Cyp26b1 inhibitor compounds and methods of use thereof

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof for inhibiting CYP26B1. Aspects of the present disclosure also include methods of using the compounds to treat diseases or disorders, including, but not limited to, skin disorders, cancer, neurological disorders, heterotopic ossification (HO), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, and diseases or disorders of the eye, including meibomian gland dysfunction and dry eye disease.

Description

CYP26B1 INHIBITOR COMPOUNDS AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 469,762, filed May 30, 2023, the disclosure of which is incorporated herein by reference in its entirety.INTRODUCTION

[0002] Retinoic acid (RA) is an active metabolite of vitamin A existing in several isomeric forms such as all-trans retinoic acid (ATRA), 13-cis retinoic acid (13cisRA), 9-cis retinoic acid (9cisRA) and 9, 13-dicis retinoic acid. Epidemiological data as well as animal studies have shown that RA is essential for a wide variety of biological processes including maintenance of skin and epithelial cells, regulation of apoptosis, maintenance and regulation of immunity, placental development and maintenance, and embryogenesis (Marill J, et al., Curr Drug Metab 2003; 4: 1- 10). Due to its many roles, it is of critical importance to control RA concentrations in various tissues.

[0003] Cytochrome P450 enzymes, namely CYP26, are believed to be responsible for clearing RA from various tissues in the body. Studies have shown that CYP26 inhibitors may be useful as therapeutic agents since they block RA clearance resulting in increased RA concentrations. For example, ketoconazole is a broad spectrum inhibitor of fungal cytochrome P450 enzymes. Following a dose of ketoconazole, cortisol response to adrenocorticotropic hormone (ACTH) is found to be inhibited, making ketoconazole useful as an inhibitor of steroid biosynthesis as a treatment for prostate cancer (Pont A, et.al. Ann Intern Med. 1982;97(3):370- 372). A compound similar to ketoconazole, liarozole inhibits testosterone biosynthesis in male rats and dogs (Mahler C, et.al. Prog Clin Biol Res. 1989; 303:205-209). In subsequent studies, compounds based on retinoic acid, a natural substrate of CYP26, were modified to generate CYP26-specific inhibition.

[0004] There still remains a need to develop compounds to be used in pharmaceutical compositions, and having improved biological activity as CYP26 inhibitors, in particular CYP26B1.SUMMARY

[0005] The present disclosure provides compounds and pharmaceutically acceptable salts thereof for inhibiting CYP26B1. Aspects of the present disclosure also include methods of using the compounds to treat diseases or disorders, including, but not limited to, skin disorders, cancer, neurological disorders, heterotopic ossification (HO), fibrodysplasia ossificans progressiva(FOP), multiple osteochondromas, and diseases or disorders of the eye, including meibomian gland dysfunction and dry eye disease.

[0006] Aspects of the present disclosure include a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7,Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:wherein:R1, R6, R10, R14, R26, R30, R34, R37, R40, R46, R64, and R65are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl;R2, R7, R11, R15, R18, R23, R27, R41, R43, R47, R50, and R66are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl;R3, R12, R16, R19, R24, R28, R31, R35, R44, R48, R51, and R67are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl;R4, R8, R17, R20, R25, R29, R32, R38, R45, R49, R52, and R68are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; andR5, R9, R13, R21, R22, R33, R36, R39, R42, and R69are each independently H or C1-6alkyl;wherein:R70is H or -CH3;R71is H or -CH3;R72and R73are each independently selected from H, F, and -CH3;X7is O, S, or NR74, wherein R74is H or -CH3; andR53is of the formula (la) or (lb):wherein: n is 0 or 1;X1, X3, X4, and X6are each independently selected from C and N, and X2and X5are each independently selected from C, N, S, and O, and wherein at least one of X1, X2, X3, X4, and X5is N, S, or O when n is 0, and at least one of X2, X3, X4, X5, and X6is N when n is 1; andR54, R55, R56, R57and R58are each independently absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-memberedheterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl, and wherein at least one of R54, R55, R56, R57and R58is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl;R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or wherein two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl, andwherein at least one of the following is present:(1) R53is of the formula (la):(2) R53is of the formula (lb):(lb), and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl;is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl;(4)is selected from moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15; andor, and

[0007] In certain embodiments, the compound is a compound of the Formula (IIA):each as described herein.

[0008] In certain embodiments, n is i.

[0009] In certain embodiments, X2is N.

[0010] In certain embodiments, X4is N.

[0011] In certain embodiments, X6is N.

[0012] In certain embodiments, X2and X6are each N.

[0013] In certain embodiments, X2and X4are each N.

[0014] In certain embodiments, X4and X6are each N.

[0015] In certain embodiments, n is 0.

[0016] In certain embodiments, X2and X4are each N.

[0017] In certain embodiments, X3and X4are each N.

[0018] In certain embodiments, X3and X5are each N.

[0019] In certain embodiments, X4and X5are each N.

[0020] In certain embodiments, X1and X2are each N.

[0021] In certain embodiments, X1and X5are each N.

[0022] In certain embodiments, X3is N and X5is S.

[0023] In certain embodiments, one of R54, R55, R56, R57and R58is C1-6alkyl or substitutedC1-6alkyl.

[0024] In certain embodiments, n is 1, X1, X3, X4, X5, and X6are each C, X2is N, R54is absent, R55, R56, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0025] In certain embodiments, n is 1, X1, X3, X5, and X6are each C, X2and X4are each N, R54and R56are each absent, R55and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-io cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0026] In certain embodiments, n is 1, X1, X3, X4, and X5are each C, X2and X6are each N, R54and R58are each absent, R55and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10 cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0027] In certain embodiments, n is 1, X1, X2, X3, and X5are each C, X4and X6are each N, R56and R58are each absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10 cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0028] In certain embodiments, n is 1, X1, X2, X3, X4, and X5are each C, X6is N, R58is absent, R54, R55, and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl

[0029] In certain embodiments, n is 1, X1, X2, X3, X5, and X6are each C, X4is N, R56is absent, R54, R55, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0030] In certain embodiments, n is 1, X1, X2, X4, and X5are each C, X3and X6are each N, R55and R58are each absent, R54and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10 cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0031] In certain embodiments, n is 0, X1, X2, and X4are each C, X3and X5are each N, R55is absent, R54and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0032] In certain embodiments, n is 0, X1, X2, and X3are each C, X4and X5are each N, R56is absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0033] In certain embodiments, R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, substituted -OC1-6alkyl is -OC1-6alkyl substituted with 1 to 3 substituents that are each independently halo, substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0034] In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0035] In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl.

[0036] In certain embodiments, R57is selected from:

[0037] In certain embodiments, R57is selected from

[0038] In certain embodiments, n is 1, X1, X3, X4, X5, and X6are each C, X2is N, R54is absent, R55, R57, and R58are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0039] In certain embodiments, n is 0, X1, X3, and X5are each C, X2and X4are each N, R54is absent, R55and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0040] In certain embodiments, n is 0, X1, X2, and X5are each C, X3and X4are each N, R55is absent, R54and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0041] In certain embodiments, n is 0, X1, X2, and X3are each C, X4and X5are each N, R57is absent, R54and R55are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0042] In certain embodiments, n is 0, X1, X2, and X4are each C, X3is N, X5is N, S or O, R55is absent, R54is H, R57is absent or H, and R56is selected from halo, C1-6alkyl, substituted C1-6 alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0043] In certain embodiments, n is 0, X3, X4, and X5are each C, X1and X2are each N, R54is absent, R55and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0044] In certain embodiments, n is 0, X2, X3, and X4are each C, X1and X5are each N, R57is absent, R54and R55are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0045] In certain embodiments, R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, substituted -OC1-6alkyl is -OC1-6alkyl substituted with 1 to 3 substituents that are each independently halo, substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0046] In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0047] In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl.

[0048] In certain embodiments, R56is selected from:

[0049] In certain embodiments,selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y13:, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15,R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as described herein.

[0050] In certain embodiments, is selected from the followingmoieties Y1, Y2, Y3, Y4, and Y5:, , , , and ,wherein R1, R2, R3, R4, R6, R7, R8, R10, R11, R12, R14, R15, R16, R17, R30, R31, and R32are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl, and R5, R9, R13, and R33are each independently H or methyl.

[0051] In certain embodiments, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R30, R31, R32, and R33are each H.

[0052] In certain embodiments, is , R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl.

[0053] In certain embodiments, R1, R2, R3, and R4are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl, and R5is H or methyl.

[0054] In certain embodiments, R1is H, R2is H, F, cyano or methyl, R3is H or F, R4is H, and R5is H.

[0055] In certain embodiments, R1, R2, R3, R4, and R5are each H

[0056] In certain embodiments, R1is H, R2is F, R3is H, R4is H, and R5is H.

[0057] In certain embodiments, R1is H, R2is H, R3is F, R4is H, and R5is H.

[0058] In certain embodiments, L is a single bond, , , , or , wherein R70and R71are each as described herein.

[0059] In certain embodiments, L is a single bond.

[0060] In certain embodiments, the compound is a compound of the Formula (IIB):wherein:, L, and R75are each as described herein; andR59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0061] In certain embodiments, one of R59, R60, R61, R62and R63is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

[0062] In certain embodiments, R59, R60, R61, and R63are each H, and R62is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

[0063] In certain embodiments, R59, R60, R61, and R63are each H, and R62is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl, wherein substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0064] In certain embodiments, wherein two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0065] In certain embodiments, two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6- membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl, wherein substituted C4-6cycloalkyl is C4-6cycloalkyl substituted with 1 to 4 substituents that are each independently C1-6alkyl, and substituted 4- to 6-membered heterocycloalkyl is 4- to 6-membered heterocycloalkyl substituted with 1 to 4 substituents that are each independently selected from C1-6 alkyl and oxo (=O).

[0066] In certain embodiments, the compound is a compound of Formula (IIC):wherein L, R53, and R75are each as described herein, R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl, and wherein one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl.

[0067] In certain embodiments, one of R1, R2, R3and R4is halo.

[0068] In certain embodiments, one of R1, R2, R3and R4is C1-6alkyl.

[0069] In certain embodiments, one of R1, R2, R3and R4is C3-6cycloalkyl.

[0070] In certain embodiments, R2is cyano.

[0071] In certain embodiments,is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:, , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R64, R65, R66, R67, R68, and R69are each as described herein.

[0072] In certain embodiments, is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y8, and Y13: , , , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as described herein.

[0073] In certain embodiments, is selected from the following moieties Y2, Y3, Y4, and Y8:14, , , and , wherein R6, R7, R8, R10, R11, R12, R14, R15, R16, R17, R30, R31, and R32are each independently selected from H, F, Br, cyano, C1-3 alkyl, and cyclopropyl, and R9, R13, and R33are each independently H or methyl.

[0074] In certain embodiments, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R30, R31, R32, and R33are each H.

[0075] In certain embodiments, is , and R6, R7, R8and R9are each as described herein.

[0076] In certain embodiments, is , and R18, R19, R20, and R21are each as described herein.

[0077] In certain embodiments, is , and R22, R23, R24, and R25are each as described herein.

[0078] In certain embodiments, is , and R10, R11, R12, and R13are each as described herein.

[0079] In certain embodiments, is , and R14, R15, R16, and R17are each as described herein.

[0080] In certain embodiments, is , and R30, R31, R32, and R33are each as described herein.

[0081] In certain embodiments, the compound is a compound of Formula (IID): (IID), wherein , R53, R70, and R75are each as described herein.

[0082] In certain embodiments, R53is of the formula (Ib): (Ib) wherein R59, R60, R61, and R63are each H, and R62is C1-6 alkyl or substituted C1-6 alkyl.

[0083] In certain embodiments, R75is -C(O)OH.

[0084] In certain embodiments, the compound is selected from:1617

[0085] Aspects of the present disclosure include a compound or a pharmaceutically acceptable salt thereof selected from:

[0086] Aspects of the present disclosure include a pharmaceutical composition comprising: a compound as described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0087] Aspects of the present disclosure include a method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound as described herein or a pharmaceutically acceptable salt thereof.

[0088] Aspects of the present disclosure include a method of treating a disease or disorder, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat the disease or disorder in the subject.

[0089] In certain embodiments, the disease or disorder is selected from acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), heterotopic ossification (HO; including trauma-induced and surgically-induced), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, vascular calcification (including that associated with chronic kidney disease (CKD)), ankylosing spondylitis, osteoarthritis, actinic keratosis, basal and squamous cell carcinoma, esophageal squamous cell carcinoma, arsenic keratosis, inflammatory acne, non-inflammatory acne, psoriasis, ichthyosis, keratinization, hyperproliferative disorders of the skin, photoaging, eczema, atopic dermatitis, Darriers disease, lichen planus, glucocorticoid damage, steroid atrophy, Alzheimer’s, Parkinson’s disease, autism spectrum disorders, schizophrenia and schizoaffective disorders, age related dementia and cognitive defects, adult T-cell leukemia / lymphoma, hair loss, atherosclerosis, and platelet disorders.

[0090] In certain embodiments, the disease or disorder is selected from heterotopic ossification (HO; including trauma-induced and surgically-induced), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, and vascular calcification (including that associated with chronic kidney disease (CKD)).

[0091] In certain embodiments, the disease or disorder is fibrodysplasia ossificans progressiva (FOP).

[0092] In certain embodiments, the disease or disorder is multiple osteochondromas.

[0093] In certain embodiments, the disease or disorder is selected from conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, ocular surface neoplasia, cicatricial conjunctival disorders (including Stevens-Johnson syndrome, graft vs. host disease, trauma, chemical burns, thermal burns, prolonged ultraviolet light exposure, rosacea-induced damage, infectious disease (chlamydia, herpetic disease)), keratinizing disorders of the conjunctiva (including radiation exposure, chemical injury, damage induced by topical medications)), disorders of the conjunctiva caused by vitamin A deficiency, pterygia, pingueculae, cicatricial pemphigoid, atopic kerato-conjunctivitis, Sjogren syndrome related conjunctival injury, meibomian gland dysfunction, blepharitis, hordeola, chalazia, eyelid neoplasms, keratitis, dry eye disease, evaporative dry eye disease, conjunctivalization, corneal intraepithelial neoplasia, stem cell deficiency, corneal injury, chemical-induced corneal injury, thermally-induced corneal injury, trauma-induced corneal injury, radiation-induced corneal injury, disorders of the cornea caused by vitamin A deficiency, Sjogren syndrome-related corneal injury, corneal neovascularization, uveitis, fibro-proliferative disorders, proliferative diabetic retinopathy, proliferative vitreo- retinopathy, epiretinal membrane formation, neovascular membrane formation, age-related macular degeneration, drusenogenesis, and retinal detachment injury.

[0094] In certain embodiments, the disease or disorder is selected conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, cicatricial conjunctival disorders (including from chemical burns, thermal burns, prolonged ultraviolet light exposure, rosacea- induced damage), keratinizing disorders of the conjunctiva, disorders of the conjunctiva caused by vitamin A deficiency, meibomian gland dysfunction, blepharitis, hordeola, chalazia, dry eye disease, evaporative dry eye disease, corneal injury, chemical-induced corneal injury, thermally- induced corneal injury, trauma-induced corneal injury, radiation-induced corneal injury, and disorders of the cornea caused by vitamin A deficiency.

[0095] In certain embodiments, the disease or disorder is meibomian gland dysfunction.

[0096] In certain embodiments, the disease or disorder is dry eye disease.

[0097] In certain embodiments, the disease or disorder is evaporative dry eye disease.

[0098] Aspects of the present disclosure include a compound of Formula (II): (II) or a pharmaceutically acceptable salt thereofwherein: is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, and Y14: , , , , , , , , , , , , , and , wherein: R1, R6, R10, R14, R26, R30, R34, R37, R40, and R46are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R2, R7, R11, R15, R18, R23, R27, R41, R43, R47, and R50are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R3, R12, R16, R19, R24, R28, R31, R35, R44, R48, and R51are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl;R4, R8, R17, R20, R25, R29, R32, R38, R45, R49, and R52are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R5, R9, R13, R21, R22, R33, R36, R39, and R42are each independently H or C1-6alkyl; L is a single bond or ; R53is of the formula (Ia) or (IIb): (Ia) or (Ib), wherein: n is 0 or 1; X1, X3, X4, and X6are each independently selected from C and N, and X2and X5are each independently selected from C, N, and S, and wherein at least one of X1, X2, X3, X4, and X5is N or S when n is 0, and at least one of X2, X3, X4, X5, and X6is N when n is 1; and R54, R55, R56, R57and R58are each independently absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl, and wherein at least one of R54, R55, R56, R57and R58is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl; R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or wherein two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl, and wherein at least one of the following is present: (1) R53is of the formula (Ia):(Ia); (2) R53is of the formula (IIb): (Ib), and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl; (3) is and at least one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl; (4) is selected from moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13and Y14; and (5) L is .

[0099] In certain embodiments, the compound is a compound of the Formula (IIIa): (IIIa)wherein , L, n, X1, X2, X3, X4, X5, X6, R54, R55, R56, R57, and R58are each as defined herein.

[0100] In certain embodiments, n is 1.

[0101] In certain embodiments, X2is N.

[0102] In certain embodiments, X4is N.

[0103] In certain embodiments, X6is N.

[0104] In certain embodiments, X2and X6are each N.

[0105] In certain embodiments, X2and X4are each N.

[0106] In certain embodiments, X4and X6are each N.

[0107] In certain embodiments, n is 0.

[0108] In certain embodiments, X2and X4are each N.

[0109] In certain embodiments, X3and X4are each N.

[0110] In certain embodiments, X3and X5are each N.

[0111] In certain embodiments, X4and X5are each N.

[0112] In certain embodiments, X1and X2are each N.

[0113] In certain embodiments, X1and X5are each N.

[0114] In certain embodiments, X3is N and X5is S.

[0115] In certain embodiments, one of R54, R55, R56, R57and R58is C1-6alkyl or substituted C1-6alkyl.

[0116] In certain embodiments, n is 1, X1, X3, X4, X5, and X6are each C, X2is N, R54is absent, R55, R56, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0117] In certain embodiments, n is 1, X1, X3, X5, and X6are each C, X2and X4are each N, R54and R56are each absent, R55and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10 cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0118] In certain embodiments, n is 1, X1, X3, X4, and X5are each C, X2and X6are each N, R54and R58are each absent, R55and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10 cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0119] In certain embodiments, n is 1, X1, X2, X3, and X5are each C, X4and X6are each N, R56and R58are each absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0120] In certain embodiments, n is 1, X1, X2, X3, X4, and X5are each C, X6is N, R58is absent, R54, R55, and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0121] In certain embodiments, n is 1, X1, X2, X3, X5, and X6are each C, X4is N, R56is absent, R54, R55, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0122] In certain embodiments, n is 0, X1, X2, and X4are each C, X3and X5are each N, R55is absent, R54and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0123] In certain embodiments, n is 0, X1, X2, and X3are each C, X4and X5are each N, R56is absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0124] In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0125] In certain embodiments, n is 0, X1, X3, and X5are each C, X2and X4are each N, R54is absent, R55and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0126] In certain embodiments, n is 0, X1, X2, and X5are each C, X3and X4are each N, R55is absent, R54and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0127] In certain embodiments, n is 0, X1, X2, and X3are each C, X4and X5are each N, R57is absent, R54and R55are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0128] In certain embodiments, n is 0, X1, X2, and X4are each C, X3is N, X5is N or S, R55is absent, R54is H, R57is absent or H, and R56is selected from halo, C1-6alkyl, substituted C1- 6 alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

[0129] In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0130] In certain embodiments, is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y8, and Y13: , , , , , , , and , wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15,R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as defined herein.

[0131] In certain embodiments, is , R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl.

[0132] In certain embodiments, R1, R2, R3, R4, and R5are each H.

[0133] In certain embodiments, L is a single bond.

[0134] In certain embodiments, the compound is a compound of the Formula (IIIb): (IIIb) wherein: and L are each as defined herein; and R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0135] In certain embodiments, one of R59, R60, R61, R62and R63is C3-10cyclopropyl, substituted C3-10cyclopropyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

[0136] In certain embodiments, R59, R60, R61, and R63are each H, and R62is C3-10cyclopropyl, substituted C3-10cyclopropyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

[0137] In certain embodiments, two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6- membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0138] In certain embodiments, the compound is a compound of Formula (IIIc): (IIIc), wherein L and R53are each as defined herein, R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl, and wherein one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl.

[0139] In certain embodiments, one of R1, R2, R3and R4is halo.

[0140] In certain embodiments, one of R1, R2, R3and R4is C1-6alkyl.

[0141] In certain embodiments, one of R1, R2, R3and R4is C3-6cycloalkyl.

[0142] In certain embodiments, R2is cyano.

[0143] In certain embodiments, is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, and Y14: , , , , , , , ,, , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, and R52are each as defined herein.

[0144] In certain embodiments, is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y8, and Y13: , , , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as defined herein.

[0145] In certain embodiments, is , and R6, R7, R8and R9are each as defined herein.

[0146] In certain embodiments, is , and R18, R19, R20, and R21are each as defined herein.

[0147] In certain embodiments, is , and R22, R23, R24, and R25are each as defined herein.

[0148] In certain embodiments, is , and R10, R11, R12, and R13are each as defined herein.

[0149] In certain embodiments, is , and R14, R15, R16, and R17are each as defined herein.

[0150] In certain embodiments, the compound is a compound of Formula (IIId):(IIId), wherein and R53are each as defined herein.

[0151] In certain embodiments, R53is of the formula (IIb): (IIb) wherein R59, R60, R61, and R63are each H, and R62is C1-6alkyl or substituted C1-6alkyl.

[0152] In certain embodiments, the compound is selected from:

[0153] Aspects of the present disclosure include a compound or a pharmaceutically acceptable salt thereof selected from:

[0154] Aspects of the present disclosure include a pharmaceutical composition comprising: a compound as described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0155] Aspects of the present disclosure include a method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound as described herein or a pharmaceutically acceptable salt thereof.

[0156] Aspects of the present disclosure include a method of treating a disease or disorder, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat the disease or disorder in the subject.

[0157] In certain embodiments, the disease or disorder is selected from acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), heterotopic ossification (HO; including trauma-induced and surgically-induced), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, vascular calcification(including that associated with chronic kidney disease (CKD)), ankylosing spondylitis, osteoarthritis, actinic keratosis, basal and squamous cell carcinoma, esophageal squamous cell carcinoma, arsenic keratosis, inflammatory acne, non-inflammatory acne, psoriasis, ichthyosis, keratinization, hyperproliferative disorders of the skin, photoaging, eczema, atopic dermatitis, Darriers disease, lichen planus, glucocorticoid damage, steroid atrophy, Alzheimer’s, Parkinson’s disease, autism spectrum disorders, schizophrenia and schizoaffective disorders, age related dementia and cognitive defects, adult T-cell leukemia / lymphoma, hair loss, atherosclerosis, and platelet disorders.

[0158] In certain embodiments, the disease or disorder is selected from conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, ocular surface neoplasia, cicatricial conjunctival disorders (including Stevens-Johnson syndrome, graft vs. host disease, trauma, chemical burns, thermal burns, prolonged ultraviolet light exposure, rosacea-induced damage, infectious disease (chlamydia, herpetic disease), keratinizing disorders of the conjunctiva (including radiation exposure, chemical injury, damage induced by topical medications)), disorders of the conjunctiva caused by vitamin A deficiency, pterygia, pingueculae, cicatricial pemphigoid, atopic kerato-conjunctivitis, Sjogren syndrome related conjunctival injury, meibomian gland dysfunction, blepharitis, hordeola, chalazia, eyelid neoplasms, keratitis, dry eye disease, evaporative dry eye disease, conjunctivalization, corneal intraepithelial neoplasia, stem cell deficiency, corneal injury, chemical-induced corneal injury, thermally-induced corneal injury, trauma-induced corneal injury, radiation-induced corneal injury, disorders of the cornea caused by vitamin A deficiency, Sjogren syndrome-related corneal injury, corneal neovascularization, uveitis, fibro-proliferative disorders, proliferative diabetic retinopathy, proliferative vitreo- retinopathy, epiretinal membrane formation, neovascular membrane formation, age-related macular degeneration, drusenogenesis, and retinal detachment injury.

[0159] In certain embodiments, the disease or disorder may be meibomian gland dysfunction. In certain embodiments, the disease or disorder may be dry eye disease. In certain embodiments, the disease or disorder may be aqueous deficient dry eye disease or evaporative dry eye disease. In certain embodiments, the disease or disorder may be evaporative dry eye disease. DEFINITIONS

[0160] The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings.

[0161] “CYP26” refers to cytochrome P450 family 26. This family of cytochrome P450 enzymes, which comprises CYP26A1 and CYP26B1, has a role in the metabolism of retinoic acid.

[0162] “CYP26A1” refers to cytochrome P450 family 26 subfamily A member 1. Details of the human homolog of CYP26A1 (including the protein sequence) are deposited in the Uniprot database as O43174 – CP26A_HUMAN.

[0163] “CYP26B1” refers to cytochrome P450 family 26 subfamily B member 1. Details of the human homolog of CYP26B1 (including the protein sequence) are deposited in the Uniprot database as Q9NR63 – CP26B_HUMAN.

[0164] “CYP26B1 inhibitor” refers to any agent, compound or molecule capable of inhibiting the activity of CYP26B1 by binding to CYP26B1, particularly the retinoic acid metabolising activity of CYP26B1.

[0165] The term Cx-Cy or Cx-y refers to a group with x to y carbon atoms.

[0166] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3), ethyl (CH3CH2), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2), isobutyl ((CH3)2CHCH2), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C- ), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0167] The term “substituted alkyl” refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain (except the C1 carbon atom) have been optionally replaced with a heteroatom such as O-, N-, S-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, SO2-heteroaryl, and -NRaRb, wherein Raand Rbmay be the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.

[0168] The term “haloalkyl” refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, C1-C6-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2- trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0169] The term “heteroalkyl” refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain (except the C1 carbon atom) have been replaced with a heteroatom such as O-, N-, S-, -S(O)n- (where n is 0 to 2), or -NR- (where R is hydrogen or alkyl).

[0170] “Alkylene” refers to divalent aliphatic hydrocarbyl groups preferably having from 1 to 6 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from -O-, -NR10-, -NR10C(O)- , -C(O)NR10- and the like, where R10is chosen from chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), and the like.

[0171] “Substituted alkylene” refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of “substituted” below.

[0172] The term “alkane” refers to alkyl group and alkylene group, as defined herein.

[0173] The term “alkylaminoalkyl”, “alkylaminoalkenyl” and “alkylaminoalkynyl” refers to the groups R’NHR”- where R’ is alkyl group as defined herein and R” is alkylene, alkenylene or alkynylene group as defined herein.

[0174] The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.

[0175] “Alkoxy” refers to the group –O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec- butoxy, n-pentoxy, and the like. The term “alkoxy” also refers to the groups alkenyl-O-, cycloalkyl-O-, heterocycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0176] The term “substituted alkoxy” refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.

[0177] The term “alkoxyamino” refers to the group –NH-alkoxy, wherein alkoxy is defined herein.

[0178] The term “haloalkoxy” refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.

[0179] The term “haloalkyl” refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group (e.g., fluorine, chlorine, bromine, iodine). Examples of such haloalkyl groups include, but are not limited to, chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g. 1-chloromethyl and 2- chloroethyl), trichloroethyl (e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g. 1- fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g.1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl, and the like.

[0180] The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl, alkylene-O- substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.

[0181] “Alkenyl” refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bivinyl, allyl, and but3en1yl. Included within this term are the cis and trans isomers or mixtures of these isomers.

[0182] The term “substituted alkenyl” refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, SO-alkyl, -SO- substituted alkyl, SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, SO2-aryl and -SO2- heteroaryl.

[0183] “Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (C≡CH), and propargyl (CH2C≡CH).

[0184] The term “substituted alkynyl” refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-substituted alkyl, -SO2-aryl, and -SO2- heteroaryl.

[0185] “Alkynyloxy” refers to the group –O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0186] “Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl- C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted arylC(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the “acetyl” group CH3C(O)-

[0187] “Acylamino” refers to the groups –NR200C(O)alkyl, -NR200C(O)substituted alkyl, N R200C(O)cycloalkyl, -NR200C(O)substituted cycloalkyl, -NR200C(O)cycloalkenyl, NR200C(O)substituted cycloalkenyl, -NR200C(O)alkenyl, -NR200C(O)substituted alkenyl, NR200C(O)alkynyl, -NR200C(O)substituted alkynyl, NR200C(O)aryl, NR200C(O)substituted aryl, NR200C(O)heteroaryl, NR200C(O)substituted heteroaryl, NR200C(O)heterocyclic, and NR200C(O)substituted heterocyclic, wherein R200is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0188] “Aminocarbonyl” or the term “aminoacyl” refers to the group C(O)NR210R220, wherein R210and R220independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21and R22are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0189] “Aminocarbonylamino” refers to the group –NR210C(O)NR220R230where R210, R220, and R230are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl,heterocyclic, and substituted heterocyclic and where R21and R22are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0190] The term “alkoxycarbonylamino” refers to the group -NRdC(O)ORdwhere each Rdis independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0191] The term “acyloxy” refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0192] “Aminosulfonyl” refers to the group –SO2NR210R220, wherein R210and R220independently are selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21and R22are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0193] “Sulfonylamino” refers to the group –NR210SO2R220, wherein R210and R220independently are selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R210and R220are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0194] “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 5 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl andnaphthyl. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2- alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl and trihalomethyl.

[0195] “Aryloxy” refers to the group –O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.

[0196] “Amino” refers to the group –NH2.

[0197] The term “substituted amino” refers to the group -NRmRmwhere each Rmis independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one Rmis not hydrogen.

[0198] The term “azido” refers to the group –N3.

[0199] “Carboxyl,” “carboxy” or “carboxylate” refers to –CO2H or salts thereof.

[0200] “Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0201] “(Carboxyl ester)oxy” or “carbonate” refers to the groups –O-C(O)O-alkyl, OC(O)Osubstituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, OC(O)Osubstituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, OC(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, andOC(O)Osubstituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0202] “Cyano” or “nitrile” refers to the group –CN.

[0203] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, bicyclo[2.1.1]hexane, bicyclo[1.1.1]pentane, and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.

[0204] The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, SO2-aryl and - SO2-heteroaryl.

[0205] “Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds.

[0206] The term “substituted cycloalkenyl” refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, SO-alkyl, SO-substituted alkyl, -SO-aryl, - SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, SO2-aryl and -SO2-heteroaryl.

[0207] “Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.

[0208] “Carbocycle” refers to non-aromatic or aromatic cyclic groups, such as cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl groups as defined herein. A carbocycle goup may be unsubstituted or substituted as defined herein.

[0209] “Cycloalkoxy” refers to –O-cycloalkyl.

[0210] “Cycloalkenyloxy” refers to –O-cycloalkenyl.

[0211] “Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

[0212] “Hydroxy” or “hydroxyl” refers to the group –OH.

[0213] “Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic. To satisfy valence requirements, any heteroatoms in such heteroaryl rings may or may not be bonded to H or a substituent group, e.g., an alkyl group or other substituent as described herein. In certain embodiments, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N- oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, - SO-substituted alkyl, -SO-aryl, SO-heteroaryl, SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and - SO2-heteroaryl, and trihalomethyl.

[0214] Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In some embodiments, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic,as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0215] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H- imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2- b][1,2,4]triazinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 8,9-dihydro-7H-purinyl, pyrazolo[1,5- a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyridinyl, furo[3,2-d]pyrimidinyl, furo[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, and the like.

[0216] Examples of heteroaryl groups comprising at least one nitrogen in a ring position include pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl and pteridinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4- tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazinyl.

[0217] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups. Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl. Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl,indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0218] The term “heteroaralkyl” refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0219] “Heteroaryloxy” refers to –O-heteroaryl.

[0220] “Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. Fused ring systems include compounds where two rings share two adjacent atoms. In fused heterocycle systems one or both of the two fused rings can be heterocyclyl. In certain embodiments, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or – SO2- moieties. To satisfy valence requirements, any heteroatoms in such heterocyclic rings may or may not be bonded to one or more H or one or more substituent group(s), e.g., an alkyl group or other substituent as described herein.

[0221] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, 1,2,3,4-tetrahydroquinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, 3,4-dihydro-1,4-benzoxazine, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

[0222] Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles comprising at least one nitrogen in a ring position include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydropyridinyl, homopiperidinyl, homopiperazinyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 8-aza-bicyclo[3.2.1]octanyl, 2,5-Diazabicyclo[2.2.1]heptanyl and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro oxathiolyl, tetrahydro oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro oxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O), for example, 2 oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5- dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. For example, in some instances, reference to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0223] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, SO-aryl, -SO-heteroaryl, SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, SO2-heteroaryl, and fused heterocycle.

[0224] “Heterocyclyloxy” refers to the group –O-heterocyclyl.

[0225] The term “heterocyclylthio” refers to the group heterocyclic-S-.

[0226] The term “heterocyclene” refers to the diradical group formed from a heterocycle, as defined herein.

[0227] The term “hydroxyamino” refers to the group -NHOH.

[0228] “Nitro” refers to the group –NO2.

[0229] “Oxo” refers to the atom (=O).

[0230] “Sulfonyl” refers to the group SO2-alkyl, SO2-substituted alkyl, SO2-alkenyl, SO2-substituted alkenyl, SO2-cycloalkyl, SO2-substituted cylcoalkyl, SO2-cycloalkenyl, SO2- substituted cylcoalkenyl, SO2-aryl, SO2-substituted aryl, SO2-heteroaryl, SO2-substituted heteroaryl, SO2-heterocyclic, and SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0231] “Sulfonyloxy” refers to the group –OSO2-alkyl, OSO2-substituted alkyl, OSO2- alkenyl, OSO2-substituted alkenyl, OSO2-cycloalkyl, OSO2-substituted cylcoalkyl, OSO2- cycloalkenyl, OSO2-substituted cylcoalkenyl, OSO2-aryl, OSO2-substituted aryl, OSO2- heteroaryl, OSO2-substituted heteroaryl, OSO2-heterocyclic, and OSO2substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0232] The term “aminocarbonyloxy” refers to the group OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0233] “Thiol” refers to the group -SH.

[0234] “Thioxo” or the term “thioketo” refers to the atom (=S).

[0235] “Alkylthio” or the term “thioalkoxy” refers to the group -S-alkyl, wherein alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. The sulfoxide may exist as one or more stereoisomers.

[0236] The term “substituted thioalkoxy” refers to the group -S-substituted alkyl.

[0237] The term “thioaryloxy” refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.

[0238] The term “thioheteroaryloxy” refers to the group heteroaryl-S- wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein.

[0239] The term “thioheterocyclooxy” refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.

[0240] In addition to the disclosure herein, the term “substituted,” when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.

[0241] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for substituting for one or more hydrogens (any two hydrogens on a single carbon can be replaced with =O, =NR700, =N-OR700, =N2or =S) on saturated carbon atoms in the specified group or radical are, unless otherwise specified, -R600, halo, =O, -OR700, -SR700, -NR800R800, trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R700, -SO2O–M+, -SO2OR700, -OSO2R700, -OSO2O–M+, -OSO2OR700, -P(O)(O–)2(M+)2, -P(O)(OR700)O–M+, -P(O)(OR700) 2, -C(O)R700, -C(S)R700, -C(NR700)R700, -C(O)O–M+, -C(O)OR700, -C(S)OR700, -C(O)NR800R800, -C(NR700)NR800R800, -OC(O)R700, -OC(S)R700, - OC(O)O-M+, -OC(O)OR700, -OC(S)OR700, -NR70C(O)R700, -NR700C(S)R700, -NR70CO2–M+, -NR700CO2R700, -NR700C(S)OR700, -NR700C(O)NR800R800, -NR700C(NR700)R700and -NR700C(NR700)NR800R800, where R600is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each R700is independently hydrogen or R600; each R800is independently R700or alternatively, two R800’s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have -H or C1-C3 alkyl substitution; and each M+is a counter ion with a net single positive charge. Each M+may independently be, for example, an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(R600)4; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the invention can serve as the counter ion for such divalent alkali earth ions). As specific examples, -NR800R800is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl and N- morpholinyl.

[0242] In addition to the disclosure herein, substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, R600, halo, O-M+, OR700, SR700, S–M+, NR800R800, trihalomethyl, CF3, CN, OCN, SCN, NO, NO2, N3, SO2R700, SO3–M+, SO3R700, OSO2R700, OSO3–M+, OSO3R700, PO32(M+)2, P(O)(OR700)O–M+, P(O)(OR700)2, C(O)R700, C(S)R700, C(NR700)R700, CO2–M+,CO2R700, C(S)OR700, C(O)NR800R800, C(NR700)NR800R800, OC(O)R700, OC(S)R700, OCO2–M+, OCO2R700, OC(S)OR700, NR700C(O)R700, NR700C(S)R700, NR700CO2–M+, NR700CO2R700, NR700C(S)OR700, NR700C(O)NR800R800, NR700C(NR700)R700and NR700C(NR700)NR800R800, where R600, R700, R800and M+are as previously defined, provided that in case of substituted alkene or alkyne, the substituents are not O-M+, OR700, SR700, or S–M+.

[0243] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R600, -O-M+, -OR700, -SR700, -S-M+, -NR800R800, trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R700, -S(O)2O-M+, -S(O)2OR700, -OS(O)2R700, -OS( O)2O-M+, -OS(O)2OR700, -P(O)(O-)2(M+)2, -P(O)(OR700)O-M+, -P(O)(OR700)(OR700), -C(O)R700, -C(S)R700, -C(NR700)R700, -C(O)OR700, -C(S)OR700, -C(O)NR800R800, -C(NR700)NR800R800, -OC( O)R700, -OC(S)R700, -OC(O)OR700, -OC(S)OR700, -NR700C(O)R700, -NR700C(S)R700, -NR700C(O) OR700, -NR700C(S)OR700, -NR700C(O)NR800R800, -NR700C(NR700)R700and -NR700C(NR700)NR800R800, where R600, R700, R800and M+are as previously defined.

[0244] In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0245] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl.

[0246] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-.

[0247] A bond terminating in a “ ” represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.

[0248] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patternswhich are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0249] The term “pharmaceutically acceptable salt” means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.

[0250] The term “salt thereof” means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0251] “Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N,N- dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.

[0252] “Stereoisomer” and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0253] “Tautomer” refers to alternate forms of a molecule that differ only in electronic bonding of atoms and / or in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.

[0254] It will be appreciated that the term “or a salt or solvate or stereoisomer thereof” is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of subject compound.

[0255] “Pharmaceutically effective amount” and “therapeutically effective amount” refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and / or to prevent the occurrence of the disease or disorder. In reference to tumorigenic proliferative disorders, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or decrease the growth rate of the tumor.

[0256] By “treating” or “treatment” is meant that at least an amelioration of the symptoms associated with the condition afflicting the subject is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom, associated with the condition being treated. As such, treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g. terminated, such that the subject no longer suffers from the condition, or at least the symptoms that characterize the condition. Thus treatment includes: (i) prevention, that is, reducing the risk of development of clinical symptoms, including causing the clinical symptoms not to develop, e.g., preventing disease progression to a harmful state or prophylactic treatment of a subject; (ii) inhibition, that is, arresting the development or further development of clinical symptoms, e.g., mitigating or completely inhibiting an active disease; and / or (iii) relief, that is, causing the regression of clinical symptoms or alleviating one or more symptoms of the disease or medical condition in the subject.

[0257] As used herein the term “isolated” is meant to describe a compound of interest that is in an environment different from that in which the compound naturally occurs. “Isolated” is meant to include compounds that are within samples that are substantially enriched for the compound of interest and / or in which the compound of interest is partially or substantially purified.

[0258] As used herein, the term “substantially purified” refers to a compound that is removed from its natural environment and is at least 60% free, at least 75% free, at least 80% free, at least 85% free, at least 90% free, at least 95% free, at least 98% free, or more than 98% free, from other components with which it is naturally associated.

[0259] The term “physiological conditions” is meant to encompass those conditions compatible with living cells, e.g., predominantly aqueous conditions of a temperature, pH, salinity, etc. that are compatible with living cells.

[0260] As used herein, the term “chronic administration” refers to repeated administration of a compound to a subject. In such treatment, the compound can be administered at least once a week, such as at least once a day, or at least twice or three times a day for a period of at least one month, such as for example five months or more.

[0261] As used herein, the term “HO” refers to heterotopic ossification.

[0262] As used herein, the term “BMP” refers to Bone Morphogenic Protein.

[0263] As used herein, the term “rhBMP2” refers to recombinant human Bone Morphogenic Protein 2 (available from GenScript, Piscataway, NJ, USA).

[0264] As used herein, the term “FOP” refers to the rare genetic condition, Fibrodysplasia Ossificans Progressiva .

[0265] As used herein, the term “μg” refers to microgram.

[0266] As used herein, the term “CD-1” refers to the outbred albino CD-1® IGS multi- purpose mouse strain available from Charles River Laboratories (strain code 022, bred in Raleigh, NC, USA).

[0267] As used herein, the term “DMSO” refers to dimethylsulfoxide.

[0268] As used herein, the term “M” refers to male.

[0269] As used herein, the term “F” refers to female.

[0270] As used herein, the terms “μCT” or “micro-CT” refer to micro computed tomography.

[0271] As used herein, the term “CT” refers to computed tomography.

[0272] As used herein, the terms “DICOM” refers to Digital Imaging and Communications in Medicine®, which is the international standard for files consisting of medical images and related information.

[0273] As used herein, the term “DMSO” refers to dimethylsulfoxide.

[0274] As used herein, the term “IFOPA” refers to the International Fibrodysplasia Ossificans Progressiva Association (North Kansas City, MO, USA).

[0275] As used herein, the term “ACVR1” refers to Activin A receptor, type I.

[0276] As used herein, the term “Pdgfra” refers to platelet-derived growth factor receptor alpha.

[0277] As used herein, the term “HMO” refers to the genetic condition, Hereditary Multiple Osteochondromas (also referred to as Multiple Osteochondromas (MO)).

[0278] As used herein, the term “P” refers to postnatal day.

[0279] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It isalso to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0280] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0281] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination. All combinations of the embodiments pertaining to the invention are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace subject matter that are, for example, compounds that are stable compounds (i.e., compounds that can be made, isolated, characterized, and tested for biological activity). In addition, all sub-combinations of the various embodiments and elements thereof (e.g., elements of the chemical groups listed in the embodiments describing such variables) are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.

[0282] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0283] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as“solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0284] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination.

[0285] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. BRIEF DESCRIPTION OF THE DRAWINGS

[0286] Figure 1 shows Rose Bengal (RB) staining of a 10-week old Rhino (Rh) mouse illustrating significant RB uptake (dark staining).

[0287] Figure 2 shows in-situ visualization of an untreated 32-week old Rh mouse illustrating meibomian gland atrophy (demarcation in black), acinar thinning and Meibomian gland obstruction (black dots).

[0288] Figure 3A shows NEI scoring of RB staining of 8-12-week old Rh mice treated with vehicle or compound H34. Pairwise statistical comparison with unpaired t-test p value depicted. N=13 eyes / group.

[0289] Figure 3B shows dental paper point (DPP) tear quantification of vehicle and compound H34 treated Rh mice. Pairwise statistical comparison with unpaired t-test p value depicted. N=13 eyes / group.

[0290] Figure 3C shows Draize scoring of Rh mice treated with vehicle or compound H34. N=13 eyes / group.

[0291] Figure 3D shows a sample in-situ visualization of an 8-12-week old vehicle- treated mouse compared to compound H34 treated Rh mouse illustrating Meibomian gland obstruction (demarcation in black).

[0292] Figure 3E shows Draize scoring of Rh mice treated with either vehicle (N=13), compound H34 (N=13) or Lifitegrast (LG) (N=16). Draize scores for H34 treated animals were statistically lower than both vehicle and LG treated animals.

[0293] Figure 4 shows a box plot representing the composite cutaneous toxicity (blackjack) score for animals treated for 14 days with vehicle (black bar), 0.2μmol atRA (greybar), or 2μmol compound H2(white bar) on dorsal skin (2M:2F per group), as described in Example 7. All animals were scored daily for flaking (0-5) and abrasions (0-4) and given a score for each metric. The limits of the box represent 5-95% confidence and the mean is shown by a horizontal bar. Standard deviation from the mean is indicated. This data illustrates that compound H2is far less irritating than atRA but provides similar anti-comedogenic effects on skin.

[0294] Figure 5 shows representative skin histological sections (stained with hematoxylin and eosin, top panels) and photographs of epidermal sheet preparations (bottom panels) from Rhino mice treated topically with vehicle, 0.2μmol atRA, or 2μmol compound H2 on dorsal skin for 2 weeks (photographs are 10x magnification, scale bar = 100µm). These data indicate that both atRA and compound H2 show epidermal thickening and decrease in utricle size, that is characteristic of retinoid treatment, and anti-acne effects in this model. The histogram on the right shows quantification of the size of epidermal utriculi from the dorsal epidermal sheet preparations described in Example 7, as percentage of vehicle-treated skin. The bars represent the mean measurements in mouse skin treated with vehicle (black bar), RA (grey bar), or compound H2 (white bar). The error bars denote standard deviation, and the asterisks denote statistically significant difference from vehicle-treated animals (* = p < 0.0001). DETAILED DESCRIPTION

[0295] The present disclosure provides compounds and pharmaceutically acceptable salts thereof for inhibiting CYP26B1. Aspects of the present disclosure also include methods of using the compounds to treat diseases or disorders, including, but not limited to, skin disorders, cancer, neurological disorders, heterotopic ossification (HO), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, and diseases or disorders of the eye, including meibomian gland dysfunction and dry eye disease. COMPOUNDS

[0296] Aspects of the present disclosure include a compound of Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:, , , , , , , , , , , , , , and wherein: R1, R6, R10, R14, R26, R30, R34, R37, R40, R46, R64, and R65are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R2, R7, R11, R15, R18, R23, R27, R41, R43, R47, R50, and R66are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R3, R12, R16, R19, R24, R28, R31, R35, R44, R48, R51, and R67are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R4, R8, R17, R20, R25, R29, R32, R38, R45, R49, R52, and R68are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R5, R9, R13, R21, R22, R33, R36, R39, R42, and R69are each independently H or C1-6alkyl;L is a single bond, , , , , , , , or ; wherein: R70is H or -CH3; R71is H or -CH3; R72and R73are each independently selected from H, F, and -CH3; X7is O, S, or NR74, wherein R74is H or -CH3; and R53is of the formula (Ia) or (Ib): (Ia) or (Ib), wherein: n is 0 or 1; X1, X3, X4, and X6are each independently selected from C and N, and X2and X5are each independently selected from C, N, S, and O, and wherein at least one of X1, X2, X3, X4, and X5is N, S or O when n is 0, and at least one of X2, X3, X4, X5, and X6is N when n is 1; and R54, R55, R56, R57and R58are each independently absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl, and wherein at least one of R54, R55, R56, R57and R58is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl; R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl,substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or wherein two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl, and R75is selected from -C(O)OH,wherein at least one of the following is present: (1) R53is of the formula (Ia): (Ia); (2) R53is of the formula (Ib): (Ib), and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl;(3) is and at least one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl; (4) is selected from moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15; and (5) L is , , , , , , , or .

[0297] In certain embodiments, the compound is not the following compound: .

[0298] In certain embodiments, is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:, , , , , , , , , , , , , , and .

[0299] In some cases, is . In some cases, when the Y-ring is Y1, at least one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl, as described herein.

[0300] In some cases, is .

[0301] In some cases, is .

[0302] In some cases, is .

[0303] In some cases, is .

[0304] In some cases, is .

[0305] In some cases, is .

[0306] In some cases, is .

[0307] In some cases, is .

[0308] In some cases, is .

[0309] In some cases, is .

[0310] In some cases, is .

[0311] In some cases, is .

[0312] In some cases, is .

[0313] In some cases, is .

[0314] As used herein, “Y”, “Y-ring”, and refer to the same functional group (e.g., Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, or Y15).

[0315] In some cases, R1, R6, R10, R14, R26, R30, R34, R37, R40, R46, R64, and R65are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl.

[0316] In some cases, R1is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R1is H. In some cases, R1is halo (e.g., F, Cl, Br or I). In some cases, R1is F. In some cases, R1is Cl. In some cases, R1is Br. In some cases, R1is I. In some cases, R1is cyano. In some cases, R1is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R1is methyl. In some cases, R1is isopropyl. In some cases, R1is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R1is cyclopropyl.

[0317] In some cases, R6is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R6is H. In some cases, R6is halo (e.g., F, Cl, Br or I). In some cases, R6is F. In some cases, R6is Cl. In some cases, R6is Br. In some cases, R6is I. In some cases, R6is cyano. In some cases, R6is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R6is methyl. In some cases, R6is isopropyl. In some cases, R6is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R6is cyclopropyl.

[0318] In some cases, R10is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R10is H. In some cases, R10is halo (e.g., F, Cl, Br or I). In some cases, R10is F. In some cases, R10is Cl. In some cases, R10is Br. In some cases, R10is I. In some cases, R10is cyano. In some cases, R10is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl(e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R10is methyl. In some cases, R10is isopropyl. In some cases, R10is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R10is cyclopropyl.

[0319] In some cases, R14is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R14is H. In some cases, R14is halo (e.g., F, Cl, Br or I). In some cases, R14is F. In some cases, R14is Cl. In some cases, R14is Br. In some cases, R14is I. In some cases, R14is cyano. In some cases, R14is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R14is methyl. In some cases, R14is isopropyl. In some cases, R14is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R14is cyclopropyl.

[0320] In some cases, R26is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R26is H. In some cases, R26is halo (e.g., F, Cl, Br or I). In some cases, R26is F. In some cases, R26is Cl. In some cases, R26is Br. In some cases, R26is I. In some cases, R26is cyano. In some cases, R26is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R26is methyl. In some cases, R26is isopropyl. In some cases, R26is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R26is cyclopropyl.

[0321] In some cases, R30is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R30is H. In some cases, R30is halo (e.g., F, Cl, Br or I). In some cases, R30is F. In some cases, R30is Cl. In some cases, R30is Br. In some cases, R30is I. In some cases, R30is cyano. In some cases, R30is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R30is methyl. In some cases, R30is isopropyl. In some cases, R30is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R30is cyclopropyl.

[0322] In some cases, R34is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R34is H. In some cases, R34is halo (e.g., F, Cl, Br or I). In some cases, R34is F. In some cases, R34is Cl. In some cases, R34is Br. In some cases, R34is I. In some cases, R34is cyano. In some cases, R34is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R34is methyl. In some cases, R34is isopropyl. In some cases, R34is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R34is cyclopropyl.

[0323] In some cases, R37is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R37is H. In some cases, R37is halo (e.g., F, Cl, Br or I). In some cases, R37is F. In some cases, R37is Cl. In some cases, R37is Br. In some cases, R37is I. In some cases, R37is cyano. In some cases, R37is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl(e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R37is methyl. In some cases, R37is isopropyl. In some cases, R37is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R37is cyclopropyl.

[0324] In some cases, R40is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R40is H. In some cases, R40is halo (e.g., F, Cl, Br or I). In some cases, R40is F. In some cases, R40is Cl. In some cases, R40is Br. In some cases, R40is I. In some cases, R40is cyano. In some cases, R40is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R40is methyl. In some cases, R40is isopropyl. In some cases, R40is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R40is cyclopropyl.

[0325] In some cases, R46is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R46is H. In some cases, R46is halo (e.g., F, Cl, Br or I). In some cases, R46is F. In some cases, R46is Cl. In some cases, R46is Br. In some cases, R46is I. In some cases, R46is cyano. In some cases, R46is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R46is methyl. In some cases, R46is isopropyl. In some cases, R46is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R46is cyclopropyl.

[0326] In some cases, R64is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R64is H. In some cases, R64is halo (e.g., F, Cl, Br or I). In some cases, R64is F. In some cases, R64is Cl. In some cases, R64is Br. In some cases, R64is I. In some cases, R64is cyano. In some cases, R64is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R64is methyl. In some cases, R64is isopropyl. In some cases, R64is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R64is cyclopropyl.

[0327] In some cases, R65is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R65is H. In some cases, R65is halo (e.g., F, Cl, Br or I). In some cases, R65is F. In some cases, R65is Cl. In some cases, R65is Br. In some cases, R65is I. In some cases, R65is cyano. In some cases, R65is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R65is methyl. In some cases, R65is isopropyl. In some cases, R65is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R65is cyclopropyl.

[0328] In some cases, R2, R7, R11, R15, R18, R23, R27, R41, R43, R47, R50, and R66are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl.

[0329] In some cases, R2is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R2is H. In some cases, R2is halo (e.g., F, Cl, Br or I). In some cases, R2is F. Insome cases, R2is Cl. In some cases, R2is Br. In some cases, R2is I. In some cases, R2is cyano. In some cases, R2is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R2is methyl. In some cases, R2is isopropyl. In some cases, R2is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R2is cyclopropyl.

[0330] In some cases, R7is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R7is H. In some cases, R7is halo (e.g., F, Cl, Br or I). In some cases, R7is F. In some cases, R7is Cl. In some cases, R7is Br. In some cases, R7is I. In some cases, R7is cyano. In some cases, R7is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R7is methyl. In some cases, R7is isopropyl. In some cases, R7is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R7is cyclopropyl.

[0331] In some cases, R11is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R11is H. In some cases, R11is halo (e.g., F, Cl, Br or I). In some cases, R11is F. In some cases, R11is Cl. In some cases, R11is Br. In some cases, R11is I. In some cases, R11is cyano. In some cases, R11is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R11is methyl. In some cases, R11is isopropyl. In some cases, R11is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R11is cyclopropyl.

[0332] In some cases, R15is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R15is H. In some cases, R15is halo (e.g., F, Cl, Br or I). In some cases, R15is F. In some cases, R15is Cl. In some cases, R15is Br. In some cases, R15is I. In some cases, R15is cyano. In some cases, R15is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R15is methyl. In some cases, R15is isopropyl. In some cases, R15is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some case,s R15is cyclopropyl.

[0333] In some cases, R18is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R18is H. In some cases, R18is halo (e.g., F, Cl, Br or I). In some cases, R18is F. In some cases, R18is Cl. In some cases, R18is Br. In some cases, R18is I. In some cases, R18is cyano. In some cases, R18is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R18is methyl. In some cases, R18is isopropyl. In some cases, R18is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R18is cyclopropyl.

[0334] In some cases, R23is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R23is H. In some cases, R23is halo (e.g., F, Cl, Br or I). In some cases, R23is F. Insome cases, R23is Cl. In some cases, R23is Br. In some cases, R23is I. In some cases, R23is cyano. In some cases, R23is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R23is methyl. In some cases, R23is isopropyl. In some cases, R23is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R23is cyclopropyl.

[0335] In some cases, R27is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R27is H. In some cases, R27is halo (e.g., F, Cl, Br or I). In some cases, R27is F. In some cases, R27is Cl. In some cases, R27is Br. In some cases, R27is I. In some cases, R27is cyano. In some cases, R27is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R27is methyl. In some cases, R27is isopropyl. In some cases, R27is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R27is cyclopropyl.

[0336] In some cases, R41is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R41is H. In some cases, R41is halo (e.g., F, Cl, Br or I). In some cases, R41is F. In some cases, R41is Cl. In some cases, R41is Br. In some cases, R41is I. In some cases, R41is cyano. In some cases, R41is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R41is methyl. In some cases, R41is isopropyl. In some cases, R41is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R41is cyclopropyl.

[0337] In some cases, R43is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R43is H. In some cases, R43is halo (e.g., F, Cl, Br or I). In some cases, R43is F. In some cases, R43is Cl. In some cases, R43is Br. In some cases, R43is I. In some cases, R43is cyano. In some cases, R43is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R43is methyl. In some cases, R43is isopropyl. In some cases, R43is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R43is cyclopropyl.

[0338] In some cases, R47is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R47is H. In some cases, R47is halo (e.g., F, Cl, Br or I). In some cases, R47is F. In some cases, R47is Cl. In some cases, R47is Br. In some cases, R47is I. In some cases, R47is cyano. In some cases, R47is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R47is methyl. In some cases, R47is isopropyl. In some cases, R47is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R47is cyclopropyl.

[0339] In some cases, R50is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R50is H. In some cases, R50is halo (e.g., F, Cl, Br or I). In some cases, R50is F. Insome cases, R50is Cl. In some cases, R50is Br. In some cases, R50is I. In some cases, R50is cyano. In some cases, R50is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R50is methyl. In some cases, R50is isopropyl. In some cases, R50is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R50is cyclopropyl.

[0340] In some cases, R66is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R66is H. In some cases, R66is halo (e.g., F, Cl, Br or I). In some cases, R66is F. In some cases, R66is Cl. In some cases, R66is Br. In some cases, R66is I. In some cases, R66is cyano. In some cases, R66is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R66is methyl. In some cases, R66is isopropyl. In some cases, R66is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R66is cyclopropyl.

[0341] In some cases, R3, R12, R16, R19, R24, R28, R31, R35, R44, R48, R51, and R67are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl.

[0342] In some cases, R3is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R3is H. In some cases, R3is halo (e.g., F, Cl, Br or I). In some cases, R3is F. In some cases, R3is Cl. In some cases, R3is Br. In some cases, R3is I. In some cases, R3is cyano. In some cases, R3is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R3is methyl. In some cases, R3is isopropyl. In some cases, R3is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R3is cyclopropyl.

[0343] In some cases, R12is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R12is H. In some cases, R12is halo (e.g., F, Cl, Br or I). In some cases, R12is F. In some cases, R12is Cl. In some cases, R12is Br. In some cases, R12is I. In some cases, R12is cyano. In some cases, R12is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R12is methyl. In some cases, R12is isopropyl. In some cases, R12is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R12is cyclopropyl.

[0344] In some cases, R16is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R16is H. In some cases, R16is halo (e.g., F, Cl, Br or I). In some cases, R16is F. In some cases, R16is Cl. In some cases, R16is Br. In some cases, R16is I. In some cases, R16is cyano. In some cases, R16is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R16is methyl. In some cases, R16is isopropyl. In some cases, R16is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R16is cyclopropyl.

[0345] In some cases, R19is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R19is H. In some cases, R19is halo (e.g., F, Cl, Br or I). In some cases, R19is F. In some cases, R19is Cl. In some cases, R19is Br. In some cases, R19is I. In some cases, R19is cyano. In some cases, R19is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R19is methyl. In some cases, R19is isopropyl. In some cases, R19is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R19is cyclopropyl.

[0346] In some cases, R24is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R24is H. In some cases, R24is halo (e.g., F, Cl, Br or I). In some cases, R24is F. In some cases, R24is Cl. In some cases, R24is Br. In some cases, R24is I. In some cases, R24is cyano. In some cases, R24is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R24is methyl. In some cases, R24is isopropyl. In some cases, R24is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R24is cyclopropyl.

[0347] In some cases, R28is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R28is H. In some cases, R28is halo (e.g., F, Cl, Br or I). In some cases, R28is F. In some cases, R28is Cl. In some cases, R28is Br. In some cases, R28is I. In some cases, R28is cyano. In some cases, R28is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R28is methyl. In some cases, R28is isopropyl. In some cases, R28is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R28is cyclopropyl.

[0348] In some cases, R31is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R31is H. In some cases, R31is halo (e.g., F, Cl, Br or I). In some cases, R31is F. In some cases, R31is Cl. In some cases, R31is Br. In some cases, R31is I. In some cases, R31is cyano. In some cases, R31is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R31is methyl. In some cases, R31is isopropyl. In some cases, R31is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R31is cyclopropyl.

[0349] In some cases, R35is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R35is H. In some cases, R35is halo (e.g., F, Cl, Br or I). In some cases, R35is F. In some cases, R35is Cl. In some cases, R35is Br. In some cases, R35is I. In some cases, R35is cyano. In some cases, R35is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R35is methyl. In some cases, R35is isopropyl. In some cases, R35is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R35is cyclopropyl.

[0350] In some cases, R44is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R44is H. In some cases, R44is halo (e.g., F, Cl, Br or I). In some cases, R44is F. In some cases, R44is Cl. In some cases, R44is Br. In some cases, R44is I. In some cases, R44is cyano. In some cases, R44is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R44is methyl. In some cases, R44is isopropyl. In some cases, R44is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R44is cyclopropyl.

[0351] In some cases, R48is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R48is H. In some cases, R48is halo (e.g., F, Cl, Br or I). In some cases, R48is F. In some cases, R48is Cl. In some cases, R48is Br. In some cases, R48is I. In some cases, R48is cyano. In some cases, R48is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R48is methyl. In some cases, R48is isopropyl. In some cases, R48is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R48is cyclopropyl.

[0352] In some cases, R51is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R51is H. In some cases, R51is halo (e.g., F, Cl, Br or I). In some cases, R51is F. In some cases, R51is Cl. In some cases, R51is Br. In some cases, R51is I. In some cases, R51is cyano. In some cases, R51is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R51is methyl. In some cases, R51is isopropyl. In some cases, R51is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R51is cyclopropyl.

[0353] In some cases, R67is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R67is H. In some cases, R67is halo (e.g., F, Cl, Br or I). In some cases, R67is F. In some cases, R67is Cl. In some cases, R67is Br. In some cases, R67is I. In some cases, R67is cyano. In some cases, R67is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R67is methyl. In some cases, R67is isopropyl. In some cases, R67is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R67is cyclopropyl.

[0354] In some cases, R4, R8, R17, R20, R25, R29, R32, R38, R45, R49, R52, and R68are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl.

[0355] In some cases, R4is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R4is H. In some cases, R4is halo (e.g., F, Cl, Br or I). In some cases, R4is F. In some cases, R4is Cl. In some cases, R4is Br. In some cases, R4is I. In some cases, R4is cyano. In some cases, R4is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R4is methyl. Insome cases, R4is isopropyl. In some cases, R4is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R4is cyclopropyl.

[0356] In some cases, R8is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R8is H. In some cases, R8is halo (e.g., F, Cl, Br or I). In some cases, R8is F. In some cases, R8is Cl. In some cases, R8is Br. In some cases, R8is I. In some cases, R8is cyano. In some cases, R8is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R8is methyl. In some cases, R8is isopropyl. In some cases, R8is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R8is cyclopropyl.

[0357] In some cases, R17is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R17is H. In some cases, R17is halo (e.g., F, Cl, Br or I). In some cases, R17is F. In some cases, R17is Cl. In some cases, R17is Br. In some cases, R17is I. In some cases, R17is cyano. In some cases, R17is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R17is methyl. In some cases, R17is isopropyl. In some cases, R17is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R17is cyclopropyl.

[0358] In some cases, R20is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R20is H. In some cases, R20is halo (e.g., F, Cl, Br or I). In some cases, R20is F. In some cases, R20is Cl. In some cases, R20is Br. In some cases, R20is I. In some cases, R20is cyano. In some cases, R20is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R20is methyl. In some cases, R20is isopropyl. In some cases, R20is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R20is cyclopropyl.

[0359] In some cases, R25is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R25is H. In some cases, R25is halo (e.g., F, Cl, Br or I). In some cases, R25is F. In some cases, R25is Cl. In some cases, R25is Br. In some cases, R25is I. In some cases, R25is cyano. In some cases, R25is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R25is methyl. In some cases, R25is isopropyl. In some cases, R25is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R25is cyclopropyl.

[0360] In some cases, R29is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R29is H. In some cases, R29is halo (e.g., F, Cl, Br or I). In some cases, R29is F. In some cases, R29is Cl. In some cases, R29is Br. In some cases, R29is I. In some cases, R29is cyano. In some cases, R29is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R29is methyl. Insome cases, R29is isopropyl. In some cases, R29is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R29is cyclopropyl.

[0361] In some cases, R32is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R32is H. In some cases, R32is halo (e.g., F, Cl, Br or I). In some cases, R32is F. In some cases, R32is Cl. In some cases, R32is Br. In some cases, R32is I. In some cases, R32is cyano. In some cases, R32is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R32is methyl. In some cases, R32is isopropyl. In some cases, R32is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R32is cyclopropyl.

[0362] In some cases, R38is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R38is H. In some cases, R38is halo (e.g., F, Cl, Br or I). In some cases, R38is F. In some cases, R38is Cl. In some cases, R38is Br. In some cases, R38is I. In some cases, R38is cyano. In some cases, R38is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R38is methyl. In some cases, R38is isopropyl. In some cases, R38is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R38is cyclopropyl.

[0363] In some cases, R45is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R45is H. In some cases, R45is halo (e.g., F, Cl, Br or I). In some cases, R45is F. In some cases, R45is Cl. In some cases, R45is Br. In some cases, R45is I. In some cases, R45is cyano. In some cases, R45is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R45is methyl. In some cases, R45is isopropyl. In some cases, R45is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R45is cyclopropyl.

[0364] In some cases, R49is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R49is H. In some cases, R49is halo (e.g., F, Cl, Br or I). In some cases, R49is F. In some cases, R49is Cl. In some cases, R49is Br. In some cases, R49is I. In some cases, R49is cyano. In some cases, R49is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R49is methyl. In some cases, R49is isopropyl. In some cases, R49is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R49is cyclopropyl.

[0365] In some cases, R52is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R52is H. In some cases, R52is halo (e.g., F, Cl, Br or I). In some cases, R52is F. In some cases, R52is Cl. In some cases, R52is Br. In some cases, R52is I. In some cases, R52is cyano. In some cases, R52is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R52is methyl. Insome cases, R52is isopropyl. In some cases, R52is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R52is cyclopropyl.

[0366] In some cases, R68is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R68is H. In some cases, R68is halo (e.g., F, Cl, Br or I). In some cases, R68is F. In some cases, R68is Cl. In some cases, R68is Br. In some cases, R68is I. In some cases, R68is cyano. In some cases, R68is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R68is methyl. In some cases, R68is isopropyl. In some cases, R68is C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R68is cyclopropyl.

[0367] In some cases, R5, R9, R13, R21, R22, R33, R36, R39, R42, and R69are each independently H or C1-6alkyl.

[0368] In some cases, R5is selected from H and C1-6alkyl. In some cases, R5is H. In some cases, R5is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n- butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R5is methyl.

[0369] In some cases, R9is selected from H and C1-6alkyl. In some cases, R9is H. In some cases, R9is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n- butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R9is methyl.

[0370] In some cases, R13is selected from H and C1-6alkyl. In some cases, R13is H. In some cases, R13is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R13is methyl.

[0371] In some cases, R21is selected from H and C1-6alkyl. In some cases, R21is H. In some cases, R21is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R21is methyl.

[0372] In some cases, R22is selected from H and C1-6alkyl. In some cases, R22is H. In some cases, R22is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R22is methyl.

[0373] In some cases, R33is selected from H and C1-6alkyl. In some cases, R33is H. In some cases, R33is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R33is methyl.

[0374] In some cases, R36is selected from H and C1-6alkyl. In some cases, R36is H. In some cases, R36is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R36is methyl.

[0375] In some cases, R39is selected from H and C1-6alkyl. In some cases, R39is H. In some cases, R39is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R39is methyl.

[0376] In some cases, R42is selected from H and C1-6alkyl. In some cases, R42is H. In some cases, R42is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R42is methyl.

[0377] In some cases, R69is selected from H and C1-6alkyl. In some cases, R69is H. In some cases, R69is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R69is methyl.

[0378] In some cases, L is a single bond, , , , , , , , or , wherein: R70is H or -CH3; R71is H or -CH3; R72and R73are each independently selected from H, F, and -CH3; X7is O, S, or NR74, wherein R74is H or -CH3.

[0379] In some cases, L is a single bond. In these instances, where L is a single bond, R53is directly attached to the Y-ring. In some cases, L is a functional group selected from , , , , , , , and . In some cases, L is . In some cases, L is . In some cases, L is . In some cases, L is . In some cases, L is . In some cases, L is . In some cases, L is . In some cases, L is . In these instances, R53is attached to the left side of the functional group and the Y-ring is attached to the right side of the functional group.

[0380] In some cases, R70is H or -CH3. In some cases R70is H. In some cases, R70is - CH3.

[0381] In some cases, R71is H or -CH3. In some cases R71is H. In some cases, R71is - CH3.

[0382] In some cases, R72and R73are each independently selected from H, F, and -CH3. In some cases, R72is selected from H, F, and -CH3. In some cases, R72is H. In some cases, R72is F. In some cases, R72is -CH3. In some cases, R73is selected from H, F, and -CH3. In some cases, R73is H. In some cases, R73is F. In some cases, R73is -CH3.

[0383] In some cases, X7is O, S, or NR74, wherein R74is H or -CH3. In some cases, X7is O. In some cases, X7is S. In some cases, X7is NR74. In some cases, R74is H or -CH3. In some cases, R74is H, and thus X7is NH. In some cases, R74is -CH3, and thus X7is NCH3.

[0384] In some cases, R70is H, and thus L is . In these instances, R53is attached to the -NH- group and the Y-ring is attached to the -C(O)- group.

[0385] In some cases, R53is of the formula (Ia) or (Ib): (Ia) or (Ib).

[0386] In some cases, R53is of the formula (Ia): (Ia).

[0387] In some cases, n is 0 or 1. In some cases, n is 0. In these cases, X6and R58are not present. In some cases, n is 1. In these cases, X6and R58are present.

[0388] In some cases, X1, X3, X4, and X6are each independently selected from C and N.

[0389] In some cases, X1is selected from C and N. In some cases, X1is C. In some cases, X1is N.

[0390] In some cases, X3is selected from C and N. In some cases, X3is C. In some cases, X3is N. When X3is N, then R55is absent.

[0391] In some cases, X4is selected from C and N. In some cases, X4is C. In some cases, X4is N. When X4is N, then R56is absent.

[0392] In some cases, X6is selected from C and N. In some cases, X6is C. In some cases, X6is N. When X6is N, then R58is absent.

[0393] In some cases, X2and X5are each independently selected from C, N, S, and O.

[0394] In some cases, X2is selected from C, N, S, and O. In some cases, X2is C. In some cases, X2is N. When X2is N, then R54is absent. In some cases, X2is S. When X2is S, then R54is absent. In some cases, X2is O. When X2is O, then R54is absent.

[0395] In some cases, X5is selected from C, N, S, and O. In some cases, X5is C. In some cases, X5is N. When X5is N, then R57is absent. In some cases, X5is S. When X5is S, then R57is absent. In some cases, X5is O. When X5is O, then R57is absent.

[0396] In some cases, at least one of X1, X2, X3, X4, and X5is N, S, or O when n is 0.

[0397] In some cases, n is 0 and at least one of X1, X2, X3, X4, and X5is N. In some cases, n is 0 and X1is N. In some cases, n is 0 and X2is N. In some cases, n is 0 and X3is N. In some cases, n is 0 and X4is N. In some cases, n is 0 and X5is N. In some cases, n is 0 and more than one of X1, X2, X3, X4, and X5is N. In some cases, n is 0 and X1and X2are N. In some cases, n is 0 and X1and X5are N. In some cases, n is 0 and X2and X4are N. In some cases, n is 0 and X3and X4are N. In some cases, n is 0 and X3and X5are N. In some cases, n is 0 and X4and X5are N.

[0398] In some cases, n is 0 and at least one of X1, X2, X3, X4, and X5is S. In some cases, n is 0 and X1is S. In some cases, n is 0 and X2is S. In some cases, n is 0 and X3is S. In some cases, n is 0 and X4is S. In some cases, n is 0 and X5is S. In some cases, n is 0 and X5is S. In some cases, n is 0 and X3is N and X5is S.

[0399] In some cases, n is 0 and at least one of X1, X2, X3, X4, and X5is O. In some cases, n is 0 and X1is O. In some cases, n is 0 and X2is O. In some cases, n is 0 and X3is O. In some cases, n is 0 and X4is O. In some cases, n is 0 and X5is O. In some cases, n is 0 and X5is O. In some cases, n is 0 and X3is N and X5is O.

[0400] In some cases, examples of formula (Ia) include, but are not limited to, embodiments where n is 0 and X3is N and X5is O, or X3is N and X5is S, or X3is N and X4is N, or X4is N and X5is N, or X3is N and X5is N, and the like.

[0401] In some cases, at least one of X2, X3, X4, X5, and X6is N when n is 1. In some cases, n is 1 and X2is N. In some cases, n is 1 and X3is N. In some cases, n is 1 and X4is N. In some cases, n is 1 and X5is N. In some cases, n is 1 and X6is N. In some cases, n is 1 and more than one of X2, X3, X4, X5, and X6is N. In some cases, n is 1 and X2and X6are N. In some cases, n is 1 and X2and X4are N. In some cases, n is 1 and X4and X6are N.

[0402] In some cases, examples of formula (Ia) include, but are not limited to, embodiments where n is 1 and X2and X4are N, or X2and X6are N, or X3and X6are N, or X4and X6are N, and the like.

[0403] In some cases, R54, R55, R56, R57and R58are each independently absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl, and wherein at least one of R54, R55, R56, R57and R58is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl.

[0404] In some cases, R54is absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R54is absent. For example, X2may be N, and R54may be absent. In some cases, R54is H. In some cases, R54is halo (e.g., F, Cl, Br or I). In some cases, R54is F. In some cases, R54is Cl. In some cases, R54is Br. In some cases, R54is I. In some cases, R54is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R54is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R54is substituted C1-6alkyl, R54may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R54is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R54is substituted -OC1-6alkyl. For example, when R54is substituted -OC1-6alkyl, R54may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R54is -OH. In some cases, R54is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R54is cyclopropyl. In some cases, R54is adamantanyl. In some cases, R54is substituted C3-10cycloalkyl. For example, when R54is substituted C3-10cycloalkyl, R54may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R54is -OC3-6cycloalkyl. In some cases, R54is -O-cyclopropyl. In some cases, R54is - NHC(O)C1-6alkyl. In some cases, R54is -NHC(O)CH(CH3)2. In some cases, R54is 3- to 6-membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R54is substituted 3- to 6-membered heterocycloalkyl. For example, when R54is substituted 3- to 6-membered heterocycloalkyl, R54may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R54is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R54is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0405] In some cases, R55is absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R55is absent. For example, X3may be N, and R55may be absent. In some cases, R55is H. In some cases, R55is halo (e.g., F, Cl, Br or I). In some cases, R55is F. In some cases, R55is Cl. In some cases, R55is Br. In some cases, R55is I. In some cases, R55is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R55is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R55is substituted C1-6alkyl, R55may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R55is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R55is substituted -OC1-6alkyl. For example, when R55is substituted -OC1-6alkyl, R55may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R55is -OH. In some cases, R55is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R55is cyclopropyl. In some cases, R55is adamantanyl. In some cases, R55is substituted C3-10cycloalkyl. For example, when R55is substituted C3-10cycloalkyl, R55may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R55is -OC3-6cycloalkyl. In some cases, R55is -O-cyclopropyl. In some cases, R55is - NHC(O)C1-6alkyl. In some cases, R55is -NHC(O)CH(CH3)2. In some cases, R55is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R55is substituted 3- to 6-membered heterocycloalkyl. For example, when R55is substituted 3- to 6-membered heterocycloalkyl, R55may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R55is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R55is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0406] In some cases, R56is absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R56is absent. For example, X4may be N, and R56may be absent. In some cases, R56is H. In some cases, R56is halo (e.g., F, Cl, Br or I). In some cases, R56is F. In some cases, R56is Cl. In some cases, R56is Br. In some cases, R56is I. In some cases, R56is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R56is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R56is substituted C1-6alkyl, R56may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R56is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R56is substituted -OC1-6alkyl. For example, when R56is substituted -OC1-6alkyl, R56may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R56is -OH. In some cases, R56is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R56is cyclopropyl. In some cases, R56is adamantanyl. In some cases, R56is substituted C3-10cycloalkyl. For example, when R56is substituted C3-10cycloalkyl, R56may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R56is -OC3-6cycloalkyl. In some cases, R56is -O-cyclopropyl. In some cases, R56is - NHC(O)C1-6alkyl. In some cases, R56is -NHC(O)CH(CH3)2. In some cases, R56is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R56is substituted 3- to 6-membered heterocycloalkyl. For example, when R56is substituted 3- to 6-membered heterocycloalkyl, R56may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R56is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R56is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0407] In some cases, R57is absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R57is absent. For example, X5may be N, and R57may be absent. In some cases, R57is H. In some cases, R57is halo (e.g., F, Cl, Br or I). In some cases, R57is F. In some cases, R57is Cl. In some cases, R57is Br. In some cases, R57is I. In some cases, R57is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R57is substituted C1-6alkyl, such as substituted methyl, substituted ethyl,substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R57is substituted C1-6alkyl, R57may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R57is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R57is substituted -OC1-6alkyl. For example, when R57is substituted -OC1-6alkyl, R57may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R57is -OH. In some cases, R57is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R57is cyclopropyl. In some cases, R57is adamantanyl. In some cases, R57is substituted C3-10cycloalkyl. For example, when R57is substituted C3-10cycloalkyl, R57may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R57is -OC3-6cycloalkyl. In some cases, R57is -O-cyclopropyl. In some cases, R57is - NHC(O)C1-6alkyl. In some cases, R57is -NHC(O)CH(CH3)2. In some cases, R57is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R57is substituted 3- to 6-membered heterocycloalkyl. For example, when R57is substituted 3- to 6-membered heterocycloalkyl, R57may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R57is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R57is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0408] In some cases, R58is absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R58is absent. For example, X6may be N, and R58may be absent. In some cases, R58is H. In some cases, R58is halo (e.g., F, Cl, Br or I). In some cases, R58is F. In some cases, R58is Cl. In some cases, R58is Br. In some cases, R58is I. In some cases, R58is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R58is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R58is substituted C1-6alkyl, R58may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R58is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R58is substituted -OC1-6alkyl. For example, when R58is substituted -OC1-6alkyl, R58may be substituted with 1 to 3 substituents thatare each independently halo (e.g., F, Cl, Br or I). In some cases, R58is -OH. In some cases, R58is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R58is cyclopropyl. In some cases, R58is adamantanyl. In some cases, R58is substituted C3-10cycloalkyl. For example, when R58is substituted C3-10cycloalkyl, R58may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R58is -OC3-6cycloalkyl. In some cases, R58is -O-cyclopropyl. In some cases, R58is - NHC(O)C1-6alkyl. In some cases, R58is -NHC(O)CH(CH3)2. In some cases, R58is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R58is substituted 3- to 6-membered heterocycloalkyl. For example, when R58is substituted 3- to 6-membered heterocycloalkyl, R58may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R58is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R58is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0409] In some cases, at least one of R54, R55, R56, R57and R58is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl, as described herein. In some cases, one of R54, R55, R56, R57and R58is C1-6alkyl or substituted C1-6alkyl, as described herein.

[0410] In some cases, R53is of the formula (Ib): (Ib).

[0411] In some cases, R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl, or wherein two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0412] In some cases, R59is selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R59is H. In some cases, R59is halo (e.g., F, Cl, Br or I). In some cases, R59is F. In some cases, R59is Cl. In somecases, R59is Br. In some cases, R59is I. In some cases, R59is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R59is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R59is substituted C1-6alkyl, R59may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R59is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R59is substituted -OC1-6alkyl. For example, when R59is substituted -OC1-6alkyl, R59may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R59is -OH. In some cases, R59is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R59is cyclopropyl. In some cases, R59is adamantanyl. In some cases, R59is substituted C3-10cycloalkyl. For example, when R59is substituted C3-10cycloalkyl, R59may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R59is -OC3-6cycloalkyl. In some cases, R59is -O-cyclopropyl. In some cases, R59is - NHC(O)C1-6alkyl. In some cases, R59is -NHC(O)CH(CH3)2. In some cases, R59is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R59is substituted 3- to 6-membered heterocycloalkyl. For example, when R59is substituted 3- to 6-membered heterocycloalkyl, R59may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R59is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R59is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0413] In some cases, R60is selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6 alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R60is H. In some cases, R60is halo (e.g., F, Cl, Br or I). In some cases, R60is F. In some cases, R60is Cl. In some cases, R60is Br. In some cases, R60is I. In some cases, R60is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R60is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R60is substituted C1-6alkyl, R60may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R60is -OC1-6alkyl,such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R60is substituted -OC1-6alkyl. For example, when R60is substituted -OC1-6alkyl, R60may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R60is -OH. In some cases, R60is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R60is cyclopropyl. In some cases, R60is adamantanyl. In some cases, R60is substituted C3-10cycloalkyl. For example, when R60is substituted C3-10cycloalkyl, R60may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R60is -OC3-6cycloalkyl. In some cases, R60is -O-cyclopropyl. In some cases, R60is - NHC(O)C1-6alkyl. In some cases, R60is -NHC(O)CH(CH3)2. In some cases, R60is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R60is substituted 3- to 6-membered heterocycloalkyl. For example, when R60is substituted 3- to 6-membered heterocycloalkyl, R60may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R60is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R60is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0414] In some cases, R61is selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R61is H. In some cases, R61is halo (e.g., F, Cl, Br or I). In some cases, R61is F. In some cases, R61is Cl. In some cases, R61is Br. In some cases, R61is I. In some cases, R61is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R61is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R61is substituted C1-6alkyl, R61may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R61is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R61is substituted -OC1-6alkyl. For example, when R61is substituted -OC1-6alkyl, R61may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R61is -OH. In some cases, R61is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R61is cyclopropyl. In some cases, R61is adamantanyl. In some cases, R61is substituted C3-10cycloalkyl. For example, when R61is substituted C3-10cycloalkyl, R61may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R61is -OC3-6cycloalkyl. In some cases, R61is -O-cyclopropyl. In some cases, R61is -NHC(O)C1-6alkyl. In some cases, R61is -NHC(O)CH(CH3)2. In some cases, R61is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R61is substituted 3- to 6-membered heterocycloalkyl. For example, when R61is substituted 3- to 6-membered heterocycloalkyl, R61may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R61is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R61is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0415] In some cases, R62is selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1- 6 alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R62is H. In some cases, R62is halo (e.g., F, Cl, Br or I). In some cases, R62is F. In some cases, R62is Cl. In some cases, R62is Br. In some cases, R62is I. In some cases, R62is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R62is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R62is substituted C1-6alkyl, R62may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R62is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R62is substituted -OC1-6alkyl. For example, when R62is substituted -OC1-6alkyl, R62may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R62is -OH. In some cases, R62is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R62is cyclopropyl. In some cases, R62is adamantanyl. In some cases, R62is substituted C3-10cycloalkyl. For example, when R62is substituted C3-10cycloalkyl, R62may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R62is -OC3-6cycloalkyl. In some cases, R62is -O-cyclopropyl. In some cases, R62is - NHC(O)C1-6alkyl. In some cases, R62is -NHC(O)CH(CH3)2. In some cases, R62is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R62is substituted 3- to 6-membered heterocycloalkyl. For example, when R62is substituted 3- to 6-membered heterocycloalkyl, R62may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R62is thioalkoxyl such as -SCH(CH3)2, -SC(CH3)3, etc. In some cases, R62is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0416] In some cases, R63is selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1- 6 alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In some cases, R63is H. In some cases, R63is halo (e.g., F, Cl, Br or I). In some cases, R63is F. In some cases, R63is Cl. In some cases, R63is Br. In some cases, R63is I. In some cases, R63is C1-6alkyl, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, iso-butyl, sec-butyl), pentyl, or hexyl. In some cases, R63is substituted C1-6alkyl, such as substituted methyl, substituted ethyl, substituted propyl (e.g., substituted n-propyl or substituted isopropyl), substituted butyl (e.g., substituted n-butyl, substituted tert-butyl, substituted iso-butyl, substituted sec-butyl), substituted pentyl, or substituted hexyl. For example, when R63is substituted C1-6alkyl, R63may be substituted with 1 to 3 substituents that are each independently selected from halo (e.g., F, Cl, Br or I), cyano, C3-6cycloalkyl, -OH, -C(O)NH2, and -C(O)OH. In some cases, R63is -OC1-6alkyl, such as -OCH3, -OCH(CH3)2, -OC(CH3)3, etc. In some cases, R63is substituted -OC1-6alkyl. For example, when R63is substituted -OC1-6alkyl, R63may be substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). In some cases, R63is -OH. In some cases, R63is C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantanyl, etc. In some cases, R63is cyclopropyl. In some cases, R63is adamantanyl. In some cases, R63is substituted C3-10cycloalkyl. For example, when R63is substituted C3-10cycloalkyl, R63may be substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, R63is -OC3-6cycloalkyl. In some cases, R63is -O-cyclopropyl. In some cases, R63is - NHC(O)C1-6alkyl. In some cases, R63is -NHC(O)CH(CH3)2. In some cases, R63is 3- to 6- membered heterocycloalkyl, such as oxetanyl, morpholinyl, etc. In some cases, R63is substituted 3- to 6-membered heterocycloalkyl. For example, when R63is substituted 3- to 6-membered heterocycloalkyl, R63may be substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R63is thioalkoxyl such as -SCH(CH3)2, -SC(CH)3, etc. In some cases, R63is 5- to 10-membered heteroaryl, such as pyrrolyl.

[0417] In some cases, at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, as described herein.

[0418] In some cases, two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl. In some cases, the two groups of R59, R60, R61, R62and R63that form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6- membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl are groups that are adjacent to each other, such as R59and R60, or R60and R61, or R61and R62, or R62and R63. In some cases, two of R59, R60, R61, R62and R63(e.g., R61and R62) together with the ring atoms to whichthey are attached form a C4-6cycloalkyl (e.g., cyclohexyl). In some cases, two of R59, R60, R61, R62and R63(e.g., R61and R62) together with the ring atoms to which they are attached form a substituted C4-6cycloalkyl (e.g., substituted cyclohexyl). For example, the substituted C4-6cycloalkyl may be substituted with 1 to 4 substituents that are each independently C1-6alkyl. In some cases, two of R59, R60, R61, R62and R63(e.g., R61and R62) together with the ring atoms to which they are attached form a 4- to 6-membered heterocycloalkyl (e.g., pyrrolidinyl, tetrahydrofuranyl, etc.). In some cases, two of R59, R60, R61, R62and R63(e.g., R61and R62) together with the ring atoms to which they are attached form a substituted 4- to 6-membered heterocycloalkyl (e.g., substituted pyrrolidinyl, substituted tetrahydrofuranyl, etc.). For example, the substituted 4- to 6-membered heterocycloalkyl may be substituted with 1 to 4 substituents that are each independently selected from C1-6alkyl and oxo.

[0419] In some cases, R75is -C(O)OH or a bioisostere of -C(O)OH. In some instances, a “bioisostere” is a functional group that has similar physical or chemical properties. In some instances, a “bioisostere” can produce similar biological properties in the same chemical compound. Carboxylic acid bioisosteres are described, for example, in Meanwell, NA., J. Agric. Food Chem., 2023, 71, 18087-18122; Bredael, et al., Hindawi J. Chem., 2022, Article ID 2164558, 21 pages; and Ballatore et al., ChemMedChem, 2013, 8, 385-395. In some cases, R75is selected from -C(O)OH,and. In some cases,75 75R is -C(O)OH. In some cases, R is. In some cases, . In some cases, R75 75 75In some cases, R is. In some cases, RN is In some cases, R75is . In some cases, R75is . In somecases, R75isIn some cases, R75is. In some cases, R75isIn some cases, R75is . In some cases, R75is . In some case75s, R is. In some cases, R75is. In some cases, R75is. In some cases, R75isIn some cases, R75is. In some cases, R75is. In some cases, R75is. In some cases, R75is

[0420] In some cases, in the compound of Formula (I), at least one of the following is present: (1) R53is of the formula (Ia):(Ia); (2) R53is of the formula (Ib):(Ib), and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl;(3) is and at least one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl; (4) is selected from moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15; and (5) L is , , , , , , , or .

[0421] In some cases, the compound is not the following compound: .

[0422] In some cases, R53is of the formula (Ia): (Ia), as described herein.

[0423] In some cases, R53is of the formula (Ib): (Ib), andat least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl, as described herein.

[0424] In some cases, is and at least one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl, as described herein.

[0425] In some cases, L is , as described herein.

[0426] Aspects of the present disclosure include a compound of Formula (II): (II) or a pharmaceutically acceptable salt thereof,

[0427] In certain embodiments, the compound is a compound of the Formula (IIA): (IIA) wherein , L, n, X1, X2, X3, X4, X5, X6, R54, R55, R56, R57, R58, and R75are each as described herein.

[0428] In certain embodiments, n is 1, X1, X3, X4, X5, and X6are each C, X2is N, R54is absent, R55, R56, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0429] In certain embodiments, n is 1, X1, X3, X5, and X6are each C, X2and X4are each N, R54and R56are each absent, R55and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0430] In certain embodiments, n is 1, X1, X3, X4, and X5are each C, X2and X6are each N, R54and R58are each absent, R55and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0431] In certain embodiments, n is 1, X1, X2, X3, and X5are each C, X4and X6are each N, R56and R58are each absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3- 10 cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0432] In certain embodiments, n is 1, X1, X2, X3, X4, and X5are each C, X6is N, R58is absent, R54, R55, and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0433] In certain embodiments, n is 1, X1, X2, X3, X5, and X6are each C, X4is N, R56is absent, R54, R55, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0434] In certain embodiments, n is 1, X1, X2, X4, and X5are each C, X3and X6are each N, R55and R58are each absent, R54and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10 cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0435] In certain embodiments, n is 0, X1, X2, and X4are each C, X3and X5are each N, R55is absent, R54and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0436] In certain embodiments, n is 0, X1, X2, and X3are each C, X4and X5are each N, R56is absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0437] In certain embodiments, R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, substituted -OC1-6alkyl is -OC1-6alkyl substituted with 1 to 3 substituents that are each independently halo, substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0438] In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl.

[0439] In certain embodiments, R57is selected from:

[0440] , , , , , , , , and . In some cases, R57is . In some cases, R57is . In some cases, R57is . In somecases, R57is . In some cases, R57is . In some cases, R57is . In some cases, R57is . In some cases, R57is . In some cases, R57is .

[0441] In certain embodiments, R57is selected from: and .

[0442] In certain embodiments, n is 1, X1, X3, X4, X5, and X6are each C, X2is N, R54is absent, R55, R57, and R58are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0443] In certain embodiments, n is 0, X1, X3, and X5are each C, X2and X4are each N, R54is absent, R55and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0444] In certain embodiments, n is 0, X1, X2, and X5are each C, X3and X4are each N, R55is absent, R54and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0445] In certain embodiments, n is 0, X1, X2, and X3are each C, X4and X5are each N, R57is absent, R54and R55are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0446] In certain embodiments, n is 0, X1, X2, and X4are each C, X3is N, X5is N, S or O, R55is absent, R54is H, R57is absent or H, and R56is selected from halo, C1-6alkyl, substituted C1-6 alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0447] In certain embodiments, n is 0, X3, X4, and X5are each C, X1and X2are each N, R54is absent, R55and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0448] In certain embodiments, n is 0, X2, X3, and X4are each C, X1and X5are each N, R57is absent, R54and R55are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0449] In certain embodiments, R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, substituted -OC1-6alkyl is -OC1-6alkyl substituted with 1 to 3 substituents that are each independently halo, substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0450] In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl.

[0451] In certain embodiments, R56is selected from: , , , , , , , and .

[0452] In certain embodiments, is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y8, and Y13: , , , , , , , and , wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as described herein.

[0453] In certain embodiments, is selected from the following moieties Y1, Y2, Y3, Y4, and Y8:, , , , and ,wherein R1, R2, R3, R4, R6, R7, R8, R10, R11, R12, R14, R15, R16, R17, R30, R31, and R32are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl, and R5, R9, R13, and R33are each independently H or methyl.

[0454] In certain embodiments, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R30, R31, R32, and R33are each H.

[0455] In certain embodiments, is , R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl. In certain embodiments, R1, R2, R3, and R4are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl, and R5is H or methyl.

[0456] In certain embodiments, R1is H, R2is H, F, cyano or methyl, R3is H or F, R4is H, and R5is H.

[0457] In certain embodiments, R1, R2, R3, R4, and R5are each H.

[0458] In certain embodiments, R1is H, R2is F, R3is H, R4is H, and R5is H.

[0459] In certain embodiments, R1is H, R2is H, R3is F, R4is H, and R5is H.

[0460] In certain embodiments, L is a single bond, , , , or , wherein R70and R71are each as defined herein.

[0461] In certain embodiments, L is a single bond.

[0462] In certain embodiments, the compound is a compound of the Formula (IIB): (IIB) wherein: , L, and R75are each as described herein, and R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0463] In certain embodiments, one of R59, R60, R61, R62and R63is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

[0464] In certain embodiments, R59, R60, R61, and R63are each H, and R62is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

[0465] In some cases, R59, R60, R61, and R63are each H, and R62is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl, wherein substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0466] In certain embodiments, two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6- membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0467] In some cases, two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl, wherein substituted C4-6cycloalkyl is C4-6cycloalkyl substituted with 1 to 4 substituents that are each independently C1-6alkyl, and substituted 4- to 6-membered heterocycloalkyl is 4- to 6-membered heterocycloalkyl substituted with 1 to 4 substituents that are each independently selected from C1-6alkyl and oxo (=O).

[0468] In certain embodiments, the compound is a compound of Formula (IIC): (IIC), wherein L, R53, and R75are each as described herein, R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl, and wherein one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl. In certain embodiments, one of R1, R2, R3and R4is selected from cyano and C3-6cycloalkyl. In certain embodiments, one of R1, R2, R3and R4is halo. In certain embodiments, one of R1, R2, R3and R4is C1-6alkyl. In certain embodiments, one of R1, R2, R3and R4is C3-6cycloalkyl. In certain embodiments, R2is cyano.

[0469] In certain embodiments, is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15: , , , , , , , ,, , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R64, R65, R66, R67, R68, and R69are each as described herein.

[0470] In certain embodiments, is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y8, and Y13: , , , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as described herein. In certain embodiments, is selected from the following moieties Y2, Y3, Y4, and Y8:

[0471] , , , and , wherein R6, R7, R8, R10, R11, R12, R14, R15, R16, R17, R30, R31, and R32are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl, and R9, R13, and R33are each independently H or methyl. In some cases, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R30, R31, R32, and R33are each H.

[0472] In certain embodiments, is , and R6, R7, R8and R9are each as described herein.

[0473] In certain embodiments, is , and R18, R19, R20, and R21are each as described herein.

[0474] In certain embodiments, is , and R22, R23, R24, and R25are each as described herein.

[0475] In certain embodiments, is , and R10, R11, R12, and R13are each as described herein.

[0476] In certain embodiments, is , and R14, R15, R16, and R17are each as described herein.

[0477] In certain embodiments, is , and R30, R31, R32, and R33are each as described herein.

[0478] In certain embodiments, the compound is a compound of Formula (IID): (IID), wherein and R53, R70, and R75are each as described herein.

[0479] In certain embodiments, the compound is a compound of Formula (IIE): (IIE), wherein and R53, R71, and R75are each as described herein.

[0480] In certain embodiments, the compound is a compound of Formula (IIF):(IIF), wherein and R53and R75are each as described herein.

[0481] In certain embodiments, the compound is a compound of Formula (IIG): (IIG), wherein and R53and R75are each as described herein.

[0482] In certain embodiments, the compound is a compound of Formula (IIH): (IIH), wherein and R53and R75are each as described herein.

[0483] In certain embodiments, the compound is a compound of Formula (III): (III), wherein and R53and R75are each as described herein.

[0484] In certain embodiments, the compound is a compound of Formula (IIJ): (IIJ), wherein and R53, R72, R73, and R75are each as described herein.

[0485] In certain embodiments, the compound is a compound of Formula (IIK): (IIK),wherein and R53, X7, and R75are each as described herein.

[0486] In certain embodiments, R53is of the formula (Ib): (Ib) wherein R59, R60, R61, and R63are each H, and R62is C1-6alkyl or substituted C1-6alkyl.

[0487] In certain embodiments, the compound is a compound of the Formula (IIIa): (IIIa) wherein , L, n, X1, X2, X3, X4, X5, X6, R54, R55, R56, R57, and R58are each as described herein.

[0488] In certain embodiments, n is 1, X1, X3, X4, X5, and X6are each C, X2is N, R54is absent, R55, R56, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0489] In certain embodiments, n is 1, X1, X3, X5, and X6are each C, X2and X4are each N, R54and R56are each absent, R55and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0490] In certain embodiments, n is 1, X1, X3, X4, and X5are each C, X2and X6are each N, R54and R58are each absent, R55and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl,substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0491] In certain embodiments, n is 1, X1, X2, X3, and X5are each C, X4and X6are each N, R56and R58are each absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0492] In certain embodiments, n is 1, X1, X2, X3, X4, and X5are each C, X6is N, R58is absent, R54, R55, and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0493] In certain embodiments, n is 1, X1, X2, X3, X5, and X6are each C, X4is N, R56is absent, R54, R55, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0494] In certain embodiments, n is 0, X1, X2, and X4are each C, X3and X5are each N, R55is absent, R54and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0495] In certain embodiments, n is 0, X1, X2, and X3are each C, X4and X5are each N, R56is absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R57is C1-6alkyl or substituted C1-6alkyl.

[0496] In certain embodiments, n is 0, X1, X3, and X5are each C, X2and X4are each N, R54is absent, R55and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0497] In certain embodiments, n is 0, X1, X2, and X5are each C, X3and X4are each N, R55is absent, R54and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0498] In certain embodiments, n is 0, X1, X2, and X3are each C, X4and X5are each N, R57is absent, R54and R55are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0499] In certain embodiments, n is 0, X1, X2, and X4are each C, X3is N, X5is N or S, R55is absent, R54is H, R57is absent or H, and R56is selected from halo, C1-6alkyl, substituted C1- 6 alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6- membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl. In certain embodiments, R56is C1-6alkyl or substituted C1-6alkyl.

[0500] In certain embodiments, is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y8, and Y13:, , , , , , , and , wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as described herein.

[0501] In certain embodiments, is , R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl. In certain embodiments, R1, R2, R3, R4, and R5are each H.

[0502] In certain embodiments, L is a single bond.

[0503] In certain embodiments, the compound is a compound of the Formula (IIIb): (IIIb) wherein:and L are each as described herein, and R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0504] In certain embodiments, one of R59, R60, R61, R62and R63is C3-10cyclopropyl, substituted C3-10cyclopropyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

[0505] In certain embodiments, R59, R60, R61, and R63are each H, and R62is C3-10cyclopropyl, substituted C3-10cyclopropyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

[0506] In certain embodiments, two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6- membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

[0507] In certain embodiments, the compound is a compound of Formula (IIIc): (IIIc), wherein L and R53are each as described herein, R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl, and wherein one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl. In certain embodiments, one of R1, R2, R3and R4is selected from cyano and C3-6cycloalkyl. In certain embodiments, one of R1, R2, R3and R4is halo. In certain embodiments, one of R1, R2, R3and R4is C1-6alkyl. In certain embodiments, one of R1, R2, R3and R4is C3-6cycloalkyl. In certain embodiments, R2is cyano.

[0508] In certain embodiments, is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, and Y14: , , , , , , , , , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, and R52are each as described herein.

[0509] In certain embodiments, is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y8, and Y13:, , , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as described herein.

[0510] In certain embodiments, is , and R6, R7, R8and R9are each as described herein.

[0511] In certain embodiments, is , and R18, R19, R20, and R21are each as described herein.

[0512] In certain embodiments, is , and R22, R23, R24, and R25are each as described herein.

[0513] In certain embodiments, is , and R10, R11, R12, and R13are each as described herein.

[0514] In certain embodiments, is , and R14, R15, R16, and R17are each as described herein.

[0515] In certain embodiments, the compound is a compound of Formula (IIId): (IIId), wherein and R53are each as described herein.

[0516] In certain embodiments, R53is of the formula (Ib): (Ib) wherein R59, R60, R61, and R63are each H, and R62is C1-6alkyl or substituted C1-6alkyl.

[0517] In certain embodiments, the compound is selected from:

[0518] In certain embodiments, the compound is selected from: , , , and .

[0519] Aspects of the present disclosure include a compound or a pharmaceutically acceptable salt thereof selected from:

[0520] Aspects of the present disclosure include a compound or a pharmaceutically acceptable salt thereof selected from: , , , , , , and .

[0521] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0522] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0523] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0524] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0525] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0526] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0527] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0528] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0529] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0530] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0531] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0532] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0533] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0534] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0535] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0536] Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof.

[0537] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0538] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0539] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0540] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0541] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof.

[0542] Aspects of the present disclosure include a pharmaceutical composition comprising: a compound as described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0543] The compounds described herein can be isolated by procedures known to those skilled in the art. The compounds described herein may be obtained, for instance, by a resolution technique or by chromatography techniques (e.g., silica gel chromatography, chiral chromatography, etc.). As used herein, the term “isolated” refers to compounds that are non- naturally occurring and can be obtained or purified from synthetic reaction mixtures. Isolated compounds may find use in the pharmaceutical compositions and methods of treatment described herein.

[0544] The compounds described herein also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to,2H,3H,11C,13C,14C,15N,15O,17O,18O,18F, etc. Thus, the disclosed compounds may be enriched in one or more of these isotopes relative to the natural abundance of such isotope. By way of example, deuterium (2H; D) has a natural abundance of about 0.015%. Accordingly, for approximately every 6,500 hydrogen atoms occurring in nature, there is one deuterium atom. Specifically contemplated herein are compounds enriched in deuterium at one or more positions. Thus, deuterium containing compounds of the disclosure have deuterium at one or more positions (as the case may be) in an abundance of greater than 0.015%. In some embodiments, one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or more) hydrogen atoms of a substituent group (e.g., an R-group) of any one of the subject compounds described herein are substituted with a deuterium. METHODS OF USE

[0545] In certain embodiments, the compounds of the present disclosure are CYP26B1 inhibitors. In some embodiments, the compounds of the present disclosure act as inhibitors with a bias of inhibition of CYP26B1 over CYP26A1. Accordingly, such compounds have the potential to provide therapeutic benefit in the treatment of, or prevention of, diseases or disorders that respond to synthetic or natural retinoids (such as RA). In some instances, the mode of action of these compounds is that by inhibiting CYP26B1 that catabolizes natural RA, endogenous levels of RA are permitted to rise to a level where desired therapeutic benefits are attained. In some embodiments, the CYP26B1 gene is directly regulated (i.e., expression is increased) by RA itself, and thus blocking CYP26B1 enzyme activity leads to increased CYP26B1 expression.

[0546] In certain embodiments, the compounds of the present disclosure are useful for prevention or treatment of diseases or conditions in mammals, including humans, in instanceswhere such diseases and conditions are prevented, treated, ameliorated, or disease onset is delayed by the administration of retinoid compounds or by the organism’s naturally occurring RA. Compounds of the present disclosure inhibit the breakdown of RA.

[0547] In certain embodiments, the compounds of the present disclosure are used as single agent therapies. In certain embodiments, the compounds of the present disclosure are used in conjunction with RA or other retinoids.

[0548] As such, methods of the present disclosure may include a method of inhibiting CYP26B1 activity by contacting CYP26B1 with a compound of the present disclosure. The contacting may be sufficient to inhibit the activity of CYP26B1 as compared to CYP26B1 activity in the absence of a compound of the present disclosure.

[0549] In certain embodiments, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of the compound as described herein or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject.

[0550] Aspects of the present disclosure include a method of treating a disease or disorder, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat the disease or disorder in the subject.

[0551] In certain embodiments, the disease or disorder is selected from heterotopic ossification (HO), fibrodysplasia ossificans progressiva (FOP), actinic keratosis, arsenic keratosis, inflammatory acne, non-inflammatory acne, psoriasis, ichthyosis, keratinization, hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, glucocorticoid damage, and steroid atrophy.

[0552] In certain embodiments, the disease or disorder is selected from heterotopic ossification (HO; including trauma-induced and surgically-induced), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, and vascular calcification (including that associated with chronic kidney disease (CKD)).

[0553] In certain embodiments, the disease or disorder is fibrodysplasia ossificans progressiva (FOP).

[0554] In certain embodiments, the disease or disorder is multiple osteochondromas.

[0555] In certain embodiments, the disease or disorder is selected from acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), heterotopic ossification (HO; including trauma-induced and surgically-induced), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, vascular calcification (including that associated with chronic kidney disease (CKD)), ankylosing spondylitis,osteoarthritis, actinic keratosis, basal and squamous cell carcinoma, esophageal squamous cell carcinoma, arsenic keratosis, inflammatory acne, non-inflammatory acne, psoriasis, ichthyosis, keratinization, hyperproliferative disorders of the skin, photoaging, eczema, atopic dermatitis, Darriers disease, lichen planus, glucocorticoid damage, steroid atrophy, Alzheimer’s, Parkinson’s disease, autism spectrum disorders, schizophrenia and schizoaffective disorders, age related dementia and cognitive defects, adult T-cell leukemia / lymphoma, hair loss, atherosclerosis, and platelet disorders.

[0556] In certain embodiments, the disease or disorder is selected from conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, ocular surface neoplasia, cicatricial conjunctival disorders (including Stevens-Johnson syndrome, graft vs. host disease, trauma, chemical burns, thermal burns, prolonged ultraviolet light exposure, rosacea-induced damage, infectious disease (chlamydia, herpetic disease), keratinizing disorders of the conjunctiva (including radiation exposure, chemical injury, damage induced by topical medications)), disorders of the conjunctiva caused by vitamin A deficiency, pterygia, pingueculae, cicatricial pemphigoid, atopic kerato-conjunctivitis, Sjogren syndrome related conjunctival injury, meibomian gland dysfunction, blepharitis, hordeola, chalazia, eyelid neoplasms, keratitis, dry eye disease, evaporative dry eye disease, conjunctivalization, corneal intraepithelial neoplasia, stem cell deficiency, corneal injury, chemical-induced corneal injury, thermally-induced corneal injury, trauma-induced corneal injury, radiation-induced corneal injury, disorders of the cornea caused by vitamin A deficiency, Sjogren syndrome-related corneal injury, corneal neovascularization, uveitis, fibro-proliferative disorders, proliferative diabetic retinopathy, proliferative vitreo- retinopathy, epiretinal membrane formation, neovascular membrane formation, age-related macular degeneration, drusenogenesis, and retinal detachment injury.

[0557] In certain embodiments, the disease or disorder is selected conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, cicatricial conjunctival disorders (including from chemical burns, thermal burns, prolonged ultraviolet light exposure, rosacea- induced damage), keratinizing disorders of the conjunctiva, disorders of the conjunctiva caused by vitamin A deficiency, meibomian gland dysfunction, blepharitis, hordeola, chalazia, dry eye disease, evaporative dry eye disease, corneal injury, chemical-induced corneal injury, thermally- induced corneal injury, trauma-induced corneal injury, radiation-induced corneal injury, and disorders of the cornea caused by vitamin A deficiency.

[0558] In certain embodiments, the disease or disorder is meibomian gland dysfunction.

[0559] In certain embodiments, the disease or disorder is dry eye disease.

[0560] In certain embodiments, the disease or disorder is evaporative dry eye disease.

[0561] In certain embodiments, the disease or disorder may be meibomian gland dysfunction. In certain embodiments, the disease or disorder may be dry eye disease. In certain embodiments, the disease or disorder may be aqueous deficient dry eye disease or evaporative dry eye disease. In certain embodiments, the disease or disorder may be evaporative dry eye disease. Methods of Treatment

[0562] The compounds of the present disclosure find use in treatment of a condition or disease in a subject that is amenable to treatment by administration of the compound. Thus, in some embodiments, provided are methods that include administering to a subject a therapeutically effective amount of any of the compounds of the present disclosure. In certain aspects, provided are methods of delivering a compound to a subject, the method including administering to the subject an effective amount of a compound of the present disclosure. In certain instances, the administering is effective to provide a therapeutically effective amount of the compound to the subject.

[0563] The subject to be treated can be one that is in need of therapy, where the subject to be treated is one amenable to treatment using the compounds disclosed herein. Accordingly, a variety of subjects may be amenable to treatment using the compounds disclosed herein. Generally, such subjects are “mammals”, with humans being of interest. Other subjects can include companion animals or domestic pets (e.g., canine and feline), livestock (e.g., cows, pigs, goats, horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease), as well as non-human primates (e.g., chimpanzees, and monkeys). In some instances, the mammal is selected from a companion animal and livestock. In some instances, the mammal is a human.

[0564] The present disclosure provides methods that include delivering a compound of the present disclosure to an individual having a disease, such as methods that include administering to the subject a therapeutically effective amount of a compound of the present disclosure. The methods are useful for treating a wide variety of conditions and / or symptoms associated with a disease. In the context of disease, the term “treating” includes one or more (e.g., each) of: reducing the severity of one or more symptoms, inhibiting the progression, reducing the duration of one or more symptoms, and ameliorating one or more symptoms associated with the disease.

[0565] The administering can be done any convenient way. Generally, administration is, for example, ocular, oral, buccal, parenteral (e.g., intravenous, intraarterial, subcutaneous), intraperitoneal (i.e., into the body cavity), topically, e.g., by inhalation or aeration (i.e., through the mouth or nose), or rectally systemic (i.e., affecting the entire body). For example, the administration may be systemic, e.g., orally (via injection of tablet, pill or liquid) or intravenously(by injection or via a drip, for example). In other embodiments, the administering can be done by pulmonary administration, e.g., using an inhaler or nebulizer. In other embodiments, the ocular administration can be topical, local ocular (i.e., subconjunctival, retrobulbar, intracameral, intravitreal) or systemic. Compounds of the present disclosure or composition comprising the compounds may be administered in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term “topically” may include injection, insertion, implantation, topical application, or parenteral application.

[0566] In certain embodiments, the compounds of the present disclosure find use in methods of treating a disease or disorder in a subject. Thus, in some embodiments, provided are methods that include administering to a subject a therapeutically effective amount of any of the compounds of the present disclosure. In certain instances, the administering is effective to provide a therapeutically effective amount of the compound to the subject to treat a disease or disorder in the subject.

[0567] In certain embodiments, the diseases or disorders may include but are not limited to heterotopic ossification (HO), trauma or surgically induced heterotopic ossification, joint replacement induced heterotopic ossification, fibrodysplasia ossificans progressiva (FOP), actinic keratosis, arsenic keratosis, nodular acne, inflammatory acne, acne conglobata, recalcitrant acne, acne vulgaris, cystic acne, non-inflammatory acne, plaque psoriasis, severe psoriasis (including erythrodermic and pustular types), ichthyosis, keratinization, hyperproliferative disorders of the skin, eczema (including severe chronic hand eczema refractory to high potency topical corticosteroids), atopic dermatitis, keratosis follicularis (Darriers disease), lichen planus, glucocorticoid damage, steroid atrophy, atherosclerosis, platelet disorders, myelodysplastic syndrome and acute promyelocytic leukemia. In certain embodiments, the disease or disorder is selected from heterotopic ossification (HO), trauma or surgically induced heterotopic ossification, joint replacement induced heterotopic ossification, and fibrodysplasia ossificans progressiva (FOP). In certain embodiments, the disease or disorder may be fibrodysplasia ossificans progressiva (FOP).

[0568] In certain embodiments, the diseases or disorders may include but are not limited to neurological diseases and neurocognitive disorders. The neurological diseases or neurocognitive disorders may include but are not limited to Parkinson’s disease, autism spectrum disorder, schizophrenia, schizoaffective disorder, age-related dementia, cognitive deficit, and Alzheimer’s disease.

[0569] In certain embodiments, the disease or disorder may be related to conjunctiva and selected from conjunctivitis, goblet cell injury, limbal stem cell deficiency, ocular surface neoplasia, cicatricial conjunctival disorders (including Stevens-Johnson syndrome, graft vs. hostdisease, trauma, chemical burns, thermal burns, prolonged ultraviolet light exposure, rosacea- induced damage, infectious disease (chlamydia, herpetic disease)), keratinizing disorders of the conjunctiva (including radiation exposure, chemical injury, damage induced by topical medications), vitamin A deficiency, pterygia, pingueculae, cicatricial pemphigoid, atopic kerato- conjunctivitis and Sjogren syndrome related conjunctival injury.

[0570] In certain embodiments, the disease or disorder may be related to eyelid and selected from meibomian gland dysfunction, blepharitis, hordeola, chalazia and eyelid neoplasms. In certain embodiments, the disease or disorder may be meibomian gland dysfunction.

[0571] In certain embodiments, the disease or disorder may be related to cornea and selected from keratitis, dry eye disease, conjunctivalization, corneal intraepithelial neoplasia, stem cell deficiency, corneal injury, chemical-induced corneal injury, thermally-induced corneal injury, trauma-induced corneal injury, radiation-induced corneal injury, disorders of the cornea caused by vitamin A deficiency, Sjogren syndrome-related corneal injury, and corneal neovascularization. In certain embodiments, the disease or disorder may be dry eye disease. In certain embodiments, the disease or disorder may be aqueous deficient dry eye disease or evaporative dry eye disease. In certain embodiments, the disease or disorder may be evaporative dry eye disease.

[0572] In certain embodiments, the disease or disorder may be related to uvea and selected from uveitis.

[0573] In certain embodiments, the disease or disorder may be related to vitreous and retina, and selected from fibro-proliferative disorders, proliferative diabetic retinopathy, proliferative vitreo-retinopathy, epiretinal membrane formation, neovascular membrane formation, age-related macular degeneration, drusenogenesis, and retinal detachment injury.

[0574] In certain embodiments, the disease or disorder may include but are not limited to pre-malignant and malignant skin conditions, basal cell carcinoma, squamous cell carcinoma (including esophageal squamous cell carcinoma), actinic lentigines, ichthyosis congenita, ichthyosis vulgaris, lamellar ichthyosis, cutaneous warts - flat subtype, epidermolytic hyperkeratosis / keratinopathic ichthyoses, verruca vulgaris, early stretch marks and adult T-cell leukemia / lymphoma.

[0575] In certain embodiments, the diseases or disorders may include but are not limited to multiple osteochondromas, vascular calcification associated with chronic kidney disease (CKD), vascular calcification, ankylosing spondylitis and osteoarthritis.

[0576] In certain embodiments, the compounds of the present disclosure find use in adjunctive palliative treatment of photoaging such as fine facial wrinkles, facial skin roughness and facial mottled hyperpigmentation (i.e., ‘liver spots’).

[0577] In certain embodiments, the compounds of the present disclosure may be useful to acute promyelocytic leukemia patients during the consolidation phase of treatment with combination chemotherapy or during the maintenance phase of treatment in intermediate- and high-risk patients with combination chemotherapy.

[0578] In certain embodiments, the compounds of the present disclosure may be useful to acute promyelocytic leukemia patients with refractory disease for remission induction who have previously relapsed from anthracycline chemotherapy or those who have a contraindication to anthracycline-based therapy.

[0579] In certain embodiments, the compounds of the present disclosure may be useful to patients who are refractory to or have had a relapse from or have contraindications to anthracycline chemotherapy with the presence of the PML / RARa gene. Pharmaceutical Compositions

[0580] In certain embodiments, the disclosed compounds thereof are useful for the treatment of a disease or disorder. Accordingly, pharmaceutical compositions comprising at least one disclosed compound are also described herein. For example, the present disclosure provides pharmaceutical compositions that include a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt or solvate or hydrate or stereoisomer thereof) and a pharmaceutically acceptable excipient.

[0581] A pharmaceutical composition that includes a subject compound may be administered to a patient alone, or in combination with other supplementary active agents. For example, one or more compounds according to the present disclosure can be administered to a patient with or without supplementary active agents. The pharmaceutical compositions may be manufactured using any of a variety of processes, including, but not limited to, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing, and the like. The pharmaceutical composition can take any of a variety of forms including, but not limited to, a sterile solution, suspension, emulsion, spray dried dispersion, lyophilisate, tablet, microtablets, pill, pellet, capsule, powder, syrup, elixir or any other dosage form suitable for administration.

[0582] A compound of the present disclosure may be administered to a subject using any convenient means capable of resulting in the desired reduction in disease condition or symptom. Thus, a compound can be incorporated into a variety of formulations for therapeutic administration. More particularly, a compound can be formulated into pharmaceutical compositions by combination with appropriate pharmaceutically acceptable excipients, carriers or diluents, and may be formulated into preparations in solid, semisolid, liquid or gaseous forms,such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, aerosols, and the like.

[0583] Formulations for pharmaceutical compositions are described in, for example, Remington’s Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition, 1995, which describes examples of formulations (and components thereof) suitable for pharmaceutical delivery of the disclosed compounds. Pharmaceutical compositions that include at least one of the compounds can be formulated for use in human or veterinary medicine. Particular formulations of a disclosed pharmaceutical composition may depend, for example, on the mode of administration and / or on the location of the subject to be treated. In some embodiments, formulations include a pharmaceutically acceptable excipient in addition to at least one active ingredient, such as a compound of the present disclosure. In other embodiments, other medicinal or pharmaceutical agents, for example, with similar, related or complementary effects on the disease or condition being treated can also be included as active ingredients in a pharmaceutical composition.

[0584] Pharmaceutically acceptable carriers useful for the disclosed methods and compositions may depend on the particular mode of administration being employed. In addition to biologically neutral carriers, pharmaceutical compositions to be administered can optionally contain non-toxic auxiliary substances (e.g., excipients), such as wetting or emulsifying agents, preservatives, and pH buffering agents, and the like. The disclosed pharmaceutical compositions may be formulated as a pharmaceutically acceptable salt of a disclosed compound.

[0585] The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a compound calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, excipient, carrier or vehicle. The specifications for a compound depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the subject.

[0586] The dosage form of a disclosed pharmaceutical composition may be determined by the mode of administration chosen. For example, in addition to injectable fluids, topical or oral dosage forms may be employed. Topical preparations may include eye drops, ointments, sprays and the like. Oral formulations may be liquid (e.g., syrups, solutions or suspensions), or solid (e.g., powders, pills, tablets, or capsules). Methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art.

[0587] Certain embodiments of pharmaceutical compositions that include a subject compound may be formulated in unit dosage form suitable for individual administration of precise dosages. The amount of active ingredient administered may depend on the subject being treated,the severity of the affliction, and the manner of administration, and is known to those skilled in the art. In certain instances, the formulation to be administered contains a quantity of the compound disclosed herein in an amount effective to achieve the desired effect in the subject being treated.

[0588] Each therapeutic compound can independently be in any dosage form, such as those described herein, and can also be administered in various ways, as described herein. For example, compounds may be formulated together, in a single dosage unit (that is, combined together in one form such as capsule, tablet, powder, or liquid, etc.) as a combination product. Alternatively, when not formulated together in a single dosage unit, an individual compound may be administered at the same time as another therapeutic compound or sequentially, in any order thereof.

[0589] A disclosed compound can be administered alone, as the sole active pharmaceutical agent, or in combination with one or more additional compounds of the present disclosure or in conjunction with other therapeutic agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered simultaneously or at different times, or the therapeutic agents can be administered together as a single composition combining two or more therapeutic agents. Thus, the pharmaceutical compositions disclosed herein containing a compound of the present disclosure optionally include other therapeutic agents. Accordingly, certain embodiments are directed to such pharmaceutical compositions, where the composition further includes a therapeutically effective amount of an agent selected as is known to those of skill in the art. Methods of Administration

[0590] The subject compounds find use for treating a disease or disorder in a subject. The route of administration may be selected according to a variety of factors including, but not limited to, the condition to be treated, the formulation and / or device used, the subject to be treated, and the like. Routes of administration useful in the disclosed methods include, but are not limited to, oral and parenteral routes, such as intravenous (iv), intraperitoneal (ip), rectal, topical, ophthalmic, nasal, intrathecal, and transdermal. Formulations for these dosage forms are described herein.

[0591] An effective amount of a subject compound may depend, at least, on the particular method of use, the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition. A “therapeutically effective amount” of a composition is a quantity of a specified compound sufficient to achieve a desired effect in a subject (e.g., patient) being treated. For example, this may be the amount of a subject compound necessary to prevent, inhibit, reduce or relieve a disease or disorder in a subject. Ideally, atherapeutically effective amount of a compound is an amount sufficient to prevent, inhibit, reduce or relieve a disease or disorder in a subject without causing a substantial cytotoxic effect on host cells in the subject.

[0592] Therapeutically effective doses of a subject compound or pharmaceutical composition can be determined by one of skill in the art. For example, in some instances, a therapeutically effective dose of a compound or pharmaceutical composition is administered with a goal of achieving local (e.g., tissue) concentrations that are at least as high as the EC50of an applicable compound disclosed herein.

[0593] The specific dose level and frequency of dosage for any particular subject may be varied and may depend upon a variety of factors, including the activity of the subject compound, the metabolic stability and length of action of that compound, the age, body weight, general health, sex and diet of the subject, mode and time of administration, rate of excretion, drug combination, and severity of the condition of the host undergoing therapy.

[0594] In some embodiments, multiple doses of a compound are administered. The frequency of administration of a compound can vary depending on any of a variety of factors, e.g., severity of the symptoms, condition of the subject, etc. For example, in some embodiments, a compound is administered once per month, twice per month, three times per month, every other week, once per week (qwk), twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily (qd / od), twice a day (bds / bid), or three times a day (tds / tid), etc. EXAMPLES

[0595] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. By “average” is meant the arithmetic mean. Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pl, picoliter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c., subcutaneous(ly); and the like.

[0596] List of Abbreviationsδ chemical shift (Bpin)2, B2pin2bis(pinacolato)diboron [Cu] copper catalysis [Pd] palladium catalysis1H NMR proton nuclear magnetic resonance Å angstrom Ac acetyl ACN, MeCN acetonitrile AcOH acetic acid Ad adamantyl aq, aq. aqueous Ar argon atm atmosphere Boc tert-butylcarbamate Bpin pinacolboryl br broad, broad singlet Bu butyl BuOH butanol calcd. calculated d doublet D deuterium dba dibenzylideneacetone dd doublet of doublets ddd doublet of doublet of doublets DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ddt doublet of doublet of triplets DEAD diethyl azodicarboxylate DIBAL-H, DIBALH diisobutylaluminum hydride dioxane 1,4-dioxane DIPEA, Hunig's base diisopropylethylamine DMAP 4-dimethylaminopyridine DME dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide, fully deuterated dimethylsulfoxide dppf 1,1′-bis(diphenylphosphino)ferrocenedq doublet of quartets dt doublet of triplets dtbpf 1,1′-bis(di-tert-butylphosphino)ferrocene eq equivalents Et ethyl Et2O diethyl ether Et3N, NEt3, TEA triethylamine EtOAc ethyl acetate EtOH ethanol g gram gem geminal h hour(s), hextet H hydrogen, proton halo halogen atom HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate hept heptet HMDS hexamethyldisilazane Hz hertz i-Pr isopropyl J coupling constant L liter LDA lithium diisopropylamine m Multiplet, meta- M molar, molarity, mass, male m / z mass to charge ratio Me methyl MeOH methanol mg milligram MHz megahertz min minutes mL milliliter mmol millimole mol mole mol % mole percentagen-BuLi n-butyllithium NCS N-chlorosuccinimide NFSI N-fluorobenzenesulfonimide NIS N-iodosuccinimide NMP N-methylpyrrolidone o ortho- OAc acetate OEt ethoxy, ethoxide Oi-Pr isopropoxy, isopropoxide OMe methoxy, methoxide OTf triflate p para- P(o-tol)3tri-o-tolylphosphine Pd / C palladium on carbon Ph phenyl pH potential of hydrogen PPh3 triphenylphosphine PPTS pyridine para-toluenesulfonate Pr, n-Pr n-propyl psi pounds per square inch PTS para-toluenesulfonic acid q quartet R, R', R" general chemical group RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl s singlet sat'd, sat. saturated SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl t tert-, triplet TBAF tetrabutylammonium fluoride t-Bu tert-butyl t-BuLi tert-butyllithium t-BuO, Ot-Bu tert-butoxide tdd triplet of doublet of doublets Tf triflyl TFA trifluoroacetic acidTHF tetrahydrofuran TMEDA tetramethylethylenediamine TMP tetramethylpiperidine TMS trimethylsilane Ts tosyl tt triplet of triplets TTMSS tris(trimethylsilyl)silane v / v volume by / per volume v / w volume by / per weight w / w weight by / per weight wt % weight percentage XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos-Pd-G3 (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate EXAMPLE 1: GENERAL SYNTHETIC PROCEDURES

[0597] The subject compounds, including compounds that are not commercially available, can be synthesized via a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods. A variety of examples of synthetic routes that can be used to synthesize the compounds disclosed herein are described in the schemes below. General Procedure A – Boc Protection of Amines

[0598] A solution of amine (1.0 eq) and di-tert-butyl decarbonate (2.0 eq) in either ACN or CH2Cl2is treated with either cesium carbonate (2.0 eq) or 4-dimethylaminopyridine (1.0 eq). After stirring at ambient temperature for 1-16 h, the mixture is diluted with H2O, extracted with EtOAc, dried over MgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography using EtOAc / hexanes as the mobile phase to give the desired protected amine. General Procedure B – Heck Cross-Coupling

[0599] Method 1: A mixture of aryl halide (1.0 eq), acrylic ester (5.0 eq), Pd(dtbpf)Cl2(15 mol %), triethylamine (6.0 eq), 4-methylbenzenesulfonic acid-pyridine (3.0 eq) and H2O was stirred at ambient temperature for 6-16 h.

[0600] Method 2: A mixture of aryl halide (1.0 eq), acrylic ester (1.3-5.0 eq), Pd(OAc)2(5-10 mol %), tri-o-tolylphosphine (10-20 mol %), triethylamine (4.0-5.0 eq) and ACN was stirred at 95 °C for 16 h or at 90 °C for 3 h with microwave irradiation.

[0601] Method 3: A sealed microwave vial containing aryl halide (1.0 eq), acrylic ester (1.5 eq), Pd(PPh3)2Cl2(5-10 mol %), triethylamine (2.0 eq) and DMF was irradiated with microwaves for 0.5-8 h at 80-110 °C.

[0602] Method 4: A mixture of aryl halide (1.0 eq), acrylic ester (1.1 eq), Pd(OAc)2(10 mol %), triphenylphosphine (20 mol %), triethylamine (3.0 eq) and DMF was stirred at 90 °C for 2-5 h.

[0603] For α-substituted acrylates: A mixture of aryl halide (1.0 eq), acrylic ester (1.5 eq), Pd(TFA)2(20 mol %), silver carbonate (2.0 eq) and dioxane was stirred at 90 °C for 16 h.

[0604] For α-substituted acrylates: A sealed microwave vial containing aryl halide (1.0 eq), acrylic ester (1.5 eq), Pd(OAc)2(10 mol %), sodium acetate (2.0 eq), tetrabutylammonium chloride (2.0 eq) and DMF was irradiated with microwaves for 5 h at 100 °C.

[0605] The reaction mixture was diluted with H2O, extracted with EtOAc, dried over MgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography using CH2Cl2 / hexanes or EtOAc / hexanes as the mobile phase to give the desired olefinated compound. General Procedure C – Boronic Ester Formation via Deprotonation with LiTMP or LDA

[0606] Preparation of fresh LiTMP and LDA: To a cold (-78 °C) stirring mixture of tetramethylpiperidine or diisopropylamine (1.0 eq) in THF (0.5 M) was added n-BuLi (2.5 M in hexanes, 0.99 eq) dropwise. The mixture was stirred at -78 °C for 1 h and then used immediately.

[0607] A 2H-indole derivative (1.0 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (3.0 eq) were dissolved in THF (0.25 M) at ambient temperature. The solution was degassed and refilled with N2(3 cycles) and cooled to -78 °C. A solution of LiTMP (or LDA)was then added dropwise (1.6-1.8 eq) at -78 °C under N2. After stirring at -78 °C for 10-90 min, the reaction mixture was quenched with sat’d aq NH4Cl and extracted with EtOAc (2x). The combined organics were washed with H2O (2x), dried over Na2SO4, filtered and concentrated. The crude product was purified via silica gel chromatography using EtOAc / Petroleum ether as the mobile phase to give the desired boronic ester. General Procedure D – Suzuki Cross-Coupling with Boronic Esters

[0608] Method 1: A mixture of aryl halide (1.0 eq), aryl boronate (1.0 eq), Pd(dppf)Cl2(10-20 mol %), cesium (or sodium) carbonate (3.0-4.0 eq), dioxane and H2O was either stirred at 80 °C for 1-4 h or at 80 °C for 1 h with microwave irradiation.

[0609] Method 2: A mixture of aryl halide (1.3 eq), aryl boronate (1.0 eq), XPhos-Pd-G3 (5 mol %), potassium phosphate (3.0 eq), THF and H2O was stirred at 75 °C for 16 h.

[0610] The reaction mixture was diluted with H2O, extracted with EtOAc, dried over MgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography using Et2O / hexanes, EtOAc / hexanes or EtOAc / Petroleum ether as the mobile phase to give the desired arylated compound. General Procedure E – Boc Deprotection of Amines and tert-Butyl Deprotection of Acids

[0611] A solution of either tert-butylcarbamate or tert-butylester in CH2Cl2was treated with excess trifluoroacetic acid. After stirring for 1-4 h, the mixture was concentrated and purified via automated flash chromatography (normal or reverse phase) using MeOH / CH2Cl2or ACN / H2O (0.1% formic acid) as the mobile phase to give the desired amine or acid compound, respectively. General Procedure F – Ester Hydrolysis

[0612] To a stirring mixture of methyl or ethyl ester (1.0 eq) in THF, MeOH and H2O was added lithium (or sodium) hydroxide (10 eq) and stirred at 20-60 °C for 2-24 h. The reaction mixture was concentrated and the crude product was purified via automated flash chromatography (normal or reverse phase) using MeOH / CH2Cl2or ACN / H2O (0.1% formic acid) as the mobile phase to give the desired carboxylic acid compound. General Procedure G – Suzuki Cross-Coupling with Vinyl Boronic Acid Pinacol Esters

[0613] Method 1: A mixture of aryl halide (1.0 eq), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)prop-2-enoate (1.2 eq), XPhos-Pd-G3 (10 mol %), potassium phosphate (3.0 eq), dioxane and H2O was stirred at 80 °C for 3 h.

[0614] Method 2: A sealed microwave vial containing aryl halide (1.0 eq), ethyl (E)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (1.5 eq), Pd(dppf)Cl2(5-10 mol %), potassium carbonate (3.0 eq), dioxane and H2O was irradiated with microwaves for 0.5-4 h at 80- 110 °C.

[0615] Method 3: A sealed microwave vial containing aryl chloride (1.0 eq), ethyl (E)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (1.5 eq), Pd(OAc)2(10 mol %), RuPhos (20 mol %), potassium phosphate (3.0 eq), THF and H2O was irradiated with microwaves for 1-4 h at 100 °C.

[0616] Method 4: A mixture of aryl triflate (1.0 eq), ethyl (E)-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)prop-2-enoate (2.0 eq), XPhos-Pd-G3 (10 mol %), potassium phosphate (3.0 eq), THF and H2O was stirred at 80 °C for 16 h.

[0617] The reaction mixture was concentrated and the crude product was purified via automated flash chromatography using Et2O / hexanes or EtOAc / hexanes as the mobile phase to give the desired olefinated compound. General Procedure I – Iodine-Mediated C–N Bond Formation

[0618] To a stirring solution of ethyl (E)-3-(1H-indol-5-yl)acrylate (1.0 eq) in dioxane was successively added a NH-pyrazole derivative (3.0 eq) and iodine (3.0 eq). After stirring at ambient temperature for 16-20 h, the mixture was quenched with aqueous Na2S2O3(1 M) and extracted with EtOAc. The combined organics was dried over MgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography using Et2O / hexanes or EtOAc / hexanes as the mobile phase to give the desired C–N coupled compound. General Procedure J – Amide Formation via HATU Coupling / Activation

[0619] To a stirring mixture of a carboxylic acid (1.0 eq) and O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (1.6 eq) in DMF was added Hunig’s base (4.0 eq). After stirring for 1-5 minutes, an amine (1.3 eq) was added and stirring continued for 1-16 h. The mixture was diluted with EtOAc, washed with H2O, sat’d aq NaHCO3, and brine, dried overMgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography (normal or reverse phase) using MeOH / CH2Cl2or ACN / H2O (0.1% TFA) as the mobile phase to give the desired aminated compound. General Procedure K – Sonogashira Cross-Coupling

[0620] A mixture of aryl halide (1.0 eq), Pd(PPh3)2Cl2or Pd(PPh3)4(5-10 mol %), CuI (10-20 mol %), alkyne (1.2 eq), triethylamine (4.0 eq) in THF or DMF was stirred at 20-100 °C. If a substituted TMS-alkyne was used instead of a substituted H-alkyne, tetrabutylammonium fluoride (1.0 M THF solution, 1.5 eq) was also added to the mixture. After 3-16 h, the reaction mixture was concentrated, and the crude product was purified via automated flash chromatography using Et2O / hexanes or EtOAc / hexanes as the mobile phase to give the desired coupled compound. General Procedure L – Base-Promoted Cyclization

[0621] To a stirring solution of alkyne (1.0 eq) in THF under N2was added KOt-Bu (solid or solution in THF, 3.0 eq) and stirred at 80 °C. After 16 h, the reaction mixture was concentrated and partitioned between H2O / brine and EtOAc. The aqueous layer was further extracted with more EtOAc (3x). The combined organics was dried over MgSO4, filtered, and concentrated to afford the desired indole product. General Procedure M – gem-Dibromo Olefination of Aldehydes

[0622] To a cold (0 °C) stirring solution of carbon tetrabromide (3.0 eq) in CH2Cl2was added triphenylphosphine (6.0 eq) portion-wise. After stirring cold for 30 min, triethylamine (6.0 eq) and aldehyde (1.0 eq) were added. The resulting mixture was stirred cold for an additional 15 min then at ambient temperature. After 1 h, hexanes was added and the mixture was passed through a silica gel plug and rinsed with Et2O. The filtrate was concentrated and the crude product was purified via automated flash chromatography using Et2O / hexanes or EtOAc / hexanes as the mobile phase to give the desired dibromo olefin compound. General Procedure N – Cu-Catalyzed Cyclization of gem-Dibromo Olefins

[0623] A sealed microwave vial containing dibromoolefin (1.0 eq), cuprous iodide (20 mol %), potassium phosphate (2.0 eq) and dioxane was irradiated with microwaves for 1 h at 80- 90 °C. The reaction mixture was concentrated and the crude product was purified via automated flash chromatography using Et2O / hexanes as the mobile phase to give the desired cyclized compound. General Procedure O – Oxidative Benzimidazole Formation

[0624] A mixture of diamine (1.0 eq), aldehyde (1.0 eq), NaHSO3 / Na2S2O5 (20 wt %) in DMF was stirred at 155 °C for 2-16 h. The reaction mixture was cooled to ambient temperature and H2O was added. The resulting suspension was stirred for 0.5 h and the solid product was collected, washed with H2O, dried in vacuo and used without further purification. General Procedure P – Indazole Formation via Copper Catalysis

[0625] A mixture of 5-bromo-2-fluorobenzaldehyde (1.0 eq), aniline derivative (1.0 eq), sodium azide (2.0 eq), cuprous iodide (10 mol %) and tetramethylethylenediamine (10 mol %) in DMSO was stirred at 40-120 °C for 5-18 h. The reaction mixture was cooled to ambient temperature, poured into ice H2O and extracted with EtOAc (3x). The combined organics wasdried over MgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography using Et2O / hexanes as the mobile phase to give the desired indazole compound. General Procedure Q – Fischer Indole Synthesis

[0626] A solution of an acetophenone derivative (1.0 eq) and an aryl hydrazine (1.1 eq) in EtOH (1 M) was stirred at 80 °C. After 2 h, the mixture was cooled to 5 °C and then slowly treated with an equal volume of sulfuric acid. The resulting mixture was stirred at 75 °C for 16- 24 h and then poured into cold (5°C) H2O. The aqueous suspension was extracted with EtOAc, dried over MgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography using either CH2Cl2 / hexanes or EtOAc / hexanes as the mobile phase to give the desired aryl indole. General Procedure R – Aldehydes via Reduction with DIBAL-H

[0627] To a cold (-78 °C) stirring mixture of cyanide (1.0 eq) in THF (1 M) was added DIBAL-H (1.15 eq) slowly under N2. The mixture was stirred at -78 °C for 30 min, poured into 2M HCl and extracted with Et2O or EtOAc (2x). The combined organics was washed with sat’d aq NaHCO3(3x), dried over Na2SO4, filtered and concentrated to give the desired aldehyde which was used without further purification. General Procedure S – Reduction and Cyclization with Iron

[0628] To a stirring mixture of nitroaldehyde (1.0 eq) and acetic acid (5.3 eq) in EtOH (0.15 M) was added iron powder (15 eq) and ferrous chloride (1.5 eq) under N2. After 1 h of stirring at 100 °C, the mixture was cooled to ambient temperature and concentrated. The residue was poured into ice H2O and extracted with EtOAc (2x). The combined organics was dried over Na2SO4, filtered and concentrated. The crude product was purified via flash chromatography using EtOAc / Petroleum ether as the mobile phase to give the desired indole. General Procedure U – Alcohols via Lewis Acid-Promoted De-methylation

[0629] To a cold (0 °C) stirring solution of methoxide (1.0 eq) in CH2Cl2under N2was added a solution of boron tribromide (1.0M CH2Cl2, 2.0 eq) dropwise and then stirred for an additional 30 min. The mixture was poured over cold sat’d aq NH4Cl and extracted with EtOAc (3x). The combined organics was dried over MgSO4, filtered, and concentrated. The crude product was purified via automated flash chromatography using Et2O / hexanes or EtOAc / hexanes as the mobile phase to give the desired alcohol compound. General Procedure V – Triflation of Alcohols

[0630] To a solution of alcohol (1.0 eq) in CH2Cl2was added N-phenyl- bis(trifluoromethanesulfonimide) (1.0 eq) and triethylamine (2.0 eq). After stirring for 1 h at ambient temperature, the mixture was concentrated and the crude product was purified via automated flash chromatography using Et2O / hexanes or EtOAc / hexanes as the mobile phase to give the desired triflate compound. General Procedure W – Hydrogenation of Olefins

[0631] A mixture of olefin (1.0 eq) and Pd / C (10% Pd w / w, 0.1 eq) in MeOH under H2(1 atm) was stirred at ambient temperature for 1-4 h. The mixture was passed through a bed of Celite and concentrated. The crude product was purified via automated flash chromatography using EtOAc / Petroleum ether of MeOH / CH2Cl2as the mobile phase to give the desired reduced compound. General Procedure X – Aryl Cyanation via Pd-Catalyzed Cross-Coupling

[0632] A mixture of aryl bromide (1.0 eq), dicyanozinc (3.5 eq), Pd2(dba)3(10 mol %), SPhos (20 mol %) and DMF (0.05 M) was stirred at 120 °C for 16 h. The mixture was diluted with H2O, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated.The crude product was purified via automated flash chromatography using EtOAc / Petroleum ether as the mobile phase to give the desired cyanated compound. General Procedure Y – Nitroarene Reduction

[0633] A mixture of nitroarene (1.0 eq), 10% Pd / C (10 mol %) and EtOH was purged with H2gas and stirred at ambient temperature for 2-5 h. The mixture was passed through a bed of Celite, rinsed with EtOH and concentrated to give the desired amine compound.

[0634] Alternatively, a mixture of nitroarene (1.0 eq), stannous chloride dihydrate (6.0 eq) and EtOH was stirred at 90 °C for 16 h. The mixture was cooled to ambient temperature, concentrated, diluted with H2O and extracted with EtOAc (3x). The combined organics was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography using EtOAc / Petroleum ether as the mobile phase to give the desired amine compound. General Procedure Z – Formylation and Olefination of Aryl Halides

[0635] To a cold (5 °C) stirring solution of a 5-bromoindole derivative (1.0 eq) in THF under N2was added sodium hydride (60%, 1.3 eq). After stirring for 20 min, the mixture was cooled down to -78 °C and t-BuLi (1.7 M hexanes, 2.5 eq) was carefully and slowly added. After stirring for an additional 10 min, DMF (2.0 eq) was added and warmed to ambient temperature. After stirring for an additional 15 min, the reaction mixture was quenched with saturated aqueous NaHCO3and extracted with EtOAc. The crude product was purified via automated flash chromatography using CH2Cl2 / hexanes as the mobile phase to give the aldehyde intermediate.

[0636] To a cold (5 °C) stirring suspension of sodium hydride (60%, 2.5 eq) in THF was added a phosphonate derivative (2.5 eq). After stirring cold for 15 min, a solution aldehyde (1.0 eq) in THF was added and warmed to ambient temperature. After stirring for an additional 1 h, the reaction mixture was quenched with saturated aqueous NaHCO3and extracted with EtOAc to give the desired acrylic ester and used in the next step without further purification. EXAMPLE2: SYNTHESES OFCOMPOUNDSScheme 1. Preparation of (E)-tert-butyl 5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (H1).tert-butyl (E)-5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-1H-indole-1-carboxylate (H1-ii)

[0637] Prepared according to general procedures A and B starting with 5-iodo-1H-indole, tert-butyl acrylate and catalyst Pd(dtbpf)Cl2 to afford the titled compound in 95% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.80 Hz, 1H), 7.94 (s, 1H), 7.71 – 7.62 (m, 3H), 6.73 (d, J = 3.60 Hz, 1H), 6.50 (d, J = 16.0 Hz, 1H), 1.63 (s, 9H), 1.49 (s, 9H). (E)-tert-butyl 5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indole-1-carboxylate (H1)

[0638] Prepared according to general procedure C starting with indolyl acrylate H1-ii to afford the titled compound in 37% yield.1H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.89 (m, 2H), 7.70 (dd, J = 8.8, 1.6 Hz, 1H), 7.64 (d, J = 15.6 Hz, 1H), 6.92 (s, 1H), 6.50 (d, J = 16.0 Hz, 1H), 1.66 (s, 9H), 1.50 (s, 9H), 1.33 (s, 12H). Scheme 2. Preparation of Compounds H2 to H14. (E)-3-(2-(4-(tert-butyl)phenyl)-1H-indol-5-yl)acrylic acid (H2)

[0639] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-bromo-4-(tert-butyl)benzene to afford the titled compound in25% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.75 (d, J = 2.2 Hz, 1H), 7.84 – 7.76 (m, 3H), 7.66 (d, J = 15.8 Hz, 1H), 7.53 – 7.38 (m, 4H), 6.89 (d, J = 2.0 Hz, 1H), 6.42 (d, J = 15.9 Hz, 1H), 1.32 (s, 9H). m / z calcd. for C21H21NO2= 319.2. Found [M+H]+= 320.2. (E)-3-(2-(m-tolyl)-1H-indol-5-yl) acrylic acid (H3)

[0640] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 3-bromotoluene to afford the titled compound in 17% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.83 (s, 1H), 7.73 – 7.64 (m, 3H), 7.51 – 7.46 (m, 1H), 7.44 – 7.33 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 6.94 (s, 1 H), 6.41 (d, J = 16.0 Hz, 1H), 2.39 (s, 3H). m / z calcd. for C18H15NO2= 277.1. Found [M+H]+= 277.9. (E)-3-(2-(p-tolyl)-1H-indol-5-yl)acrylic acid (H4)

[0641] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 4-bromotoluene to afford the titled compound in 15% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.40 Hz, 2H), 7.68 (d, J = 16.0 Hz, 1H), 7.49 – 7.44 (m, 1 H), 7.43 – 7.39 (m, 1 H), 7.29 (d, J = 8.0 Hz, 2H), 6.90 (s, 1H), 6.41 (d, J = 16.0 Hz, 1H), 2.35 (s, 3H). m / z calcd. for C18H15NO2= 277.1. Found [M+H]+= 277.9. (E)-3-(2-(3-(difluoromethyl)phenyl)-1H-indol-5-yl)acrylic acid (H5)

[0642] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-bromo-3-(difluoromethyl)benzene to afford the titled compound in 1% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.94 (d, J = 2.3 Hz, 1H), 8.10 – 8.02 (m, 2H), 7.72 – 7.58 (m, 2H), 7.56 – 7.47 (m, 2H), 7.29 – 6.92 (m, 2H), 6.42 (d, J = 15.9 Hz, 1H). m / z calcd. for C18H13F2NO2= 313.3. Found [M+H]+= 314.1. (E)-3-(2-(3-isobutylphenyl)-1H-indol-5-yl)acrylic acid (H6)

[0643] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-bromo-3-isobutylbenzene to afford the titled compound in 19% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 7.83 (s, 1H), 7.73 – 7.64 (m, 3H), 7.51 – 7.33 (m, 3H), 7.13 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 15.9 Hz, 1H), 1.93 (hept, J = 6.8 Hz, 1H), 0.92 (d, J = 6.6 Hz, 6H). m / z calcd. for C21H21NO2= 319.4. Found [M+H]+= 320.2. (E)-3-(2-(3-cyclopropylphenyl)-1H-indol-5-yl)acrylic acid (H7)

[0644] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-bromo-3-cyclopropylbenzene to afford the titled compound in 40% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 11.74 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 1.6 Hz, 1H), 7.72 – 7.59 (m, 2H), 7.55 (t, J = 1.8 Hz, 1H), 7.47 (dd, J = 8.6, 1.6 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.06 (dt, J = 7.7, 1.3 Hz, 1H), 6.95 (dd, J = 2.2, 0.8 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 1.98 (tt, J = 8.4, 5.1 Hz, 1H), 1.07 – 0.96 (m, 2H), 0.83 – 0.75 (m, 2H). m / z calcd. for C20H17NO2= 303.4. Found [M+H]+= 304.1. 2-((2-(4-cyclopropyl-3-fluorophenyl)-1H-indol-5-yl)thio)acetic acid (H8)

[0645] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 4-bromo-1-cyclopropyl-2-fluorobenzene to afford the titled compound in 19% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.27 (s, 1H), 11.78 (s, 1H), 7.81 (s, 1H), 7.73 – 7.57 (m, 3H), 7.48 (dd, J = 8.6, 1.6 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.08 (t, J = 8.2 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 2.12 – 2.01 (m, 2H), 1.05 – 0.96 (m, 2H), 0.83 – 0.74 (m, 2H). m / z calcd. for C19H16FNO2S = 321.4. Found [M+H]+= 322.1 (E)-3-(2-(3-(tert-butyl)-5-methylphenyl)-1H-indol-5-yl)acrylic acid (H9)

[0646] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-bromo-3-(tert-butyl)-5-methylbenzene to afford the titled compound in 32% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.14 (s, 1H), 11.74 (s, 1H), 7.82 (s, 1H), 7.72 – 7.64 (m, 2H), 7.53 – 7.38 (m, 3H), 7.18 (s, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.40 (d, J = 15.9 Hz, 1H), 2.37 (s, 3H), 1.34 (s, 9H). m / z calcd. for C22H23NO2= 333.4. Found [M+H]+= 334.2. (E)-3-(2-(3,5-di-tert-butylphenyl)-1H-indol-5-yl)acrylic acid (H10)

[0647] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-bromo-3,5-di-tert-butylbenzene to afford the titled compound in 13% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 11.75 (s, 1H), 7.81 (s, 1H), 7.72 – 7.63 (m, 3H), 7.50 – 7.39 (m, 2H), 7.36 (t, J = 1.8 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 15.9 Hz, 1H), 1.36 (s, 18H). m / z calcd. for C25H29NO2= 375.5. Found [M+H]+= 376.2. (E)-3-[2-[3-(1-cyano-1-methyl-ethyl)phenyl]-1H-indol-5-yl]prop-2-enoic acid (H11)

[0648] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 2-(3-bromophenyl)-2-methyl-propanenitrile to afford the titled compound in 14% yield over two synthetic steps.1H NMR (400 MHz, MeOD) δ 7.96 (s, 1H), 7.82 – 7.78 (m, 3H), 7.53 – 7.51 (m, 2H), 7.46 (s, 2H), 6.95 (s, 1H), 6.43 (d, J = 15.6 Hz, 1H), 1.83 (s, 6H). m / z calcd. for C21H18N2O2= 330.1. Found [M+H]+= 331.0. (E)-3-(2-(4-(2-cyanopropan-2-yl)phenyl)-1H-indol-5-yl)acrylic acid (H12)

[0649] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 2-(4-bromophenyl)-2-methylpropanenitrile to afford the titled compound in 10% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.84 (d, J = 2.3 Hz, 1H), 7.96 – 7.89 (m, 2H), 7.84 (d, J = 1.6 Hz, 1H), 7.73 – 7.57 (m, 3H), 7.49 (dd, J = 8.6, 1.6 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 1.72 (s, 6H). m / z calcd. for C21H18N2O2= 330.4. Found [M+H]+= 331.1 (E)-3-(2-(3-(1-cyanocyclopropyl)phenyl)-1H-indol-5-yl)acrylic acid (H13)

[0650] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-(3-bromophenyl)cyclopropane-1-carbonitrile to afford the titled compound in 4% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 7.82 (d, J = 10.9 Hz, 2H), 7.74 – 7.62 (m, 2H), 7.53 – 7.34 (m, 4H), 7.03 (d, J = 2.0 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 1.85 – 1.77 (m, 2H), 1.72 – 1.60 (m, 2H). m / z calcd. for C21H16N2O2= 328.4. Found [M+H]+= 329.1 (E)-3-(2-(4-(1-cyanocyclopropyl)phenyl)-1H-indol-5-yl)acrylic acid (H14)

[0651] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-(4-bromophenyl)cyclopropane-1-carbonitrile to afford the titled compound in 29% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.82 (d, J = 2.2 Hz, 1H), 7.97 – 7.79 (m, 3H), 7.67 (d, J = 15.9 Hz, 1H), 7.54 – 7.35 (m, 4H), 6.98 (d, J = 2.4 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 1.79 (q, J = 4.9 Hz, 2H), 1.61 – 1.54 (m, 2H). m / z calcd. for C21H16N2O2= 328.4. Found [M+H]+= 329.1 Scheme 3. Preparation of (E)-3-[2-[3-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-indol-5- yl]prop-2-enoic acid (H15)1-(benzenesulfonyl)-5-bromo-indole (H15-i)

[0652] To a cold (0 °C) stirring mixture of 5-bromo-1H-indole (10 g, 51.0 mmol, 1.0 eq) in THF (100 mL) was added sodium hydride (2.45 g, 61.2 mmol, 60%, 1.2 eq) under N2. After stirring for 30 min at ambient temperature, benzenesulfonyl chloride (9.9 g, 56.1 mmol, 1.1 eq) was added under N2. After stirring for an additional 3 h at ambient temperature, the mixture was poured into H2O (100 mL) and extracted with EtOAc (150 mL x 3). The combined organics was washed with brine (150 mL x 2), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 0-5% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (15.8 g, 92%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 7.6 Hz, 2H), 7.92 – 7.90 (m, 2H), 7.89 (s, 1H), 7.76 – 7.70 (m, 1H), 7.63 – 7.60 (m, 2H), 7.51 – 7.48 (m, 1H), 6.86 – 6.85 (m, 1H). m / z calcd. for C14H10BrNO2S = 335.0, 337.0. Found [M+H]+= 337.8. 1-(benzenesulfonyl)-5-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole (H15-ii)

[0653] To a cold (-78 °C) stirring mixture of 1-(benzenesulfonyl)-5-bromo-indole H15-i (5.0 g, 14.9 mmol, 1.0 eq) in THF (50 mL) was slowly added LDA (2 M hexanes, 14.9 mL, 2.0 eq) under N2. After stirring cold for 30 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (5.5 g, 29.7 mmol, 2.0 eq) was added. The mixture was warmed to ambient temperature and stirred for an additional 3 h. The mixture was then quenched with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organics was washed with brine (50 mL), dried over Na2SO4filtered and concentrated The crude product was purified by silica gelchromatography using 0-3% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (0.82 g, 12%) as a yellow solid. (E)-3-[2-[3-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-indol-5-yl]prop-2-enoic acid (H15)

[0654] Prepared according to general procedures D, B and F starting with catalysts Pd(dppf)Cl2, Pd(OAc)2, boronate H15-ii, 2-(3-bromophenyl)propan-2-ol and methyl acrylate to afford the titled compound in 3% yield over three synthetic steps.1H NMR (400 MHz, DMSO- d6) δ 11.78 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.70 – 7.66 (m, 2H), 7.48 – 7.37 (m, 4H), 6.93(s, 1H), 6.41 (d, J = 16.0 Hz, 1H), 5.11 (s, 1H), 1.50 (s, 6H). m / z calcd. for C20H19NO3= 321.1. Found [M+H]+= 321.9. Scheme 4. Preparation of Compounds H16 to H20. (E)-3-[2-(3-hydroxyphenyl)-1H-indol-5-yl]prop-2-enoic acid (H16)

[0655] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 3-bromophenol to afford the titled compound in 23% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.81 (s, 1H), 7.66 (d, J = 16.0 Hz, 1H), 7.45 – 7.41 (m, 2H), 7.28 – 7.23 (m, 3H), 6.85 (s, 1H), 6.84 – 6.77 (m, 1H), 6.40 (d, J = 16.0 Hz, 1H). m / z calcd. for C17H13NO3= 279.1. Found [M+H]+= 279.9. (E)-3-[2-(3-methoxyphenyl)-1H-indol-5-yl]prop-2-enoic acid (H17)

[0656] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 3-bromoanisole to afford the titled compound in 9% yield over two synthetic steps.1H NMR (400 MHz, MeOD) δ 7.81 – 7.77 (m, 2H), 7.42 (s, 2H), 7.38 – 7.34 (m, 3H), 6.90 – 6.87 (m, 2H), 6.40 (d, J = 15.6 Hz, 1H), 3.88 (s, 3H). m / z calcd. for C18H15NO3= 293.1. Found [M+H]+= 293.9.(E)-3-(2-(3-isopropoxyphenyl)-1H-indol-5-yl) acrylic acid (H18)

[0657] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 1-bromo-3-isopropoxybenzene to afford the titled compound in 37% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 11.74 (s, 1H), 7.83 (s, 1H), 7.69 (d, J = 16.0 Hz, 1H), 7.50 – 7.34 (m, 5H), 6.98 (s, 1H), 6.92 – 6.86 (m, 1H), 6.41 (d, J = 16.0 Hz, 1H), 4.77 – 4.71 (m, 1H), 1.32 (d, J = 6.0 Hz, 6H). m / z calcd. for C20H19NO3= 321.1. Found [M+H]+= 321.9. (E)-3-(2-(3-(isopropylthio)phenyl)-1H-indol-5-yl)acrylic acid (H19)

[0658] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and (3-bromophenyl)(isopropyl)sulfane to afford the titled compound in 18% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.83 (s, 1H), 7.90 – 7.82 (m, 2H), 7.78 – 7.72 (m, 1H), 7.68 (d, J = 15.8 Hz, 1H), 7.50 (dd, J = 8.5, 1.6 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.42 (d, J = 15.9 Hz, 1H), 3.65 (p, J = 6.6 Hz, 1H), 1.30 (d, J = 6.6 Hz, 6H). m / z calcd. for C20H19NO2S = 337.4. Found [M+H]+= 338.1 (E)-3-(2-(3-(tert-butylthio)phenyl)-1H-indol-5-yl)acrylic acid (H20)

[0659] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and (3-bromophenyl)(tert-butyl)sulfane to afford the titled compound in 5% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.89 (d, J = 2.2 Hz, 1H), 8.01 (t, J = 1.7 Hz, 1H), 7.84 (s, 1H), 7.68 (d, J = 15.9 Hz, 1H), 7.54 – 7.40 (m, 4H), 7.02 (d, J = 2.1 Hz, 1H), 6.43 (d, J = 15.9 Hz, 1H), 1.30 (s, 9H). m / z calcd. for C21H21NO2S = 351.5. Found [M+H]+= 352.1.Scheme 5. Preparation of (E)-3-[2-(3-tert-butoxyphenyl)-1H-indol-5-yl]prop-2-enoic acid (H21) (E)-3-[2-(3-tert-butoxyphenyl)-1H-indol-5-yl]prop-2-enoic acid (H21)

[0660] Prepared according to general procedures D, G and F starting with catalysts Pd(dppf)Cl2, XPhos-Pd-G3, boronate H15-ii and 1-bromo-3-tert-butoxy-benzene to afford the titled compound in 9% yield over three synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 11.73 (s, 1H), 7.82 (s, 1H), 7.68 (d, J = 15.6 Hz, 1H), 7.46 (d, J = 1.2 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.38 - 7.36 (m, 2H), 6.90 (d, J = 2.8 Hz, 2H), 6.40 (d, J = 15.6 Hz, 1H), 1.35 (s, 9H). m / z calcd. for C21H21NO3= 335.1. Found [M+H]+= 336.0. Scheme 6. Preparation of Compounds H22 to H24. (E)-3-[2-[3-(cyclopropoxy)phenyl]-1H-indol-5-yl]prop-2-enoic acid (H22)

[0661] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 1-bromo-3-(cyclopropoxy)benzene to afford the titled compound in 20% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.83 (s, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.53 – 7.47 (m, 3H), 7.42– 7.39 (m, 2H), 7.05 – 7.03 (m, 1H), 6.96 (s, 1H),6.40 (d, J = 16.0 Hz, 1H), 3.96 – 3.91 (m, 1H), 0.87 – 0.82 (m, 2H), 0.72 – 0.68 (m, 2H). m / z calcd. for C20H17NO3= 319.1. Found [M+H]+= 319.9. (E)-3-(2-(4-(cyanomethyl)-3-(trifluoromethoxy)phenyl)-1H-indol-5-yl)acrylic acid (H23)

[0662] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 2-(4-bromo-2-(trifluoromethoxy)phenyl)acetonitrile to afford the titled compound in 8% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.97 (d, J = 2.2 Hz, 1H), 8.03 – 7.81 (m, 3H), 7.74 – 7.63 (m, 2H), 7.53 (dd, J = 8.6, 1.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 6.43 (d, J = 15.9 Hz, 1H), 4.11 (s, 2H). m / z calcd. for C20H13F3N2O3= 386.3. Found [M+H]+= 387.1. (E)-3-(2-(3-isobutyramidophenyl)-1H-indol-5-yl) acrylic acid (H24)

[0663] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and N-(3-bromophenyl)-2-methyl-propanamide to afford the titled compound in 28% yield over two synthetic steps.1H NMR (400 MHz, MeOD) δ 8.17 (s, 1H), 7.86 – 7.75 (m, 2H), 7.60 – 7.52 (m, 1H), 7.50 - 7.40 (m, 4H), 6.87 (s, 1H), 6.42 (d, J = 16.0 Hz, 1H), 2.66 – 2.60 (m, 1H), 1.25 (d, J = 6.80 Hz, 6H). m / z calcd. for C18H15NO2= 348.1. Found [M+H]+= 348.9. Scheme 7. Preparation of (E)-3-(2-(4-((1s,3s)-adamantan-1-yl)phenyl)-1H-indol-5- yl)acrylic acid (H25). 4-((1s,3s)-adamantan-1-yl)phenyl trifluoromethanesulfonate (H25-i)

[0664] To a cold (0 °C) stirring mixture of 4-((1s,3s)-adamantan-1-yl)phenol (1.0 g, 4.38 mmol, 1.0 eq) and Et3N (1.33 g, 13.1 mmol, 3.0 eq) in CH2Cl2(20 mL) was and N-(5- chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.06 g, 5.26 mmol, 1.2 eq) under N2. After stirring cold for 3 hours, the mixture was poured into H2O (50 mL) and extracted with EtOAc (30 mL x 2). The combined organics was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 10-20% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (1.3 g, 82%) as yellow oil. (E)-3-(2-(4-((1s,3s)-adamantan-1-yl)phenyl)-1H-indol-5-yl)acrylic acid (H25)

[0665] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and triflate H25-i to afford the titled compound in 72% yield over two synthetic steps.1H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 7.70 – 7.62 (m, 4H), 7.41 – 7.30 (m, 4H), 6.73 (s, 1H), 6.34 (d, J = 16.0 Hz, 1H), 2.04 (s, 3H), 1.92 – 1.89 (m, 6H), 1.84 – 1.71 (m, 6H). m / z calcd. for C27H27NO2= 397.2. Found [M+H]+= 398.1. Scheme 8. Preparation of (E)-3-(2-(3-((3r,5r,7r)-adamantan-1-yl)phenyl)-1H-indol-5- yl)acrylic acid (H26). N-(4-((1s, 3s)-adamantan-1-yl)phenyl) acetamide (H26-i)

[0666] To a stirring mixture of N-phenylacetamide (5.0 g, 37.0 mmol, 1.0 eq) and (1s,3s)- 1-bromoadamantane (8.75 g, 40.7 mmol, 1.1 eq) in DCE (50 mL) was added ZnCl2(10.1 g, 74.0 mmol, 2.0 eq) in one portion under N2. After stirring at 80 °C for 16 h, the mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 2). The combined organics was washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 20-25% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (5.92 g, 59%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 2.05–2.01 (m, 6H), 1.84–1.82 (m, 6H), 1.75–1.71 (m, 6H). m / z calcd. for C18H23NO = 269.2. Found [M+H]+= 270.1. N-(4-((1s,3s)-adamantan-1-yl)-2-bromophenyl) acetamide (H26-ii)

[0667] To a cold (0 °C) stirring mixture of N-(4-((1s, 3s)-adamantan-1-yl)phenyl) acetamide H26-i (5.0 g, 18.6 mmol, 1.0 eq) in acetic acid (50 mL) was slowly added bromine (2.97 g, 18.6 mmol, 1.0 eq) under N2. The mixture was stirred at 0 °C for 30 min, then at ambient temperature for an additional 2 h. The mixture was poured into sat’d aq NaHCO3(200 mL) and extracted with EtOAc (50 mL x 2). The combined organics was washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 20-25% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (5.30 g, 82%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 7.54 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 2.08 – 2.07 (m, 6H), 1.85 – 1.84 (m, 6H), 1.78 – 1.68 (m, 6H). m / z calcd. for C18H22BrNO = 347.1. Found [M+H]+= 347.9. 4-((1s,3s)-adamantan-1-yl)-2-bromoaniline (H26-iii)

[0668] A mixture of N-(4-((1s,3s)-adamantan-1-yl)-2-bromophenyl) acetamide H26-ii (2.0 g, 5.74 mmol, 1.0 eq) in HCl (6 M dioxane, 30 mL) was stirred at 100 °C for 16 h. The mixture was cooled to ambient temperature, poured into sat’d aq NaHCO3(100 mL) and extractedwith EtOAc (40 mL x 2). The combined organics was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 2-5% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (845 mg, 48%) as yellow solid. m / z calcd. for C16H20BrN = 305.1. Found [M+H]+= 305.9. (1s,3s)-1-(3-bromophenyl) adamantane (H26-iv)

[0669] To a cold (-5 °C) stirring mixture of 4-((1s,3s)-adamantan-1-yl)-2-bromoaniline H26-iii (0.3 g, 0.98 mmol, 1.0 eq) and sulfuric acid (400 mg, 3.92 mmol, 4.0 eq) in EtOH (5 mL) was added a solution of sodium nitrite (111 mg, 1.64 mmol, 1.67 eq) in H2O (2.5 mL). After stirring for 30 min, copper metal (934 mg, 14.7 mmol, 15 eq) was added. The resulting mixture was stirred at 90 °C for 4 h, cooled to 0 °C, poured into H2O (30 mL) and extracted with EtOAc (20 mL x 2). The combined organics was washed with brine (30 mL x 3), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 5- 10% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (182 mg, 64%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 1H), 7.41 – 7.34 (m, 2H), 7.31 – 7.25 (m, 1H), 2.08 – 2.04 (m, 3H), 1.85 – 1.84 (m, 6H), 1.76 – 1.71 (m, 6H). (E)-3-(2-(3-((3r,5r,7r)-adamantan-1-yl)phenyl)-1H-indol-5-yl)acrylic acid (H26)

[0670] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and bromide H26-iv to afford the titled compound in 39% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.79 – 7.75 (m, 2H), 7.65 – 7.57 (m, 2H), 7.43 – 7.30 (m, 3H), 7.28 – 7.23 (m, 1H), 6.90 (s, 1H), 6.35 (d, J = 16.0 Hz, 1H), 2.05 – 2.01 (m, 3H), 1.90 – 1.87 (m, 6H), 1.73 – 1.70 (m, 6H). m / z calcd. for C27H27NO2= 397.2. Found [M+H]+= 398.1. Scheme 9. Preparation of (E)-3-[2-[3-(3-methyloxetan-3-yl)phenyl]-1H-indol-5-yl]prop-2- enoic acid (H27).dimethyl 2-(3-bromophenyl)propanedioate (H27-i)

[0671] To a cold (0 °C) stirring mixture of methyl 2-(3-bromophenyl)acetate (10 g, 43.6 mmol, 1.0 eq) in THF (100 mL) was added NaH (3.5 g, 87.3 mmol, 60%, 2.0 eq) under N2. After stirring for 30 min, dimethyl carbonate (15.7 g, 174.6 mmol, 14.7 mL, 4.0 eq) was added and stirred at ambient temperature for 16 h. The mixture was poured into H2O (100 mL) and extracted with EtOAc (200 mL x 2). The combined organics was washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 15% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (6.8 g, 54%) as a yellow solid. m / z calcd. for C11H11BrO4= 286.0, 288.0. Found [M+H]+= 288.5. dimethyl 2-(3-bromophenyl)-2-methyl-propanedioate (H27-ii)

[0672] To a cold (0 °C) stirring mixture of dimethyl 2-(3-bromophenyl)propanedioate H27-i (5.7 g, 19.9 mmol, 1.0 eq) in THF (35 mL) was added NaH (873 mg, 21.8 mmol, 60%, 1.1 eq) under N2. After stirring cold for 30 min, iodomethane (11.3 g, 79.4 mmol, 4.0 eq) was added. The resulting mixture was stirred at ambient temperature for 4 h, poured into ice H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics was washed with brine (30 x 2 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 0-2% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (4.7 g, 79%) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.55 – 7.50 (m, 2H), 7.34 – 7.29 (m, 2H), 3.71 (s, 6H), 1.78 (s, 3H). m / z calcd. for C12H13BrO4= 300.0. Found [M+H]+= 301.0.2-(3-bromophenyl)-2-methyl-propane-1,3-diol (H27-iii)

[0673] To a stirring mixture of dimethyl 2-(3-bromophenyl)-2-methyl-propanedioate H27-ii (4.2 g, 13.9 mmol, 1.0 eq) in THF (30 mL) under N2, was slowly and carefully added LiAlH4(1.59 g, 41.8 mmol, 3.0 eq). After stirring at ambient temperature for 4 h, the mixture was slowly quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics was washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 0-2% MeOH / CH2Cl2as the mobile phase to afford the titled compound (1.2 g, 35%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 7.54 – 7.53 (m, 1H), 7.37 – 7.35 (m, 2H), 7.26 – 7.24 (m, 1H), 4.61 (t, J = 5.6 Hz, 1H), 4.51 (t, J = 5.2Hz, 1H), 3.58 – 3.50 (m, 4H), 1.17 (s, 3H). 3-(3-bromophenyl)-3-methyl-oxetane (H27-iv)

[0674] To a stirring mixture of 2-(3-bromophenyl)-2-methyl-propane-1,3-diol H27-iii (0.9 g, 3.67 mmol, 1.0 eq) in toluene (10 mL) was successively added triphenylphosphine (1.93 g, 7.3 mmol, 2 eq) and diethyl azodicarboxylate (1.28 g, 7.34 mmol, 2.0 eq) under N2. After stirring at ambient temperature for 16 h, the reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organics was washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 0-5% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (0.4 g, 48%) as colorless oil.1H NMR (400 MHz, DMSO-d6) δ 7.44 – 7.43 (m, 1H), 7.35 – 7.32 (m, 1H), 7.26 – 7.22 (m, 2H), 4.81 – 4.77 (m, 2H), 4.53(t, J = 5.6 Hz, 2H), 1.61 (s, 3H). (E)-3-[2-[3-(3-methyloxetan-3-yl)phenyl]-1H-indol-5-yl]prop-2-enoic acid (H27)

[0675] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and bromide H27-iv to afford the titled compound in 15% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.83 (s, 1H), 7.75 – 7.66 (m,3H), 7.49 – 7.43 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.91 (d, J = 5.6 Hz, 2H), 4.59 (d, J = 5.6 Hz, 2H), 1.69 (s, 3H). m / z calcd. for C21H19NO3= 333.1. Found [M+H]+= 333.9. Scheme 10. Preparation of (E)-3-[2-(3-pyrrol-1-ylphenyl)-1H-indol-5-yl]prop-2-enoic acid (H28). tert-butyl 5-[(E)-3-tert-butoxy-3-oxo-prop-1-enyl]-2-(3-pyrrol-1-ylphenyl)indole-1- carboxylate (H28-i)

[0676] Prepared according to general procedure D starting with catalyst XPhos-Pd-G3, boronate H1 and 4-(3-bromophenyl)morpholine to afford the titled compound in 53% yield. m / z calcd. for C30H32N2O4= 484.2. Found [M+H]+= 485.2. (E)-3-[2-(3-pyrrol-1-ylphenyl)-1H-indol-5-yl]prop-2-enoic acid (H28)

[0677] To a stirring mixture of tert-butyl coupled intermediate H28-i (85 mg, 0.175 mmol, 1.0 eq) in THF (1 mL) was added formic acid (2.3 mL) in one portion. After stirring at 40 °C for 16 h, the mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organics was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by reverse phase preparative HPLC using 50-80% ACN / H2O (0.225% formic acid) as the mobile phase to afford the titled compound (16 mg, 28%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.72 – 7.66 (m, 1H), 7.55 (s, 1H), 7.53 – 7.51 (m, 5H), 7.50 – 7.45 (m, 1H), 7.13 (d, J = 1.2 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 6.33 – 6.30 (m, 2H). m / z calcd. for C21H16N2O2= 328.1. Found [M+H]+= 328.9. Scheme 11. Preparation of Compounds H29 to H34.(E)-3-[2-(3-morpholinophenyl)-1H-indol-5-yl]prop-2-enoic acid (H29)

[0678] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 4-(3-bromophenyl)morpholine to afford the titled compound in 2% yield over two synthetic steps.1H NMR (400 MHz, MeOD) δ 7.79 – 7.75 (m, 2H), 7.42 – 7.39 (m, 3H), 7.35 – 7.32 (m, 2H), 6.96 – 6.93 (m, 1H), 6.86 (s, 1H), 6.40 (d, J = 16.0 Hz, 1H), 3.89 – 3.87 (m, 4H), 3.25 – 3.23 (m, 4H). m / z calcd. for C21H20N2O3= 348.2. Found [M+H]+= 349.0. (E)-3-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indol-5-yl)acrylic acid (H30)

[0679] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene to afford the titled compound in 37% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 11.71 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.0 Hz, 2H), 7.67 (d, J = 15.9 Hz, 1H), 7.61 (dd, J = 8.3, 1.9 Hz, 1H), 7.52 – 7.33 (m, 3H), 6.91 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 15.8 Hz, 1H), 1.67 (s, 4H), 1.34 (s, 6H), 1.27 (s, 6H). m / z calcd. for C25H27NO2= 373.5. Found [M+H]+= 374.2. (E)-3-[2-(3,3-dimethyl-2H-benzofuran-5-yl)-1H-indol-5-yl]prop-2-enoic acid (H31)

[0680] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 5-bromo-3,3-dimethyl-2H-benzofuran to afford the titled compound in 3% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.79 (s, 1H), 7.73 – 7.61 (m, 3H), 7.44 – 7.39 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H), 6.39(d, J = 15.6 Hz, 1H), 4.27 (s, 2H), 1.36 (s, 6H). m / z calcd. for C21H19NO3= 333.1. Found [M+H]+= 333.9. (E)-3-[2-(3,3-dimethyl-2-oxo-indolin-5-yl)-1H-indol-5-yl]prop-2-enoic acid (H32)

[0681] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 5-bromo-3,3-dimethyl-indolin-2-one to afford the titled compound in 9% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 10.48 (s, 1H), 7.82 – 7.79 (m, 2H), 7.69 – 7.65 (m, 2H), 7.42 – 7.39 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 6.39 (d, J = 15.6 Hz, 1H), 1.32 (s, 6H). m / z calcd. for C21H18N2O3= 346.1. Found [M+H]+= 346.9. (E)-3-(2-(2,3-dihydrobenzofuran-5-yl)-1H-indol-5-yl)acrylic acid (H33)

[0682] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 5-bromo-2,3-dihydrobenzofuran to afford the titled compound in 18% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 11.63 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 11.8, 1.7 Hz, 2H), 7.71 – 7.57 (m, 2H), 7.48 – 7.33 (m, 2H), 6.86 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.39 (d, J = 15.9 Hz, 1H), 4.58 (t, J = 8.7 Hz, 2H), 3.25 (t, J = 8.7 Hz, 2H). m / z calcd. for C19H15NO3= 305.3. Found [M+H]+= 306.1. (E)-3-[2-(4-tert-butyl-2-pyridyl)-1H-indol-5-yl]prop-2-enoic acid (H34)

[0683] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 2-bromo-4-(tert-butyl)-pyridine to afford the titled compound in 3% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.53 (d, J = 5.2 Hz, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.68 (d, J = 16 Hz, 1H), 7.48 – 7.46 (m, 2H), 7.33 (d, J = 5.2 Hz, 1H), 7.27 (s, 1H), 6.41 (d, J = 15.6 Hz, 1H), 1.35 (s, 9H). m / z calcd. for C20H20N2O2= 320.2. Found [M+H]+= 321.1. (E)-3-(2-(4-(tert-butyl)pyridin-2-yl)-3-chloro-1H-indol-5-yl)acrylic acid (H35)

[0684] To a stirring solution of acid H34 (1.0 eq) in DMF was added N-chlorosuccinimide (1.0 eq). After stirring for 16 h, the mixture was diluted with H2O and extracted with EtOAc. The crude product was purified via automated flash chromatography (reverse phase) using ACN / H2O (0.1% formic acid) as the mobile phase to afford the titled compound in 17% yield.1H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 15.9 Hz, 1H), 7.64 (dd, J = 8.7, 1.7 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 5.3, 1.8 Hz, 1H), 6.50 (d, J = 15.9 Hz, 1H), 1.37 (s, 9H). m / z calcd. for C20H19ClN2O2= 354.1. Found [M+H]+= 355.1. Scheme 12. Preparation of Compounds H36 to H41. (E)-3-(2-(4-(2-cyanopropan-2-yl)pyridin-2-yl)-1H-indol-5-yl)acrylic acid (H36)

[0685] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 2-(2-chloropyridin-4-yl)-2-methylpropanenitrile to afford the titled compound in 48% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.99 (s, 1H), 8.69 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.91 (s, 1H), 7.70 (d, J = 15.9 Hz, 1H), 7.54 (dd, J = 8.7, 1.6 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.35 (d, J = 2.1 Hz, 1H), 6.43 (d, J = 15.9 Hz, 1H), 1.79 (s, 6H). m / z calcd. for C20H17N3O2= 331.1. Found [M+H]+= 332.1. (E)-3-(2-(6-(tert-butyl) pyridin-2-yl)-1H-indol-5-yl) acrylic acid (H37)

[0686] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 2-bromo-6-(tert-butyl)-pyridine to afford the titled compound in 52% yield over two synthetic steps1H NMR (400 MHz DMSO-d6) δ 1217 (s 1H) 1158 (s 1H)7.88 (s, 1H), 7.83 – 7.77 (m, 2H), 7.70 (d, J = 16.0 Hz, 1H), 7.58 – 7.50 (m, 2H), 7.37 – 7.31 (m, 1H), 7.19 (d, J = 1.60 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 1.42 (s, 9H). m / z calcd. for C20H20N2O2= 320.2. Found [M+H]+= 321.0. (E)-3-[2-(2-tert-butyl-4-pyridyl)-1H-indol-5-yl]prop-2-enoic acid (H38)

[0687] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 4-bromo-2-(tert-butyl)-pyridine to afford the titled compound in 23% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 7.89 – 7.86 (m, 2H), 7.70 (d, J = 16.0 Hz, 1H), 7.66 – 7.64 (m, 1H), 7.54 – 7.48 (m, 1H), 7.47 – 7.45 (m, 1H), 7.25 (d, J = 1.2 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 1.38 (s, 9H). m / z calcd. for C20H20N2O2= 320.2. Found [M+H]+= 321.0. (E)-3-(2-(4-(tert-butyl)pyrimidin-2-yl)-1H-indol-5-yl)acrylic acid (H39)

[0688] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 4-tert-butyl-2-chloropyrimidine to afford the titled compound in 19% over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 8.77 (dd, J = 5.4, 1.5 Hz, 1H), 7.94 (s, 1H), 7.69 (d, J = 15.9 Hz, 1H), 7.61 – 7.51 (m, 2H), 7.42 (dd, J = 5.3, 1.5 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.48 – 6.39 (m, 1H), 1.40 (d, J = 1.5 Hz, 10H). m / z calcd. for C19H19N3O2= 321.1. Found [M+H]+= 322.2. (E)-3-(2-(6-(tert-Butyl)pyrimidin-4-yl)-1H-indol-5-yl)acrylic acid (H40)

[0689] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 4-tert-butyl-6-chloropyrimidine to afford the titled compound in 46% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.15 (d, J = 2.1 Hz, 1H), 9.13 (d, J = 1.3 Hz, 1H), 8.07 (d, J = 1.4 Hz, 1H), 7.94 (s, 1H), 7.71 (d, J = 15.9 Hz, 1H), 7.64 – 7.48 (m, 3H), 6.45 (d, J = 15.9 Hz, 1H), 1.38 (s, 9H). m / z calcd. for C19H19N3O2= 321.1. Found [M+H]+= 322.1 (E)-3-[2-(2-tert-butylpyrimidin-4-yl)-1H-indol-5-yl]prop-2-enoic acid (H41)

[0690] Prepared according to general procedures D and E starting with catalyst XPhos- Pd-G3, boronate H1 and 4-bromo-2-(tert-butyl)-pyrimidine to afford the titled compound in 13% yield over two synthetic steps.1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.75 (d, J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.82 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 16.0 Hz, 1H), 7.61 – 7.56 (m, 2H), 7.45 (s, 1H), 6.44 (d, J = 16.0 Hz, 1H), 1.44 (s, 9H). m / z calcd. for C19H19N3O2= 321.2. Found [M+H]+= 322.4. Scheme 13. Preparation of Compounds H42 to H56. (E)-3-(2-(1-isopropyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylic acid (H42)

[0691] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 4-bromo-1-isopropyl-1H-imidazole to afford the titled compound in 9% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.28 (s, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.50 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 1.6 Hz, 1H), 7.14 (d, J = 15.8 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 6.24 (d, J = 15.8 Hz, 1H), 4.47 (p, J = 6.7 Hz, 1H), 1.46 (d, J = 6.6 Hz, 6H). m / z calcd. for C17H17N3O2= 295.1. Found [M+H]+= 296.1. (E)-3-(2-(1-isobutyl-1H-imidazol-4-yl)-1H-indol-5-yl)acrylic acid (H43)

[0692] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 4-iodo-1-(2-methylpropyl)-1H-imidazole to afford the titled compound in 15% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.31 (s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.5, 1.6 Hz, 1H), 715 (d J = 157 Hz 1H) 656 (d J = 19 Hz 1H) 624 (d J = 158 Hz 1H) 384 (d J = 71 Hz2H), 2.05 (dq, J = 13.6, 6.9 Hz, 1H), 0.89 (d, J = 6.7 Hz, 6H). m / z calcd. for C18H19N3O2= 309.1. Found [M+H]+= 310.1. (E)-3-(2-(1-(cyclopropylmethyl)-1H-imidazol-4-yl)-1H-indol-5-yl)acrylic acid (H44)

[0693] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-(cyclopropylmethyl)-4-iodo-1H-imidazole to afford the titled compound in 9% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.35 – 11.30 (m, 1H), 7.76 (d, J = 1.3 Hz, 1H), 7.68 (d, J = 1.3 Hz, 1H), 7.51 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.25 – 7.11 (m, 2H), 6.56 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 15.8 Hz, 1H), 3.98 – 3.85 (m, 2H), 1.24 (tdd, J = 10.3, 7.7, 4.0 Hz, 1H), 0.63 – 0.50 (m, 2H), 0.41 (dt, J = 6.2, 4.3 Hz, 2H). m / z calcd. for C18H17N3O2= 307.1. Found [M+H]+= 308.2. (E)-3-(2-(1-isobutyl-1H-imidazol-5-yl)-1H-indol-5-yl)acrylic acid (H45)

[0694] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 5-iodo-1-(2-methylpropyl)-1H-imidazole to afford the titled compound in 35% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 7.76 (d, J = 1.1 Hz, 1H), 7.70 (s, 1H), 7.44 – 7.31 (m, 4H), 6.61 (d, J = 2.0 Hz, 1H), 6.36 (d, J = 15.8 Hz, 1H), 4.04 (d, J = 7.4 Hz, 2H), 1.93 (hept, J = 6.8 Hz, 1H), 0.80 (d, J = 6.7 Hz, 6H). m / z calcd. for C18H19N3O2= 309.1. Found [M+H]+= 310.3. (E)-3-(2-(1-(cyclopropylmethyl)-1H-imidazol-5-yl)-1H-indol-5-yl)acrylic acid (H46)

[0695] Prepared according to general procedures D and E starting with catalyst Pd(dppf)Cl2, boronate H1 and 1-(cyclopropylmethyl)-5-iodo-1H-imidazole to afford the titled compound in 53% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 11.50 (s, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.63 (s, 1H), 7.38 – 7.29 (m, 3H), 7.23 (d, J = 15.8 Hz, 1H), 6.66 (d, J =2.1 Hz, 1H), 6.30 (d, J = 15.8 Hz, 1H), 4.07 (d, J = ...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15: , , , , , , , ,, , , , , , and , wherein: R1, R6, R10, R14, R26, R30, R34, R37, R40, R46, R64, and R65are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R2, R7, R11, R15, R18, R23, R27, R41, R43, R47, R50, and R66are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R3, R12, R16, R19, R24, R28, R31, R35, R44, R48, R51, and R67are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R4, R8, R17, R20, R25, R29, R32, R38, R45, R49, R52, and R68are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R5, R9, R13, R21, R22, R33, R36, R39, R42, and R69are each independently H or C1-6alkyl; L is a single bond, , , , , , , , or , wherein: R70is H or -CH3; R71is H or -CH3; R72and R73are each independently selected from H, F, and -CH3; X7is O, S, or NR74, wherein R74is H or -CH3; and R53is of the formula (Ia) or (Ib):(Ia) or (Ib), wherein: n is 0 or 1; X1, X3, X4, and X6are each independently selected from C and N, and X2and X5are each independently selected from C, N, S, and O, and wherein at least one of X1, X2, X3, X4, and X5is N, S, or O when n is 0, and at least one of X2, X3, X4, X5, and X6is N when n is 1; and R54, R55, R56, R57and R58are each independently absent or selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl, and wherein at least one of R54, R55, R56, R57and R58is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10- membered heteroaryl; R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or wherein two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl, and R75is selected from -C(O)OH H3C, , , , ,wherein at least one of the following is present: (1) R53is of the formula (Ia): (Ia); (2) R53is of the formula (Ib): (Ib), and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl; (3) is and at least one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl; (4) is selected from moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15; and(5) L is , , , , , , , or , and wherein the compound is not .

2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the Formula (IIA): (IIA) wherein , L, n, X1, X2, X3, X4, X5, X6, R54, R55, R56, R57, R58, and R75are each as defined in Claim 1.

3. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1.

4. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X2is N.

5. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X4is N.

6. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X6is N.

7. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X2and X6are each N.

8. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X2and X4are each N.

9. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X4and X6are each N.

10. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0.

11. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein X2and X4are each N.

12. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein X3and X4are each N.

13. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein X3and X5are each N.

14. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein X4and X5are each N.

15. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein X1and X2are each N.

16. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein X1and X5are each N.

17. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein X3is N and X5is S.

18. The compound of any one of Claims 2-17 or a pharmaceutically acceptable salt thereof, wherein one of R54, R55, R56, R57and R58is C1-6alkyl or substituted C1-6alkyl.

19. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, X1, X3, X4, X5, and X6are each C, X2is N, R54is absent, R55, R56, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH,C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

20. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, X1, X3, X5, and X6are each C, X2and X4are each N, R54and R56are each absent, R55and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, - NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

21. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, X1, X3, X4, and X5are each C, X2and X6are each N, R54and R58are each absent, R55and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, - NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

22. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, X1, X2, X3, and X5are each C, X4and X6are each N, R56and R58are each absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, - NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

23. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, X1, X2, X3, X4, and X5are each C, X6is N, R58is absent, R54, R55, and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

24. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, X1, X2, X3, X5, and X6are each C, X4is N, R56is absent, R54, R55, and R58are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH,C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

25. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, X1, X2, X4, and X5are each C, X3and X6are each N, R55and R58are each absent, R54and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, - NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

26. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0, X1, X2, and X4are each C, X3and X5are each N, R55is absent, R54and R56are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, - OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

27. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0, X1, X2, and X3are each C, X4and X5are each N, R56is absent, R54and R55are each H, and R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, - OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

28. The compound of any one of Claims 19-27 or a pharmaceutically acceptable salt thereof, wherein R57is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted - OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, - C(O)NH2, -C(O)OH, and C3-6cycloalkyl, substituted -OC1-6alkyl is -OC1-6alkyl substituted with 1 to 3 substituents that are each independently halo, substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyanoand C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl.

29. The compound of any one of Claims 19-27 or a pharmaceutically acceptable salt thereof, wherein R57is C1-6alkyl or substituted C1-6alkyl.

30. The compound of Claim 29 or a pharmaceutically acceptable salt thereof, wherein R57is C1-6alkyl or substituted C1-6alkyl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl.

31. The compound of any one of Claims 19-27 or a pharmaceutically acceptable salt thereof, wherein R57is selected from: , , , , , , , , and .

32. The compound of Claim 31 or a pharmaceutically acceptable salt thereof, wherein R57is selected from: and .

33. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 1, X1, X3, X4, X5, and X6are each C, X2is N, R54is absent, R55, R57, and R58are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

34. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0, X1, X3, and X5are each C, X2and X4are each N, R54is absent, R55and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, - OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

35. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0, X1, X2, and X5are each C, X3and X4are each N, R55is absent, R54and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, - OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

36. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0, X1, X2, and X3are each C, X4and X5are each N, R57is absent, R54and R55are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, - OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

37. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0, X1, X2, and X4are each C, X3is N, X5is N, S or O, R55is absent, R54is H, R57is absent or H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

38. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0, X3, X4, and X5are each C, X1and X2are each N, R54is absent, R55and R57are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, - OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

39. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein n is 0, X2, X3, and X4are each C, X1and X5are each N, R57is absent, R54and R55are each H, and R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, - OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl.

40. The compound of any one of Claims 33-39 or a pharmaceutically acceptable salt thereof, wherein R56is selected from halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted - OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, - C(O)NH2, -C(O)OH, and C3-6cycloalkyl, substituted -OC1-6alkyl is -OC1-6alkyl substituted with 1 to 3 substituents that are each independently halo, substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl.

41. The compound of any one of Claims 33-39 or a pharmaceutically acceptable salt thereof, wherein R56is C1-6alkyl or substituted C1-6alkyl.

42. The compound of Claim 41 or a pharmaceutically acceptable salt thereof, wherein R56is C1-6alkyl or substituted C1-6alkyl, wherein substituted C1-6alkyl is C1-6alkyl substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl.

43. The compound of any one of Claims 33-39 or a pharmaceutically acceptable salt thereof, wherein R56is selected from: , , , , , , , and .

44. The compound of any one of Claims 2-43 or a pharmaceutically acceptable salt thereof, wherein is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y8, and Y13:, , , , , , , and , wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as defined in Claim 1.

45. The compound of Claim 44 or a pharmaceutically acceptable salt thereof, wherein is selected from the following moieties Y1, Y2, Y3, Y4, and Y8: , , , , and ,wherein R1, R2, R3, R4, R6, R7, R8, R10, R11, R12, R14, R15, R16, R17, R30,R31, and R32are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl, and R5, R9, R13, and R33are each independently H or methyl.

46. The compound of Claim 45 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R30, R31, R32, and R33are each H.

47. The compound of Claim 44 or a pharmaceutically acceptable salt thereof, wherein is , R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl.

48. The compound of Claim 47 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl, and R5is H or methyl.

49. The compound of Claim 47 or 48 or a pharmaceutically acceptable salt thereof, wherein R1is H, R2is H, F, cyano or methyl, R3is H or F, R4is H, and R5is H.

50. The compound of any one of Claims 47-49 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, and R5are each H.

51. The compound of any one of Claims 47-49 or a pharmaceutically acceptable salt thereof, wherein R1is H, R2is F, R3is H, R4is H, and R5is H.

52. The compound of any one of Claims 47-49 or a pharmaceutically acceptable salt thereof, wherein R1is H, R2is H, R3is F, R4is H, and R5is H.

53. The compound of any one of Claims 2-52 or a pharmaceutically acceptable salt thereof, wherein L is a single bond, , , , or , wherein R70and R71are each as defined in Claim 1.

54. The compound of any one of Claims 2-53 or a pharmaceutically acceptable salt thereof, wherein L is a single bond.

55. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of the Formula (IIB): (IIB) wherein: , L, and R75are each as defined in Claim 1; and R59, R60, R61, R62and R63are each independently selected from H, halo, C1-6alkyl, substituted C1-6alkyl, -OC1-6alkyl, substituted -OC1-6alkyl, -OH, C3-10cycloalkyl, substituted C3-10cycloalkyl, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, and at least one of R59, R60, R61, R62and R63is selected from C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkyl, thioalkoxyl, and 5- to 10-membered heteroaryl, or two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

56. The compound of Claim 55 or a pharmaceutically acceptable salt thereof, wherein one of R59, R60, R61, R62and R63is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

57. The compound of Claim 56 or a pharmaceutically acceptable salt thereof, wherein R59, R60, R61, and R63are each H, and R62is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6- membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl.

58. The compound of Claim 57 or a pharmaceutically acceptable salt thereof, wherein R59, R60, R61, and R63are each H, and R62is C3-10cycloalkyl, substituted C3-10cycloalkyl, 3- to 6- membered heterocycloalkyl, or substituted 3- to 6-membered heterocycloalkyl, wherein substituted C3-10cycloalkyl is C3-10cycloalkyl substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, and substituted 3- to 6-membered heterocycloalkyl is 3- to 6-membered heterocycloalkyl substituted with 1 or 2 substituents that are each independently C1-6alkyl.

59. The compound of Claim 55 or a pharmaceutically acceptable salt thereof, wherein two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl.

60. The compound of Claim 59 or a pharmaceutically acceptable salt thereof, wherein two of R59, R60, R61, R62and R63together with the ring atoms to which they are attached form a C4-6cycloalkyl, substituted C4-6cycloalkyl, 4- to 6-membered heterocycloalkyl, or substituted 4- to 6-membered heterocycloalkyl, wherein substituted C4-6cycloalkyl is C4-6cycloalkyl substituted with 1 to 4 substituents that are each independently C1-6alkyl, and substituted 4- to 6-membered heterocycloalkyl is 4- to 6-membered heterocycloalkyl substituted with 1 to 4 substituents that are each independently selected from C1-6alkyl and oxo (=O).

61. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIC): (IIC), wherein L, R53, and R75are each as defined in Claim 1, R1, R2, R3, and R4are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl, and R5is H or C1-6alkyl, and wherein one of R1, R2, R3and R4is selected from halo, cyano, C1-6alkyl and C3-6cycloalkyl.

62. The compound of Claim 61 or a pharmaceutically acceptable salt thereof, wherein one of R1, R2, R3and R4is halo.

63. The compound of Claim 61 or a pharmaceutically acceptable salt thereof, wherein one of R1, R2, R3and R4is C1-6alkyl.

64. The compound of Claim 61 or a pharmaceutically acceptable salt thereof, wherein one of R1, R2, R3and R4is C3-6cycloalkyl.

65. The compound of Claim 61 or a pharmaceutically acceptable salt thereof, wherein R2is cyano.

66. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15: , , , , , , , ,, , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R64, R65, R66, R67, R68, and R69are each as defined in Claim 1.

67. The compound of Claim 66 or a pharmaceutically acceptable salt thereof, wherein is selected from the following moieties Y2, Y3, Y4, Y5, Y6, Y8, and Y13: , , , , , , and , and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R30, R31, R32, R33, R46, R47, R48, and R49are each as defined in Claim 1.

68. The compound of Claim 67 or a pharmaceutically acceptable salt thereof, wherein is selected from the following moieties Y2, Y3, Y4, and Y8: , , , and , wherein R6, R7, R8, R10, R11, R12, R14, R15, R16, R17, R30, R31, and R32are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl, and R9, R13, and R33are each independently H or methyl.

69. The compound of Claim 68 or a pharmaceutically acceptable salt thereof, wherein R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R30, R31, R32, and R33are each H.

70. The compound of Claim 66 or 67 or a pharmaceutically acceptable salt thereof, wherein is , and R6, R7, R8and R9are each as defined in Claim 1.

71. The compound of Claim 66 or 67 or a pharmaceutically acceptable salt thereof, wherein is , and R18, R19, R20, and R21are each as defined in Claim 1.

72. The compound of Claim 66 or 67 or a pharmaceutically acceptable salt thereof, wherein is , and R22, R23, R24, and R25are each as defined in Claim 1.

73. The compound of Claim 66 or 67 or a pharmaceutically acceptable salt thereof, wherein is , and R10, R11, R12, and R13are each as defined in Claim 1.

74. The compound of Claim 66 or 67 or a pharmaceutically acceptable salt thereof, wherein is , and R14, R15, R16, and R17are each as defined in Claim 1.

75. The compound of Claim 66 or 67 or a pharmaceutically acceptable salt thereof, wherein is , and R30, R31, R32, and R33are each as defined in Claim 1.

76. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IID): (IID), wherein , R53, R70, and R75are each as defined in Claim 1.

77. The compound of Claim 76 or a pharmaceutically acceptable salt thereof, wherein R53is of the formula (Ib): (Ib) wherein R59, R60, R61, and R63are each H, and R62is C1-6alkyl or substituted C1-6alkyl.

78. The compound of any one of Claims 1-77, or a pharmaceutically acceptable salt thereof, wherein R75is -C(O)OH.

79. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

80. A compound or a pharmaceutically acceptable salt thereof selected from:

81. A pharmaceutical composition comprising: a compound of any one of Claims 1-80 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

82. A method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound of any one of Claims 1-80 or a pharmaceutically acceptable salt thereof.

83. A method of treating a disease or disorder, the method comprising:administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Claims 1-80 or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat the disease or disorder in the subject.

84. The method of Claim 83, wherein the disease or disorder is selected from acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), heterotopic ossification (HO; including trauma-induced and surgically- induced), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, vascular calcification (including that associated with chronic kidney disease (CKD)), ankylosing spondylitis, osteoarthritis, actinic keratosis, basal and squamous cell carcinoma, esophageal squamous cell carcinoma, arsenic keratosis, inflammatory acne, non-inflammatory acne, psoriasis, ichthyosis, keratinization, hyperproliferative disorders of the skin, photoaging, eczema, atopic dermatitis, Darriers disease, lichen planus, glucocorticoid damage, steroid atrophy, Alzheimer’s, Parkinson’s disease, autism spectrum disorders, schizophrenia and schizoaffective disorders, age related dementia and cognitive defects, adult T-cell leukemia / lymphoma, hair loss, atherosclerosis, and platelet disorders.

85. The method of Claim 83 or 84, wherein the disease or disorder is selected from heterotopic ossification (HO; including trauma-induced and surgically-induced), fibrodysplasia ossificans progressiva (FOP), multiple osteochondromas, and vascular calcification (including that associated with chronic kidney disease (CKD)).

86. The method of any one of Claims 83-85, wherein the disease or disorder is fibrodysplasia ossificans progressiva (FOP).

87. The method of any one of Claims 83-85, wherein the disease or disorder is multiple osteochondromas.

88. The method of Claim 83, wherein the disease or disorder is selected from conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, ocular surface neoplasia, cicatricial conjunctival disorders (including Stevens-Johnson syndrome, graft vs. host disease, trauma, chemical burns, thermal burns, prolonged ultraviolet light exposure, rosacea-induced damage, infectious disease (chlamydia, herpetic disease), keratinizing disorders of the conjunctiva (including radiation exposure, chemical injury, damage induced by topical medications)), disorders of the conjunctiva caused by vitamin A deficiency, pterygia, pingueculae, cicatricialpemphigoid, atopic kerato-conjunctivitis, Sjogren syndrome related conjunctival injury, meibomian gland dysfunction, blepharitis, hordeola, chalazia, eyelid neoplasms, keratitis, dry eye disease, evaporative dry eye disease, conjunctivalization, corneal intraepithelial neoplasia, stem cell deficiency, corneal injury, chemical-induced corneal injury, thermally-induced corneal injury, trauma-induced corneal injury, radiation-induced corneal injury, disorders of the cornea caused by vitamin A deficiency, Sjogren syndrome-related corneal injury, corneal neovascularization, uveitis, fibro-proliferative disorders, proliferative diabetic retinopathy, proliferative vitreo-retinopathy, epiretinal membrane formation, neovascular membrane formation, age-related macular degeneration, drusenogenesis, and retinal detachment injury.

89. The method of Claim 83 or 88, wherein the disease or disorder is selected conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, cicatricial conjunctival disorders (including from chemical burns, thermal burns, prolonged ultraviolet light exposure, rosacea- induced damage), keratinizing disorders of the conjunctiva, disorders of the conjunctiva caused by vitamin A deficiency, meibomian gland dysfunction, blepharitis, hordeola, chalazia, dry eye disease, evaporative dry eye disease, corneal injury, chemical-induced corneal injury, thermally- induced corneal injury, trauma-induced corneal injury, radiation-induced corneal injury, and disorders of the cornea caused by vitamin A deficiency.

90. The method of any one of Claims 83, 88 and 89, wherein the disease or disorder is meibomian gland dysfunction.

91. The method of any one of Claims 83, 88 and 89 wherein the disease or disorder is dry eye disease.

92. The method of any one of Claims 83, 88 and 89, wherein the disease or disorder is evaporative dry eye disease.

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