Small molecule activators of bestrophins for the treatment of disease

Abstract

Described herein are compounds for the treatment of disease, including bestrophin-related disease, and methods of treatment thereof.

Description

Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026SMALL MOLECULE ACTIVATORS OF BESTROPHINS FOR THE TREATMENT OF DISEASE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U. S. Provisional Patent Application No. 63 / 760,343, filed on February 19, 2025; U. S. Provisional Patent Application No. 63 / 775,572, filed on March 21, 2025; and U. S. Provisional Patent Application No.63 / 909,022, filed on October 31, 2025; each of which are incorporated herein by reference in their entireties.

[0002] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosure of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described herein.GOVERNMENT SUPPORT

[0003] This invention was made with government support under Grant No.R35 / GM149252. The Government has certain rights in the invention.BACKGROUND

[0004] The bestrophins are a family of Ca2+-activated anion channels consisting of four members in mammals (Bestl-Best4). They are widely distributed in various human organs including the airways, colon, kidney, pancreas and central nervous system, but they are best known for their physiological roles in the eye. In particular, Bestl is predominantly expressed in retinal pigment epithelium (RPE) and genetically linked to a spectrum of retinal degenerative disorders collectively known as bestrophinopathies. Over 350 different mutations in Bestl have been identified to cause bestrophinopathies, including Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and retinitis pigmentosa (RP). Additionally, bestrophins have roles in multiple aspects of physiology. The patients are susceptible to progressive vision loss that may eventually lead to blindness, and there is no treatment. On the other hand, Best2 resides in non-pigmented epithelium (NPE) regulating intra-ocular pressure (IOP), which must be properly maintained at all times as both hypertension and hypotension are deleterious conditions.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0005] The early-onset form of vitelliform macular dystrophy (VMD), also known as Best vitelliform macular dystrophy (BVMD), results from any one of over 350 point mutations in the BEST1 gene. Typically starting to appear in childhood, BVMD progresses to blindness by the fifth decade of life. BEST1 encodes a chloride (C1-) channel, namely Bestl, expressed on the basolateral membrane of retinal pigment epithelium (RPE) cells. The vast majority of BVMD cases are associated with Bestl loss-of-function (LOF), which decreases or extinguishes Bestl’s capacity to efflux C1-, causing fluid accumulation in the subretinal space that separates photoreceptor cells from the RPE. The dysfunction leads to elevated short- wavelength fundus autofluorescence within the lesion, photoreceptor cell impairment, and increased production of bisretinoid lipofuscin in photoreceptor outer segments. Currently, there is neither a clinical treatment nor any ongoing trial for BVMD.SUMMARY OF THE INVENTION

[0006] A rational therapeutic strategy is to overcome Bestl LOF by Bestl -specific small molecule activators, thereby compensating for the mutation-induced deficits. In recent studies, we have identified two small molecules, para-aminobenzoic acid (PABA) and gamma-aminobutyric Acid (GABA), as potent interacting activators of Bestl. To optimize the potency of Bestl activators, we synthesized PABA and GABA analogs as well as various other structures based on the PABA- and GABA-bound Bestl structures. Several of these newly synthesized compounds showed significantly elevated activities compared to the parent molecules, representing promising lead compounds for the development of BVMD-specific drugs.

[0007] In certain aspects, compound of Formula I:Ior a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein:Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, C1-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-Cealkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci-C6alkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-C6haloalkyl, -O-Ci-C6-alkylaryl, -OCi-C6alkylheteroaryl, -O-Ci-C6alkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkenylCOORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 R8is H, -N(R1)2, Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-C6alkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR', -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -C1-C6alkyl-SO2N(R1)2, -C1-C6alkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -C1-C6alkyl-OSO2(OR1), -(C=NH)R1, or -C1-C6alkyl-NR3CON(R2)2; wherein if n is 0, R8is C1-C6alkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-C6alkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -C1-C6alkyl-SO2N(R1)2, -C1-C6alkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -C1-C6alkyl-OSO2(OR1), -(C=NH)R1, or -C1-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, -C(=O)Ci-C6alkyl, CORx, Ci-Cealkylheteroaryl, Ci-Cealkylaryl, C3-C9heterospirocycloalkyl or C3-C7cycloalkyl;each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-CealkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 C6haloalkyl, C1-C6alkylOH, C1-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or C1-C6haloalkyl; wherein if Y1is -SO2N(R1)2or -N(R2)SO2R1, n is 2, and R5is halogen, -O-Ci-C2alkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkenyl COORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-Cealkyl-SO3Ra, Ci-Cealkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-Cealkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl; andwherein if Y2is O, R8is Ci-CealkylN(R1)2, Ci-Cealkyl, Ci-Cealkynyl, Ci -Cehaloalkyl, Ci-Cealkyl-ORa, Ci-Cealkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, heteroaryl, Ci-Cealkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -C1-C6alkyl-NR3COR1, -Ci-Cealkyl-N(R2)SO2R1, Ci-Cealkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -C1-C6alkyl-SO2N(R1)2, -C1-C6alkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -C1-C6alkyl-OSO2(OR1), -(C=NH)R1, or -C1-C6alkyl-NR3CON(R2)2.

[0008] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R5is independently H, halogen, -O-Ci-C2alkyl, -O-Ci-CealkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-CealkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is S, -NR7-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-SRa, Ci-Cealkyl-COOR1, -(C=NH)R1, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkyl-aryl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, or heteroaryl; wherein if n is 0, R8is Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkyl-ORX, Ci-C6alkyl-N(RX)2, CORx, or C3-C7cycloalkyl;each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl

[0009] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, or -CON(R2)2.

[0010] In some embodiments, each occurrence of R1is independently H, Ci-Cealkyl, Ci- Cehaloalkyl, Ci-CealkylORa, or C3-C7cycloalkyl.

[0011] In some embodiments, each occurrence of R1is independently H or Ci-Cealkyl.

[0012] In some embodiments, each occurrence of R1is independently H or CH3.

[0013] In some embodiments, each occurrence of R2is independently H, Ci-Cealkyl, Ci- Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, or Ci-C6alkyl-CON(Rb)2.

[0014] In some embodiments, each occurrence of R2is independently H, Ci-Cealkyl, Ci-C6alkyl-COORa, or Ci-C6alkyl-CON(Rb)2.

[0015] In some embodiments, each occurrence of R2is independently H, Ci-Cealkyl, Ci-C6alkyl-COORa, or Ci-C6alkyl-CON(Rb)2.

[0016] In some embodiments, each occurrence of R3is independently H, Ci-Cealkyl, C3-C7cycloalkyl.O O O

[0017] In some embodiments, Y1has the structure ofHOju \0JU0Ju UO O JU

[0018] In some embodiments, Y1has the structure ofHO0

[0019] In some embodiments, L1is absent.

[0020] In some embodiments, L1is -(CR4)2-.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0021] In some embodiments, each occurrence of R4is independently H, halogen, -ORa, or Ci-Cealkyl.

[0022] In some embodiments, each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci-C6alkylN(Rb)2, -O-Ci-C6alkylORa, -O-Ci-C6alkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-C6alkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-C6haloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -COORa, or -CON(Rb)2.

[0023] In some embodiments, each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci-C6alkylN(Rb)2, -O-Ci-C6alkylORa, -O-Ci-C6alkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-C6alkylCOORa, -N(Rb)2, or Ci-C6alkylORa

[0024] In some embodiments, each occurrence of R5is independently H, -OCH2CH2F, -OCH2CHF2, -CH2OCH3, -OCH2CF3, -OCH2CH2CH2CF3, -OCH2CH3, -OCH2CH(CH3)2, -OCH2NH2, -O(CH2)6OH, -OCH2CH2NH2, -O(CH2)6COOH, NH2,,or \

[0025] In some embodiments, n is 0 or 1.

[0026] In some embodiments, n is 1.

[0027] In some embodiments, m is 1 or 2.

[0028] In some embodiments, L2is absent.

[0029] In some embodiments, L2is -C(R6)2-.

[0030] In some embodiments, each occurrence of R6is independently H, halogen, -ORa, or Ci-Cealkyl.

[0031] In some embodiments, R6is H.

[0032] In some embodiments, Y2is -NR7-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-.

[0033] In some embodiments, Y2is -NR7-, -NR7CO-, or -NR7COO-.

[0034] In some embodiments, Y2is -NR7-.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0035] In some embodiments, Y2is -NR7CO-, or -NR7COO-.

[0036] In some embodiments, each occurrence of R7is independently H or Ci-Cealkyl.

[0037] In some embodiments, each occurrence of R7is independently H or CH3.

[0038] In some embodiments, R8is H, Ci-Cealkyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci- Cealkyl-SRa, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, Ci-Cealkyl-aryl, aryl, heteroaryl, C3-C7cycloalkyl, C1-C6COOR1, (C=NH)R1, Ci-CealkylORa, or Ci-C6alkylN(Rb)2.

[0039] In some embodiments, R8is H, Ci-Cealkyl, Ci-Cealkynyl Ci-Cefluoroalkyl, Ci-Cealkyl-SRa, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, Ci-Cealkyl-aryl, aryl, heteroaryl, C3-C7cycloalkyl, C1-C6COOR1, (C=NH)R1, Ci-CealkylOH, C1-C6alkylOCH3, Ci-C6alkyl-O-Ci-C6alkylORx, Ci-C6alkylNHCH3, or Ci-C6alkylNH2.

[0040] In some embodiments, R8is H, CH3, C(CH3)3, CH2CCH, CH2CH(CH3)2, CH2CH2F, CH2CF3, CH2CH2OH, CH2CH2NH2, CH2CH2SCH3, CH2CH2NHCH3, CH2CH2CH2OCH3, CH2CH2CH2COOH, (C=NH)CH3, cyclohexyl, pyridyl, naphthyl,O r^NH 1^^^

[0041] In some embodiments, Y2-R8has the structure of *,

[0042] In some embodiments, each occurrence of Rais independently H, Ci-Cealkyl, -Ci-CealkylORx, or Ci-Cehaloalkyl.

[0043] In some embodiments, each occurrence of Rais independently H, CH3, -CH2CH2OCH3, or CH2CHF2.

[0044] In some embodiments, each occurrence of Rbis independently H, CORx, or Ci-Cealkyl.

[0045] In some embodiments, each occurrence of Rbis H, C(=O)CH3, or CH3.

[0046] In some embodiments, each occurrence of Rcis H or Ci-Cealkyl.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0047] In some embodiments, each occurrence of Rxis independently H, C1-C6alkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, -OC1-C6alkyl, or C1-C6haloalkyl.

[0048] In some embodiments, Y1is -COOR1or -CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, aryl, or heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, aryl, or heteroaryl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci-C6alkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-C6haloalkyl, -O-Ci-C6-alkylaryl, -OCi-C6alkylheteroaryl, -O-Ci-C6alkylCOORa, -N(Rb)2, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -COORa, -CON(Rb)2, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; Y2is -NR7-, -NR7CO-, or -NR7COO-;each occurrence of R7is independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;R8is H, Ci-Cealkyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-SRa, Ci-Cealkyl-COOR1, -(C=NH)R1, C3-C7cycloalkyl, heterocyclyl, Ci-C6alkyl-aryl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, or heteroaryl; wherein if n is 0, R8is Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkyl-ORX, Ci-Cealkyl-N(RX)2, CORx, or C3-C7cycloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl.

[0049] In some embodiments, Y1is -COOH;L1is absent;each occurrence of R5is independently -O-Ci-C6alkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, or -N(Rb)2;n is 1, 2, or 3;L2is absent or -CH2-;Y2is -NH-;R8is H, Ci-Cealkyl, or Ci-Cehaloalkyl; andeach occurrence of Rbis independently H, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0050] In certain aspects, a compound of Formula II:Rio DR9 / N^C(R11)^Y3IIor a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein:R9is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, or C3- C7cycloalkyl;R10is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, or Ci-Cealkyl-spirocycloalkyl, or alternatively R9and R10, and the nitrogen atom R9and R10are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cehaloalkyl;p is 2, 3, or 4;Y3is OR12or N(R13)2;R12is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-CealkylN(Re)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-C6alkyl-COORd, Ci-Cealkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, or heteroaryl; or alternatively both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry;each occurrence of Rdis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Reis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-Cealkyl-COORd, Ci-Cealkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, and / or heteroaryl in R9, R10, R11, R12, R13, Rd, and Rewhere applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -OCi-Cehaloalkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Ryis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, or Ci-Cehaloalkyl; andwherein if R10is H, each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, Ci-Cealkyl, Ci-Cealkenyl; and at least one Reis Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl.

[0051] In some embodiments, R9is H, Ci-Cealkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl.

[0052] In some embodiments, R9is H, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0053] In some embodiments, R9is H,CH2CH(CH3)NH2, or CH2CH2F.

[0054] In some embodiments, R10is H, Ci-Cealkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl.

[0055] In some embodiments, R10is H, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl.

[0056] In some embodiments, R10is H,CH2CH(CH3)NH2, or CH2CH2F.

[0057] In some embodiments, R9is H and R10is CH2CH2F, R9is CH2CH2F and R10is H, or R9is CH2CH2F and R10is CH2CH2F.

[0058] In some embodiments, R11is independently H, halogen, -ORd, -N(Re)2, or Ci-Cealkyl.

[0059] In some embodiments, R11is independently H, -ORd, or -N(Re)2.

[0060] In some embodiments, R11is independently H, -OH, or -NH2.

[0061] In some embodiments, p is 3.

[0062] In some embodiments, Y3is OR12.

[0063] In some embodiments, Y3is OH.

[0064] In some embodiments, R12is H, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0065] In some embodiments, Y3is N(R13)2.

[0066] In some embodiments, each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkyl-COORd, Ci-C6alkyl-CON(Re)2, or Ci-C6alkylaryl.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0067] In some embodiments, each occurrence of R13is independently H, Ci-Cealkyl, Ci- C6alkyl-COORd, or Ci-C6alkylaryl.

[0068] In some embodiments, each occurrence of R13is independently H, CH2CH(CH3)2, CH2CH2COOH, CH2CH2CH2COOH, benzyl, or 4-trifluoromethlybenzyl.

[0069] In some embodiments, both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry.

[0070] In some embodiments, both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O or NRe.

[0072] In some embodiments, each occurrence of Rdis independently H or Ci-Cealkyl.

[0073] In some embodiments, each occurrence of Reis independently H or Ci-Cealkyl.

[0074] In some embodiments, each occurrence of Ryis independently H, halogen, OH, or Ci-Cehaloalkyl.

[0075] In certain aspects, a compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein the compound is selected from the group consistingAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0076] In some embodiments, the compound is selected from the group consisting ofO

[0078] In certain aspects, a compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein the compound is selected from the group consistingAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0079] In some embodiments, the compound is selected from the group consisting ofF

[0080] In certain aspects, a compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein the compound is selected from the group consisting of.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0082] In certain aspects, a compound of Formula IV:Formula IVor a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein:Zi to Z4 are each independently CH, C-L1-Y1, C-L2-Y2, CR5, or N; and Z5 is S, NH, N-L1-Y1, N-L2-Y2, NR5, or O;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 C6alkyl-OSO2Ra, C1-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, -S(O)mRc, C1-C6alkyl, C1-C6alkenyl, C1-C6alkenyl COORa, C1-C6alkyl-SRa, C1-C6alkyl-SO2Ra, C1-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7COO-, or -NR7CONR7-; each occurrence of R7is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2,, Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-aryl, -Ci-Cealkyl-heteroaryl, -Ci-Cealkyl-cycloalkyl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -1Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-Cealkyl-NR3CON(R2)2; or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0083] In some embodiments, Z1is CH, C-L1-Y1, C-L2-Y2, or CR5.

[0084] In some embodiments, Z1is CH, N, or CR5.

[0085] In some embodiments, Z1is C-L1-Y1.

[0086] In some embodiments, Z1is C-L2-Y2.

[0087] In some embodiments, Z2is CH, C-L1-Y1, C-L2-Y2, or CR5.

[0088] In some embodiments, Z2is CH, N, or CR5.

[0089] In some embodiments, Z2is C-L1-Y1.

[0090] In some embodiments, Z2is C-L2-Y2.

[0091] In some embodiments, Z3is CH, C-L1-Y1, C-L2-Y2, or CR5.

[0092] In some embodiments, Z3is CH or CR5.

[0093] In some embodiments, Z3is C-L1-Y1.

[0094] In some embodiments, Z3is C-L2-Y2.

[0095] In some embodiments, Z4is CH, C-L1-Y1, C-L2-Y2, or CR5.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0096] In some embodiments, Z4 is CH or CR5.

[0097] In some embodiments, Z4is C-L1-Y1.

[0098] In some embodiments, Z4 is C-L2-Y2.

[0099] In some embodiments, Z5 is S, NH, or O.

[0100] In some embodiments, Z5 is S.

[0101] In some embodiments, L1is absent.

[0102] In some embodiments, L1is -C(R4)2-.

[0103] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, - N(R2)SO2R1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, or -OSO2(OR1).

[0104] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, or -NR3COR1.

[0105] In some embodiments, Y1is -N(R2)SO2R1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, or -OSO2(OR1).

[0106] In some embodiments, Y1is -N(R2)SO2R1or -SO2N(R1)2.

[0107] In some embodiments, Y1is SO2NH2.

[0108] In some embodiments, R5is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci- CealkylORa, Ci-C6alkylN(Rb)2, Ci-Ce haloalkoxy, heterocyclyl, aryl, or heteroaryl.

[0109] In some embodiments, n is 0 or 1.

[0110] In some embodiments, L2is absent.

[0111] In some embodiments, L2is -C(R6)2-.

[0112] In some embodiments, Y2is O, S, or -NR7-.

[0113] In some embodiments, R7is H or Ci-Cealkyl.

[0114] In some embodiments, R8is H, Ci-Cealkyl, Ci-Cehaloalkyl, -Ci-Cealkyl-aryl, -Ci-Cealkyl-heteroaryl, or -Ci-Cealkyl-cycloalkyl.

[0115] In some embodiments, R8isNTF

[0116] In certain aspects, a compound of Formula VII:Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Formula VIIor a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein:ZZ1is -CH2-, -CHR1-, -C(R1)R2-, -NH-, -N(R1)-, O, or S;Z2is -N(R1)-;Z3is -CH2-, -CHR1-, -C(R1)R2-, -NH-, -N(R1)-, O, or S;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, C1-C6alkyl-SO2N(Ra)2, C1-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, C3-C8cycloalkenyl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, C1-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is absent, O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-; each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , Ci-C6alkylN(R1)2, Ci-C6alkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0117] In some embodiments, Zi is -CH2-, -CHR1-, or -C(R1)R2-.

[0118] In some embodiments, Zi is -CH2-.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0119] In some embodiments, Z3 is -CH2-, -CHR1-, or -C(R1)R2-.

[0120] In some embodiments, Z3 is -CH2-.

[0121] In some embodiments, R1is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci- C6alkylN(Rb)2, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-aryl, Ci-C6alkyl-heteroaryl, C3-Cscycloalkenyl, heterocyclyl, aryl, or heteroaryl.

[0123] In some embodiments, R2is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2.

[0124] In some embodiments, R2is H.

[0125] In some embodiments, L1is absent.

[0126] In some embodiments, L1is -C(R4)2-.

[0127] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, or -NR3CON(R2)2.

[0128] In some embodiments, Y1is -COOR1.

[0129] In some embodiments, Y1is -COOH.

[0130] In some embodiments, L2is absent.

[0131] In some embodiments, Y2is O, S, or -NR7-.

[0132] In some embodiments, Y2is -NR7-.

[0133] In some embodiments, R7is H, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0134] In some embodiments, R7is H.

[0135] In some embodiments, R8is H, -N(R1)2,, Ci-CealkylN(R1)2, Ci-Cealkyl, Ci- Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0136] In some embodiments, R8is H.

[0137] In certain aspects, a compound of Formula VIII:n(R5)Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Formula VIII;or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein: f A )is C3-C8carbocyclyl;Y1is -COOR1or -CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, aryl, heteroaryl, Ci-Cealkyl-aryl, or Ci-Cealkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, C3-C7cycloalkyl, aryl, heteroaryl, C1-C6alkyl-aryl, or C1-C6alkyl-heteroarylL1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, Ci-Cealkyl, or Ci-Cehaloalkyl;n is 0, 1, 2, 3, or 4;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; Y2is O, S, -NR7-, or -NR7CO-;each occurrence of R7is independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;R8is H, Ci-Cealkyl, Ci-Cehaloalkyl, aryl, heteroaryl, Ci-Cealkylaryl, Ci-Cealkylheteroaryl, or -Ci-Cealkyl-CON(R2)2;each occurrence of Rais independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;the Ci-Cealkyl, Ci-Cehaloalkyl, C3-C7cycloalkyl, C1-C6alkyl-CON(Rb)2, aryl, and / or heteroaryl in R1, R2, R4, R5, R6, R7, R8, Ra, and Rb, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, and Ci-Cehaloalkyl.I A J

[0138] In some embodiments, is cyclohexyl.

[0139] In some embodiments, Li is -CH2-.

[0140] In some embodiments, Yi is -CON(R2)2.

[0141] In some embodiments, R2is Ci-Cealkylheteroaryl.OH

[0142] In some embodiments, L1-Y1 has the structureofN'OAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0143] In some embodiments, L2 is absent.

[0144] In some embodiments, Y2 is -NR7-.

[0145] In some embodiments, R7is H or Ci-Cealkyl.

[0146] In some embodiments, Rs is Ci-Cealkylheteroaryl.;-NH

[0147] In some embodiments, Y2-R8 has the structureofNH \=N F

[0148] In some embodiments, the compoundis /

[0149] In certain aspects, a pharmaceutical composition is described comprising at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0150] In some embodiments, a method of treating or preventing a disease or condition in a subject in need thereof is described, comprising administering to the subject a pharmaceutical composition according to any one of the embodiments described herein.

[0151] In some embodiments, the subject is a human.

[0152] In some embodiments, the disease or condition is caused by a dysregulation of one or more bestrophins.

[0153] In some embodiments, the disease or condition is a Bestrophin (Best)-related disease.

[0154] In some embodiments, the Bestrophin-related disease is caused by one or more mutations on a gene selected from BEST1, BEST2, BEST3, and BEST4.

[0155] In some embodiments, the Bestrophin-related disease is a bestrophinopathy.

[0156] In some embodiments, the bestrophinopathy is Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract, posterior staphyloma syndrome (MRCS syndrome), age-related macular degeneration (AMD), retinitis pigmentosa (RP), or combinations thereof.

[0157] In some embodiments, the bestrophinopathy is Best vitelliform macular dystrophy (BVMD).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0158] In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, an oral route of delivery, or a parenteral route of delivery.

[0159] In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, wherein the pharmaceutical composition is administered topically.

[0160] In some embodiments, the pharmaceutical composition is administered via eye drops.

[0161] In certain aspects, a method of maintaining intraocular pressure (IOP) in a subject in need thereof is described, the method comprising administering a pharmaceutical composition according to any one of the embodiments described herein, wherein the pharmaceutical composition increases Best2-mediated Ca2+-dependent Cl’ currents in nonpigmented epithelium (NPE) cells.

[0162] In some embodiments, the subject is a human.

[0163] In some embodiments, the disease is caused by a dysregulation of one or more bestrophins.

[0164] In some embodiments, the subject suffers from a Bestrophin-related disease.

[0165] In some embodiments, the Bestrophin-related disease is associated with increased or decreased intraocular pressure (IOP) in the subject.

[0166] In some embodiments, the subject suffers from ocular hypertension or ocular hypotension.

[0167] In some embodiments, the Bestrophin-related disease is glaucoma, myopia, pigment dispersion syndrome, pseudoexfoliation syndrome, age-related macular degeneration, or combinations thereof.

[0168] In certain aspects, a compound or a pharmaceutically acceptable enantiomer, salt, or solvated thereof is described, wherein the compound is selected from the group consisting of:Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 OHAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026oAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026vMt Mt o o9Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 20260V-.•<. to 8 hH **0 0 $ 0 & 0 ’’t’:j:000 S hO &0s0 OKAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026' 0 OC?Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026HQ ” -s<FCl " N';'"V" Q Cr" -Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026□ OAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026MH0 HMMM,6Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0169] In certain aspects, a pharmaceutical composition is described, comprising at least one compound according to any one of the embodiments described herein or aAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0170] In certain aspects, a method of treating or preventing a disease or condition in a subject in need thereof is described, comprising administering to the subject a pharmaceutical composition according to any one of the embodiments described herein.

[0171] In certain aspects, a method of treating or preventing a disease or condition in a subject in need thereof is described, comprising administering to the subject a compound of Formula VIII:n(R5)Formula VIII;or a pharmaceutically acceptable enantiomer, salt, or solvate thereof wherein:Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R2)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryleach occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -O-Ci-Cealkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-CealkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkenylCOORa, -O-Ci-C6alkylCOORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl; n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-C6alkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR', -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -Ci-C6alkyl-SO2R1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -Ci-C6alkyl-OSO(OR1), -Ci-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), -(C=NH)R1, or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, -C(=O)Ci-C6alkyl, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C?cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, or Ci-Cehaloalkyl; andwherein the disease or condition is a Bestrophin (Best)-related disease.

[0172] In some embodiments, each occurrence of R5is independently H, halogen, -ORa, -O-Ci-C6alkyl, -O-Ci-C6haloalkyl, -O-Ci-C6-alkylaryl, -O-Ci-C6alkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkenylCOORa, -O-Ci-C6alkylCOORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl.

[0173] In certain aspects, a pharmaceutical composition is described including at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0174] In certain aspects, a method of treating or preventing a disease or condition in a subject in need thereof is described, including administering to the subject a pharmaceutical composition according to any one of the embodiments described herein.

[0175] In some embodiments, the subject is a human.

[0176] In some embodiments, the disease or condition is caused by a dysregulation of one or more bestrophins.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0177] In some embodiments, the disease or condition is a Bestrophin (Best)-related disease.

[0178] In some embodiments, the Bestrophin-related disease is caused by one or more mutations on a gene selected from BEST1, BEST2, BEST3, and BEST4.

[0179] In some embodiments, the Bestrophin-related disease is a bestrophinopathy.

[0180] In some embodiments, the bestrophinopathy is Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract, posterior staphyloma syndrome (MRCS syndrome), age-related macular degeneration (AMD), retinitis pigmentosa (RP), or combinations thereof.

[0181] In some embodiments, the bestrophinopathy is Best vitelliform macular dystrophy (BVMD).

[0182] In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, an oral route of delivery, or a parenteral route of delivery.

[0183] In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, wherein the pharmaceutical composition is administered topically.

[0184] In some embodiments, the pharmaceutical composition is administered via eye drops.

[0185] In certain aspects, method of maintaining intraocular pressure (IOP) in a subject in need thereof is described, the method including administering the pharmaceutical composition of any one of the embodiments described herein, wherein the pharmaceutical composition increases Best2-mediated Ca2+-dependent Cl’ currents in non-pigmented epithelium (NPE) cells.

[0186] In some embodiments, the subject is a human.

[0187] In some embodiments, the disease is caused by a dysregulation of one or more bestrophins.

[0188] In some embodiments, the subject suffers from a Bestrophin-related disease.

[0189] In some embodiments, the Bestrophin-related disease is associated with increased or decreased intraocular pressure (IOP) in the subject.

[0190] In some embodiments, the subject suffers from ocular hypertension or ocular hypotension.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0191] In some embodiments, the Bestrophin-related disease is glaucoma, myopia, pigment dispersion syndrome, pseudoexfoliation syndrome, age-related macular degeneration, or combinations thereof.BRIEF DESCRIPTION OF FIGURES

[0192] The patent or application file contains at least one drawing originally in color.

[0193] FIG. 1 shows a bar chart showing the steady-state current densities at +100 mV from HEK293 cells transiently expressing Bestl treated with 100 pM of the indicated small compounds at 1 pM [Ca2+]i, when CF is the only anion in both internal and external solutions; n = 5-9; *p < 0.05 compared to currents from untreated cells by two-tailed unpaired Student’s t test. All error bars in this figure represent s.e.m.

[0194] FIGS. 2A-2OOOO show NMR Spectrums for certain compounds described herein.

[0195] FIGS. 3A-3C show bar charts showing the steady-state current densities at +100 mV from HEK293 cells transiently expressing Bestl treated with 100 pM of the indicated small compounds (BA54-119) at 1 pM [Ca2+]i, when CF is the only anion in both internal and external solutions; n = 5-9; p < 0.05 for all tested BA compounds, except for BA-91, when compared to currents from untreated cells by two-tailed unpaired Student’s t test. All error bars in this figure represent s.e.m.DETAILED DESCRIPTION OF THE INVENTION

[0196] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments.

[0197] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms. The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0198] Reference throughout this specification to “one embodiment” or “an embodiment,” etc. means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various placesAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 throughout this specification are not necessarily all referring to the same embodiment.Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0199] “Alkyl” and “alk” refer to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, / / -butyl, / -butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term “Ci-Cxalkyl,” “(Ci-Cx)alkyl,” or “Ci-Xalkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to x carbon atoms. For example, the term “Ci-C4alkyl,” “(Ci-Cxalkyl,” or “Ci-4alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, / -butyl, / -butyl, and isobutyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0200] “Halogen” or “halo” refer to chlorine, bromine, fluorine, or iodine.

[0201] “Cycloalkyl” refers to a fully saturated cyclic hydrocarbon radical group containing from 1 to 4 rings and 3 to 8 carbon atoms per ring. For example, “C3-C7 cycloalkyl” or “C3-7cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Unless stated otherwise specifically in the specification, a cycloalkyl can be optionally substituted.

[0202] “Cycloalkenyl” refers to a partially saturated cyclic hydrocarbon radical group containing from 1 to 4 rings and 3 to 8 carbon atoms per ring wherein there is one or more double bonds between two or more carbon atoms within the ring or rings. For example, “C3-Cs cycloalkenyl” or “Cs-scycloalkenyl” refers to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclooctatetraenyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkenyl can be optionally substituted.

[0203] “Spirocycloalkyl” or “bicycloalkyl” refers to a compound containing at least one cycloalkyl ring that shares one or more ring atoms with at least one other cycloalkyl ring. Exemplary bicycloalkyl groups include adamantyl, bicyclo[l.l.l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-lH-indenyl, bicyclo[4.2.1]nonanyl, and the like. Exemplary spirocycloalkyl groups include spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, spiro[4.5]decyl, and the like. “Heterospirocycloalkyl” refers to a spirocycloalkyl compound where at least one of the rings is a heterocyclyl ring. Unless stated otherwise specifically in the specification, a spirocycloalkyl, bicycloalkyl, or heterospirocycloalkyl can be optionally substituted

[0204] “Heterocyclyl,” “heterocyclic ring,” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclyl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0205] “Carbocycle” or “carbon cycle” refers to a fully saturated or partially saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring, or cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. The term “carbocycle” encompasses cycloalkyl and aryl as defined herein above. Unless stated otherwise specifically in the specification, a carbocycle or carbon cycle can be optionally substituted.

[0206] “Aryl” refers to a hydrocarbon ring system radical comprising hydrogen, 5 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals that are optionally substituted.

[0207] “Heteroaryl” refers to a 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in this disclosure, a heteroaryl group can be optionally substituted.

[0208] “Alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. The term “C2-Cxalkenyl” or “C2-xalkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon double bond. For example, the term “C2-C6alkenyl” or “C2-6alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-l-enyl, (Z)-hex-l-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 enyl, (Z)-hex-l-enyl, (E)-hex-l-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-l,3-dienyl. Unless stated otherwise specifically in the specification, an alkenyl can be optionally substituted.

[0209] “ Alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary such groups include ethynyl or 2-propynyl. The term “C2-Cxalkynyl” or “C2-xalkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to x carbon atoms and at least one carbon-carbon triple bond. For example, the term “C2-C6alkynyl” or “C2-6alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, 2-propynyl, but-2-ynyl, 2-methyl-but-3-ynyl, 2-pentynyl, 3 -pentynyl, 2-hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl can be optionally substituted.

[0210] The term “substituted” used herein means any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with NRgC(=O)ORh, NRgSO2Rh, OC(=O)NRgRh, ORg, SRg, SORg, SO2Rg, OSO2Rg, SO2ORg, =NSO2Rg, and SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with C(=O)Rg, C(=O)ORg, C(=O)NRgRh, CH2SO2Rg, CH2SO2NRgRh. In the foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0211] “Optional” or “optionally” means that the subsequently described event of circumstances can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical can or cannot be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0212] The compounds of the invention, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0213] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposableAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 mirror images of one another.

[0214] A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds.

[0215] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug” as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and / or solvate thereof.Solvates of the compounds of the present invention include, for example, hydrates.

[0216] “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0217] “Pharmaceutically acceptable salt” includes both acid and base addition salts.

[0218] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthal ene- 1,5-disulfonic acid, naphthal ene-2-sulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0219] “Pharmaceutically acceptable base addition salt” refers to those salts which retainAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0220] As used herein, a “subject” can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, insect and the like. The subject can be suspected of having or at risk for AD, tauopathy, dementia or another disease or condition. Diagnostic methods for these conditions are known to those of ordinary skill in the art.

[0221] A “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.

[0222] An “effective amount” refers to a therapeutically effective amount or a prophylactically effective amount. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a compound can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages andAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 for periods of time necessary, to achieve the desired prophylactic result, increased life span, increased life expectancy or prevention of the progression of the disease or condition.Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount can be less than a therapeutically effective amount.

[0223] “Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes (but is not limited to):a) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it;b) inhibiting the disease or condition, e.g., arresting its development;c) relieving the disease or condition, e.g., causing regression of the disease or condition (ranging from reducing the severity of the disease or condition to curing the disease of condition); ord) relieving the symptoms resulting from the disease or condition, e.g., relieving pain without addressing the underlying disease or condition. As used herein, the terms “disease” and “condition” can be used interchangeably or can be different in that the particular malady or condition cannot have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.

[0224] Throughout the present specification, the terms “about” and / or “approximately” can be used in conjunction with numerical values and / or ranges. The term “about” is understood to mean those values near to a recited value. For example, “about 40 [units]” can mean within ± 25% of 40 (e.g., from 30 to 50), within ± 20%, ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, less than ± 1%, or any other value or range of values herein. Furthermore, the phrases “less than about [a value]” or “greater than about [a value]” should be understood in view of the definition of the term “about” provided herein. The terms “about” and “approximately” can be used interchangeably.

[0225] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range can be an endpoint for theAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

[0226] Following below are more detailed descriptions of various concepts related to, and embodiments of inventive compounds and methods for the treatment of disease, including bestrophin-related disease. It should be appreciated that various concepts introduced above and discussed in greater detail below may be implemented in any of numerous ways, as the disclosed concepts are not limited to any particular manner of implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes. Bestrophins and Bestrophin-related Diseases

[0227] The bestrophins are a family of Ca2+-activated anion channels consisting of four members in mammals. They are widely distributed in various human organs including the airways, colon, kidney, pancreas and central nervous system, but best known for their physiological roles in the eye. In particular, Bestl is predominantly expressed in retinal pigment epithelium (RPE) and genetically linked to a spectrum of retinal degenerative disorders collectively known as bestrophinopathies. Over 350 different mutations in Bestl have been identified to cause bestrophinopathies. The patients are susceptible to progressive vision loss that may eventually lead to blindness, and there is no treatment. On the other hand, Best2 resides in non-pigmented epithelium (NPE) regulating intra-ocular pressure (IOP), which must be properly maintained at all times as both hypertension and hypotension are deleterious conditions. Therefore, bestrophins are potential drug targets for various human diseases, especially of the eye.

[0228] According to one aspect, the present disclosure is directed to a method for treating, ameliorating, or preventing the effects of a disease in a subject in need thereof. This method comprises administering an effective amount of a Best activator to the subject. In some embodiments, the disease is a Bestrophin (Best)-related disease.

[0229] In some embodiments, the Bestrophin-related disease is caused by one or more mutations on a gene selected from BEST1, BEST2, BEST3, and BEST4. In some embodiments, the Bestrophin-related disease is caused by one or more loss-of-function mutations on BEST1. In some embodiments, the Bestrophin-related disease is caused by one or more loss-of-function mutations on BEST2.

[0230] In some embodiments, the Bestrophin-related disease is a bestrophinopathy. As used herein, “bestrophinopathies” refer to are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central highAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 acuity vision. This spectrum of disorders is believed to be caused by mutations in BEST1, which acts as a Ca2+-activated Cl’ channel in the retinal pigment epithelium (RPE) of the eye. Non-limiting examples of a bestrophinopathy include best vitelliform macular dystrophy (BVMD), autosomal recessive bestrophinopathy (ARB), adult-onset vitelliform dystrophy (AVMD), autosomal dominant vitreoretinoehoroidopathy (ADVIRC), autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract, posterior staphyloma syndrome (MRCS syndrome), retinitis pigmentosa (RP), age-related macular degeneration (AMD), any eye disease with subretinal fluid accumulation such as chorioretinopathy and wet AMD, or combinations thereof.

[0231] In some embodiments, the Bestrophin-related disease is associated with increased or decreased intraocular pressure (IOP) in the subject. As used herein, “intraocular pressure” or “IOP” refers to the fluid pressure inside the eye. It is maintained by the constant production and outflow of fluids, such as the aqueous humor, a watery liquid that fills the front part of the eye. In a healthy eye, a small amount of new aqueous humor enters the eye while an equal amount drains out. However, if the fluid abnormally accumulates or disperses, IOP can build up or decrease, resulting in ocular hypertension or hypotension, respectively. For example, in some embodiments of the present disclosure, the subject has ocular hypertension.

[0232] A normal range for IOP is between 10 and 21 millimeters of mercury (mmHg). Elevated IOP is a symptom and risk factor for various eye diseases such as glaucoma, and untreated high eye pressure can harm vision, or lead to vision loss. In some embodiments of the present disclosure, the IOP in the subject is above 21 mmHg.

[0233] Accordingly, in some embodiments of the present disclosure, the Bestrophin-related disease is glaucoma, myopia, pigment dispersion syndrome, pseudoexfoliation syndrome, age-related macular degeneration, or combinations thereof. In some embodiments the Bestrophin-related disease is glaucoma.

[0234] In some embodiments, the disease is not a Bestrophin-related disease. One nonlimiting example of such a disease is Alzheimer’s disease. Thus, in some embodiments, the disease is Alzheimer’s disease.

[0235] In some embodiments, the Best activator is a small molecule.

[0236] In some embodiments, the Best activator is an activator for Bestl.

[0237] In some embodiments, the Best activator is an activator for Best2.

[0238] As used herein, “Loss-of-function mutations” refers to mutations in the bestrophinAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 gene that result in reduced anion currents mediated by the mutant bestrophin protein and reduced channel activity compared to a wild-type protein. Exemplary BEST1 loss-of-function mutations include, but are not limited to, A10T, R218H, L234P, A243T, Q293K, and D302A.

[0239] In some embodiments, the Best activator is administered in a composition that comprises a pharmaceutically acceptable carrier and excipient. The small molecule activators of the present invention can be administered in combination with other pharmaceutical agents in a variety of protocols and at effective doses for treating, ameliorating, or preventing disease.

[0240] Pharmaceutical compositions are administered to a subject in a manner known in the art. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.Compounds

[0241] In certain aspects, described herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026fi.Q

[0242] In certain aspects, described herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:Io YV-J.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0243] In certain aspects, described herein is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0244] In certain aspects, described herein is a pharmaceutical composition comprising any one of the compounds described herein.

[0245] In certain aspects, described herein is a method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject any of the pharmaceutical compositions described herein.

[0246] In some embodiments, the disease or condition is caused by a dysregulation of one or more bestrophins.

[0247] In some embodiments, the disease or condition is a bestrophinopathy, wherein the bestrophinopathy is Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract, posterior staphyloma syndrome (MRCS syndrome), age-related macular degeneration (AMD), retinitis pigmentosa (RP), or combinations thereof.

[0248] In certain aspects, described herein is a compound of Formula I:Ior a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described; wherein:Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO2R1, -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryleach occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -O-Ci-Cealkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-C6alkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkenylCOORa, -O-Ci-C6alkylCOORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -0C(=0)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-C6alkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR', -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -Ci-C6alkyl-SO2R1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -Ci-C6alkyl-OSO(OR1), -Ci-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), -(C=NH)R1, or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, -C(=O)Ci-C6alkyl, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C?cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0249] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -N(R2)SO2R1, NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-Cealkyl-ORa, Ci-Ce haloalkoxy, Ci-Ce alkanoyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), C1-C6alkyl-OSO2Ra, C1-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci-CealkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-CealkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, C1-C6alkenyl COORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-C6alkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR', -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -Ci-C6alkyl-SO2R1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -Ci-C6alkyl-OSO(OR1), -Ci-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), -(C=NH)R1, or -Ci-C6alkyl-NR3CON(R2)2;wherein if n is 0, R8is Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-C6alkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -Ci-C6alkyl-SO2R1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -Ci-C6alkyl-OSO(OR1), -Ci-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), -(C=NH)R1, or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, -C(=O)Ci-C6alkyl, CORx, or C3-C7cycloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, Ci-C6alkylheteroaryl, Ci-C6alkylaryl, C3-C9heterospirocycloalkyl or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl; andwherein if Y1is -SO2N(R1)2or -N(R2)SO2R1, n is 2, and R5is halogen, -O-Ci-C6alkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, C1-C6alkenyl COORa, Ci-Cealkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-Cealkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-Cealkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R2)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl; andwherein if Y2is O, R8is Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci-Cealkyl-ORa, Ci-Cealkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, heteroaryl, Ci-Cealkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-Cealkyl-CON(R2)2, -Ci-Cealkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-Cealkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -Ci-C6alkyl-SO2R1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -Ci-Cealkyl-OSO(OR1), -Ci-Cealkyl-OSOzR1, -Ci-Cealkyl-OSO(OR1), -(C=NH)R1, or -Ci-C6alkyl-NR3CON(R2)2.

[0250] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl; or alternatively any two occurrences ofAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci-CealkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-CealkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is S, -NR7-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-SRa, Ci-Cealkyl-COOR1, -(C=NH)R1, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkyl-aryl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, or heteroaryl; wherein if n is 0, R8is Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORX, Ci-C6alkyl-N(RX)2, CORx, or C3-C7cycloalkyl;each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-CealkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl.

[0251] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2. In some embodiments, Y1is -COR1, -COOR1, -OCOR1, or -CON(R2)2. In some embodiments, Y1is -COOR1or -CON(R2)2.

[0252] In some embodiments, each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl. In some embodiments, each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, or C3-C7cycloalkyl. In some embodiments, each occurrence of R1is independently H or Ci-Cealkyl. In some embodiments, each occurrence of R1is independently H or CH3.

[0253] In some embodiments, each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionallyAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 substituted by one or more Rx. In some embodiments, each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, or Ci-Cealkyl-CON(Rb)2. In some embodiments, each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkyl-COORa, or Ci-Cealkyl-CON(Rb)2. In some embodiments, each occurrence of R2is independently H, CH2CH2COOH, or CH2CH2CH2COOH.

[0254] In some embodiments, each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl. In some embodiments, each occurrence of R3is independently H, Ci-Cealkyl, C3-C7cycloalkyl.O O O JG \ X X /

[0255] In some embodiments, Y1has the structure ofHO0 0

[0256] In some embodiments, L1is absent or -(CR4)2-. In some embodiments, L1is absent. In some embodiments, L1is -(CR4)2-.

[0257] In some embodiments, each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cehaloalkyl. In some embodiments, each occurrence of R4is independently H, halogen, -ORa, or Ci-Cealkyl. In some embodiments, each occurrence of R4is independently H.

[0258] In some embodiments, each occurrence of R5is independently H, halogen, -ORa, -O-Ci-C6alkylN(Rb)2, -O-Ci-C6alkylORa, -O-Ci-C6alkylheterocyclyl, -O-Ci- Cealkylcycloalkyl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, C1-C6alkenyl COORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, -O-Ci-C6alkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-C6alkylCOORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 heterocyclyl, aryl, or heteroaryl. In some embodiments, each occurrence of R5is independently H, halogen, -ORa, -O-Ci-C2alkyl, -O-Ci-CealkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-C6alkylheteroaryl, -O-Ci-C6alkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -COORa, or -C0N(Rb)2. In some embodiments, each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, or Ci-CealkylORa. In some embodiments, each occurrence of R5is independently H, -OCH2CH2F, -OCH2CHF2, -CH2OCH3, -OCH2CF3, -OCH2CH2CH2CF3, -OCH2CH3, -OCH2CH(CH3)2, -OCH2NH2, NH2, -O(CH2)6OH, -OCH2CH2NH2, -O(CH2)6COOH,

[0259] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0260] In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1 or 2.

[0261] In some embodiments, L2is absent or -C(R6)2-. In some embodiments, L2is absent. In some embodiments, L2is -C(R6)2-.

[0262] In some embodiments, each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cehaloalkyl. In some embodiments, each occurrence of R6is independently H, halogen, -ORa, or Ci-Cealkyl. In some embodiments, each occurrence of R6is independently H.

[0263] In some embodiments, Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-. In some embodiments, Y2is -NR7-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-. In some embodiments, Y2is -NR7-, -NR7CO-, or -NR7COO-. In some embodiments, Y2is -NR7-. In some embodiments, Y2is -NR7CO-, or -NR7COO-.

[0264] In some embodiments, each occurrence of R7is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl. In some embodiments,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R7is independently H or Ci-Cealkyl. In some embodiments, each occurrence of R7is independently H or CH3.

[0265] In some embodiments, R8is H, -N(R' )2,, Ci-CealkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkynyl, Ci-C6haloalkyl, Ci-CeCOOR1, (C=NH)Ri, Ci-C6alkylORa, Ci-Cealkyl-SRa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR', -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-Cealkyl-NR3CON(R2)2. In some embodiments, R8is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, or Ci-CealkylN(Rb)2. In some embodiments, R8is H, Ci-Cealkyl, Ci-Cealkyl-F, Ci-Cealkyl-SRa, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, Ci-Cealkyl-aryl, aryl, heteroaryl, C3-C7cycloalkyl, C1-C6COOR1, (C=NH)R1, Ci-CealkylOH, Ci-CealkylOCHs, Ci-Cealkyl-O-Ci-CealkylOR*, Ci-CealkylNHCHs, or Ci-CealkylNBfc. In some embodiments, R8is H, CH3, C(CH3)3, CH2CCH, CH2CH(CH3)2, CH2CH2F, CH2CF3, CH2CH2OH, CH2CH2NH2, CH2CH2SCH3, CH2CH2NHCH3, CH2CH2CH2OCH3,CH2CH2CH2COOH, (C=NH)CH3, cyclohexyl, pyridyl, naphthyl,

[0266] In some embodiments, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx. In some embodiments, Y2-R8hasO

[0267] In some embodiments, each occurrence of Rais independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl. In some embodiments,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rais independently H, Ci-Cealkyl, -Ci-CealkylORx, or Ci-Cehaloalkyl. In some embodiments, each occurrence of Rais independently H, CEE, -CH2CH2OCH3, or CH2CHF2.

[0268] In some embodiments, each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, -C(=O)Ci-C6alkyl, CORx, Ci-Cealkylheteroaryl, Ci-Cealkylaryl, Cs-Cgheterospirocycloalkyl or C3-C7cycloalkyl. In some embodiments, each occurrence of Rbis independently H, CORx, or Ci-Cealkyl. In some embodiments, each occurrence of Rbis H C(=O)CH3, or CEE.

[0269] In some embodiments, each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl. In some embodiments, each occurrence of Rcis H or Ci-Cealkyl.

[0270] In some embodiments, the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl.

[0271] In some embodiments, each occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, C3-C?cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl. In some embodiments, each occurrence of Rxis independently H, Ci-Cealkyl, -OCi-Cealkyl, or Ci-Cehaloalkyl.

[0272] In some embodiments:Y1is -COOR1or -CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, aryl, or heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, aryl, or heteroaryl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; each occurrence of R5is independently H, halogen, -O-Ci-C2alkyl, -O-Ci- CealkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Ci-Cehaloalkyl, -O-Ci-C6-alkylaryl, -OCi-C6alkylheteroaryl, -O-Ci-C6alkylCOORa, -N(Rb)2, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -COORa, -CON(Rb)2, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; Y2is -NR7-, -NR7CO-, or -NR7COO-;each occurrence of R7is independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;R8is H, Ci-Cealkyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-SRa, Ci-Cealkyl-COOR1, -(C=NH)R1, C3-C7cycloalkyl, heterocyclyl, Ci-C6alkyl-aryl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, or heteroaryl; wherein if n is 0, R8is Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkyl-ORX, Ci-Cealkyl-N(RX)2, CORx, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl.

[0273] The compound of any one of claims 1-2 and 43, wherein:Y1is -COOH;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 L1is absent;each occurrence of R5is independently -O-Ci-C2alkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, or -N(Rb)2;n is 1, 2, or 3;L2is absent or -CH2-;Y2is -NH-;R8is H, Ci-Cealkyl, or Ci-Cehaloalkyl; andeach occurrence of Rbis independently H, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0274] In certain aspects, a compound of Formula II:IIor a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described herein; wherein:R9is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, or C3-Cvcycloalkyl;R10is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, or C3-Cvcycloalkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, or Ci-Cealkyl-spirocycloalkyl, or alternatively R9and R10, and the nitrogen atom R9and R10are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry;each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cehaloalkyl;p is 2, 3, or 4;Y3is OR12or N(R13)2;R12is H, Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-CealkylN(Re)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-C6alkyl-COORd, Ci-C6alkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, or heteroaryl; or alternatively both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rdis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Reis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-Cealkyl-COORd, Ci-Cealkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, and / or heteroaryl in R9, R10, R11, R12, R13, Rd, and Rewhere applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -OCi-Cehaloalkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Ryis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0275] R9is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, or C3-C7cycloalkyl;R10is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, or Ci-Cealkyl-spirocycloalkyl, or alternatively R9and R10, and the nitrogen atom R9and R10are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry;each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cehaloalkyl;p is 2, 3, or 4;Y3is OR12or N(R13)2;R12is H, Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-CealkylN(Re)2, C3-C?cycloalkyl, heterocyclyl, aryl, or heteroaryl;each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-C6alkyl-COORd, Ci-C6alkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, or heteroaryl; or alternatively both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rdis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Reis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3- C7cycloalkyl, Ci-Cealkyl-COORd, Ci-Cealkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, and / or heteroaryl in R9, R10, R11, R12, R13, Rd, and Rewhere applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -OCi-Cehaloalkyl, -NH2, Ci-Cealkyl, Ci- Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, - COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Ryis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, or Ci-Cehaloalkyl; andwherein if R10is H, each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, Ci-Cealkyl, Ci-Cealkenyl; and at least one Reis Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl.

[0276] In some embodiments, R9is H, Ci-Cealkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, Ci-Cehaloalkyl, Ci-CealkylORd, Ci- CealkylN(Re)2, or C3-C7cycloalkyl. R9is H, Ci-Cealkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl- aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl. In some embodiments, R9is H or Ci-Cehaloalkyl. In some embodiments, R9is H,, CH2CH(CH3)NH2, or CH2CH2F.

[0277] In some embodiments, R10is H, Ci-Cealkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl- aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, Ci-Cehaloalkyl, Ci-CealkylORd, Ci-CealkylN(Re)2, or C3-C7cycloalkyl. In some embodiments, R10is H, Ci-Cealkyl, Ci- Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl. In some embodiments, R10is H or Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, Ci-Cehaloalkyl. In some embodiments,

[0278] In some embodiments, R9is H and R10is CH2CH2F, R9is CH2CH2F and R10is H, or R9is CH2CH2F and R10is CH2CH2F.

[0279] In some embodiments, R9and R10, and the nitrogen atom R9and R10are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry.

[0280] In some embodiments, each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cehaloalkyl. In some embodiments, each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, or Ci-Cealkyl. In some embodiments, each occurrence of R11is independently H, -ORd, or -N(Re)2. In some embodiments, each occurrence of R11is independently H, -OH, or -NH2.

[0281] In some embodiments, p is 2, 3, or 4. In some embodiments, p is 3.

[0282] In some embodiments, Y3is OR12orN(R13)2. In some embodiments, Y3is OR12. In some embodiments, Y3is OH. In some embodiments, Y3is N(R13)2.

[0283] In some embodiments, R12is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORd, Ci-CealkylN(Re)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R12is H, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0284] In some embodiments, each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-C6alkyl-COORd, Ci-Cealkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, or heteroaryl; or alternatively both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry. In some embodiments, each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkyl-COORd, Ci-Cealkyl-CON(Re)2, or Ci-Cealkylaryl. In some embodiments, each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cealkyl-COORd, or Ci-Cealkylaryl. In some embodiments, eachAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 occurrence of R13is independently H, CH2CH(CH3)2, CH2CH2COOH, CH2CH2CH2COOH, benzyl, or 4-trifluoromethlybenzyl. In some embodiments, both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry. In some embodiments, both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O or NRe.O OA3A

[0285] In some embodiments, the structural moiety Y has the structure of OH,

[0286] In some embodiments, each occurrence of Rdis independently H, Ci-Cealkyl, Ci- Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl. In some embodiments, each occurrence of Rdis independently H or Ci-Cealkyl.

[0287] In some embodiments, each occurrence of Reis independently H, Ci-Cealkyl, Ci- Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl. In some embodiments, each occurrence of Reis independently H or Ci-Cealkyl.

[0288] In some embodiments, the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci- CealkylORd, Ci-CealkylN(Re)2, C3-C7cycloalkyl, Ci-Cealkyl-COORd, Ci-Cealkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, and / or heteroaryl in R9, R10, R11, R12, R13, Rd, and Rewhere applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci- Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl.

[0289] In some embodiments, each occurrence of Ryis independently H, halogen, -OH, - OCi-Cealkyl, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments, each occurrence of Ryis independently H, halogen, OH, or Ci-Cehaloalkyl.

[0290] In certain aspects a compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein the compound is selected from the group consistingAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0291] In some embodiments, the compound is selected from the group consisting ofO

[0293] In certain aspects, a compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein the compound is selected from the group consistingAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0294] In some embodiments, the compound is selected from the group consisting ofF

[0295] In certain aspects, a compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described, wherein the compound is selected from the group consistingAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026F FNH2o=s=oNH2o=s=o

[0296] In certain aspects, a compound of Formula III:Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Formula IIIor a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described; wherein:Z1to Z5are each independently CH, N, C-L1-Y1, C-L2-Y2, or CR5;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R2)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, C1-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-Cealkyl-OSO2Ra, Ci-Cealkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl;each occurrence of R2is independently H, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, C3-C7cycloalkyl, C1-C6alkyl-COORa, C1-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, C1-C6alkyl-aryl, C1-C6alkyl-heteroaryl, C1-C6haloalkyl-aryl, C1-C6haloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or N, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, -S(O)mRc, C1-C6alkyl, C1-C6alkenyl, C1-C6alkenyl COORa, C1-C6alkyl-SRa, C1-C6alkyl-SO2Ra, C1-C6alkyl-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 SO3Ra, C1-C6alkyl-OSORa, C1-C6alkyl-SO2NRa, C1-C6alkyl-OSO2(ORa), C1-C6alkyl-OSO(ORa), C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is absent, O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , C1-C6alkylN(R1)2, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R')2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, C3-C7cycloalkyl, C1-C6alkyl-COORa, C1-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the groupAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 consisting of halogen, -OH, -OC1-C6alkyl, -NH2, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6alkylOH, C1-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0297] In certain aspects, a compound of Formula IV:Formula IVor a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described; wherein:Z1to Z4are each independently CH, C-L1-Y1, C-L2-Y2, CR5, or N; and Z5is S, NH, N-L1-Y1, N-L2-Y2, NR5, or O;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, C1-C6alkyl-SO2N(Ra)2, C1-C6alkyl-OSORa, C1-C6alkyl-OSO(ORa), C1-C6alkyl-OSO2Ra, C1-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, C1-C6alkyl-aryl, C1-C6alkyl-heteroaryl, C1-C6haloalkyl-aryl, C1-C6haloalkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form aAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkenyl COORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is absent, O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , C1-C6alkylN(R1)2, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R')2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0298] In some embodiments, Z1to Z4are each independently CH, C-L1-Y1, C-L2-Y2, CR5, or N; and Z5is S, NH, N-L1-Y1, N-L2-Y2, NR5, or O;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R2)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-Cealkyl-OSO2Ra, Ci-Cealkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkenyl COORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7COO-, or -NR7CONR7-; each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , C1-C6alkylN(R1)2, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-aryl, -Ci-Cealkyl-heteroaryl, -Ci-Cealkyl-cycloalkyl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R')2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-Cealkyl-OSO(OR1), or -Ci-C6alkyl-NR3CON(R2)2; or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0299] In some embodiments, wherein Zi is CH, C-L1-Y1, C-L2-Y2, or CR5. In some embodiments, wherein Zi is CH, N, or CR5. In some embodiments, wherein Zi is C-L1-Y1. The compound of claim 75 or 76, wherein Zi is C-L2-Y2.

[0300] In some embodiments, wherein Z2is CH, C-L1-Y1, C-L2-Y2, or CR5. In some embodiments, wherein Z2is CH, N, or CR5. In some embodiments, wherein Z2is C-L1-Y1. In some embodiments, wherein Z2is C-L2-Y2. In some embodiments, wherein Z3is CH, C-L1-Y1, C-L2-Y2, or CR5.

[0301] In some embodiments, wherein Z3is CH or CR5. In some embodiments, wherein Z3is C-L1-Y1. In some embodiments, wherein Z3is C-L2-Y2.

[0302] In some embodiments, wherein Z4 is CH, C-L1-Y1, C-L2-Y2, or CR5. In some embodiments, wherein Z4 is CH or CR5. In some embodiments, wherein Z4is C-L1-Y1. In some embodiments, wherein Z4 is C-L2-Y2.

[0303] In some embodiments, wherein Z5 is S, NH, or O. In some embodiments, wherein Z5is S.

[0304] In some embodiments, wherein L1is absent. In some embodiments, wherein L1is -C(R4)2-.

[0305] In some embodiments, wherein Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, or -OSO2(OR1). In some embodiments, wherein Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, or -NR3COR1. In some embodiments, wherein Y1is -N(R2)SO2R1, -SOR1, -SO2R1-SO3R1, -SO2N(R2)2, -OSOR1, -OSO(OR1), -OSO2R1, or -OSO2(OR1). In some embodiments, Y1is -N(R2)SO2R1or -SO2N(R1)2. In some embodiments, Y1is SO2NH2.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0306] In some embodiments, R5is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, Ci-Ce haloalkoxy, heterocyclyl, aryl, or heteroaryl.

[0307] In some embodiments, n is 0 or 1.

[0308] In some embodiments, L2is absent. In some embodiments, L2is -C(R6)2-.

[0309] In some embodiments, Y2is O, S, or -NR7-.

[0310] In some embodiments, R7is H or Ci-Cealkyl.

[0311] In some embodiments, R8is H, Ci-Cealkyl, Ci-Cehaloalkyl, -Ci-Cealkyl-aryl, -Ci- Cealkyl-heteroaryl, or -Ci-Cealkyl-cycloalkyl.

[0313] In certain aspects, a compound of Formula V:Formula V:or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described; wherein:ring A and ring B are each independently aromatic;Zi to Zs are each independently CH, C-L1-Y1, C-L2-Y2, CR5, or N;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl- SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, -S(O)mRc, C1-C6alkyl, C1-C6alkenyl, C1-C6alkenyl COORa, C1-C6alkyl-SRa, C1-C6alkyl-SO2Ra, C1-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is absent, O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-Cealkyl-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -Ci-C6alkyl-SO2R1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -Ci-Cealkyl-OSO(OR1), -Ci-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-CealkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0314] In certain aspects, a compound of Formula VI:Formula VIor a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described; wherein:Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 ring A and ring B are each independently aromatic;when the ring is aromatic, Z1to Z6are independently CH, C-L1-Y1, C-L2-Y2, CR5or N; and Z7is O, S, NH, N-L1-Y1, N-L2-Y2, or NR5;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-Cealkanoyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-Cealkyl-SRa, Ci-Cealkyl-SeRa, Ci-Cealkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-Cealkyl-OSORa, Ci-Cealkyl-OSO(ORa), C1-C6alkyl-OSO2Ra, C1-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, -S(O)mRc, C1-C6alkyl, C1-C6alkenyl, C1-C6alkenyl COORa, C1-C6alkyl-SRa, C1-C6alkyl-SO2Ra, C1-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is absent, O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , Ci-C6alkylN(R1)2, Ci-C6alkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0315] In certain aspects, a compound of Formula VII:Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Formula VIIor a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described; wherein:Z1to Z3are each independently -CH2-, -CHR1-, -C(R1)R2-, -NH-, -N(R1)-, O, or S; Y1is absent, -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, C3-C8cycloalkenyl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;L2is absent or -C(R6)2-;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is absent, O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , Ci-C6alkylN(R1)2, Ci-C6alkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -Ci-Cealkyl-OSO(OR1), -Ci-C6alkyl-OSO2R1, -Ci-Cealkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2; or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0316] In some embodiments, Z1is -CH2-, -CHR1-, -C(R1)R2-, -NH-, -N(R1)-, O, or S;Z2is -N(R1)-;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Z3is -CH2-, -CHR1-, -C(R1)R2-, -NH-, -N(R1)-, O, or S;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, C3-C8cycloalkenyl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is absent, O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-; each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , Ci-C6alkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0317] In some embodiments, Z1is -CH2-, -CHR1-, or -C(R1)R2-. In some embodiments, Zi is -CH2-.

[0318] In some embodiments, Z3is -CH2-, -CHR1-, or -C(R1)R2-. In some embodiments, Z3is -CH2-.

[0319] In some embodiments, R1is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci- C6alkylN(Rb)2, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-aryl, Ci-C6alkyl-heteroaryl, C3- C8cycloalkenyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R1isAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0320] In some embodiments, R2is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-Ce alkylN(Rb)2. In some embodiments, R2is H.

[0321] In some embodiments, L1is absent. In some embodiments, L1is -C(R4)2-.

[0322] In some embodiments, Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, or -NR3CON(R2)2. In some embodiments, Y1is -COOR1. In some embodiments, Y1is -COOH.

[0323] In some embodiments, L2is absent. In some embodiments, L2is -C(R6)2-.

[0324] In some embodiments, Y2is O, S, or -NR7-. In some embodiments, Y2is -NR7-.

[0325] In some embodiments, R7is H, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments, R7is H.

[0326] In some embodiments, R8is H, -N(R1)2,, Ci-CealkylN(R1)2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R8is H.

[0327] In certain aspects, a compound of Formula VIII:Formula VIII;or a pharmaceutically acceptable enantiomer, salt, or solvate thereof is described; wherein:f A )is Ce-Cioaryl, Cs-Cioheteroaryl, C3-Cscarbocyclyl, or C3-Csheterocyclyl;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-Cealkyl-OSO2Ra, Ci-Cealkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, andAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkenyl COORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , C1-C6alkylN(R1)2, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, Ci-Cealkylaryl, Ci-C6alkylheteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-C6alkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R', Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR')2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-C6alkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R')2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-CealkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

[0328] In some embodiments,f A )is C3-Cscarbocyclyl;Y1is -COOR1or -CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, aryl, heteroaryl, Ci-Cealkyl-aryl, or Ci-Cealkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, C3-C7cycloalkyl, aryl, heteroaryl, Ci-Cealkyl-aryl, or Ci-Cealkyl-heteroarylL1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, Ci-Cealkyl, or Ci-Cehaloalkyl;n is 0, 1, 2, 3, or 4;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; Y2is O, S, -NR7-, or -NR7CO-;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R7is independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;R8is H, Ci-Cealkyl, Ci-Cehaloalkyl, aryl, heteroaryl, Ci-Cealkylaryl, Ci-Cealkylheteroaryl, or -Ci-C6alkyl-CON(R2)2;each occurrence of Rais independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;the Ci-Cealkyl, Ci-Cehaloalkyl, C3-C7cycloalkyl, Ci-C6alkyl-CON(Rb)2, aryl, and / or heteroaryl in R1, R2, R4, R5, R6, R7, R8, Ra, and Rb, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, and Ci-Cehaloalkyl.

[0329] In some embodiments, A is cyclohexyl.

[0330] In some embodiments, Li is -CH2-.

[0331] In some embodiments, Yi is -CON(R2)2.

[0332] In some embodiments, R2is Ci-Cealkylheteroaryl.

[0333] In some embodiments, L1-Y1 has the structure of

[0334] In some embodiments, L2 is absent.

[0335] In some embodiments, Y2 is -NR7-.

[0336] In some embodiments, R7is H or Ci-Cealkyl.

[0337] In some embodiments, Rs is Ci-Cealkylheteroaryl.

[0338] In some embodiments, Y2-R8 has the structure of

[0339] In some embodiments, the compoundis N

[0340] In certain aspects described herein is a compound selected from the group consisting of:Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 OH5Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026vMt Mt o o3Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 20260HV-.•<. to 8 hH **0 0 $ 0 & 0 ’’t’:j:000 S hO &0s0 OKAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026' 0 OC?Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 20269 HN HQ ” -s<FCl "Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026□ OAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026&Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026o □Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0341] In certain aspects, a pharmaceutical composition is described including at least one compound according to any one of the embodiments described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0342] In certain aspects, described herein is a method of treating or preventing a disease or condition in a subject in need thereof, including administering to the subject a pharmaceutical composition according to any one of the embodiments described herein.

[0343] In some embodiments, the subject is a human.

[0344] In some embodiments, the disease or condition is caused by a dysregulation of one or more bestrophins.

[0345] In some embodiments, the disease or condition is a Bestrophin (Best)-related disease.

[0346] In some embodiments, the Bestrophin-related disease is caused by one or more mutations on a gene selected from BEST1, BEST2, BEST3, and BEST4.

[0347] In some embodiments, the Bestrophin-related disease is a bestrophinopathy.

[0348] In some embodiments, the bestrophinopathy is Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract, posterior staphyloma syndrome (MRCS syndrome), age-related macular degeneration (AMD), retinitis pigmentosa (RP), or combinations thereof.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0349] In some embodiments, the bestrophinopathy is Best vitelliform macular dystrophy (BVMD).

[0350] In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, an oral route of delivery, or a parenteral route of delivery.

[0351] In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, wherein the pharmaceutical composition is administered topically.

[0352] In some embodiments, the pharmaceutical composition is administered via eye drops.

[0353] In certain aspects, a method of maintaining intraocular pressure (IOP) in a subject in need thereof is described, the method including administering a pharmaceutical composition according to any one of the embodiments described herein, wherein the pharmaceutical composition increases Best2-mediated Ca2+-dependent Cl-currents in nonpigmented epithelium (NPE) cells.

[0354] In some embodiments, the subject is a human.

[0355] In some embodiments, the disease is caused by a dysregulation of one or more bestrophins.

[0356] In some embodiments, the subject suffers from a Bestrophin-related disease.

[0357] In some embodiments, the Bestrophin-related disease is associated with increased or decreased intraocular pressure (IOP) in the subject.

[0358] In some embodiments, the subject suffers from ocular hypertension or ocular hypotension.

[0359] In some embodiments, the Bestrophin-related disease is glaucoma, myopia, pigment dispersion syndrome, pseudoexfoliation syndrome, age-related macular degeneration, or combinations thereof.Routes of Administration and Dosages

[0360] Routes of administration and dosages of effective amounts of the pharmaceutical compositions are also disclosed. These pharmaceutical compositions or formulations may be designed for various routes of administration, including but not limited to oral, parenteral, intravenous, intramuscular, subcutaneous, intranasal, intraperitoneal, intradermal, or topical delivery. The agents of the present invention can be administered in combination with other pharmaceutical agents in a variety of protocols for effective treatment of disease. In some embodiments, the pharmaceutical composition is administered locally via an ophthalmicAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 route of delivery, i.e., administered to a subject’s eye. Ophthalmic routes of delivery include, but are not limited to, topical, periocular (e.g., subconjunctival, sub-Tenon, retrobulbar, and peribulbar), intravitreal and intracameral. In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, wherein the pharmaceutical composition is administered topically. In some embodiments, the pharmaceutical composition is administered topically via eye drops. In some embodiments, the pharmaceutical composition is administered systemically, e.g., via an oral route or a parenteral route. Oral routes include, but are not limited to, administration by pills, tablets, or liquid formulations. Parenteral routes include, but are not limited to, intravenous, intramuscular, subcutaneous, intranasal, intraperitoneal, intradermal injection.

[0361] Pharmaceutical compositions are administered to a subject in a manner known in the art. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.Pharmaceutical Compositions

[0362] One of ordinary skill in the art will appreciate that a method of administering pharmaceutically effective amounts of the pharmaceutical compositions to a patient in need thereof, can be determined empirically, or by standards currently recognized in the medical arts. The pharmaceutical compositions can be administered to a patient as pharmaceutical compositions in combination with one or more pharmaceutically acceptable excipients.Suitable excipients include, but are not limited to, stabilizers, preservatives, solubilizers, emulsifiers, buffers, and agents that enhance bioavailability or control release kinetics. Other examples of suitable excipients are known in the art and are described in e.g., Remington’s: The Science and Practice of Pharmacy, 22ndEd. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)), the disclosure of which is incorporated herein by reference in its entirety. Such pharmaceutical compositions or formulations may be tailored to improve stability, shelf-life, patient compliance, and therapeutic performance. The pharmaceutical compositions or formulations may be provided in dosage forms such as tablets, pills, capsules, solutions, suspensions, emulsions, injectables, topicals, eye drops, or transdermal patches, depending on the intended use and delivery method. It will be understood that, when administered to a human patient, the total daily usage of the agents of the pharmaceutical compositions will be decided within the scope of sound medical judgment by the attending physician. The specific therapeutically effective dose level for any particular patient will depend upon a variety ofAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 factors: the type and degree of the cellular response to be achieved; activity of the specific agent or composition employed; the specific agents or composition employed; the age, body weight, general health, gender and diet of the patient; the time of administration, route of administration, and rate of excretion of the agent; the duration of the treatment; drugs used in combination or coincidental with the specific agent; and like factors well known in the medical arts. It is well within the skill of the art to start doses of the agents at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosages until the desired effect is achieved.

[0363] In certain aspects, described herein is a method of maintaining intraocular pressure (IOP) in a subject in need thereof, the method comprising administering a pharmaceutical composition, wherein the composition increases Best2 -mediated Camdependent Cl’ currents in non-pigmented epithelium (NPE) cells. In some embodiments, the subject is a human. In some embodiments, the subject suffers from ocular hypertension or ocular hypotension. In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, an oral route of delivery, or a parenteral route of delivery. In some embodiments, the pharmaceutical composition is administered via an ophthalmic route of delivery, wherein the pharmaceutical composition is administered topically. In some embodiments, the pharmaceutical composition is administered via eye drops.Prodrugs

[0364] A "pro-drug" or "pro-drug" refers to an agent which is converted into the active drug in vivo. Pro-drugs are often useful because, in some situations, they are easier to administer than the parent drug. They are bioavailable, for instance, by oral administration whereas the parent drug is either less bioavailable or not bioavailable. In some embodiments, the pro-drug has improved solubility in pharmaceutical compositions over the parent drug. For example, the compound carries protective groups that are removed in vivo, thus releasing active compound. The term "pro-drug" may apply to such functionalities as, for example, the acid functionalities of the compounds of Formula (I). Pro-drugs may be comprised of structures wherein an acid group is masked, for example, as an ester or amide. Further examples of pro-drugs are discussed herein and, for example, by Alexander et al., J Med Chem. 1988, 31, 318 (hereby incorporated by reference in its entirety). In some embodiments, a prodrug form of a compound of Formula (I) can be used to improve pharmacokinetic or penetration of cell membrane. In some embodiments, a prodrug form of a compound of Formula (I) includes but is not limited to an ester of a carboxylic acid.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0365] In one embodiment, the present invention also encompasses methods comprising pro-drugs of compounds of Formula (I) and / or pharmaceutical compositions thereof.Prodrugs include derivatives of compounds that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound of the invention. Examples of pro-drugs include, but are not limited to, derivatives and metabolites of a compound of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable phosphate analogues. Pro-drugs are often useful because, in some situations, they are easier to administer than the parent drug. They are bioavailable, for instance, by oral administration whereas the parent drug is either less bioavailable or not bioavailable. In some embodiments, the pro-drug has improved solubility in pharmaceutical compositions over the parent drug. For example, the compound carries protective groups that are removed in vivo, thus releasing active compound.

[0366] The following examples are provided to further illustrate the methods of the present disclosure. These examples are illustrative only and are not intended to limit the scope of the disclosure in any way.EXAMPLESExample 1 - Small molecule activators of Bestrophins for the treatment of Best vitelliform macular dystrophy

[0367] BVMD is a macular disorder that leads to blindness in the fifth decade of life [1], This disease arises from any one of over 350 point mutations in the BEST1 gene, which encodes a Ca2+-activated chloride (C1‘) channel, namely bestrophin-1 (Bestl), predominantly expressed on the basolateral membrane of retinal pigment epithelium (RPE) cells [1-3], BVMD has an estimated prevalence of 1 to 5,500 in the population, which calculates to more than 60,000 patients in the US and 1.5 million patients in the world. The vast majority of BVMD cases are associated with Bestl loss-of-function (LOF), while gain-of-function (GOF) is very rare (< 1 in 1,000,000) [4], LOF mutations decrease or extinguish Bestl’ s capacity to efflux C1-, causing fluid accumulation in the subretinal space that separates photoreceptor cells from the RPE [5, 6], The results are elevated short- wavelength fundus autofluorescence within the lesion, photoreceptor cell impairment, and increased productionAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 of bisretinoid lipofuscin in photoreceptor outer segments [1], Currently, there is neither a clinical treatment nor any ongoing trial for BVMD.

[0368] To cure BVMD, a rational strategy is to overcome Bestl LOF by Bestl -specific small molecule activators, such that the enhanced Bestl channel function can compensate for the LOF caused by the mutation. In recent studies, two small molecules, para-aminobenzoic acid (PABA) and gamma-aminobutyric acid (GABA), have been identified as novel activators of Bestl: using whole-cell patch clamp, we showed that PABA and GABA are both capable of stimulating the Bestl function; by single-particle cryogenic electron microscopy (cryo-EM), we solved the structure of PABA- and GABA-bound Bestl structures [7, 8], Further details of these studies may be found in PCT / US24 / 51856 and U. S.Provisional Application Nos. 63 / 591,019 and 63 / 693686, which are incorporated by reference for their disclosures of these studies including, but not limited to, disclosure of GABA-bound Bestl structure at (FIGS, la-f of PCT / US24 / 51856, the GABA-bound Best2 structure at FIGS. 2a-l of PCT / US24 / 51856, and the PABA-bound Bestl and Best 2 structures at FIGS.4a-h of PCT / US24 / 51856). Further, each of PCT / US24 / 51856 and U. S. Provisional Application Nos. 63 / 591,019 and 63 / 693686 is herein incorporated by reference in its entirety for all purposes.Results and Conclusions

[0369] To optimize the potency of Bestl activators for potential clinical applications, we designed and synthesized PABA and GABA analogs (Scheme 1 and Scheme 2) as well as various other structures (Scheme 3) based on the PABA- and GABA-bound Bestl structures. The synthetic procedure and the NMR characterization data are summarized in the experimental section. We then tested the effects of these newly synthesized compounds on Bestl channel function in transiently transfected HEK293 cells by whole-cell patch clamp. Bestl -mediated Cl- currents were significantly elevated by 100 pM of each substance, except for BA-33, in the external solution during patch clamp recording (Fig. 1). In particular, BA-1, BA-5, BA-7, BA-12, BA-32, BA-52, and BA-53 showed the strongest stimulating effect on Bestl, representing promising drug candidates for the treatment of BVMD.

[0370] Further, the binding pocket of these PABA and GABA analogs is conserved across Bestl to Best 4. See, PCT / US24 / 51856 throughout, e.g., at FIGS 1, 2, and 4 (disclosing GABA-bound Bestl structure at FIGS, la-f, the GABA-bound Best2 structure at FIGS. 2a-l, and the PABA-bound Bestl and Best 2 structures at FIGS. 4a-h); see also id. at [0006-0009] (disclosing bonds formed between small molecule activators an Bestl -Best4).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 Thus, the compounds disclosed herein are promising drug candidates for the treatment of other Bestrophin-related diseases associated with any of Bestl-Best4.

[0371] Figs. 3A-C depict steady state current densities measured in HEK293 cells transiently expressing Bestl. HEK293 cells were treated with 100 pM of one of BA54-119 at 1 pM [Ca2+]i. Compared to the currents of untreated cells, cells treated with the BA compounds generally had significantly different currents.

[0372] Scheme 1. Structures of PABA analogs.BA-10 BA-11BA-30 BA-31BA-45: n=1, R=FBA-43: n=2, R=F BA-47: n=2, R=OHBA-48: n=1, R=OHBA-46: n=1, R=NH2BA-44: n=2, R=NH2Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026Q Q+ 1). r.

[0373] Scheme 2. Structures of GABA analogs.o Io A..1. t!' rarAttorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0374] Scheme 3. Structures of additional synthesized Bestl activators.Experimental SectionCell Lines

[0375] HEK293 cells were purchased from ATCC (Cat. #CRL-1573) and cultured in DMEM (Corning, Cat. #10013CV) supplemented with 100 pg / mL penicillin-streptomycin and 10% fetal bovine serum. The cells used in this study were authenticated by short tandem repeat (STR) DNA profiling and tested negative for mycoplasma contamination. No mycoplasma contamination was found by DAPI staining.Transfection

[0376] 20-24 hours before transfection, cells were split into new 3.5 cm culture dishes at 50% confluency. Plasmid transfections were conducted using the PolyJet Transfection Reagent (SignaGen, Cat. #SL100688). The transfection mix was removed after 4-8 hours, and cells were washed with PBS and fed with fresh media.Statistics and Reproducibility

[0377] A sufficient number of samples were examined to reach statistical conclusion according to the specific method utilized in that experiment. Statistically significant differences (p < 0.05) between means of two groups were determined by two-tailed unpaired Student’s / test. Data are presented as means values + / - SEM.Electrophysiology

[0378] Whole-cell patch clamp recording was conducted 48-96 hour after transfection with an EPC 10 patch clamp amplifier (HEKA Electronics) controlled by Patchmaster v2x90.5 (HEKA). Micropipettes were pulled and fashioned from filamented 1.5 mm thinwalled glass (WPI Instruments). Series resistance was typically 1.5-2.5 MQ, with noAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 electronic series resistance compensation. Experiments were conducted at room temperature (23 ± 2 °C). Liquid junction potentials were measured and corrected using HEKA built-in functions. The standard zero Ca2+pipette solution contained (mM): 146 CsCl, 2 MgCl2, 5 EGTA, 2 MgATP (added fresh), 10 HEPES, pH 7.3 adjusted with NMDG. Solutions with 1 pM free Ca2+concentrations were made by mixing CaCh with EGTA as calculated by the MaxChelator Program, and the free Ca2+concentration was verified using a Ca2+ion-selective electrode. The standard extracellular solution contained (mM): 140 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 15 glucose, 10 HEPES, pH 7.4 with NMDG. In small molecule containing solutions, 100 pM small molecule was added in the external solution, pH 7.4 adjusted with NMDG. Solution osmolarity was 290-310 mOsm / L with glucose, and -5 mOsm lower in the internal solutions than the external solutions of the same experiment.Electrophysiological Data Collection and Analyses

[0379] Traces were acquired at a repetition interval of 4 seconds. Currents were sampled at 25 kHz and filtered at 5 or 10 kHz. I-V curves were generated from a group of step potentials (-100 to +100 mV from a holding potential of 0 mV). Data were processed off-line in Patchmaster. Statistical analyses were performed using built-in functions in OriginPro 8.5. The value in patch clamp recording figure legends indicates the total number of individual cells.Organic synthesis

[0380] All solvents were of reagent grade and were purchased from Fisher Scientific and Aldrich. Chemical reagents were purchased from Aldrich, Fisher, AA Block, Oakwood, Enamine, and Asta Tech. Silica gel TLC plate was purchased from Sorbtech.1H-NMR. (400 MHz) and13C-NMR (100 MHz) spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer.

[0381] Summary of Synthesis of BA-1BA-1

[0382] Synthesis of methyl 4-((2-fluoroethyl)(methyl)amino)benzoate. Methyl 4-(methylamino) benzoate (379.9 mg, 2.3 mmol) and l-fluoro-2-iodoethane (0.2 mL, 2.3 mmol) was stirred at 90 °C for 48 h. The reaction was allowed to cool to room temperature.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Then EtOAc (20 mL) was added to dilute the reaction mixture and the organic phrase was washed sequentially by H2O (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: EtOAc =50:1) to give a white solid (230 mg, 47 %).

[0383] Synthesis of BA-1. Methyl 4-((2-fluoroethyl)(methyl)amino)benzoate (42.2 mg, 0.2 mmol) and sodium hydroxide (32 mg, 0.8 mmol) was stirred in 1.5 ml MEOH / H2O (2:1) for 24 h at room temperature. The reaction was neutralized by IM HC1 (3 mL) and extracted by EtOAc (3 mL). The organic layer was concentrated by high vacuo to afford BA-1 (32.9 mg, 81%). 'H NMR (400 MHz, MeOD): 87.87 (d, J= 8.0 Hz, 2H), 6.77 (d, J= 8.0 Hz, 2H), 4.68 (t, J= 6.0 Hz, 1H), 4.56 (t, J= 6.0 Hz, 1H), 3.81 (t, J= 6.0 Hz, 1H), 3.74 (t, J= 6.0 Hz, 1H), 3.10 (s, 3H).

[0384] Summary of Synthesis of BA-5BA-5 BA-2

[0385] Synthesis of BA-5. Methyl 4-aminobenzoate (348 mg, 2.3 mmol) and l-fluoro-2-iodoethane (0.2 ml, 2.3 mmol) was stirred at 90 °C for 48 h. The reaction was allowed to cool to room temperature. Then EtOAc (20 mL) was added to dilute the reaction mixture and the organic phrase was washed sequentially by H2O (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hex: EtOAc =25:1) to give a white solid (220 mg, 52 %). ¹H NMR (400 MHz, CDCh): 67.91 (d, J= 8.0 Hz, 2H), 6.63 (d, J= 8.0 Hz 2H), 4.72 (t, J= 4.0 Hz, 1H), 4.60 (t, J= 4.0 Hz, 1H), 3.88 (s, 3H), 3.57 (t, J= 4.0 Hz, 1H), 3.51 (t, J = 6.0 Hz, 1H).Summary of Synthesis of BA-2

[0386] Synthesis of BA-2. Methyl 4-((2-fluoroethyl)amino)benzoate (35 mg, 0.2 mmol) and sodium hydroxide (32 mg, 0.8 mmol) was stirred in 1.5 ml MEOH / H2O (2:1) for 24 h at room temperature. The reaction was neutralized by IM HC1 (3 mL) and extracted by EtOAc (3 mL). The compound The organic layer was concentrated by high vacuo to afford BA-2 (30 mg, 81%).XH NMR (400 MHz, MeOD): 67.81 (d, J= 8.8 Hz, 2H), 6.66 (d, J= 8.8 Hz,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 2H), 4.65 (t, J= 6.0 Hz, 1H), 4.53 (t, J= 6.0 Hz, 1H), 3.53 (t, J= 6.0 Hz, 1H), 3.46 (t, J= 6.0 Hz, 1H).

[0387] Summary of Synthesis of BA-3o omethyl 2-(4-aminophenyl)acetate methyl 2-(4-(methylamino)phenyl)acetate methyl 2-(4-((2-fluoroethyl)(methyl)amino)phenyl)acetate BA-3

[0388] Synthesis of methyl 2-(4-(methylamino)phenyl) acetate. To a stirred solution of methyl 2-(4-aminophenyl) acetate (3 g, 18.16 mmol) and potassium carbonate (2.51 g, 18.16 mmol) in anhydrous acetonitrile (50 ml) was added iodomethane (2.58 g, 18.16 mmol) dropwise at room temperature. The mixture was stirred at r.t. for 6 h. Then 50 ml H2O was added to quench the reaction and 300 mL ethyl acetate was added. The organic phrase was collected and washed with brine (50 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1: 1) to give a white solid (2.18 g, 67 %).

[0389] Synthesis of methyl 2-(4-((2-fluoroethyl)(methyl)amino)phenyl)acetate. To a stirred solution of methyl 2-(4-(methylamino)phenyl)acetate (2 g, 11.16 mmol) and potassium carbonate (1.85 g, 13.39 mmol) in anhydrous acetonitrile (30 ml) was added 1-fluoro-2-iodoethane (2.33 g, 13.39 mmol) dropwise at room temperature. The mixture was stirred at 80 °C for 6 h. Then 50 ml H2O was added to quench the reaction and 150 mL ethyl acetate was added. The organic phrase was collected and washed with brine (50 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 3:1) to give a white solid (1.98 g, 83 %).

[0390] Synthesis of BA-3. To a stirred solution of methyl 2-(4-((fluoromethyl)(methyl)amino)phenyl)acetate (1.5 g, 6.66 mmol) in methanol (5 ml) was added sodium hydroxide (1.14 g, 26.64 mmol) in 5 mL water at room temperature. The mixture was stirred at r.t. for 2 h. Then 5 ml H2O and 20 mL ethyl acetate was added. The organic phrase was collected, washed with brine (10 mL) dried over anhydrous Na2SO4, and evaporated under reduced pressure to give the crude product to give a white solid (1.35 g, 96 %). ¹H NMR (400 MHz, CDCh) 67.17 (d, J= 6.6 Hz, 2H), 6.71 (d, J= 6.6 Hz, 2H), 4.75 -4.48 (m, 2H), 3.71 - 3.60 (m, 2H), 3.57 (s, 2H), 3.03 (s, 3H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0391] Summary of Synthesis of BA-4methyl 2 (4 aminophenyl)acetate methyl 2-(4-((2-fluoroethyl)amino)phenyl)acetate BA-4

[0392] Synthesis of Methyl 2-(4-((2-fluoroethyl)amino)phenyl)acetate. To a stirred solution of methyl 2-(4-aminophenyl) acetate (2 g, 12.11 mmol) and potassium carbonate (5.02 g, 36.32 mmol) in anhydrous acetonitrile (30 ml) was added 1-fluoro-2-iodoethane (6.32 g, 36.32 mmol) dropwise at room temperature. The mixture was stirred at 80 °C for 6 h. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phrase was collected and washed with brine (20 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1:1) to give a white solid (3.05 g, 79 %).

[0393] Synthesis of BA-4. To a stirred solution of methyl 2-(4-aminophenyl) acetate (3 g, 14.20 mmol) in methanol (5 ml) was added sodium hydroxide (2.27 g, 56.81 mmol) in 5 mL water at room temperature. The mixture was stirred at r.t. for 2 h. Then 20 ml H2O and 50 mL ethyl acetate was added. The organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product to give a white solid (1.35 g, 96 %).1H NMR (400 MHz, CDCl3) δ 7.12 (s, 2H), 6.66 (s, 2H), 4.63 (d, J= 52.3 Hz, H-F coupling, 2H), 3.59 - 3.40 (m, 4H).

[0394] Summary of Synthesis of BA-7Fmethyl 4-aminobutanoate methyl 4-(bis(2-fluoroethyl)amino)butanoate

[0395] Synthesis of Methyl 4-(bis(2-fluoroethyl)amino)butanoate. To a stirred solution of methyl 4-aminobutanoate (2 g, 17.07 mmol) and N,N-Diisopropylethylamine (1.05 g, 25.61 mmol) in anhydrous acetonitrile (20 ml) was added 1-fluoro-2-iodoethane (8.91 g, 51.22 mmol) dropwise at room temperature. The mixture was stirred at 80 °C for 6 h. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. TheAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1:1) to give a colorless oil (3.16 g, 89 %).

[0396] Synthesis of BA-7. To a stirred solution of Methyl 4-(bis(2-fluoroethyl) amino)butanoate (3 g, 14.34 mmol) in methanol (5 ml) was added sodium hydroxide (2.29 g, 57.35 mmol) in 5 mL water at room temperature. The mixture was stirred at r.t. for 2 h. Then50 ml H2O was added, and the mixture was acidified with IM HC1. Then 50 mL ethyl acetate was added. The organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product as a colorless oil (1.35 g, 96 %). 'H NMR (400 MHz, MeOD) δ 5.01 - 4.94 (m, 2H), 4.88 - 4.84 (m, 2H), 3.82 - 3.65 (m, 4H), 3.47 - 3.39 (m, 2H), 2.51 (t, J= 6.9 Hz, 2H), 2.19 - 1.96 (m, 2H).

[0397] Summary of Synthesis of BA-10 and BA-40o

[0398] Synthesis of Methyl 4-acetamido-2-hydroxybenzoate. To a stirred solution of methyl 4-amino-2-hydroxybenzoate (50 mg, 0.3 mmol) in DCM (3 mL) was added TEA (90 mg, 0.9 mmol) and acetic anhydride (34 mg, 0.33 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was diluted with 30 mL ethyl acetate and then washed with 30 mL saturated NaHCO3 and 30 mL brine, and dried over Na2SO4. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 2: 1) to give the compound as a white solid (33mg, 52.74%).XH NMR (400 MHz, CDCh) δ 10.88 (s, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 3.97 (s, 3H), 2.22 (s, 3H).

[0399] Synthesis of Methyl 4-acetamido-2-(2,2-difluoroethoxy)benzoate (BA-10). To a stirred solution of compound Methyl 4-acetamido-2-hydroxybenzoate (120 mg, 573.61pmol) in DMF (0.5 mL) was added 60 % NaH in mineral (22.94 mg, 573.61 pmol) at 0 °C.The reaction mixture was stirred at 0 °C for 30 min before adding l,l-difluoro-2-iodoethane (121.11 mg, 630.97 pmol). The reaction mixture was warmed to room temperature andstirred overnight. The solvent was removed under reduced pressure. The residue was diluted with 5 mL ethyl acetate and then washed with 5 mL water, dried over Na2SO4. The crudeAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 product was purified through column chromatography (silica gel, hexane / ethyl acetate = 5:1) to give a brown solid (71.00 mg, 45.30%). 'H NMR (400 MHz, MeOD) δ 7.77 (d, J= 7.1 Hz, 1H), 7.58 (s, 1H), 7.17 (d, J= 10.0 Hz, 1H), 6.23 (t, J= 64 Hz, H-F coupling, 1H), 4.28 (t, J = 16 Hz, H-F coupling, 2H), 3.86 (s, 3H), 2.16 (s, 3H).

[0400] Synthesis of 4-acetamido-2-(2,2-difluoroethoxy)benzoic acid (BA-40). To a stirred solution of compound BA-10 (40.00 mg, 146.39 pmol) in MeCN (0.5 mL) was added LiBr (127.13 mg, 1.46 mmol), H2O (2.90 mg, 161.03 pmol) and TEA (74.07 mg, 731.97 pmol) at room temperature. The reaction mixture was stirred at room temperature for 6 h.H2O (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue was adjusted to pH 2 with IM HC1 and extracted with DCM (10 mL x 3 times). The combined organic layer was washed with brine and dried over Na2SO4. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 5:1) to give the a yellow solid (35.00 mg, 92.23%). ¹H NMR (400 MHz, MeOD) δ 7.83 (d, J= 8.5 Hz, 1H), 7.61 (d, J= 1.9 Hz, 1H), 7.18 (dd, J= 8.5, 1.9 Hz, 1H), 6.26 (t, J = 64 Hz, H-F coupling, 1H), 5.51 (s, 1H), 4.31 (td, J = 20, 4.0 Hz, 2H), 2.17 (s, 3H).

[0401] Summary of Synthesis of BA-6 and BA-11o O 1. NaOH, HoO, refluxed Dimethyl sulfate, NaOH 2. 1M HCI H2O 0 ~ 45°C 5-aminoisobenzofuran-1 (3H)-one BA- 11

[0402] Synthesis of 4-amino-2-(hydroxymethyl)benzoic acid (BA-6). To a stirred solution of NaOH (200 mg, 5 mmol) in H2O (5 mL), 5-aminoisobenzofuran-l(3H)-one (500 mg, 3.35 mmol) was added. The mixture was refluxed for 3h. The mixture was allowed to cool down to room temperature and was adjusted pH to 4 with IM HCI. The crude product was purified through C18 column chromatography (0.1%TFA in H2O / MeCN = 85%) toafford a yellow solid (470 mg, 83.87%).

[0403] Synthesis of 4-(dimethylamino)-2-(methoxymethyl)benzoic acid (BA-11). To a stirred solution of NaOH (29.9 mg, 0.748 mmol) in H2O (0.3 mL), compound 1 (50 mg,0.299 mmol) was added at 0 °C. Dimethyl sulfate (60.3 mg, 0.479 mmol) was added at 0 °C.The mixture was warmed to room temperature and stirred for 30 min before additional dimethyl sulfate (60.3 mg, 0.479 mmol) was added. The mixture was heated at 45 °C for 10 min and heated to 95 °C for 2 h. A solution of 4M NaOH was added and refluxed for 3 h. The reaction was monitored by TLC. Upon reaction completion, the mixture was allowed to coolAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 down to room temperature and was acidified by IM HC1 until pH to 1. The mixture was extracted with DCM (10 mL x 3 times). The combined organic layer was evaporated under reduced pressure. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 2: 1) to afford a yellow solid (37 mg, 59.12%). 'H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 6.96 (s, 1H), 6.61 (s, 1H), 4.91 (s, 2H), 3.54 (s, 3H), 3.10 (s, 6H).

[0404] Summary of Synthesis of BA-12

[0405] Synthesis of 4-amino-2-(2,2-difluoroethoxy)benzoic acid (BA-12). To a stirred solution of BA-10 (70 mg, 256.19 pmol) in H2O (1 mL) was added concentrated HC1 (1 mL, 32.64 mmol). The reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, adjusted to pH 5 with aqueous Na2CO3, and extracted with DCM (20 mL x 3 times). The combined organic layer was washed with brine and dried over Na2SO4. The crude product was purified through C18 column chromatography (0.1% TFA in H2O / MeCN = 90%) to afford a yellow solid (50.0 mg, 89.87%).1H NMR (400 MHz, DMSO) ¹H NMR (400 MHz, DMSO) δ 7.38 (d, J= 8.3 Hz, 1H), 6.99 (d, J= 8.2 Hz, 1H), 6.95 (s, 1H), 6.40 (t, J= 64 Hz, H-F coupling 1H), 4.33 (td, J= 14.7, 3.3 Hz, 2H).

[0406] Summary of Synthesis of BA-30OH OH OHBA-30

[0407] Synthesis of methyl 4-(((2-hydroxyethyl)amino)methyl)-3-nitrobenzoate. Methyl 4-formyl-3 -nitrobenzoate (2 g, 9.56 mmol) and 2-aminoethan-l-ol (641 mg, 10.5 mmol) was stirred in methanal (10 mL) at room temperature for 24 h. Then sodium triacetoxyborohydride (2.2 g, 10.5 mmol) was added at room temperature to stir for 24 h. Subsequently, EtOAc (20 mL) was added to dilute the reaction mixture and the organic phrase was washed sequentially by H2O (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crudeAttorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 product, which was then purified by column chromatography (silica gel, DCM: MeOH=100: 1) to give a white solid (980 mg, 42 %).

[0408] Synthesis of methyl 3-amino-4-(((2-hydroxyethyl)amino)methyl)benzoate.Methyl 4-(((2-hydroxyethyl)amino)methyl)-3-nitrobenzoate (127.1 mg, 0.5 mmol) and zinc metal powder (75 mg, 2.5 mmol) was stirred in acetic acid (5 mL) at room temperature for 24 h. The organic solution was collected by filtration and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, DCM: MeOH =50:1) to give a yellow solid (91.9 mg, 82 %).

[0409] Synthesis of BA-30. Methyl 3-amino-4-(((2-hydroxyethyl)amino)methyl)benzoate (44.9 mg, 0.2 mmol) and sodium hydroxide (32 mg, 0.8 mmol) was stirred in 1.5 ml MEOH / H2O (2:1) for 24 h at room temperature. The reaction was neutralized by IM HC1 (3 mL) and extracted by EtOAc (3 mL). The organic phase was evaporated under reduced pressure to give the gray solid BA-30 (35.7 mg, 85%). 'H NMR (400 MHz, D2O): δ 7.36 (s, 1H), 7.31 (d, J= 8.0 Hz, 1H), 7.09 (d, J= 8.0 Hz, 1H), 3.78 (s, 2H), 3.68 (t, J= 8.0 Hz, 2H), 2.73 (t, J= 8.0 Hz, 2H).

[0410] Summary of Synthesis of BA-31BA-31

[0411] Synthesis of methyl 4-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-3-nitrobenzoate. Methyl 4-formyl-3 -nitrobenzoate (1 g, 4.78 mmol) and tert-butyl (2-aminoethyl)carbamate (842.6 mg, 5.26 mmol) was stirred in methanal (10 mL) at room temperature for 24 h. Then sodium triacetoxyborohydride (1.1 g, 5.26 mmol) was added and then mixture was stirred at room temperature for 24 h. Then EtOAc (20 mL) was added to dilute the reaction mixture and the organic phrase was washed sequentially by H2O (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: EtOAc =20: 1) to give a white solid (876 mg, 52 %).

[0412] Synthesis of methyl 3-amino-4-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)benzoate. Methyl 4-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-3-nitrobenzoate (176.7 mg, 0.5 mmol) and zincAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 metal powder (75 mg, 2.5 mmol) was added to stir in acetic acid (5 mL) at room temperature for 24 h. The organic solution was collected by filtration and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: EtOAc =25:1) to give a yellow solid (127.7 mg, 79 %).

[0413] Synthesis of 3-amino-4-(((2-(( / ‘c / 7-butoxycarbonyl)amino)ethyl)amino)methyl)benzoic acid. Methyl 3-amino-4-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)benzoate (65 mg, 0.2 mmol) and sodium hydroxide (32 mg, 0.8 mmol) was stirred in 1.5 ml MEOH / H2O (2:1) for 24 h at room temperature. The reaction was neutralized by IM HC1 (3 mL) and extracted by EtOAc (3 mL). The organic phase was evaporated under reduced pressure to give the dark yellow solid compound (53.8 mg, 87%).

[0414] Synthesis of BA-31. 3-amino-4-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)benzoic acid (50 mg, 0.16 mmol) was stirred in 4 M HC1 in dioxane (3 mL) at r.t. for 6 h. Then diethyl ether (5 mL) was added to the reaction mixture, and a yellow precipitate was formed and collected by filtration. The yellow solid was further dried under reduced pressure to give BA-31 in HC1 salt form (30.1 mg, 90 %). 'H NMR (400 MHz, D2O) δ 7.78 -7.75 (m, 2H), 7.58 (d, J= 8.0 Hz, 1H), 4.43 (s, 2H), 3.57 (t, J = 8.0 Hz, 2H), 3.44 (t, J= 8.0 Hz, 2H).

[0415] Summary of Synthesis of BA-32BA-32

[0416] Synthesis of methyl 4-(((2-fluoroethyl)amino)methyl)-3-nitrobenzoate. To a stirred solution of Methyl 4-formyl-3-nitrobenzoate (1 g, 4.78 mmol) in 20 mL acetonitrile, 2-Fluoroethylamine hydrochloride (475.8 mg, 4.78 mmol) and triethylamine (0.67 mL, 4.78 mmol) was added under argon. The mixture was stirred at r.t. for 45 mins. Then the reaction mixture was refluxed at 60 °C for another 4 h and cooled to room temperature to stir for overnight. Then the reaction mixture was concentrated under reduced pressure to give a yellow solid. The solid was dissolved in methanol (10 mL), then sodium triacetoxyborohydride (1.1 g, 5.26 mmol) was added at room temperature to stir for 24 hrs.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Then EtOAc (20 mL) was added to dilute the reaction mixture and the organic phrase was washed sequentially by H2O (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: EtOAc =100:1) to give a yellow solid (673 mg, 55 %).

[0417] Synthesis of methyl 3-amino-4-(((2-fluoroethyl)amino)methyl)benzoate.Methyl 4-(((2-fluoroethyl)amino)methyl)-3-nitrobenzoate (128.1 mg, 0.5 mmol) and zinc metal powder (75 mg, 2.5 mmol) was added to stir in acetic acid (5 mL) at room temperature for 24 hrs. The organic solution was collected by filtration and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: EtOAc =50:1) to give a yellow solid (92.3 mg, 86 %).

[0418] Synthesis of BA-32. Methyl 3-amino-4-(((2-fluoroethyl)amino)methyl)benzoate (45.3 mg, 0.2 mmol) and sodium hydroxide (32 mg, 0.8 mmol) was stirred in 1.5 ml MEOH / H2O (2: 1) for 24 hrs at room temperature. The reaction was neutralized by IM HC1 (3 mL) and extracted by EtOAc (3 mL). The organic phase was evaporated under reduced pressure to give the yellow solid compound BA-32 (35.2 mg, 83%). 'H NMR (400 MHz, MeOD) δ 7.37 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.07 (d, J= 8.0 Hz, 1H), 4.60 (t, J= 6.0 Hz, 1H), 4.48 (t, J= 6.0 Hz, 1H), 3.81 (s, 2H), 2.91 (t, J= 6.0 Hz, 1H), 2.84 (t, J= 6.0 Hz, 1H).

[0419] Summary of Synthesis of BA-33F F EDC. DMAP, TEAL _NDCM, rt NL _N

[0420] Synthesis of BA-33. To a stirred solution of BA-7 (1.5 g, 7.68 mmol) and 1-methylpiperazine (770 mg, 7.68 mmol) in anhydrous DCM (20 ml) was added DMAP (94 mg, 0.768 mmol), TEA (1.2g, 11.53 mmol) and EDC (1.61g, 10.37 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1:2) to give a colorless oil (1.87 g, 88 %). 1HNMR (CDC13): δ 4.54 - 4.43 (m, 4H), 3.63 - 3.49 (m, 4H), 2.90 - 2.82 (m, 4H), 2.64 -2.31 (m, 10H), 1.76 (s, 3H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0421] Summary of Synthesis of BA-34EDC, DMAP, TEADCM, r.t.BA-7

[0422] Synthesis of BA-34. To a stirred solution of BA-7 (1.5 g, 7.68 mmol) and (4 (trifluoromethyl)phenyl)methanamine (770 mg, 7.68 mmol) in anhydrous DCM (20 ml) was added DMAP (94 mg, 0.768 mmol), TEA (1.2g, 11.53 mmol) and EDC (1.61g, 10.37 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1:1) to give a colorless oil (1.68 g, 77 %). 'H NMR (400 MHz, CDCI3) 67.57 (d, J= 8.0 Hz, 2H), 7.40 (d, J= 8.1 Hz, 2H), 4.53 (t, J= 5.2 Hz, 2H), 4.47 (d, J= 6.2 Hz, 2H), 4.40 (d, J= 5.2 Hz, 2H), 2.86 (t, J= 5.2 Hz, 2H), 2.80 (t, J= 5.2 Hz, 2H), 2.63 (d, J= 13.1 Hz, 2H), 2.33 (t, J= 6.9 Hz, 2H), 1.87 - 1.77 (m, 2H).

[0423] Summary of Synthesis of BA-35F EDC, DMAP, TEABA-7 DCM, r.t.BA-35

[0424] Synthesis of BA-35. To a stirred solution of 4-(bis(2-fluoroethyl) amino)butanoic acid (1.5 g, 7.68 mmol) and morpholine (669.5 mg, 7.68 mmol) in anhydrous DCM (20 ml) was added DMAP (94 mg, 0.768 mmol), TEA (1.2g, 11.53 mmol) and EDC (1.61g, 10.37 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, DCM: Methanol = 20:1) to give a colorless oil (1.79 g, 88 %). 'H NMR (400 MHz, CDCl3) δ 4.60 (s, 2H), 4.48 (s, 2H), 3.69 (s, 4H), 3.64 (s, 2H), 3.50 (s, 2H), 2.99 - 2.82 (m, 4H), 2.68 (t, J= 8.0 Hz, 2H), 2.40 (t, J= 8.7 Hz, 2H), 1.82 (t, J= 8.3 Hz, 2H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0425] Summary of Synthesis of BA-36F EDC, DMAP, TEA DCM, r.t.BA-36

[0426] Synthesis of BA-36. To a stirred solution of 4-(bis(2-fluoroethyl) amino)butanoic acid (1.5 g, 7.68 mmol) and Phenylmethanamine (823 mg, 7.68 mmol) in anhydrous DCM (20 ml) was added DMAP (94 mg, 0.768 mmol), TEA (1.2g, 11.53 mmol) and EDC (1.61g, 10.37 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1:2) to give a colorless oil (1.98 g, 91 %). ¹H NMR (400 MHz, CDCl3) δ 7.39 - 7.25 (m, 5H), 6.19 (s, 1H), 4.54 (t, J= 5.0 Hz, 2H), 4.48 - 4.39 (m, 4H), 2.89 (t, J= 5.0 Hz, 2H), 2.82 (t, J= 5.0 Hz, 2H), 2.65 (t, J= 6.7 Hz, 2H), 2.32 (t, J= 7.0 Hz, 2H), 1.84 (p, J= 6.8 Hz, 2H).

[0427] Summary of Synthesis of BA-37EDC, DMAP, TEADCM, rtBA-7BA-37

[0428] Synthesis of BA-37. To a stirred solution of 4-(bis(2-fluoroethyl) amino)butanoic acid (1.5 g, 7.68 mmol) and 2-methylpropan-l -amine (562 mg, 7.68 mmol) in anhydrous DCM (20 ml) was added DMAP (94 mg, 0.768 mmol), TEA (1.2g, 11.53 mmol) and EDC (1.61g, 10.37 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1: 1) to give a colorless oil (1.74 g, 90 %). 'H NMR (400 MHz, CDCl3) δ 4.56 (t, J= 5.0 Hz, 2H), 4.44 (t, J= 5.0 Hz, 2H), 3.06 (t, J= 6.4 Hz, 2H), 2.90 (s, 2H), 2.83 (t, J= 5.1 Hz, 2H), 2.63 (t, J= 6.8 Hz, 2H), 2.24 (t, J= 7.2 Hz, 2H), 1.90 - 1.69 (m, 3H), 0.90 (d, J= 6.7 Hz, 6H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0429] Summary of Synthesis of BA-38(R)-4-amino-2-((tert-butoxycarbonyl)amino)butanoic acid (R)-2-(( / ert-butoxycarbonyl)amino)-4-((2-fluoroethyl)amino)butanoic acid

[0430] Synthesis of tert-butyl 3-(4-(bis(2-fluoroethyl)amino)butanamido)propanoate.To a stirred solution of 4-(bis(2-fluoroethyl) amino)butanoic acid (1.5 g, 7.68 mmol) and tertbutyl 3-aminobutanoate (1.12 mg, 7.68 mmol) in anhydrous DCM (20 ml) was added DMAP(94 mg, 0.768 mmol), TEA (1.2g, 11.53 mmol) and EDC (1.61g, 10.37 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phase was collected andwashed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4andevaporated under reduced pressure to give the crude product, which was then purified bycolumn chromatography (silica gel, Hexane: Ethyl acetate= 1:3) to give a colorless oil (2.05 g, 82 %).

[0431] Synthesis of BA-38. To a stirred solution of tert-butyl 4-((5-(bis(2-fluoroethyl)amino)-2-oxopentyl)amino)butanoate (1.5 g, 4.65 mmol) in 1,4-dioxane (5 ml) was added 4 M HC1 in 1,4-dioxane at room temperature. The mixture was stirred at r.t. for 2 h. The organic solution was then evaporated under reduced pressure to afford the crudeproduct, which was then purified by column chromatography (Cl 8, Acetonitrile: water = 10 to 90) to give a colorless oil (987 g, 80 %). 'H NMR (400 MHz, MeOD) 85.01 - 4.95 (m,2H), 4.88 - 4.82 (m, 2H), 3.78 - 3.73 (m, 2H), 3.71 - 3.67 (m, 2H), 3.47 (t, J= 6.6 Hz, 2H), 3.41 (t, J= 7.3 Hz, 2H), 2.57 (t, J= 6.6 Hz, 2H), 2.46 (t, J= 6.5 Hz, 2H), 2.12 - 2.01 (m,2H).

[0432] Summary of Synthesis of BA-39o

[0433] Synthesis of tert-butyl (l-oxo-l,3-dihydroisobenzofuran-5-yl)carbamate. To a stirred solution of triethylamine (TEA, 407 mg, 4.02 mmol) and 5-aminoisobenzofuran-l(3H)-one (500 mg, 3.35 mmol) in MeCN (1.5 mL) was added di -tert-butyl decarbonate (878 mg, 4.02 mmol) dropwise at 0 °C during a 30 min period. The mixture was warmed to roomAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 temperature and stirred overnight. The solvent was removed under reduced pressure, diluted with 20 mL ethyl acetate and then washed with 20 mL saturated NH₄Cl, 20 mL saturated NaHCO3 and 20 mL brine. The organic layer was dried over Na2SO4. The crude product was concentrated without further purification.

[0434] Synthesis of 4-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)benzoic acid.To a stirred solution of NaOH (45 mg, 1.13 mmol) in H2O (1 mL), Tert-butyl (tert-butoxycarbonyl)(l -oxo-1,3-dihydroisobenzofuran-5-yl)carbamate (1.01 g, 4.05 mmol) was added. The mixture was refluxed for 3 h. The reaction was monitored by TLC. Upon reaction completion, the mixture was allowed to cool down to room temperature and was acidified by saturated citric acid until pH to 4. The mixture was extracted with DCM (10 mL x 3). The combined organic layer was washed with 30 mL brine and dried over Na2SO4. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 10:1) to give a colorless oil (520 mg, 58.03%).

[0435] Synthesis of Methyl 4-((tert-butoxycarbonyl)amino)-2- (methoxymethyl)benzoate (BA-39). To a stirred solution of 4-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)benzoic acid (50 mg, 1.87 mmol) in 5 mL THF at 0 °C, 60 % NaH in mineral (23 mg, 0.56 mmol) and CH3I (100 mg, 0.75 mmol) was added. The reaction mixture was heated at 45 °C for 6 h. The reaction was monitored by TLC. Upon reaction completion, the reaction was quenched by adding 20 mL H2O and was extracted with ethyl acetate (20 mL x 3 times). The combined organic layer was washed with 60 mL saturated NH4CI and 60 mL brine, and then dried over Na2SO4. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 5: 1) to give the product as a white solid (38 mg, 68.78%). 'H NMR (400 MHz, CDCh) 68.08 (d, J= 8.5 Hz, 1H), 7.61 (s, 1H), 7.32 (d, J= 8.5, 1H), 4.89 (s, 2H), 3.53 (s, 3H), 3.34 (s, 3H), 1.50 (s, 9H).

[0436] Summary of Synthesis of BA-42F OH O 1-fluoro-2-iodoethane, DIPEAMeCN4-amino-3-hydroxybutanoic acid hydrochloride

[0437] Synthesis of 4-(bis(2-fluoroethyl)amino)-3-hydroxybutanoic acid (BA-42). To a solution of 4-amino-3 -hydroxybutanoic acid hydrochloride (100.00 mg, 642.76 pmol) in MeCN (2 mL) was added DIPEA (290.76 mg, 2.25 mmol) and l-fluoro-2-iodoethane (279.53 mg, 1.61 mmol). The reaction mixture was stirred at 50 °C overnight. The mixture was concentrated under reduced pressure. The residue was adjusted to pH 4 with IM HC1 andAttorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 extracted with DCM (20 mL x 3 times).. The combined organic layer was washed with brine and dried over Na2SO4. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 1: 1) to give a yellow solid (33 mg, 24.31 %).1H NMR (400 MHz, CDCh) 64.70 - 4.55 (m, 3H), 4.50 (q, J= 5.5 Hz, 2H), 4.44 - 4.31 (m, 1H), 4.17 -4.04 (m, 1H), 3.73 (s, 1H), 3.01 (d, J= 24.9 Hz, 4H), 2.82 (d, J= 16.9 Hz, 1H), 2.64 - 2.46 (m, 3H).

[0438] Summary of Synthesis of BA-45, BA-43, BA-47, BA-44, BA-48, BA-46EDC Et₃N DMF CH₃CN, rtA< n=1 R = F, NHBoc, OSi(CH3)2C(CH3)3A2: n=2Zn 4M HCI Acetic acid 1,4-dioxane, rtB n=1, R=F C n=1, R=F BA-45: n=1, R=F B2: n=2, R=F C2: n=2, R=F BA-43: n=2, R=F B3: n=2, R= OSi(CH3)2C(CH3)3C3: n=2, R= OSi(CH3)2C(CH3)3BA-47: n=2, R=OH B4: n=1, R=OSi(CH3)2C(CH3)3C4: n=1, R=OSi(CH3)2C(CH3)3BA-48: n=1, R=OH B5: n=1, R=NHBoc C5: n=1, R=NHBoc BA-46: n=1, R=NH2B6: n=2, R=NHBoc C6: n=2, R=NHBoc BA-44: n=2, R=NH2

[0439] Synthesis of intermediate A. 4-fluoro-3 -nitrobenzoic acid (1 g, 5.4 mmol) and starting material 1 (SM-1, 5.4 mmol) was dissolved in anhydrous THF (40 ml). Then 1-Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl, 1.5 g, 8.1 mmol) was added at room temperature. The mixture was stirred at room temperature for 24 h.Subsequently, EtOAc (100 ml) was added to dilute the reaction mixture and the organic phrase was washed sequentially by H2O (50 mL) and brine (50 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crudeAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 product, which was then purified by column chromatography (silica gel, Hexane:EtOAc=80: 1) to give a yellow solid.

[0440] Synthesis of intermediate B. Intermediate A (500 mg, 1.6 mmol), starting material 2 (SM-2, 1.6 mmol) and triethylamine (0.22 ml, 1.6 mmol) was added in acetonitrile (10 ml) at room temperature. The mixture was stirred at room temperature for 24 h. Then EtOAc (30 ml) was added to dilute the reaction mixture and the organic phrase was washed sequentially by H2O (15 mL) and brine (15 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: EtOAc=50: 1) to give a yellow solid.

[0441] Synthesis of intermediate C. Intermediate B (200 mg, 0.5 mmol) and zinc metal powder (75 mg, 2.5 mmol) was added to stir in acetic acid (5 mL) at room temperature for 24 h. The organic solution was collected by filtration and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: EtOAc =25: 1) to give a dark yellow oil.

[0442] Synthesis of BA-45, BA-43, BA-47, BA-44, BA-48, BA-46 Intermediate C (100 mg) was stirred in 4 M HC1 in dioxane (4 mL) at r.t. for 3 h. Then diethyl ether (5 mL) was added to the reaction mixture, and a yellow precipitate was formed and dried under reduced pressure to give compounds in HC1 salt form (90 %).

[0443] BA-45: 'H NMR (400 MHz, D2O) 87.66 - 7.61 (m, 2H), 6.92 (d, J= 8.0 Hz, 1H), 4.65 (t, J= 6.0 Hz, 1H), 4.59 (t, J= 6.0 Hz, 1H), 3.61 - 3.52 (m, 4H), 2.64 (t, J= 6.0 Hz, 2H).

[0444] BA-43: 'H NMR (400 MHz, D2O) 67.69 - 7.61 (m, 2H), 6.93 (d, J= 8.0 Hz, 1H), 4.65 (t, J= 6.0 Hz, 1H), 4.58 (t, J= 6.0 Hz, 1H), 3.60 (t, J= 4.0 Hz, 1H), 3.53 (t, J= 4.0 Hz, 1H), 3.35 (t, J= 6.0 Hz, 2H), 2.39 (t, J= 8.0 Hz, 2H), 1.84 (t, J= 6.0 Hz, 2H ).

[0445] BA-46: 'H NMR (400 MHz, D2O) 67.72 - 7.63 (m, 2H), 6.93 (d, J= 8.0 Hz, 1H), 3.69 - 3.56 (m 4H), 3.22 (t, J= 6.0 Hz, 2H), 2.64 (t, J= 6.0 Hz, 2H).

[0446] BA-44: 'H NMR (400 MHz, D2O) 67.79 (d, J= 8.0 Hz, 1H), 7.64 (s, 1H), 6.94 (d, J= 8.0 Hz, 1H), 3.59 (t, J= 6.0 Hz, 2H), 3.36 (t, J= 8.0 Hz, 2H), 3.22 (t, J= 6.0 Hz, 2H), 2.40 (t, J= 8.0 Hz, 2H), 1.86 (t, J= 6.0 Hz, 2H).

[0447] BA-48: 'H NMR (400 MHz, D2O) 67.65 - 7.61 (m, 2H), 6.93 (d, J= 12.0 Hz, 1H), 3.75 (t, J= 4.0 Hz, 2H), 3.57 (t, J= 8.0 Hz, 2H), 3.39 (t, J= 4.0 Hz, 2H), 2.64 (t, J= 6.0 Hz, 2H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0448] BA-47: 'H NMR (400 MHz, D2O) 67.64 - 7.59 (m, 2H), 6.92 (d, J= 8.0 Hz, 1H), 3.74 (t, J= 6.0 Hz, 2H), 3.39 - 3.31 (m, 4H), 2.38 (t, J= 8.0 Hz, 2H), 1.83 (t, J= 8.0 Hz,2H).

[0449] Summary of Synthesis of BA-49, BA-50, and BA-51

[0450] Synthesis of BA-49 to 51. BA-49, 50, and 51 were synthesized following asimilar procedure with BA-43 to 48 and BA32.

[0451] BA-49: 'H NMR (400 MHz, D2O) 67.36 (d, J= 7.9 Hz, 1H), 7.24 - 7.17 (m, 2H), 4.29 (s, 2H), 3.58 (t, J= 6.5 Hz, 2H), 3.48 - 3.41 (m, 2H), 3.39 - 3.31 (m, 2H), 2.65 (t, J =6.5 Hz, 2H)

[0452] BA-50:1H NMR (400 MHz, D2O) 67.48 (d, J= 7.9 Hz, 1H), 7.39 - 7.31 (m, 2H), 4.40 (s, 2H), 3.56 (dd, J= 8.0, 5.9 Hz, 2H), 3.46 (dq, J= 6.6, 3.0 Hz, 4H), 2.50 (t, J= 7.2 Hz, 2H), 1.95 (p, J = 7.0 Hz, 2H).

[0453] BA-51: 'H NMR (400 MHz, D2O) 67.60 - 7.36 (m, 3H), 4.92 - 4.88 (m, 2H),4.41 (s, 2H), 3.65 - 3.51 (m, 2H), 3.47 (t, J= 6.7 Hz, 2H), 2.51 (t, J= 7.2 Hz, 2H), 1.96 (p, J= 7.0 Hz, 2H).

[0454] Summary of Synthesis of BA-52

[0455] Synthesis of tert-butyl 3-(4-(bis(2-fluoroethyl)amino)butanamido)propanoate. To a stirred solution of 4-(bis(2-fluoroethyl) amino)butanoic acid (1.5 g, 7.68 mmol) and tert-butyl 3-aminobutanoate (1.12 mg, 7.68mmol) in anhydrous DCM (20 ml) was added DMAP (94 mg, 0.768 mmol), TEA (1.2g,11.53 mmol) and EDC (1.61g, 10.37 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phase was collected and washed with brine (10 mL). The organicphase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1:3) to give a colorless oil (2.05 g, 82 %).

[0456] Synthesis of BA-52. To a stirred solution of tert-butyl 4-((5-(bis(2-fluoroethyl)amino)-2-oxopentyl)amino)butanoate (1.5 g, 4.65 mmol) in 1,4-dioxane (5 ml) was added 4 M HCI in 1,4-dioxane at room temperature. The mixture was stirred at r.t. for 2 h. The organic solution was then evaporated under reduced pressure to afford the crudeAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 product, which was then purified by column chromatography (Cl 8, Acetonitrile: water = 10 to 90) to give a colorless oil (987 g, 80 %). 'H NMR (400 MHz, MeOD) 65.01 - 4.95 (m, 2H), 4.88 - 4.82 (m, 2H), 3.78 - 3.73 (m, 2H), 3.71 - 3.67 (m, 2H), 3.47 (t, J= 6.6 Hz, 2H), 3.41 (t, J= 7.3 Hz, 2H), 2.57 (t, J= 6.6 Hz, 2H), 2.46 (t, J= 6.5 Hz, 2H), 2.12 - 2.01 (m, 2H).

[0457] Summary of Synthesis of BA-53

[0458] Synthesis of tert-butyl 4-((5-(bis(2-fluoroethyl)amino)-2-oxopentyl)amino)butanoate. To a stirred solution of 4-(bis(2-fluoroethyl) amino)butanoic acid (1.5 g, 7.68 mmol) and tert-butyl 4-aminobutanoate (1.22 mg, 7.68 mmol) in anhydrous DCM (20 ml) was added DMAP (94 mg, 0.768 mmol), TEA (1.2g, 11.53 mmol) and EDC (1.61g, 10.37 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 20 ml H2O was added to quench the reaction and 200 mL ethyl acetate was added. The organic phrase was collected and washed with brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1:3) to give a colorless oil (2.13 g, 79 %).

[0459] Synthesis of BA-53. To a stirred solution of tert-butyl 4-((5-(bis(2-fluoroethyl)amino)-2-oxopentyl)amino)butanoate (1.5 g, 4.28 mmol) in 1,4-dioxane solvent (5 ml) was added hydrochloric acid ( 625 mg, 17.12 mmol) in 1,4-dioxane at room temperature. The mixture was stirred at r.t. for 2 h. The organic solution was then evaporated under reduced pressure to afford the crude product, which was then purified by column chromatography(C18, Acetonitrile: water = 10 to 90) to give a colorless oil (1.06 g, 88 %). ¹H NMR (400 MHz, MeOD) 85.01 - 4.95 (m, 2H), 4.88 - 4.82 (m, 2H), 3.78 - 3.73 (m, 2H), 3.71 - 3.67 (m, 4H), 3.47 (t, J= 6.6 Hz, 2H), 3.41 (t, J= 7.3 Hz, 2H), 2.57 (t, J= 6.6 Hz, 2H), 2.46 (t, J= 6.5 Hz, 2H), 2.12 - 2.01 (m, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0460] Summary of Synthesis of BA-54BA-54

[0461] Synthesis of methyl 4-(((2-(methylthio)ethyl)amino)methyl)benzoate. Methyl 4-formylbenzoate (1 g, 6.1 mmol) and 2-(methylthio)ethan-l -amine (611 mg, 6.7 mmol) was stirred in methanal (5 mL) at room temperature for 2 h. Then sodium triacetoxyborohydride (1.42 g, 6.7 mmol) was added at room temperature to stir for 24 h. Subsequently, EtOAc (10 mL) was added to dilute the reaction mixture and the organic phrase was washed sequentially by H2O (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, DCM: MeOH =100: 1) to give a white solid (590 mg, 41 %).

[0462] Synthesis of BA-54. Methyl 4-(((2-(methylthio)ethyl)amino)methyl)benzoate (100 mg, 0.42 mmol) and sodium hydroxide (67 mg, 1.67 mmol) was stirred in 3 ml MeOH / LLO (2: 1) for 24 h at room temperature. The reaction was neutralized by IM HC1 (3 mL) and extracted by EtOAc (3 mL). The organic phase was evaporated under reduced pressure to give the gray solid BA-54 (85 mg, 90%).1H NMR (400 MHz, MeOD): 87.96 (d, J = 8.0 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 4.26 (s, 2H), 3.23 (t, J = 8.0Hz, 2H), 2.75 (t, J= 8.0 Hz, 2H), 1.99 (s, 3H).

[0463] Summary of synthesis of methyl 4-(bromomethyl)-2-(2,2-difluoroethoxy)benzoate.methyl 2-hydroxy- 1, 1 -difluoro-2- methyl 2-(2,2-difluoroethoxy)- methyl 4-(bromomethyl)-2- 4-methylbenzoate iodoethane 4-methylbenzoate (2,2-difluoroethoxy)benzoate

[0464] Synthesis of methyl 4-(bromomethyl)-2-(2,2-difluoroethoxy)benzoate. To a stirred solution of methyl 2-hydroxy -4-methylbenzoate (2.0 g, 12.04 mmol) in DMF (10 mL) was added l,l-difluoro-2-iodoethane (2.91 mL, 24.07 mmol) and K2CO3 (3.33 g, 24.07 mmol) at room temperature. The mixture was heated to 80 °C and stirred overnight. UponAttorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 reaction completion, the mixture was allowed to cool down to room temperature and brine (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL, 2 times) and dried over Na2SO4. The organic layer was evaporated under reduced pressure. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 10:1) to afford methyl 2-(2,2-difluoroethoxy)-4-methylbenzoate, a white solid (2.26 g, 81.57 %). 'H NMR (400 MHz, CDCh) 67.76 (d, J = 10.7 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.39 - 5.95 (m, 1H), 4.25 (td, J = 13.0, 2.5 Hz, 2H), 3.88 (s, 3H), 2.39 (s, 3H).

[0465] To a solution of methyl 2-(2,2-difluoroethoxy)-4-methylbenzoate (400 mg, 1.74 mmol) in 1,2-Dichloroethane (anhydrous, 5 mL) was added N-Bromosuccinimide (324.72 mg, 1.82 mmol) and Azobisisobutyronitrile (57.06 mg, 347.51 pmol). The mixture was refluxed at 85 °C overnight. The crude product methyl 4-(bromomethyl)-2-(2,2-difluoroethoxy)benzoate was concentrated without further purification.

[0466] General Synthesis Route for Compounds BA-55, BA-59 to BA-66, BA-69 to BA- 82.

[0467] Compounds BA-55, BA-59 to BA-66, BA-69 to BA-75 were synthesized as follows: To a stirred solution of the amine compound (aliphatic or aromatic, 5.0 equiv) in DMF (10 mL) was added CS2CO3 (1.2 equiv), and the mixture was stirred for 10 min. Crude methyl 4-(bromomethyl)-2-(2,2-difluoroethoxy)benzoate (1.0 equiv) was then added. The reaction mixture was stirred overnight at room temperature for aliphatic amines or at 50 °C for aromatic amines. Upon completion, the reaction mixture was allowed to cool to room temperature (if heated), and brine (100 mL) was added. The mixture was extracted with ethyl acetate (50 mL), and the organic layer was washed with brine (50 mL, twice), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate = 10:1 to 1:1) to afford the methyl 3-(2,2-difluoroethoxy)-5-[(R, R'-amino)methyl]benzoate.

[0468] To a stirred solution of methyl 3-(2,2-difluoroethoxy)-5-[(R, R'-amino)methyl]benzoate (1.0 equiv) in MeOH was added a solution of 4M NaOH (4.0 equiv).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 The mixture was stirred at room temperature for 6 h. Upon reaction completion, an excess amount of 4M HC1 in dioxane was added until pH reached 1 to 3. The solvent was evaporated under reduced pressure. The residue was re-dissolved in MeOH (5 mL) and filtered to remove salt. The solvent was evaporated again, and the crude product was purified through C18 column chromatography (0.1% TFA in H2O / MeCN = 80% to 50%) to afford BA-55, BA-59 to BA-66, BA-69 to BA-75.

[0469] Summary of synthesis of BA-55.methyl 4-(bromomethyl)-2- „ th -1 methyl 2-(2,2-difluoroethoxy)-4-(((2- (2,2-difluoroethoxy)benzoate uoroe an amine f|uoroethyl)amino)methyl)benzoate BA-55

[0470] 2-(2,2-difluoroethoxy)-4-(((2-fluoroethyl)amino)methyl)benzoic acid (BA-55). 'H NMR (400 MHz, D2O) 6 7.68 (d, J= 7.8 Hz, 1H), 7.20 - 7.00 (m, 2H), 6.16 (tt, J= 55.2, 3.9 Hz, 1H), 4.76 -4.73 (m, 2H), 4.64 -4.61 (m, 1H), 4.31 (td, J= 14.3, 3.5 Hz, 2H), 4.23 (s, 2H), 3.37 (dt, J= 27.4, 4.5 Hz, 2H).

[0471] Summary of synthesis of BA-59.CS2CO3 NaOH DMF MeOH, H2Omethyl 4-(bromomethyl)-2- methyl 4-(2,2-difluoroethoxy)benzoate phenylmethanamine ((benzylamino)methyl)-2-(2,2-difluoroethoxy)benzoate

[0472] 4-((benzylamino)methyl)-2-(2,2-difluoroethoxy)benzoic acid (BA-59). ¹H NMR (400 MHz, MeOD) 6 7.77 (d, J= 8.2 Hz, 1H), 7.54 - 7.33 (m, 5H), 7.15 (s, 2H), 6.44 - 5.99 (m, 1H), 4.35 (td, J= 14.3, 4.2 Hz, 2H), 4.25 (d, J= 4.4 Hz, 4H).

[0473] Summary of synthesis of BA-60.CS2CO3 NaOH DMF MeOH, H2Omethyl 2-(2,2-difluoroethoxy)-4- methyl 4-(bromomethyl)-2- (4-(2,2-difluoroethoxy)benzoate (trifluoromethyl)ph «(4- enyl)methanamine (trifluoromethyl)benzyl)amino)methyljbenzoateAttorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0474] 2-(2,2-difluoroethoxy)-4-(((4-(trifluoromethyl)benzyl)amino)methyl)benzoic acid (BA-60). 'H NMR (400 MHz, D2O) 67.79 - 7.68 (m, 3H), 7.56 (d, J= 8.5 Hz, 2H), 7.17 - 7.11 (m, 2H), 6.40 - 6.06 (m, 1H), 4.42 - 4.23 (m, 6H).

[0475] Summary of synthesis of BA-61.methyl 4-(bromomethyl)-2- P-trifluoroethan-1 -aminemethyl 2-(2,2-difluoroethoxy)-4-(((2,2,2- BA-61 (2,2-difluoroethoxy)benzoate ’ ’ trifluoroethyl)amino)methyl)benzoate

[0476] 2-(2,2-difluoroethoxy)-4-(((2,2,2-trifluoroethyl)amino)methyl)benzoic acid (BA-61). ‘HNMR (400 MHz, MeOD) 67.76 (d, J= 8.0 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J= 8.0 Hz, 1H), 6.24 (tt, J= 52.0, 4.0 Hz, 2H), 4.47 - 4.33 (m, 4H), 3.96 (q, J= 8.0 Hz, 2H).

[0477] Summary of synthesis of BA-62.NaOH MeOH, H2Omethyl 4-(bromomethyl)-2- methyl 2-(2,2-difluoroethoxy)-4- (2 2-methylpropan-1 -amine BA-62,2-difluoroethoxy)benzoate ((isobutylamino)methyl)benzoate

[0478] 2-(2,2-difluoroethoxy)-4-((isobutylamino)methyl)benzoic acid (BA-62). ’ll NMR (400 MHz, MeOD) 6 7.67 (d, J= 7.7 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J= 7.7 Hz, 1H), 6.29 (tt, J= 55.5 Hz, 1H), 4.42 - 4.34 (m, 2H), 4.23 (s, 2H), 2.89 (d, J= 7.2 Hz, 2H), 2.00 (dq, J= 7.2, 6.4 Hz, 1H), 0.93 (d, J= 6.7 Hz, 6H).

[0479] Summary of synthesis of BA-63.NaOH MeOH, H2Omethyl 4-(((5-cyclopropyl-1H- methyl 4-(bromomethyl)-2- 5-cyclopropyl-1H- pyrazol-3-yl)amino)methyl)-2- BA-63 (2,2-difluoroethoxy)benzoate pyrazol-3-amine (2,2-difluoroethoxy)benzoate

[0480] 4-(((5-cyclopropyl-lH-pyrazol-3-yl)amino)methyl)-2-(2,2-difluoroethoxy)benzoic acid (BA-63). 'H NMR (400 MHz, MeOD) 67.79 (d, J= 7.7 Hz, 1H), 7.23 (s, 1H), 6.97 (d, J= 8.0 Hz, 1H), 6.45 - 6.04 (m, 1H), 5.46 (s, 2H), 4.42 - 4.33 (m,Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 2H), 2.00 - 1.91 (m, 1H), 1.16 (d, J= 8.3 Hz, 2H), 0.92 (d, J= 5.4 Hz, 2H).

[0481] Summary of synthesis of BA-64.

[0482] 2-(2,2-difluoroethoxy)-4-(piperazin-l-ylmethyl)benzoic acid (BA-64). ’l l NMR (400 MHz, MeOD) 6 7.87 (d, J= 9.5 Hz, 1H), 7.61 (s, 1H), 7.35 (d, J= 9.5 Hz, 1H), 6.48 - 6.07 (m, 1H), 4.57 (s, 2H), 4.45 (td, J= 13.5, 4.0 Hz, 2H), 3.75 - 3.61 (m, 8H).

[0483] Summary of synthesis of BA-65.methyl 4-(bromomethyl)-2- methyl 2-(2,2-difluoroethoxy)-(2,2-difluoroethoxy)benzoate prop-2-yn-1 -amine 4-((prop-2-yn-1- BA-65ylamino)methyl)benzoate

[0484] 2-(2,2-difluoroethoxy)-4-((prop-2-yn-l-ylamino)methyl)benzoic acid (BA-65). ¹H NMR (400 MHz, MeOD) 67.87 (d, J= 8.0 Hz, 1H), 7.35 (s, 1H), 7.24 (d, J= 7.8 Hz, 1H), 6.26 (tt, J= 54.9, 3.9 Hz, 1H), 4.45 - 4.32 (m, 4H), 4.02 (s, 2H), 2.69(m, 1H).

[0485] Summary of synthesis of BA-66.methyl 2-(2,2- methyl 4-(bromomethyl)-2- 1 -methylpiperazine difluoroethoxy)-4-((4-(2,2-difluoroethoxy)benzoate methylpiperazin-1-yl)methyl)benzoate

[0486] 2-(2,2-difluoroethoxy)-4-((4-methylpiperazin-l-yl)methyl)benzoic acid (BA-66).XH NMR (400 MHz, MeOD) 6 7.87 (d, J= 8.1Hz, 1H), 7.51 (s, 1H), 7.29 (d, J= 8.1 Hz, 1H), 6.43 - 6.10 (m, 1H), 4.52 - 4.31 (m, 4H), 3.89 - 3.39 (m, 8H), 3.02 (s, 3H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0487] Summary of synthesis of BA-69.CS2CO3 NaOH DMF MeOH, H2Omethyl 2-(2,2- methyl 4-(bromomethyl)-2- 2-morpholinoethan-1 -amine difluoroethoxy)-4-(((2-(2,2-difluoroethoxy)benzoate morpholinoethyl)amino)methyl)benzoate

[0488] 2-(2,2-difluoroethoxy)-4-(((2-morpholinoethyl)amino)methyl)benzoic acid (BA-69). ‘HNMR (400 MHz, MeOD) 67.88 (d, J= 8.0 Hz, 1H), 7.50 (s, 1H), 7.29 (d, J= 8.0 Hz, 1H), 6.46 - 6.06 (m, 1H), 4.48 - 4.35 (m, 4H), 4.09 - 3.94 (m, 4H), 3.69 - 3.62 (m, 2H), 3.61 - 3.53 (m, 2H), 3.49 - 3.34 (m, 4H).

[0489] Summary of synthesis of BA- 70.CS2CO3 DMF,,.. „ methyl 2-(2,2-difluoroethoxy)-4- methyl 4-(bromomethyl)-2-,,......., ’.., ",, „.4 '. 3-(pyrro idin-1-y )propan-1 -amine <((3-(pyrro lidm-1- BA-70 (2,2-difluoroethoxy)benzoate > / r r w w- / ' ” y )propy )ammo)methy I benzoate

[0490] 2-(2,2-difluoroethoxy)-4-(((3-(pyrrolidin-l-yl)propyl)amino)methyl)benzoic acid (BA-70). ¹H NMR (400 MHz, MeOD) 67.87 (d, J= 7.8 Hz, 1H), 7.49 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 6.48 - 6.08 (m, 1H), 4.43 (tt, J= 13.6, 3.4 Hz, 2H), 4.33 (s, 2H), 3.72 (t, J = 10.7 Hz, 2H), 3.33 (s, 2H), 3.26 (t, J= 7.8 Hz, 2H), 3.20 - 3.08 (m, 2H), 2.33 - 2.23 (m, 2H), 2.18 (m, 2H), 2.12 - 2.01 (m, 2H).

[0491] Summary of synthesis of BA- 71.

[0492] 4-(((2-aminoethyl)amino)methyl)-2-(2,2-difluoroethoxy)benzoic acid (BA-71). ¹H NMR (400 MHz, D2O) 67.55 (d, J= 7.7 Hz, 1H), 7.20 - 7.06 (m, 2H), 6.37 - 5.98 (m, 1H), 4.40 - 4.21 (m, 4H), 3.43 (d, J= 6.3 Hz, 2H), 3.39 (d, J= 6.3 Hz, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0493] Summary of synthesis of BA- 72.NaOH MeOH, H2Omethyl 4-(bromomethyl)-2- methyl 2-(2,2-difluoroethoxy)-4- naphthalen-1 -amine ((naphthalen-1- BA-72 (2,2-difluoroethoxy)benzoate ylamino)methyl)benzoate

[0494] Methyl 2-(2,2-difluoroethoxy)-4-((naphthalen-l-ylamino)methyl) benzoic acid (BA-72). ¹H NMR (400 MHz, MeOD) 68.16 - 8.09 (m, 1H), 7.82 - 7.73 (m, 2H), 7.49 - 7.41 (m, 2H), 7.23 - 7.13 (m, 4H), 6.43 (d, J= 7.3 Hz, 1H), 6.16 (tt, J= 55.2, 4.0 Hz, 1H), 4.62 (s, 2H), 4.24 (td, J= 12.8, 4.0 Hz, 2H).

[0495] Summary of synthesis of BA- 73.methyl 4-(bromomethyl)-2- methyl 2-(2,2-difluoroethoxy)-4- (2,2-difluoroethoxy)benzoate methyl 4-aminobutanoate (((4-methoxy-4- BA-73oxobutyl)amino)methyl)benzoate

[0496] 2-(2,2-difluoroethoxy)-4-((naphthalen-l-ylamino)methyl)benzoic acid (BA- 73). 'H NMR (400 MHz, MeOD) 67.81 (d, J= 8.0 Hz, 1H), 7.05 (s, 1H), 7.00 (d, J= 8.0 Hz, 1H), 6.23 (tt, J= 55.8, 4.2 Hz, 1H), 4.51 (s, 2H), 4.34 (td, J= 13.5, 4.2 Hz, 2H), 3.39 (t, J = 6.4 Hz, 2H), 2.47 (t, J= 6.4 Hz, 2H), 2.07 (p, J= 6.4Hz, 2H).

[0497] Summary of synthesis of BA- 74.methyl 4-(bromomethyl)-2-,.. methyl 2-(2,2- / (2o,2-difluoroethoxy \)ubenzoa.te morprholine difluoroethoxy)-4- BA-74(morpholinomethyl)benzoate

[0498] 2-(2,2-difluoroethoxy)-4-(morpholinomethyl)benzoic acid (BA-74). ’l l NMR (400 MHz, MeOD) 67.87 (d, J= 7.8 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J= 7.8 Hz, 1H), 6.27 (tt, J= 55.2, 4.7 Hz, 1H), 4.48 - 4.39 (m, 4H), 4.11 - 3.99 (m, 2H), 3.90 (t, J= 12.4 Hz, 2H), 3.45 - 3.37 (m, 2H), 3.31 - 3.21 (m, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0499] Summary of synthesis of BA- 75.methyl 4-(bromomethyl)-2- methyl 4-((4-acetylpiperazin-1-(2,2-difluoroethoxy)benzoate 1 -(piperazin-1 -yl)ethan-1 -one yl)methyl)-2-(2,2-difluoroethoxy)benzoate

[0500] 4-((4-acetylpiperazin-l-yl)methyl)-2-(2,2-difluoroethoxy)benzoic acid (BA- 75). ¹H NMR (400 MHz, MeOD) δ 7.87 (d, J = 7.8 Hz, 1H), 7.35 (s, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.25 (tt, J = 55.2, 4.8 Hz, 1H), 4.47 – 4.23 (m, 4H), 3.94 – 3.79 (m, 4H), 3.34 – 3.23 (m, 4H), 2.15 (s, 3H).

[0501] Summary of synthesis of BA- 76.

[0502] 2-(2,2-difluoroethoxy)-4-((methyl(2- (methylamino)ethyl)amino)methyl)benzoic acid (BA-76). ’l l NMR (400 MHz, MeOD) 6 7.87 (d, J= 7.9 Hz, 1H), 7.37 (s, 1H), 7.25 (d, J= 7.9 Hz, 1H), 6.24 (tt, J= 55.0, 3.9 Hz, 1H), 4.44 > 4.29 (m, 4H), 3.56 - 3.44 (m, 4H), 2.83 (s, 3H), 2.78 (s, 3H).

[0503] Summary of synthesis of BA-77.NaOH DMF MeOH, H2O 3-(2- methoxyethoxy)p ropan-1-amine methyl 2-(2,2- methyl 4-(bromomethyl)-2- difluoroethoxy)-4-(((3-(2-(2,2-difluoroethoxy)benzoate methoxyethoxy)propyl)amin BA-77o)methyl)benzoate

[0504] 2-(2,2-difluoroethoxy)-4-(((3-(2-methoxyethoxy)propyl)amino)methyl)benzoic acid (BA-77). ¹H NMR (400 MHz, MeOD) δ 7.88 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.23 (dd, J = 7.9, 1.6 Hz, 1H), 6.28 (m, 1H), 4.37 (td, J = 13.4, 4.0 Hz, 2H), 4.29 (s, 2H), 3.69 – 3.61 (m, 4H), 3.59 – 3.51 (m, 2H), 3.32 (s, 3H), 3.24 (t, J = 6.8 Hz, 2H), 2.09 – 1.95 (m, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0505] Summary of synthesis of BA- 78.CS2CO3 NaOH DMF MeOH, H2Omethyl 2-(2,2- methyl 4-(bromomethyl)-2- 3-methoxypropan-1 -amine difluoroethoxy)-4-(((3- (2,2-difluoroethoxy)benzoate methoxypropyl)amino)me BA-78 thyl)benzoate

[0506] 2-(2,2-difluoroethoxy)-4-(((3-methoxypropyl)amino)methyl)benzoic acid (BA-78). ¹H NMR (400 MHz, MeOD) δ 7.88 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 1.5 Hz, 1H), 7.22 (dd, J = 7.9, 1.5 Hz, 1H), 6.26 (tt, J = 55.0, 4.0 Hz, 1H), 4.37 (td, J = 13.4, 4.0 Hz, 2H), 4.27 (s, 2H), 3.54 (t, J = 5.7 Hz, 2H), 3.37 (s, 3H), 3.19 (t, J = 7.2 Hz, 2H), 2.07 – 1.95 (m, 2H).

[0507] Summary of synthesis of BA- 79.CS2CO3 NaOH DMF MeOH, H2Omethyl 4- methyl 4-(bromomethyl)-2- acetimidamide (acetimidamidomethyl)-2-(2,2- BA-79 (2, 2-d if I u 0 roeth oxy )be n zoatedifluoroethoxy)benzoate

[0508] 4-(acetimidamidomethyl)-2-(2,2-difluoroethoxy)benzoic acid (BA-79). ’ll NMR (400 MHz, MeOD) 6 7.86 (d, J= 8.0 Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.42 - 6.07 (m, 1H), 4.55 (s, 2H), 4.37 (td, J= 13.5, 3.9 Hz, 2H), 2.33 (s, 3H).

[0509] Summary of synthesis of BA-80.methyl 2-(2,2- methyl 4-(bromomethyl)-2-pyridin-2-amine difluoroethoxy)-4-((pyridin- (2, 2-d ifluoroethoxy )benzoate2-ylamino)methyl)benzoate

[0510] 2-(2,2-difluoroethoxy)-4-((pyridin-2-ylamino)methyl)benzoic acid (BA-80). ’ll NMR (400 MHz, MeOD) 68.04 - 7.96 (m, 1H), 7.93 - 7.89 (m, 1H), 7.88 - 7.83 (m, 1H), 7.22 (s, 1H), 7.17 - 7.09 (m, 2H), 7.00 - 6.94 (m, 1H), 6.39 - 6.08 (m, 1H), 4.68 (s, 2H), 4.40 -4.31 (m, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0511] Summary of synthesis of BA-81.methyl 4-(bromomethyl)-2- methyl 4-((cyclohexylamino)methyl)- (2,2-difluoroethoxy)benzoate cyclohexanamine 2-(2,2-difluoroethoxy)benzoate BA-81

[0512] 4-((cyclohexylamino)methyl)-2-(2,2-difluoroethoxy)benzoic acid (BA-81). ’ll NMR (400 MHz, MeOD) 6 7.89 (d, J= 8.0 Hz, 1H), 7.32 (s, 1H), 7.23 (d, J= 8.0 Hz, 1H), 6.26 (tt, J= 55.0, 4.0 Hz, 1H), 4.37 (td, J= 13.4, 4.0 Hz, 2H), 4.29 (s, 2H), 3.63 (tt, J= 10.9, 3.9 Hz, 1H), 2.63 - 2.55 (m, 2H), 2.49 - 2.42 (m, 2H), 2.29 - 2.18 (m, 2H), 1.96 - 1.90 (m, 2H), 1.81 - 1.76 (m, 2H).

[0513] Summary of synthesis of BA-82.NaOH DMF MeOH, H2Omethyl 4-(bromomethyl)-2- 2-amino-2- methyl 2-(2,2-d ifluo roethoxy)-4-(((1,3- (2,2-difluoroethoxy)benzoate (hydroxymethyl) dihydroxy-2-(hydroxymethyl)propan-2- BA-82 propane-1,3-diol yl)amino)methyl)benzoate

[0514] 2-(2,2-difluoroethoxy)-4-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)benzoic acid (BA-82). ¹H NMR (400 MHz, MeOD) δ 7.87 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.26 (tt, J = 55.2, 4.0 Hz, 1H), 4.48 – 4.30 (m, 4H), 3.84 (s, 6H).

[0515] General Synthesis Route for Compounds BA-56 to BA-57 and BA-83 to BA-94.methyl 4-acetamido-2-hydroxybenzoate hydroxyalkylated products

[0516] To a stirred solution of compound Methyl 4-acetamido-2-hydroxybenzoate (300 mg, 1.13 mmol) in DMF (1 mL) was added K2CO3 (1.32 g, 9.56 mmol) and R-X (9.56 mmol) at room temperature. The reaction mixture was stirred at 80 °C overnight. Upon reactionAttorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 completion, an excess amount of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL, 2 times) and dried over Na2SO4. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 5:1) to give hydroxyalkylated products.

[0517] To a stirred solution of hydroxyalkylated product (1 equiv) in H₂O (1 mL) was added conc. HCl (1 mL). The reaction was refluxed overnight. Upon reaction completion, the solvent was evaporated under reduced pressure. The crude product was purified through C18 column chromatography (0.1% TFA in H₂O / MeCN = 80%) to afford BA-56 to BA-57 orBA-83 to BA-94.

[0518] Summary of synthesis of BA-56.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2- 1-iodo-2- methyl 4-acetamido-2-hydroxybenzoate methylpropane isobutoxybenzoate

[0519] 4-amino-2-isobutoxybenzoic acid (BA-56). ’l l NMR (400 MHz, D2O) 87.40 (t, J= 7.4 Hz, 1H), 7.03 (d, J= 7.4Hz, 1H), 6.93 (s, 1H), 3.80 (d, J= 6.7 Hz, 2H), 2.12 - 1.84 (m, 1H), 0.93 (d, J= 6.7 Hz, 6H).

[0520] Summary of synthesis of BA-57.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4- methyl 4-acetamido- iodoethane acetamido-2-2-hydroxybenzoate ethoxybenzoate

[0521] 4-amino-2-ethoxybenzoic acid (BA-57). ’l l NMR (400 MHz, D2O) 67.47 - 7.36 (m, 1H), 7.03 (d, <7= 10.9 Hz, 1H), 6.95 (d, J= 7.8 Hz, 1H), 4.19 - 3.96 (m, 2H), 1.40 - 1.26 (m, 3H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0522] Summary of synthesis of BA-83.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2- 1,1,1 -trifluoro-3- methyl 4-acetamido-2-(4,4,4- trifluorobutoxy)benzoate BA-83 hydroxybenzoate iodopropane

[0523] 4-amino-2-(4,4,4-trifluorobutoxy)benzoic acid(BA-83). ’l l NMR (400 MHz, MeOD) 67.81 (d, = 8.5 Hz, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.15 - 7.07 (m, 1H), 4.16 - 4.11 (m, 2H), 2.54 - 2.41 (m, 2H), 2.13 - 2.06 (m, 3H).

[0524] Summary of synthesis of BA-84.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4- methyl 4-acetamido-2- acetamido-2- 3-(iodomethyl)oxetane (oxetan-3- hydroxybenzoate ylmethoxyjbenzoate

[0525] 4-amino-2-(oxetan-3-ylmethoxy)benzoic acid(BA-84). ’l l NMR (400 MHz, MeOD) 67.43 (t, J= 8.0 Hz, 1H), 7.06 (dd, J= 8.0, 4.0 Hz 1H), 7.00 - 6.95 (m, 1H), 4.94 - 4.84 (m, 2H), 4.65 - 4.57 (m, 2H), 4.28 - 4.21 (m, 2H), 3.56 - 3.42 (m, 1H).

[0526] Summary of synthesis of BA-85.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2- methyl 4-acetamido-2-(2- BA-85 hydroxy benzoate 1 -fluoro-2-iodoethane fluoroethoxy)benzoate

[0527] 4-amino-2-(2-fluoroethoxy)benzoic acid(BA-85). ’l l NMR (400 MHz, MeOD) 6 7.72 (d, J= 8.4 Hz, 1H), 7.06 - 6.88 (m, 1H), 6.37 (s, 1H), 4.88 - 4.65 (m, 2H), 4.42 - 4.20 (m, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0528] Summary of synthesis of BA-86.K2CO3cone. HC1 DMF 80 °C H2O Refluxmethyl 4-acetamido-2- tert-butyl 3-(2- tert-butyl 3-(2-(5-acetamido-2- hydroxybenzoate iodoethyl)azetidine-1- (methoxycarbonyl)phenoxy)et BA-86carboxylate hyl)azetidine-1-carboxylate

[0529] 4-amino-2-(2-(azetidin-3-yl)ethoxy)benzoic acid (BA-86). ’l l NMR (400 MHz, MeOD) 67.50 - 7.38 (m, 1H), 7.09 - 6.98 (m, 1H), 6.95 (dd, J= 7.3, 4.5 Hz, 1H), 4.23 -3.93 (m, 4H), 3.73 - 3.67 (m, 1H), 3.63 - 3.45 (m, 1H), 3.25 - 3.17 (m, 1H), 2.22 - 2.04 (m, 2H).

[0530] Summary of synthesis of BA-87.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2- (2- methyl 4-acetamido-2-(2- hydroxybenzoate iodoethyl)cyclopr cyclopropylethoxy)benzoate BA-87opane

[0531] 4-amino-2-(2-cyclopropylethoxy)benzoic acid (BA-87). ’l l NMR (400 MHz, MeOD) 67.40 (t, J= 9.4 Hz, 1H), 6.98 (d, J= 9.4 Hz, 1H), 6.89 (m, 2H,-NH2), 6.43 - 6.29 (m, 1H), 4.10 (t, J= 6.5 Hz, 2H), 1.70 (q, J= 6.5 Hz, 2H), 0.94 - 0.84 (m, 1H), 0.55 - 0.50 (m, 2H), 0.19 - 0.15 (m, 2H).

[0532] Summary of synthesis of BA-88.K2CO3cone HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2- methyl 4-acetamido-2-((6-hydroxybenzoate 6-iodohexan-1-ol hydroxyhexyl)oxy)benzoate

[0533] 4-amino-2-((6-hydroxyhexyl)oxy)benzoic acid (BA-88). ’l l NMR (400 MHz, MeOD) 67.43 (t, J= 7.8 Hz, 1H), 7.07 - 6.92 (m, 3H), 6.47 - 6.34 (m, 1H), 4.04 (t, J= 6.3 Hz, 2H), 3.58 (t, J= 6.5 Hz, 2H), 1.94 - 1.77 (m, 2H), 1.60 - 1.46 (m, 6H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0534] Summary of synthesis of BA-89.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2- 6-(5-acetamido-2- hydroxybenzoate 6-bromohexanoic acid (methoxycarbonyl)phe BA-89noxy)hexanoic acid

[0535] 4-amino-2-((5-carboxypentyl)oxy)benzoic acid (BA-89). ’l l NMR (400 MHz, MeOD) 67.62 (d, J= 8.6 Hz, 1H), 7.44 - 7.26 (m, 1H), 6.96 - 6.91 (m, 1H), 6.27 (dd, J = 8.6, 2.1 Hz, 1H), 4.00 (t, J= 6.3 Hz, 2H), 2.34 (t, J= 7.3 Hz, 2H), 1.84 - 1.76 (m, 2H), 1.67 (h, J= 7.7 Hz, 2H), 1.61 - 1.43 (m, 2H).

[0536] Summary of synthesis of BA-90.OK2CO3 cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido- tert-butyl (2- methyl 4-acetamido-2-(2-((fert- BA-90 2-hydroxybenzoate iodoethyljcarbamate butoxycarbonyl)amino)ethoxy)benzoate

[0537] 4-amino-2-(2-aminoethoxy)benzoic acid (BA-90). ¹H NMR (400 MHz, MeOD) δ 7.71 (m, 1H), 7.45 (m, 1H), 7.07 (m, 2H), 6.40 (d, J = 2.1 Hz, 1H), 4.32 – 4.30 (m, 2H), 3.45 – 3.40 (m, 2H).

[0538] Summary of synthesis of BA-91.O NH K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2-((2-methyl 4-acetamido-2- 5-(bromomethyl)-2- (trifluoromethyl)pyrimidin-5- BA-91hydroxybenzoate (trifluoromethyl)pyrimidine yl)methoxy)benzoate

[0539] 4-amino-2-((2-(trifluoromethyl)pyrimidin-5-yl)methoxy)benzoic acid(BA-91). ¹H NMR (400 MHz, MeOD) 69.02 (s, 2H), 8.21 (s, 1H), 7.77 (d, J= 14.8 Hz, 2H), 7.52 (s, 1H), 7.41 (s, 1H), 6.51 - 6.42 (m, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0540] Summary of synthesis of BA-92.K2CO3 cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2- 4- methyl 4-acetamido-2- hydroxybenzoate (bromomethyl)benzo[ (benzo[c][1,2,5]thiadiazol-4- BA-92c][1,2,5]thiadiazole ylmethoxy)benzoate

[0541] 4-amino-2-(benzo[c][l,2,5]thiadiazol-4-ylmethoxy)benzoic acid(BA-92). ’l l NMR (400 MHz, MeOD) 68.01 (d, J= 9.0 Hz, 1H), 7.95 (d, J= 8.0 Hz, 1H), 7.72 (t, J= 8.0 Hz, 2H), 6.50 (d, J= 2.0 Hz, 1H), 6.32 (dd, J= 9.0, 2.0 Hz, 1H), 5.73 (s, 2H).

[0542] Summary of synthesis of BA-93.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido-2- 3- methyl 4-acetamido-2-((3- hydroxybenzoate (bromomethyl)benze sulfamoylbenzyl)oxy)benzoate BA-93nesulfonamide

[0543] 4-amino-2-((3-sulfamoylbenzyl)oxy)benzoic acid(BA-93). ’l l NMR (400 MHz, MeOD) 67.95 (d, J= 8.5 Hz, 1H), 7.47 (d, J= 8.4 Hz, 1H), 6.90 - 6.78 (m, 4H), 6.72 (d, J = 2.2 Hz, 1H), 4.90 (s, 2H).

[0544] Summary of synthesis BA-94.K2CO3cone. HCI DMF 80 °C H2O Refluxmethyl 4-acetamido- 5-(bromomethyl)-2-methyl- methyl 4-acetamido-2-((2-methyl-4- (trifluoromethyl)thiazol-5- BA-94 2-hydroxybenzoate 4-(trifluoromethyl)thiazoleyl)methoxy)benzoate

[0545] 4 -amino-2-((2-methyl-4-(trifluoromethyl)thiazol-5-yl)methoxy)benzoic acid (BA- 94). 'H NMR (400 MHz, MeOD) 67.02 (t, J= 8.0 Hz, 1H), 6.43 - 6.28 (m, 2H), 5.57 (s, 2H), 2.68 (s, 3H).

[0546] Synthesis of 4-(aminomethyl)-2-(2,2-difluoroethoxy)benzoic acid (BA-58). To a stirred solution of crude product methyl 4-(bromomethyl)-2-(2,2-difluoroethoxy)benzoate (0.54g, 1.74 mmol) in DMF (10 mL) was added NaNs (225.88 mg, 3.47 mmol). The mixture was stirred at room temperature overnight. Upon reaction completion, an excess amount of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL, 2 times) and dried over Na2SO4. The organicAttorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 layer was evaporated under reduced pressure. The residue was re-dissolved in THF (5 mL) and PPh₃ (909.04 mg, 3.47 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 h. Followed by adding water (1 mL) and stirred at room temperature overnight. The reaction was quenched by adding HC1 (1 mol / L, 4 mL). The mixture was extracted with ethyl acetate (10 mL). The aqueous layer was basified by adding concentrated NH₃·H₂O until pH reached 12. The mixture was then extracted with DCM (10 mL, 3 times). The combined organic layer was dried over Na2SO4and was concentrated under reduced pressure. The crude product was purified through C18 column chromatography (0.1% TFA in H2O / MeCN = 50%) to afford BA-58 ester (0.24g, 56.48%).

[0547] To a stirred solution of BA-58 ester (0.1g, 407 pmol) in MeOH (2 mL) was added a solution of 4M NaOH (0.47 mL). The mixture was stirred at room temperature for 6 h. Upon reaction completion, an excess amount of 4M HC1 in dioxane was added until pH reached 1 to 3. The solvent was evaporated under reduced pressure. The residue was re-dissolved in MeOH (5 mL) and filtered to remove salt. The solvent was evaporated again, and the crude product was purified through C18 column chromatography (0.1% TFA in H2O / MeCN = 50%) to afford BA-58 (81 mg, 85.91%).methyl 4-(bromomethyl)-2-(2,2- methyl 4-(azidomethyl)-2-(2,2- BA-58 ester BA-58difluoroethoxy Jbenzoate difluoroethoxy)benzoate

[0548] 4-(aminomethyl)-2-(2,2-difluoroethoxy)benzoic acid (BA-58). ’l l NMR (400 MHz, D2O) 87.72 (d, J= 7.9 Hz, 1H), 7.14 - 7.02 (m, 2H), 6.17 (tt, J= 54.2, 3.4 Hz, 1H), 4.39 -4.23 (m, 2H), 4.12 (s, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0549] Synthesis of 4-acetamido-2-(2,2,2-trifluoroethoxy)benzoic acid (67) and 4-amino-2-(2,2,2-trifluoroethoxy)benzoic acid (BA-68).methyl 4-acetamido-2-(2,2,2-trifluoroethoxy)benzoateBA-67 methyl 4-acetamido-2-(2,2,2-trifluoroethoxy)benzoate BA-68

[0550] To a stirred solution of compound Methyl 4-acetamido-2-hydroxybenzoate (1.0 g, 4.78 mmol) in DMF (5 mL) was added K2CO3 (1.32 g, 9.56 mmol) and l,l,l-trifluoro-2-iodoethane (2.01g, 9.56 mmol) at room temperature. The reaction mixture was stirred at 80 °C overnight. Upon reaction completion, an excess amount of water was added to the reaction mixture. The mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL, 2 times) and dried over Na2SO4. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 5:1) to give methyl 4-acetamido-2-(2,2,2-trifluoroethoxy)benzoate (0.51g, 36.64%).

[0551] To a stirred solution of compound methyl 4-acetamido-2-(2,2,2-trifluoroethoxy)benzoate (0.1 g, 343.4 pM) in MeOH (1 mL) was added a solution of 4M NaOH (0.34 mL). The mixture was stirred at room temperature for 6 h. Upon reaction completion, an excess amount of 4M HC1 in dioxane was added until pH reached 1 to 3. The solvent was evaporated under reduced pressure. The residue was re-dissolved in MeOH (5 mL) and filtered to remove salt. The solvent was evaporated again, and the crude product was purified through C18 column chromatography (0.1% TFA in H2O / MeCN = 90%) to afford BA-67 (67mg, 82.97%).

[0552] 4-acetamido-2-(2,2,2-trifluoroethoxy)benzoic acid (BA-67). ’l l NMR (400 MHz, MeOD) 87.84 (d, J= 8.5 Hz, 1H), 7.62 (s, 1H), 7.22 (d, J= 8.5 Hz, 1H), 4.58 (q, J = 8.5 Hz, 2H), 2.17 (s, 3H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0553] To a stirred solution of compound methyl 4-acetamido-2-(2,2,2-trifluoroethoxy)benzoate (0.1 g, 343.4 pM) in MeOH (3 mL) was added a solution of IM NaOH (1.37 mL). The mixture was stirred at 60 °C overnight. Upon reaction completion, an excess amount of 4M HC1 in dioxane was added until pH reached 1 to 3. The solvent was evaporated under reduced pressure. The residue was re-dissolved in MeOH (5 mL) and filtered to remove salt. The solvent was evaporated again, and the crude product was purified through C18 column chromatography (0.1% TFA in H2O / MeCN = 80%) to afford BA-68 (53 mg, 65.64 %).

[0554] 4-amino-2-(2,2,2-trifluoroethoxy)benzoic acid (BA-68). ’l l NMR (400 MHz, MeOD) 67.70 (dd, J= 8.6, 1.4 Hz, 1H), 6.49 - 6.26 (m, 2H), 4.53 (q, J= 8.6, 2H).

[0555] General synthesis of 4-[(R-aminomethyl)amino]butanoic acid.AcOH (cat.) NaBH(OAc)3+ R-CHO - -OH MeOH HO 4-aminobutanoic acid 4-[(R-aminomethyl)amino]butanoic acid

[0556] To a stirred solution of 4-aminobutanoic acid (1.5 mmol) and R-CHO (1.0 mmol) in MeOH (2 mL) was added one drop of AcOH. The resulting mixture was stirred at 45 °C for 40 min. After that, NaBH(OAc)s (2.0 mmol) was added in portions and the reaction was stirred for 12 h. The reaction was then quenched by the addition of aqueous NaOH (1 M, 5 mL), followed by the addition of ethyl acetate (10 mL). The organic phase was separated and washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (DCM / MeOH = 10:1) to afford the desired product (44% ~ 91%). Deprotection of the Boc group was carried out under the same conditions as described above, affording the corresponding amine.

[0557] Summary of synthesis of BA-95AcOH (cat.) NaBH(OAc)3MeOH 6-(2,2,2- 4-(((6-(2,2,2-trifluoroethoxy)pyridin-3- 4-aminobutanoic acidtrifluoroethoxyjnicotinaldehyde yl)methyl)amino)butanoic acid

[0558] 4-(((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)amino)butanoic acid (BA-95).¹H NMR (400 MHz, CDCh) 68.03 (s, 1H), 7.60 (d, J= 8.5 Hz, 1H), 6.86 (d, J= 8.5 Hz, 1H), 4.76 (q, J= 7.6 Hz, 2H), 4.42 (s, 2H), 3.29 (t, J= 7.3 Hz, 2H), 2.45 (t, J= 7.3 Hz, 2H), 2.02Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 (p, J= 7.3 Hz, 2H).

[0559] Summary of synthesis of BA-96.o AcOH (cat.) NaBH(OAc)3MeOH4-aminobutanoic acid 6,7-dihydro-5 / 7-pyrrolo[1,2- 4-(((6,7-dihydro-5 / 7-pyrrolo[1,2-a]imidazol-2- a]imidazole-2-carbaldehyde yl)methyl)amino)butanoic acid

[0560] 4-(((6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-2-yl)methyl)amino)butanoic acid(BA-96). ¹H NMR (400 MHz, CDCh) 66.84 (s, 1H), 4.38 (s, 2H), 3.95 (t, J= 7.1 Hz, 2H),3.51 (t, J= 7.1 Hz, 2H), 2.87 (t, J= 7.5 Hz, 3H), 2.60 (q, J= 7.5 Hz, 2H), 2.40 (t, J= 8.0 Hz, 2H), 2.00 (p, J = 7.0 Hz, 2H).

[0561] Summary of synthesis of BA-97.F O AcOH (cat) NaBH(OAc)3H2N — N‘OH MeOH N—HOCl Cl4-aminobutanoic acid 5-chloro-3-(difluoromethyl)-1-methyl- 4-(((5-chloro-3-(difluoromethyl)-1-methyl- 1 / - / -pyrazole-4-carbaldehyde 1H-pyrazol-4-yl)methyl)amino)butanoic acid

[0562] 4-(((5-chloro-3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)methyl)amino)butanoic acid (BA-97).1H NMR (400 MHz, MeOD) 66.88 (t, J= 54.1 Hz, 1H), 4.25 (s, 2H), 3.94 (s, 3H), 3.22 - 3.15 (m, 2H), 2.49 (t, J= 7.0 Hz, 2H), 2.01 (p, J= 7.0 Hz, 2H).

[0563] Summary of synthesis of BA-98.o AcOH (cat ) NaBH(OAc)3MeOHtert-butyl 2-formyl-6- 4-(((6-(tert-butoxycarbonyl)-6- 4-aminobutanoic acid azaspiro

[0034] octane-6- azaspiro

[0034] octan-2- 4-(((6-azaspiro

[0034] octan-2-carboxylate yl)methyl)amino)butanoic acid yl)methyl)amino)butanoic acid

[0564] 4-(((6-azaspiro[3.4]octan-2-yl)methyl)amino)butanoic acid (BA-98). 'H NMR(400 MHz, MeOD) δ 3.14 - 2.78 (m, 2H), 2.70 - 2.53 (m, 2H), 2.45 - 2.33 (m, 4H), 2.26 -2.12 (m, 2H), 2.11 - 1.90 (m, 2H), 1.86 - 1.69 (m, 2H), 1.31 (s, 2H), 1.13 (d, J= 6.4 Hz, 2H), 0.91 (d, J= 7.5 Hz, 1H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0565] Summary of synthesis of BA-99.AcOH (cat ) NaBH(OAc)3TFA MeOH DCM tert-butyl (R)-(1-oxopropan- (R)-4-((2-((tert- 4-aminobutanoic acid 2-yl)carbamate butoxycarbonyl)amino)pro (R)-4-((2-aminopropyl)amino)butanoic acidpyl)amino)butanoic acid

[0566] (R)-4-((2-aminopropyl)amino)butanoic acid (BA-99).1H NMR (400 MHz, MeOD) δ 3.64 - 3.54 (m, 2H), 3.51 - 3.43 (m, 1H), 3.41 - 3.25 (m, 2H), 2.43 (t, J= 8.9 Hz, 2H), 2.12 (p, J= 7.6 Hz, 2H), 1.32 (d, J= 6.3 Hz, 3H).

[0567] Summary of synthesis of BA-100.o AcOH (cat.) NaBH(OAc)s TFA MeOH DCMtert-butyl (S)-3- (R)-4-(((4-(tert- (R)-4-((morpholin-3- 4-aminobutanoic acid butoxycarbonyl)morpholin-3-formylmorpholine-4-carboxylate yl)methyl)amino)butanoic acid ylmethyl)amino)butanoic acid

[0568] (R)-4-((morpholin-3-ylmethyl)amino)butanoic acid (BA- 100). 'H NMR (400 MHz, MeOD) δ 4.09 - 3.94 (m, 2H), 3.84 - 3.68 (m, 2H), 3.65 -3.54 (m, 3H), 3.48 - 3.31(m, 3H), 3.27- 3.14 (m, 1H), 2.49 - 2.36 (m, 2H), 2.11 (p, J= 8.0 Hz, 2H).

[0569] Summary of synthesis of BA-101.AcOH (cat.) NaBH(OAc)3MeOH4-aminobutanoic acid 2-methyl-2-(4-(oxetan-3- 4-((2-methyl-2-(4-(oxetan-3-yl)piperazin-1- yl)piperazin-1-yl)propanal yl)propyl)amino)butanoic acid

[0570] 4-((2-methyl-2-(4-(oxetan-3-yl)piperazin-l-yl)propyl)amino)butanoic acid (BA-101). 'H NMR (400 MHz, MeOD) δ 4.66 (dt, J= 37.1, 6.5 Hz, 4H), 3.69 (t, J= 7.1 Hz, 2H), 3.53 (p, J= 6.3 Hz, 1H), 3.38 (s, 2H), 2.87 (s, 4H), 2.62 - 2.24 (m, 6H), 2.05 (p, J= 7.5 Hz, 2H), 1.14 (s, 6H).

[0571] Summary of synthesis of BA-102.o AcOH (cat.) NaBH(OAc)s MeOH tert-butyl 3- 4-(((1-(tert- 4-aminobutanoicacid formylpyrrolidine-1- butoxycarbonyl)pyrrolidin-3- 4-((pyrrolidin-3-carboxylate yl)methyl)amino)butanoic acid ylmethyl)amino)butanoic acid

[0572] 4-((pyrrolidin-3-ylmethyl)amino)butanoic acid (BA- 102). 'H NMR (400 MHz, D2O) δ 3.37 (t, J= 7.2 Hz, 2H), 3.34 - 3.25 (m, 2H), 3.21 (d, J= 7.9 Hz, 2H), 3.17- 3.09 (m, 1H), 2.88 -2.74 (m, 1H), 2.58 (p, J= 7.9 Hz, 1H), 2.30 (t, J= 7.2 Hz, 2H), 2.10 - 1.98 (m,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 1H), 1.95 - 1.87 (m, 2H), 1.67 - 1.49 (m, 1H).

[0573] Synthesis of tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)glycinate.xj II + HNCS2C°3Al A N AJH H tert-butyl 2-bromoacetate tert-butyl (2-aminoethyl)carbamate tert-butyl (2-((fert-butoxycarbonyl)amino)ethyl)glycinate

[0574] To a stirred solution of tert-butyl (2-aminoethyl)carbamate (4.11g, 25.63 mmol) in DMF (20 mL) was added CS2CO3 (3.34g, 10.25 mmol) at room temperature. The mixture was stirred for 30 mins followed by adding tert-butyl 2-bromoacetate (1.0g, 5.13 mmol) dropwise.The resulting mixture was stirred at room temperature for 12 h. The reaction was thenquenched by the addition of brine (200 mL), followed by the addition of ethyl acetate (100 mL). The organic phase was separated and washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (Hexane: Ethyl acetate = 1:1) to afford the desired product as a colorless oil (1.21g, 86%).

[0575] Synthesis of tert-Butyl 2-[(2-(tert-butoxycarbonyl)aminoethyl)(R)amino]acetate and 2-[(2-aminoethyl)(R)amino]acetic acid.I OH9 I Cs2CO31 9? 9 1. TFA R O A A A + R-X — A A A A - - N A0N n0DMF0N H0DCM H?N'^X''-'" AH tert-butyl (2-((tert- tert-Butyl 2-[(2-(tert- butoxycarbonyl)am butoxycarbonyljaminoeth 2-[(2-aminoethyl)(R)amino]acetic acid ino)ethyl)glycinate yl)(R)amino]acetate

[0576] To a stirred solution of tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)glycinate(1.0 mmol) and R-X (1.1 mmol) in DMF (2 mL) was added CS2CO3 (1.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reactionwas then quenched by the addition of brine (20mL), followed by the addition of ethyl acetate (10 mL). The organic phase was separated and washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (Hexane: Ethyl acetate = 5: 1) to afford the desired product (41% ~ 86%).

[0577] To a stirred solution of tert-Butyl 2-[(2-(tert-butoxycarbonyl)aminoethyl)(R)amino]acetate (1.0 mmol) in DCM (2 mL) was added TFA(10 mmol). The resulting mixture was stirred at room temperature for 4h. The solvent was concentrated under reduced pressure. The crude product was purified by columnAttorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 chromatography (Cl 8, Acetonitrile: water = 10 to 90%) to give the title product (74% ~ 95%).

[0578] Summary of synthesis of BA-103.■otert-butyl (2-((tert- 2-bromo-W- tert-butyl A / -(2-((tert- A / -(2-a m I noethyl )-A / -(2- butoxycarbonyljam cyclopropylace butoxycarbonyl)amino)ethyl)-A / -(2- (cyclopropylamino)-2- ino)ethyl (glycinate tamide (cyclopropylamino)-2-oxoethyl)glycinate oxoethyl)g lycine

[0579] N-(2-aminoethyl)-N-(2-(cyclopropylamino)-2-oxoethyl)glycine (BA- 103). 'H NMR (400 MHz, CDCh) δ 5.86 - 5.67 (m, 1H), 5.19 - 5.04 (m, 2H), 4.00 - 3.87 (m, 2H), 3.84 - 3.58 (m, 2H), 3.41 - 3.22 (m, 2H), 2.36 - 2.12 (m, 4H)

[0580] Summary of synthesis of BA-104.Cs2CO3TEA DMF DCMtert-butyl (2-((tert- 4- tert-butyl A / -(benzo[c][1,2, 5]thiadiazol- A / -(2-aminoethyl)-N- butoxycarbonyljam (bromomethyl)benzo[c][ 4-ylmethyl)-N-(2-((tert- (benzo[c][1,2, 5]thiadiazol ino)ethyl)glycinate 1,2,5]thiadiazole butoxycarbonyl)amino)ethyl (glycinate -4-ylmethyl (glycine

[0581] N-(2-aminoethyl)-N-(benzo[c][l,2,5]thiadiazol-4-ylmethyl)glycine (BA-104). 'H NMR (400 MHz, MeOD) δ 8.01 (d, J= 8.6 Hz, 1H), 7.70 - 7.58 (m, 2H), 4.29 (s, 2H), 3.33 - 3.29 (m, 4H), 3.17 - 3.04 (m, 2H).

[0582] Summary of synthesis of BA-105.tert-butyl (2-((tert- tert-butyl A / -(2-((tert- A / -(2-aminoethyl)-A / - 1 -(bromomethyl)cyclopent- butoxycarbonyljam butoxycarbonyl)amino)ethyl)-A / - (cyclopent-1-en-1- 1-eneino)ethyl)glycinate (cyclopent-1 -en-1 -ylmethyljglycmate ylmethyljglycine

[0583] N-(2-aminoethyl)-N-(cyclopent-l-en-l-ylmethyl)glycine (BA-105).XH NMR (400 MHz, MeOD) δ 6.10 (s, 1H), 3.97 (s, 2H), 3.84 (s, 2H), 3.61 (t, J= 5.6 Hz, 2H), 3.51 (t, J = 5.6 Hz, 2H), 2.52 - 2.40 (m, 4H), 2.11 - 1.98 (m, 2H).

[0584] Summary of synthesis of BA-106.Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026tert-butyl (2-((tert- tert-butyl A / -(3-((tert- N-(2-aminoethyl)- / V-(4,4,4- butoxycarbonyl)am 1,1,1 -trifluoro-3-iodopropane butoxycarbonyl)amino)propyl)-A / - ino)ethyl)glycinate (3,3,3-trifluoropropyl)glycinate trifluorobutyl)glycine

[0585] N-(2-aminoethyl)-N-(4,4,4-trifluorobutyl)glycine (BA- 106). 'H NMR (400 MHz, MeOD) δ 3.95 (s, 2H), 3.67 - 3.56 (m, 4H), 3.34 - 3.28 (m, 2H), 2.44 - 2.28 (m, 2H), 2.14 - 2.01 (m, 2H).

[0586] Summary of synthesis of BA-107.DMFtert-butyl (2-((tert- tert-butyl A / -(2-((tert-butoxycarbonyl)amino)ethyl)- / V-(2-aminoethyl)-A / -((2- butoxycarbonyl)am 5-(bromomethyl)-2- (trifluoromethyl)pyrimidine A / -((2-(trifluoromethyl)pyrimidin-5- (trifluoromethyl)pyrimidin-5- ino)ethyl)glycinate yl)methyl)glycinate yl)methyl)g lycine

[0587] N-(2-aminoethyl)-N-((2-(trifluoromethyl)pyrimidin-5-yl)methyl)glycine (BA- 107). 'H NMR (400 MHz, D2O) δ 9.13 (s, 2H), 4.33 (s, 2H), 3.74- 3.73 (m, 3H), 3.37 -3.28 (m, 4H).

[0588] Summary of synthesis of BA-108.TFA H DMF DCMtert-butyl (2-((tert- tert-butyl / V-(2-((tert- 4-(bromomethyl)-1-methyl- / V-(2-aminoethyl)- / V-((1 -methyl- butoxycarbonyl)am butoxycarbonyl)amino)ethyl)- / V-((1-methyl- 1H-pyrazole hydrobromide ino)ethyl)glycinate 1H-pyrazol-4-yl)methyl)g lycine 1H-pyrazol-4-yl)methyl)glycinate

[0589] N-(2-aminoethyl)-N-((l-methyl-lH-pyrazol-4-yl)methyl)glycine (BA-108). 'H NMR (400 MHz, MeOD) δ 7.87 (s, 1H), 7.66 (s, 1H), 4.40 (s, 2H), 3.95 (s, 3H), 3.85 (s, 2H), 3.63 - 3.50 (m, 4H).

[0590] General synthesis of 4-[(R-amino)methyl]thiophene-2-sulfonamide.CS2CO3 + R-XDMF 5-(aminomethyl)thiophene- 4-[(R-amino)methyl]thiophene- 2-sulfonamide2-sulfonamidehydrochloride

[0591] To a stirred solution of 5-(aminomethyl)thiophene-2-sulfonamide hydrochloride (1.0 mmol) and R-X (0.7 mmol) in DMF (2 mL) was added CS2CO3 at room temperature.Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026 The resulting mixture was stirred at room temperature for 12 h. The reaction was then quenched by the addition of brine (20 mL), followed by the addition of ethyl acetate (10 mL). The organic phase was separated and washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (Hexane / Ethyl acetate = 1:1) to afford the desired product (27% ~ 62%).

[0592] Summary of synthesis of BA-109.Cs2CO3DMF 5-(((4,4,4- 5-(aminomethyl)thiophene- 1,1,1 -trifluoro-4-iodobutane trifluorobutyl)amino)methyl 2-sulfonamide hydrochloride )thiophene-2-sulfonamide

[0593] 5-(((4,4,4-trifluorobutyl)amino)methyl)thiophene-2-sulfonamide (BA- 109).JH NMR (400 MHz, MeOD) δ 7.46 (d, J= 3.8 Hz, 1H), 6.97 (d, J= 3.8 Hz, 1H), 4.47 (s, 2H), 4.15 (t, J= 6.3 Hz, 2H), 2.35 - 2.22 (m, 3H), 1.95 - 1.87 (m, 2H).

[0594] Summary of synthesis of BA-110.5-(aminomethyl)thiophene-2- 5-(bromomethyl)-2- 5-((((2-(trifluoromethyl)pyrimidin-5- sulfonamide hydrochloride (trifluoromethyl)pyri yl)methyl)amino)methyl)thiophene- midine 2-sulfonamide

[0595] 5-((((2-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)methyl)thiophene-2-sulfonamide (BA-110). 'H NMR (400 MHz, MeOD) δ 8.99 (d, J= 12.8 Hz, 2H), 7.47 (dd, J = 10.1, 3.8 Hz, 1H), 6.99 (dd, J= 10.1, 3.8 Hz, 1H), 5.30 (s, 2H), 4.50 (s, 2H).

[0596] Summary of synthesis of BA-111.Cs2CO3DMF5-(aminomethyl)thiophene-2- 1, 1 -difluoro-2- 5-(((2,2- sulfonamide hydrochloride difluoroethyl)amino)methy iodoethane l)thiophene-2-sulfonamide

[0597] 5-(((2,2-difluoroethyl)amino)methyl)thiophene-2-sulfonamide (BA-111). 'H NMR (400 MHz, MeOD) δ 7.55 (d, J= 4.0 Hz, 1H), 7.17 (d, J= 4.0 Hz, 1H), 5.89 (tt, J= 55.8, 4.0 Hz, 1H), 4.22 (s, 2H), 3.32 - 3.27 (m, 2H).Attorney Docket No.: 0019240.01354WO1 Date of Electronic Filing: February 19, 2026

[0598] Summary of synthesis of BA-112.5-(((2- 5-(aminomethyl)thiophene-2- (2- iodoethyl)cy cyclopropylethyl)amin sulfonamide hydrochloride o)methyl)thiophene-2- clopropane sulfonamide

[0599] 5-(((2-cyclopropylethyl)amino)methyl)thiophene-2-sulfonamide (BA-112). 'H NMR (400 MHz, MeOD) δ 7.53 (d, J= 3.8 Hz, 1H), 7.21 (d, J= 3.8 Hz, 1H), 4.28 (s, 2H), 3.07 - 3.00 (m, 2H), 1.43 - 1.36 (m, 2H), 0.75 - 0.63 (m, 1H), 0.46 - 0.41 (m, 2H), 0.07 - 0.02 (m, 2H).

[0600] Summary of synthesis of BA-113.5-(aminomethyl)thiophene- 4- 5-(((benzo[c][1,2,5]thiadiazol-4- 2-sulfonamide (bromomethyl)benzo[c ylmethyl)amino)methyl)thiophen hydrochloride ][1,2,5]thiadiazole e-2-sulfonamide

[0601] 5-(((benzo[c][l,2,5]thiadiazol-4-ylmethyl)amino)methyl)thiophene-2-sulfonamide (BA-113).XH NMR (400 MHz, MeOD) δ 7.93 (dd, J= 8.4, 1.6 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.47 (d, J= 3.8 Hz, 1H), 6.98 (d, J= 3.8 Hz, 1H), 4.31 (s, 2H), 4.05 (s, 2H).

[0602] Synthesis of tert-butyl ((1 s,4s)-4-(2-(((5-methyl-l,2,4-oxadiazol-3-yl)methyl)amino)-2-oxoethyl)cyclohexyl)carbamate andN-((5-methyl-l,2,4-oxadiazol-3-yl)methyl)-2-((ls,4s)-4-(((2-(trifluoromethyl)pyrimidin-5-yl) methyl) amino) cyclohexyl) acetamide (BA-114).DMAP EDC HCI TEA DCM tert-butyl ((1s,4s)-4- 2-((1s,4s)-4-((tert- (2-(((5-methyl-1,2,4- butoxycarbonyl)amino (5-methyl-1,2,4-oxadiazol-3- oxadiazol-3- )cyclohexyl)acetic acid yl)methanamine hydrochloride2-((1s,4s)-4-aminocyclohexyl)-A / - 5-(bromomethyl)-2- A / -((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2- ((5-methyl-1,2,4-oxadiazol-3- ((1s,4s)-4-(((2-(trifluoromethyl)pyrimidin-5- yl)methyl)acetamide (trifluoromethyl)pyrimidine yl)methyl)amino)cyclohexyl)acetamideAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0603] Summary of synthesis of BA-114. To a stirred solution of 2-((\s,4.s)-4-((lerl-butoxycarbonyl)amino)cyclohexyl)acetic acid (200 mg, 777.21 mmol) and (5-methyl-l,2,4-oxadiazol-3-yl)methanamine hydrochloride (116.3 mg, 777.52 mmol) in dry DCM (3 ml) was added DMAP(9.5 mg, 777.72 mmol), TEA (120mg, 1.19 mmol) and EDC (200mg, 1.04 mmol) at room temperature. The mixture was stirred at r.t. overnight. Then 3 ml H2O was added to quench the reaction and 10 mL ethyl acetate was added. The organic phrase was collected and washed with brine (3 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the crude product, which was then purified by column chromatography (silica gel, Hexane: Ethyl acetate= 1:1) to give a colorless oil (256.3g, 94%). Deprotection of the Boc group was carried out under the same conditions as described above, affording the corresponding amine.

[0604] To a stirred solution of 2-((ls,4s)-4-aminocyclohexyl)-N-((5-methyl-l,2,4-oxadiazol-3-yl)methyl)acetamide (52mg, 215.76pmol) in DMA (5 mL) was added Cs2CO3 (139.46mg, 428.03 pmol), and the mixture as stirred for 10 min. Then 5-(bromomethyl)-2-(trifluoromethyl) pyrimidine (140mg, 510.3pmol) was added, and the reaction was stirred at room temperature overnight. Upon reaction completion, water (30 mL) was added, and the mixture was extracted with ethyl acetate (5 mL). The organic layer was washed with brine (30 mL, 2 times) and dried over Na2SO4. The organic layer was evaporated under reduced pressure. The crude product was purified through column chromatography (silica gel, hexane / ethyl acetate = 1:1) to afford the desired product as oil (121.33 mg, 83% yield). 'H NMR (400 MHz, MeOD) 88.98 (s, 2H), 4.46 (s, 2H), 3.92 (s, 2H), 2.81 - 2.68 (m, 1H), 2.58 (s, 3H), 2.26 (d, J= 7.4 Hz, 2H), 2.08 - 1.96 (m, 1H), 1.74 - 1.60 (m, 4H), 1.60 - 1.47 (m, 4H).

[0605] General synthesis of N, N-(R, R f4-chloro-5-sulfamoyl-2-l(tetrahydrofuran-2-yl) methyl jaminojbenz amide.4-chloro-5-sulfamoyl-2- N, N-(R, R')-4-chloro-5-sulfamoyl-2- (((tetrahydrofuran-2- [(tetrahydrofuran-2- yl)methyl)amino)benzoic acid yl)methyl]amino]benzamide

[0606] To a stirred solution of 4-chloro-5-sulfamoyl-2-(((tetrahydrofuran-2-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 yl)methyl)amino)benzoic acid (1.0 mmol), amine (1.5 mmol) and TEA (1.5 mmol) in DMF(2 mL) was added EDC-HC1 (1.5 mmol) at room temperature. The resulting mixture wasstirred at room temperature for 12 h. The reaction was then quenched by the addition of aqueous HC1 (1 M, 5 mL), followed by the addition of ethyl acetate (10 mL). The organic phase was separated and washed with brine (10 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (Hexane / Ethyl acetate = 5:1) to afford the desired product(66% ~ 89%). Deprotection of the Boc group was carried out under the same conditions as described above, affording the corresponding amine.

[0607] Summary of synthesis of BA- 115O-f4-chloro-5-sulfamoyl-2- 2-chloro-5-(4,4-difluoropiperidine-1-carbonyl)-4- (((tetrahydrofuran-2- 4,4-difluoropiperidine (((tetrahydrofuran-2- yl)methyl)amino)benzoic acid yl)methyl)amino)benzenesulfonamide

[0608] 2-chloro-5-(4,4-difluoropiperidine-l-carbonyl)-4-(((tetrahydrofuran-2-yl)methyl)amino)benzenesulfonamide (BA-115). I I WIR (400 MHz, CDCh) 87.80 (s,1H), 6.80 (s, 1H), 6.26 - 6.07 (m, 1H, -NH-), 5.06 (s, 2H,-SO2NH2), 4.23 - 4.03 (m, 1H),3.98 - 3.87 (m, 1H), 3.87 - 3.77 (m, 1H), 3.77 - 3.65 (m, 3H), 3.40 - 3.10 (m, 2H), 2.16 -1.90 (m, 7H), 1.76 - 1.53 (m, 2H).

[0609] Summary of synthesis of BA-116.4-chloro-5-sulfamoyl-2-. „... ■ 4-chloro-A / -(pyrazin-2-ylmethyl)-5- (,(,(,t,et.ra.hyd,rof,uran-2- pyrazin-2-ylmethanamme sulfamoyl- f2-(((tetrahydrof,uran L-2,-yl)methyl)amino)benzoic acidyyl)methyl)amino)benzamide

[0610] 4-chloro-N-(pyrazin-2-ylmethyl)-5-sulfamoyl-2-(((tetrahydrofuran-2-yl)methyl)amino)benzamide (BA-116). ¹H NMR (400 MHz, CDCh) 68.08 (s, 1H), 6.90 - 6.83 (m, 3H), 6.75 (s, 1H), 5.17 (s, 1H, -NH-), 4.43 -4.28 (m, 2H, -SO2NH2), 4.19 - 4.13 (m, 1H), 4.03 - 3.93 (m, 2H), 3.85 - 3.63 (m, 2H), 3.42 - 3.12 (m, 2H), 2.12 - 2.04 (m, 1H), 2.03 - 1.91 (m, 2H), 1.75 - 1.57 (m, 1H).Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026

[0611] Summary of synthesis of BA-117.NH2o=s=o4-chloro-5-sulfamoyl-2- (2,3- 4-chloro-N-((2,3- (((tetrahydrofuran-2- dihydrobenzo[b][1,4]dio dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-5- yl)methyl)amino)benzoic acid xin-2-yl)methanamine sulfamoyl-2-(((tetrahydrofuran-2- yl)methyl)amino)benzamide

[0612] 4-chloro-N-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-5-sulfamoyl-2-(((tetrahydrofuran-2-yl)methyl)amino)benzamide (BA-117). ¹H NMR (400 MHz, MeOD) 6 8.66 (d, J= 1.6 Hz, 1H), 8.59 (dd, J= 2.6, 1.6 Hz, 1H), 8.51 (d, J= 2.6 Hz, 1H), 8.26 (s,1H), 6.94 (s, 2H), 4.70 (s, 2H), 4.18 - 4.10 (m, 1H), 3.92 - 3.75 (m, 3H), 3.44 - 3.37 (m, 2H), 3.31 - 3.21 (m, 2H), 2.11 - 2.03 (m, 1H), 1.95 (tt, J= 8.3, 5.9 Hz, 2H), 1.75 - 1.65 (m, 1H).

[0613] Summary of BA-118.TEA EDC HCI DMF4-chloro-5-sulfamoyl-2- M-(but-3-en-1-yl)-4-chloro-5-sulfamoyl-2- (((tetrahydrofuran-2- but-3-en-1 -amine hydrochloride (((tetrahydrofuran-2- yl)methyl)amino)benzoic acid yl)methyl)amino)benzamide

[0614] N-(but-3-en-l-yl)-4-chloro-5-sulfamoyl-2-(((tetrahydrofuran-2-yl)methyl)amino)benzamide (BA-118). ¹H NMR (400 MHz, MeOD) 6 8.58 (t, J= 5.4 Hz, 1H), 7.97 (s, 1H), 6.74 (s, 1H), 6.38 (t, J= 5.4 Hz, 1H), 5.92 - 5.70 (m, 1H), 4.20 - 4.06 (m, 1H), 3.98 - 3.75 (m, 2H), 3.45 (q, J= 6.9 Hz, 2H), 3.36 - 3.11 (m, 2H), 2.35 (q, J= 6.9 Hz, 2H), 2.10 - 1.91 (m, 3H), 1.73 - 1.61 (m, 1H).

[0615] Summary of synthesis of BA-119.

[0616] 4-chloro-N-(7-azaspiro[3.5]nonan-l-yl)-5-sulfamoyl-2-(((tetrahydrofuran-2-yl)methyl)amino)benzamide (BA-119). ¹H NMR (400 MHz, MeOD) 68.14 (s, 1H), 6.92 (d, J= 2.8 Hz, 1H), 4.33 -4.21 (m, 1H), 4.19 - 4.06 (m, 2H), 3.97 - 3.88 (m, 1H), 3.81 - 3.63Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 (m, 3H), 3.42 - 3.36 (m, 1H), 3.30 - 3.20 (m, 1H), 2.08 - 2.02 (m, 2H), 2.00 - 1.91 (m, 2H), 1.86 - 1.78 (m, 2H), 1.75 - 1.55 (m, 6H).

[0617] References1. Johnson, A. A., et al., Bestrophin 1 and retinal disease. Prog Retin Eye Res, 2017.2. Owji, A. P., et al., Structure and Function of the Bestrophin family of calcium-activated chloride channels. Channels (Austin), 2021. 15(1): p. 604-623.3. Petrukhin, K., et al., Identification of the gene responsible for Best macular dystrophy. Nat Genet, 1998. 19(3): p. 241-7.4. Navines-Ferrer, A., et al., Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation. Int J Mol Sci, 2022. 23(13).5. Ji, C., et al., Investigation and Restoration ofBESTl Activity in Patient-derived RPEs with Dominant Mutations. Sci Rep, 2019. 9(1): p. 19026.6. Li, Y., et al., Patient-specific mutations impair BESTROPHINl's essential role in mediating Ca2+ -dependent Cl- currents in human RPE. Elife, 2017. 6.7. Wang, J., et al., GAD65 tunes the junctions of Best 1 as a GABA receptor and a neurotransmitter conducting channel. Nat Commun, 2024. 15(1): p. 8051.8. Owji, A. P., et al., Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment. Nat Commun, 2024. Accepted

Claims

Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 CLAIMSWhat is claimed is:

1. A compound of Formula I:Ior a pharmaceutically acceptable enantiomer, salt, or solvate thereof, wherein:Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -N(R2)SO2R1, NO2, - P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R2)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci- Cehaloalkyl, Ci-Cealkyl-ORa, Ci-Ce haloalkoxy, Ci-Ce alkanoyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci- C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci- C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci- Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryleach occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci- Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl- heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci- C6alkylN(Rb)2, -O-Ci-C6alkylORa, -O-Ci-C6alkylheterocyclyl, -O-Ci-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-C6alkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkenylCOORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, C1-C6alkyl-OSORa, C1-C6alkyl-SO2NRa, C1-C6alkyl-OSO2(ORa), C1-C6alkyl-OSO(ORa), C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(RJ)2, Ci-CealkylNfR'k, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-Cealkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR', -Ci-C6alkyl-N(R2)SO2R', Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R')2, -Ci-Cealkyl-OSOR1, -Ci-Cealkyl-OSO(OR1), -Ci-C6alkyl-OSChR1, -Ci-C6alkyl-OSO2(OR1), -(C=NH)R1, or -Ci-C6alkyl-NR3CON(R2)2;wherein if n is 0, R8is Ci-CealkyINfR'h, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-Cealkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R', Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -Ci-Cealkyl-OSO(OR1), -Ci-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), -(C=NH)R1, or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or Cs-Cvcycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, -C(=O)Ci-C6alkyl, CORx, Ci-Cealkylheteroaryl, Ci-Cealkylaryl, Cs-Cgheterospirocycloalkyl or Cs-Cvcycloalkyl; each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2,heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl;wherein if Y1is -SO2N(R1)2 or -N(R2)SO2R1, n is 2, and R5is halogen, -O-Ci-C2alkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, C1-C6alkenyl COORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl; andwherein if Y2is O, R8is Ci-CealkylN(R1)2, Ci-Cealkyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci-Cealkyl-ORa, Ci-Cealkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, heteroaryl, Ci-C6alkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci- Cealkyl-SOR1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci- Cealkyl-OSOR1, -Ci-Cealkyl-OSO(OR1), -Ci-C6alkyl-OSO2R', -Ci-C6alkyl- OSO2(OR1), -(C=NH)RI, or -Ci-C6alkyl-NR3CON(R2)2.

2. The compound of claim 1, wherein:Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci- Cehaloalkyl, Ci-CealkylORa, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci- Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORa, Ci-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci- C6alkylN(Rb)2, -O-Ci-C6alkylORa, -O-Ci-C6alkylheterocyclyl, -O-Ci- Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, - O-Ci-C6alkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, - COORa, -CON(Rb)2, azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is S, -NR7-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R7is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORa, Ci-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci- C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-SRa, Ci-Cealkyl-COOR1, -(C=NH)R1, C3- Cvcycloalkyl, heterocyclyl, Ci-Cealkyl-aryl, Ci-Cealkylheteroaryl, Ci- Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, or heteroaryl; wherein if n is 0, R8is Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3- C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cealkyl-ORX, Ci-Cealkyl-N(RX)2, CORx, or C3-C7cycloalkyl;each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci- C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi- Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci- CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci- Cealkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl.

3. The compound of claim 1 or claim 2, wherein Y1is -COR1, -COOR1, -OCOR1, or -CON(R2)2.

4. The compound any one of claims 1-3, wherein Y1is -COOR1or -CON(R2)2.

5. The compound of any one of claims 1-4, wherein each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, or C3-C7cycloalkyl.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 6. The compound of any one of claims 1-5, wherein each occurrence of R1is independently H or Ci-Cealkyl.

7. The compound of any one of claims 1-6, wherein each occurrence of R1is independently H or CH3.

8. The compound of any one of claims 1-7, wherein each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-Cvcycloalkyl, Ci-C6alkyl-COORa, or Ci-C6alkyl-CON(Rb)2.

9. The compound of any one of claims 1-8, wherein each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkyl-COORa, or Ci-Cealkyl-CON(Rb)2.

10. The compound of any one of claims 1-9, wherein each occurrence of R2is independently H, CH2CH2COOH, or CH2CH2CH2COOH.

11. The compound of any one of claims 1-10, wherein each occurrence of R3is independently H, Ci-Cealkyl, Cs-Cvcycloalkyl.

12. The compound of any one of claims 1-10, wherein Y1has the structureofHO13. The compound of any one of claims 1-10 or 12, wherein Y1has the structure of14. The compound of any one of claims 1-13, wherein L1is absent.

15. The compound of any one of claims 1-13, wherein L1is -(CR4)2-.

16. The compound of any one of claims 1-13 or 15, wherein each occurrence of R4is independently H, halogen, -ORa, or Ci-Cealkyl.

17. The compound of any one of claims 1-13 or 15-16, wherein each occurrence of R4is independently H.

18. The compound of any one of claims 1-17, wherein each occurrence of R5is independently H, halogen, -O-Ci-C2alkyl, -O-Ci-CealkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Cealkylheteroaryl, -O-Ci-C6alkylCOORa, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-C6haloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -COORa, or -CON(Rb)2.

19. The compound of any one of claims 1-18, wherein each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci-CealkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-CealkylCOORa, -N(Rb)2, or Ci-CealkylORa.

20. The compound of any one of claims 1-18, wherein each occurrence of R5is independently H, -OCH2CH2F, -OCH2CHF2, -CH2OCH3, -OCH2CF3, -OCH2CH2CH2CF3, - OCH2CH3, -OCH2CH(CH3)2, -OCH2NH2, -O(CH2)6OH, -OCH2CH2NH2, -O(CH2)6COOH,21. The compound of any one of claims 1-20, wherein n is 0 or 1.

22. The compound of any one of claims 1-20, wherein n is 1.

23. The compound of any one of claims 1-18, wherein m is 1 or 2.

24. The compound of any one of claims 1-23, wherein L2is absent.

25. The compound of any one of claims 1-23, wherein L2is -C(R6)2-.

26. The compound of any one of claims 1-23 or 25, wherein each occurrence of R6is independently H, halogen, -ORa, or Ci-Cealkyl.

27. The compound of any one of claims 1-23 or 25-26, wherein R6is H.

28. The compound of any one of claims 1-27, wherein Y2is -NR7-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-.

29. The compound of any one of claims 1-28, wherein Y2is -NR7-, -NR7CO-, or - NR7COO-.

30. The compound of any one of claims 1-29, wherein Y2is -NR7-.

31. The compound of any one of claims 1-29, wherein Y2is -NR7CO-, or -NR7COO-.

32. The compound of any one of claims 1-31, wherein each occurrence of R7is independently H or Ci-Cealkyl.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 33. The compound of any one of claims 1-32, wherein each occurrence of R7is independently H or CH3.

34. The compound of any one of claims 1-33, wherein R8is H, Ci-Cealkyl, Ci-Cealkynyl, Ci-Cehaloalkyl, Ci-Cealkyl-SRa, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, Ci-Cealkyl-aryl, aryl, heteroaryl, C3-C7cycloalkyl, C1-C6COOR1, (C=NH)R1, Ci-C6alkylORa, or Ci-C6alkylN(Rb)2.

35. The compound of any one of claims 1-34, wherein R8is H, Ci-Cealkyl, Ci-Cealkynyl Ci-Cefluoroalkyl, Ci-Cealkyl-SRa, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, Ci-Cealkyl-aryl, aryl, heteroaryl, C3-C7cycloalkyl, C1-C6COOR1, (C=NH)R1, Ci-CealkylOH, Ci-C6alkylOCH3, Ci-C6alkyl-O-Ci-C6alkylORx, Ci-CealkylNHCEE, or Ci-C6alkylNH2.

36. The compound of any one of claims 1-35, wherein R8is H, CH3, C(CH3)3, CH2CCH, CH2CH(CH3)2, CH2CH2F, CH2CF3, CH2CH2OH, CH2CH2NH2, CH2CH2SCH3, CH2CH2NHCH3, CH2CH2CH2OCH3, CH2CH2CH2COOH, (C=NH)CH3, cyclohexyl, pyridyl,38. The compound of any one of claims 1-37, wherein each occurrence of Rais independently H, Ci-Cealkyl, -Ci-CealkylORx, or Ci-Cehaloalkyl.

39. The compound of any one of claims 1-38, wherein each occurrence of Rais independently H, CH3, -CH2CH2OCH3, or CH2CHF2.

40. The compound of any one of claims 1-39, wherein each occurrence of Rbis independently H, CORx, or Ci-Cealkyl.

41. The compound of any one of claims 1-40, wherein each occurrence of Rbis H, C(=O)CH3, or CH3.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 42. The compound of any one of claims 1-41, wherein each occurrence of Rcis H or Ci-Cealkyl.

43. The compound of any one of claims 1-42, wherein each occurrence of Rxis independently H, Ci-Cealkyl, C3-C7cycloalkyl, Cs-Cvheterocycloalkyl, -OCi-Cealkyl, or Ci-Cehaloalkyl.

44. The compound of claim 1 or claim 2, wherein:Y1is -COOR1or -CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- CealkylORa, aryl, or heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, aryl, or heteroaryl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, Ci-Cealkyl, or Ci- Cehaloalkyl;each occurrence of R5is independently H, halogen, -O-Ci-C6alkyl, -O-Ci- C6alkylN(Rb)2, -O-Ci-C6alkylORa, -O-Ci-C6alkylheterocyclyl, -O-Ci- Cealkylcycloalkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, - O-Ci-C6alkylCOORa, -N(Rb)2, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci- CealkylN(Rb)2, C3-C7cycloalkyl, -COORa, -CON(Rb)2, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, Ci-Cealkyl, or Ci- Cehaloalkyl;Y2is -NR7-, -NR7CO-, or -NR7COO-;each occurrence of R7is independently H, Ci-Cealkyl, or Ci-Cehaloalkyl; R8is H, Ci-Cealkyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci- C6alkylN(Rb)2, Ci-C6alkyl-SRa, Ci-Cealkyl-COOR1, -(C=NH)R1, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkyl-aryl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci- Cealkylcycloalkyl, aryl, or heteroaryl; wherein if n is 0, R8is Ci-Cealkyl, Ci- Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cealkyl-ORX, Ci-Cealkyl-N(RX)2, CORx, or C3-C7cycloalkyl;each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci- C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi- Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci- CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci- Cealkyl, C3-C7cycloalkyl, C3-C7heterocycloalkyl, or Ci-Cehaloalkyl.

45. The compound of any one of claims 1-2 and 44, wherein:Y1is -COOH;L1is absent;each occurrence of R5is independently -O-Ci-C6alkyl, -O-Ci-Ce-alkylaryl, - OCi-Cealkylheteroaryl, or -N(Rb)2;n is 1, 2, or 3;L2is absent or -CH2-;Y2is -NH-;R8is H, Ci-Cealkyl, or Ci-Cehaloalkyl; andeach occurrence of Rbis independently H, Ci-Cealkyl, or Ci-Cehaloalkyl.

46. A compound of Formula II:IIAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 or a pharmaceutically acceptable enantiomer, salt, or solvate thereof; wherein:R9is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, or C3-C7cycloalkyl;R10is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, or Ci-Cealkyl-spirocycloalkyl, or alternatively R9and R10, and the nitrogen atom R9and R10are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry;each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, Ci-Cealkyl, Ci-Cealkenyl, or Ci-Cehaloalkyl;p is 2, 3, or 4;Y3is OR12or N(R13)2;R12is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-CealkylN(Re)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl;each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-C6alkyl-COORd, Ci-C6alkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, or heteroaryl; or alternatively both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry;each occurrence of Rdis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Reis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-CealkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORd, Ci-C6alkylN(Re)2, C3-C7cycloalkyl, Ci-Cealkyl-COORd, Ci-Cealkyl-CON(Re)2, heterocyclyl, Ci-Cealkylaryl, aryl, and / or heteroaryl in R9, R10, R11, R12, R13, Rd, and Rewhere applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -OCi-Cehaloalkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Ryis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, or Ci-Cehaloalkyl; andAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 wherein if R10is H, each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, Ci-Cealkyl, Ci-Cealkenyl; and at least one Reis Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl.

47. The compound of claim 46, wherein R9is H, Ci-Cealkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl.

48. The compound of claim 46 or claim 47, wherein R9is H, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl.CH2CH(CH3)NH2, or CH2CH2F.

50. The compound of any one of claims 46-49, wherein R10is H, Ci-Cealkyl, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl.

51. The compound of any one of claims 46-50, wherein R10is H, Ci-Cealkylheteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heterocyclyl, Ci-Cealkyl-spirocycloalkyl, or Ci-Cehaloalkyl.CH2CH(CH3)NH2, or CH2CH2F.

53. The compound of any one of claims 46-52, wherein R9is H and R10is CH2CH2F, R9is CH2CH2F and R10is H, or R9is CH2CH2F and R10is CH2CH2F.

54. The compound of any one of claims 46-53, wherein each occurrence of R11is independently H, halogen, -ORd, -N(Re)2, or Ci-Cealkyl.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 55. The compound of any one of claims 46-54, wherein each occurrence of R11is independently H, -ORd, or -N(Re)2.

56. The compound of any one of claims 46-55, wherein each occurrence of R11is independently H, -OH, or -NH2.

57. The compound of any one of claims 46-56, wherein p is 3.

58. The compound of any one of claims 46-57, wherein Y3is OR12.

59. The compound of any one of claims 46-58, wherein Y3is OH.

60. The compound of any one of claims 46-58, wherein R12is H, Ci-Cealkyl, or Ci- Cehaloalkyl.

61. The compound of any one of claims 46-57, wherein Y3is N(R13)2.

62. The compound of any one of claims 46-57 or 61, wherein each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkyl-COORd, Ci-Cealkyl-CON(Re)2, or Ci-Cealkylaryl.

63. The compound of any one of claims 46-57 or 61-62, wherein each occurrence of R13is independently H, Ci-Cealkyl, Ci-Cealkyl-COORd, or Ci-Cealkylaryl.

64. The compound of any one of claims 46-57 or 61-63, wherein each occurrence of R13is independently H, CH2CH(CH3)2, CH2CH2COOH, CH2CH2CH2COOH, benzyl, or 4-trifluoromethlybenzyl.

65. The compound of any one of claims 46-57 or 61, wherein both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRe, and optionally substituted by one or more Ry.

66. The compound of any one of claims 46-57, 61, or 65, wherein both occurrences of R13, and the nitrogen atom the two occurrences of R13are connected to, taken together, form a heterocycle optionally comprising one or more O or NRe.O3 67. The compound of any one of claims 46-66, wherein the structural moietyY hasAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 68. The compound of any one of claims 46-67, wherein each occurrence of Rdis independently H or Ci-Cealkyl.

69. The compound of any one of claims 46-68, wherein each occurrence of Reis independently H or Ci-Cealkyl.

70. The compound of any one of claims 46-69, wherein each occurrence of Ryis independently H, halogen, OH, or Ci-Cehaloalkyl.

71. A compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof,Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 202672. The compound of claim 71, wherein the compound is selected from the groupconsisting of and74. A compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof,Fwherein the compound is selected from the group consisting ofAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 75. The compound of claim 74, wherein the compound is selected from the groupF76. A compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof,H, O, A... A.. 4.* wherein the compound is selected from the group consisting ofAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 202677. A compound of Formula IV:Formula IVor a pharmaceutically acceptable enantiomer, salt, or solvate thereof; wherein:Z1 to Z4 are each independently CH, C-L1-Y1, C-L2-Y2, CR5, or N; and Z5 is S, NH, N-L1-Y1, N-L2-Y2, NR5, or O;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), C1-C6alkyl-OSO2Ra, C1-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, -S(O)mRc, C1-C6alkyl, C1-C6alkenyl, C1-C6alkenyl COORa, C1-C6alkyl-SRa, C1-C6alkyl-SO2Ra, C1-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl;n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7COO-, or -NR7CONR7-;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , Ci-C6alkylN(R1)2, Ci-C6alkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-aryl, -Ci-Cealkyl-heteroaryl, -Ci-Cealkyl-cycloalkyl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R')2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-Cealkyl-OSO(OR1), or -Ci-Cealkyl-NR3CON(R2)2; or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-CealkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

78. The compound of claim 77, wherein Zi is CH, C-L1-Y1, C-L2-Y2, or CR5.

79. The compound of claim 77, wherein Z1is CH, N, or CR5.

80. The compound of claim 77 or 78, wherein Z1is C-L1-Y1.

81. The compound of claim 77 or 78, wherein Z1is C-L2-Y2.

82. The compound of any one of claims 77-81, wherein Z2is CH, C-L1-Y1, C-L2-Y2, or CR5.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 83. The compound of any one of claims 77-81, wherein Z2 is CH, N, or CR5.

84. The compound of any one of claims 77-82, wherein Z2 is C-L1-Y1.

85. The compound of any one of claims 77-82, wherein Z2 is C-L2-Y2.

86. The compound of any one of claims 77-85, wherein Z3 is CH, C-L1-Y1, C-L2-Y2, or CR5.

87. The compound of any one of claims 77-85, wherein Z3 is CH or CR5.

88. The compound of any one of claims 77-86, wherein Z3 is C-L1-Y1.

89. The compound of any one of claims 77-86, wherein Z3 is C-L2-Y2.

90. The compound of any one of claims 77-89, wherein Z4 is CH, C-L1-Y1, C-L2-Y2, or CR5.

91. The compound of any one of claims 77-89, wherein Z4 is CH or CR5.

92. The compound of any one of claims 77-90, wherein Z4is C-L1-Y1.

93. The compound of any one of claims 77-90, wherein Z4 is C-L2-Y2.

94. The compound of any one of claims 77-93, wherein Z5 is S, NH, or O.

95. The compound of any one of claims 77-94, wherein Z5 is S.

96. The compound of any one of claims 77-95, wherein L1is absent.

97. The compound of any one of claims 77-96, wherein L1is -C(R4)2-.

98. The compound of any one of claims 77-97, wherein Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, or -OSChCOR1).

99. The compound of any one of claims 77-98, wherein Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, or -NR3COR1.

100. The compound of any one of claims 77-98, wherein Y1is -N(R2)SO2R1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, or -OSO2(OR1).

101. The compound of any one of claims 77-98 and 100, wherein Y1is -N(R2)SO2R1or -SO2N(R1)2.

102. The compound of any one of claims 77-98 and 100-101, wherein Y1is SO2NH2.

103. The compound of any one of claims 77-102, wherein R5is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, Ci-Ce haloalkoxy, heterocyclyl, aryl, or heteroaryl.

104. The compound of any one of claims 77-103, wherein n is 0 or 1.

105. The compound of any one of claims 77-104, wherein L2is absent.

106. The compound of any one of claims 77-104, wherein L2is -C(R6)2-.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 107. The compound of any one of claims 77-106, wherein Y2is O, S, or -NR7-.

108. The compound of any one of claims 77-107, wherein R7is H or Ci-Cealkyl.

109. The compound of any one of claims 77-108, wherein R8is H, Ci-Cealkyl, Ci- Cehaloalkyl, -Ci-Cealkyl-aryl, -Ci-Cealkyl-heteroaryl, or -Ci-Cealkyl-cycloalkyl.

110. The compound of any one of claims 77-109, wherein R8is111. A compound of Formula VII:Formula VIIor a pharmaceutically acceptable enantiomer, salt, or solvate thereof; wherein:Z1is -CH2-, -CHR1-, -C(R1)R2-, -NH-, -N(R1)-, O, or S;Z2is -N(R1)-;Z3is -CH2-, -CHR1-, -C(R1)R2-, -NH-, -N(R1)-, O, or S;Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R1)2, -OSOR1, -OSO(OR1), -OSO2R1, -0S02C0R1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, C1-C6alkyl-SO2N(Ra)2, C1-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, C3-C8cycloalkenyl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 C0N(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is absent, O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-; each occurrence of R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORa, C1-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, , Ci-C6alkylN(R1)2, Ci-C6alkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR1, -Ci-C6alkyl-N(R2)SO2R1, C1-C6alkyl-NO2, -C1-C6alkyl-P(O)(OR1)2, -Ci-C6alkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -C1-C6alkyl-SO2R1, -C1-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R1)2, -Ci-Cealkyl-OSOR1, -C1-C6alkyl-OSO(OR1), -C1-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rcis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORx, Ci-C6alkylN(Rx)2, or C3-C7cycloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 the Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OC1-C6alkyl, -NH2, C1-C6alkyl, C1-C6alkenyl, C1-C6haloalkyl, C1-C6alkylOH, C1-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OC1-C6alkyl, C1-C6alkyl, or C1-C6haloalkyl.

112. The compound of claim 111, wherein Zi is -CH2-, -CHR1-, or -C(R1)R2-.

113. The compound of claim 111 or 112, wherein Zi is -CH2-.

114. The compound of any one of claims 111-113, wherein Z3is -CH2-, -CHR1-, or -C(R1)R2-.

115. The compound of any one of claims 111-114, wherein Z3 is -CH2-.

116. The compound of any one of claims 111-115, wherein R1is H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-aryl, Ci-Cealkyl-heteroaryl, C3-C8cycloalkenyl, heterocyclyl, aryl, or heteroaryl.

117. The compound of any one of claims 111-116, wherein R1is118. The compound of any one of claims 111-117, wherein R2is H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2.

119. The compound of any one of claims 111-118, wherein R2is H.

120. The compound of any one of claims 111-119, wherein L1is absent.

121. The compound of any one of claims 111-119, wherein L1is -C(R4)2-.

122. The compound of any one of claims 111-120, wherein Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, or -NR3CON(R2)2.

123. The compound of any one of claims 111-121, wherein Y1is -COOR1.

124. The compound of any one of claims 111-120, wherein Y1is -COOH.

125. The compound of any one of claims 111-124, wherein L2is absent.

126. The compound of any one of claims 111-124, wherein L2is -C(R6)2-.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 127. The compound of any one of claims 111-126, wherein Y2is O, S, or -NR7-.

128. The compound of any one of claims 111-127, wherein Y2is -NR7-.

129. The compound of any one of claims 111-128, wherein R7is H, Ci-Cealkyl, or Ci- Cehaloalkyl.

130. The compound of any one of claims 111-129, wherein R7is H.

131. The compound of any one of claims 111-130, wherein R8is H, -N(R')2, CI- C6alkylN(R1)2, Ci-Cealkyl, Ci-C6alkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl.

132. The compound of any one of claims 111-131, wherein R8is H.

133. A compound of Formula VIII:n(R5)Formula VIII;or a pharmaceutically acceptable enantiomer, salt, or solvate thereof; wherein:f A )is C3-C8carbocyclyl;Y1is -COOR1or -CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, aryl, heteroaryl, Ci-Cealkyl-aryl, or Ci-Cealkyl-heteroaryl;each occurrence of R2is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, C3-C7cycloalkyl, aryl, heteroaryl, C1-C6alkyl-aryl, or C1-C6alkyl-heteroarylL1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; each occurrence of R5is independently H, halogen, -ORa, -N(Rb)2, Ci-Cealkyl, or Ci-Cehaloalkyl;n is 0, 1, 2, 3, or 4;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl; Y2is O, S, -NR7-, or -NR7CO-;each occurrence of R7is independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;R8is H, Ci-Cealkyl, Ci-Cehaloalkyl, aryl, heteroaryl, Ci-Cealkylaryl, Ci-Cealkylheteroaryl, or -Ci-C6alkyl-CON(R2)2;each occurrence of Rais independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 each occurrence of Rbis independently H, Ci-Cealkyl, or Ci-Cehaloalkyl;the Ci-Cealkyl, Ci-Cehaloalkyl, C3-C7cycloalkyl, Ci-C6alkyl-CON(Rb)2, aryl, and / or heteroaryl in R1, R2, R4, R5, R6, R7, R8, Ra, and Rb, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, and Ci-Cehaloalkyl.

134. The compound of claim 133, whereinis cyclohexyl.

135. The compound of claim 133 or claim 134, wherein Li is -CH2-.

136. The compound of any one of claims 133-135, wherein Yi is -CON(R2)2.

137. The compound of any one of claims 133-136, wherein R2is Ci-Cealkylheteroaryl.

138. The compound of any one of claims 133-137, wherein L1-Y1 has the structure of" O139. The compound of any one of claims 133-138, wherein L2 is absent.

140. The compound of any one of claims 133-139, wherein Y2 is -NR7-.

141. The compound of any one of claims 133-140, wherein R7is H or Ci-Cealkyl.

142. The compound of any one of claims 133-141, wherein Rs is Ci-Cealkylheteroaryl.

143. The compound of any one of claims 133-142, wherein Y2-R8 has the structure of144. The compound of any one of claims 133-143, wherein the compound isN F N FN145. A pharmaceutical composition comprising at least one compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

146. A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 145.

147. The method of claim 146, wherein the subject is a human.

148. The method of any of claims 146-147, wherein the disease or condition is caused by a dysregulation of one or more bestrophins.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 149. The method of any of claims 146-148, wherein the disease or condition is a Bestrophin (Best)-related disease.

150. The method of claim 149, wherein the Bestrophin-related disease is caused by one or more mutations on a gene selected from BEST1, BEST2, BEST3, and BEST4.

151. The method of any of claims 149-150, wherein the Bestrophin-related disease is a bestrophinopathy.

152. The method of claim 151, wherein the bestrophinopathy is Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract, posterior staphyloma syndrome (MRCS syndrome), age-related macular degeneration (AMD), retinitis pigmentosa (RP), or combinations thereof.

153. The method of any one of claims 151-152, wherein the bestrophinopathy is Best vitelliform macular dystrophy (BVMD).

154. The method of any of claims 146-153, wherein the pharmaceutical composition is administered via an ophthalmic route of delivery, an oral route of delivery, or a parenteral route of delivery.

155. The method of claim 154, wherein the pharmaceutical composition is administered via an ophthalmic route of delivery, wherein the pharmaceutical composition is administered topically.

156. The method of claim 155, wherein the pharmaceutical composition is administered via eye drops.

157. A method of maintaining intraocular pressure (IOP) in a subject in need thereof, the method comprising administering the pharmaceutical composition of claim 145, wherein the pharmaceutical composition increases Best2-mediated Ca2+-dependent Cl’ currents in nonpigmented epithelium (NPE) cells.

158. The method of claim 157, wherein the subject is a human.

159. The method of any of claims 157-158, wherein the disease is caused by a dysregulation of one or more bestrophins.

160. The method of any of claims 157-159, wherein the subject suffers from a Bestrophin-related disease.

161. The method of claim 160, wherein the Bestrophin-related disease is associated with increased or decreased intraocular pressure (IOP) in the subject.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 162. The method of any of claims 157-161, wherein the subject suffers from ocular hypertension or ocular hypotension.

163. The method of claim 160, wherein the Bestrophin-related disease is glaucoma, myopia, pigment dispersion syndrome, pseudoexfoliation syndrome, age-related macular degeneration, or combinations thereof.

164. A compound or a pharmaceutically acceptable enantiomer, salt, or solvate thereof, wherein the compound is selected from the group consisting of:Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026O■■■ § — A — Cl i; A # U? —Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026vMt Mt o o2Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 20260 \ 0 0- -0...■'<•.. A. 0 0 ■■■■• 0H H0 0 0 £ 0. A. 0.. 0 **•' * 000 S * 00 0..00 0 0 F“00 0^ K0 0 00Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026' 0 OC?Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 20269 HN HQ ” -s<FCl "Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026□ OAttorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026MH0 HMMM,99Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026165. A pharmaceutical composition comprising at least one compound according to claim 164 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 166. A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 165.

167. A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject a compound of Formula VIII,n(R5)Formula VIII;or a pharmaceutically acceptable enantiomer, salt, or solvate thereof wherein:Y1is -COR1, -COOR1, -OCOR1, -CON(R2)2, -NR3COR1, -N(R2)SO2R1, -NO2, -P(O)(OR1)2, -SR1, -SeR1, -SOR1, -SO2R1, -SO3R1, -SO2N(R2)2, -OSOR1, -OSO(OR1), -OSO2R1, -OSO2(OR1), or -NR3CON(R2)2;each occurrence of R1is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, Ci-C6haloalkoxy, Ci-C6alkanoyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, Ci-C6alkyl-SRa, Ci-C6alkyl-SeRa, Ci-C6alkyl-SORa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-SO2N(Ra)2, Ci-C6alkyl-OSORa, Ci-C6alkyl-OSO(ORa), Ci-C6alkyl-OSO2Ra, Ci-C6alkyl-OSO2(ORa), C3-C7cycloalkyl, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryleach occurrence of R2is independently H, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, Ci-C6alkyl-COORa, Ci-C6alkyl-CON(Rb)2, heterocyclyl, aryl, or heteroaryl, Ci-Cealkyl-aryl, Ci-Cealkyl-heteroaryl, Ci-Cehaloalkyl-aryl, Ci-Cehaloalkyl-heteroaryl; or alternatively any two occurrences of R2, and the nitrogen atom the two occurrences of R2are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of R3is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-CealkylN(Rb)2, or C3-C7cycloalkyl;L1is absent or -C(R4)2-;each occurrence of R4is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;each occurrence of R5is independently H, halogen, -ORa, -O-Ci-Cealkyl, -O-Ci-Cehaloalkyl, -O-Ci-Ce-alkylaryl, -OCi-Cealkylheteroaryl, -O-Ci-CealkylN(Rb)2, -O-Ci-Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkenylCOORa, -O-Ci-C6alkylCOORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-C6alkyl-OSO2(ORa), Ci-C6alkyl-OSO(ORa), Ci-C6haloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-C7cycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl; n is 0, 1, 2, 3, or 4;m is 0, 1, 2, or 3;L2is absent or -C(R6)2-;each occurrence of R6is independently H, halogen, -ORa, -N(Rb)2, C1-C6alkyl, C1-C6alkenyl, or C1-C6haloalkyl;Y2is O, S, -NR7-, -SOR7-, -P(O)(OR7)-, -OC(=O)-, -NR7CO-, -NR7COO-, or -NR7CONR7-;each occurrence of R7is independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CealkylORa, Ci-C6alkylN(Rb)2, or C3-C7cycloalkyl;R8is H, -N(R1)2, Ci-CealkylN(R1)2, Ci-Cealkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-SRa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, heterocyclyl, Ci-Cealkylheteroaryl, Ci-Cealkylheterocyclyl, Ci-Cealkylcycloalkyl, aryl, heteroaryl, Ci-C6alkyl-aryl, -Ci-Cealkyl-COR1, -Ci-Cealkyl-COOR1, -Ci-Cealkyl-OCOR1, -Ci-C6alkyl-CON(R2)2, -Ci-C6alkyl-NR3COR', -Ci-C6alkyl-N(R2)SO2R1, Ci-C6alkyl-NO2, -Ci-C6alkyl-P(O)(OR1)2, -Ci-Cealkyl-SR1, -Ci-Cealkyl-SeR1, -Ci-Cealkyl-SOR1, -Ci-C6alkyl-SChR1, -Ci-C6alkyl-SO3R1, -Ci-C6alkyl-SO2N(R')2, -Ci-Cealkyl-OSOR1, -Ci-C6alkyl-OSO(OR1), -Ci-C6alkyl-OSO2R1, -Ci-C6alkyl-OSO2(OR1), -(C=NH)R1, or -Ci-C6alkyl-NR3CON(R2)2;or alternatively, when Y2is -NR7-, R7and R8, and the nitrogen atom R7and R8are connected to, taken together, form a heterocycle optionally comprising one or more O, S, or NRb, and optionally substituted by one or more Rx;each occurrence of Rais independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;each occurrence of Rbis independently H, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-C6alkylORx, Ci-C6alkylN(Rx)2, -C(=O)Ci-C6alkyl, or C3-C7cycloalkyl;each occurrence of Rcis independently H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkylORx, C1-C6alkylN(Rx)2, or C3-C7cycloalkyl;Attorney Docket No.: 0019240.01354WO1Date of Electronic Filing: February 19, 2026 the Ci-Cealkyl, Ci-Cealkenyl, Ci-C6haloalkyl, Ci-C6alkyl-ORa, Ci-C6alkyl-N(Rb)2, C3-C7cycloalkyl, Ci-Cealkyl-COORa, Ci-Cealkyl-CON(Rb)2, heterocyclyl, aryl, and / or heteroaryl in R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, and Rc, where applicable, are each optionally independently substituted by 1-4 substituents each independently selected from the group consisting of halogen, -OH, -OCi-Cealkyl, -NH2, Ci-Cealkyl, Ci-Cealkenyl, Ci-Cehaloalkyl, Ci-CealkylOH, Ci-C6alkylNH2, C3-C7cycloalkyl, oxo, -CN, -COOH, -CONH2, SO2NH2, heterocyclyl, aryl, or heteroaryl; andeach occurrence of Rxis independently H, halogen, -OH, -OCi-Cealkyl, Ci-Cealkyl, or Ci-Cehaloalkyl; andwherein the disease or condition is a Bestrophin (Best)-related disease.

168. The method of claim 167, wherein each occurrence of R5is independently H, halogen, -ORa, -O-Ci-C6alkyl, -O-Ci-C6haloalkyl, -O-Ci-C6-alkylaryl, -O-Ci-C6alkylN(Rb)2, -O-Ci-CealkylORa, -O-Ci-Cealkylheterocyclyl, -O-Ci-Cealkylcycloalkyl, -N(Rb)2, -S(O)mRc, Ci-Cealkyl, Ci-Cealkenyl, Ci-C6alkenylCOORa, -O-Ci-C6alkylCOORa, Ci-C6alkyl-SRa, Ci-C6alkyl-SO2Ra, Ci-C6alkyl-SO3Ra, Ci-C6alkyl-OSORa, Ci-C6alkyl-SO2NRa, Ci-Cealkyl-OSO2(ORa), Ci-Cealkyl-OSO(ORa), Ci-Cehaloalkyl, Ci-C6alkylORa, Ci-C6alkylN(Rb)2, C3-Cvcycloalkyl, -NRbSO2Rc, -NO2, -CN, -COORa, -CON(Rb)2, -P(O)(OR1)2, -SR1, -SeR1, -OSOR1, -SO2N(R1)2, -OSO2(OR1), -OSO(OR1), azide, heterocyclyl, aryl, or heteroaryl.

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