen.

[0065] In some of the methods described herein, the rhodopsin corrector molecule is a compound of Formula (I), (Ia), or (Ib) selected from:pharmaceutically acceptable salt or solvate thereof.

[0066] In some of the methods described herein, the rhodopsin corrector molecule is a compound of Formula (I), (Ia), or (Ib) selected from:pharmaceutically acceptable salt or solvate thereof.

[0067] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:WSGR Docket No.52652-721.601 Formula (II); wherein: X, Y, and Z are each independently C(R3) or N, wherein at least one of Y and Z is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selectedWSGR Docket No.52652-721.601 from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0068] In some embodiments of the methods described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X, Y, and Z are each C(R3). In some embodiments of the methods described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X and Y are C(R3) and Z is N. In some embodiments of the methods described herein is a compound of Formula (II), or a some embodiments of the methods described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X and Z are C(R3) and Y is N. In some embodiments of the methods described herein is a compound of Formula (II), or a some embodiments of the methods described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Y and Z are C(R3) and X is N.

[0069] In some embodiments of the methods described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIa):Formula (IIa).WSGR Docket No.52652-721.601

[0070] In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from hydrogen, halogen, and -CH3. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0071] In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2OH. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. InWSGR Docket No.52652-721.601 some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0072] In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0073] In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments of the methodsWSGR Docket No.52652-721.601 described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen or C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0074] In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0075] In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or aWSGR Docket No.52652-721.601 pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments of the methods described herein is a compound of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0076] In some of the methods described herein, the rhodopsin corrector molecule is a compound of Formula (II) or (IIa) is selected from:pharmaceutically acceptable salt or solvate thereof.

[0077] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:Formula (III); wherein: Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); J is O or S; R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-WSGR Docket No.52652-721.601 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; R3is selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-WSGR Docket No.52652-721.601 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0078] In some embodiments of the methods described herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is S. In some embodiments of the methods described herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is O.

[0079] In some embodiments of the methods described herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (IIIa):Formula (IIIa).

[0080] In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C3-6cycloalkyl are optionally substituted with 1-5 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1- 6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-5 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy, wherein C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy are optionally substituted with 1-3 R5cgroups. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen, and -CH3. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.WSGR Docket No.52652-721.601

[0081] In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with 1-5 R5bgroups. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from C1-6alkyl optionally substituted with -OH. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2OH. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH3. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH2CH3. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -CH(CH3)2. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from -OR10, wherein R10is C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is -OCH3.

[0082] In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 4. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.WSGR Docket No.52652-721.601

[0083] In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is halogen. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CN. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OR10, wherein R10is hydrogen or C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OH. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -OCH3. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH3. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CF3. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from halogen, -CN, -OH, -OCH3, -CH3, and -CF3.

[0084] In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1, Z2, and Z3are each independently C(R4). In some embodiments of the methods described herein is a compound ofWSGR Docket No.52652-721.601 Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z2are C(R4) and Z3is N. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are N and Z2is C(R4). In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z1and Z3are C(R4) and Z2is N. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z2and Z3are C(R4) and Z1is N.

[0085] In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen, halogen, and unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from hydrogen and halogen. In some embodiments of the methods described herein is a compound of Formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is hydrogen.

[0086] In some of the methods described herein, the rhodopsin corrector molecule is a compound of Formula (III) or (IIIa) is selected from:pharmaceutically acceptable salt or solvate thereof.

[0087] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:WSGR Docket No.52652-721.601Formula (IV); wherein: R1, R2, R3, R4, R5, R6, R7, R8, and R9are each independently selected from hydrogen, C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C4-8cycloalkenyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C4-8cycloalkenyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R9agroups; each R9ais independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, - -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; andWSGR Docket No.52652-721.601 each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl.

[0088] In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, and R9are each independently selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, C4-8cycloalkenyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C4-8cycloalkenyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R9agroups. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, and R8are each independently selected from hydrogen, C1-6alkyl, C3- 6cycloalkyl, C4-8cycloalkenyl, and C2-9heterocycloalkyl, wherein hydrogen, C1-6alkyl, C3-6cycloalkyl, C4-8cycloalkenyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R9agroups. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, and R8are each independently selected from hydrogen and C1-6alkyl optionally substituted with 1-5 R9agroups. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, and R8are each independently selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, and R8are each independently selected from hydrogen and -CH3.

[0089] In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is selected from C1-6alkyl, C3-6cycloalkyl, C4-8cycloalkenyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C4-8cycloalkenyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R9agroups. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is selected from C3-6cycloalkyl, C4-8cycloalkenyl, and C2-9heterocycloalkyl, wherein C3-6cycloalkyl, C4-8cycloalkenyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R9agroups. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is C4-8cycloalkenylWSGR Docket No.52652-721.601 optionally substituted with 1-5 R9agroups. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is C3-6cycloalkyl optionally substituted with 1-5 R9agroups. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is C2-9heterocycloalkyl optionally substituted with 1-5 R9agroups. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R9ais independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), and -S(O)2N(R10)(R11)-, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from -OR10and -N(R10)(R11). In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R9ais independently selected from halogen, oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R9ais independently selected from unsubstituted C1-6alkyl.

[0090] In some of the methods described herein, the rhodopsin corrector molecule is a compound of Formula (IV) that is:cis retinal).

[0091] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:Formula (V); wherein: R1and R2are each independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R3groups;WSGR Docket No.52652-721.601 each R3is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl.

[0092] In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvateWSGR Docket No.52652-721.601 thereof, wherein R1is C1-9heteroaryl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-9heteroaryl selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and pyridyl, wherein thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and pyridyl are optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is thiophenyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted thiophenyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is furanyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted furanyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrrolyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted pyrrolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is oxazolyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted oxazolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is thiazolyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted thiazolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazolyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted pyrazolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyridyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted pyridyl.WSGR Docket No.52652-721.601

[0093] In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C1-9heteroaryl selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and pyridyl, wherein thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and pyridyl are optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is thiophenyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted thiophenyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is furanyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted furanyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is pyrrolyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrrolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is oxazolyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted oxazolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is thiazolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted thiazolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2WSGR Docket No.52652-721.601 is pyrazolyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyrazolyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is pyridyl optionally substituted with 1-5 R3groups. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted pyridyl.

[0094] In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), and -S(O)2N(R10)(R11)-, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from -OR10and -N(R10)(R11). In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is halogen. In some embodiments of the methods described herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from unsubstituted C1-6alkyl.

[0095] In some of the methods described herein, the rhodopsin corrector molecule is a compound of Formula (V) that is:

[0096] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof:Formula (VI); wherein:WSGR Docket No.52652-721.601 each R1is independently selected from hydrogen, C1-6alkyl optionally substituted with 1-5 R5groups; R2and R3are independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with 1-5 R5groups; R4is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups; each R5is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, - -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-WSGR Docket No.52652-721.601 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl.

[0097] In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1is independently C1- 6alkyl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1is independently unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1is -CH3. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1is hydrogen.

[0098] In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C6-10aryl, and -CH2-C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C6-10aryl, and -CH2-C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen, C1-6alkyl, and -CH2-C6-10aryl, wherein C1-6alkyl and -CH2-C6-10aryl are optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen, unsubstituted C1-6alkyl, and unsubstituted -CH2-C6-10aryl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is hydrogen. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is unsubstituted -CH2-phenyl.

[0099] In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C6-10aryl, and -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C6-10aryl, and -CH2-C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptableWSGR Docket No.52652-721.601 salt or solvate thereof, wherein R3is hydrogen. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is unsubstituted C1-6alkyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-6haloalkyl.

[0100] In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is selected from C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is selected from C6-10aryl and C1-9heteroaryl, wherein C6-10aryl and C1-9heteroaryl are optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is C1-9heteroaryl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is C1-9heteroaryl selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and pyridyl, wherein thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, and pyridyl are optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is thiophenyl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is unsubstituted thiophenyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is furanyl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is unsubstituted furanyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is pyrrolyl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is unsubstituted pyrrolyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is oxazolyl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is unsubstituted oxazolyl. In some embodiments ofWSGR Docket No.52652-721.601 the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is thiazolyl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is unsubstituted thiazolyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is pyrazolyl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is unsubstituted pyrazolyl. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is pyridyl optionally substituted with 1-5 R5groups. In some embodiments of the methods described herein is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is unsubstituted pyridyl.

[0101] In some of the methods described herein, the rhodopsin corrector molecule is a compound of Formula (VI) that is:

[0102] In some embodiments, the rhodopsin corrector molecule is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof:Formula (VII); wherein: R1is selected from C3-6cycloalkyl, C4-8cycloalkenyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C3-6cycloalkyl, C4-8cycloalkenyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R4groups; each R2is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -WSGR Docket No.52652-721.601CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, and -N(R10)(R11); R3is selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2- C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -C(O)OR10, -C(O)R13, -S(O)R13, - C(O)N(R10)(R11), -S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R4is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, - OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-WSGR Docket No.52652-721.601 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0103] In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from C3- 6cycloalkyl, C4-8cycloalkenyl, and C2-9heterocycloalkyl, wherein C3-6cycloalkyl, C4-8cycloalkenyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R4groups. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C4-8cycloalkenyl optionally substituted with 1-5 R4groups. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-6cycloalkyl optionally substituted with 1-5 R4groups. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-9heterocycloalkyl optionally substituted with 1-5 R4groups. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, - C(O)N(R10)(R11), and -S(O)2N(R10)(R11)-, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from -OR10and -N(R10)(R11). In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from halogen, oxo, unsubstituted C1-6alkyl, and C1-6haloalkyl. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently selected from unsubstituted C1-6alkyl.

[0104] In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independentlyWSGR Docket No.52652-721.601 selected from halogen, oxo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -S(O)R13, -OC(O)R13, - C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR10, -N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1- 9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl, C1-6haloalkyl, -OR10, - N(R10)(R11), -C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -S(O)2R13, and -S(O)2N(R10)(R11)-. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from unsubstituted C1-6alkyl.

[0105] In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3.

[0106] In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, - C(O)OR10, -C(O)R13, -C(O)N(R10)(R11), -S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C6-10aryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-WSGR Docket No.52652-721.601 6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and - N(R10)(R11). In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -C(O)R13, -C(O)N(R10)(R11), -S(O)2R13, and - S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from C1-6alkyl, - C(O)R13, -C(O)N(R10)(R11), -S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl is optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments of the methods described herein is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is -C(O)N(R10)(R11).

[0107] In some of the methods described herein, the rhodopsin corrector molecule is a compound of Formula (VII) that is:

[0108] A corrector molecule or, optionally, one or more additional agents can be administered to a subject as a pharmaceutical compositions. The corrector molecule and / or one or more agents (or pharmaceutically acceptable salts, esters or amides thereof) can be administered per se or in the form of a pharmaceutical composition wherein the corrector molecule and / or one or more active agent(s) is in an admixture or mixture with one or more pharmaceutically acceptable carriers. A pharmaceutical composition, as used herein, can be any composition prepared for administration to a subject. Pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable carriers, comprising excipients, diluents, and / or auxiliaries, e.g., that facilitate processing of the active agents into preparations that can be administered. Proper formulation can depend at least in part upon the route of administration chosen. The corrector molecule and / or one or more agents, or pharmaceutically acceptable salts, esters, or amides thereof, can be delivered to a patient using a number of routes or modes of administration, including oral, buccal, topical, rectal, transdermal, transmucosal, subcutaneous, intravenous, intramuscular applications, inhalation, intravitreal, subconjuctival, and subretinal.

[0109] For oral administration, the corrector molecule and / or one or more agents can be formulated readily by combining the corrector molecule and / or one or more agents withWSGR Docket No.52652-721.601 pharmaceutically acceptable carriers well known in the art. Such carriers can enable the corrector molecule and / or one or more agents to be formulated as tablets, including chewable tablets, pills, dragees, capsules, lozenges, hard candy, liquids, gels, syrups, slurries, powders, suspensions, elixirs, wafers, and the like, for oral ingestion by a patient to be treated. Such formulations can comprise pharmaceutically acceptable carriers including solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Generally, the agents of the invention can be included at concentration levels ranging from about 0.5%, about 5%, about 10%, about 20%, or about 30% to about 50%, about 60%, about 70%, about 80% or about 90% by weight of the total composition of oral dosage forms, in an amount sufficient to provide a desired unit of dosage.

[0110] Aqueous suspensions for oral use can contain corrector molecule and / or one or more agents with pharmaceutically acceptable excipients, such as a suspending agent (e.g., methyl cellulose), a wetting agent (e.g., lecithin, lysolecithin and / or a long-chain fatty alcohol), as wellas coloring agents, preservatives, flavoring agents, and the like.

[0111] Oils or non-aqueous solvents can be required to bring the corrector molecule and / or one or more agents into solution, due to, for example, the presence of large lipophilic moieties. Alternatively, emulsions, suspensions, or other preparations, for example, liposomal preparations, can be used. With respect to liposomal preparations, any known methods for preparing liposomes for treatment of a condition can be used. See, for example, Bangham et al, J Mol. Biol.23: 238- 252 (1965) and Szoka et al, Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein by reference. Ligands can also be attached to the liposomes to direct these compositions to particular sites of action. The corrector molecule and / or one or more agents can also be integrated into foodstuffs, e.g., cream, cheese, butter, salad dressing, or ice cream to facilitate solubilization, administration, and / or compliance in certain patientpopulations.

[0112] Pharmaceutical preparations for oral use can be obtained as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; flavoring elements, cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone (PVP). Disintegrating agents can be added, for example, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The corrector molecule and / or one or more agents can also beWSGR Docket No.52652-721.601formulated as a sustained release preparation.

[0113] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of one or moreactive agents.

[0114] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active agents can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration can be in dosages suitable foradministration.

[0115] In some embodiments, the corrector molecule is formulated for once daily administration. In other embodiments, the corrector molecule is formulated for twice daily, thrice daily, four times daily, once every other day, once weekly, once bi-weekly, or monthly administration.

[0116] Described herein are methods of identifying and treating class 2 or class 3 adRP mutations. The method comprises determining whether a patient expressing a mutant RHO protein will be a candidate for rhodopsin corrector molecule therapy, wherein a person, for example, a patient's physician or doctor, can look up the patient specific mutation in RHO protein in a treatment reference table to determine if the patient's mutation will respond to the therapy. The reference table is generated from the results of the in vitro assay analysis of RHO mutants.

[0117] A patient may be selected by detecting genetic expression of a mutant Rho gene. The patient is assayed for the sequence and / or level of expression of Rho genes which can be performed by detecting gene expression, e.g., mRNA expression. Techniques selected from the group consisting of Northern blot analysis, polymerase chain reaction (PCR), reverse transcription-polymerase chain reaction (RT-PCR), or TaqMan-based assays can be used.

[0118] Furthermore, the method comprises a “Treatment Reference Table” that provides information describing if a particular rhodopsin corrector molecule will be a successful therapy for enhancing the activity of a specific RHO mutation. The method further comprises, providingWSGR Docket No.52652-721.601 information indicating if a candidate corrector molecule can increase the presence of RHO on the plasma membrane, thereby rescuing RHO activity. Based on the response of different mutations to different corrector molecule therapies, the method can provide corrector molecule therapies tailored to the patient's specific mutation. DEFINITIONS

[0119] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0120] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0121] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0122] As used herein, C1-Cx includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.

[0123] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1- C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., upWSGR Docket No.52652-721.601 to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1- C6alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0124] An “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C2alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4 alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2- , -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0125] “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

[0126] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula –C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non- limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, - C(CH3)=CHCH3, and –CH2CH=CH2.

[0127] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3- C≡CCH2CH3, -CH2C≡CH.

[0128] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0129] The term “alkylamine” refers to the –N(alkyl)xHygroup, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.WSGR Docket No.52652-721.601

[0130] The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.

[0131] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.

[0132] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0133] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3- C6cycloalkyl. In some embodiments, a cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl- bicyclo[2.2.1]heptanyl, and the like.

[0134] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0135] The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl.

[0136] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl. In someWSGR Docket No.52652-721.601 embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0137] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. –NH-, - N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl.

[0138] The term “heteroalkylene” refers to a divalent heteroalkyl radical.

[0139] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non- aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non- aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 5- azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 8- azabicyclo[3.2.1]octanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, aWSGR Docket No.52652-721.601 group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0140] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl.

[0141] A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2- C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0142] The term “oxo” refers to the =O radical.WSGR Docket No.52652-721.601

[0143] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0144] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0145] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, - C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, - CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, - S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and - S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0146] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0147] The terms “comprises”, “comprising”, are intended to have the broad meaning ascribed to them and can mean “includes”, “including” and the like.

[0148] The term “subject”, “patient” or “individual” are used interchangeably herein and refer to mammals and non-mammals, e.g., suffering from a disorder described herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-WSGR Docket No.52652-721.601 human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non- mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0149] The terms “treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, inhibiting or reducing symptoms, reducing or inhibiting severity of, reducing incidence of, prophylactic treatment of, reducing or inhibiting recurrence of, delaying onset of, arresting progression of, delaying recurrence of, abating or ameliorating a disease or condition symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. With regard to treatment of Retinitis Pigmentosa treating may include improving or preventing degeneration of rods, secondary degeneration of cones, night blindness or nyctalopia, decreased visual acuity, decrease in peripheral vision, tunnel vision, narrowing of visual field, and / or vision loss.

[0150] The terms “prevent,” “preventing” or “prevention,” and other grammatical equivalents as used herein, include preventing additional symptoms, preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition and are intended to include prophylaxis. The terms further include achieving a prophylactic benefit. For prophylactic benefit, the compositions are optionally administered to a patient at risk of developing a particular disease, to a patient reporting one or more of the physiological symptoms of a disease, or to a patient at risk of reoccurrence of the disease.

[0151] The terms “effective amount” or “therapeutically effective amount” as used herein, refer to a sufficient amount of at least one agent being administered which achieve a desired result, e.g., to relieve to some extent one or more symptoms of a disease or condition being treated. In certain instances, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In certain instances, an “effective amount” for therapeutic uses is the amount of the composition comprising an agent as set forth herein required to provide a clinically significant decrease in a disease. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0152] The terms “administer,” “administering”, “administration,” and the like, as used herein, refer to the methods that are used to enable delivery of agents or compositions to the desired siteWSGR Docket No.52652-721.601 of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Administration techniques that in some instances are employed with the agents and methods described herein include, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics (current edition), Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In certain embodiments, the agents and compositions described herein are administered orally. In some embodiments, the compositions described herein are administered parenterally.

[0153] The term “pharmaceutically acceptable” as used herein, refers to a material that does not abrogate the biological activity or properties of the agents described herein, and is relatively nontoxic (i.e., the toxicity of the material significantly outweighs the benefit of the material). In some instances, a pharmaceutically acceptable material is administered to an individual without causing significant undesirable biological effects or significantly interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0154] The term “pharmaceutically acceptable excipient,” as used herein, refers to carriers and vehicles that are compatible with the active ingredient (for example, a compound of the invention) of a pharmaceutical composition of the invention (and preferably capable of stabilizing it) and not deleterious to the subject to be treated. For example, solubilizing agents that form specific, more soluble complexes with the compounds of the invention can be utilized as pharmaceutical excipients for delivery of the compounds. Suitable carriers and vehicles are known to those of extraordinary skill in the art. The term “excipient” as used herein will encompass all such carriers, adjuvants, diluents, solvents, or other inactive additives. Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The pharmaceutical compositions of the invention can also be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and / or aromatic substances and the like, which do not deleteriously react with the active compounds of the invention.

[0155] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.WSGR Docket No.52652-721.601

[0156] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Polypeptides, including the provided polypeptide chains and other peptides, e.g., linkers and binding peptides, may include amino acid residues including natural and / or non-natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides may contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0157] The polypeptides of the systems described herein can be encoded by a nucleic acid. A nucleic acid is a type of polynucleotide comprising two or more nucleotide bases. In certain embodiments, the nucleic acid is a component of a vector that can be used to transfer the polypeptide encoding polynucleotide into a cell. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a genomic integrated vector, or “integrated vector,” which can become integrated into the chromosomal DNA of the host cell. Another type of vector is an “episomal” vector, e.g., a nucleic acid capable of extra-chromosomal replication. Vectors capable of directing the expression of genes to which they are operatively linked are referred to herein as “expression vectors.” Suitable vectors comprise plasmids, bacterial artificial chromosomes, yeast artificial chromosomes, viral vectors and the like. In the expression vectors regulatory elements such as promoters, enhancers, polyadenylation signals for use in controlling transcription can be derived from mammalian, microbial, viral or insect genes. The ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants may additionally be incorporated. Vectors derived from viruses, such as lentiviruses, retroviruses, adenoviruses, adeno-associated viruses, and the like, may be employed. Plasmid vectors can be linearized for integration into a chromosomal location. Vectors can comprise sequences that direct site-specific integration into a defined location or restricted set of sites in the genome (e.g., AttP-AttB recombination). Additionally, vectors can comprise sequences derived from transposable elements for integration.

[0158] As used herein the term “transfection” or “transfected” refers to methods that intentionally introduce an exogenous nucleic acid into a cell through a process commonly used in laboratories. Transfection can be affected by, for example, lipofection, calcium phosphate precipitation, viral transduction, or electroporation. Transfection can be either transient or stable.WSGR Docket No.52652-721.601

[0159] As used herein the terms, “RHO” or “rhodopsin” are used interchangeably and refer to the protein encoded by Rho gene. The amino acid sequence of human RHO can be found at www.uniprot.org / uniprotkb / P08100 / entry, with accession number P08100. The terms, “RHO mutant”, “RHO variant”, or “RHO mutation” are used interchangeably and refer to a RHO protein with a change in at least one amino acid residue relative to wildtype RHO of SEQ ID NO: 1. The variant may suitably comprise a missense, insertion, or substitution mutation. Table 2.EMBODIMENTS Described herein are the following embodiments: 1. A method of treating a subject with retinitis pigmentosa, the method comprising administering to the subject a therapeutically effective dose of a rhodopsin corrector molecule thereby treating the retinitis pigmentosa. 2. The method of embodiment 1, wherein the retinitis pigmentosa comprises an autosomal dominant retinitis pigmentosa. 3. The method of any one of embodiments 1 or 2, wherein the subject is identified as having a RHO gene mutation that results in a mutation of a wild-type RHO protein. 4. The method of embodiment 3, wherein the mutation of the wild-type RHO protein is a missense mutation. 5. The method of embodiment 3 or 4, wherein a function of the mutation of the wild-type RHO protein is determined by a deep mutational scan of the wild-type RHO protein. 6. The method of any one of embodiments 1 to 5, wherein the subject is identified as having a RHO mutation that results in mistrafficking of RHO due to RHO misfolding, RHO instability, retention of RHO in the endoplasmic reticulum, disrupted vesicular traffic, and / or disrupted endocytosis.WSGR Docket No.52652-721.601 7. The method of any one of embodiments 1 to 6, wherein the subject is identified as having a class 2 or class 3 RHO mutation. 8. The method of any one of embodiments 1 to 7, wherein the subject is identified as having a class 2 RHO mutation. 9. The method of any one of embodiments 1 to 8, wherein the subject is identified as having a class 3 RHO mutation. 10. The method of any one of embodiments 1 to 9, wherein the class 2 or class 3 mutation results in reduced RHO on the plasma membrane. 11. The method of any one of embodiments 1 to 10, wherein the class 2 or class 3 mutation results in RHO misfolding, RHO instability, retention of RHO in the endoplasmic reticulum, disrupted vesicular traffic, and / or disrupted endocytosis. 12. The method of any one of embodiments 1 to 11, wherein the class 2 or class 3 mutation comprises a missense mutation at any one or more of N15, T17, V20, P23, Q28, G51, P53, T58, V87, G89, G106, C110, E113, L125, W161, A164, C167, P171, Y178, E181, G182, C185, C187, G188, D190, H211, C222, P267, S270, K296, or R135. 13. The method of embodiments 7 or 12, wherein the class 2 or class 3 mutation comprises N15S, T17M, V20G, P23A, P23H, P23L, Q28H, G51R, G51V, P53R, T58R, T58M, V87D, G89D, G106R G106W, C110F, C110R, C110S, C110Y, E113K, L125R, W161R, A164E, A164V, C167R, C167W, P171Q, P171L, P171S, Y178N, Y178D, Y178C, E181K, G182S, G182V, C185R, C187G, C187Y, G188R, G188E, D190N, D190G, D190Y, H211R, H211P, C222R, P267R, P267L, S270R, K296E, K296M, R135G, R135L, R135P, or R135W. 14. The method of any one of embodiments 7 to 13, wherein the class 2 or class 3 mutation comprises P23H. 15. The method of embodiment 7, wherein the class 2 or class 3 mutation comprises a missense mutation at any one or more of M1, G3, T4, G6, N8, F9, Y10, V11, P12, F13, A16, G18, R21, S22, F24, E25, Y26, P27, Y30, L31, A32, F37, M39, L40, A41, Y43, M44, F45, L46, L47, I48, V49, L50, F52, I54, N55, F56, L57, L59, V61, I75, L76, N78, V81, L84, F85, V87, L88, G90, F91, T92, T94, L95, T97, S98, L99, H100, G101, Y102, F103, L112, G114, F115, F116, T118, L119, I123, W126, S127, L128, V129, V130, L131, A132, I133, E134, A153, V157, A158, F159, T160, V162, M163, L165, A166, A168, A169, P170, L172, A173, G174, W175, S176, R177, I179, P180, L183, Q184, S186, I189, Y191, Y192, T193, N200, F203, V204, Y206, M207, F208, V209, V210, F212, T213, I214, P215, M216, I217, I218, I219, F220, F221, M253, V254, M257, V258, A260, L262, I263, V266, Y268, V271, A272, F273, Y274, I275, F276, T277, H278, P285, M288, T289, I290, P291, F293, F294, S297, A299, I300, N302, P303, V304, I305, I307, M308, M309, N310, F313, R314, M317, T320, S334, A335, or E341.WSGR Docket No.52652-721.601 16. The method of embodiments 7 or 15, wherein the class 2 or class 3 mutation comprises any one or more variants listed in Table 3. 17. The method of embodiments 7, 15, or 16, wherein the class 2 or class 3 mutation comprises any one or more of the variants listed in Table 4, 5, or 6. 18. The method of any one of embodiments 1 to 17, wherein the class 2 or class 3 mutation is determined by deep mutational scanning. 19. The method of embodiment 1, wherein the rhodopsin corrector molecule is therapeutically effective at treating at least 80% of disease associated mutations. 20. The method of embodiment 19, wherein the at least 80% of disease associated mutations are selected from the list consisting of F9L, N15S, T17K, T17M, V20L, R21P, P23H, P23L, F24C, Q28H, Q28K, Q28R, G51R, L59H, G89D, L95P, Y102N, G106R, L131R, R135G, R135L, R135P, R135W, P171S, A173P, I179N, P180A, P180L, P180S, E181K, G182D, G182E, G182S, Q184R, C185R, C185Y, S186P, G188E, D190E, D190G, D190N, D190Y, P267L, H278P, and T289P. 21. The method of any one of embodiments 1 to 20, wherein the rhodopsin corrector molecule is a gene therapy. 22. The method of embodiment 19, wherein the gene therapy comprises overexpression of GRP78. 23. The method of any one of embodiments 1 to 18, wherein the rhodopsin corrector molecule comprises a small molecule. 24. The method of any one of embodiments 1 to 23, wherein the rhodopsin corrector molecule comprises 9-cis retinal, YC001, F5257-0462, or SRD005825. 25. The method of any one of embodiments 1 to 24, wherein the rhodopsin corrector molecule comprises 9-cis retinal. 26. The method of any one of embodiments 1 to 25, wherein the rhodopsin corrector molecule comprises YC001. 27. The method of any one of embodiments 1 to 24, wherein the rhodopsin corrector molecule comprises F5257-0462. 28. The method of any one of embodiments 1 to 26, wherein the rhodopsin corrector molecule comprises SRD005825. 29. The method of any one of embodiments 1 to 28, wherein the rhodopsin corrector molecule is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure:WSGR Docket No.52652-721.601Formula (I); wherein: Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y2and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, - S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, - S(=O)(=NH)N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -WSGR Docket No.52652-721.6016alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. 30. The method of embodiment 29, wherein the rhodopsin corrector molecule is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (Ia). 31. The method of any one of embodiments 1 to 28, wherein the rhodopsin corrector molecule is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure:WSGR Docket No.52652-721.601Formula (II); wherein: X, Y, and Z are each independently C(R3) or N, wherein at least one of Y and Z is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, - -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl,WSGR Docket No.52652-721.601 C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. 32. The method of embodiment 31, wherein the rhodopsin corrector molecule is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (IIa). 33. The method of any one of embodiments 1 to 28, wherein the rhodopsin corrector molecule is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (III); wherein: Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4);WSGR Docket No.52652-721.601 J is O or S; R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; R3is selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1- 5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), - C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, - -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, -wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-WSGR Docket No.52652-721.601 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. 34. The method of embodiment 33, wherein the rhodopsin corrector molecule is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (IIIa). 35. The method of any one of embodiments 29-34, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3. 36. The method of any one of embodiments 29-31, wherein each R3is independently selected from hydrogen, halogen, and -CH3. 37. The method of any one of embodiments 29-36, wherein each R3is hydrogen. 38. The method of any one of embodiments 29-37, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, and wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups. 39. The method of any one of embodiments 29-38, wherein each R2is independently selected from unsubstituted C1-6alkyl. 40. The method of any one of embodiments 29-39, wherein each R2is -CH3. 41. The method of any one of embodiments 29-40, wherein n is 1. 42. The method of any one of embodiments 29-41, wherein R1is selected from halogen, - CN, -OR10, C1-6alkyl, and C1-6haloalkyl, and wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups. 43. The method of any one of embodiments 29-42, wherein R1is selected from halogen, - CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl.WSGR Docket No.52652-721.601 44. The method of any one of embodiments 29-43, wherein R1is halogen. 45. The method of any one of embodiments 29-44, wherein Z1, Z2, and Z3are each independently C(R4). 46. The method of any one of embodiments 29-44, wherein Z1and Z2are each independently C(R4), and Z3is N. 47. The method of any one of embodiments 29-46, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups. 48. The method of any one of embodiments 1 to 28, wherein the rhodopsin corrector molecule is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (Ib); wherein: Z3is C(R4) or N; R1is selected from halogen, -CN, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl; and each R4is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl. 49. The method of embodiment 48, wherein R1is halogen. 50. The method of embodiment 48, wherein R1is unsubstituted C1-6alkyl. 51. The method of any one of embodiments 48 to 50, wherein Z3is C(R4). 52. The method of any one of embodiments 48 to 50, wherein Z3is N. 53. The method of any one of embodiments 29-52, wherein each R4is independently selected from hydrogen and halogen. 54. The method of any one of embodiments 29-49, wherein each R4is hydrogen.WSGR Docket No.52652-721.601 55. The method of embodiment 29, wherein the rhodopsin corrector molecule is selectedpharmaceutically acceptable salt or solvate thereof. 56. The method of embodiment 29, wherein the rhodopsin corrector molecule is selectedpharmaceutically acceptable salt or solvate thereof. 57. The method of embodiment 31, wherein the rhodopsin corrector molecule is selected ,pharmaceutically acceptable salt or solvate thereof.WSGR Docket No.52652-721.601 58. The method of embodiment 33, wherein the rhodopsin corrector molecule is selectedpharmaceutically acceptable salt or solvate thereof. 59. The method of any one of embodiments 1 to 58, wherein the rhodopsin corrector molecule increases cell surface expression of rhodopsin compared to vehicle control. 60. The method of any one of embodiments 1 to 59, wherein the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 25% of that observed for wild-type rhodopsin. 61. The method of any one of embodiments 1 to 60, wherein the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 30% of that observed for wild-type rhodopsin. 62. The method of any one of embodiments 1 to 61, wherein the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 40% of that observed for wild-type rhodopsin. 63. The method of any one of embodiments 1 to 62, wherein the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 50% of that observed for wild-type rhodopsin. 64. The method of any one of embodiments 1 to 63, wherein the rhodopsin corrector molecule is administered to a human. 65. The method of any one of embodiments 1 to 64, wherein the rhodopsin corrector molecule is administered orally. 66. The method of any one of embodiments 1 to 65, wherein a therapeutically effective concentration of the rhodopsin corrector molecule is delivered to an ocular tissue. 67. The method of any one of embodiments 1 to 66, wherein a therapeutically effective concentration of the rhodopsin corrector molecule is delivered to the retina. 68. The method of any one of embodiments 1 to 67, wherein the therapeutically effective concentration of the rhodopsin corrector molecule increases cell surface expression of rhodopsin. 69. The method of any one of embodiments 1 to 68, wherein a therapeutically effective concentration of the rhodopsin corrector molecule drug is delivered to an ocular tissue.WSGR Docket No.52652-721.601 70. The method of any one of embodiments 1 to 69, wherein the rhodopsin corrector molecule exhibits oral bioavailability of greater than about 60%. 71. The method of any one of embodiments 1 to 69, wherein the rhodopsin corrector molecule exhibits oral bioavailability of greater than about 70%. 72. The method of any one of embodiments 1 to 71, wherein the rhodopsin corrector molecule exhibits microsomal stability of greater than about 90 minutes. 73. The method of any one of embodiments 1 to 72, wherein the rhodopsin corrector molecule exhibits an EC50 for rescue of rhodopsin surface expression of 1 uM or less. 74. The method of any one of embodiments 1 to 72, wherein the rhodopsin corrector molecule exhibits an EC50 for rescue of rhodopsin surface expression of less than about 200 nM. 75. The method of any one of embodiments 1 to 72, wherein the rhodopsin corrector molecule exhibits an EC50 for rescue of rhodopsin surface expression of less than about 100 nM. EXAMPLES Example 1 – In vitro diagnostic assay for determination of Retinitis Pigmentosa disease class

[0160] Described in this example is an in vitro diagnostic assay to determine a class for a Retinitis Pigmentosa disease variant and potential for response to a specific rhodopsin corrector molecule. An assay as depicted in FIG.1 was utilized for examples 1 and 2.

[0161] The following assay protocol was followed: Day 1 - Seed cells 1. Cells were grown in culture. 2. Cells were trypsinized, collected, spun down, and counted. 3. Cells were diluted to desired amount in a new tube. 4. Cells were resuspended in media with serum. 5. Cells were seeded into a dish. 6. Dishes were incubated overnight at 37° C. Day 2 – Doxycycline inducing cells 1. Prepared 6x Doxycycline media in Opti-MEM. 2. Dispensed Doxycycline Opti-MEM mixture into the dish. 3. Mixed dishes thoroughly 4. Incubated plates overnight at 37° C. Day 3 – Read signal outputWSGR Docket No.52652-721.601 1. Barcodes were isolated, and quantified by next generation sequencing.

[0162] As shown in FIG.3, a heatmap was generated by deep mutational screening of the trafficking score of each missense mutation against wildtype RHO. Each individual amino acid of RHO was mutated to one of twenty amino acids. All 348 amino acids of RHO were tested with twenty amino acid changes, including a stop codon. Each mutant RHO was encoded with a unique barcode for identification. The assay was performed as described above and the barcode reads for each unique mutation was quantified and normalized against wildtype. The normalized trafficking was evaluated for each variant of RHO. Variant RHO with trafficking defects of less than about 50% compared to wildtype were considered to be class 2 or class 3 RP disease mutations. Overall, about 15% of missense mutations resulted in a <50% trafficking score relative to wildtype. Mutations throughout RHO were shown to affect trafficking, and the most sensitive regions were the N-terminus and second extracellular domain. Additionally, substantially all of the stop codon nonsense mutations had trafficking defects. Mutations identified in this assay as being class 2 or class 3 are listed in Table 3.WSGR Docket No.52652-721.601 G106V, G106W, G106Y, C110A, C110D, C110E, C110F, C110G, C110H, C110I, C110K, C110L, C110M, C110N, C110P, C110Q, C110R, C110S, C110T, C110V, C110W, C110Y, L112D, L112P, E113G, E113K, E113P, E113R, E113W, G114C, G114D, G114E, G114F, G114H, G114I, G114K, G114L, G114M, G114N, G114P, G114Q, G114R, G114S, G114T, G114V, G114W, G114Y, F115D, F115E, F115H, F115K, F115N, F115P, F115Q, F115R, F116K, F116R, T118P, L119D, L119K, L119P, L119R, I123P, I123R, L125D, W126D, W126I, W126K, W126P, W126R, W126V, S127F, S127I, S127K, S127L, S127P, S127R, S127W, S127Y, L128P, V129H, V129K, V129R, V129Y, V130K, V130R, L131D, L131P, L131R, A132P, A132R, I133D, E134P, R135F, R135G, R135I, R135L, R135M, R135P, R135W, R135Y, A153V, V157H, V157K, V157R, A158D, F159D, F159E, F159K, F159P, F159R, T160D, T160F, T160H, T160K, T160R, T160W, T160Y, W161K, W161P, W161R, V162D, V162R, M163D, M163K, M163R, M163Y, A164D, A164E, A164F, A164H, A164I, A164K, A164L, A164N, A164P, A164Q, A164R, A164W, A164Y, L165D, L165E, L165K, L165P, L165R, A166K, A166P, A166R, C167P, C167W, A168D, A168E, A168F, A168H, A168I, A168K, A168L, A168M, A168N, A168P, A168Q, A168R, A168W, A168Y, A169D, A169K, A169P, A169R, P170D, P170E, P170H, P170I, P170K, P170N, P170R, P170T, P170V, P170Y, P171A, P171C, P171D, P171E, P171F, P171G, P171H, P171I, P171K, P171L, P171M, P171N, P171Q, P171R, P171S, P171T, P171V, P171W, P171Y, L172D, L172E, L172H, L172K, L172P, L172Q, L172R, A173P, G174C, G174P, W175C, W175D, W175E, W175G, W175K, W175N, W175P, W175Q, W175R, W175S, W175T, S176D, S176E, S176F, S176H, S176I, S176K, S176L, S176M, S176P, S176Q, S176R, S176T, S176V, S176W, S176Y, R177C, R177D, R177E, R177F, R177G, R177I, R177K, R177L, R177N, R177P, R177T, R177V, R177W, R177Y, Y178A, Y178C, Y178D, Y178E, Y178G, Y178H, Y178I, Y178K, Y178L, Y178M, Y178N, Y178P, Y178Q, Y178R, Y178S, Y178T, Y178V, Y178W, I179A, I179C, I179D, I179E, I179F, I179G, I179H, I179K, I179N, I179P, I179Q, I179R, I179S, I179W, I179Y, P180A, P180C, P180D, P180E, P180F, P180G, P180H, P180I, P180K, P180L, P180M, P180N, P180Q, P180R, P180S, P180T, P180V, P180W, P180Y, E181C, E181G, E181K, E181P, E181R, G182C, G182D, G182E, G182F, G182H, G182I, G182K, G182L, G182M, G182N, G182P, G182Q, G182R, G182S, G182T, G182V, G182W, G182Y, L183D, L183E, L183G, L183K, L183P, L183R, Q184A, Q184D, Q184E, Q184F, Q184H, Q184I, Q184K, Q184N, Q184P, Q184R, Q184S, Q184T, Q184V, Q184W, Q184Y, C185D, C185E, C185K, C185P, C185R, C185W, C185Y, S186K, S186P, S186R, C187A, C187D, C187E, C187F, C187G, C187H, C187I, C187K, C187L, C187M, C187N, C187P, C187Q, C187R, C187S, C187T, C187V, C187W, C187Y, G188C, G188E, G188H, G188I, G188K, G188L, G188M, G188P, G188Q, G188R, G188V, G188Y, I189C, I189D, I189E, I189G, I189K, I189N, I189Q, I189R, I189S, I189T, I189W, D190A, D190C, D190E, D190F, D190G, D190H, D190I, D190K, D190L, D190M, D190N, D190P, D190Q, D190R, D190S, D190T, D190V, D190W, D190Y, Y191D, Y191E, Y191G, Y191N, Y191P, Y191Q, Y191R, Y191S, Y192D, Y192G, Y192K, Y192P, T193E, T193P, T193W, N200E, N200F, N200L, N200W, F203C, F203D, F203E, F203G, F203H, F203I, F203K, F203L, F203M, F203N, F203P, F203Q, F203R, F203S, F203V, V204D, V204E, Y206D, Y206E, Y206G, Y206K, Y206L, Y206N, Y206P, Y206R, M207P, F208D, F208K, F208P, F208R, V209D, V209K, V209P, V210D, V210K, V210P, V210R, H211I, H211K, H211L, H211P, H211R, H211V, H211W, F212P, T213P, T213R, I214D, I214K, I214P, I214R, P215A, P215C, P215D, P215E, P215F, P215G, P215H, P215I, P215K, P215L, P215M, P215N, P215Q, P215R, P215S, P215T, P215V, P215W, P215Y, M216R, I217R, I218D, I218E, I218H, I218K, I218N, I218R, I218Y, I219D, I219E, I219P, F220R, F221D, C222D, C222R, M253K, V254K, M257D, M257G, M257P, V258R, A260R, L262R, I263R, V266D, V266H, V266K, V266R, P267C, P267D, P267E, P267F, P267H, P267I, P267K, P267L, P267M, P267N, P267R, P267V, Y268I, Y268P, S270P, V271P, A272F, F273D, F273P, Y274P, I275P, F276D, F276P, T277P, T277W, H278P, P285D, M288D, M288K, T289K, T289P, T289R, I290D, I290E, I290K, P291D, P291K, F293P, F293R, F294D, F294R, K296F, K296I, K296T,WSGR Docket No.52652-721.601

[0163] As shown in FIGS.5A-5B, a select number of known mutations were examined. Using the data from the heatmap, select mutations of interest were highlighted to demonstrate the effect of those mutations in this assay. Class 1-7 variants putatively identified in Athanasiou, et al. were selected to demonstrate efficacy of the assay for selectively identifying class 2 and class 3 disease states. Using this assay, substantially all of the putative class 2 and class 3 mutations were identified as such by having <50% trafficking score relative to wildtype, such as N15S, T17M, V20G, P23A, P23H, P23L, Q28H, G51R, P53R, V87D, G89D, G106R G106W, C110F, C110R, C110S, C110Y, E113K, W161R, A164E, C167W, P171Q, P171L, P171S, Y178N, Y178D, Y178C, E181K, G182S, G182V, C185R, C187G, C187Y, G188R, G188E, D190N, D190G, D190Y, H211R, H211P, C222R, P267R, P267L, R135G, R135L, R135P, and R135W. Example 2 – In vitro diagnostic assay for evaluating variant responsiveness to a rhodopsin corrector molecule

[0164] Herein provides an in vitro diagnostic assay to determine a patient's potential responsiveness to a rhodopsin corrector molecule based on the mutation / class of RP disease.

[0165] The following assay protocol was followed: Day 1 - Seed cells 1. Cells were grown in culture. 2. Cells were trypsinized, collected, spun down, and counted. 3. Cells were diluted to desired amount in a new tube. 4. Cells were resuspended in media with serum. 5. Cells were seeded into a dish. 6. Dishes were incubated overnight at 37° C. Day 2 – Doxycycline inducing cells and treatment 1. Prepared 6x Doxycycline media in Opti-MEM. 2. Dispensed Doxycycline Opti-MEM mixture into the dish. 3. Cells were treated with DMSO or a rhodopsin corrector molecule. 4. Mixed dishes thoroughly 5. Incubated plates overnight at 37° C. Day 3 – Read signal output 1. Barcodes were isolated, and quantified by next generation sequencing.WSGR Docket No.52652-721.601

[0166] As shown in FIG.4, a heatmap was generated by deep mutational screening of the trafficking score of each missense mutation against wildtype RHO. Cells were additionally treated with a rhodopsin corrector molecule before the RHO trafficking was measured. The assay was performed, except with addition of a RHO corrector molecule (Compound of Example 12), as described above and the barcode reads for each unique mutation was quantified and normalized against wildtype. The normalized trafficking was evaluated for each variant RHO. Variant RHO with trafficking defects of less than about 50% compared to wildtype were considered to be class 2 or class 3 RP disease mutations. If a variant RHO had <50% trafficking score without treatment, but had >50% trafficking score with treatment, the variant is considered rescued. Compared against no treatment as shown in FIG.3, the corrector molecule rescued ~70% of RHO variants. Additionally, substantially all of the stop codon nonsense mutation variants were not rescued by the corrector molecule. Mistrafficking mutations identified and rescued in this assay are listed in Table 4.WSGR Docket No.52652-721.601

[0167] As shown in FIGS.6A-6B, the select number of known mutations in the art were examined. Using the data from the heatmap, select mutations of interest were highlighted to demonstrate the effect of the rhodopsin corrector molecule in rescuing RHO variants in this assay. Many known class 2 and class 3 mutations were rescued by the treatment, such as N15S, T17M, V20G, P23A, P23H, P23L, Q28H, G51R, V87D, G89D, G106R G106W, E113K, P171S, E181K, G182S, G182V, C185R, G188E, D190N, D190G, D190Y, C222R, P267L, R135G, R135L, R135P, and R135W. Surprisingly, some of the rescued mutations had recovered trafficking scores equivalent to wildtype. Different compounds according to Formula (I) were also tested. As shown in FIGs 7A-7AJ, a subset of RHO mutations were tested with a variety ofWSGR Docket No.52652-721.601 different compounds at different concentrations. A bar graph shows the relative amount of mutated RHO trafficked to the plasma membrane relative to wildtype RHO with and without treatment of a rhodopsin corrector molecule. For example, Compound A (FIG 7I and 7J), Compound B (FIG.7AC and 7AD), Compound C (FIG.7AA and 7AB), or Compound D (FIG.7Y and 7Z), Compound of Example 9 (FIG.7AQ and 7AR), Compound of Example 10A (FIG.7O and 7P), Compound of Example 11 (FIG.7AO and 7AP), Compound of Example 12 (FIG.7S and 7T), Compound of Example 13 (FIG.7W and 7X), Compound of Example 14 (FIG.7AG and 7AH), Compound of Example 16A (FIG.7U and 7V), Compound of Example 17A (FIG.7AE and 7AF), Compound of Example 19A (FIG.7AK and 7AL), and Compound of Example 19B (FIG.7AM and 7AN), show correction of several known mutants associated with mistrafficking.) The compound of Example 17A rescued the following mistrafficking mutations listed in Table 5. Compound A rescued the following mistrafficking mutations listed in Table 6.WSGR Docket No.52652-721.601WSGR Docket No.52652-721.601Example 3 – In vivo RhoP23H / +Mouse 21-day Efficacy Study

[0168] To test the efficacy of a corrector molecule on the early progression of Rho-adRP, heterozygous RhoP23H / + mice were generated. RhoP23H / + knock-in mouse model demonstrated rapid and severe degeneration of the retina outer nuclear layer (ONL) and photoreceptor loss due to the retention of RhoP23H in the ER. Consequently, mutant animals had reduced density of Rho in their optical discs in the rod OS and diminished retinal function, as assessed using a full-field electroretinogram (ffERG).

[0169] Seven heterozygous RhoP23H / +mice (JAX strain #017628) were assigned to each arm, balancing the arms based on the light stimulated B-wave amplitude determined using ffERG on post-natal day (PND)20. Five RhoWTmice were included as controls. Mice were administered vehicle or a corrector according to a compound of Formula (I) (Compound A) (100 mg / kg / dose) twice daily (BID) by oral gavage for 21 days (PND21 to PND42). ffERGs were repeated on PND42, after which animals were sacrificed. Eyeballs were extracted, fixed, paraffin embeddedWSGR Docket No.52652-721.601 and mounted, and stained using standard eosin and hematoxylin counterstaining. Three slices from each retina were analyzed at 8 discrete points spread over 1500 micrometers in each direction from the optic nerve (16 points analyzed in triplicate per animal). To test the impact of drug on morphometric values, a model was fit that estimates signals for each group at each distance, factoring in variability at each level of nesting. Signals across the measured distances were aggregated at the end to determine the significance of differences between groups (p < 0.05 was considered statistically significant).

[0170] As shown in Table 7, ffERG taken on day PND42 showed an improved retina function in the drug group relative the vehicle group, with significant increases in A-wave (66% over vehicle treated) and B-wave (41% over vehicle treated) amplitudes. As shown in FIGs.8A-8B, Morphometric analysis of retina indicated positive drug effect for each retinal anatomical subcompartment investigated, with significant increases in ONL nuclei retained per column, and OS thickness. Table 7

[0171] A repeat study was performed with the compound of Example 12. As shown in FIG. 9A-9C, the Rhodopsin corrector compound of Example 12 had similar positive effect on morphometric measures. There was a clear drug dose response over the three doses tested (10, 50 and 100 mg / kg BID) with significant effect in ONL and OS thickness over 21 days. Example 4 – In vivo RhoP23H / +Mouse 42-day Efficacy Study

[0172] To further evaluate the activity of Rhodopsin corrector molecules discovered in a DMS screen, chronic dosing and the ability of to preserve retinal function was assessed over a 42-day treatment period.

[0173] Seven heterozygous RhoP23H / +mice (JAX strain #017628) were assigned to each arm, balancing the arms based on the light stimulated B-wave amplitude determined using ffERG on PND20. Five RhoWTmice were included as controls. Mice were administered vehicle or Compound A (100 mg / kg / dose) BID by oral gavage for 42 days (PND21 to PND63). ffERG were repeated on PND63, after which animals were sacrificed. Eyeballs were extracted, fixed, paraffin embedded and mounted, and stained using standard eosin hematoxylin counterstaining. Three slices from each retina were analyzed at 8 discrete points spread over 1500 micrometers inWSGR Docket No.52652-721.601 each direction from the optic nerve (16 points analyzed in triplicate per animal). To test the impact of drug on morphometric values, we fit a model that estimates signals for each group at each distance, factoring in variability at each level of nesting. Signals across the measured distances were aggregated at the end to determine the significance of differences between groups (p < 0.05 considered statistically significant).

[0174] As shown in Table 8, ffERG on PND63 demonstrated improvement in retina function in the Compound A treated group relative the vehicle group, with significant increases in A- wave (39% increase in Compound A treated animals versus vehicle-controlled animals, p < 0.05 Student’s t test) and B wave amplitudes (26% increase in Compound A treated animals versus vehicle-controlled animals, p < 0.05 Student’s t test). Unlike Compound A treated animals, vehicle treated animals showed a significant drop in A-wave amplitude over the PND21-63 period. As shown in FIGS.10 and 11, morphometric analyses of the retina indicated beneficial drug effects for each retinal anatomical sub-compartment investigated, with significant increases in ONL nuclei retained per column and a strong trend of increased OS thickness. Table 8

[0175] Taken together, these data are consistent with a potential beneficial impact of the corrector molecule on retinal health and function for the extended drug treatment period (PND21-63). The absence of an increase in effect size with an extended treatment period suggests that Compound A slows or arrests retina degeneration but, as expected, does not mediate regeneration that might restore anatomy and function. These data also demonstrated that Compound A was well tolerated at 200 mg / kg / day for 42 days. Example 5: Synthesis of (R)-(7-chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone (Compound A)

[0176] Step A: A mixture of (R)-5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (890 mg, 4.65 mmol), 7-chloro-1H-benzimidazole-2-carboxylic acid (1.10 g, 5.58 mmol), HATU (885 mg, 2.30 mmol) and DIEA (1.80 g, 14.0 mmol) in DMF (15.0 mL) was stirred at 20 °C for 1 h. TheWSGR Docket No.52652-721.601 reaction mixture was poured into H2O (20.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Waters Xbridge C18 (150 × 50 mm, 10 μm); flow rate: [H2O (10mM NH4HCO3)-ACN]; gradient: 20% – 50% B over 8 min; mobile phase A: 10mM aqueous NH4HCO3, mobile phase B: acetonitrile) to afford (R)-(7- chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC-MS: [MH]+= 327.1.1H NMR (400 MHz, CD3OD) δ 8.48 – 8.30 (m, 1H), 7.84 – 7.50 (m, 2H), 7.41 – 7.16 (m, 3H), 5.81 (br d, J = 6.8 Hz, 1H), 4.89 (br s, 1H), 3.81 – 3.32 (m, 2H), 3.17 – 2.99 (m, 1H), 1.80 – 1.63 (m, 3H). Example 6: Synthesis of (R)-(4-chloro-7-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone (Compound B)

[0177] Step A: 3-Chloro-2-nitroaniline (1.00 g, 5.79 mmol) was dissolved in MeCN (40.0 mL) under nitrogen, and SelectFluor (2.14 g, 5.79 mmol) was added. The reaction was heated at 85 °C for 30 min, after which the solvent was removed, and the residue diluted with EtOAc and water. The organic layer was removed, concentrated onto silica, and purified by normal phase chromatography (0 to 100% EtOAc in heptanes, 40 g column) to give 3-chloro-6-fluoro-2- nitroaniline (1.10 g, 100 %).

[0178] Step B: 3-Chloro-6-fluoro-2-nitroaniline (1.10 g, 5.79 mmol) was dissolved in MeOH (40.0 mL) under nitrogen, and palladium on carbon (10 % loading, 308 mg, 0.290 mmol) was added. Hydrogen atmosphere was introduced via purge cycle, and the reaction stirred at r. t. for 16 h. The atmosphere was removed, the mixture filtered over celite, and the filtrate concentrated to afford 3-chloro-6-fluorobenzene-1,2-diamine (931 mg) as a black solid. The resulting crude material was used without further purification (considered 100% yield).WSGR Docket No.52652-721.601

[0179] Steps C, D, and E: (R)-(4-Chloro-7-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone was prepared from 3-chloro-6-fluorobenzene- 1,2-diamine according to Example 8, Steps A, B, and C. UPLC-MS: [MH]+= 345.1.1H NMR (500 MHz, CDCl3) δ 11.33 – 10.75 (m, 1H), 8.55 – 8.43 (m, 1H), 7.64 (d, J = 40.7 Hz, 1H), 7.31 – 7.13 (m, 2H), 7.08 – 6.92 (m, 1H), 6.44 – 4.92 (m, 2H), 3.86 – 3.68 (m, 1H), 3.47 – 3.32 (m, 1H), 3.32 – 3.13 (m, 1H), 1.85 – 1.60 (m, 3H). Example 7: Synthesis of (R)-(6,7-dichloro-1H-imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone (Compound C)

[0180] Step A: To a solution of 4,5-dichloro-3-nitropyridin-2-amine (1.00 g, 4.81 mmol) in MeOH (20.0 mL) was added Fe (1.34 g, 24.0 mmol) and NH4Cl (1.29 g, 24.0 mmol). The mixture was stirred at 70 °C for 12 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 5.4,5-Dichloropyridine-2,3-diamine (450 mg, 52% yield) was obtained as a white solid. LC-MS: [MH]+= 178.2.

[0181] Step B: To a solution of 4,5-dichloropyridine-2,3-diamine (350 mg, 1.97 mmol) in 2- hydroxyacetic acid (299 mg, 3.93 mmol) was stirred at 140 °C for 4 h. After cooling the reaction mixture was treated with NaHCO3solution until p H 7. The reaction mixture was filtered and the filter cake was washed with 20.0 mL of H2O, dried in vacuum to afford (6,7-dichloro-1H- imidazo[4,5-b]pyridin-2-yl)methanol (250 mg, 58% yield) as a yellow solid. LC-MS: [M-H] = 216.0.

[0182] Step C: A solution of KMnO4 (272 mg, 1.72 mmol) in H2O (25.0 mL) was stirred at 100 °C. Then (6,7-dichloro-1H-imidazo[4,5-b]pyridin-2-yl)methanol (250 mg, 1.15 mmol) and Na2CO3(88.7 mg, 0.837 mmol) in H2O (25.0 mL) was added. The mixture was stirred at 100 °C for 2 h. The mixture was filtered and the filtrate was acidified to pH 2 – 3 with HCl. TheWSGR Docket No.52652-721.601 resulting precipitate was filtered off and the cake was dried in vacuum to give 6,7-dichloro-1H- imidazo[4,5-b]pyridine-2-carboxylic acid (200 mg, 75 % yield) as a white solid. LC-MS: [M-H] = 229.8.

[0183] Step D: A mixture of 6,7-dichloro-1H-imidazo[4,5-b]pyridine-2-carboxylic acid (60.0 mg, 0.259 mmol), (R)-5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (47.8 mg, 0.259 mmol), HATU (49.1 mg, 0.129 mmol) and DIEA (66.8 mg, 0.517 mmol) in DMF (1.00 mL) was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. NaOH (2M, 0.50 mL) was added. Then mixture was stirred at 20 °C for 10 mins. The reaction mixture was poured into H2O (2.00 mL) and extracted with EtOAc (3.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 × 30 mm, 3 ^m); flow rate: 25 mL / min; gradient: 10% – 40% B over 8 min; mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile). (R)-(6,7-dichloro-1H- imidazo[4,5-b]pyridin-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone (35.7 mg, 38%) was obtained as a yellow solid. LC-MS: [MH]+= 362.0.1H NMR (400 MHz, DMSO d6) δ 14.35 (br s, 1H), 8.69 – 8.53 (m, 1H), 8.48 – 8.35 (m, 1H), 7.85 – 7.55 (m, 1H), 7.39 – 7.07 (m, 1H), 6.05 – 5.62 (m, 1H), 5.36 – 4.61 (m, 1H), 3.85 – 3.38 (m, 1H), 3.25 – 2.88 (m, 2H), 1.76 – 1.52 (m, 3H). Example 8: Synthesis of (R)-(7-chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone (Compound D)

[0184] Step A: A solution of 3-chloro-4-fluorobenzene-1,2-diamine (300 mg, 1.87 mmol) and methyl 2,2,2-trichloroacetimidate (378 mg, 2.14 mol) in AcOH (3.00 mL) was stirred at 20 °C for 1 h. The mixture was poured into H2O (10.0 mL). The resulting precipitate was filtered offWSGR Docket No.52652-721.601 and the cake was dried under vacuum to give product 7-chloro-6-fluoro-2-(trichloromethyl)-1H- benzo[d]imidazole (500 mg, crude) as a yellow solid. LC-MS: [MH]+= 287.0.

[0185] Step B: A solution of 7-chloro-6-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole (300 mg, 1.04 mmol) and NaOH (2M aqueous, 7.00 mL) was stirred at 20 °C for 1 h. The mixture was acidified to pH 5 – 6 with HCl (6M aqueous). The resulting precipitate was filtered off and the cake concentrated under vacuum to give 7-chloro-6-fluoro-1H-benzo[d]imidazole-2- carboxylic acid (150 mg, crude) as a yellow solid. LC-MS: [MH]+= 215.1.

[0186] Step C: To a solution of 7-chloro-6-fluoro-1H-benzo[d]imidazole-2-carboxylic acid (60.0 mg, 0.280 mmol) and (R)-5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (51.6 mg, 0.280 mmol) in DMF (2.00 mL) was added DIEA (36.1 mg, 0.280 mmol) and HATU (106 mg, 0.280 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was poured into water (5.00 mL) and extracted with DCM (3.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (100 × 30 mm, 10 µm); flow rate: 25 mL / min; gradient: 25% – 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (R)-(7-Chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone (29.0 mg, 30%) was obtained as a yellow solid. LC-MS: [MH]+= 345.1.1H NMR (400 MHz, CDCl3) δ 10.90 – 10.58 (m, 1H), 8.51 – 8.42 (m, 1H), 7.75 – 7.36 (m, 2H), 7.26 – 7.15 (m, 2H), 7.14 – 6.21 (m, 1H), 5.95 – 4.90 (m, 1H), 3.11 (br s, 3H), 1.84 – 1.75 (m, 1H), 1.64 (d, J = 6.9 Hz, 2H). Example 9: (4-Fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin- 6(5H)-yl)methanone

[0187] Step A: A solution of 3-fluorobenzene-1,2-diamine (1.00 g, 7.93 mmol) and methyl 2,2,2-trichloroacetimidate (1.40 g, 7.93 mmol) in AcOH (8.00 mL) was stirred at 25 °C for 3 h. The reaction mixture was filtered and the filter cake was washed with H2O (5.00 mL) and dried in vacuum to give 4-fluoro-2-(trichloromethyl)-1H-benzo [d]imidazole which was used in the next step without any further purification. LC-MS: 253.0 [M+H]+.

[0188] Step B: A solution of 4-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole (2.00 g, 7.90 mmol) in NaOH aqueous (2M, 40 mL) was stirred at 20 °C for 1 h. The reaction mixture was poured into H2O (25.0 mL), extracted with MTBE (20.0 mL x 2). The combined organic layers were discarded. The water phase was adjusted pH 7 by using HCl aqueous (1M) and lyophilizedWSGR Docket No.52652-721.601 further to give a residue The residue was washed with DCM (10.0 mL x 2) and filtered. The combined filtrates layers were dried over Na2SO4and concentrated under vacuum to give 4- fluoro-1H-benzo[d]imidazole-2-carboxylic acid which was used in the next step without any further purification. LC-MS: 181.2 [M+H]+.

[0189] Step C: To a solution of 4-fluoro-1H-benzo[d]imidazole-2-carboxylic acid (20.0 mg, 0.111 mmol) and 5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (16.5 mg, 0.111 mmol) in DMF (1.00 mL) was added HATU (42.2 mg, 0.111 mmol) and DIEA (14.3 mg, 0.111 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was poured into H2O (1.00 mL) and extracted with EtOAc (1.00 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 × 30 mm, 10 μm); flow rate: 25 mL / min; gradient: 25% – 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to afford (4-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)- yl)methanone. LC-MS: 311.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 10.51 (br s, 1H), 8.57 – 8.46 (m, 1H), 7.78 – 7.60 (m, 1H), 7.33 (br s, 2H), 7.14 – 7.01 (m, 1H), 6.55 – 5.84 (m, 1H), 3.87 – 3.68 (m, 1H), 3.48 – 3.18 (m, 3H), 1.90 – 1.67 (m, 3H). Example 10: (6-Chloro-7-methyl-1H-benzimidazol-2-yl)-(5-methyl-7,8-dihydro-5H-1,6- naphthyridin-6-yl)methanone

[0190] The title compound was prepared from 4-chloro-3-methylbenzene-1,2-diamine according to the procedure of Example 9, Steps A, B, and C. LC-MS: 341.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.64 – 10.29 (m, 1H), 8.55 – 8.42 (m, 1H), 7.65 – 7.53 (m, 1H), 7.38 – 7.28 (m, 1H), 7.27 – 7.18 (m, 2H), 6.50 – 4.77 (m, 1H), 3.76 (dt, J = 3.8, 13.0 Hz, 1H), 3.53 – 3.06 (m, 3H), 2.81 – 2.53 (m, 3H), 1.79 (br dd, J = 6.4, 12.5 Hz, 1H), 1.65 (s, 2H). Examples 10A and 10B: (R)-(6-Chloro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8- dihydro-1,6-naphthyridin-6(5H)-yl)methanone and (S)-(6-Chloro-7-methyl-1H- benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone

[0191] Step A: (6-Chloro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone (40.0 mg, 0.120 mmol) was separated by SFC separation (Phenomenex-CHIRALPAK IH (250 × 30 mm, 10 µm); flow rate: 30 mL / min; gradient: 42% BWSGR Docket No.52652-721.601 over 14 min; mobile phase A: heptane, mobile phase B: EtOH(0.1% NH3H2O) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 10B): LC- MS: 340.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.22 (br dd, J = 4.4, 7.6 Hz, 1H), 8.51 – 8.23 (m, 1H), 7.59 – 7.21 (m, 3H), 7.16 – 7.08 (m, 1H), 6.44 – 5.67 (m, 1H), 5.09 – 3.59 (m, 1H), 3.45 – 2.91 (m, 3H), 2.72 – 2.40 (m, 3H), 1.73 – 1.55 (m, 3H). Second eluted compound (Example 10A): LC-MS: 340.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.52 – 10.21 (m, 1H), 8.55 – 8.42 (m, 1H), 7.69 – 7.29 (m, 3H), 727 – 7.15 (m, 1H), 6.53 – 5.75 (m, 1H), 5.09 – 3.67 (m, 1H), 3.53 – 3.01 (m, 3H), 2.79 – 2.52 (m, 3H), 1.84 – 1.63 (m, 3H). Example 11: (R)-(4-Chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0192] Step A: A mixture of 3-chloro-5-fluorobenzene-1,2-diamine (200 mg, 1.26 mmol) and methyl 2,2,2-trichloroethanimidate (219 mg,1.25 mmol) in AcOH (2.00 mL) was stirred at 20 °C for 2 h. The reaction mixture was filtered and the filter cake was washed with 10.0 mL water, dried in vacuum to give 7-chloro-5-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole. LC-MS: 288.9 [M+H]+.

[0193] Step B: A mixture of 7-chloro-5-fluoro-2-(trichloromethyl)-1H-benzo[d]imidazole (360 mg, 1.25 mmol) in NaOH (2M in aqueous, 4.00 mL) was stirred at 20 °C for 2 h. The reaction mixture was poured into H2O (5.0 mL) and extracted with MTBE (5.00 mL x 2). The aqueous phase was adjusted to pH 4 by adding HCl (1M aqueous) and extracted with DCM (5.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 7-chloro-5-fluoro-1H-benzo[d]imidazole-2-carboxylic acid. LC-MS: 213.1 [M+H]+.

[0194] Step C: A mixture of 7-chloro-5-fluoro-1H-benzo[d]imidazole-2-carboxylic acid (30.0 mg, 0.140 mmol), (R)-5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (21.0 mg, 0.112 mmol), HATU (27.0 mg, 0.070 mmol) and DIEA (54.0 mg, 0.419 mmol) in DMF (2.00 mL) was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column 75× 30mm× 3um); flow rate: 25 mL / min; gradient: 15% – 40% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (R)-(4-chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)(5- methyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC-MS: 344.9 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.77 – 8.48 (m, 2H), 8.01 – 7.86 (m, 1H), 7.36 – 6.97 (m, 2H), 6.09 – 5.88 (m, 1H), 4.97 (br dd, J = 4.6, 13.2 Hz, 1H), 3.84 – 3.31 (m, 3H), 1.96 – 1.64 (m, 3H).WSGR Docket No.52652-721.601 Example 12: (R)-(4-Fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0195] Step A: A solution of 3-fluoro-6-methyl-2-nitroaniline (500 mg, 6.25 mmol) and 10% palladium on carbon (500 mg) in EtOAc (100 mL) was degassed and purged with hydrogen for three times. The mixture was stirred at 20 °C for 1 h under hydrogen (15 psi). The suspension was filtered through a pad of Celite, and the cake was washed with EtOAc (20.0 mL×3). The combined filtrates were concentrated under vacuum to give 3-fluoro-6-methylbenzene-1,2- diamine. LC-MS: 141.3 [M+H]+.

[0196] Steps B, C, and D: The title compound was prepared from 3-fluoro-6-methylbenzene- 1,2-diamine according to the procedure of Example 11, Steps A, B, and C. LC-MS: 325.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.61 (br t, J = 5.8 Hz, 1H), 8.33 – 8.15 (m, 1H), 7.82 – 7.58 (m, 1H), 7.14 – 6.96 (m, 2H), 6.70 – 6.52 (m, 1H), 6.15 – 5.06 (m, 1H), 4.03 – 3.27 (m, 3H), 2.57 (d, J = 8.8 Hz, 3H), 1.88 – 1.71 (m, 3H). Example 13: (R)-(5-Fluoro-4-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone

[0197] (R)-(5-Fluoro-4-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro-1,6- naphthyridin-6(5H)-yl)methanone was prepared from 4-fluoro-3-methylbenzene-1,2-diamine according to the procedure of Example 11, Steps A, B, and C. LC-MS: 325.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.79 – 8.71 (m, 1H), 8.58 – 8.42 (m, 1H), 8.00 – 7.69 (m, 1H), 7.48 (br d, J = 3.3 Hz, 1H), 7.19 – 7.12 (m, 1H), 6.93 – 6.64 (m, 1H), 6.05 – 5.72 (m, 2H), 4.80 (br dd, J = 4.8, 13.8 Hz, 1H), 3.78 – 3.61 (m, 1H), 3.54 – 3.12 (m, 3H), 1.78 (d, J = 6.8 Hz, 1H), 1.61 (d, J = 6.8 Hz, 2H).WSGR Docket No.52652-721.601 Example 14: (R)-(4,6-Difluoro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone

[0198] Step A: To a solution of 1,5-difluoro-2-methyl-4-nitrobenzene (800 mg, 4.62 mmol) in EtOH (24.0 mL) and H2O (8.00 mL) was added iron powder (2.06 g, 37.0 mmol) and ammonium chloride (1.98 g, 37.0 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 2,4- difluoro-5-methylaniline.1H NMR (400 MHz, DMSO-d6) δ 6.92 (dd, J = 9.8, 11.3 Hz, 1H), 6.61 (dd, J = 8.4, 9.7 Hz, 1H), 4.88 (br s, 2H), 2.10 – 2.05 (m, 3H).

[0199] Step B: To a solution of 2,4-difluoro-5-methylaniline (500 mg, 3.49 mmol) in DCM (20.0 mL) was added acetic anhydride (428 mg, 4.19 mmol) and TEA (1.06 g, 10.5 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of petroleum / EtOAc ether from 30 / 1 to 19 / 1 to give N-(2,4- difluoro-5-methylphenyl)acetamide. LC-MS: 186.5 [M+H]+.

[0200] Step C: To a solution of N-(2,4-difluoro-5-methylphenyl)acetamide (350 mg, 1.89 mmol) in H2SO4(6.00 mL) was added HNO3(595 mg, 9.45 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into water. The precipitate was collected by filtration and dried in vacuo to give crude product. N-(4,6-difluoro-3-methyl-2- nitrophenyl)acetamide. LC-MS: 231.4 [M+H]+.

[0201] Step D: To a solution of N-(4,6-difluoro-3-methyl-2-nitrophenyl)acetamide (350 mg, 1.52 mmol) in MeOH (4.00 mL) was added HCl aqueous (2M, 3.80 mL). The mixture was stirred at 70 °C for 12 h. The reaction mixture was poured into H2O (10.0 mL) and extractedWSGR Docket No.52652-721.601 with EtOAc (30.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of petroleum / EtOAc ether from 30 / 1 to 19 / 1 to give 4,6- difluoro-3-methyl-2-nitroaniline. LC-MS: 187.5 [M–H]–.1H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J = 9.6, 11.2 Hz, 1H), 6.72 – 5.41 (m, 2H), 2.15 (dd, J = 1.2, 2.3 Hz, 3H).

[0202] Step E: To a solution of 4,6-difluoro-3-methyl-2-nitroaniline (130 mg, 0.691 mmol) in EtOH (6.00 mL) and H2O (2.00 mL) was added iron powder (309 mg, 5.53 mmol) and ammonium chloride (296 mg, 5.53 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give 4,6-difluoro-3- methylbenzene-1,2-diamine. LC-MS: 157.1 [M–H]–.

[0203] Step F: To a solution of 4,6-difluoro-3-methylbenzene-1,2-diamine (100 mg, 0.632 mmol) in HOAc (2.00 mL) was added methyl 2,2,2-trichloroethanimidate (112 mg, 0.632 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered. The filter cake was washed with H2O (2.00 mL), and dried under reduced pressure to give 4,6-difluoro-7- methyl-2-(trichloromethyl)-1H-benzo[d]imidazole. LC-MS: 285.1 [M+H]+.

[0204] Step G: A solution of 4,6-difluoro-7-methyl-2-(trichloromethyl)-1H- benzo[d]imidazole (70 mg, 0.245 mmol) and NaOH (2M aqueous, 7.00 mL) was stirred at 25 °C for 1 h. The mixture was adjusted to pH 5 – 6 with HCl (6M aqueous). The resulting precipitate was filtered and the filter cake was dried under vacuum to give 4,6-difluoro-7-methyl-1H- benzo[d]imidazole-2-carboxylic acid. LC-MS: 213.2 [M+H]+.

[0205] Step H: To a solution of 4,6-difluoro-7-methyl-1H-benzo[d]imidazole-2-carboxylic acid (35.0 mg, 0.165 mmol) in DMF (1.00 mL) was added (R)-5-methyl-5,6,7,8-tetrahydro-1,6- naphthyridine (30.5 mg, 0.165 mmol), DIEA (42.6 mg, 0.330 mmol) and HATU (31.4 mg, 0.082 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into H2O (2.00 mL) and extracted with EtOAc (1.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by prep-HPLC (Phenomenex luna C18 column (100 × 40 mm, 5 um); flow rate: 25 mL / min; gradient: 10% – 40% B over 8 min; mobile phase A: H2O (0.04% HCl), mobile phase B: acetonitrile). (R)-(4,6-difluoro-7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-7,8-dihydro- 1,6-naphthyridin-6(5H)-yl)methanone. LC-MS: 343.1[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 14.01 – 13.40 (m, 1H), 8.83 – 8.53 (m, 1H), 8.47 – 7.99 (m, 1H), 7.84 – 7.51 (m, 1H), 7.29 – 7.05 (m, 1H), 6.58 – 5.76 (m, 1H), 5.61 – 4.53 (m, 1H), 3.74 – 3.67 (m, 1H), 3.22 – 3.14 (m, 2H), 2.45 – 2.41 (m, 3H), 1.79 – 1.55 (m, 3H). Example 15: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanoneWSGR Docket No.52652-721.601

[0206] Step A: To a solution of 6-methylpyrazine-2-carbaldehyde (1.80 g, 14.7 mmol) in EtOH (45.0 mL) was added NH2OH.HCl (1.23 g, 17.7 mmol) and NaOAc (1.63 g, 19.9 mmol) in H2O (25.0 mL). The mixture was stirred at 80 °C for 2 h. The mixture was concentrated under vacuum to give (E)-6-methylpyrazine-2-carbaldehyde oxime. LC-MS: 138.3 [M+H]+.

[0207] Step B: To a solution of (E)-6-methylpyrazine-2-carbaldehyde oxime (1.70 g, 12.4 mmol) in MeOH (50.0 mL) was added palladium on carbon (2.00 g, 10% purity) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen and repeated three times. The mixture was stirred at 20 °C for 12 h under a hydrogen (15 Psi) atmosphere. The suspension was filtered through a pad of Celite and the pad was washed with MeOH (10.0 mL × 3). The combined filtrates were concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 3 to afford 6-methylpyrazin-2-yl)methanamine. LC-MS: 124.3 [M+H]+.

[0208] Step C: To a solution of (6-methylpyrazin-2-yl)methanamine (410 mg, 3.33 mmol) in DCM (10.0 mL) was added TFAA (0.50 mL, 3.99 mmol) at -10 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 1 / 100 to 1 / 3 to afford 2,2,2-trifluoro-N-((6-methylpyrazin-2-yl)methyl)acetamide. LC-MS: 220.2 [M+H]+.

[0209] Step D: A solution of 2,2,2-trifluoro-N-((6-methylpyrazin-2-yl)methyl)acetamide (370 mg, 1.69 mmol) in POCl3(6.91 g, 451 mmol) was stirred at 130 °C for 5 h. The mixture was concentrated under vacuum to give a residue and then poured into ice-water (5.00 mL), treated with saturated Na2CO3 aqueous (5.00 mL) to pH = 8, and extracted with EtOAc (5.00 mL x 2). The combined organic phase was washed with H2O (2.00 mL x 2) and brine (2.00 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc / petroleum ether from 0 / 1 to 1 / 0 to afford 5-methyl- 3-(trifluoromethyl)imidazo[1,5-a]pyrazine. LC-MS: 202.2 [M+H]+.

[0210] Step E: To a solution of 5-methyl-3-(trifluoromethyl)imidazo[1,5-a]pyrazine (35.0 mg, 0.174 mmol) in 2,2,2-trifluoroethanol (1.00 mL) was added palladium on carbon (185 mg, 10% purity) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogenWSGR Docket No.52652-721.601 and repeated three times. The mixture was stirred at 20 °C for 6 h under a hydrogen (15 Psi.) atmosphere. The suspension was filtered through a pad of Celite and the cake was washed with 2,2,2-trifluoroethanol (2.00 mL × 3). The combined filtrates were concentrated under vacuum to give 5-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine. LC-MS: 206.2 [M+H]+.

[0211] Step F: To a solution of 5-methyl-3-(trifluoromethyl)imidazo[1,5-a]pyrazine (30.0 mg, 0.146 mmol), 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (28.7 mg, 0.146 mmol), HATU (16.7 mg, 0.044 mmol) in DMF (1.00 mL) was added DIEA (0.051 mL, 0.292 mmol). The mixture was stirred at 25oC for 1 h. The mixture was poured into H2O (1.00 mL) and extracted with DCM (1.00 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 × 30 mm, 3 μm); flow rate: 25 mL / min; gradient: 35% – 65% B over 8 min; mobile phase A: 0.04% aqueous HCl mobile phase B: acetonitrile). The relevant fractions were lyophilized to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone. LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 7.65 – 7.56 (m, 1H), 7.43 – 7.30 (m, 2H), 7.17 – 7.07 (m, 1H), 6.20 (br d, J = 13.8 Hz, 1H), 5.10 (br d, J = 17.3 Hz, 1H), 5.01– 4.93 (m, 1H), 4.70 – 4.60 (m, 1H), 3.96 – 3.58 (m, 1H), 1.66 – 1.51 (m, 3H). Examples 15A and 15B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (R) or (S)-(7- Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)methanone

[0212] Step A: (7-Chloro-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (15.7 mg, 0.037 mmol) was separated by SFC separation ((DAICEL CHIRALCEL IG (250 × 30 mm, 10 μm); flow rate: 64 mL / min; gradient: 25% B over 4 min; mobile phase A: CO2, mobile phase B: MeOH(0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 15A): LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 7.71 – 7.55 (m, 1H), 7.44 – 7.29 (m, 2H), 7.11 – 7.01 (m, 1H), 6.94 – 6.65 (m, 1H), 5.68 – 5.10 (m, 1H), 5.03 – 4.48 (m, 2H), 3.91 – 3.39 (m, 1H), 1.66 – 1.46 (m, 3H). Second eluted compound (Example 15B): LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 7.66 – 7.46 (m, 1H), 7.40 – 7.21 (m, 2H), 7.07 –WSGR Docket No.52652-721.601 6.94 (m, 1H), 6.90 – 6.53 (m, 1H), 5.58 – 5.03 (m, 1H), 4.96 – 4.46 (m, 2H), 3.81 – 3.38 (m, 1H), 1.55 – 1.42 (m, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 16: (7-Chloro-1H-benzo[d]imidazol-2-yl)(6-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

[0213] The title compound was prepared from (5-methylpyrazin-2-yl)methanamine according to the procedure of Example 15, Steps C, D, E, and F. LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CD3OD) δ 7.65 - 7.50 (m, 1H), 7.46 - 7.31 (m, 2H), 7.20 - 6.97 (m, 1H), 5.51 - 5.31 (m, 1H), 4.52 - 4.25 (m, 2H), 3.92 - 3.75 (m, 1H), 3.37 (s, 2H), 1.37 (d, J = 6.8 Hz, 3H). Examples 16A and 16B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(6-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (R) or (S)-(7- Chloro-1H-benzo[d]imidazol-2-yl)(6-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)methanone

[0214] (7-Chloro-1H-benzo[d]imidazol-2-yl)(6-methyl-3-(trifluoromethyl)-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (7.90 g, 20.6 mmol) was separated by SFC separation (DAICEL CHIRALCEL OD (250 × 30 mm, 10 μm); flow rate: 30 mL / min; gradient:38% B over 14 min; mobile phase A: heptane, mobile phase B: CO2- MeOH(0.1% NH3H2O) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 16A): LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.64 (br s, 1H), 7.45 – 7.38 (m, 1H), 7.37 – 7.29 (m, 1H), 7.11 (br d, J = 5.8 Hz, 1H), 7.07 – 6.72 (m, 1H), 5.53 – 4.59 (m, 2H), 4.47 – 4.21 (m, 2H), 1.43 – 1.37 (m, 3H). Second eluted compound (Example 16B): LC-MS: 384.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.74 – 7.60 (m, 1H), 7.48 – 7.39 (m, 1H), 7.38 – 7.31 (m, 1H), 7.12 (br d, J = 5.1 Hz, 1H), 7.09 – 6.71 (m, 1H), 5.57 – 4.60 (m, 2H), 4.53 – 4.17 (m, 2H), 1.48 – 1.37 (m, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined.WSGR Docket No.52652-721.601 Examples 17A and 17B: (R) or (S)-(7-Chloro-1H-benzo[d]imidazol-2-yl)(4-methyl-6,7- dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methanone (enantiomer 1) and (R) or (S)-(7- Chloro-1H-benzo[d]imidazol-2-yl)(4-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)- yl)methanone (enantiomer 2)

[0215] Step A: To a flask was added palladium on carbon 10 % loading (84.0 mg, 0.0789 mmol) and vacuum purged, then replaced the atmosphere with N2. Added trifluoroethanol (4.00 mL) to form a suspension, then tert-butyl 2-bromo-4-methyl-6,7-dihydrothiazolo[5,4-c]pyridine- 5(4H)-carboxylate (263 mg, 0.789 mmol) in trifluoroethanol (4.00 mL) and vacuum purged, replacing the atmosphere with H2. Repeated the purge / refill cycle twice and allowed the mixture to stir for 16 h at 25 °C. Degassed and re-filled with air, then filtered on a PTFE filter (0.45 µm) and concentrated under reduced pressure to provide tert-butyl 4-methyl-6,7-dihydrothiazolo[5,4- c]pyridine-5(4H)-carboxylate. LCMS: 255.1 [M+H]+.

[0216] Step B: To a solution of tert-butyl 4-methyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)- carboxylate (200 mg, 0.786 mmol) in dioxane (4.00 mL) was added hydrochloric acid (4.0 M in dioxane, 1.97 mL, 7.86 mmol) and stirred for 30 min at 25 °C. The mixture was concentrated under reduced pressure to provide 4-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine, which was used without purification. LCMS: 155.1 [M+H]+.

[0217] Step C: 4-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (109 mg, 0.707 mmol) was dissolved in MeCN (7.12 mL) and aq. sat. NaHCO3 (3.21 mL, 3.53 mmol) was added until neutral pH. Then, 7-chloro-2-(trichloromethyl)-1H-benzo[d]imidazole (191 mg, 0.707 mmol) was added and the mixture and stirred at 25 °C for 15 min. The mixture was concentrated and partitioned between MeTHF and water. The aqueous layer was extracted with MeTHF once more. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography on SiO2 (40 g, 0-100% EtOAc / heptanes, 0-5% iPrOH) to give (7-chloro-1H-benzo[d]imidazol-2- yl)(4-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methanone. LCMS: 333.3 [M+H]+.WSGR Docket No.52652-721.601

[0218] Step D: Racemic (7-chloro-1H-benzo[d]imidazol-2-yl)(4-methyl-6,7- dihydrothiazolo[4,5-c]pyridin-5(4H)-yl)methanone (60 mg, 0.180 mmol) (60 mg) was separated into its constituent enantiomers by chiral HPLC (LC: Autopurification LC-MS (2545 Binary, Solvent heater, 2767, SFO, 515, 515, 2998, 3100MSD Performance), UV detection: Waters PDA 2998 (198-360nm), MS detection: Waters 3100MSD Performance, ESI (ES (+), 100-1200 amu), Eluant B: MeCN, Eluant A: 10.0 mM AMF pH3.8, Column: Phenomenex, i-Amylose-3, 5 µm, 10 x 250 mm, Gradient: isocratic 70% B at 8mL / min for 16 minutes, Run time: 16.0 minutes) to afford a first eluted compound and a second eluted compound. LC-MS: 333.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.59 – 7.52 (m, 1H), 7.39 – 7.33 (m, 1H), 7.33 – 7.26 (m, 1H), 6.55 (q, J = 7.1 Hz, 0.4H), 5.92 (q, J = 6.4 Hz, 0.6H), 5.66 – 5.56 (m, 0.6H), 4.78 (dd, J = 13.3, 4.7 Hz, 0.4H), 3.64 – 3.56 (m, 1H), 3.06 – 2.91 (m, 2H), 1.72 (d, J = 6.6 Hz, 1H), 1.55 (d, J = 6.7 Hz, 2H). The absolute stereochemistry for the first and second eluted compounds was not determined. Example 18: (7-Chloro-1H-benzo[d]imidazol-2-yl)(3,4-dihydro-1,4-methanoisoquinolin- 2(1H)-yl)methanone

[0219] Step A: To a solution of 1,2,3,4-tetrahydro-1,4-methanoisoquinoline (50.0 mg, 0.275 mmol) in DMF (1.00 mL) was added 7-chloro-1H-benzo[d]imidazole-2-carboxylic acid (54.1 mg, 0.275 mmol), DIEA (71.1 mg, 0.550 mmol) and HATU (52.3 mg, 0.138 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into H2O (2.00 mL) and extracted with EtOAc (1.00 mL x 3). The combined organic layers were washed with brine (1.00 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by prep-HPLC (Phenomenex Luna C18 column (100 × 40 mm, 5 um); flow rate: 25 mL / min; gradient: 35% – 65% B over 8 min; mobile phase A: 0.04% aqueous HCl, mobile phase B: acetonitrile) to afford (7-chloro-1H-benzo[d]imidazol-2-yl)(3,4-dihydro-1,4- methanoisoquinolin-2(1H)-yl)methanone. LC-MS: 324.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.96 – 10.06 (m, 1H), 7.47 – 7.29 (m, 4H), 7.24 – 7.07 (m, 3H), 5.80 – 3.00 (m, 4H), 2.21 – 2.05 (m, 2H). Examples 19A and 19B: (R) or (S)-(7-Methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3- (trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone and (R) or (S)-(7- Methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5- a]pyrazin-7(8H)-yl)methanoneWSGR Docket No.52652-721.601

[0220] Step A: Racemic (7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)- 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone was prepared from 5-methyl-3- (trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine and 7-methyl-1H- benzo[d]imidazole-2-carboxylic acid according to the procedure of Example 18, Step A. LC- MS: 364.1 [M+H]+.

[0221] Step B: Racemic (7-methyl-1H-benzo[d]imidazol-2-yl)(5-methyl-3-(trifluoromethyl)- 5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone (10.0 mg, 0.0275 mmol, HCl salt) was further separated by SFC separation ((DAICEL CHIRALCEL OZ (250 × 25 mm, 10 μm); flow rate: 64 mL / min; gradient: 35% B over 4 min; mobile phase A: CO2, mobile phase B: MeOH(0.1%NH3H2O)) to afford a first eluted compound and a second eluted compound. First eluted compound (Example 19A): LC-MS: 364.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 10.37 – 10.12 (m, 1H), 7.77 – 7.28 (m, 2H), 7.23 – 6.74 (m, 3H), 5.71 – 5.05 (m, 1H), 4.98 – 4.47 (m, 2H), 3.89 – 3.43 (m, 1H), 2.80 – 2.50 (m, 3H), 1.62 – 1.56 (m, 3H). Second eluted compound (Example 19B): LC-MS: 364.1[M+H]+.1H NMR (400 MHz, CDCl3) δ 10.45 – 10.12 (m, 1H), 7.76 – 7.20 (m, 2H), 7.16 – 6.61 (m, 3H), 5.68 – 4.95 (m, 1H), 4.93 – 4.43 (m, 2H), 3.81 – 3.28 (m, 1H), 2.71 – 2.40 (m, 3H), 1.49 (br s, 3H). The absolute stereochemistry for the first and second eluted compounds was not determined.

[0222] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0223] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to beWSGR Docket No.52652-721.601 incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Claims

WSGR Docket No.52652-721.601 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a subject with retinitis pigmentosa, the method comprising administering to the subject a therapeutically effective dose of a rhodopsin corrector molecule thereby treating the retinitis pigmentosa.

2. The method of claim 1, wherein the retinitis pigmentosa comprises an autosomal dominant retinitis pigmentosa.

3. The method of claim 1, further comprising assaying a biological sample from the subject for a RHO gene mutation, wherein the subject is identified as having a RHO gene mutation if the assay determines the presence of a mutation compared to a wild-type RHO protein as shown in SEQ ID NO: 1 in the subject.

4. The method of claim 3, wherein the mutation of the wild-type RHO protein is a missense mutation.

5. The method of claim 3, wherein a function of the mutation of the wild-type RHO protein is determined by a deep mutational scan of the wild-type RHO protein.

6. The method of claim 1, wherein the subject is identified as having a RHO mutation that results in mistrafficking of RHO due to RHO misfolding, RHO instability, retention of RHO in the endoplasmic reticulum, disrupted vesicular traffic, and / or disrupted endocytosis.

7. The method of claim 1, wherein the subject is identified as having a class 2 or class 3 RHO mutation.

8. The method of claim 1, wherein the subject is identified as having a class 2 RHO mutation.

9. The method of claim 1, wherein the subject is identified as having a class 3 RHO mutation.

10. The method of claim 7, wherein the class 2 or class 3 mutation results in reduced RHO on the plasma membrane.

11. The method of claim 7, wherein the class 2 or class 3 mutation results in RHO misfolding, RHO instability, retention of RHO in the endoplasmic reticulum, disrupted vesicular traffic, and / or disrupted endocytosis.

12. The method of claim 7, wherein the class 2 or class 3 mutation comprises a missense mutation at any one or more of N15, T17, V20, P23, Q28, G51, P53, T58, V87, G89, G106, C110, E113, L125, W161, A164, C167, P171, Y178, E181, G182, C185, C187, G188, D190, H211, C222, P267, S270, K296, or R135.WSGR Docket No.52652-721.601 13. The method of claim 7, wherein the class 2 or class 3 mutation comprises N15S, T17M, V20G, P23A, P23H, P23L, Q28H, G51R, G51V, P53R, T58R, T58M, V87D, G89D, G106R G106W, C110F, C110R, C110S, C110Y, E113K, L125R, W161R, A164E, A164V, C167R, C167W, P171Q, P171L, P171S, Y178N, Y178D, Y178C, E181K, G182S, G182V, C185R, C187G, C187Y, G188R, G188E, D190N, D190G, D190Y, H211R, H211P, C222R, P267R, P267L, S270R, K296E, K296M, R135G, R135L, R135P, or R135W.

14. The method of claim 7, wherein the class 2 or class 3 mutation comprises P23H.

15. The method of claim 7, wherein the class 2 or class 3 mutation comprises a missense mutation at any one or more of M1, G3, T4, G6, N8, F9, Y10, V11, P12, F13, A16, G18, R21, S22, F24, E25, Y26, P27, Y30, L31, A32, F37, M39, L40, A41, Y43, M44, F45, L46, L47, I48, V49, L50, F52, I54, N55, F56, L57, L59, V61, I75, L76, N78, V81, L84, F85, V87, L88, G90, F91, T92, T94, L95, T97, S98, L99, H100, G101, Y102, F103, L112, G114, F115, F116, T118, L119, I123, W126, S127, L128, V129, V130, L131, A132, I133, E134, A153, V157, A158, F159, T160, V162, M163, L165, A166, A168, A169, P170, L172, A173, G174, W175, S176, R177, I179, P180, L183, Q184, S186, I189, Y191, Y192, T193, N200, F203, V204, Y206, M207, F208, V209, V210, F212, T213, I214, P215, M216, I217, I218, I219, F220, F221, M253, V254, M257, V258, A260, L262, I263, V266, Y268, V271, A272, F273, Y274, I275, F276, T277, H278, P285, M288, T289, I290, P291, F293, F294, S297, A299, I300, N302, P303, V304, I305, I307, M308, M309, N310, F313, R314, M317, T320, S334, A335, or E341.

16. The method of claim 7, wherein the class 2 or class 3 mutation comprises any one or more variants listed in Table 3.

17. The method of claim 7, wherein the class 2 or class 3 mutation comprises any one or more of the variants listed in Table 4, 5, or 6.

18. The method of claim 7, wherein the class 2 or class 3 mutation is determined by deep mutational scanning.

19. The method of claim 1, wherein the rhodopsin corrector molecule is therapeutically effective at treating at least 80% of disease associated mutations.

20. The method of claim 19, wherein the at least 80% of disease associated mutations are selected from the list consisting of F9L, N15S, T17K, T17M, V20L, R21P, P23H, P23L, F24C, Q28H, Q28K, Q28R, G51R, L59H, G89D, L95P, Y102N, G106R, L131R, R135G, R135L, R135P, R135W, P171S, A173P, I179N, P180A, P180L, P180S, E181K, G182D, G182E, G182S, Q184R, C185R, C185Y, S186P, G188E, D190E, D190G, D190N, D190Y, P267L, H278P, and T289P.WSGR Docket No.52652-721.601 21. The method of claim 1, wherein the rhodopsin corrector molecule is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (I); wherein: Y1, Y2, and Y3are each independently C(R3) or N, wherein at least one of Y2and Y3is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, - C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl,WSGR Docket No.52652-721.601 C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - -CH2C(O)N(R10)(R11), -, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl; and n is 0, 1, 2, 3, or 4.

22. The method of claim 21, wherein the rhodopsin corrector molecule is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, having the structure:WSGR Docket No.52652-721.601Formula (Ia).

23. The method of claim 1, wherein the rhodopsin corrector molecule is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (II); wherein: X, Y, and Z are each independently C(R3) or N, wherein at least one of Y and Z is C(R3); Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); R1is selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; each R3is independently selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl,WSGR Docket No.52652-721.601 C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

24. The method of claim 23, wherein the rhodopsin corrector molecule is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, having the structure:WSGR Docket No.52652-721.601Formula (IIa).

25. The method of claim 1, wherein the rhodopsin corrector molecule is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure:Formula (III); wherein: Z1, Z2, and Z3are each independently C(R4) or N, wherein at least one of Z1, Z2, and Z3is C(R4); J is O or S; R1is selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5agroups; each R2is independently selected from halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5bgroups; R3is selected from hydrogen, halogen, -CN, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5cgroups; each R4is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -N(R10)(R11), C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl,WSGR Docket No.52652-721.601 C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R5dgroups; each R5a, R5b, R5c, and R5dis each independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, - CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1- 6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

26. The method of claim 25, wherein the rhodopsin corrector molecule is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, having the structure:WSGR Docket No.52652-721.601Formula (IIIa).

27. The method of claim 21, wherein each R3is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, -CF3, and -OCH3.

28. The method of claim 21, wherein each R3is independently selected from hydrogen, halogen, and -CH3.

29. The method of claim 21, wherein each R3is hydrogen.

30. The method of claim 21, wherein each R2is independently selected from -OR10, C1-6alkyl, and C1-6haloalkyl, and wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5bgroups.

31. The method of claim 21, wherein each R2is independently selected from unsubstituted C1-6alkyl.

32. The method of claim 21, wherein each R2is -CH3.

33. The method of claim 21, wherein n is 1.

34. The method of claim 21, wherein R1is selected from halogen, -CN, -OR10, C1-6alkyl, and C1-6haloalkyl, and wherein C1-6alkyl and C1-6haloalkyl are optionally substituted with 1-5 R5agroups.

35. The method of claim 21, wherein R1is selected from halogen, -CN, -OR10, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl.

36. The method of claim 21, wherein R1is halogen.

37. The method of claim 21, wherein Z1, Z2, and Z3are each independently C(R4).

38. The method of claim 21, wherein Z1and Z2are each independently C(R4), and Z3is N.

39. The method of claim 21, wherein each R4is independently selected from hydrogen, halogen, -CN, -OR10, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl, wherein C1-6alkyl, C1- 6haloalkyl, and C3-6cycloalkyl are optionally substituted with 1-5 R5dgroups.

40. The method of claim 1, wherein the rhodopsin corrector molecule is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, having the structure:WSGR Docket No.52652-721.601Formula (Ib); wherein: Z3is C(R4) or N; R1is selected from halogen, -CN, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl; and each R4is independently selected from hydrogen, halogen, -CN, unsubstituted C1-6alkyl, and unsubstituted C1-6haloalkyl.

41. The method of claim 40, wherein R1is halogen.

42. The method of claim 40, wherein R1is unsubstituted C1-6alkyl.

43. The method of claim 40, wherein Z3is C(R4).

44. The method of claim 40, wherein Z3is N.

45. The method of claim 21, wherein each R4is independently selected from hydrogen and halogen.

46. The method of claim 21, wherein each R4is hydrogen.

47. The method of claim 21, wherein the rhodopsin corrector molecule is selected from:pharmaceutically acceptable salt or solvate thereof.

48. The method of claim 21, wherein the rhodopsin corrector molecule is selected from:WSGR Docket No.52652-721.601pharmaceutically acceptable salt or solvate thereof.

49. The method of claim 31, wherein the rhodopsin corrector molecule is selected from:pharmaceutically acceptable salt or solvate thereof.

50. The method of claim 33, wherein the rhodopsin corrector molecule is selected from:pharmaceutically acceptable salt or solvate thereof.

51. The method of claim 1, wherein the rhodopsin corrector molecule is a gene therapy.

52. The method of claim 51, wherein the gene therapy comprises overexpression of GRP78.

53. The method of claim 1, wherein the rhodopsin corrector molecule comprises a small molecule.

54. The method of claim 1, wherein the rhodopsin corrector molecule comprises 9-cis retinal, YC001, F5257-0462, or SRD005825.

55. The method of claim 1, wherein the rhodopsin corrector molecule comprises 9-cis retinal.

56. The method of claim 1, wherein the rhodopsin corrector molecule comprises YC001.WSGR Docket No.52652-721.601 57. The method of claim 1, wherein the rhodopsin corrector molecule comprises F5257- 0462.

58. The method of claim 1, wherein the rhodopsin corrector molecule comprises SRD005825.

59. The method of claim 1, wherein the rhodopsin corrector molecule increases cell surface expression of rhodopsin compared to vehicle control.

60. The method of claim 1, wherein the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 25% of that observed for wild-type rhodopsin.

61. The method of claim 1, wherein the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 30% of that observed for wild-type rhodopsin.

62. The method of claim 1, wherein the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 40% of that observed for wild-type rhodopsin.

63. The method of claim 1, wherein the rhodopsin corrector molecule increases cell surface expression of a rhodopsin mutant to at least about 50% of that observed for wild-type rhodopsin.

64. The method of claim 1, wherein the rhodopsin corrector molecule is administered to a human.

65. The method of claim 1, wherein the rhodopsin corrector molecule is administered orally.

66. The method of claim 1, wherein a concentration of the rhodopsin corrector molecule is delivered to an ocular tissue.

67. The method of claim 1, wherein a therapeutically effective concentration of the rhodopsin corrector molecule is delivered to the retina.

68. The method of claim 1, wherein the therapeutically effective concentration of the rhodopsin corrector molecule increases cell surface expression of rhodopsin.

69. The method of claim 1, wherein a therapeutically effective concentration of the rhodopsin corrector molecule drug is delivered to an ocular tissue.

70. The method of claim 1, wherein the rhodopsin corrector molecule exhibits oral bioavailability of greater than about 60%.

71. The method of claim 1, wherein the rhodopsin corrector molecule exhibits oral bioavailability of greater than about 70%.

72. The method of claim 1, wherein the rhodopsin corrector molecule exhibits microsomal stability of greater than about 90 minutes.WSGR Docket No.52652-721.601 73. The method of claim 1, wherein the rhodopsin corrector molecule exhibits an EC50 for rescue of rhodopsin surface expression of 1 uM or less.

74. The method of claim 1, wherein the rhodopsin corrector molecule exhibits an EC50for rescue of rhodopsin surface expression of less than about 200 nM.

75. The method of claim 1, wherein the rhodopsin corrector molecule exhibits an EC50 for rescue of rhodopsin surface expression of less than about 100 nM.

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