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 / 469,742, 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, having improved properties for drug development, such as chemical stability or 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.DEFINITIONS

[0006] The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings.

[0007] “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.

[0008] “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.

[0009] “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.

[0010] “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.

[0011] The term Cx-Cy or Cx-y refers to a group with x to y carbon atoms.

[0012] “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-).

[0013] The term “substituted alkyl” refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain (except the C1carbon 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.

[0014] The term “haloalkyl” refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromineand 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.

[0015] 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).

[0016] “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.

[0017] “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.

[0018] The term “alkane” refers to alkyl group and alkylene group, as defined herein.

[0019] 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.

[0020] The term “alkaryl” or “aralkyl” refers to the groups -alkylene-aryl and substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.

[0021] “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.

[0022] 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.

[0023] The term “alkoxyamino” refers to the group –NH-alkoxy, wherein alkoxy is defined herein.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] “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.

[0028] 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.

[0029] “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).

[0030] 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.

[0031] “Alkynyloxy” refers to the group –O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0032] “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)-

[0033] “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.

[0034] “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.

[0035] “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.

[0036] 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.

[0037] 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.

[0038] “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.

[0039] “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.

[0040] “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 and naphthyl. 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.

[0041] “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.

[0042] “Amino” refers to the group –NH2.

[0043] 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.

[0044] The term “azido” refers to the group –N3.

[0045] “Carboxyl,” “carboxy” or “carboxylate” refers to –CO2H or salts thereof.

[0046] “Carboxyl ester” or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)Oalkenyl, C(O)Osubstituted alkenyl, C(O)Oalkynyl, C(O)Osubstituted alkynyl, C(O)Oaryl, C(O)Osubstituted aryl, C(O)Ocycloalkyl, C(O)Osubstituted cycloalkyl, C(O)Ocycloalkenyl, C(O)Osubstituted cycloalkenyl, C(O)Oheteroaryl, C(O)Osubstituted heteroaryl, C(O)Oheterocyclic, and C(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.

[0047] “(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, and OC(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.

[0048] “Cyano” or “nitrile” refers to the group –CN.

[0049] “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.

[0050] 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.

[0051] “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.

[0052] 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.

[0053] “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.

[0054] “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.

[0055] “Cycloalkoxy” refers to –O-cycloalkyl.

[0056] “Cycloalkenyloxy” refers to –O-cycloalkenyl.

[0057] “Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

[0058] “Hydroxy” or “hydroxyl” refers to the group –OH.

[0059] “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.

[0060] 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 sixmembered 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.

[0061] 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.

[0062] 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.

[0063] 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 heteroarylgroups 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.

[0064] 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.

[0065] “Heteroaryloxy” refers to –O-heteroaryl.

[0066] “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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] “Heterocyclyloxy” refers to the group –O-heterocyclyl.

[0071] The term “heterocyclylthio” refers to the group heterocyclic-S-.

[0072] The term “heterocyclene” refers to the diradical group formed from a heterocycle, as defined herein.

[0073] The term “hydroxyamino” refers to the group -NHOH.

[0074] “Nitro” refers to the group –NO2.

[0075] “Oxo” refers to the atom (=O).

[0076] “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-.

[0077] “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.

[0078] 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.

[0079] “Thiol” refers to the group -SH.

[0080] “Thioxo” or the term “thioketo” refers to the atom (=S).

[0081] “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.

[0082] The term “substituted thioalkoxy” refers to the group -S-substituted alkyl.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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, =N2 or =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.

[0088] In addition to the disclosure herein, substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwisespecified, 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+.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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)-.

[0093] 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.

[0094] 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 patterns which are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0095] 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.

[0096] 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.

[0097] “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.

[0098] “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.

[0099] “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.

[0100] 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.

[0101] “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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] As used herein, the term “HO” refers to heterotopic ossification. As used herein, the term “BMP” refers to Bone Morphogenic Protein. As used herein, the term “rhBMP2” refers to recombinant human Bone Morphogenic Protein 2 (available from GenScript, Piscataway, NJ, USA). As used herein, the term “FOP” refers to the rare genetic condition, Fibrodysplasia Ossificans Progressiva. As used herein, the term “μg” refers to microgram. 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). As used herein, the term “DMSO” refers to dimethylsulfoxide. As used herein, the term “QD” refers to once-daily administration. As used herein, the term “BID” refers to twice-daily administration. As used herein, the term “mg / kg” refers to milligrams of compound per kilogram body weight. As used herein, the term “M” refers to male. As used herein, the term “F” refers to female. As used herein, the terms “μCT” or “micro-CT” refer to micro computed tomography. As used herein, the term “CT” refers to computed tomography. As used herein, the term “kVp” refers to kilovoltage peak. As used herein, the term “μA” refers to microampere. As used herein, the term “ms” refers to millisecond. As used herein, the term “μm” refers to micrometer. 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. As used herein, the term “DMSO” refers to dimethylsulfoxide. As used herein, the term “IFOPA” refers to the International Fibrodysplasia Ossificans Progressiva Association (North Kansas City, MO, USA). As used herein, the term “ACVR1” refers to Activin A receptor, type I. As used herein, the term “Pdgfra” refers to platelet-derived growth factor receptor alpha. As used herein, the term “HMO” refers to the genetic condition, Hereditary Multiple Osteochondromas (also referred to as Multiple Osteochondromas (MO)). As used herein, the term “P” refers to postnatal day.

[0108] 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 is also 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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 inthe context of a single embodiment, may also be provided separately or in any suitable sub- combination.

[0114] 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

[0115] Figure 1 shows Rose Bengal (RB) staining of a 10 week Rhino (Rh) mouse illustrating significant RB uptake (dark staining).

[0116] Figure 2 shows in-situ visualization of a 32 week old Rh mouse illustrating meibomian gland atrophy (demarcation in black and delineated by arrow heads), acinar thinning and gland obstruction (black dots).

[0117] Figure 3A shows National Eye Institute (NEI) scoring of RB staining of 8-12 week Rh mice treated with vehicle (OS – Left Eye) or compound T17 (OD – Right Eye). Pairwise statistical comparison with unpaired t-test p value depicted. N=8 eyes / group, 2 female mice, 2 male mice per group.

[0118] Figure 3B shows photographs of RB staining in a 8-12 week Rh mouse treated with compound T17 (OD – Right Eye) or vehicle (OS – Left Eye).

[0119] Figure 3C shows dental paper point (DPP) tear quantification of vehicle- and compound T17-treated Rh mice. N=5 eyes.

[0120] Figure 3D shows Draize scoring of Rh mice treated with vehicle or compound T17.

[0121] Figure 3E shows sample in-situ visualization of a 8-12 week Rh mouse treated with vehicle (V) compared to compound T17 (T) illustrating meibomian gland atrophy (demarcation in black, delineated by arrowheads) and gland obstruction (demarcation in black).

[0122] Figure 4A shows NEI scoring of RB staining of 12-14 week Rh mice treated with vehicle or compound T50, T59 or T62. Pairwise statistical comparison with unpaired t-test p value depicted. N=8 eyes / group, 4 female mice, 4 male mice per group.

[0123] Figure 4B shows DPP tear quantification of Rh mice treated with vehicle or compound T50, T59 or T62. Pairwise statistical comparison with unpaired t-test p value depicted. N=12 vehicle. N=24 eyes / vehicle group; 12 female mice, 12 male mice per group. N=8 eyes / compound group; 4 female mice, 4 male mice per group.

[0124] Figure 4C shows Draize scoring of Rh mice treated with vehicle or compound T50, T59 or T62.

[0125] Figure 4D shows sample in-situ visualization of a 12-14 week Rh mouse treated with vehicle (V) compared to compound T59 (T) illustrating meibomian gland atrophy (demarcation in black, delineated by arrowheads) and gland obstruction (black dots).

[0126] Figure 5A shows NEI scoring following RB staining of 18-20 week Rh mice treated with vehicle or compound T65. N=8 eyes / group, 4 female mice, 4 male mice per group.

[0127] Figure 5B shows DPP tear quantification of vehicle- and compound T65-treated Rh mice. Pairwise statistical comparison with unpaired t-test p value depicted. N=8 eyes / group, 2 female mice and 2 male mice per group.

[0128] Figure 5C shows Draize scoring of Rh mice treated with vehicle or compound T65.

[0129] Figure 5D shows Meibomian gland atrophy (atrophic glands per eyelid) in 18-20 week Rh mice treated with vehicle compared to compound T65. Pairwise statistical comparison with unpaired t-test; p<0.001. N=8 eyes per group.

[0130] Figure 5E shows sample in-situ visualization of a 18-20 week Rh mouse treated with vehicle (V) compared to compound T59 (T) illustrating meibomian gland atrophy (black demarcation, delineated by arrowheads and individual gland loss (black dots).

[0131] Figure 6A shows NEI scoring of RB staining of 14-18 week Rh mice treated with Lifitegrast (LG) or compound T62. Pairwise statistical comparison with unpaired t-test p value depicted. N=16 eyes / group, 8 mice per group.

[0132] Figure 6B shows DPP tear quantification of Lifitegrast (LG)- and compound T62- treated Rh mice. Pairwise statistical comparison with unpaired t-test p value depicted. N=16; N=8 eyes / compound group.

[0133] Figure 6C shows Draize scoring of Rh mice treated with Lifitegrast (LG) or compound T62. P<0.0001.

[0134] Figure 6D shows Meibomian gland atrophy (atrophic glands per eyelid) in 18-20 week Rh mice treated with Lifitegrast (LG) or compound T62. Pairwise statistical comparison with unpaired t-test; p<0.001. N=8 eyes per group.

[0135] Figure 6E shows sample in-situ visualization of a 14-18 week Rh mouse treated with compound T62 (T) compared to Lifitigrast (LG) illustrating meibomian gland atrophy (black demarcation) and individual gland loss (black dots).

[0136] Figure 7A shows NEI scoring of RB staining of 16-20 week Rh mice treated with vehicle (pooled) or compound T62 at 2mM, 10mM and 50mM doses. Group statistical comparison with a one-way ordinary ANOVA using Dunnett’s multiple comparisons test. N=8 eyes (2mM, 50mM), N=9 eyes (10mM) and N=23 eyes (pooled vehicle).

[0137] Figure 7B shows DPP tear quantification of Rh mice treated with vehicle or compound T62 at 2mM, 10mM, and 50mM doses. Group statistical comparison with one-way ordinary ANOVA with Dunnett’s multiple comparisons test. p value depicted. N=59 eyes pooled vehicle; N=8 eyes (2mM); N=21 eyes (10mM); N=12 eyes (50mM).

[0138] Figure 7C shows the fold change of absolute tear weight over vehicle in compound T62-treated Rh mice. Tear production was normalized to vehicle treatment.

[0139] Figure 7D shows Draize scoring of Rh mice treated with vehicle or compound T62 at 2mM, 10mM, and 50mM doses.

[0140] Figure 7E shows meibomian gland atrophy (atrophic glands per eyelid) in 16-20 week Rh mice treated with vehicle compared to treatment with 2mM, 10mM, and 50mM doses of compound T62. Group statistical comparison with one-way ordinary ANOVA with Dunnett’s multiple comparisons test. p<0.05. N=27 eyelids (vehicle); N=8 eyelids (2mM); N=18 eyelids (10mM); N=12 eyelids (50mM).

[0141] Figure 8 shows a box plot representing the composite cutaneous toxicity (blackjack) score for animals treated for 14 days with vehicle (black bar), as compared to 0.2µmol atRA (dark grey bar), 2μmol compound T62 (light grey bar), or 2μmol compound T66 (white bar) to dorsal skin (2M:2F per group), as described in Example 12. 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 by error bars. Asterisks denote statistically significant difference from vehicle-treated animals following ordinary one-way ANOVA analysis (*** = p < 0.001). These data illustrate that the test compounds cause significantly less flaking and irritation than atRA in this model, but are able to provide anti-comedogenic effects on skin (as shown in Figure 9).

[0142] Figure 9 shows representative photographs of dorsal skin epidermal sheet preparations from rhino mice treated topically with vehicle, 0.2µmol atRA, 2μmol compound T62, or 2μmol compound T66 to dorsal skin, once daily, for 2 weeks (photographs are 10x magnification, scale bar = 100µm). These data indicate that test compounds elicit a decrease in utricle size that is similar to that of retinoid treatment and indicative of 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 12, as a percentage of the size of utriculi in vehicle-treated skin (Table 4). The bars represent the mean relative utricule area in mouse skin treated with vehicle (black bar), atRA (dark grey bar), compound T62 (light grey bar), or compound T66 (white bar). The error bars denote standard deviation, and the asterisks denote statistically significant difference from vehicle-treated animals following ordinary one-wayANOVA analysis (**** = p < 0.0001). Both test compounds and atRA show a statistically significant reduction in average utricle area as compared to vehicle.

[0143] Figure 10 shows DICOM renderings obtained from micro-CT imaging of the tibia / fibula region surrounding the surgically-manipulated gastrocnemius muscle following surgical induction of HO and 13 days of administration of 50mg / kg compound T62 (BID), as compared to vehicle, as described in Example 13. Highly enhancing areas seen within the gastrocnemius muscle represent ectopic bone formed at the site of collagen disk implantation. The number of animals examined in each group is indicated.

[0144] Figure 11 shows a whisker plot illustrating the volume (mm3; y-axis) of ectopic bone that was formed after 13 days of treatment with either vehicle or 50 mg / kg BID of compound T62, indicated on the x-axis, as described in Example 13. “Veh” refers to vehicle. Each point represents one individual animal, with mean ± standard deviation shown. Statistical significance from the vehicle-treated group was calculated using an unpaired student’s t-test (*** = p<0.001). Compound T62 at 50 mg / kg BID was able to significantly inhibit ectopic bone formation in this model, as compared to vehicle. DETAILED DESCRIPTION

[0145] 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

[0146] Aspects of the present disclosure include a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: A is selected from: (1) -(CR1R2)m-X-(CR3R4)-, wherein: R1and R2are each independently selected from H, halo and C1-6alkyl; R3and R4are each independently selected from H, halo and C1-6alkyl, or R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl;m is 0 or 1; and X is selected from S, SO, SO2, O, and NH; (2) -(CR6R7)n-CR8R9-(CR10R11)p-, wherein: R6and R7are each independently H or C1-6alkyl; R8and R9are each independently halo or C1-6alkyl, or R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl; R10and R11are each independently H or C1-6alkyl; n is 0 or 1; and p is 0 or 1; (3), wherein B is a C3-6cycloalkyl; (4) -CH2CHR12-, wherein R12is C1-6alkyl; (5) -CHR13CH2-, wherein R13is C1-6alkyl; and (6) -CH2CH2CH2-;is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:wherein: R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, - N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), - SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, - S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), - SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, - S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, - N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), - SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, - S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionallysubstituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, - N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), - SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, - S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; each Rais independently selected from F, cyano, -OH, C3-4cycloalkyl, 3- to 5- membered heterocycloalkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, - C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, - NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl; each Rbis independently selected from F, cyano, -OH, oxo (=O), C1-3alkyl, - C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3 alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-3alkyl is optionally substituted with -OC1-3alkyl; each Rcis independently selected from F, cyano, -OH, oxo (=O), C1-3alkyl, - C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3 alkyl)2, -NH2, -NHC1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-3alkyl is optionally substituted with -OC1-3alkyl;R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently selected from H, -OH, and C1-6alkyl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from F, cyano, -OH, -OC1-3alkyl, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -SH, and -SC1-3alkyl;wherein: R72is H or -CH3; R73is H or -CH3; R74and R75are each independently selected from H, F, and -CH3; X1is O, S, or NR76, wherein R76is H or -CH3; and R77is of the formula (a), (b), or (c):wherein: X2, X3, X4, X5, and X6are each independently selected from C and N, wherein at least one of X2, X3, X4, X5, and X6is N; R78is absent, H, or F; R79, R80, and R81are each independently absent or selected from H, halo, cyano, - OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10- membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, - C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, - N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, R82is absent, H, or F; and wherein at least one of the following (a), (b), and (c) is present: (a) R78is F; (b) at least one of R79, R80, and R81is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, - C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted - S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6-membered heterocycloalkyl); and (c) R82is F; wherein when R77is of the formula (a) and R81is substituted phenyl, then R81is not substituted with 2 -OC1-3alkyl; R83is H or F; R84, R85, and R86are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, - N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, and R87is H or F; and wherein at least one of the following (d), (e), and (f) is present: (d) R83is F; (e) at least one of R84, R85, and R86is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, - C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted - S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6-membered heterocycloalkyl); and (f) R87is F; orwherein R83is H, R84is H, R87is H, and R85and R86together with the ring atoms to which they are attached form a C4-6cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein C4-6cycloalkyl is optionally substituted with 1 to 4 substituents that are each independently C1-6alkyl, and 4- to 6-membered heterocycloalkyl is optionally substituted with 1 to 4 substituents that are each independently selected from C1-6alkyl and oxo (=O); X7is C or N; X8, X9, X10, and X11are each independently selected from C, N, S, and O, wherein at least one of X7, X8, X9, X10, and X11is N, S, or O; and R88, R89, R90, and R91are each independently absent or selected from H, halo, cyano, -OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, - C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6- membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, and wherein at least one of R88, R89, R90, and R91is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted -S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6-membered heterocycloalkyl), each Rdis independently selected from F, cyano, -OH, C3-4cycloalkyl, 3- to 5- membered heterocycloalkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, - C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, - NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl; each of Reis independently selected from F, cyano, -OH, oxo (=O), C1-6alkyl, - C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3 alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-6alkyl is optionally substituted with -OC1-3alkyl; each Rfis independently selected from F, cyano, -OH, oxo (=O), C1-6alkyl, - C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3 alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-6alkyl is optionally substituted with -OC1-3alkyl; each Rgis independently selected from F, cyano, -OH, C1-6alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl; each Rhis independently selected from F, cyano, -OH, C1-6alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl; and R92is selected from -C(O)OH,

[0147] In some cases, A is: (1) -(CR1R2)m-X-(CR3R4)-, wherein: R1and R2are each independently selected from H, halo and C1-6alkyl; R3and R4are each independently selected from H, halo and C1-6alkyl, or R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl; m is 0 or 1; and X is selected from S, SO, SO2, O, and NH.

[0148] In some cases, m is 0, and thus A is -X-(CR3R4)-. In some cases, m is 1, and thus A is -(CR1R2)-X-(CR3R4)-.

[0149] In some cases, R1and R2are each independently selected from H, halo and C1-6alkyl. In some cases, R1is selected from H, halo and C1-6alkyl. 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 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 selected from H, halo and C1-6alkyl. In some cases, R2is H. In some cases, R2is halo (e.g., F, Cl, Br or I). In some cases, R2is F. In some cases, R2is Cl. In some cases, R2is Br. In some cases, R2is I. 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.

[0150] In some cases, R3and R4are each independently selected from H, halo and C1-6alkyl. In some cases, R3is selected from H, halo and C1-6alkyl. 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 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, R4is selected from H, halo and C1-6alkyl. 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 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.

[0151] In some cases, R3is H and R4is H. In some cases, R3is methyl and R4is methyl. In some cases, R3is halo and R4is halo (e.g., R3and R4are each F, Cl, Br or I).

[0152] In some cases, R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R3and R4together with the carbon atom to which they are attached form a cyclopropyl.

[0153] In some cases, X is selected from S, SO, SO2, O, and NH. In some cases, X is S. In some cases, X is SO. In some cases, X is SO2. In some cases, X is O. In some cases, X is NH.

[0154] In some cases, A is: (2) -(CR6R7)n-CR8R9-(CR10R11)p-, wherein: R6and R7are each independently H or C1-6alkyl; R8and R9are each independently halo or C1-6alkyl, or R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl; R10and R11are each independently H or C1-6alkyl; n is 0 or 1; and p is 0 or 1.

[0155] In some cases, n is 0 and p is 0, and thus A is -CR8R9-. In some cases, n is 1 and p is 0, and thus A is -(CR6R7)-CR8R9-. In some cases, n is 0 and p is 1, and thus A is -CR8R9- (CR10R11)-. In some cases, n is 1 and p is 1, and thus A is -(CR6R7)-CR8R9-(CR10R11)-.

[0156] In some cases, R6and R7are each independently H or C1-6alkyl. In some cases, R6is H or C1-6alkyl. In some cases, R6is H. 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, R7is H or C1-6alkyl. In some cases, R7is H. 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.

[0157] In some cases, R6is H and R7is H. In some cases, R6is methyl and R7is methyl. In some cases, R6is halo and R7is halo (e.g., R6and R7are each F, Cl, Br or I).

[0158] In some cases, R8and R9are each independently halo or C1-6alkyl. In some cases, R8is halo or C1-6alkyl. 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 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, R9is halo or C1-6alkyl. In some cases, R9is halo (e.g., F, Cl, Br or I). In some cases, R9is F. In some cases, R9is Cl. In some cases, R9is Br. In some cases, R9is I. 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.

[0159] In some cases, R8is H and R9is H. In some cases, R8is methyl and R9is methyl. In some cases, R8is halo and R9is halo (e.g., R8and R9are each F, Cl, Br or I).

[0160] In some cases, R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R8and R9together with the carbon atom to which they are attached form a cyclopropyl.

[0161] In some cases, R10and R11are each independently H or C1-6alkyl. In some cases, R10is H or C1-6alkyl. In some cases, R10is H. 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, R11is H or C1-6alkyl. In some cases, R11is H. 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.

[0162] In some cases, A is: (3), wherein B is a C3-6cycloalkyl.

[0163] As used herein, “B” andrefer to the same functional group (e.g., C3-6cycloalkyl). In some cases, C3-6cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, B is selected from cyclopropyl, cyclobutyl, and bicyclo[1.1.1]pentane. In some cases, B is cyclopropyl. In some cases, B is cyclobutyl. In some cases, B is bicyclo[1.1.1]pentane.

[0164] In some cases, A is -CH2CH2-. In some cases, A is not -CH2CH2-.

[0165] In some cases, A is -CH2CHR12-, where 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.

[0166] In some cases, A is CHR13CH2-, where 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.

[0167] In some cases, A is -CH2CH2CH2-.

[0168] In some cases,selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:

[0169] As used herein, “Y” 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). In some cases, Y is . In some cases, Y is. In some cases, Y isIn some cases, Y is . In some cases, Y is In some cases,

[0170] In some cases, R14is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R14is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R19is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R19is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R23is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R23is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R27is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R27is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R39is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R39is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R43is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R43is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R44is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R44is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R49is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R49is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R53is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R53is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R56is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R56is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R59is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R59is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R65is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R65is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R15is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R15is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R20is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R20is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R24is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R24is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R28is selected from H, halo, cyano, C1-6alkyl, and C3-6 cycloalkyl. In some cases, R28is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R31is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R31is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R36is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R36is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R40is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R40is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R45is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R45is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R60is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R60is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R62is selected from H, halo, cyano, C1-6alkyl, and C3-6 cycloalkyl. In some cases, R62is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R66is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R66is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R69is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R69is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R16is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R16is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R25is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R25is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R29is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R29is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R32is selected from H, halo, cyano, C1-6alkyl, and C3-6 cycloalkyl. In some cases, R32is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R37is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R37is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R41is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R41is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R46is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R46is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R50is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R50is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R54is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R54is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R63is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R63is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R67is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R67is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R70is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R70is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R17is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R17is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R21is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R21is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R30is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R30is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R33is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R33is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R38is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R38is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R42is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R42is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R47is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R47is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R51is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R51is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R57is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R57is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R64is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R64is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R68is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R68is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R71is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R71is selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl. In some cases, R18is selected from H and C1-6alkyl. In some cases, R18is H or methyl. In some cases, R22is selected from H and C1-6alkyl. In some cases, R22is H or methyl. In some cases, R26is selected from H and C1-6alkyl. In some cases, R26is H or methyl. In some cases, R34is selected from H and C1-6alkyl. In some cases, R34is H or methyl. In some cases, R35is selected from H and C1-6alkyl. In some cases, R35is H or methyl. In some cases, R48is selected from H and C1-6alkyl. In some cases, R48is H or methyl. In some cases, R52is selectedfrom H and C1-6alkyl. In some cases, R52is H or methyl. In some cases, R55is selected from H and C1-6alkyl. In some cases, R55is H or methyl. In some cases, R58is selected from H and C1-6alkyl. In some cases, R58is H or methyl. In some cases, R61is selected from H and C1-6alkyl. In some cases, R61is H or methyl.

[0171] In some cases, L is selected from a single bond,, , , , and . In some cases, L is a single bond. 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 .

[0172] In some cases, R72is H or -CH3. In some cases, R72is H. In some cases, R72is -CH3.

[0173] In some cases, R73is H or -CH3. In some cases, R73is H. In some cases, R73is -CH3.

[0174] In some cases, R74is selected from H, F, and -CH3. In some cases, R74is H. In some cases, R74is F. In some cases, R74is -CH3.

[0175] In some cases, R75is selected from H, F, and -CH3. In some cases, R75is H. In some cases, R75is F. In some cases, R75is -CH3.

[0176] In some cases, X1is O, S, or NR76, wherein R76is H or -CH3. In some cases, X1is O, S, or NR76. In some cases, X1is O. In some cases, X1is S. In some cases, X1is NR76. In some cases, R76is H or -CH3. In some cases, R76is H. In some cases, R76is -CH3.

[0177] In some cases, R77is of the formula (a), (b), or (c): (a), (b), or (c).

[0178] In some cases, R77is of the formula (a):

[0179] In some cases, X2, X3, X4, X5, and X6are each independently selected from C and N, wherein at least one of X2, X3, X4, X5, and X6is N. In some cases, X2is C. In some cases, X2is N. When X2is N, then R78is absent. In some cases, X3is C. In some cases, X3is N. When X3is N, then R79is absent. In some cases, X4is C. In some cases, X4is N. When X4is N, then R80is absent. In some cases, X5is C. In some cases, X5is N. When X5is N, then R81is absent. In some cases, X6is C. In some cases, X6is N. When X6is N, then R82is absent. In some cases, at least one of X2, X3, X4, X5, and X6is N. In some cases, one of X2, X3, X4, X5, and X6is N. For example, in some cases, X2is N, or X3is N, or X4is N, or X5is N, or X6is N. In some cases, two of X2, X3, X4, X5, and X6is N. For example, in some cases, X2and X4are N, or X2and X6are N, or X3and X6are N, or X4and X6are N.

[0180] In some cases, R78is absent, H, or F. In some cases, R78is absent. In some cases, R78is H. In some cases, R78is F.

[0181] In some cases, R79is absent or selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independentlyC1-6 alkyl.

[0182] In some cases, R80is absent or selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0183] In some cases, R81is absent or selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0184] In some cases, R82is absent, H, or F. In some cases, R82is absent. In some cases, R82is H. In some cases, R82is F.

[0185] In some cases, when R77is of the formula (a), then at least one of the following (a), (b), and (c) is present: (a) R78is F; (b) at least one of R79, R80, and R81is selected from the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, -SC1-6alkyl, the optionally substituted - OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; and (c) R82is F.

[0186] In some cases, when R77is of the formula (a), and R81is substituted phenyl, then R81is not substituted with 2 -OC1-3alkyl.

[0187] In some cases, R77is of the formula (b):

[0188] In some cases, R83is H or F. In some cases, R83is H. In some cases, R83is F.

[0189] In some cases, R84is selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, - OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-memberedheterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0190] In some cases, R85is selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, - OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0191] In some cases, R86is selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, - OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0192] In some cases, R87is H or F. In some cases, R87is H. In some cases, R87is F.

[0193] In some cases, when R77is of the formula (b), then at least one of the following (d), (e), and (f) is present: (d) R83is F; (e) at least one of R84, R85, and R86is selected from the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, -SC1-6alkyl, the optionally substituted - OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; and (f) R87is F; or wherein R83is H, R84is H, R87is H, and R85and R86together with the ring atoms to which they are attached form a C4-6cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein C4-6cycloalkyl is optionally substituted with 1 to 4 substituents that are each independently C1-6alkyl, and 4- to 6-membered heterocycloalkyl is optionally substituted with 1 to 4 substituents that are each independently selected from C1-6alkyl and oxo (=O).

[0194] In some cases, R77is of the formula (c):

[0195] In some cases, X7is C or N. In some cases, X7is C. In some cases, X7is N.

[0196] In some cases, X8, X9, X10, and X11are each independently selected from C, N, S, and O, wherein at least one of X7, X8, X9, X10, and X11is N, S, or O. In some cases, X8is selected from C, N, S, and O. In some cases, X8is C. In some cases, X8is N. When X8is N, then R88is absent. In some cases, X8is S. When X8is S, then R88is absent. In some cases, X8is O. When X8is O, then R88is absent. In some cases, X9is selected from C, N, S, and O. In some cases, X9is C. In some cases, X9is N. When X9is N, then R89is absent. In some cases, X9is S. When X9is S, then R89is absent. In some cases, X9is O. When X9is O, then R89is absent. In some cases, X10is selected from C, N, S, and O. In some cases, X10is C. In some cases, X10is N. When X10is N, then R90is absent. In some cases, X10is S. When X10is S, then R90is absent. In some cases, X10is O. When X10is O, then R90is absent. In some cases, X11is selected from C, N, S, and O. In some cases, X11is C. In some cases, X11is N. When X11is N, then R91is absent. In some cases, X11is S. When X11is S, then R91is absent. In some cases, X11is O. When X11is O, then R91is absent. In some cases, at least one of X7, X8, X9, X10, and X11is N, S, or O. For example, in some cases, X9is N and X11is O, or X9is N and X11is S, or X9is N and X10is N, or X10is N and X11is N, or X9is N and X11is N, and the like.

[0197] In some cases, R88is absent or selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0198] In some cases, R89is absent or selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0199] In some cases, R90is absent or selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6 alkyl.

[0200] In some cases, R91is absent or selected from H, C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, - C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0201] In some cases, at least one of R88, R89, R90, and R91is selected from the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, -SC1-6alkyl, the optionally substituted -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl.

[0202] In some cases, R92is -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.

[0203] In some cases, R92is selected from -C(O)OH,

[0204] In some cases, the compound of formula (I) is not selected from:

[0205] Embodiments of the compounds of the present disclosure include one or more of the following embodiments.

[0206] In some cases, the compound is selected from:and B is as defined herein.

[0207] In some cases, the compound is a compound of Formula (IA): wherei1 2 3 4 77 92n each of L, X, R, R, R, R, R , R , m, andis as defined herein. In some cases, m is 0. In some cases, m is 1. In some cases, R1and R2are each independently selected from H, F, and methyl. In some cases, X is selected from S, SO, SO2, and O. In some cases, X is selected from S, SO, and SO2. In some cases, X is S. In some cases, X is SO. In some cases, X is SO2. In some cases, X is O. In some cases, R3and R4are each independently selected from H, F, and methyl. In some cases, R3is methyl. In some cases, R3and R4are each methyl. In some cases, R3and R4are each H. In some cases, R3and R4are each halo. In some cases, R3and R4are each F. In some cases, R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl. In some cases, R3and R4together with the carbon atom to which they are attached form cyclopropyl.

[0208] In some cases, the compound is a compound of Formula (IB): (IB), wherein ea6 7 8 9 10 11ch of L, R, R, R, R, R , R , R77, R92, n, p, andis as defined herein. In some cases, n is 1 and p is 0. In some cases, R8and R9are each independently selected from F and methyl. In some cases, R8and R9are each methyl. In some cases, R8and R9are each halo. In some cases, R8and R9are each F. In some cases, R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl. In some cases, R8and R9together with the carbon atom to which they are attached form cyclopropyl. In some cases, R6and R7are each independently selected from H and methyl. In some cases, R6and R7are each H.

[0209] In some cases, the compound is a compound of Formula (IC): whe77 92rein each of L, R , R ,, and B is as defined herein. In some cases, B is selected from cyclopropyl, cyclobutyl, and bicyclo[1.1.1]pentane.

[0210] In some cases, the compound is a compound of Formula (IE): (IE), or a compound of Formula (IF):(IF), wherein each of L, R12, R13, R77, R92, andis as defined herein. In some cases, R12and R13is methyl.

[0211] In some cases, the compound is a compound of Formula (IG): (IG), wherein each of L77 92, R , R , andis as defined herein.

[0212] In some cases, R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently H or C1-6alkyl. In some cases, R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; and R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently H or methyl.

[0213] In some cases,is moiety Y1, wherein each of R14, R15, R16, R17and R18is as defined herein. In some cases, R14is H, R15is H, F, cyano or methyl, R16is H or F, R17is H, and R18is H. In some cases, each of R14, R15, R16, R17, and R18is H. In some cases, R14is H, R15is F, R16is H, R17is H, and R18is H. In some cases, R14is H, R15is H, R16is F, R17is H, and R18is H.

[0214] In some cases, is moiety Y2: wherein each ofR19, R20, R21, and R22is as defined herein. In some cases, R19is H, R20is H, F, cyano or methyl, R21is H, and R22is H. In some cases, each of R19, R20, R21, and R22is H.

[0215] In some cases,is moiety Y3:, wherein each of R23, R24, R25, and R26is as defined herein. In some cases, each of R23, R24, R25, and R26is H.

[0216] In some cases, is moiety Y4:wherein each of R27, R28, R29, and R30is as defined herein. In some cases, each of R27, R28, R29, and R30is H.

[0217] In some cases,is moiety Y5:, wherein each of R31, R32, R33, and R34is as defined herein.

[0218] In some cases,is moiety Y6: wherein each of 35 36 3R , R , R7, and R38is as defined herein.

[0219] In some cases,is moiety Y7:wherein each of R39, R40, R41, and R42is as defined herein.

[0220] In some cases,is moiety Y8: where each of R43, R44, R45, R46, R47, and R48is as defined herein.

[0221] In some cases,is moiety Y9:, wherein each of R49, R50, R51and R52is as defined herein. In some cases, each of R49, R50, R51and R52is H.

[0222] In some cases,is moiety Y10: wherein each of 53 54 55R , R and R is as defined herein.

[0223] In some cases,is moiety Y11: wherein each ofR56, R57and R58is as defined herein.

[0224] In some cases,is moiety Y12: wherein each ofR59, R60and R61is as defined herein.

[0225] In some cases, is moiety Y13: wherein each of 62 6R , R3and R64is as defined herein.

[0226] In some cases, is moiety Y14:, wherein each of R65, R66, R67and R68is as defined herein.

[0227] In some cases, is moiety Y15: wherein each of 69 70R , R and R70is as defined herein.

[0228] In some cases, L is a single bond, wherein R72is H. In some cases, L is a single bond.

[0229] In some cases, R77is selected from , andwherein each of R84, R85, and R86are as defined herein. In some77cases, R is wherein R86is as defined herein. In some cases, R77is wherein R86isselected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0230] In some cases, R77is selected fromwherein R81is as defined herein. In some cases, R77is wherein R81is as defined herein. In some cases81, R is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0231] In some cases, R77is selected fromwherein R90is as defined herein. In some cases, R90is selectedfrom C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, - NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0232] In some cases, R77is selected from:

[0233] In some cases, R77is selected from:

[0234] In some cases, R92is -C(O)OH.

[0235] In some cases, the compound is selected from:pharmaceutically acceptable salt thereof.

[0236] In some cases, a compound of the present disclosure is a compound selected from:or a pharmaceutically acceptable salt thereof. Additional Embodiments of Compounds of the Invention

[0237] Aspects of the present disclosure also include a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: Aa is selected from: (1) -(CR1aR2a)m-Xa-(CR3aR4a)-, wherein: R1aand R2aare each independently selected from H, halo and C1-6alkyl; R3aand R4aare each independently selected from H, halo and C1-6alkyl, or R3aand R4atogether with the carbon atom to which they are attached form a C3-6cycloalkyl; m is 0 or 1; and Xa is selected from S, SO, and SO2, O, and NH;(2) -(CR6aR7a)n-CR8aR9a-(CR10aR11a)p-, wherein: R6aand R7aare each independently H or C1-6alkyl; R8aand R9aare each independently halo or C1-6alkyl, or R8aand R9atogether with the carbon atom to which they are attached form a C3-6cycloalkyl; R10aand R11aare each independently H or C1-6alkyl; n is 0 or 1; and p is 0 or 1; (3), wherein Bb is a C3-6cycloalkyl; (4) -CH2CHR12a-, wherein R12ais C1-6alkyl; (5) -CHR13aCH2-, wherein R13ais C1-6alkyl; and (6) -CH2CH2CH2-;is selected from the following moieties Ya1, Ya2, Ya3, Ya4, Ya5, Ya6, Ya7, and Ya8:wherein: R14a, R19a, R23a, R27a, R39a, R43a, and R44aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R15a, R20a, R24a, R28a, R31a, R36a, R40a, and R45aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R16a, R25a, R29a, R32a, R37a, R41a, and R46aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R17a, R21a, R30a, R33a, R38a, R42a, and R47aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R18a, R22a, R26a, R34a, R35a, and R48aare each independently H or C1-6alkyl; and R49ais selected from:wherein: R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R70a, and R72aare each independently selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, and -OH, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6- membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl; R58a, R59a, and R60aare each independently C1-6alkyl optionally substituted with 1 to 3 substituents that are each independently halo; R61aand R62aare each independently C1-6alkyl optionally substituted with 1 or 2 substituents that are each independently selected from C3-6cycloalkyl and cyano; R63a, R64a, R65a, R66a, R67a, and R68aare each independently selected from H and C1-6alkyl; R69aand R73aare each independently selected from C1-6alkyl, C3-10cycloalkyl, and -OC1-6alkyl, wherein C1-6alkyl is optionally substituted with cyano, and C3-10cycloalkyl is optionally substituted with cyano; and R71ais C1-6alkyl, wherein the compound is not selected from:

[0238] In certain embodiments, Aa is -(CR1aR2a)m-Xa-(CR3aR4a)-, wherein R1aand R2aare each independently selected from H, halo and C1-6alkyl, R3aand R4aare each independently selected from H, halo and C1-6alkyl, or R3aand Ra4together with the carbon atom to which they are attached form a C3-6cycloalkyl, m is 0 or 1, and Xa is selected from S, SO, SO2, O, and NH.

[0239] In some cases, m is 0, and thus Aa is -Xa-(CR3aR4a)-. In some cases, m is 1, and thus Aa is -(CR1aR2a)-Xa-(CR3aR4a)-.

[0240] In some cases, R1aand R2aare each independently selected from H, halo and C1-6alkyl. In some cases, R1ais selected from H, halo and C1-6alkyl. In some cases, R1ais H. In some cases, R1ais halo (e.g., F, Cl, Br or I). In some cases, R1ais F. In some cases, R1ais Cl. In some cases, R1ais Br. In some cases, R1ais I. In some cases, R1ais 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, R2ais selected from H, halo and C1-6alkyl. In some cases, R2ais H. In some cases, R2ais halo (e.g., F, Cl, Br or I). In some cases, R2ais F. In some cases, R2ais Cl. In some cases, R2ais Br. In some cases, R2ais I. In some cases, R2ais 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.

[0241] In some cases, R3aand R4aare each independently selected from H, halo and C1-6alkyl. In some cases, R3ais selected from H, halo and C1-6alkyl. In some cases, R3ais H. In some cases, R3ais halo (e.g., F, Cl, Br or I). In some cases, R3ais F. In some cases, R3ais Cl. In some cases, R3ais Br. In some cases, R3ais I. In some cases, R3ais 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, R3ais methyl. In some cases, R4ais selected from H, halo and C1-6alkyl. In some cases, R4ais H. In some cases, R4ais halo (e.g., F, Cl, Br or I). In some cases, R4ais F. In some cases, R4ais Cl. In some cases, R4ais Br. In some cases, R4ais I. In some cases, R4ais 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.

[0242] In some cases, R3ais H and R4ais H. In some cases, R3ais methyl and R4ais methyl. In some cases, R3ais halo and R4ais halo (e.g., R3aand R4aare each F, Cl, Br or I).

[0243] In some cases, R3aand R4atogether with the carbon atom to which they are attached form a C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R3aand R4atogether with the carbon atom to which they are attached form a cyclopropyl.

[0244] In some cases, Xa is selected from S, SO, SO2, O, and NH. In some cases, Xa is S. In some cases, Xa is SO. In some cases, Xa is SO2. In some cases, Xa is O. In some cases, Xa is NH.

[0245] In some cases, Aa is -(CR6aR7a)n-CR8aR9a-(CR10aR11a)p-, wherein R6aand R7aare each independently H or C1-6alkyl, R8aand R9aare each independently halo or C1-6alkyl, or R8aand R9atogether with the carbon atom to which they are attached form a C3-6cycloalkyl, R10aand R11aare each independently H or C1-6alkyl, n is 0 or 1, and p is 0 or 1.

[0246] In some cases, n is 0 and p is 0, and thus Aa is -CR8aR9a-. In some cases, n is 1 and p is 0, and thus Aa is -(CR6aR7a)-CR8aR9a-. In some cases, n is 0 and p is 1, and thus Aa is -CR8aR9a- (CR10aR11a)-. In some cases, n is 1 and p is 1, and thus Aa is -(CR6aR7a)-CR8aR9a-(CR10aR11a)-.

[0247] In some cases, R6aand R7aare each independently H or C1-6alkyl. In some cases, R6ais H or C1-6alkyl. In some cases, R6ais H. in some cases, R6ais 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, R6ais methyl. In some cases, R7ais H or C1-6alkyl. In some cases, R7ais H. in some cases, R7ais 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, R7ais methyl.

[0248] In some cases, R6ais H and R7ais H. In some cases, R6ais methyl and R7ais methyl. In some cases, R6ais halo and R7ais halo (e.g., R6aand R7aare each F, Cl, Br or I).

[0249] In some cases, R8aand R9aare each independently halo or C1-6alkyl. In some cases, R8ais halo or C1-6alkyl. In some cases, R8ais halo (e.g., F, Cl, Br or I). In some cases, R8ais F. In some cases, R8ais Cl. In some cases, R8ais Br. In some cases, R8ais I. In some cases, R8ais 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, R8ais methyl. In some cases, R9ais halo or C1-6alkyl. In some cases, R9ais halo (e.g., F, Cl, Br or I). In some cases, R9ais F. In some cases, R9ais Cl. In some cases, R9ais Br. In some cases, R9ais I. In some cases, R9ais 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, R9ais methyl.

[0250] In some cases, R8ais H and R9ais H. In some cases, R8ais methyl and R9ais methyl. In some cases, R8ais halo and R9ais halo (e.g., R8aand R9aare each F, Cl, Br or I).

[0251] In some cases, R8aand R9atogether with the carbon atom to which they are attached form a C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R8aand R9atogether with the carbon atom to which they are attached form a cyclopropyl.

[0252] In some cases, R10aand R11aare each independently H or C1-6alkyl. In some cases, R10ais H or C1-6alkyl. In some cases, R10ais H. In some cases, R10ais 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, R11ais H or C1-6alkyl. In some cases, R11ais H. In some cases, R11ais 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.

[0253] In some cases, Aa is , where Bb is a C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, Bb is selected from cyclopropyl, cyclobutyl, and bicyclo[1.1.1]pentane. In some cases, Bb is cyclopropyl. In some cases, Bb is cyclobutyl. In some cases, Bb is bicyclo[1.1.1]pentane. As used herein, “Bb” and refer to the same functional group (e.g., C3-6cycloalkyl).

[0254] In some cases, Aa is -CH2CH2-. In some cases, Aa is not -CH2CH2-.

[0255] In some cases, Aa is -CH2CHR12a-, where R12ais 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.

[0256] In some cases, Aa is CHR13aCH2-, where R13ais 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.

[0257] In some cases, Aa is -CH2CH2CH2-.

[0258] In some cases,selected from the following moieties Ya1, Ya2, Ya3, Ya4, Ya5, Ya6, Ya7, and Ya8:

[0259] As used herein, “Ya” and refer to the same functional group (e.g., Ya1, Ya2, Ya3, Ya4, Ya5, Ya6, Ya7, or Ya8). In some cases, Ya is . In some cases, Ya is . In some cases, Ya is . In some cases, Ya is . In some cases, Ya is . In some cases, Ya is . In some cases, Ya is . In some cases, Ya is .

[0260] In some cases, R14a, R19a, R23a, R27a, R39a, R43a, and R44aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl.

[0261] In some cases, R14ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R14ais H. In some cases, R14ais halo (e.g., F, Cl, Br or I). In some cases, R14ais F. In some cases, R14ais Cl. In some cases, R14ais Br. In some cases, R14ais I. In some cases, R14ais cyano. In some cases, R14ais 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, R14ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0262] In some cases, R19ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R19ais H. In some cases, R19ais halo (e.g., F, Cl, Br or I). In some cases, R19ais F. In some cases, R19ais Cl. In some cases, R19ais Br. In some cases, R19ais I. In some cases, R19ais cyano. In some cases, R19ais 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, R19ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0263] In some cases, R23ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R23ais H. In some cases, R23ais halo (e.g., F, Cl, Br or I). In some cases, R23ais F. In some cases, R23ais Cl. In some cases, R23ais Br. In some cases, R23ais I. In some cases, R23ais cyano. In some cases, R23ais 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, R23ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0264] In some cases, R27ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R27ais H. In some cases, R27ais halo (e.g., F, Cl, Br or I). In some cases, R27ais F. In some cases, R27ais Cl. In some cases, R27ais Br. In some cases, R27ais I. In some cases, R27ais cyano. In some cases, R27ais 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, R27ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0265] In some cases, R39ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R39ais H. In some cases, R39ais halo (e.g., F, Cl, Br or I). In some cases, R39ais F. In some cases, R39ais Cl. In some cases, R39ais Br. In some cases, R39ais I. In some cases, R39ais cyano. In some cases, R39ais 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, R39ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0266] In some cases, R43ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R43ais H. In some cases, R43ais halo (e.g., F, Cl, Br or I). In some cases, R43ais F. In some cases, R43ais Cl. In some cases, R43ais Br. In some cases, R43ais I. In some cases, R43ais cyano. In some cases, R43ais 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, R43ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0267] In some cases, R44ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R44ais H. In some cases, R44ais halo (e.g., F, Cl, Br or I). In some cases, R44ais F. In some cases, R44ais Cl. In some cases, R44ais Br. In some cases, R44ais I. In some cases, R44ais cyano. In some cases, R44ais 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, R44ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0268] In some cases, R15a, R20a, R24a, R28a, R31a, R36a, R40a, and R45aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl.

[0269] In some cases, R15ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R15ais H. In some cases, R15ais halo (e.g., F, Cl, Br or I). In some cases, R15ais F. In some cases, R15ais Cl. In some cases, R15ais Br. In some cases, R15ais I. In some cases, R15ais cyano. In some cases, R15ais 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, R15ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0270] In some cases, R20ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R20ais H. In some cases, R20ais halo (e.g., F, Cl, Br or I). In some cases, R20ais F. In some cases, R20ais Cl. In some cases, R20ais Br. In some cases, R20ais I. In some cases, R20ais cyano. In some cases, R20ais 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, R20ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0271] In some cases, R24ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R24ais H. In some cases, R24ais halo (e.g., F, Cl, Br or I). In some cases, R24ais F. In some cases, R24ais Cl. In some cases, R24ais Br. In some cases, R24ais I. In some cases, R24ais cyano. In some cases, R24ais 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, R24ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0272] In some cases, R28ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R28ais H. In some cases, R28ais halo (e.g., F, Cl, Br or I). In some cases, R28ais F. In some cases, R28ais Cl. In some cases, R28ais Br. In some cases, R28ais I. In some cases, R28ais cyano. In some cases, R28ais 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, R28ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0273] In some cases, R31ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R31ais H. In some cases, R31ais halo (e.g., F, Cl, Br or I). In some cases, R31ais F. In some cases, R31ais Cl. In some cases, R31ais Br. In some cases, R31ais I. In some cases, R31ais cyano. In some cases, R31ais 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, R31ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0274] In some cases, R36ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R36ais H. In some cases, R36ais halo (e.g., F, Cl, Br or I). In some cases, R36ais F. In some cases, R36ais Cl. In some cases, R36ais Br. In some cases, R36ais I. In some cases, R36ais cyano. In some cases, R36ais 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, R36ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0275] In some cases, R40ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R40ais H. In some cases, R40ais halo (e.g., F, Cl, Br or I). In some cases, R40ais F. In some cases, R40ais Cl. In some cases, R40ais Br. In some cases, R40ais I. In some cases, R40ais cyano. In some cases, R40ais 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, R40ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0276] In some cases, R45ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R45ais H. In some cases, R45ais halo (e.g., F, Cl, Br or I). In some cases, R45ais F. In some cases, R45ais Cl. In some cases, R45ais Br. In some cases, R45ais I. In some cases, R45ais cyano. In some cases, R45ais 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, R45ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0277] In some cases, R16a, R25a, R29a, R32a, R37a, R41a, and R46aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl.

[0278] In some cases, R16ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R16ais H. In some cases, R16ais halo (e.g., F, Cl, Br or I). In some cases, R16ais F. In some cases, R16ais Cl. In some cases, R16ais Br. In some cases, R16ais I. In some cases, R16ais cyano. In some cases, R16ais 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, R16ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0279] In some cases, R25ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R25ais H. In some cases, R25ais halo (e.g., F, Cl, Br or I). In some cases, R25ais F. In some cases, R25ais Cl. In some cases, R25ais Br. In some cases, R25ais I. In some cases, R25ais cyano. In some cases, R25ais 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, R25ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0280] In some cases, R29ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R29ais H. In some cases, R29ais halo (e.g., F, Cl, Br or I). In some cases, R29ais F. In some cases, R29ais Cl. In some cases, R29ais Br. In some cases, R29ais I. In some cases, R29aiscyano. In some cases, R29ais 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, R29ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0281] In some cases, R32ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R32ais H. In some cases, R32ais halo (e.g., F, Cl, Br or I). In some cases, R32ais F. In some cases, R32ais Cl. In some cases, R32ais Br. In some cases, R32ais I. In some cases, R32ais cyano. In some cases, R32ais 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, R32ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0282] In some cases, R37ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R37ais H. In some cases, R37ais halo (e.g., F, Cl, Br or I). In some cases, R37ais F. In some cases, R37ais Cl. In some cases, R37ais Br. In some cases, R37ais I. In some cases, R37ais cyano. In some cases, R37ais 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, R37ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0283] In some cases, R41ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R41ais H. In some cases, R41ais halo (e.g., F, Cl, Br or I). In some cases, R41ais F. In some cases, R41ais Cl. In some cases, R41ais Br. In some cases, R41ais I. In some cases, R41ais cyano. In some cases, R41ais 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, R41ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0284] In some cases, R46ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R46ais H. In some cases, R46ais halo (e.g., F, Cl, Br or I). In some cases, R46ais F. In some cases, R46ais Cl. In some cases, R46ais Br. In some cases, R46ais I. In some cases, R46ais cyano. In some cases, R46ais 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, R46ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0285] In some cases, R17a, R21a, R30a, R33a, R38a, R42a, and R47aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl.

[0286] In some cases, R17ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R17ais H. In some cases, R17ais halo (e.g., F, Cl, Br or I). In some cases, R17ais F. In some cases, R17ais Cl. In some cases, R17ais Br. In some cases, R17ais I. In some cases, R17ais cyano. In some cases, R17ais 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, R17ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0287] In some cases, R21ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R21ais H. In some cases, R21ais halo (e.g., F, Cl, Br or I). In some cases, R21ais F. In some cases, R21ais Cl. In some cases, R21ais Br. In some cases, R21ais I. In some cases, R21ais cyano. In some cases, R21ais 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, R21ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0288] In some cases, R30ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R30ais H. In some cases, R30ais halo (e.g., F, Cl, Br or I). In some cases, R30ais F. In some cases, R30ais Cl. In some cases, R30ais Br. In some cases, R30ais I. In some cases, R30ais cyano. In some cases, R30ais 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, R30ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0289] In some cases, R33ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R33ais H. In some cases, R33ais halo (e.g., F, Cl, Br or I). In some cases, R33ais F. In some cases, R33ais Cl. In some cases, R33ais Br. In some cases, R33ais I. In some cases, R33ais cyano. In some cases, R33ais 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, R33ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0290] In some cases, R38ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R38ais H. In some cases, R38ais halo (e.g., F, Cl, Br or I). In some cases, R38ais F. In some cases, R38ais Cl. In some cases, R38ais Br. In some cases, R38ais I. In some cases, R38ais cyano. In some cases, R38ais 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, R38ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0291] In some cases, R42ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R42ais H. In some cases, R42ais halo (e.g., F, Cl, Br or I). In some cases, R42ais F. In some cases, R42ais Cl. In some cases, R42ais Br. In some cases, R42ais I. In some cases, R42ais cyano. In some cases, R42ais 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, R42ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0292] In some cases, R47ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl. In some cases, R47ais H. In some cases, R47ais halo (e.g., F, Cl, Br or I). In some cases, R47ais F. In some cases, R47ais Cl. In some cases, R47ais Br. In some cases, R47ais I. In some cases, R47ais cyano. In some cases, R47ais 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, R47ais C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0293] In some cases, R18a, R22a, R26a, R34a, R35a, and R48aare each independently H or C1-6alkyl.

[0294] In some cases, R18ais selected from H and C1-6alkyl. In some cases, R18ais H. In some cases, R18ais 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.

[0295] In some cases, R22ais selected from H and C1-6alkyl. In some cases, R22ais H. In some cases, R22ais 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.

[0296] In some cases, R26ais selected from H and C1-6alkyl. In some cases, R26ais H. In some cases, R26ais 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.

[0297] In some cases, R34ais selected from H and C1-6alkyl. In some cases, R34ais H. In some cases, R34ais 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.

[0298] In some cases, R35ais selected from H and C1-6alkyl. In some cases, R35ais H. In some cases, R35ais 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.

[0299] In some cases, R48ais selected from H and C1-6alkyl. In some cases, R48ais H. In some cases, R48ais 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.

[0300] In some cases, R49ais selected from:

[0301] In some cases, R49ais In some cases, R49aisIn some cases, R49ais In some cases, R49ais49aIn some cases, R isIn some cases, R49ais . In some cases, R49ais. In somecases, R49ais In s49a 49aome cases, R is In some cases, R isIn some c49a 49aases, R is In some cases, R isIn somecases, R49aisIn some cases, R49ais. In some cases, R49ais In some cases, R49ais . I49an some cases, R isIn some cases, R49ais.

[0302] In some cases, R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R70a, and R72aare each independently selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are eachindependently selected from halo, cyano, and -OH, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6- membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0303] In some cases, R50ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R50ais 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, R50ais tert-butyl. In some cases, R50ais iso-butyl. In some cases, R50ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R50ais cyclopropyl. In some cases, R50ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R50ais -SCH(CH3)2or -SC(CH3)3. In some cases, R50ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R50ais -OC(CH3)3or -OCH(CH3)2. In some cases, R50ais halo (e.g., F, Cl, Br or I). In some cases, R50ais -OH. In some cases, R50ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R50ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R50ais 3- to 6-membered heterocycloalkyl. In some cases, R50ais 5- to 10-membered heteroaryl.

[0304] In some cases, R51ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R51ais 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, R51ais tert-butyl. In some cases, R51ais iso-butyl. In some cases, R51ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R51ais cyclopropyl. In some cases, R51ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R51ais -SCH(CH3)2or -SC(CH3)3. In some cases, R51ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R51ais -OC(CH3)3or -OCH(CH3)2. In some cases, R51ais halo (e.g., F, Cl, Br or I). In some cases, R51ais -OH. In some cases, R51ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R51ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, -NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R51ais 3- to 6-membered heterocycloalkyl. In some cases, R51ais 5- to 10-membered heteroaryl.

[0305] In some cases, R52ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R52ais 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, R52ais tert-butyl. In some cases, R52ais iso-butyl. In some cases, R52ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R52ais cyclopropyl. In some cases, R52ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R52ais -SCH(CH3)2or -SC(CH3)3. In some cases, R52ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R52ais -OC(CH3)3or -OCH(CH3)2. In some cases, R52ais halo (e.g., F, Cl, Br or I). In some cases, R52ais -OH. In some cases, R52ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R52ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R52ais 3- to 6-membered heterocycloalkyl. In some cases, R52ais 5- to 10-membered heteroaryl.

[0306] In some cases, R53ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6 alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R53ais 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, R53ais tert-butyl. In some cases, R53ais iso-butyl. In some cases, R53ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R53ais cyclopropyl. In some cases, R53ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R53ais -SCH(CH3)2or -SC(CH3)3. In some cases, R53ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R53ais -OC(CH3)3or -OCH(CH3)2. In some cases, R53ais halo (e.g., F, Cl, Br or I). In some cases, R53ais -OH. In some cases, R53ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R53ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R53ais 3- to 6-membered heterocycloalkyl. In some cases, R53ais 5- to 10-membered heteroaryl.

[0307] In some cases, R54ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R54ais 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, R54ais tert-butyl. In some cases, R54ais iso-butyl. In some cases, R54ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R54ais cyclopropyl. In some cases, R54ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R54ais -SCH(CH3)2or -SC(CH3)3. In some cases, R54ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R54ais -OC(CH3)3or -OCH(CH3)2. In some cases, R54ais halo (e.g., F, Cl, Br or I). In some cases, R54ais -OH. In some cases, R54ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R54ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R54ais 3- to 6-membered heterocycloalkyl. In some cases, R54ais 5- to 10-membered heteroaryl.

[0308] In some cases, R55ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R55ais 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, R55ais tert-butyl. In some cases, R55ais iso-butyl. In some cases, R55ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R55ais cyclopropyl. In some cases, R55ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R55ais -SCH(CH3)2or -SC(CH3)3. In some cases, R55ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R55ais -OC(CH3)3or -OCH(CH3)2. In some cases, R55ais halo (e.g., F, Cl, Br or I). In some cases, R55ais -OH. In some cases, R55ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R55ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R55ais 3- to 6-membered heterocycloalkyl. In some cases, R55ais 5- to 10-membered heteroaryl.

[0309] In some cases, R56ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R56ais 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, R56ais tert-butyl. In some cases, R56ais iso-butyl. In some cases, R56ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R56ais cyclopropyl. In some cases, R56ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R56ais -SCH(CH3)2or -SC(CH3)3. In some cases, R56ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R56ais -OC(CH3)3or -OCH(CH3)2. In some cases, R56ais halo (e.g., F, Cl, Br or I). In some cases, R56ais -OH. In some cases, R56ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R56ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R56ais 3- to 6-membered heterocycloalkyl. In some cases, R56ais 5- to 10-membered heteroaryl.

[0310] In some cases, R57ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6 alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R57ais 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, R57ais tert-butyl. In some cases, R57ais iso-butyl. In some cases, R57ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R57ais cyclopropyl. In some cases, R57ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R57ais -SCH(CH3)2or -SC(CH3)3. In some cases, R57ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R57ais -OC(CH3)3or -OCH(CH3)2. In some cases, R57ais halo (e.g., F, Cl, Br or I). In some cases, R57ais -OH. In some cases, R57ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R57ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R57ais 3- to 6-membered heterocycloalkyl. In some cases, R57ais 5- to 10-membered heteroaryl.

[0311] In some cases, R70ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6 alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R70ais 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, R70ais tert-butyl. In some cases, R70ais iso-butyl. In some cases, R70ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl,cycloconyl, or cyclodecyl. In some cases, R70ais cyclopropyl. In some cases, R70ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R70ais -SCH(CH3)2or -SC(CH3)3. In some cases, R70ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R70ais -OC(CH3)3or -OCH(CH3)2. In some cases, R70ais halo (e.g., F, Cl, Br or I). In some cases, R70ais -OH. In some cases, R70ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R70ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R70ais 3- to 6-membered heterocycloalkyl. In some cases, R70ais 5- to 10-membered heteroaryl.

[0312] In some cases, R72ais selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl. In some cases, R72ais 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, R72ais tert-butyl. In some cases, R72ais iso-butyl. In some cases, R72ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R72ais cyclopropyl. In some cases, R72ais -SC1-6alkyl, such as -SCH3, -SCH2CH3, -S(CH2)2CH3, -S(CH2)3CH3, -S(CH2)4CH3, -S(CH2)5CH3, and the like. In some cases, R72ais -SCH(CH3)2or -SC(CH3)3. In some cases, R72ais -OC1-6alkyl, such as - OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R72ais -OC(CH3)3or -OCH(CH3)2. In some cases, R72ais halo (e.g., F, Cl, Br or I). In some cases, R72ais -OH. In some cases, R72ais -OC3-6cycloalkyl, such as -O-cyclopropyl, -O- cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl. In some cases, R72ais -NHC(O)C1-6alkyl, such as -NHC(O)CH3, -NHC(O)CH2CH3, -NHC(O)(CH2)2CH3, -NHC(O)(CH2)3CH3, - NHC(O)(CH2)4CH3, -NHC(O)(CH2)5CH3, and the like. In some cases, R72ais 3- to 6-membered heterocycloalkyl. In some cases, R72ais 5- to 10-membered heteroaryl.

[0313] In some cases, where R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R70a, or R72ais C1-6 alkyl, the C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, and -OH. In some cases, C1-6alkyl is substituted with 1 to 3 halo substituents. For example, R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R70a, or R72acan be -CF3, - CHF2, -CH2F, and the like. In some cases, C1-6alkyl is substituted with 1 to 3 cyano substituents. In some cases, C1-6alkyl is substituted with 1 to 3 -OH substituents.

[0314] In some cases, where R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R70a, or R72ais C3-10 cycloalkyl, the C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl. In some cases, the C3-10cycloalkyl is substitutedwith 1 or 2 cyano substituents. In some cases, the C3-10cycloalkyl is substituted with 1 or 2 C1-6alkyl substituents, 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.

[0315] In some cases, where R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R70a, or R72ais - OC1-6alkyl, the -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo. In some cases, -OC1-6alkyl is substituted with 1 to 3 halo substituents (e.g., F, Cl, Br or I).

[0316] In some cases, where R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R70a, or R72ais 3- to 6-membered heterocycloalkyl, the 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, 3- to 6-membered heterocycloalkyl is substituted with 1 or 2 C1-6alkyl substituents, 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.

[0317] In some cases, R58a, R59a, and R60aare each independently C1-6alkyl optionally substituted with 1 to 3 substituents that are each independently halo.

[0318] In some cases, R58ais C1-6alkyl. In some cases, R58ais C1-6alkyl substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). For example, R58acan be -CF3, -CHF2, -CH2F, and the like.

[0319] In some cases, R59ais C1-6alkyl. In some cases, R59ais C1-6alkyl substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). For example, R59acan be -CF3, -CHF2, -CH2F, and the like.

[0320] In some cases, R60ais C1-6alkyl. In some cases, R60ais C1-6alkyl substituted with 1 to 3 substituents that are each independently halo (e.g., F, Cl, Br or I). For example, R60acan be -CF3, -CHF2, -CH2F, and the like.

[0321] In some cases, R61aand R62aare each independently C1-6alkyl optionally substituted with 1 or 2 substituents that are each independently selected from C3-6cycloalkyl and cyano.

[0322] In some cases, R61ais C1-6alkyl. In some cases, R61ais C1-6alkyl substituted with 1 or 2 substituents that are each independently selected from C3-6cycloalkyl and cyano. In some cases, R61ais substituted with 1 or 2 C3-6cycloalkyl substituents, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R61ais substituted with 1 or 2 cyano substituents.

[0323] In some cases, R62ais C1-6alkyl. In some cases, R62ais C1-6alkyl substituted with 1 or 2 substituents that are each independently selected from C3-6cycloalkyl and cyano. In some cases, R62ais substituted with 1 or 2 C3-6cycloalkyl substituents, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some cases, R62ais substituted with 1 or 2 cyano substituents.

[0324] In some cases, R63a, R64a, R65a, R66a, R67a, and R68aare each independently selected from H and C1-6alkyl.

[0325] In some cases, R63ais selected from H and C1-6alkyl. In some cases, R63ais H. In some cases, R63ais 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.

[0326] In some cases, R64ais selected from H and C1-6alkyl. In some cases, R64ais H. In some cases, R64ais 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.

[0327] In some cases, R65ais selected from H and C1-6alkyl. In some cases, R65ais H. In some cases, R65ais 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.

[0328] In some cases, R66ais selected from H and C1-6alkyl. In some cases, R66ais H. In some cases, R66ais 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.

[0329] In some cases, R67ais selected from H and C1-6alkyl. In some cases, R67ais H. In some cases, R67ais 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.

[0330] In some cases, R68ais selected from H and C1-6alkyl. In some cases, R68ais H. In some cases, R68ais 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.

[0331] In some cases, R69aand R73aare each independently selected from C1-6alkyl, C3-10cycloalkyl, and -OC1-6alkyl, wherein C1-6alkyl is optionally substituted with cyano, and C3-10cycloalkyl is optionally substituted with cyano.

[0332] In some cases, R69ais selected from C1-6alkyl, C3-10cycloalkyl, and -OC1-6alkyl. In some cases, R69ais 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, R69ais C3-10cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, cycloconyl, or cyclodecyl. In some cases, R69ais -OC1-6alkyl, such as -OCH3, -OCH2CH3, - O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, and the like. In some cases, R69ais - OC(CH3)3or -OCH(CH3)2. In some cases, where R69ais C1-6alkyl, the C1-6alkyl is substituted with cyano. In some cases, where R69ais C3-10cycloalkyl, the C3-10cycloalkyl is substituted with cyano.

[0333] In some cases, R71ais 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.

[0334] In some cases, the compound of Formula (III) is not selected from:

[0335] In certain embodiments, the compound is selected from: Formula (IIIa):; Formula (IIIb):; Formula (IIIc):Formula; Formula (IIIf):and Formula wherein each of Xa, R1a, R2a, R3a, R4a, R6a, R7a, R8a, R9a,R10a, R11a, R12a, R13a, R49a, m, n, p,and Bb is as defined herein.

[0336] In certain embodiments, the compound is a compound of Formula (IIIa):wherein each of Xa, R1a, R2a, R3a, R4a, R49a, m, andis as defined herein.

[0337] In certain embodiments, the compound is a compound of Formula (IIIb):wherein each of R6a, R7a, R8a, R9a, R10a, R11a, R49a, n, p, andis as defined herein.

[0338] In certain embodiments, the compound is a compound of Formula (IIIc):wherein each of R49a,and Bb is as defined herein.

[0339] In certain embodiments, the compound is a compound of Formula (IIIe):a compound of Formula (IIIf):wherein each of R12a, R13a, R49aandis as defined herein.

[0340] In certain embodiments, the compound is a compound of Formula (IIIg):wherein each of R49aand is as defined herein.

[0341] In certain embodiments,is moiety Ya1:wherein each of R14a, R15a, R16a, R17aand R18ais as defined herein.

[0342] In certain embodiments,is moiety Ya2:, wherein each of R19a, R20a, R21a, and R22ais as defined herein.

[0343] In certain embodiments,is moiety Ya3:wherein each of R23a, R24a, R25a, and R26ais as defined herein.

[0344] In certain embodiments,is moiety Ya4: ein each of R27a, R28a, R2wher9a, and R30ais as defined herein.

[0345] In certain embodiments,is moiety Ya5:wherein each of R31a, R32a, R33a, and R34ais as defined herein.

[0346] In certain embodiments,is moiety Ya6:wherein each of R35a, R36a, R37a, and R38ais as defined herein.

[0347] In certain embodiments,is moiety Ya7: wherein each of R39a, R40a, R41a, and R42ais as defined herein.

[0348] In certain embodiments, is moiety Ya8:, where each of R43a, R44a, R45a, R46a, R47a, and R48ais as defined herein.

[0349] In certain embodiments, R49ais selected fromwherein each of R50a, R69a, R70a, R71a, R72a,73aand R is as defined herein.

[0350] In certain embodiments, R49ais50awherein R is as defined herein.

[0351] In certain embodiments, R49ais selected fromwherein each of R51a, R52a, R53a, R54a, R55a, R56aand R57ais as defined herein.

[0352] In certain embodiments, R49ais51awherein R is as defined herein.

[0353] In certain embodiments, R49ais selected fromwherein each of R58a, R59a, R60a, R61a, and R62ais as defined herein.

[0354] In certain embodiments, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0355] Aspects of the present disclosure also include a compound selected from:or a pharmaceutically acceptable salt thereof.

[0356] Aspects of the present disclosure also include a compound selected from:or a pharmaceutically acceptable salt thereof.

[0357] Aspects of the present disclosure also include a compound selected from:or a pharmaceutically acceptable salt thereof.

[0358] Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound: or a pharmaceutically acceptable salt thereof. Aspects of the presentdisclosure also include the compound:or a pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceutically acceptable salt thereof. Aspects of the present disclosure also include the compound:pharmaceuticallyacceptable salt thereof. Aspects of the present disclosure also include the compound:or a pharmaceutically acceptable salt thereof.

[0359] Aspects of the present disclosure include a compound of Formula (IVd):or a pharmaceutically acceptable salt thereof, wherein:is as defined herein; and R49ais selected from:wh51a 52a 53a 54a 55a 56a 57aerein: R , R , R , R , R , R , and R are each independently selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, - NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, and -OH, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6- membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases,14awherein: R is selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R15ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R16ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R17ais selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R18ais H orC1-6alkyl. In some cases, R49ais where51ain R is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6- membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, and - OH, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl. In some cases, R51ais C1-6alkyl optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, and -OH.

[0360] 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.

[0361] 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.

[0362] 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

[0363] 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.

[0364] In certain embodiments, the compounds of the present disclosure are useful for prevention or treatment of diseases or conditions in mammals, including humans, in instances where 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.

[0365] 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.

[0366] 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.

[0367] Aspects of the present disclosure include a method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: A is selected from: (1) -(CR1R2)m-X-(CR3R4)-, wherein: R1and R2are each independently selected from H, halo and C1-6alkyl; R3and R4are each independently selected from H, halo and C1-6alkyl, or R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl;m is 0 or 1; and X is selected from S, SO, SO2, O, and NH; (2) -(CR6R7)n-CR8R9-(CR10R11)p-, wherein: R6and R7are each independently H or C1-6alkyl; R8and R9are each independently halo or C1-6alkyl, or R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl; R10and R11are each independently H or C1-6alkyl; n is 0 or 1; and p is 0 or 1; (3)wherein B is a C3-6cycloalkyl; (4) -CH2CH2-; (5) -CH2CHR12-, wherein R12is C1-6alkyl; (6) -CHR13CH2-, wherein R13is C1-6alkyl; and (7) -CH2CH2CH2-;is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:wherein: R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, - N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), - SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, - S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), - SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, - S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, - N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), - SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, - S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionallysubstituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, - N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), - SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, - S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; each Rais independently selected from F, cyano, -OH, C3-4cycloalkyl, 3- to 5- membered heterocycloalkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, - C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, - NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl; each Rbis independently selected from F, cyano, -OH, oxo (=O), C1-3alkyl, - C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3 alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-3alkyl is optionally substituted with -OC1-3alkyl; each Rcis independently selected from F, cyano, -OH, oxo (=O), C1-3alkyl, - C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3 alkyl)2, -NH2, -NHC1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-3alkyl is optionally substituted with -OC1-3alkyl;R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently selected from H, -OH, and C1-6alkyl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from F, cyano, -OH, -OC1-3alkyl, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -SH, and -SC1-3alkyl;wherein: R72is H or -CH3; R73is H of -CH3; R74and R75are each independently selected from H, F, and -CH3; X1is O, S, or NR76, wherein R76is H or -CH3; and R77is of the formula (a), (b), or (c):wherein: X2, X3, X4, X5, and X6are each independently selected from C and N, wherein at least one of X2, X3, X4, X5, and X6is N; R78is absent, H, or F; R79, R80, and R81are each independently absent or selected from H, halo, cyano, - OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10- membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, - C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, - N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, R82is absent, H, or F; and wherein at least one of the following (a), (b), and (c) is present: (a) R78is F; (b) at least one of R79, R80, and R81is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, - C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted - S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6-membered heterocycloalkyl); and (c) R82is F; wherein when R77is of the formula (a) and R81is substituted phenyl, then R81is not substituted with 2 -OC1-3alkyl; R83is H or F; R84, R85, and R86are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, - N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, and R87is H or F; and wherein at least one of the following (d), (e), and (f) is present: (d) R83is F; (e) at least one of R84, R85, and R86is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, - C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, - NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted - S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6-membered heterocycloalkyl); and (f) R87is F; orwherein R83is H, R84is H, R87is H, and R85and R86together with the ring atoms to which they are attached form a C4-6cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein C4-6cycloalkyl is optionally substituted with 1 to 4 substituents that are each independently C1-6alkyl, and 4- to 6-membered heterocycloalkyl is optionally substituted with 1 to 4 substituents that are each independently selected from C1-6alkyl and oxo (=O); X7is C or N; X8, X9, X10, and X11are each independently selected from C, N, S, and O, wherein at least one of X7, X8, X9, X10, and X11is N, S, or O; and R88, R89, R90, and R91are each independently absent or selected from H, halo, cyano, -OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, - C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6- membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, - O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, and wherein at least one of R88, R89, R90, and R91is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3 alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted -S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6-membered heterocycloalkyl), each Rdis independently selected from F, cyano, -OH, C3-4cycloalkyl, 3- to 5- membered heterocycloalkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, - C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, - NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl; each of Reis independently selected from F, cyano, -OH, oxo (=O), C1-6alkyl, - C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3 alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-6alkyl is optionally substituted with -OC1-3alkyl; each Rfis independently selected from F, cyano, -OH, oxo (=O), C1-6alkyl, - C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3 alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-6alkyl is optionally substituted with -OC1-3alkyl; each Rgis independently selected from F, cyano, -OH, C1-6alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl; each Rhis independently selected from F, cyano, -OH, C1-6alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl; and

[0368] In Formula (II), each of A, B, L, X, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, , Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, Y15, R1, R2, R3, R4, 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, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh, m, n, and p are as defined herein.

[0369] In some cases, the compound is selected from:

[0370] In some cases, the compound is a compound of Formula (IIA):wherein each of L,1 2 3 4 77 92X, R , R , R , R , R , R , m, andis as defined herein. In some cases, m is 0. In some cases, m is 1. In some cases, R1and R2are each independently selected from H, F, and methyl. In some cases, X is selected from S, SO, SO2, and O. In some cases, X is selected from S, SO, and SO2. In some cases, X is S. In some cases, X is SO. In some cases, X is SO2. In some cases, X is O. In some cases, R3and R4are each independently selected from H, F, and methyl. In some cases, R3is methyl. In some cases, R3and R4are each methyl. In some cases, R3and R4are each H. In some cases, R3and R4are each halo. In some cases, R3and R4are each F. In some cases, R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl. In some cases, R3and R4together with the carbon atom to which they are attached form cyclopropyl.

[0371] In some cases, the compound is a compound of Formula (IIB): wherein each of6 7 8 9 10 11L, R , R , R , R , R , R , R77, R92, n, p, andis as defined herein. In some cases, n is 1 and p is 0. In some cases, R8and R9are each independently selected from F and methyl. In some cases, R8and R9are each methyl. In some cases, R8and R9are each halo. In some cases, R8and R9are each F. In some cases, R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl. In some cases, R8and R9together with the carbon atom to which they are attached form cyclopropyl. In some cases, R6and R7are each independently selected from H and methyl. In some cases, R6and R7are each H.

[0372] In some cases, the compound is a compound of Formula (IIC): wherein each77 92of L, R , R ,and B is as defined herein. In some cases, B is selected from cyclopropyl, cyclobutyl, and bicyclo[1.1.1]pentane.

[0373] In some cases, the compound is a compound of Formula (IID):( ) wherein each of L, R77,92R , andis as defined herein.

[0374] In some cases, the compound is a compound of Formula (IIE):or a compound of Formula (IIF): wherein each of L, R12, R13, R77, R92, andis as defined herein. In some cases, each of R12and R13is methyl.

[0375] In some cases, the compound is a compound of Formula (IIG): wherein each of L, R77, R92, andis as defined herein.

[0376] In some cases, R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently H or C1-6alkyl. In some cases, R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; and R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently H or methyl.

[0377] In some cases, is moiety Y1: wherein each ofR14, R15, R16, R17and R18is as defined herein. In some cases, R14is H, R15is H, F, cyano or methyl, R16is H or F, R17is H, and R18is H. In some cases, each of R14, R15, R16, R17, and R18is H. In some cases, R14is H, R15is F, R16is H, R17is H, and R18is H. In some cases, R14is H, R15is H, R16is F, R17is H, and R18is H.

[0378] In some cases, is moiety Y2: wherein each ofR19, R20, R21, and R22is as defined herein. In some cases, R19is H, R20is H, F, cyano or methyl, R21is H, and R22is H. In some cases, each of R19, R20, R21, and R22is H.

[0379] In some cases, is moiety Y3:wherein each of R23, R24, R25, and R26is as defined herein. In some cases, each of R23, R24, R25, and R26is H.

[0380] In some cases, is moiety Y4:wherein each of R27, R28, R29, and R30is as defined herein. In some cases, each of R27, R28, R29, and R30is H.

[0381] In some cases, is moiety Y5: wherein each of 31 32R , R , R33, and R34is as defined herein.

[0382] In some cases,is moiety Y6: wherein each ofR35, R36, R37, and R38is as defined herein.

[0383] In some cases,is moiety Y7: wherein each ofR39, R40, R41, and R42is as defined herein.

[0384] In some cases,is moiety Y8where each of R43, R44, R45, R46, R47, and R48is as defined herein.

[0385] In some cases,moiety Y9:wherein each of R49, R50, R51and R52is as defined herein. In some cases, each of R49, R50, R51and R52is H.

[0386] In some cases,is moiety Y10: wherein each ofR53, R54and R55is as defined herein.

[0387] In some cases,moiety Y11: wherein each of 56 57 58R , R and R is as defined herein.

[0388] In some cases, is moiety Y12: , wherein each of R59, R60and R61is as defined herein.

[0389] In some cases, is moiety Y13: , wherein each of R62, R63and R64is as defined herein.

[0390] In some cases, is moiety Y14: , wherein each of R65, R66, R67and R68is as defined herein.

[0391] In some cases,is moiety Y15: , wherein each of R69, R70and R70is as defined herein.

[0392] In some cases, L is a single bond, , , or , wherein R72is H. In some cases, L is a single bond.

[0393] In some cases, R77is selected from , , , and , wherein each of R84, R85, and R86are as defined herein. In some cases, R77is, wherein R86is as defined herein. In some cases, R77is , wherein R86is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0394] In some cases, R77is selected from , , , , , , and , wherein R81is as defined herein. In some cases, R77is or , wherein R81is as defined herein. In some cases, R81is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0395] In some cases, R77is selected from , , , , and , wherein R90is as defined herein. In some cases, R90is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, - NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independentlyselected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

[0396] In some cases, R77is selected from:

[0397] In some cases, R77is selected from:

[0398] In some cases, R92is -C(O)OH.

[0399] In some cases, the compound is selected from:pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable saltthereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In somecases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound isor a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable saltthereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In somecases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound isor a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof. In some cases, the compound is or a pharmaceutically acceptable salt thereof.

[0400] Aspects of the present disclosure include, a method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound selected from:or a pharmaceutically acceptable salt thereof.

[0401] Aspects of the present disclosure include a method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein:Aa is selected from: (1) -(CR1aR2a)m-Xa-(CR3aR4a)-, wherein: R1aand R2aare each independently selected from H, halo and C1-6alkyl; R3aand R4aare each independently selected from H, halo and C1-6alkyl, or R3aand R4atogether with the carbon atom to which they are attached form a C3-6cycloalkyl; m is 0 or 1; and Xa is selected from S, SO, and SO2, O, and NH; (2) -(CR6aR7a)n-CR8aR9a-(CR10aR11a)p-, wherein: R6aand R7aare each independently H or C1-6alkyl; R8aand R9aare each independently halo or C1-6alkyl, or R8aand R9atogether with the carbon atom to which they are attached form a C3-6cycloalkyl; R10aand R11aare each independently H or C1-6alkyl; n is 0 or 1; and p is 0 or 1; (3) , wherein Bb is a C3-6cycloalkyl; (4) -CH2CH2-; (5) -CH2CHR12a-, wherein R12ais C1-6alkyl; (6) -CHR13aCH2-, wherein R13ais C1-6alkyl; and (7) -CH2CH2CH2-; is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, and Y8:wherein: R14a, R19a, R23a, R27a, R39a, R43a, and R44aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R15a, R20a, R24a, R28a, R31a, R36a, R40a, and R45aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R16a, R25a, R29a, R32a,R37a, R41a, and R46aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R17a, R21a, R30a, R33a, R38a, R42a, and R47aare each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R18a, R22a, R26a, R34a, R35a, and R48aare each independently H or C1-6alkyl; and R49ais selected from: wherein: R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R70a, and R72aare eachindependently selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10- membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, and -OH, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl; R58a, R59a, and R60aare each independently C1-6alkyl optionally substituted with 1 to 3 substituents that are each independently halo; R61aand R62aare each independently C1-6alkyl optionally substituted with 1 or 2 substituents that are each independently selected from C3-6cycloalkyl and cyano; R63a, R64a, R65a, R66a, R67a, and R68aare each independently selected from H and C1-6alkyl; R69aand R73aare each independently selected from C1-6alkyl, C3-10cycloalkyl, and -OC1-6alkyl, wherein C1-6alkyl is optionally substituted with cyano, and C3-10cycloalkyl is optionally substituted with cyano; and R71ais C1-6alkyl.

[0402] In Formula (V), each of Aa, Bb, Xa, , Ya1, Ya2, Ya3, Ya4, Ya5, Ya6, Ya7, Ya8, R1a, R2a, R3a, R4a, R6a, R7a, R8a, R9a, R10a, R11a, R12a, R13a, R14a, R15a, R16a, R17a, R18a,R19a, R20a, R21a, R22a, R23a, R24a, R25a, R26a, R27a, R28a, R29a, R30a, R31a, R32a, R33a, R34a, R35a, R36a, R37a, R38a, R39a, R40a, R41a, R42a, R43a, R44a, R45a, R46a, R47a, R48a, R49a, R50a, R51a, R52a, R53a, R54a, R55a, R56a, R57a, R58a, R59a, R60a, R61a, R62a, R63a, R64a, R65a, R66a, R67a, R68a, R69a, R70a, R71a, R72a, R73a, m, n, and p are as defined herein.

[0403] In certain embodiments, the compound is selected from: Formula (Va): ; Formula (Vb): ; Formula (Vc): ; Formula (Vd): ; Formula (Ve): ; Formula (Vf): ; and Formula (Vg): , wherein each of Xa, R1a, R2a, R3a, R4a, R6a, R7a, R8a, R9a, R10a, R11a, R12a, R13a, R49a, m, n, p, , and Bb is as defined herein.

[0404] In certain embodiments, the compound is a compound of Formula (Va): (Va), wherein each of Xa, R1a, R2a, R3a, R4a, R49a, m, and is as defined herein.

[0405] In certain embodiments, the compound is a compound of Formula (Vb):(Vb), wherein each of R6a, R7a, R8a, R9a, R10a, R11a, R49a, n, p, and is as defined herein.

[0406] In certain embodiments, the compound is a compound of Formula (Vc): (Vc), wherein each of R49a, , and Bb is as defined herein.

[0407] In certain embodiments, the compound is a compound of Formula (Vd): (Vd), wherein each of R49aand is as defined herein.

[0408] In certain embodiments, the compound is a compound of Formula (Ve): (Ve), or a compound of Formula (Vf): (Vf), wherein each of R12a, R13a, R49aand is as defined herein.

[0409] In certain embodiments, the compound is a compound of Formula (Vg): (Vg), wherein each of R49aand is as defined herein.

[0410] In certain embodiments, is moiety Ya1: , wherein each of R14a, R15a, R16a, R17aand R18ais as defined herein.

[0411] In certain embodiments,is moiety Ya2:, wherein each of R19a, R20a, R21a, and R22ais as defined herein.

[0412] In certain embodiments,is moiety Ya3:, wherein each of R23a, R24a, R25a, and R26ais as defined herein.

[0413] In certain embodiments,is moietywherein each of R27a, R28a, R29a, and R30ais as defined herein.

[0414] In certain embodiments,is moietywherein each of R31a, R32a, R33a, and R34ais as defined herein.

[0415] In certain embodiments,is moietywherein each of R35a, R36a, R37a, and R38ais as defined herein.

[0416] In certain embodiments,is moietywherein each of R39a, R40a, R41a, and R42ais as defined herein.

[0417] In certain embodiments, is moiety Ya8: 43a 44a 45a 46a 47a 48awhere each of R , R , R , R , R , and R is as defined herein.

[0418] In certain embodiments, R49ais selected from , , R71aR70a, and , wherein each of R50a, R69a, R70a, R71a, R72a, and R73ais as defined herein.

[0419] In certain embodiments, R49ais , wherein R50ais as defined herein.

[0420] In certain embodiments, R49ais selected from , , , , , , , wherein each of R51a, R52a, R53a, R54a, R55a, R56aand R57ais as defined herein.

[0421] In certain embodiments, R49ais , wherein R51ais as defined herein.

[0422] In certain embodiments, R49ais selected from , , , , , wherein each of R58a, R59a, R60a, R61a, and R62ais as defined herein.

[0423] In certain embodiments, the compound is selected from:

[0424] In certain embodiments, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IIA) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IIB) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IIC) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IID) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IIE) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IIF) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (IIG) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject.

[0425] In certain embodiments, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (V) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Va) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Vb) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject inneed thereof a therapeutically effective amount of a compound of Formula (Vc) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Vd) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ve) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Vf) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject. In some cases, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Vg) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject.

[0426] 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.

[0427] 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)).

[0428] In certain embodiments, the disease or disorder is fibrodysplasia ossificans progressiva (FOP).

[0429] In certain embodiments, the disease or disorder is multiple osteochondromas.

[0430] 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.

[0431] In certain embodiments, the disease or disorder is selected from conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, cicatricial conjunctival disorders (including 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.

[0432] In certain embodiments, the disease or disorder is meibomian gland dysfunction.

[0433] In certain embodiments, the disease or disorder is dry eye disease.

[0434] In certain embodiments, the disease or disorder is evaporative dry eye disease.

[0435] Aspects of the present disclosure also include a method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound selected from:or a pharmaceutically acceptable salt thereof.

[0436] In certain embodiments, the contacting comprises administering to a subject in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject.

[0437] 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.

[0438] 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)).

[0439] In certain embodiments, the disease or disorder is fibrodysplasia ossificans progressiva (FOP).

[0440] In certain embodiments, the disease or disorder is multiple osteochondromas.

[0441] 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.

[0442] In certain embodiments, the disease or disorder is selected from conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, cicatricial conjunctival disorders (including 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.

[0443] In certain embodiments, the disease or disorder is meibomian gland dysfunction.

[0444] In certain embodiments, the disease or disorder is dry eye disease.

[0445] In certain embodiments, the disease or disorder is evaporative dry eye disease. Methods of Treatment

[0446] 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, providedare 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.

[0447] 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.

[0448] 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.

[0449] 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.

[0450] 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 thecompounds 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.

[0451] 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.

[0452] 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.

[0453] 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).

[0454] In certain embodiments, the disease or disorder may be fibrodysplasia ossificans progressiva (FOP).

[0455] 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.

[0456] 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. 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 topicalmedications), vitamin A deficiency, pterygia, pingueculae, cicatricial pemphigoid, atopic kerato- conjunctivitis and Sjogren syndrome related conjunctival injury.

[0457] In certain embodiments, the disease or disorder may be related to eyelid and selected from meibomian gland dysfunction, blepharitis, hordeola, chalazia and eyelid neoplasms.

[0458] In certain embodiments, the disease or disorder may be meibomian gland dysfunction.

[0459] 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.

[0460] In certain embodiments, the disease or disorder may be dry eye disease.

[0461] In certain embodiments, the disease or disorder may be aqueous deficient dry eye disease or evaporative dry eye disease.

[0462] In certain embodiments, the disease or disorder may be evaporative dry eye disease.

[0463] In certain embodiments, the disease or disorder may be related to uvea and selected from uveitis.

[0464] 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.

[0465] 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.

[0466] 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.

[0467] 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’).

[0468] 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.

[0469] 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. 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.

[0470] Methods of the present disclosure may include a method of treating meibomian gland dysfunction, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a CYP26B1 inhibitor or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat meibomian gland dysfunction in the subject. Pharmaceutical Compositions

[0471] 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.

[0472] 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.

[0473] 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 therapeuticadministration. 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.

[0474] 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.

[0475] 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.

[0476] 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.

[0477] 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.

[0478] 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.

[0479] 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.

[0480] 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

[0481] 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.

[0482] 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, a therapeutically 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.

[0483] 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.

[0484] 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.

[0485] 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

[0486] 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” means 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.Example 1: General Synthetic Procedures

[0488] 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 – Fischer Indole Synthesis

[0489] 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 B – Ester Hydrolysis

[0490] 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 C – Boc Protection of Amines

[0491] 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 D – Boc Deprotection of Amines and tert-Butyl Deprotection of Acids

[0492] 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 E – Suzuki Cross-Coupling with Vinyl Boronic Acid Pinacol Esters

[0493] For aryl bromides and iodides: A sealed microwave vial containing aryl halide (1.0 eq), olefinic boronate (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.

[0494] For aryl chlorides: A sealed microwave vial containing aryl chloride (1.0 eq), olefinic boronate (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.

[0495] 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 F – Hydrogenation of Olefins

[0496] A mixture of olefin (1.0 eq) and Pd / C (10% Pd w / w, 0.1 eq) in THF or MeOH under H2(1 atm) was stirred at ambient temperature for 12-24 h. The mixture was passed through a bed of Celite and concentrated. 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 reduced compound. General Procedure G – Hydrazine Synthesis

[0497] To a cold (5 °C) stirring solution of the aniline (1.0 eq) in concentrated HCl was added sodium nitrite (1.05 eq). After stirring for 0.5-1 h, this mixture was added dropwise to a cold (5 °C) stirring solution of dichlorostannane (3.0 eq) in concentrated HCl. After stirring for an additional 0.5-1 h, the desired hydrazine compound precipitated, collected by filtration, washed with H2O and dried in vacuo. If no precipitate resulted, the mixture was concentrated and the crude product was purified via reverse phase automated flash chromatography using ACN / H2O (0.1% TFA) as the mobile phase to give the desired hydrazine compound. General Procedure I – Nitroarene Reduction

[0498] A mixture of nitroarene (1.0 eq), dichlorostannane (4.0 eq) and concentrated HCl was stirred at 90 °C for 0.5-3 h. The mixture was cooled to ambient temperature, neutralized and extracted with EtOAc (3x). The combined organics was washed with H2O and brine, dried over MgSO4, filtered and concentrated. Alternatively, a mixture of nitroarene (1.0 eq), 10% Pd / C (10 mol %) and MeOH was purged with H2gas and stirred at ambient temperature for 2-5 h. The mixture was passed through a bed of Celite, rinsed with MeOH and concentrated. The crude product was purified via automated flash chromatography (normal or reverse phase) usingEtOAc / hexanes, MeOH / CH2Cl2or ACN / H2O (0.1% TFA) as the mobile phase to give the desired amine compound. General Procedure J – Heck Cross-Coupling

[0499] For aryl iodides: A mixture of aryl iodide (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.

[0500] For unsubstituted acrylates: 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.

[0501] For ^-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.

[0502] 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 K – Boronic Ester Formation via Deprotonation with LiTMP or LDA

[0503] 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. 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 1.5 h, 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 L – Suzuki Cross-Coupling with 2-Boryl Indoles

[0504] A sealed microwave vial containing aryl halide (1.0 eq), aryl boronate (1.0 eq), Pd(dppf)Cl2(10-18 mol %), cesium (or sodium) carbonate (3.0-3.4 eq), dioxane and H2O was either stirred at 80 °C for 1-4 h or irradiated with microwaves for 1 h at 80 °C. 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. 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 or EtOAc / hexanes as the mobile phase to give the desired arylated compound. General Procedure M – Cyclopropanation of Olefins

[0505] To a mixture of sodium hydride (60%, 2.0 eq) or potassium tert-butoxide (2.0 eq) in DMSO was added trimethylsulfoxonium iodide (2.0 eq), followed by the addition of a solution of olefin (1.0 eq) in DMSO (0.5 M total). The mixture was stirred at 20-50 °C for 2-16 h before it was diluted with H2O and extracted with EtOAc (3x). The combined organics was dried over MgSO4, filtered and concentrated. The crude product was purified via reverse or normal phase automated flash chromatography using ACN / H2O (0.1% TFA or formic acid) or EtOAc / Petroleum ether as the mobile phase to give the desired cyclopropanated compound. General Procedure N – Oxidative Benzimidazole Formation

[0506] 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 O – Formylation of Aryl Halides

[0507] 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 the mixture was warmed to ambient temperature. After stirring for an additional 15 min, the mixture was quenched with saturated aqueous NaHCO3and extracted with EtOAc (3x). The crude product was purified via automated flash chromatography using CH2Cl2 / hexanes as the mobile phase to give the aldehyde intermediate. General Procedure P – Olefination of Benzaldehydes

[0508] 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 of aldehyde (1.0 eq) in THF was added and the mixture was 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. General Procedure Q – Alkylation of Benzylic Halides with LDA

[0509] Preparation of fresh LDA: To a cold (-78 °C) stirring mixture of 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. To a cold (-78 °C) stirring mixture of LDA (1.55 eq) in THF was added an appropriate ester (1.5 eq) slowly under N2. After stirring cold for 1-4 h, an appropriate benzylic halide (1.0 eq) was slowly added. The resulting mixture was stirred at -78 °C for 2-16 h, poured into sat’d aq NH4Cl and extracted with EtOAc (2x). The combined organics was washed with H2O, dried over MgSO4, filtered and concentrated. The crude product was purified via automated flash chromatography using either CH2Cl2 / hexanes or EtOAc / Petroleum ether as the mobile phase to give the desired alkylated compound. General Procedure R – Sonogashira Cross-Coupling

[0510] 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 S – Base-Promoted Cyclization

[0511] 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 U – Base-Promoted Desulfonylation

[0512] A mixture of N-phenylsulfone (1.0 eq), aq. NaOH (5 M, 25 eq), EtOH and THF (1:2 v / v) was stirred at 60 °C. After 2 h, the mixture was poured into H2O and extracted with EtOAc (2x). The combined organics was washed with brine, dried over Na2SO4, filtered, andconcentrated. The crude product was purified via silica gel chromatography using MeOH / CH2Cl2as the mobile phase to give the desired NH compound. General Procedure V – Phenol Formation via Pd-Catalyzed Oxidation of Aryl Halides

[0513] A mixture of aryl bromide (1.0 eq), t-BuBrettPhos-Pd-G3 (5 mol %), t- BuBrettPhos (5 mol %) and potassium hydroxide (3.0 eq) in 1:5 v / v H2O / dioxane was stirred at 80 °C for 16-24 h. The mixture was diluted with H2O and extracted with EtOAc. The crude product was purified via automated flash chromatography using EtOAc / hexanes as the mobile phase to give the desired phenolic compound. General Procedure W – Phenoxide Formation via Alkylation

[0514] Method 1: To a stirring solution of a phenol derivative (1.0 eq) in DMF was added sodium hydride (60%, 1.3 eq). After stirring for 10 min, an alkyl halide (2.0 eq) was added. After stirring for an additional 1-16 h, the mixture was quenched with saturated aqueous NaHCO3and extracted with EtOAc.

[0515] Method 2: To a stirring solution of a phenol derivative (1.0 eq) and an alkyl halide (2.6 eq) in DMF was added potassium carbonate (2.6 eq). After stirring for 16-48 h, the mixture was diluted with H2O and extracted with EtOAc.

[0516] The crude product was purified via automated flash chromatography using either CH2Cl2 / hexanes or EtOAc / hexanes as the mobile phase to give the desired phenoxide compound. General Procedure X – Aldehydes via Reduction with DIBAL-H

[0517] 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 saturated aqueous NaHCO3(3x), dried over Na2SO4, filtered, and concentrated to give the desired aldehyde which was used without further purification. General Procedure Y – Reduction and Cyclization with Iron

[0518] To a stirring mixture of nitro aldehyde (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 Z – Alcohols via Lewis Acid-Promoted De-methylation

[0519] Using boron tribromide: To a cold (0 °C) stirring solution of methoxide (1.0 eq) in CH2Cl2under N2was added a solution of BBr3(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.

[0520] Using aluminum trichloride: To a cold (0 °C) stirring solution of methoxide (1.0 eq) in CH2Cl2under N2was slowly added AlCl3(10.0 eq) followed by propane-1-thiol (10.0 eq). The mixture was stirred cold for 1-3 h and then poured over ice. After stirring for an additional 20 min, the mixture was treated with Na2CO3(until pH >7) and extracted with EtOAc (3x). The combined organics were dried over MgSO4, filtered, and concentrated.

[0521] 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 AA – Aryl Fluorides via Lithium-Halogen Exchange

[0522] To a cold (-78 °C) stirring mixture of bromoindole (1.0 eq) in THF was slowly added n-BuLi (2.5 M hexanes, 1.1 eq) under N2. After stirring cold for 5 min, N- fluorobenzenesulfonimide (2.0 eq) was added. The resulting mixture was stirred at -78 °C for 2 h, poured into saturated aqueous NH4Cl and extracted with EtOAc (2x). The combined organics was washed with brine (2x), 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 aryl fluoride.General Procedure BB – Boronic Ester Formation via [Pd] Cross-Coupling

[0523] To a stirring mixture of aryl bromide (1.0 eq) and 4,4,4’,4’,5,5,5’,5’-octamethyl- 2,2’-bi(1,3,2-dioxaborolane) (1.5 eq) in dioxane under N2was added potassium acetate (3.0 eq). After stirring for 15 min, Pd(dppf)Cl2(10 mol %) was added and stirred at 80 °C for 2-24 h. The mixture was concentrated and either used in the next step without purification or the crude product was purified via automated flash chromatography using EtOAc / hexanes as the mobile phase to give the desired boronic ester. General Procedure CC – Phenol Formation via Oxidation with Peroxide

[0524] A mixture of boronic ester (1.0 eq), hydrogen peroxide (30% v / v, 2.0 eq) and sodium bicarbonate (2.0 eq) in 5:2 v / v ACN / H2O was stirred at ambient temperature. After 2 h, the mixture was quenched with aq 1M Na2S2O3and extracted with EtOAc. The crude product was purified via automated flash chromatography using EtOAc / hexanes as the mobile phase to give the desired hydroxyindole. General Procedure DD – Suzuki Cross-Coupling with 2-Boryl-5-bromoindoles

[0525] To a solution of 5-bromo-2-indolylboronic acid (1.5 eq) and aryl halide (1.0 eq) in t-BuOH was added aq. K2CO3(1.5 M, 3.5 eq.) and Pd(dppf)Cl2(5 mol %). The reaction was stirred at 50 °C for 3 h (conventionally or with microwave irradiation), diluted with brine, and extracted with EtOAc (3x). The combined organics was dried over MgSO4, filtered, andconcentrated. The crude product was purified via automated flash chromatography using EtOAc / hexanes as the mobile phase to give the desired product. General Procedure EE – [Pd] Cross-Coupling with Thioglycolate

[0526] A microwave vial was charged with aryl halide or aryl triflate (1.0 eq), methyl (or ethyl) thioglycolate (5.0 eq), Pd2(dba)3(7.5-20 mol %), XantPhos (15-40 mol %) and Hunig’s base (5.0 eq) under N2. The resulting dark brown solution was irradiated with microwaves for 1 h at 100–130 °C. The reaction was then filtered through a bed of Celite, concentrated and purified using automated flash column chromatography using EtOAc / CH2Cl2or Et2O / hexanes as the mobile phase to give the desired sulfide. General Procedure FF – Dimethylation of ^-Methylenes

[0527] To a cold (5 °C for NaH and -78 °C for LiHMDS) stirring solution of a methylene reagent (1.0 eq) in DMF or THF was added sodium hydride (60%, 2.1 eq) or LiHMDS (1.0 M in THF, 2.0 eq), respectively, under N2. After 10 min, methyl iodide (5.0 eq) was added slowly to the reaction. The resulting solution was stirred for 1-5 h while slowly warming to ambient temperature. The reaction was quenched with cold H2O and extracted with Et2O or EtOAc (3x). The crude product was purified via automated flash column chromatography using Et2O / hexanes or EtOAc / hexanes as the mobile phase to give the desired dimethylated compound. General Procedure GG – Triflation of Alcohols

[0528] 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 atambient 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 HH – Suzuki Cross-Coupling of 2-Borylindoles with Aryl and Azole Halides

[0529] For aryl halides: A sealed microwave vial containing aryl halide (2.0 eq), boronic acid (1.0 eq), Pd(PPh3)2Cl2(5 mol %), potassium carbonate (3.5 eq), t-BuOH and H2O (1:1 v / v) was irradiated with microwaves for 1 h at 80 °C. The reaction mixture was concentrated.

[0530] For azole halides: A mixture of azole halide (1.0 eq), boronic acid (1.0 eq), Pd(PPh3)4(5 mol %), aq. Na2CO3(1.2 M, 2.5 eq), LiCl (4.0 eq) in toluene and EtOH (2:1 v / v) was stirred at 85-90 °C for 16 h (or 1 h with microwave irradiation). The mixture was cooled to ambient temperature and extracted with EtOAc (3x). The combined organics was dried over MgSO4, filtered and concentrated.

[0531] The crude product was purified via automated flash chromatography using Et2O / hexanes or EtOAc / hexanes as the mobile phase to give the desired arylated compound. General Procedure II – Aryl Cyanation via [Pd] Cross-Coupling

[0532] 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 JJ – Sulfoxide Formation via [Pd] Cross-Coupling

[0533] To a solution of indolyl halide (1.0 eq.) in isopropanol was added triethylamine (3.0 eq), DABSO (0.6 eq), Pd(OAc)2(5 mol %) and PAd2Bu (7.5 mol %). Nitrogen was bubbled through the resulting orange-red solution for 10 min before the reaction vessel was sealed and stirred at 75 °C for 16 h. The solution was cooled to ambient temperature, a solution of tert- butylbromoacetate (1.0 eq) or methyl 2,4-dibromobutanoate (1.0 eq.) in DMF was added dropwise. The resulting mixture was stirred at 75 °C for an additional 2 h and then concentrated. The crude product was purified via automated flash column chromatography using Et2O / hexanes as the mobile phase to give the desired sulfoxide compound. General Procedure KK – gem-Dibromo Olefination of Aldehydes

[0534] 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 were 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 LL – Cu-Catalyzed Cyclization of gem-Dibromo Olefins

[0535] A sealed microwave vial containing dibromo olefin (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 MM – Cyanide Hydrolysis and Decarboxylation

[0536] A mixture of alkyl cyanide (1.0 eq) and lithium hydroxide (3.5 eq) in THF and H2O was stirred at 70 or 90 °C. After 16 h, the mixture was concentrated and the crude product was purified via automated reverse phase flash chromatography using ACN / H2O (0.1% formic acid) as the mobile phase to give the desired amide or decarboxylated compound. General Procedure NN – Alkynylation of Aryl Bromides and Chlorides

[0537] A mixture of N-heteroaryl halide (1.0 eq), Pd(PPh3)2Cl2(10 mol %), CuI (10-30 mol %), triethylamine (3.0-6.0 eq) and ethynyl(trimethyl)silane (2.0-4.0 eq) in DMF was stirred at 50-100 °C for 1-16 h under an inert atmosphere. The mixture was filtered through a bed of Celite and concentrated. The residue was dissolved in EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. The crude intermediate was purified via automated flash chromatography using EtOAc / hexanes as the mobile phase to give the silyl alkyne intermediate. The intermediate was dissolved in methanol and treated with potassium carbonate (1.0-3.0 eq). The resulting mixture was stirred at ambient temperature for 10-120 min and concentrated. The residue was dissolved in EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified via automated flash chromatography using EtOAc / hexanes as the mobile phase to give the desired terminal heteroaryl alkyne compound. General Procedure OO – Cu-Free Sonogashira Cross-Coupling

[0538] A mixture of aryl iodide (1.0 eq), aryl alkyne (1.2 eq), XPhos-Pd-G3 (10 mol %), N-cyclohexyl-N-methylcyclohexanamine or Hunig’s base (3.0-6.0 eq) in ACN was stirred at 80 °C under an inert atmosphere. After 3-16 h, the mixture was passed through a bed of Celite andconcentrated. The residue was dissolved in EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified via automated flash chromatography using EtOAc / hexanes as the mobile phase to give the desired coupled compound. General Procedure PP – Amide Formation via HATU Coupling / Activation

[0539] 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 min, an amine (1.0-1.3 eq) was added and stirred at ambient temperature. After 16 h, the mixture was diluted with EtOAc, washed with H2O, sat’d aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated. The crude product was purified via trituration with small amounts of CH2Cl2to afford the desired aminated compound. EXAMPLE 2: SYNTHESES OF COMPOUNDS Scheme 1. Preparation of Compounds T1 and T2.2-(3-(tert-butyl)phenyl)-1H-indole-5-carboxylic acid (T1)

[0540] Prepared according to general procedures A and B starting with 4- hydrazinylbenzoic acid hydrochloride and 1-(3-(tert-butyl)phenyl)ethan-1-one to afford the titled compound in 2% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.46 (s, 1H), 11.89 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 8.5, 1.6 Hz, 1H), 7.70 (dt, J = 7.0, 1.8 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.44 – 7.34 (m, 2H), 7.06 (d, J = 2.0 Hz, 1H), 1.37 (s, 9H). m / z calcd. for C19H19NO2= 293.1. Found [M+H]+= 294.1. 2-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)acetic acid (T2)

[0541] Prepared according to general procedures A and B starting with 2-(4- hydrazinylphenyl)acetic acid hydrochloride and 1-(3-(tert-butyl)phenyl)ethan-1-one to afford the titled compound in 12% yield over two synthetic steps.1H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 11.50 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.67 (dt, J = 7.4, 1.6 Hz, 1H), 7.43 – 7.30 (m, 4H), 7.01 (dd, J = 8.3, 1.6 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 3.59 (s, 2H), 1.36 (s, 9H). m / z calcd. for C20H21NO2= 307.2. Found [M+H]+= 308.1. Scheme 2. Preparation of Compounds T3 and T4.tert-butyl 2-(3-(tert-butyl)phenyl)-5-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (T3-i)

[0542] Prepared according to general procedures A and C starting with 2-(4- hydrazinylphenyl)acetic acid hydrochloride and 1-(3-(tert-butyl)phenyl)ethan-1-one to afford the titled compound in 80% yield over two synthetic steps.1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.5 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.42 (dt, J = 6.4, 1.6 Hz, 2H), 7.35 (dd, J = 8.8, 7.2 Hz, 1H), 7.27 – 7.19 (m, 2H), 6.54 (d, J = 0.7 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.73 (s, 2H), 1.37 (s, 9H), 1.30 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H). 2-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)propanoic acid (T3)

[0543] To a cold (5 °C) stirring solution of ester T3-i (1.0 eq) in DMF was added sodium hydride (60%, 1.3 eq). After stirring for 10 min, iodomethane (1.05 eq) was added. After stirring for an additional 50 min, the mixture was quenched with sat’d aq NaHCO3, extracted with EtOAc, dried over MgSO4, filtered and concentrated. The crude methylated compound was thendeprotected and hydrolyzed using general procedures D and B to afford the titled compound in 13% yield over three synthetic steps.1H NMR (400 MHz, DMSO) δ 11.49 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.66 (dt, J = 7.3, 1.7 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.40 – 7.31 (m, 3H), 7.04 (dd, J = 8.4, 1.7 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 3.69 (q, J = 7.1 Hz, 1H), 1.40 (d, J = 7.1 Hz, 3H), 1.36 (s, 9H). m / z calcd. for C21H23NO2 = 321.2. Found [M+H]+= 322.2. 2-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)-2-methylpropanoic acid (T4)

[0544] To a cold (–78 °C) stirring solution of ester T3-i (1.0 eq) in THF was added LiHMDS (1 M THF, 2.5 eq). After stirring for 10 min, iodomethane (2.2 eq) was added and warmed to 5 °C. After stirring for an additional 1 h, the mixture was quenched with sat’d aq NaHCO3, 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 afford a 1:1 mixture of monomethylated and dimethylated products. This mixture was then deprotected and hydrolyzed using general procedures D and B to afford the titled compound in 14% yield over three synthetic steps.1H NMR (400 MHz, DMSO) δ 11.49 (d, J = 2.2 Hz, 1H), 7.86 (t, J = 1.8 Hz, 1H), 7.66 (dt, J = 7.4, 1.6 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.43 – 7.30 (m, 3H), 7.11 (dd, J = 8.5, 1.9 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 1.53 (s, 6H), 1.36 (s, 9H). m / z calcd. for C22H25NO2 = 335.2. Found [M+H]+= 336.2. Scheme 3. Preparation of 3-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)propanoic acid (T5).5-bromo-2-(3-(tert-butyl)phenyl)-1H-indole (T5-i)

[0545] Prepared according to general procedure A starting with (4- bromophenyl)hydrazine hydrochloride and 1-(3-(tert-butyl)phenyl)ethan-1-one to afford the titled compound in 80% yield.1H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 7.88 (t, J = 1.8 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.68 – 7.63 (m, 1H), 7.44 – 7.33 (m, 3H), 7.21 (dd, J = 8.6, 2.0 Hz, 1H), 6.91 (q, J = 0.8 Hz, 1H), 1.36 (s, 9H). m / z calcd. for C18H18BrN = 327.1. Found [M+H]+= 328.1. ethyl (E)-3-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)acrylate (T5-ii)

[0546] Prepared according to general procedure E starting with aryl halide T5-i to afford the titled compound in 60% yield.1H NMR (400 MHz, DMSO) δ 11.81 (d, J = 2.2 Hz, 1H), 7.89 (dt, J = 7.1, 1.4 Hz, 2H), 7.76 (d, J = 15.9 Hz, 1H), 7.69 (dt, J = 7.1, 1.8 Hz, 1H), 7.52 (dd, J = 8.6, 1.6 Hz, 1H), 7.47 – 7.33 (m, 3H), 6.98 (dd, J = 2.2, 0.9 Hz, 1H), 6.51 (d, J = 15.9 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.36 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H). m / z calcd. for C23H25NO2 = 347.2. Found [M+Na]+= 370.1. (E)-3-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)acrylic acid (T5-iii)

[0547] Prepared according to general procedure B starting with acrylic ester T5-ii to afford the titled compound in 70% yield.1H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 11.79 (d, J = 2.2 Hz, 1H), 7.92 – 7.77 (m, 2H), 7.74 – 7.65 (m, 2H), 7.54 – 7.31 (m, 4H), 6.97 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 15.9 Hz, 1H), 1.36 (s, 9H). m / z calcd. for C21H21NO2 = 319.2. Found [M+H]+= 320.1. 3-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)propanoic acid (T5)

[0548] Prepared according to general procedure F starting with acrylic acid T5-iii to afford the titled compound in 70% yield.1H NMR (400 MHz, DMSO) δ 12.10 (s, 1H), 11.43 (s, 1H),7.86 (d, J = 1.8 Hz, 1H), 7.69 – 7.62 (m, 1H), 7.41 – 7.28 (m, 4H), 6.97 (dd, J = 8.3, 1.7 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 2.88 (t, J = 7.7 Hz, 2H), 2.55 (t, J = 7.7 Hz, 2H), 1.36 (s, 9H). m / z calcd. for C21H23NO2= 321.2. Found [M+H]+= 322.2. Scheme 4. Preparation of 3-(2-(3-(tert-butyl)phenyl)indolin-5-yl)propanoic acid (T6).3-(2-(3-(tert-butyl)phenyl)indolin-5-yl)propanoic acid (T6)

[0549] Prepared according to general procedures C, F, B and D starting with acrylic ester T5-ii to afford the titled compound in 14% yield over four synthetic steps.1H NMR (400 MHz, DMSO) δ 7.44 (d, J = 1.9 Hz, 1H), 7.32 – 7.16 (m, 3H), 6.87 (s, 1H), 6.80 (dd, J = 7.9, 1.8 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 5.95 (s, 1H), 4.84 (t, J = 9.3 Hz, 1H), 3.37 – 3.27 (m, 1H), 2.70 (dt, J = 15.3, 8.7 Hz, 3H), 2.43 (t, J = 7.6 Hz, 2H), 1.28 (s, 9H), 1.24 (t, J = 4.4 Hz, 1H). m / z calcd. for C21H25NO2= 323.2. Found [M+H]+= 324.2. Scheme 5. Preparation of 3-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)cyclobutane-1- carboxylic acid (T7).methyl 3-[2-(3-tert-butylphenyl)-1H-indol-5-yl]cyclobutanecarboxylate (T7-i)

[0550] A mixture of NiCl2.glyme (6.7 mg, 0.031 mmol, 0.1 eq) and dtbbpy (8.2 mg, 0.031 mmol, 0.1 eq) in DME (1 mL) was stirred at ambient temperature for 10 min under N2. To the resulting light green solution, 5-bromo-2-(3-tert-butylphenyl)-1H-indole (0.1 g, 0.305 mmol, 1.0 eq), methyl 3-bromocyclobutanecarboxylate (88.2 mg, 0.457 mmol, 1.5 eq), [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5- (trifluoromethyl)-2-pyridinyl- N]phenyl-C]iridium(III) hexafluorophosphate (17.1 mg, 0.015 mmol, 0.05 eq), tris(trimethylsilyl)silane (75.8 mg, 0.305 mmol, 1.0 eq) and sodium carbonate (96.9 mg, 0.914 mmol, 3.0 eq) in DME (1.5 mL) was added under N2. The mixture was sealed and irradiated in a Merck Photo reactor (Fan 5200 rpm; stirred at 1000 rpm; LED 50%) at ambient temperature for 16 h. The mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 2). The combined organics was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 0-3% EtOAc / Petroleum ether as the mobile phase to afford the titled compound (0.03 g, 27%) as a yellow solid. m / z calcd. for C24H27NO2= 361.2. Found [M+H]+= 361.9. 3-(2-(3-(tert-butyl)phenyl)-1H-indol-5-yl)cyclobutane-1-carboxylic acid (T7)

[0551] Prepared according to general procedure B starting with ester T7-i to afford the titled compound in 51% yield.1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 11.43 (s, 1H), 7.85 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.69 - 7.31 (m, 4H), 7.03 - 7.00 (m, 1H), 6.84 (s, 1H), 3.70 - 3.33 (m, 1H), 3.07 - 3.01 (m, 1H), 2.56 - 2.55 (m, 2H), 2.41 - 2.39 (m, 1H), 2.26 - 2.23 (m, 1H), 1.35 (s, 9H). m / z calcd. for C23H25NO2 = 347.2. Found [M+H]+= 348.0. Scheme 6. Preparation of 3-[2-(3-tert-butylphenyl)-1H-indol-5-yl]bicyclo[1.1.1]pentane-1- carboxylic acid (T8).methyl 3-[2-(3-tert-butylphenyl)-1H-indol-5-yl]bicyclo[1.1.1]pentane-1-carboxylate (T8-i)

[0552] A mixture of NiCl2.glyme (20.1 mg, 0.091 mmol, 0.1 eq) and dtbbpy (24.5 mg, 0.091 mmol, 0.1 eq) in DME (1.5 mL) was stirred at ambient temperature for 10 mi...

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: A is selected from: (1) -(CR1R2)m-X-(CR3R4)-, wherein: R1and R2are each independently selected from H, halo and C1-6alkyl; R3and R4are each independently selected from H, halo and C1-6alkyl, or R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl; m is 0 or 1; and X is selected from S, SO, SO2, O, and NH; (2) -(CR6R7)n-CR8R9-(CR10R11)p-, wherein: R6and R7are each independently H or C1-6alkyl; R8and R9are each independently halo or C1-6alkyl, or R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl; R10and R11are each independently H or C1-6alkyl; n is 0 or 1; and (3), wherein B is a C3-6cycloalkyl; (4) -CH2CHR12-, wherein R12is C1-6alkyl; (5) -CHR13CH2-, wherein R13is C1-6alkyl; and (6) -CH2CH2CH2-;selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:wherein: R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, - O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl isoptionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6 alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, - O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, - O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionallysubstituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, - O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; each Rais independently selected from F, cyano, -OH, C3-4 cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, - C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl; each Rbis independently selected from F, cyano, -OH, oxo (=O), C1-3alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, - NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, - SH, and -SC1-3alkyl, wherein C1-3alkyl is optionally substituted with -OC1-3alkyl;each Rcis independently selected from F, cyano, -OH, oxo (=O), C1-3alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, - NHC1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-3alkyl is optionally substituted with -OC1-3alkyl; R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently selected from H, -OH, and C1-6alkyl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from F, cyano, -OH, -OC1-3alkyl, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -SH, and -SC1-3alkyl; L is a single bond,wherein: R72is H or -CH3; R73is H or -CH3; R74and R75are each independently selected from H, F, and -CH3; X1is O, S, or NR76, wherein R76is H or -CH3; and R77is of the formula (a), (b), or (c): wherein:X2, X3, X4, X5, and X6are each independently selected from C and N, wherein at least one of X2, X3, X4, X5, and X6is N; R78is absent, H, or F; R79, R80, and R81are each independently absent or selected from H, halo, cyano, -OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, - C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-memberedheterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), - S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, - OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6- membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, R82is absent, H, or F; and wherein at least one of the following (a), (b), and (c) is present: (a) R78is F; (b) at least one of R79, R80, and R81is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), - N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted -S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6- membered heterocycloalkyl); and (c) R82is F; wherein when R77is of the formula (a) and R81is substituted phenyl, then R81is not substituted with 2 -OC1-3alkyl; R83is H or F; R84, R85, and R86are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), - NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), - S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, - OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6- membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, and R87is H or F; and wherein at least one of the following (d), (e), and (f) is present: (d) R83is F; (e) at least one of R84, R85, and R86is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), - N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted -S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6- membered heterocycloalkyl); and (f) R87is F; orwherein R83is H, R84is H, R87is H, and R85and R86together with the ring atoms to which they are attached form a C4-6cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein C4-6cycloalkyl is optionally substituted with 1 to 4 substituents that are each independently C1-6alkyl, and 4- to 6-membered heterocycloalkyl is optionally substituted with 1 to 4 substituents that are each independently selected from C1-6alkyl and oxo (=O); X7is C or N; X8, X9, X10, and X11are each independently selected from C, N, S, and O, wherein at least one of X7, X8, X9, X10, and X11is N, S, or O; and R88, R89, R90, and R91are each independently absent or selected from H, halo, cyano, - OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, - C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, and wherein at least one of R88, R89, R90, and R91is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, - NHC3-6cycloalkyl, -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionallysubstituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted -S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6- membered heterocycloalkyl), each Rdis independently selected from F, cyano, -OH, C3-4cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, - C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl; each of Reis independently selected from F, cyano, -OH, oxo (=O), C1-6alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, - NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-6alkyl is optionally substituted with -OC1-3alkyl; each Rfis independently selected from F, cyano, -OH, oxo (=O), C1-6alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, - NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-6alkyl is optionally substituted with -OC1-3alkyl; each Rgis independently selected from F, cyano, -OH, C1-6alkyl, -C(O)C1-3alkyl, - C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl; each Rhis independently selected from F, cyano, -OH, C1-6alkyl, -C(O)C1-3alkyl, - C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl; andwherein the compound is not selected from:

2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: Formula (IA):Formula (IB): Formula (IC): Formula (IE): Formula (IF): Formula (IG):wherein each of L, X, R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R77, R92, m, n, p, , and B is as defined in Claim 1.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IA):wherein each of L, X, R1, R2, R3, R4, R77, R92, m, and is as defined in Claim 1.

4. The compound of any one of Claims 1-3 or a pharmaceutically acceptable salt thereof, wherein m is 0.

5. The compound of any one of Claims 1-3 or a pharmaceutically acceptable salt thereof, wherein m is 1.

6. The compound of Claim 5 or a pharmaceutically acceptable salt thereof, wherein R1and R2are each independently selected from H, F, and methyl.

7. The compound of any one of Claims 1-6 or a pharmaceutically acceptable salt thereof, wherein X is selected from S, SO, SO2, and O.

8. The compound of any one of Claims 1-7 or a pharmaceutically acceptable salt thereof, wherein X is selected from S, SO, and SO2.

9. The compound of any one of Claims 1-8 or a pharmaceutically acceptable salt thereof, wherein X is S.

10. The compound of any one of Claims 1-8 or a pharmaceutically acceptable salt thereof, wherein X is SO.

11. The compound of any one of Claims 1-8 or a pharmaceutically acceptable salt thereof, wherein X is SO2.

12. The compound of any one of Claims 1-7 or a pharmaceutically acceptable salt thereof, wherein X is O.

13. The compound of any one of Claims 1-12 or a pharmaceutically acceptable salt thereof, wherein R3and R4are each independently selected from H, F, and methyl.

14. The compound of any one of Claims 1-13 or a pharmaceutically acceptable salt thereof, wherein R3is methyl.

15. The compound of any one of Claims 1-14 or a pharmaceutically acceptable salt thereof, wherein R3and R4are each methyl.

16. The compound of any one of Claims 1-13 or a pharmaceutically acceptable salt thereof, wherein R3and R4are each H.

17. The compound of any one of Claims 1-12 or a pharmaceutically acceptable salt thereof, wherein R3and R4are each halo.

18. The compound of any one of Claims 1-13 or a pharmaceutically acceptable salt thereof, wherein R3and R4are each F.

19. The compound of any one of Claims 1-12 or a pharmaceutically acceptable salt thereof, wherein R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl.

20. The compound of Claim 19 or a pharmaceutically acceptable salt thereof, wherein R3and R4together with the carbon atom to which they are attached form cyclopropyl.

21. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IB):wherein each of L, R6, R7, R8, R9, R10, R11, R77, R92, n, p, and is asdefined in Claim 1.

22. The compound of any one of Claims 1, 2 and 21, or a pharmaceutically acceptable salt thereof, wherein n is 1 and p is 0.

23. The compound of any one of Claims 1, 2, and 21-22, or a pharmaceutically acceptable salt thereof, wherein R8and R9are each independently selected from F and methyl.

24. The compound of any one of Claims 1, 2, and 21-23, or a pharmaceutically acceptable salt thereof, wherein R8and R9are each methyl.

25. The compound of any one of Claims 1, 2, and 21-22, or a pharmaceutically acceptable salt thereof, wherein R8and R9are each halo.

26. The compound of any one of Claims 1, 2, and 21-23, or a pharmaceutically acceptable salt thereof, wherein R8and R9are each F.

27. The compound of any one of Claims 1, 2 and 21-22, or a pharmaceutically acceptable salt thereof, wherein R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl.

28. The compound of Claim 27 or a pharmaceutically acceptable salt thereof, wherein R8and R9together with the carbon atom to which they are attached form cyclopropyl.

29. The compound of any one of Claims 1, 2 and 21-28, or a pharmaceutically acceptable salt thereof, wherein R6and R7are each independently selected from H and methyl.

30. The compound of any one of Claims 1, 2 and 21-29, or a pharmaceutically acceptable salt thereof, wherein R6and R7are each H.

31. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IC):wherein each of L, R77, R92,and B is as defined in Claim 1.

32. The compound of any one of Claims 1, 2 and 31, or a pharmaceutically acceptable salt thereof, wherein B is selected from cyclopropyl, cyclobutyl, and bicyclo[1.1.1]pentane.

33. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IE):a compound of Formula (IF):wherein each of L, R12, R13, R77, R92, andis as defined in Claim 1.

34. The compound of Claim 1, 2 and 33, or a pharmaceutically acceptable salt thereof, wherein each of R12and R13is methyl.

35. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IG):wherein each of L, R77, R92, andis as defined in Claim 1.

36. The compound of any one of Claims 1-35, or a pharmaceutically acceptable salt thereof, wherein: R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently H or C1-6alkyl.

37. The compound of any one of Claims 1-36, or a pharmaceutically acceptable salt thereof, wherein: R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; and R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently H or methyl.

38. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y : wherein each of R14, R15 161, R , R17and R18is as defined in Claim 1, 36 or 37.

39. The compound of Claim 38 or a pharmaceutically acceptable salt thereof, wherein R14is H, R15is H, F, cyano or methyl, R16is H or F, R17is H, and R18is H.

40. The compound of Claim 38 or a pharmaceutically acceptable salt thereof, wherein each of R14, R15, R16, R17, and R18is H.

41. The compound of Claim 38 or a pharmaceutically acceptable salt thereof, wherein R14is H, R15is F, R16is H, R17is H, and R18is H.

42. The compound of Claim 38 or a pharmaceutically acceptable salt thereof, wherein R14is H, R15is H, R16is F, R17is H, and R18is H.

43. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein19 20 21is moiety Y2: wherein each of R , R , R ,and R22is as defined in Claim 1, 36 or 37.

44. The compound of Claim 43 or a pharmaceutically acceptable salt thereof, wherein R19is H, R20is H, F, cyano or methyl, R21is H, and R22is H.

45. The compound of Claim 43 or a pharmaceutically acceptable salt thereof, wherein each of R19, R20, R21, and R22is H.

46. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y3: wherein each of R23, R24, R25,and R26is as defined in Claim 1, 36 or 37.

47. The compound of Claim 46 or a pharmaceutically acceptable salt thereof, wherein each of R23, R24, R25, and R26is H.

48. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y4: wherein each of R27, R28, R29, 30and R is as defined in Claim 1, 36 or 37.

49. The compound of Claim 48 or a pharmaceutically acceptable salt thereof, wherein each of R27, R28, R29, and R30is H.

50. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y5:wherein each of R31, R32, R33, and R34is as defined in Claim 1, 36 or 37.

51. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein35 36 37is moiety Y6:wherein each of R , R , R , and R38is as defined in Claim 1, 36 or 37.

52. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y7: wherein ea39 40 41ch of R , R , R , and R42is as defined in Claim 1, 36 or 37.

53. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y8: , where each of R43, R44, R45, R46, R47, and R48is as defined in Claim 1, 36 or 37.

54. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y9: , wherein each of R49, R50, R51and R52is as defined in Claim 1, 36 or 37.

55. The compound of Claim 54 or a pharmaceutically acceptable salt thereof, wherein each of R49, R50, R51and R52is H.

56. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y10: , wherein each of R53, R54and R55is as defined in Claim 1, 36 or 37.

57. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y11: , wherein each of R56, R57and R58is as defined in Claim 1, 36 or 37.

58. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y12: , wherein each of R59, R60and R61is as defined in Claim 1, 36 or 37.

59. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y13: , wherein each of R62, R63and R64is as defined in Claim 1, 36 or 37.

60. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y14: , wherein each of R65, R66, R67and R68is as defined in Claim 1, 36 or 37.

61. The compound of any one of Claims 1-37 or a pharmaceutically acceptable salt thereof, wherein is moiety Y15: , wherein each of R69, R70and R70is as defined in Claim 1, 36 or 37.

62. The compound of any one of Claims 1-61 or a pharmaceutically acceptable salt thereof, wherein L is a single bond, , , or , wherein R72is H.

63. The compound of any one of Claims 1-62 or a pharmaceutically acceptable salt thereof, wherein L is a single bond.

64. The compound of any one of Claims 1-63 or a pharmaceutically acceptable salt thereof, wherein R77is selected from , , , and , wherein each of R84, R85, and R86are as defined in Claim 1.

65. The compound of Claim 64 or a pharmaceutically acceptable salt thereof, wherein R77is , wherein R86is as defined in Claim 1.

66. The compound of Claim 65 or a pharmaceutically acceptable salt thereof, wherein R77is , wherein R86is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

67. The compound of any one of Claims 1-63 or a pharmaceutically acceptable salt thereof, wherein R77is selected from , , , , , , and , wherein R81is as defined in Claim 1.

68. The compound of Claim 67 or a pharmaceutically acceptable salt thereof, wherein R77is or , wherein R81is as defined in Claim 1.

69. The compound of Claim 67 or 68 or a pharmaceutically acceptable salt thereof, wherein R81is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, - OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10- membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6- membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

70. The compound of any one of Claims 1-63 or a pharmaceutically acceptable salt thereof, wherein R77is selected from, wherein R90is as defined in Claim 1.

71. The compound of Claim 70 or a pharmaceutically acceptable salt thereof, wherein R90is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10- membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6- membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

72. The compound of any one of Claims 1-63 or a pharmaceutically acceptable salt thereof, wherein R77is selected from:73 The compound of any one of Claims 1-63 or a pharmaceutically acceptable salt thereof, wherein R77is selected from:

74. The compound of any one of Claims 1-73, or a pharmaceutically acceptable salt thereof, wherein R92is -C(O)OH.

75. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

76. A pharmaceutical composition comprising: a compound of any one of Claims 1-75 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

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

78. A pharmaceutical composition comprising: a compound of Claim 77 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

79. A method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: A is selected from: (1) -(CR1R2)m-X-(CR3R4)-, wherein: R1and R2are each independently selected from H, halo and C1-6alkyl; R3and R4are each independently selected from H, halo and C1-6alkyl, or R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl; m is 0 or 1; and X is selected from S, SO, SO2, O, and NH; (2) -(CR6R7)n-CR8R9-(CR10R11)p-, wherein: R6and R7are each independently H or C1-6alkyl;R8and R9are each independently halo or C1-6alkyl, or R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl; R10and R11are each independently H or C1-6alkyl; n is 0 or 1; and p is 0 or 1; (3) , wherein B is a C3-6cycloalkyl; (4) -CH2CH2-; (5) -CH2CHR12-, wherein R12is C1-6alkyl; (6) -CHR13CH2-, wherein R13is C1-6alkyl; and (7) -CH2CH2CH2-; is selected from the following moieties Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, and Y15:wherein:R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6 alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, - O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6 alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, - O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6 alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, - O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-6cycloalkyl, 3- to 6-membered heterocycloalkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6 alkyl), -N(C1-3alkyl)(C3-6cycloalkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, - O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 3 Rcsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rasubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Rbsubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 3 Rcsubstituents; each Rais independently selected from F, cyano, -OH, C3-4 cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, - C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl; each Rbis independently selected from F, cyano, -OH, oxo (=O), C1-3alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, - NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, - SH, and -SC1-3alkyl, wherein C1-3alkyl is optionally substituted with -OC1-3alkyl; each Rcis independently selected from F, cyano, -OH, oxo (=O), C1-3alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, - NHC1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-3alkyl is optionally substituted with -OC1-3alkyl; R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently selected from H, -OH, and C1-6alkyl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from F, cyano, -OH, -OC1-3alkyl, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -SH, and -SC1-3alkyl; L is a single bond,wherein: R72is H or -CH3; R73is H or -CH3; R74and R75are each independently selected from H, F, and -CH3; X1is O, S, or NR76, wherein R76is H or -CH3; and R77is of the formula (a), (b), or (c):wherein: X2, X3, X4, X5, and X6are each independently selected from C and N, wherein at least one of X2, X3, X4, X5, and X6is N; R78is absent, H, or F; R79, R80, and R81are each independently absent or selected from H, halo, cyano, -OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, - C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), - S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, - OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6- membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, R82is absent, H, or F; and wherein at least one of the following (a), (b), and (c) is present: (a) R78is F; (b) at least one of R79, R80, and R81is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), - N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted -S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6- membered heterocycloalkyl); and (c) R82is F; wherein when R77is of the formula (a) and R81is substituted phenyl, then R81is not substituted with 2 -OC1-3alkyl; R83is H or F; R84, R85, and R86are each independently selected from H, halo, cyano, -OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, - C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), - NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), - S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, - OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6- membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, and R87is H or F; and wherein at least one of the following (d), (e), and (f) is present:(d) R83is F; (e) at least one of R84, R85, and R86is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -N(C1-3alkyl)(C1-6alkyl), -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), - N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted -S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6- membered heterocycloalkyl); and (f) R87is F; or wherein R83is H, R84is H, R87is H, and R85and R86together with the ring atoms to which they are attached form a C4-6cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein C4-6cycloalkyl is optionally substituted with 1 to 4 substituents that are each independently C1-6alkyl, and 4- to 6-membered heterocycloalkyl is optionally substituted with 1 to 4 substituents that are each independently selected from C1-6alkyl and oxo (=O); X7is C or N; X8, X9, X10, and X11are each independently selected from C, N, S, and O, wherein at least one of X7, X8, X9, X10, and X11is N, S, or O; and R88, R89, R90, and R91are each independently absent or selected from H, halo, cyano, - OH, C1-6alkyl, C3-10cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, - C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, -NHC3-6cycloalkyl, -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), -OC1-6alkyl, -OC3-6cycloalkyl, -O(3- to 6-membered heterocycloalkyl), -SC1-6alkyl, -SC3-6cycloalkyl, -S(3- to 6-membered heterocycloalkyl), -S(O)2C1-6alkyl, -S(O)2C3-6cycloalkyl, and -S(O)2(3- to 6-membered heterocycloalkyl), wherein C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, C3-10cycloalkyl is optionally substituted with 1 to 3 Resubstituents, 3- to 6-membered heterocycloalkyl is optionally substituted with 1 to 2 Rfsubstituents, phenyl is optionally substituted with 1 to 2 Rgsubstituents, 5- to 10-membered heteroaryl is optionally substituted with 1 to 2 Rhsubstituents, -OC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -OC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -O(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -SC1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -SC3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, -S(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, -S(O)2C1-6alkyl is optionally substituted with 1 to 3 Rdsubstituents, -S(O)2C3-6cycloalkyl is optionally substituted with 1 to 3 Resubstituents, and -S(O)2(3- to 6-membered heterocycloalkyl) is optionally substituted with 1 to 2 Rfsubstituents, and wherein at least one of R88, R89, R90, and R91is selected from halo, cyano, -OH, the optionally substituted C1-6alkyl, the optionally substituted C3-10cycloalkyl, the optionally substituted 3- to 6-membered heterocycloalkyl, the optionally substituted phenyl, the optionally substituted 5- to 10-membered heteroaryl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)NHC3-6cycloalkyl, -C(O)N(C1-3alkyl)2, -C(O)N(C1-3alkyl)(C3-6cycloalkyl), -NH2, -NHC1-6alkyl, - NHC3-6cycloalkyl, -NHC(O)C1-3alkyl, -NHC(O)C3-6cycloalkyl, -N(C1-3alkyl)(C(O)C1-3alkyl), -N(C1-3alkyl)(C(O)C3-6cycloalkyl), the optionally substituted -OC1-6alkyl, the optionally substituted -OC3-6cycloalkyl, the optionally substituted -O(3- to 6-membered heterocycloalkyl), the optionally substituted -SC1-6alkyl, the optionally substituted -SC3-6cycloalkyl, the optionally substituted -S(3- to 6-membered heterocycloalkyl), the optionally substituted -S(O)2C1-6alkyl, the optionally substituted -S(O)2C3-6cycloalkyl, and the optionally substituted -S(O)2(3- to 6- membered heterocycloalkyl), each Rdis independently selected from F, cyano, -OH, C3-4 cycloalkyl, 3- to 5-membered heterocycloalkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, - C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -OC1-3alkyl, -SH, and -SC1-3alkyl; each of Reis independently selected from F, cyano, -OH, oxo (=O), C1-6alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, - NHC1-3alkyl, -N(C1-3alkyl)2, -NHC(O)C1-3alkyl, -N(C1-3alkyl)C(O)C1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-6alkyl is optionally substituted with -OC1-3alkyl; each Rfis independently selected from F, cyano, -OH, oxo (=O), C1-6alkyl, -C(O)C1-3alkyl, -C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, - NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl, wherein C1-6alkyl is optionally substituted with -OC1-3alkyl; each Rgis independently selected from F, cyano, -OH, C1-6alkyl, -C(O)C1-3alkyl, - C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl;each Rhis independently selected from F, cyano, -OH, C1-6alkyl, -C(O)C1-3alkyl, - C(O)OH, -C(O)OC1-3alkyl, -C(O)NH2, -C(O)NHC1-3alkyl, -C(O)N(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2, -OC1-3alkyl, -SH, and -SC1-3alkyl; and80. The method of Claim 79, wherein the contacting comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject.

81. The method of Claim 80, 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.

82. The method of Claim 80, wherein the disease or disorder is selected from heterotopic ossification (HO; including trauma-induced and surgically-induced), fibrodysplasiaossificans progressiva (FOP), multiple osteochondromas, and vascular calcification (including that associated with chronic kidney disease (CKD)).

83. The method of Claim 80, wherein the disease or disorder is fibrodysplasia ossificans progressiva (FOP).

84. The method of Claim 80, wherein the disease or disorder is multiple osteochondromas.

85. The method of Claim 80, 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, 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.

86. The method of Claim 80, wherein the disease or disorder is selected from conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, cicatricial conjunctival disorders (including 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.

87. The method of Claim 80, wherein the disease or disorder is meibomian gland dysfunction.

88. The method of Claim 80, wherein the disease or disorder is dry eye disease.

89. The method of Claim 80, wherein the disease or disorder is evaporative dry eye disease.

90. The method of any one of Claims 79-89, wherein the compound is selected from: Formula (IIA): Formula (IIB): Formula (IIC): Formula (IID): Formula (IIE): Formula (IIF): Formula (IIG):wherein each of L, X, R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R77, R92, m, n, p, , and B is as defined in Claim 79.

91. The method of any one of Claims 79-90, wherein the compound is a compound of Formula (IIA):wherein each of L, X, R1, R2, R3, R4, R77, R92, m, and is as defined in Claim 79.

92. The method of any one of Claims 79-91, wherein m is 0.

93. The method of any one of Claims 79-91, wherein m is 1.

94. The method of Claim 93, wherein R1and R2are each independently selected from H, F, and methyl.

95. The method of any one of Claims 79-94, wherein X is selected from S, SO, SO2, and O.

96. The method of any one of Claims 79-95, wherein X is selected from S, SO, and SO2.

97. The method of any one of Claims 79-96, wherein X is S.

98. The method of any one of Claims 79-96, wherein X is SO.

99. The method of any one of Claims 79-96, wherein X is SO2.

100. The method of any one of Claims 79-95, wherein X is O.

101. The method of any one of Claims 79-100, wherein R3and R4are each independently selected from H, F, and methyl.

102. The method of any one of Claims 79-101, wherein R3is methyl.

103. The method of any one of Claims 79-102, wherein R3and R4are each methyl.

104. The method of any one of Claims 79-101, wherein R3and R4are each H.

105. The method of any one of Claims 79-100, wherein R3and R4are each halo.

106. The method of any one of Claims 79-101, wherein R3and R4are each F.

107. The method of any one of Claims 79-100, wherein R3and R4together with the carbon atom to which they are attached form a C3-6cycloalkyl.

108. The method of Claim 107, wherein R3and R4together with the carbon atom to which they are attached form cyclopropyl.

109. The method of any one of Claims 79-90, wherein the compound is a compound of Formula (IIB):wherein each of L, R6, R7, R8, R9, R10, R11, R77, R92, n, p, and is as defined in Claim 79.

110. The method of any one of Claims 79-90 and 109, wherein n is 1 and p is 0.

111. The method of any one of Claims 79-90 and 109-110, wherein R8and R9are each independently selected from F and methyl.

112. The method of any one of Claims 79-90 and 109-111, wherein R8and R9are each methyl.

113. The method of any one of Claims 79-90 and 109-110, wherein R8and R9are each halo.

114. The method of any one of Claims 79-90 and 109-111, wherein R8and R9are each F.

115. The method of any one of Claims 79-90 and 109-110, wherein R8and R9together with the carbon atom to which they are attached form a C3-6cycloalkyl.

116. The method of Claim 115, wherein R8and R9together with the carbon atom to which they are attached form cyclopropyl.

117. The method of any one of Claims 79-90 and 109-116, wherein R6and R7are each independently selected from H and methyl.

118. The method of any one of Claims 79-90 and 109-117, wherein R6and R7are each H.

119. The method of any one of Claims 79-90, wherein the compound is a compound of Formula (IIC): (IIC), wherein each of L, R77, R92, , and B is as defined in Claim 79.

120. The method of any one of Claims 79-90 and 119, wherein B is selected from cyclopropyl, cyclobutyl, and bicyclo[1.1.1]pentane.

121. The method of any one of Claims 79-90 wherein the compound is a compound of Formula (IID): (IID), wherein each of L, R77, R92, and is as defined in Claim 79.

122. The method of any one of Claims 79-90, wherein the compound is a compound of Formula (IIE): (IIE), or a compound of Formula (IIF): (IIF), wherein each of L, R12, R13, R77, R92, and is as defined in Claim 79.

123. The method of any one of Claims 79-90 and 122, wherein each of R12and R13is methyl.

124. The method of any one of Claims 79-90, wherein the compound is a compound of Formula (IIG): (IIG), wherein each of L, R77, R92, and is as defined in Claim 79.

125. The method of any one of Claims 79-124, wherein: R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, halo, cyano, C1-6alkyl, and C3-6cycloalkyl; and R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently H or C1-6alkyl.

126. The method of any one of Claims 79-124, wherein: R14, R19, R23, R27, R39, R43, R44, R49, R53, R56, R59, and R65are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R15, R20, R24, R28, R31, R36, R40, R45, R60, R62, R66, and R69are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R16, R25, R29, R32, R37, R41, R46, R50, R54, R63, R67, and R70are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; R17, R21, R30, R33, R38, R42, R47, R51, R57, R64, R68, and R71are each independently selected from H, F, Br, cyano, C1-3alkyl, and cyclopropyl; and R18, R22, R26, R34, R35, R48, R52, R55, R58, and R61are each independently H or methyl.

127. The method of any one of Claims 79-126, wherein is moiety Y1: , wherein each of R14, R15, R16, R17and R18is as defined in Claim 79, 125 or 126.

128. The method of Claim 127, wherein R14is H, R15is H, F, cyano or methyl, R16is H or F, R17is H, and R18is H.

129. The method of Claim 127, wherein each of R14, R15, R16, R17, and R18is H.

130. The method of Claim 127, wherein R14is H, R15is F, R16is H, R17is H, and R18is H.

131. The method of Claim 127, wherein R14is H, R15is H, R16is F, R17is H, and R18is H.

132. The method of any one of Claims 79-126, wherein is moiety Y2: , wherein each of R19, R20, R21, and R22is as defined in Claim 79, 125 or 126.

133. The method of Claim 132, wherein R19is H, R20is H, F, cyano or methyl, R21is H, and R22is H.

134. The method of Claim 132, wherein each of R19, R20, R21, and R22is H.

135. The method of any one of Claims 79-126 wherein is moiety Y3: , wherein each of R23, R24, R25, and R26is as defined in Claim 79, 125 or 126.

136. The method of Claim 135, wherein each of R23, R24, R25, and R26is H.

137. The method of any one of Claims 79-126, wherein is moiety Y4: , wherein each of R27, R28, R29, and R30is as defined in Claim 79, 125 or 126.

138. The method of Claim 137, wherein each of R27, R28, R29, and R30is H.

139. The method of any one of Claims 79-126, wherein is moiety Y5: , wherein each of R31, R32, R33, and R34is as defined in Claim 79, 125 or 126.

140. The method of any one of Claims 79-126, wherein is moiety Y6: , wherein each of R35, R36, R37, and R38is as defined in Claim 79, 125 or 126.

141. The method of any one of Claims 79-126, wherein is moiety Y7: , wherein each of R39, R40, R41, and R42is as defined in Claim 79, 125 or 126.

142. The method of any one of Claims 79-126, wherein is moiety Y8: , where each of R43, R44, R45, R46, R47, and R48is as defined in Claim 79, 125 or 126.

143. The method of any one of Claims 79-126, wherein is moiety Y9: , wherein each of R49, R50, R51and R52is as defined in Claim 79, 125 or 126.

144. The method of Claim 143, wherein each of R49, R50, R51and R52is H.

145. The method of any one of Claims 79-126, wherein is moiety Y10: , wherein each of R53, R54and R55is as defined in Claim 79, 125 or 126.

146. The method of any one of Claims 79-126, wherein is moiety Y11: , wherein each of R56, R57and R58is as defined in Claim 79, 125 or 126.

147. The method of any one of Claims 79-126, wherein is moiety Y12: , wherein each of R59, R60and R61is as defined in Claim 79, 125 or 126.

148. The method of any one of Claims 79-126, wherein is moiety Y13: , wherein each of R62, R63and R64is as defined in Claim 79, 125 or 126.

149. The method of any one of Claims 79-126, wherein is moiety Y14: , wherein each of R65, R66, R67and R68is as defined in Claim 79, 125 or 126.

150. The method of any one of Claims 79-126, wherein is moiety Y15: , wherein each of R69, R70and R70is as defined in Claim 79, 125 or 126.

151. The method of any one of Claims 79-150, wherein L is a single bond, , , or , wherein R72is H.

152. The method of any one of Claims 79-151, wherein L is a single bond.

153. The method of any one of Claims 79-152, wherein R77is selected from , , , and , wherein each of R84, R85, and R86are as defined in Claim 79.

154. The method of any one of Claims 79-152, wherein R77is , wherein R86is as defined in Claim 79.

155. The method of any one of Claims 79-152, wherein R77is , wherein R86is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10- membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6- membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

156. The method of any one of Claims 79-152, wherein R77is selected from , , , , , , and , wherein R81is as defined in Claim 79.

157. The method of Claim 156, wherein R77is or , wherein R81is as defined in Claim 79.

158. The method of Claim 156 or 157, wherein R81is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

159. The method of any one of Claims 79-152, wherein R77is selected fromwherein R90is as definedin Claim 79.

160. The method of Claim 159, wherein R90is selected from C1-6alkyl, C3-10cycloalkyl, -SC1-6 alkyl, -OC1-6alkyl, halo, -OH, -OC3-6cycloalkyl, -NHC(O)C1-6alkyl, 3- to 6-membered heterocycloalkyl, and 5- to 10-membered heteroaryl, wherein C1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently selected from halo, cyano, -OH, -C(O)NH2, -C(O)OH, and C3-6cycloalkyl, C3-10cycloalkyl is optionally substituted with 1 or 2 substituents that are each independently selected from cyano and C1-6alkyl, -OC1-6alkyl is optionally substituted with 1 to 3 substituents that are each independently halo, and 3- to 6-membered heterocycloalkyl is optionally substituted with 1 or 2 substituents that are each independently C1-6alkyl.

161. The method of any one of Claims 79-152, wherein R77is selected from:162. The method of any one of Claims 79-152, wherein R77is selected from:

163. The method of any one of Claims 79-162, wherein R92is -C(O)OH.

164. The method of Claims 79-90, wherein the compound is selected from:

165. A method of inhibiting CYP26B1, the method comprising: contacting CYP26B1 with a compound selected from:or a pharmaceutically acceptable salt thereof.

166. The method of Claim 165, wherein the contacting comprises administering to a subject in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, wherein the administering is effective to treat a disease or disorder in the subject.

167. The method of Claim 166, 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-infl ammatory acne, psoriasis, ichthyosis, keratinization, hyperproliferative disorders of the skin, photoaging, eczema, atopic dermatitis, Darners 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.

168. The method of Claim 166, 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)).

169. The method of Claim 166, wherein the disease or disorder is fibrodysplasia ossificans progressiva (FOP).

170. The method of Claim 166, wherein the disease or disorder is multiple osteochondromas.

171. The method of Claim 166, 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, 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.

172. The method of Claim 166, wherein the disease or disorder is selected from conjunctivitis, conjunctival goblet cell injury, limbal stem cell deficiency, cicatricial conjunctival disorders (including 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.

173. The method of Claim 166, wherein the disease or disorder is meibomian gland dysfunction.

174. The method of Claim 166, wherein the disease or disorder is dry eye disease.

175. The method of Claim 166, wherein the disease or disorder is evaporative dry eye disease.

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